U.S. patent application number 15/737683 was filed with the patent office on 2018-12-27 for fused bicyclic pyrimidine derivatives 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 Nathanael S. Gray, Tinghu Zhang.
Application Number | 20180369243 15/737683 |
Document ID | / |
Family ID | 57585794 |
Filed Date | 2018-12-27 |
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United States Patent
Application |
20180369243 |
Kind Code |
A9 |
Gray; Nathanael S. ; et
al. |
December 27, 2018 |
FUSED BICYCLIC PYRIMIDINE DERIVATIVES 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 or preventing proliferative diseases
(e.g., cancers (e.g., lung cancer, breast cancer, leukemia,
lymphoma, melanoma, multiple myeloma, Ewing's sarcoma,
osteosarcoma, brain cancer, neuroblastoma), benign neoplasms,
angiogenesis, 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 (e.g. a
protein kinase (e.g. a cyclin-dependent kinase (CDK) (e.g. CDK7,
CDK12, or CDK13) or a lipid kinase such as a
phosphatidylinositol-5-phosphate 4-kinase (PIP4K) (e.g.,
PI5P4K.alpha., PI5P4K.beta., or PI5P4K.gamma.)) in the subject.
##STR00001##
Inventors: |
Gray; Nathanael S.; (Boston,
MA) ; Zhang; Tinghu; (Brookline, 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 20180153894 A1 |
June 7, 2018 |
|
|
Family ID: |
57585794 |
Appl. No.: |
15/737683 |
Filed: |
June 24, 2016 |
PCT Filed: |
June 24, 2016 |
PCT NO: |
PCT/US2016/039302 PCKC 00 |
371 Date: |
December 18, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62185366 |
Jun 26, 2015 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/166 20130101;
A61K 31/381 20130101; A61K 31/519 20130101; A61P 35/02 20180101;
A61K 31/34 20130101; C07D 491/048 20130101; A61K 31/167 20130101;
C07D 519/00 20130101; C07D 495/04 20130101; A61K 31/437 20130101;
A61K 45/06 20130101; A61K 31/519 20130101; A61K 2300/00 20130101;
A61K 31/437 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 31/437 20060101 A61K031/437; A61K 31/34 20060101
A61K031/34; A61K 31/381 20060101 A61K031/381; A61K 31/166 20060101
A61K031/166; A61K 31/167 20060101 A61K031/167; A61K 45/06 20060101
A61K045/06; C07D 491/048 20060101 C07D491/048; C07D 495/04 20060101
C07D495/04; C07D 519/00 20060101 C07D519/00 |
Goverment Interests
GOVERNMENT SUPPORT
[0002] This invention was made with government support under grant
number R01CA197329 awarded by The National Institutes of Health.
The government has certain rights in the invention.
Claims
1. A compound of Formula (I): ##STR00263## or a pharmaceutically
acceptable salt thereof, wherein: Ring A is a substituted or
unsubstituted, monocyclic or bicyclic heteroaryl ring or a
substituted or unsubstituted, monocyclic heterocyclic ring; each
instance of R.sup.A is independently hydrogen, halogen, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; each
instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted, heterocyclic ring, or
substituted or unsubstituted, heteroaryl ring; k is 0, 1, 2, 3, 4,
5, or 6; M is NR.sup.M, O, or S; R.sup.M is hydrogen, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, or
a nitrogen protecting group; L is a bond, --C(R.sup.b).sub.2--,
--C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, or
--NR.sup.c--; each instance of R.sup.b is independently hydrogen,
halogen, or substituted or unsubstituted C.sub.1-6 alkyl; each
instance of R.sup.c is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;
R.sup.B1 is hydrogen, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; R.sup.B2 is
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; X is
--C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
--NR.sup.cS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, or --NR.sup.cS(.dbd.O).sub.2--; Ring C
is a substituted or unsubstituted phenyl ring; Ring D is a
substituted or unsubstituted phenyl ring; each instance of R.sup.C
is independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; n is 0, 1,
2, 3, or 4; L.sup.2 is --C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--,
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
--NR.sup.cS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, --NR.sup.cS(.dbd.O).sub.2--,
--OC(.dbd.O)O--, --NR.sup.cC(.dbd.O)O--, --OC(.dbd.O)NR.sup.c--,
--NR.sup.cC(.dbd.O)NR.sup.c--,
--C(R.sup.b).sub.2C(.dbd.O)C(R.sup.b).sub.2--,
--OC(.dbd.O)C(R.sup.b).sub.2--, --C(R.sup.b).sub.2C(.dbd.O)O--,
--NR.sup.cC(.dbd.O)C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)NR.sup.c--, or a substituted or
unsubstituted 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--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, or --NR.sup.c--; each instance of R.sup.D is
independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; p is 0, 1,
2, 3, or 4; R.sup.E is of the formula: ##STR00264## ##STR00265##
##STR00266## ##STR00267## ##STR00268## ##STR00269## L.sup.3 is
--C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
--NR.sup.CS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, --NR.sup.cS(.dbd.O).sub.2--,
--OC(.dbd.O)O--, --NR.sup.cC(.dbd.O)O--, --OC(.dbd.O)NR.sup.c--,
--NR.sup.cC(.dbd.O)NR.sup.c--,
--C(R.sup.b).sub.2C(.dbd.O)C(R.sup.b).sub.2--,
--OC(.dbd.O)C(R.sup.b).sub.2--, --C(R.sup.b).sub.2C(.dbd.O)O--,
--NR.sup.cC(.dbd.O)C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)NR.sup.c--, or a substituted or
unsubstituted 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--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, or --NR.sup.c--; L.sup.4 is a bond or
substituted or unsubstituted C.sub.1-6 hydrocarbon chain; each of
R.sup.E1, R.sup.E2, and R.sup.E3 is independently hydrogen,
halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --CH.sub.2OR.sup.a,
--CH.sub.2N(R.sup.a).sub.2, --CH.sub.2SR.sup.a, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, or --Si(R.sup.a).sub.3; 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 a substituted or unsubstituted, carbocyclic
ring, or substituted or unsubstituted, 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.c; a is 1 or 2; and each instance of z is independently 0,
1, 2, 3, 4, 5, or 6.
2. The compound of claim 1, wherein the compound is of Formula
(I-a), (I-a-i), (I-a-ii), (I-a-iii), or (I-a-iv): ##STR00270## or a
pharmaceutically acceptable salt thereof.
3-6. (canceled)
7. The compound of claim 1, wherein the compound is of Formula
(I-b), (I-b-i), (I-b-ii), (I-b-iii), or (I-b-iv): ##STR00271## or a
pharmaceutically acceptable salt thereof.
8-11. (canceled)
12. The compound of claim 1, wherein Ring A is a substituted or
unsubstituted, bicyclic heteroaryl ring.
13-14. (canceled)
15. The compound of claim 12, wherein Ring A is of Formula (A-i):
##STR00272## wherein: R.sup.A1 is selected from the group
consisting of hydrogen, substituted or unsubstituted acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, and a nitrogen protecting group; and each
instance of R.sup.A2 is independently selected from the group
consisting of hydrogen, halogen, substituted or unsubstituted acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --CN, --OR.sup.A2a, --N(R.sup.A2a).sub.2,
and --SR.sup.A2a, wherein each occurrence of R.sup.A2a is
independently selected from the group consisting of hydrogen,
substituted or unsubstituted acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, a
nitrogen protecting group when attached to a nitrogen atom, an
oxygen protecting group when attached to an oxygen atom, and a
sulfur protecting group when attached to a sulfur atom, or two
R.sup.A2a groups are joined to form a substituted or unsubstituted
heterocyclic ring.
16-18. (canceled)
19. The compound of claim 12, wherein Ring A is of Formula (A-ii):
##STR00273## wherein: R.sup.A1 is selected from the group
consisting of hydrogen, substituted or unsubstituted acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, and a nitrogen protecting group; and each
instance of R.sup.A2 is independently selected from the group
consisting of hydrogen, halogen, substituted or unsubstituted acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --CN, --OR.sup.A2a, --N(R.sup.A2a).sub.2,
and --SR.sup.A2a, wherein each occurrence of R.sup.A2a is
independently selected from the group consisting of hydrogen,
substituted or unsubstituted acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, a
nitrogen protecting group when attached to a nitrogen atom, an
oxygen protecting group when attached to an oxygen atom, and a
sulfur protecting group when attached to a sulfur atom, or two
R.sup.A2a groups are joined to form a substituted or unsubstituted
heterocyclic ring.
20-21. (canceled)
22. The compound of claim 12, wherein Ring A is of Formula (A-iii):
##STR00274## wherein: R.sup.A1 is selected from the group
consisting of hydrogen, substituted or unsubstituted acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, and a nitrogen protecting group; and each
instance of R.sup.A2 is independently selected from the group
consisting of hydrogen, halogen, substituted or unsubstituted acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --CN, --OR.sup.A2a, --N(R.sup.A2a).sub.2,
and --SR.sup.A2a, wherein each occurrence of R.sup.A2a is
independently selected from the group consisting of hydrogen,
substituted or unsubstituted acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, a
nitrogen protecting group when attached to a nitrogen atom, an
oxygen protecting group when attached to an oxygen atom, and a
sulfur protecting group when attached to a sulfur atom, or two
R.sup.A2a groups are joined to form a substituted or unsubstituted
heterocyclic ring.
23-24. (canceled)
25. The compound of claim 1, wherein Ring A is a substituted or
unsubstituted, monocyclic heteroaryl ring.
26-27. (canceled)
28. The compound of claim 25, wherein Ring A is of Formula (A-v):
##STR00275## wherein: each instance of R.sup.A2 is independently
selected from the group consisting of hydrogen, halogen,
substituted or unsubstituted acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, --CN,
--OR.sup.A2a, --N(R.sup.A2a).sub.2, and --SR.sup.A2a, wherein each
occurrence of R.sup.A2a is independently selected from the group
consisting of hydrogen, substituted or unsubstituted acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, a nitrogen protecting group when attached
to a nitrogen atom, an oxygen protecting group when attached to an
oxygen atom, and a sulfur protecting group when attached to a
sulfur atom, or two R.sup.A2a groups are joined to form a
substituted or unsubstituted heterocyclic ring.
29-30. (canceled)
31. The compound of claim 1, wherein Ring A is a substituted or
unsubstituted, monocyclic heterocyclic ring.
32-33. (canceled)
34. The compound of claim 31, wherein Ring A is of Formula (A-vi):
##STR00276## wherein: J is C(R.sup.CJ).sub.2 or NR.sup.NJ; each
instance of R.sup.CJ is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; and R.sup.NJ
is hydrogen, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, optionally substituted
acyl, or a nitrogen protecting group; and each instance of R.sup.A2
is independently selected from the group consisting of hydrogen,
halogen, substituted or unsubstituted acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--CN, --OR.sup.A2a, --N(R.sup.A2a).sub.2, and --SR.sup.A2a, wherein
each occurrence of R.sup.A2a is independently selected from the
group consisting of hydrogen, substituted or unsubstituted acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, a nitrogen protecting group when attached
to a nitrogen atom, an oxygen protecting group when attached to an
oxygen atom, and a sulfur protecting group when attached to a
sulfur atom, or two R.sup.A2a groups are joined to form a
substituted or unsubstituted heterocyclic ring.
35-40. (canceled)
41. The compound of claim 1, wherein L.sup.1 is a bond.
42. (canceled)
43. The compound of claim 1, wherein L.sup.1 is --O--.
44. The compound of claim 1, wherein L.sup.1 is --NR.sup.c--.
45-47. (canceled)
48. The compound of claim 1, wherein X is --NR.sup.c--.
49-50. (canceled)
51. The compound of claim 1, wherein L.sup.2 is
--NR.sup.cC(.dbd.O)-- or --C(.dbd.O)NR.sup.c--.
52-59. (canceled)
60. The compound of claim 1, wherein R.sup.E is of Formula (i-18):
##STR00277##
61-67. (canceled)
68. The compound of claim 60, wherein R.sup.E is of the formula:
##STR00278##
69-70. (canceled)
71. The compound of claim 60, wherein R.sup.E is of the formula:
##STR00279##
72-74. (canceled)
75. The compound of claim 1, wherein the compound is of the
formula: ##STR00280## ##STR00281## ##STR00282## ##STR00283##
##STR00284## or a pharmaceutically acceptable salt thereof.
76-77. (canceled)
78. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt thereof, and optionally a
pharmaceutically acceptable excipient.
79. (canceled)
80. 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 thereof.
81-88. (canceled)
89. A method of modulating the activity of a kinase 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 thereof.
90-112. (canceled)
Description
RELATED APPLICATION
[0001] The present application claims priority under 35 U.S.C.
.sctn. 119(e) to U.S. provisional application, U.S. Ser. No.
62/185,366, filed Jun. 26, 2015, which is incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0003] Lung cancer is the leading cancer killer worldwide
accounting for 1.37 million deaths annually. In the United States,
lung cancer causes more deaths than the next three most common
cancers combined (colon, breast and pancreatic) and in 2014, an
estimated 159,260 Americans will die from lung cancer. Lung cancer
arises as a result of environmental exposures, such as smoking,
combined with genetic alterations such as deregulation of
oncoproteins, including Myc and RAS, and loss of tumor suppressors,
such as p53. The vast majority of patients that develop lung cancer
will have non-small cell lung cancer (NSCLC), and 50% of patients
will initially present with advanced NSCLC, which is incurable
using currently available therapies. The median survival of
patients with advanced NSCLC treated with chemotherapy is 8-10
months.
[0004] A major therapeutic goal in lung cancer is to identify
agents against targets that are critical to the growth of lung
cancers. This has been clinically achieved for patients that harbor
activating mutations in EGFR or chromosomal translocations such as
EML4-ALK using selective ATP-competitive kinase inhibitors.
Unfortunately the duration of response to targeted kinase
inhibitors is typically less than 2 years, and most lung tumors do
not express an oncogene that is targeted by an available drug. For
example, loss of p53 is a common event in lung cancer, but there
are currently limited drugs that can exploit its loss.
[0005] Phosphatidylinositol 4,5-bisphosphate (PIP.sub.2) is a
membrane bound lipid molecule with the ability to affect a wide
array of signaling pathways that regulate different cellular
processes (Camilli et al., Science, 1996, 271: 1533-1539).
PIP.sub.2 is used as a precursor to generate the second messengers
PIP.sub.3, DAG, and IP.sub.3, indispensable molecules for signaling
events generated by membrane receptors. However, PIP.sub.2 can also
directly regulate a vast array of proteins and is emerging as a
crucial messenger with the potential to distinctly modulate
biological processes critical for both normal and pathogenic cell
physiology (Martin, T. F. J. (1998) Annu. Rev. Cell Dev. Biol. 14,
231-264). PIP.sub.2 directly associates with effector proteins via
unique phosphoinositide binding domains, altering their
localization and/or enzymatic activity. The spatial and temporal
generation of PIP.sub.2 synthesized by the phosphatidylinositol
phosphate kinases (PIPKs) tightly regulates the activation of
receptor signaling pathways, endocytosis and vesicle trafficking,
cell polarity, focal adhesion dynamics, actin assembly, and 3' mRNA
processing (Balla et al., Phosphoinositides I: Enzymes of Synthesis
and Degradation, 2012, Chapter 2, PIP Kinases from the Cell
Membrane to the Nucleus, p 25). Two types of PIP kinases have been
identified, type I and type II PI(4)P 5-kinases (Fruman et al.,
Annu. Rev. Biochem., 1998, 67: 481-507). Type I phosphorylates
PI(4)P at the 5-position to make PI(4,5)P2 and type II can
phosphorylate PI(5)P and PI(3)P at the 4-position to make PI(4,5)P2
and PI(3,4)P2.
[0006] Recently, it has been discovered that RNAi-mediated
depletion of two type II PIP kinases, PIP4K2A and PIP4K2B,
selectively inhibited the proliferation of TP53 mutant breast
cancer cell line (BT474 cells) while cells that were wild-type for
TP53 were unaffected (Emerling et al., Cell, 2013, 155: 844-857).
These kinases phosphorylate the lipid
phosphatidylinositol-5-phosphate (PI-5-P) at the 4-position of the
inositol ring to generate phosphatidylinositol-4,5-bisphosphate
(PI-4,5-P2) and are in the same kinase family as the PI3 kinases
which are now targeted by a number of clinical stage drugs. Genetic
studies in mice demonstrate that homozygous germline deletion of
PIP4K2B results in healthy mice with a normal life span, while
combined deletion of PIP4K2B and TP53 results in early embryonic
lethality (FIG. 1) (Rameh et al., Nature, 1997, 390: 192-196). Mice
expressing one allele of PIP4K2B and homozygous deletion of PIP4K2A
and TP53 are viable and exhibit a dramatic reduction in cancers and
an extended lifespan compared to their littermates that were TP53
deleted with wild type PIP4K2A. These studies suggest that
PIP4K2A/B becomes essential when TP53 function is lost. Therefore,
small molecule inhibitors of PIP4K2A/B may hold promise as a
therapeutic agent for treating cancer.
SUMMARY OF THE INVENTION
[0007] The phosphoinositide family of lipids includes seven
derivatives of phosphatidylinositol (PI) that are formed through
the phosphorylation of the 3-, 4-, and 5-positions on the inositol
ring (Emerling et al., Cell, 2013, 155: 844-857). Phosphoinositides
have distinct biological roles and regulate many cellular
processes, including proliferation survival, glucose uptake, and
migration. Phosphoinositide kinases, phosphatases and
phospholipases, spatially and temporally regulate the generation of
the different phosphoinositide species, which localize to different
subcellular compartments. phosphorylation of lipid
phosphatidylinositol-5-phosphate (PI-5-P) at the 4-position to
generate phosphatidylinositol-4,5-bisphosphate (PI-4,5-P.sub.2) is
catalyzed by the enzymes PIP4K2A, B and C. Germ line deletion of
PIP4K2A and PIP4K2B in mice suppresses tumor formation in the
context of TP53 deletion (Rameh et al., Nature, 1997, 390:
192-196). Loss or mutations in the tumor suppressor gene TP53
(encoding p53) is one of the most frequent events in cancer.
Clinical and functional studies have unequivocally validated the
functional importance of the loss of p53 in cancer. Therefore, it
is advantageous to develop PIP4K2A and/or PIP4K2B inhibitors to
provide therapeutic benefit in cancers, for example, TP53-deleted
tumors.
[0008] 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 a protein kinase. In certain
embodiments, the protein kinase is a CDK (e.g., cyclin-dependent
kinases (CDKs)). In certain embodiments, the kinase is a lipid
kinase. In certain embodiments, the lipid kinase is a
phosphatidylinositol phosphate kinase (PIPK). In certain
embodiments, the PIPK is PIP4K, catalyzing phosphorylation of lipid
phosphatidylinositol-5-phosphate (PI-5-P) at the 4-position to
generate phosphatidylinositol-4,5-bisphosphate (PI-4,5-P.sub.2). In
some embodiments, the PIP4K is class I PIP4K, i.e., PIP4K1. In some
embodiments, the PIP4K is class II PIP4K, i.e., PIP4K2. In some
embodiments, the PIP4K2 is PIP4K2A protein. In some embodiments,
the PIP4K2 is PIP4K2B protein. In some embodiments, the PIP4K2 is
PIP4K2C protein. In certain embodiments, the compound of Formula
(I) is selective for a lipid kinase compared to other kinases. In
certain embodiments, the compound of Formula (I) is selective for
PIP4K compared to other kinases.
[0009] 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.,
PIP4K) and as therapeutics for the prevention and/or treatment of
diseases associated with overexpression and/or aberrant activity of
a kinase (e.g., PIP4K). In certain embodiments, the inventive
compounds are used for the prevention and/or treatment of
proliferative diseases (e.g., cancers (e.g., lung cancer, breast
cancer, leukemia, lymphoma, melanoma, multiple myeloma, Ewing's
sarcoma, osteosarcoma, brain cancer, neuroblastoma), benign
neoplasms, angiogenesis, inflammatory diseases, autoinflammatory
diseases, and autoimmune diseases) in a subject.
[0010] In one aspect, the present invention 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 A, L.sup.1,
L.sup.2, R.sup.B1, R.sup.B2, M, X, R.sup.A, R.sup.C, R.sup.D,
R.sup.E, n, and p are as defined herein.
[0011] In certain embodiments, a compound of Formula (I) is of
Formula (I-a):
##STR00003##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0012] In certain embodiments, a compound of Formula (I) is Formula
(I-b):
##STR00004##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0013] In certain embodiments, a compound of Formula (I) is Formula
(I-c):
##STR00005##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0014] In another aspect, the present invention provides
pharmaceutical compositions comprising a compound of Formula (I),
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof, and optionally a pharmaceutically
acceptable excipient. In certain embodiments, the pharmaceutical
compositions described herein include a therapeutically effective
amount of a compound of Formula (I), or a pharmaceutically
acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,
stereoisomer, isotopically labeled derivative, or prodrug thereof.
The pharmaceutical composition may be useful for treating and/or
preventing a proliferative disease (e.g., cancer) or an infectious
disease.
[0015] In another aspect, the present invention provides methods
for treating and/or preventing proliferative diseases. Exemplary
proliferative diseases include cancer (e.g., lung cancer, breast
cancer, leukemia, lymphoma, melanoma, multiple myeloma, Ewing's
sarcoma, osteosarcoma, brain cancer, neuroblastoma), benign
neoplasm, angiogenesis, inflammatory diseases, autoinflammatory
diseases, and autoimmune diseases. In certain embodiments, the
cancer has one or more mutations. In certain embodiments, the
cancer is TP53-deleted cancer. In other embodiments, the present
invention provides methods for treating and/or preventing an
infectious disease (e.g., a viral infection).
[0016] Another aspect of the invention relates to methods of
modulating the activity of a kinase (e.g., PIP4K (e.g., PIP4K2)
enzyme) in a biological sample or subject. In certain embodiments,
the method involves the selective inhibition of the PIP4K enzyme
over other kinases. In certain embodiments, the method involves the
selective inhibition of the PIP4K2 enzyme over other kinases.
[0017] The present invention also provides methods of inhibiting
cell growth in a biological sample or subject.
[0018] Another aspect of the invention relates to methods of
screening a library of compounds (e.g., compounds of Formula (I))
to identify one or more compounds useful in the treatment of a
proliferative disease (e.g., cancer (e.g., lung cancer, breast
cancer, leukemia, lymphoma, melanoma, multiple myeloma, Ewing's
sarcoma, osteosarcoma, brain cancer, neuroblastoma), benign
neoplasm, angiogenesis, inflammatory diseases, autoinflammatory
diseases, and autoimmune diseases) or an infectious disease (e.g.,
viral infection) in a subject, in inhibiting a kinase (e.g., PIP4K
enzyme), or in inhibiting cell growth.
[0019] 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 proliferative
disease in a subject.
[0020] 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 or prevention of an
infectious disease in a subject. In certain embodiments, the
infectious disease is a viral infection.
[0021] Another aspect of the present invention relates to kits
comprising a container with a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof, or a pharmaceutical composition
thereof. The kits of the invention may include a single dose or
multiple doses of a compound of Formula (I), or a pharmaceutically
acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,
stereoisomer, isotopically labeled derivative, or prodrug thereof,
or a pharmaceutical composition thereof. The provided kits may be
useful for the treatment and/or prevention of a proliferative
disease (e.g., cancer (e.g., lung cancer, breast cancer, leukemia,
lymphoma, melanoma, multiple myeloma, Ewing's sarcoma,
osteosarcoma, brain cancer, neuroblastoma), benign neoplasm,
angiogenesis, inflammatory diseases, autoinflammatory diseases, and
autoimmune diseases) or an infectious disease in a subject. In
certain embodiments, the kits described herein further include
instructions for administering the compound of Formula (I), or the
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof, or the pharmaceutical composition
thereof.
[0022] 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, the
Examples, and the Claims.
Definitions
[0023] 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.rd Edition, Cambridge
University Press, Cambridge, 1987. The disclosure is not intended
to be limited in any manner by the exemplary listing of
substituents described herein.
[0024] 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 disclosure additionally encompasses compounds described
herein as individual isomers substantially free of other isomers,
and alternatively, as mixtures of various isomers.
[0025] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6" 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.
[0026] The term "aliphatic" includes both saturated and
unsaturated, straight chain (i.e., unbranched), branched, acyclic,
cyclic, or polycyclic aliphatic hydrocarbons, which are substituted
or unsubstituted with one or more functional groups. As will be
appreciated by one of ordinary skill in the art, "aliphatic" is
intended herein to include, but is not limited to, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus,
the term "alkyl" includes straight, branched and cyclic alkyl
groups. An analogous convention applies to other generic terms such
as "alkenyl", "alkynyl", and the like. Furthermore, the terms
"alkyl", "alkenyl", "alkynyl", and the like encompass both
substituted and unsubstituted groups. In certain embodiments,
"lower alkyl" is used to indicate those alkyl groups (cyclic,
acyclic, substituted, unsubstituted, branched or unbranched) having
1-6 carbon atoms.
[0027] In certain embodiments, the alkyl, alkenyl, and alkynyl
groups employed in the disclosure contain 1-20 aliphatic carbon
atoms. In certain other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the disclosure contain 1-10 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the disclosure contain 1-8 aliphatic
carbon atoms. In still other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the disclosure contain 1-6 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the disclosure contain 1-4 carbon atoms.
Illustrative aliphatic groups thus include, but are not limited to,
for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
--CH.sub.2-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl,
tert-butyl, cyclobutyl, --CH.sub.2-cyclobutyl, n-pentyl,
sec-pentyl, isopentyl, tert-pentyl, cyclopentyl,
--CH.sub.2-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl,
--CH.sub.2-cyclohexyl moieties and the like, which again, may bear
one or more substituents. Alkenyl groups include, but are not
limited to, for example, ethenyl, propenyl, butenyl,
1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups
include, but are not limited to, ethynyl, 2-propynyl (propargyl),
1-propynyl, and the like.
[0028] The term "alkyl" refers to a radical of a straight-chain or
branched saturated hydrocarbon group having from 1 to 10 carbon
atoms ("C.sub.1-10 alkyl"). In some embodiments, an alkyl group has
1 to 9 carbon atoms ("C.sub.1-9 alkyl"). In some embodiments, an
alkyl group has 1 to 8 carbon atoms ("C.sub.1-8 alkyl"). In some
embodiments, an alkyl group has 1 to 7 carbon atoms ("C.sub.1-7
alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon
atoms ("C.sub.1-6 alkyl"). In some embodiments, an alkyl group has
1 to 5 carbon atoms ("C.sub.1-5 alkyl"). In some embodiments, an
alkyl group has 1 to 4 carbon atoms ("C.sub.1-4 alkyl"). In some
embodiments, an alkyl group has 1 to 3 carbon atoms ("C.sub.1-3
alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon
atoms ("C.sub.1-2 alkyl"). In some embodiments, an alkyl group has
1 carbon atom ("C.sub.1 alkyl"). In some embodiments, an alkyl
group has 2 to 6 carbon atoms ("C.sub.2-6 alkyl"). Examples of
C.sub.1-6 alkyl groups include methyl (C.sub.1), ethyl (C.sub.2),
propyl (C.sub.3) (e.g., n-propyl, isopropyl), butyl (C.sub.4)
(e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C.sub.5)
(e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl,
tertiary amyl), and hexyl (C.sub.6) (e.g., n-hexyl). Additional
examples of alkyl groups include n-heptyl (C.sub.7), n-octyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkyl group is independently unsubstituted (an "unsubstituted
alkyl") or substituted (a "substituted alkyl") with one or more
substituents (e.g., halogen, such as F). In certain embodiments,
the alkyl group is an unsubstituted C.sub.1-10 alkyl (such as
unsubstituted C.sub.1-6 alkyl, e.g., --CH.sub.3 (Me), unsubstituted
ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl
(n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu,
e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl
(tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu),
unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl
group is a substituted C.sub.1-10 alkyl (such as substituted
C.sub.1-6 alkyl, e.g., benzyl (Bn) or --CF.sub.3).
[0029] "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.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkenyl groups as well as pentenyl (C.sub.5), pentadienyl
(C.sub.5), hexenyl (C.sub.6), and the like. Additional examples of
alkenyl include heptenyl (C.sub.7), octenyl (C.sub.8), octatrienyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkenyl group is independently 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. In an alkenyl group, a C.dbd.C double bond for which the
stereochemistry is not specified (e.g., --CH.dbd.CHCH.sub.3 or
##STR00006##
may be an (E)- or (Z)-double bond.
[0030] "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.2-6 alkynyl"). In
some embodiments, an alkynyl group has 2 to 5 carbon atoms
("C.sub.2-5 alkynyl"). In some embodiments, an alkynyl group has 2
to 4 carbon atoms ("C.sub.2-4 alkynyl"). In some embodiments, an
alkynyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkynyl"). In
some embodiments, an alkynyl group has 2 carbon atoms ("C.sub.2
alkynyl"). The one or more carbon-carbon triple bonds can be
internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
Examples of C.sub.2-4 alkynyl groups include, without limitation,
ethynyl (C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3),
1-butynyl (C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkynyl groups as well as pentynyl (C.sub.5), hexynyl (C.sub.6),
and the like. Additional examples of alkynyl include heptynyl
(C.sub.7), octynyl (C.sub.8), and the like. Unless otherwise
specified, each instance of an alkynyl group is independently
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.
[0031] "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 zero 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 substituted C.sub.3-10 carbocyclyl.
[0032] 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.3-6 cycloalkyl groups as well as cycloheptyl
(C.sub.7) and cyclooctyl (C.sub.8). Unless otherwise specified,
each instance of a cycloalkyl group is independently unsubstituted
(an "unsubstituted cycloalkyl") or substituted (a "substituted
cycloalkyl") with one or more substituents. In certain embodiments,
the cycloalkyl group is unsubstituted C.sub.3-10 cycloalkyl. In
certain embodiments, the cycloalkyl group is substituted C.sub.3-10
cycloalkyl.
[0033] "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 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.
[0034] In some embodiments, a heterocyclyl group is a 5-10
membered, non-aromatic ring system having ring carbon atoms and 1-4
ring heteroatoms, wherein each heteroatom is independently selected
from nitrogen, oxygen, 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 nitrogen, oxygen, and sulfur ("5-8
membered heterocyclyl"). In some embodiments, a heterocyclyl group
is a 5-6 membered non-aromatic ring system having ring carbon atoms
and 1-4 ring heteroatoms, wherein each heteroatom is independently
selected from nitrogen, oxygen, and sulfur ("5-6 membered
heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl
has 1-3 ring heteroatoms selected from nitrogen, oxygen, and
sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2
ring heteroatoms selected from nitrogen, oxygen, and sulfur. In
some embodiments, the 5-6 membered heterocyclyl has one ring
heteroatom selected from nitrogen, oxygen, and sulfur.
[0035] Exemplary 3-membered heterocyclyl groups containing one
heteroatom include, without limitation, azirdinyl, oxiranyl,
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.
[0036] "Aryl" refers to a radical of a monocyclic or polycyclic
(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g.,
having 6, 10, or 14 pi electrons shared in a cyclic array) having
6-14 ring carbon atoms and zero heteroatoms provided in the
aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an
aryl group has 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.
[0037] "Aralkyl" refers to a substituted or unsubstituted alkyl
group substituted by a substituted or unsubstituted aryl group. In
certain embodiments, the aralkyl is substituted or unsubstituted
benzyl. In certain embodiments, the aralkyl is benzyl. In certain
embodiments, the aralkyl is substituted or unsubstituted phenethyl.
In certain embodiments, the aralkyl is phenethyl.
[0038] "Heteroaryl" refers to a radical of a 5-10 membered,
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10 pi electrons shared in a cyclic array) having ring carbon atoms
and 1-4 ring heteroatoms provided in the aromatic ring system,
wherein each heteroatom is independently selected from nitrogen,
oxygen and sulfur ("5-10 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).
[0039] In some embodiments, a heteroaryl group is a 5-10 membered
aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from nitrogen, oxygen, and
sulfur ("5-10 membered heteroaryl"). In some embodiments, a
heteroaryl group is a 5-8 membered aromatic ring system having ring
carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur ("5-6
membered heteroaryl"). In some embodiments, the 5-6 membered
heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen,
and sulfur. In some embodiments, the 5-6 membered heteroaryl has
1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In
some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom
selected from nitrogen, oxygen, and sulfur. Unless otherwise
specified, each instance of a heteroaryl group is independently
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.
[0040] 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.
[0041] "Heteroaralkyl" is a subset of alkyl and heteroaryl and
refers to a substituted or unsubstituted alkyl group substituted by
a substituted or unsubstituted heteroaryl group.
[0042] "Unsaturated" or "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).
Likewise, "saturated" refers to a group that does not contain a
double or triple bond, i.e., contains all single bonds.
[0043] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups, which are divalent linking groups, are
further referred to using the suffix -ene, e.g., alkylene,
alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene,
and heteroarylene.
[0044] An atom, moiety, or group described herein may be
unsubstituted or substituted, as valency permits, unless otherwise
provided expressly. The term "optionally substituted" refers to
substituted or unsubstituted.
[0045] A group is substituted or unsubstituted unless expressly
provided otherwise. The term "optionally substituted" refers to
being substituted or unsubstituted. In certain embodiments, alkyl,
alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl
groups are substituted or unsubstituted (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 disclosure contemplates any and all such
combinations in order to arrive at a stable compound. For purposes
of this disclosure, 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. In certain embodiments, the
substituent is a carbon atom substituent. In certain embodiments,
the substituent is a nitrogen atom substituent. In certain
embodiments, the substituent is an oxygen atom substituent. In
certain embodiments, the substituent is a sulfur atom
substituent.
[0046] 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(.dbd.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.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa,
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R, --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)(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;
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;
[0047] 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;
[0048] 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,
--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;
[0049] 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;
[0050] 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)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;
[0051] 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;
[0052] 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
[0053] 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.
[0054] In certain embodiments, the carbon atom substituents are
independently halogen, substituted or unsubstituted C.sub.1-6
alkyl, or --OR.sup.aa.
[0055] The term "hydroxyl" or "hydroxy" refers to the group --OH.
The term "substituted hydroxyl" or "substituted hydroxyl," by
extension, refers to a hydroxyl group wherein the oxygen atom
directly attached to the parent molecule is substituted with a
group other than hydrogen, and includes groups selected from
--OR.sup.aa, --ON(R.sup.bb).sub.2, --OC(.dbd.O)SR.sup.aa,
--OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--OC(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.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, --OSi(R.sup.aa).sub.3, --OP(R.sup.cc).sub.2,
--OP(R.sup.cc).sub.3.sup.+X.sup.-, --OP(OR.sup.cc).sub.2,
--OP(OR.sup.cc).sub.3.sup.+X.sup.-, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, and --OP(.dbd.O)(N(R.sup.bb)).sub.2,
wherein R.sup.aa, R.sup.bb, and R.sup.cc are as defined herein.
[0056] A "counterion" or "anionic counterion" is a negatively
charged group associated with a cationic quaternary amino group in
order to maintain electronic neutrality. 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.-,
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), and carboxylate ions (e.g.,
acetate, ethanoate, propanoate, benzoate, glycerate, lactate,
tartrate, glycolate, and the like). Further exemplary counterions
include, but are not limited to, 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
[0057] "Halo" or "halogen" refers to fluorine (fluoro, --F),
chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine (iodo,
--I).
[0058] "Acyl" refers to a moiety selected from the group consisting
of --C(.dbd.O)R.sup.aa, --CHO, --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,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, or --C(.dbd.S)SR.sup.aa, wherein R.sup.aa and
R.sup.bb are as defined herein.
[0059] 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.
[0060] 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.
[0061] 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-nitrophenylacetamide,
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.
[0062] Nitrogen protecting groups such as carbamate groups (e.g.,
--C(.dbd.O)OR.sup.aa) include, but are not limited to, methyl
carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc),
9-(2-sulfo)fluorenylmethyl carbamate,
9-(2,7-dibromo)fluorenylmethyl 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 or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc),
allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc),
cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),
8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio
carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),
p-nitrobenzyl 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, isobornyl
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.
[0063] 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), 3-trimethylsilylethanesulfonamide (SES),
9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide.
[0064] 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). In certain embodiments, a
nitrogen protecting group is Bn, BOC, Cbz, Fmoc, trifluoroacetyl,
triphenylmethyl, acetyl, or Ts.
[0065] 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 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.
[0066] Exemplary oxygen atom substituents include, but are not
limited to, --R.sup.aa, --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, --P(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2,
--P(.dbd.O).sub.2N(R.sup.bb).sub.2, and
--P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein. In certain embodiments, the oxygen
atom substituent present on an oxygen atom is an oxygen protecting
group (also referred to as a hydroxyl protecting group). 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. Exemplary oxygen
protecting groups include, but are not limited to, methyl,
t-butyloxycarbonyl (BOC or Boc), 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-naphthyl 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, a-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,
borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,
sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate
(Ts). In certain embodiments, an oxygen protecting group is silyl,
TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl,
pivaloyl, or benzoyl.
[0067] In certain embodiments, the substituent present on a sulfur
atom is a sulfur protecting group (also referred to as a "thiol
protecting group"). Sulfur protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3.sup.+X.sup.-,
--P(OR.sup.cc).sub.2, --P(OR.sup.cc).sub.3.sup.+X.sup.-,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2, and
--P(.dbd.O)(N(R.sup.bb).sub.2).sub.2, wherein R.sup.aa, R.sup.bb,
and R.sup.cc are as defined herein. Sulfur protecting groups are
well known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference. In certain embodiments, a sulfur protecting
group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl,
2-pyridine-sulfenyl, or triphenylmethyl.
[0068] A "hydrocarbon chain" refers to a substituted or
unsubstituted divalent alkyl, alkenyl, or alkynyl group. A
hydrocarbon chain includes (1) one or more chains of carbon atoms
immediately between the two radicals of the hydrocarbon chain; (2)
optionally one or more hydrogen atoms on the chain(s) of carbon
atoms; and (3) optionally one or more substituents ("non-chain
substituents," which are not hydrogen) on the chain(s) of carbon
atoms. A chain of carbon atoms consists of consecutively connected
carbon atoms ("chain atoms" or "carbon units") and does not include
hydrogen atoms or heteroatoms. However, a non-chain substituent of
a hydrocarbon chain may include any atoms, including hydrogen
atoms, carbon atoms, and heteroatoms. For example, hydrocarbon
chain --C.sup.AH(C.sup.BH.sub.2C.sup.CH.sub.3)-- includes one chain
atom C.sup.A, one hydrogen atom on C.sup.A, and non-chain
substituent --(C.sup.BH.sub.2C.sup.CH.sub.3). The term "C.sub.x
hydrocarbon chain," wherein x is a positive integer, refers to a
hydrocarbon chain that includes x number of chain atom(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
##STR00007##
is a C.sub.3 hydrocarbon chain. When a range of values is used, the
meaning of the range is as described herein. For example, a
C.sub.3-10 hydrocarbon chain refers to a hydrocarbon chain where
the number of chain atoms of the shortest chain of carbon atoms
immediately between the two radicals of the hydrocarbon chain is 3,
4, 5, 6, 7, 8, 9, or 10. 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.C--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., --C.ident.C-- or
--(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 a substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl
ring. For instance,
##STR00008##
and are all examples of a hydrocarbon chain. In contrast, in
certain embodiments,
##STR00009##
H and N are not within the scope of the hydrocarbon chains
described herein. When a chain atom of a C.sub.x hydrocarbon chain
is replaced with a heteroatom, the resulting group is referred to
as a C.sub.x hydrocarbon chain wherein a chain atom is replaced
with a heteroatom, as opposed to a C.sub.x-1 hydrocarbon chain. For
example,
##STR00010##
is a C.sub.3 hydrocarbon chain wherein one chain atom is replaced
with an oxygen atom.
[0069] The term "leaving group" is given its ordinary meaning in
the art of synthetic organic chemistry and refers to an atom or a
group capable of being displaced by a nucleophile. Examples of
suitable leaving groups include, but are not limited to, halogen
(such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy,
aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy,
alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy,
methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In
some cases, the leaving group is a sulfonic acid ester, such as
toluenesulfonate (tosylate, --OTs), methanesulfonate (mesylate,
--OMs), p-bromobenzenesulfonyloxy (brosylate, --OBs),
--OS(.dbd.O).sub.2(CF.sub.2).sub.3CF.sub.3 (nonaflate, --ONf), or
trifluoromethanesulfonate (triflate, --OTf). In some cases, the
leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In
some cases, the leaving group is a nosylate, such as
2-nitrobenzenesulfonyloxy. The leaving group may also be a
phosphineoxide (e.g., formed during a Mitsunobu reaction) or an
internal leaving group such as an epoxide or cyclic sulfate. Other
non-limiting examples of leaving groups are water, ammonia,
alcohols, ether moieties, thioether moieties, zinc halides,
magnesium moieties, diazonium salts, and copper moieties. Further
exemplary leaving groups include, but are not limited to, halo
(e.g., chloro, bromo, iodo) and activated substituted hydroxyl
groups (e.g., --OC(.dbd.O)SR.sup.aa, --OC(.dbd.O)R.sup.aa,
--OCO.sub.2R, --OC(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.NR.sup.bb)R,
--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, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--OP(.dbd.O).sub.2R, --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).
Other Definitions
[0070] 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 described herein 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 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.
[0071] 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 described herein may be
prepared, e.g., in crystalline form, and may be solvated. Suitable
solvates include pharmaceutically acceptable solvates and further
include both stoichiometric solvates and non-stoichiometric
solvates. In certain instances, the solvate will be capable of
isolation, for example, when one or more solvent molecules are
incorporated in the crystal lattice of a crystalline solid.
"Solvate" encompasses both solution-phase and isolatable solvates.
Representative solvates include hydrates, ethanolates, and
methanolates.
[0072] The term "hydrate" refers to a compound that is associated
with water. Typically, the number of the water molecules contained
in a hydrate of a compound is in a definite ratio to the number of
the compound molecules in the hydrate. Therefore, a hydrate of a
compound may be represented, for example, by the general formula
R.x H.sub.2O, wherein R is the compound, and x is a number greater
than 0. A given compound may form more than one type of hydrate,
including, e.g., monohydrates (x is 1), lower hydrates (x is a
number greater than 0 and smaller than 1, e.g., hemihydrates (R.0.5
H.sub.2O)), and polyhydrates (x is a number greater than 1, e.g.,
dihydrates (R.2 H.sub.2O) and hexahydrates (R.6 H.sub.2O)).
[0073] The term "tautomers" or "tautomeric" refers to two or more
interconvertible compounds resulting from at least one formal
migration of a hydrogen atom and at least one change in valency
(e.g., a single bond to a double bond, a triple bond to a single
bond, or vice versa). The exact ratio of the tautomers depends on
several factors, including temperature, solvent, and pH.
Tautomerizations (i.e., the reaction providing a tautomeric pair)
may catalyzed by acid or base. Exemplary tautomerizations include
keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine,
and enamine-to-(a different enamine) tautomerizations.
[0074] 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".
[0075] 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".
[0076] 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.
[0077] The term "co-crystal" refers to a crystalline structure
composed of at least two components. In certain embodiments, a
co-crystal may contain a compound of the present invention and one
or more other component, including but not limited to, atoms, ions,
molecules, or solvent molecules. In certain embodiments, a
co-crystal may contain a compound of the present invention and one
or more components related to said compound, including not limited
to, an isomer, tautomer, salt, solvate, hydrate, synthetic
precursor, synthetic derivative, fragment or impurity of said
compound.
[0078] The term "isotopically labeled derivative" or "isotopically
labeled" refers to a compound wherein one or more atoms in the
compound (or in an associated ion or molecule of a salt, hydrate,
or solvate) has been replaced with an isotope of the same element.
For the given element or position in the molecule the isotope will
be enriched, or present in a higher percentage of all atoms of the
element or of all atoms at the position in the molecule in a
sample, relative to an unlabeled variant. In certain embodiments,
the enriched isotope will be a stable isotope. In certain
embodiments, the enriched isotope will be an unstable or
radioactive isotope (e.g., a radionuclide). In certain embodiments,
the enriched isotope may be detected by a measurement technique,
including but not limited to nuclear magnetic resonance, mass
spectrometry, infrared spectroscopy, or a technique that measures
radioactive decay.
[0079] The term "prodrugs" refers to compounds that have cleavable
groups and become by solvolysis or under physiological conditions
the compounds described herein, which are pharmaceutically active
in vivo. Such examples include, but are not limited to, choline
ester derivatives and the like, N-alkylmorpholine esters and the
like. Other derivatives of the compounds described herein have
activity in both their acid and acid derivative forms, but in the
acid sensitive form often offer advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism (see,
Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives well known to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides, and anhydrides derived
from acidic groups pendant on the compounds described herein are
particular prodrugs. In some cases it is desirable to prepare
double ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. C.sub.1-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 described herein may be preferred.
[0080] The term "inhibition", "inhibiting", "inhibit," or
"inhibitor" refer to the ability of a compound to reduce, slow,
halt or prevent activity of a particular biological process (e.g.,
activity of a bromodomain and/or a bromodomain-containing protein)
in a cell relative to vehicle.
[0081] When a compound, pharmaceutical composition, method, use, or
kit is referred to as "selectively," "specifically," or
"competitively" binding a first protein or a first chromatin, the
compound, pharmaceutical composition, method, use, or kit binds the
first protein or the first chromatin with a higher binding affinity
(e.g., not less than about 2-fold, not less than about 5-fold, not
less than about 10-fold, not less than about 30-fold, not less than
about 100-fold, not less than about 1,000-fold, or not less than
about 10,000-fold) than binding a second protein or second
chromatin that is different from the first protein and the first
chromatin. When a compound, pharmaceutical composition, method,
use, or kit is referred to as "selectively," "specifically," or
"competitively" modulating (e.g., increasing or inhibiting) the
activity of a bromodomain-containing protein, the compound,
pharmaceutical composition, method, use, or kit modulates the
activity of the bromodomain-containing protein to a greater extent
(e.g., not less than about 2-fold, not less than about 5-fold, not
less than about 10-fold, not less than about 30-fold, not less than
about 100-fold, not less than about 1,000-fold, or not less than
about 10,000-fold) than the activity of at least one protein that
is different from the bromodomain-containing protein.
[0082] The term "aberrant activity" refers to activity deviating
from normal activity, that is, abnormal activity. The term
"increased activity" refers to activity higher than normal
activity.
[0083] The terms "composition" and "formulation" are used
interchangeably.
[0084] A "subject" to which administration is contemplated refers
to a human (i.e., male or female of any age group, e.g., pediatric
subject (e.g., infant, child, or adolescent) or adult subject
(e.g., young adult, middle-aged adult, or senior adult)) or
non-human animal. In certain embodiments, the non-human animal is a
mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey),
commercially relevant mammal (e.g., cattle, pig, horse, sheep,
goat, cat, or dog), or bird (e.g., commercially relevant bird, such
as chicken, duck, goose, or turkey)). In certain embodiments, the
non-human animal is a fish, reptile, or amphibian. The non-human
animal may be a male or female at any stage of development. The
non-human animal may be a transgenic animal or genetically
engineered animal. A "patient" refers to a human subject in need of
treatment of a disease.
[0085] The term "biological sample" refers to any sample including
tissue samples (such as tissue sections and needle biopsies of a
tissue); cell samples (e.g., cytological smears (such as Pap or
blood smears) or samples of cells obtained by microdissection);
samples of whole organisms (such as samples of yeasts or bacteria);
or cell fractions, fragments or organelles (such as obtained by
lysing cells and separating the components thereof by
centrifugation or otherwise). Other examples of biological samples
include blood, serum, urine, semen, fecal matter, cerebrospinal
fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied
tissue (e.g., obtained by a surgical biopsy or needle biopsy),
nipple aspirates, milk, vaginal fluid, saliva, swabs (such as
buccal swabs), or any material containing biomolecules that is
derived from another biological sample.
[0086] The terms "administer," "administering," or "administration"
refers to implanting, absorbing, ingesting, injecting, inhaling, or
otherwise introducing a compound described herein, or a composition
thereof, into, in, or on a subject.
[0087] The terms "treatment," "treat," and "treating" refer to
reversing, alleviating, delaying the onset of, or inhibiting the
progress of a disease described herein. In some embodiments,
treatment may be administered after one or more signs or symptoms
of the disease have developed or have been observed. In other
embodiments, treatment may be administered in the absence of signs
or symptoms of the disease. For example, treatment may be
administered to a susceptible subject prior to the onset of
symptoms (e.g., in light of a history of symptoms and/or in light
of exposure to a pathogen). Treatment may also be continued after
symptoms have resolved, for example, to delay or prevent
recurrence.
[0088] The terms "condition," "disease," and "disorder" are used
interchangeably.
[0089] An "effective amount" of a compound described herein 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
described herein may vary depending on such factors as the desired
biological endpoint, the pharmacokinetics of the compound, the
condition being treated, the mode of administration, and the age
and health of the subject. In certain embodiments, an effective
amount is a therapeutically effective amount. In certain
embodiments, an effective amount is a prophylactic treatment. In
certain embodiments, an effective amount is the amount of a
compound described herein in a single dose. In certain embodiments,
an effective amount is the combined amounts of a compound described
herein in multiple doses.
[0090] A "therapeutically effective amount" of a compound described
herein is an amount sufficient to provide a therapeutic benefit in
the treatment of a condition or to delay or minimize one or more
symptoms associated with the condition. A therapeutically effective
amount of a compound means an amount of therapeutic agent, alone or
in combination with other therapies, which provides a therapeutic
benefit in the treatment of the condition. The term
"therapeutically effective amount" can encompass an amount that
improves overall therapy, reduces or avoids symptoms, signs, or
causes of the condition, and/or enhances the therapeutic efficacy
of another therapeutic agent.
[0091] A "prophylactically effective amount" of a compound
described herein 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.
[0092] 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,
diseases associated with angiogenesis, inflammatory diseases, and
autoimmune diseases.
[0093] The term "angiogenesis" refers to the physiological process
through which new blood vessels form from pre-existing vessels.
Angiogenesis is distinct from vasculogenesis, which is the de novo
formation of endothelial cells from mesoderm cell precursors. The
first vessels in a developing embryo form through vasculogenesis,
after which angiogenesis is responsible for most blood vessel
growth during normal or abnormal development. Angiogenesis is a
vital process in growth and development, as well as in wound
healing and in the formation of granulation tissue. However,
angiogenesis is also a fundamental step in the transition of tumors
from a benign state to a malignant one, leading to the use of
angiogenesis inhibitors in the treatment of cancer. Angiogenesis
may be chemically stimulated by angiogenic proteins, such as growth
factors (e.g., VEGF). "Pathological angiogenesis" refers to
abnormal (e.g., excessive or insufficient) angiogenesis that
amounts to and/or is associated with a disease.
[0094] The terms "neoplasm" and "tumor" are used herein
interchangeably and refer to an abnormal mass of tissue wherein the
growth of the mass surpasses and is not coordinated as in the
growth of 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. 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.
[0095] The term "cancer" refers to a class of diseases
characterized by the development of abnormal cells that proliferate
uncontrollably and have the ability to infiltrate and destroy
normal body tissues. See, e.g., Stedman's Medical Dictionary, 25th
ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.
Exemplary cancers include, but are not limited to, hematological
malignancies. Additional 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, triple negative
breast cancer (TNBC)); 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; ocular 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));
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 neuroendocrine
tumor (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).
[0096] The term "hematological malignancy" refers to tumors that
affect blood, bone marrow, and/or lymph nodes. Exemplary
hematological malignancies include, but are not limited to,
leukemia, such as acute lymphoblastic 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 (DLBCL, e.g., activated B-cell (ABC)
DLBCL (ABC-DLBCL))), follicular lymphoma, chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma
(MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated
lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell
lymphoma, splenic marginal zone B-cell lymphoma), primary
mediastinal B-cell lymphoma, Burkitt's lymphoma, Waldenstrom's
macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairy cell
leukemia (HCL), immunoblastic large cell lymphoma, precursor
B-lymphoblastic lymphoma, central nervous system (CNS) lymphoma
(e.g., primary CNS lymphoma and secondary 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); lymphoma of an immune privileged site (e.g., cerebral
lymphoma, ocular lymphoma, lymphoma of the placenta, lymphoma of
the fetus, testicular lymphoma); a mixture of one or more
leukemia/lymphoma as described above; myelodysplasia; and multiple
myeloma (MM).
[0097] The term "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, hay fever, 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.
[0098] 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 disease,
Guillain-Barre syndrome, Hashimoto's thyroiditis, and
cardiomyopathy.
[0099] The term "kinase" is a type of enzyme that transfers
phosphate groups from high energy donor molecules, such as ATP, to
specific substrates, referred to as phosphorylation. Kinases are
part of the larger family of phosphotransferases. Kinases are used
extensively to transmit signals and control complex processes in
cells. Various other kinases act on small molecules such as lipids,
carbohydrates, amino acids, and nucleotides, either for signaling
or to prime them for metabolic pathways. Kinases are often named
after their substrates. More than 500 different protein kinases
have been identified in humans. In some embodiments, the kinase is
a protein kinase. A protein kinase is a kinase enzyme that modifies
other proteins by chemically adding phosphate groups to them
(phosphorylation). In some embodiments, the protein kinase is
Cyclin dependent kinases (CDKs). CDKs are a group of several
different kinases involved in regulation of the cell cycle. They
phosphorylate other proteins on their serine or threonine residues,
but CDKs must first bind to a cyclin protein in order to be active.
In some embodiments, the protein kinase is mitogen-activated
protein kinases (MAPKs). MAP kinases (MAPKs) are a family of
serine/threonine kinases that respond to a variety of extracellular
growth signals. In some embodiments, the kinase is a lipid kinases
that phosphorylate lipids in the cell, both on the plasma membrane
as well as on the membranes of the organelles. The addition of
phosphate groups can change the reactivity and localization of the
lipid and can be used in signal transmission. In some embodiments,
the lipid kinase is a phosphatidylinositol kinase that
phosphorylates phosphatidylinositol species, to create species such
as phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2),
phosphatidylinositol 3,4,5-trisphosphate (PIP3), and
phosphatidylinositol 3-phosphate (PI3P). In some embodiments, the
lipid kinase is sphingosine kinase (SK), a lipid kinase that
catalyzes the conversion of sphingosine to sphingosine-1-phosphate
(S1P). In certain embodiments, the SK is SK1 or SK2. Exemplary
human protein kinases include, but are not limited to, AAK1, ABL,
ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7,
AMPKa1, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARG, AurA,
AurAps1, AurAps2, AurB, AurBps1, AurC, AXL, BARK1, BARK2, BIKE,
BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B, BMPR2, BMX, BRAF,
BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a, CaMK1b,
CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1,
CaMKK2, caMLCK, CASK, CCK4, CCRK, CDC2, CDC7, CDK10, CDK11, CDK2,
CDK3, CDK4, CDK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK8ps,
CDK9, CDKL1, CDKL2, CDKL3, CDKL4, CDKL5, CGDps, CHED, CHK1, CHK2,
CHK2ps1, CHK2ps2, CK1a, CK1a2, CK1aps1, CK1aps2, CK1aps3, CK1d,
CK1e, CK1g1, CK1g2, CK1g2ps, CK1g3, CK2a1, CK2a1-rs, CK2a2, CLIK1,
CLIKIL, CLK1, CLK2, CLK2ps, CLK3, CLK3ps, CLK4, COT, CRIK, CRK7,
CSK, CTK, CYGD, CYGF, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2,
DCAMKL3, DDR1, DDR2, DLK, DMPK1, DMPK2, DRAK1, DRAK2, DYRK1A,
DYRK1B, DYRK2, DYRK3, DYRK4, EGFR, EphA1, EphA10, EphA2, EphA3,
EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4,
EphB6, Erk1, Erk2, Erk3, Erk3ps1, Erk3ps2, Erk3ps3, Erk3ps4, Erk4,
Erk5, Erk7, FAK, FER, FERps, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR,
FLT1, FLT1ps, FLT3, FLT4, FMS, FRK, Fused, FYN, GAK, GCK, GCN2,
GCN22, GPRK4, GPRK5, GPRK6, GPRK6ps, GPRK7, GSK3A, GSK3B, Haspin,
HCK, HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, HH498, HIPK1, HIPK2,
HIPK3, HIPK4, HPK1, HRI, HRIps, HSER, HUNK, ICK, IGF1R, IKKa, IKKb,
IKKe, ILK, INSR, IRAK1, IRAK2, IRAK3, IRAK4, IRE1, IRE2, IRR, ITK,
JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR, KHS1, KHS2, KIS, KIT,
KSGCps, KSR1, KSR2, LATS1, LATS2, LCK, LIMK1, LIMK2, LIMK2ps, LKB1,
LMR1, LMR2, LMR3, LOK, LRRK1, LRRK2, LTK, LYN, LZK, MAK, MAP2K1,
MAP2K1ps, MAP2K2, MAP2K2ps, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7,
MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8,
MAPKAPK2, MAPKAPK3, MAPKAPK5, MAPKAPKps1, MARK1, MARK2, MARK3,
MARK4, MARKps01, MARKps02, MARKps03, MARKps04, MARKps05, MARKps07,
MARKps08, MARKps09, MARKps10, MARKps11, MARKps12, MARKps13,
MARKps15, MARKps16, MARKps17, MARKps18, MARKps19, MARKps20,
MARKps21, MARKps22, MARKps23, MARKps24, MARKps25, MARKps26,
MARKps27, MARKps28, MARKps29, MARKps30, MAST1, MAST2, MAST3, MAST4,
MASTL, MELK, MER, MET, MISR2, MLK1, MLK2, MLK3, MLK4, MLKL, MNK1,
MNK1ps, MNK2, MOK, MOS, MPSK1, MPSK1ps, MRCKa, MRCKb, MRCKps, MSK1,
MSK12, MSK2, MSK22, MSSK1, MST1, MST2, MST3, MST3ps, MST4, MUSK,
MYO3A, MYO3B, MYT1, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK2ps1,
NEK2ps2, NEK2ps3, NEK3, NEK4, NEK4ps, NEK5, NEK6, NEK7, NEK8, NEK9,
NIK, NIM1, NLK, NRBP1, NRBP2, NuaK1, NuaK2, Obscn, Obscn2, OSR1,
p38a, p38b, p38d, p38g, p70S6K, p70S6Kb, p70S6Kps1, p70S6Kps2,
PAK1, PAK2, PAK2ps, PAK3, PAK4, PAK5, PAK6, PASK, PBK, PCTAIRE1,
PCTAIRE2, PCTAIRE3, PDGFRa, PDGFRb, PDK1, PEK, PFTAIRE1, PFTAIRE2,
PHKg1, PHKg1ps1, PHKg1ps2, PHKg1ps3, PHKg2, PIK3R4, PIM1, PIM2,
PIM3, PINK1, PIP4K2A, PIP4K2B, PIPK.quadrature., PITSLRE, PKACa,
PKACb, PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh, PKCi, PKCips,
PKCt, PKCz, PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2, PKN3, PKR,
PLK1, PLK1ps1, PLK1ps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY, PRP4,
PRP4ps, PRPK, PSKH1, PSKH1ps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps,
RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1,
ROR2, ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42,
RSKL1, RSKL2, RYK, RYKps, SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3,
SGK, SgK050ps, SgK069, SgK071, SgK085, SgK110, SgK196, SGK2,
SgK223, SgK269, SgK288, SGK3, SgK307, SgK384ps, SgK396, SgK424,
SgK493, SgK494, SgK495, SgK496, SIK (e.g., SIK1, SIK2), skMLCK,
SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM, SRPK1, SRPK2,
SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6, STLK6ps1,
STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1, TEC,
TESK1, TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2,
TLK2ps1, TLK2ps2, TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB,
TRKC, TSSK1, TSSK2, TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2,
TTK, TTN, TXK, TYK2, TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4,
VACAMKL, VRK1, VRK2, VRK3, VRK3ps, Wee1, Wee1B, Wee1Bps, Wee1ps1,
Wee1ps2, Wnk1, Wnk2, Wnk3, Wnk4, YANK1, YANK2, YANK3, YES, YESps,
YSK1, ZAK, ZAP70, ZC1/HGK, ZC2/TNIK, ZC3/MINK, and ZC4/NRK.
[0100] The term "CDK" refers to a cyclin-dependent kinase. A CDK
binds a cyclin (e.g., Cyclin H), which is a regulatory protein.
CDKs phosphorylate their substrates at serines and threonines. The
consensus sequence for the phosphorylation site in the amino acid
sequence of a CDK substrate is [S/T*]PX[K/R], where S/T* is the
phosphorylated serine or threonine, P is proline, X is any amino
acid, K is lysine, and R is arginine. CDKs include CDK1, CDK2,
CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12,
CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDK19 and CDK20.
[0101] CDK7, cyclin-dependent kinase 7, is a CDK, wherein the
substrate is Cyclin H, MAT1 (e.g., MNAT1), or Cyclin H and MAT1.
CDK7 is alternatively referred to as CAK1, HCAK, MO15, STK1, CDKN7,
and p39MO15. Non-limiting examples of the nucleotide and protein
sequences for human CDK7 are described in GenBank Accession Number
NP_001790, incorporated herein by reference. The amino acid
sequence of this CDK7 is as follows:
TABLE-US-00001 MALDVKSRAKRYEKLDFLGEGQFATVYKARDKNTNQIVAIKKIKLGHRSE
AKDGINRTALREIKLLQELSHPNIIGLLDAFGHKSNISLVFDFMETDLEV
IIKDNSLVLTPSHIKAYMLMTLQGLEYLHQHWILHRDLKPNNLLLDENGV
LKLADFGLAKSFGSPNRAYTHQVVTRWYRAPELLFGARMYGVGVDMWAVG
CILAELLLRVPFLPGDSDLDQLTRIFETLGTPTEEQWPDMCSLPDYVTFK
SFPGIPLHHIFSAAGDDLLDLIQGLFLFNPCARITATQALKMKYFSNRPG
PTPGCQLPRPNCPVETLKEQSNPALAIKRKRTEALEQGGLPKKLIF
[0102] CDK12, cyclin-dependent kinase 12, is a CDK, wherein the
substrate is Cyclin K or Flavopiridol. CDK12 is alternatively
referred to as Cdc2-related kinase, CDC2-related protein kinase 7,
Cell division cycle 2-related protein kinase 7, Cell division
protein kinase 12, CRK7, CRKR, CRKRS, cyclin-dependent kinase 12,
or KIAA0904. Non-limiting examples of the nucleotide and protein
sequences for human CDK12 are described in Uniprot Number Q9NYV4,
which is incorporated herein by reference. The amino acid sequence
of this CDK12 is as follows:
TABLE-US-00002 MPNSERHGGKKDGSGGASGTLQPSSGGGSSNSRERHRLVSKHKRHKSKHS
KDMGLVTPEAASLGTVIKPLVEYDDISSDSDTFSDDMAFKLDRRENDERR
GSDRSDRLHKHRHHQHRRSRDLLKAKQTEKEKSQEVSSKSGSMKDRISGS
SKRSNEETDDYGKAQVAKSSSKESRSSKLHKEKTRKERELKSGHKDRSKS
HRKRETPKSYKTVDSPKRRSRSPHRKWSDSSKQDDSPSGASYGQDYDLSP
SRSHTSSNYDSYKKSPGSTSRRQSVSPPYKEPSAYQSSTRSPSPYSRRQR
SVSPYSRRRSSSYERSGSYSGRSPSPYGRRRSSSPFLSKRSLSRSPLPSR
KSMKSRSRSPAYSRHSSSHSKKKRSSSRSRHSSISPVRLPLNSSLGAELS
RKKKERAAAAAAAKMDGKESKGSPVFLPRKENSSVEAKDSGLESKKLPRS
VKLEKSAPDTELVNVTHLNTEVKNSSDTGKVKLDENSEKHLVKDLKAQGT
RDSKPIALKEEIVTPKETETSEKETPPPLPTIASPPPPLPTTTPPPQTPP
LPPLPPIPALPQQPPLPPSQPAFSQVPASSTSTLPPSTHSKTSAVSSQAN
SQPPVQVSVKTQVSVTAAIPHLKTSTLPPLPLPPLLPGDDDMDSPKETLP
SKPVKKEKEQRTRHLLTDLPLPPELPGGDLSPPDSPEPKAITPPQQPYKK
RPKICCPRYGERRQTESDWGKRCVDKFDIIGIIGEGTYGQVYKAKDKDTG
ELVALKKVRLDNEKEGFPITAIREIKILRQLIHRSVVNMKEIVTDKQDAL
DFKKDKGAFYLVFEYMDHDLMGLLESGLVHFSEDHIKSFMKQLMEGLEYC
HKKNFLHRDIKCSNILLNNSGQIKLADFGLARLYNSEESRPYTNKVITLW
YRPPELLLGEERYTPAIDVWSCGCILGELFTKKPIFQANLELAQLELISR
LCGSPCPAVWPDVIKLPYFNTMKPKKQYRRRLREEFSFIPSAALDLLDHM
LTLDPSKRCTAEQTLQSDFLKDVELSKMAPPDLPHWQDCHELWSKKRRRQ
RQSGVVVEEPPPSKTSRKETTSGTSTEPVKNSSPAPPQPAPGKVESGAGD
AIGLADITQQLNQSELAVLLNLLQSQTDLSIPQMAQLLNIHSNPEMQQQL
EALNQSISALTEATSQQQDSETMAPEESLKEAPSAPVILPSAEQTTLEAS
STPADMQNILAVLLSQLMKTQEPAGSLEENNSDKNSGPQGPRRTPTMPQE
EAAACPPHILPPEKRPPEPPGPPPPPPPPPLVEGDLSSAPQELNPAVTAA
LLQLLSQPEAEPPGHLPHEHQALRPMEYSTRPRPNRTYGNTDGPETGFSA
IDTDERNSGPALTESLVQTLVKNRTFSGSLSHLGESSSYQGTGSVQFPGD
QDLRFARVPLALHPVVGQPFLKAEGSSNSVVHAETKLQNYGELGPGTTGA
SSSGAGLHWGGPTQSSAYGKLYRGPTRVPPRGGRGRGVPY
[0103] CDK13, cyclin-dependent kinase 13, is a CDK, wherein the
relevant cyclin is cyclin K and a reference inhibitor is the
pan-CDK inhibitor Flavopiridol and the c-terminal domain (CTD) of
RNA-polymerase II is a physiological substrate. CDK13 is
alternatively referred to as CHED; CDC2L; CDC2L5; or hCDK13.
Non-limiting examples of the nucleotide and protein sequences for
human CDK12 are described in GenBank Accession Number M80629, which
is incorporated herein by reference. The amino acid sequence of
this CDK13 is as follows:
TABLE-US-00003 MPSSSDTALGGGGGLSWAEKKLEERRKRRRFLSPQQPPLLLPLLQPQLLQ
PPPPPPPLLFLAAPGTAAAAAAAAAASSSCFSPGPPLEVKRLARGKRRAG
GRQKRRRGPRAGQEAEKRRVFSLPQPQQDGGGGASSGGGVTPLVEYEDVS
SQSEQGLLLGGASAATAATAAGGTGGSGGSPASSSGTQRRGEGSERRPRR
DRRSSSGRSKERHREHRRRDGQRGGSEASKSRSRHSHSGEERAEVAKSGS
SSSSGGRRKSASATSSSSSSRKDRDSKAHRSRTKSSKEPPSAYKEPPKAY
REDKTEPKAYRRRRSLSPLGGRDDSPVSHRASQSLRSRKSPSPAGGGSSP
YSRRLPRSPSPYSRRRSPSYSRHSSYERGGDVSPSPYSSSSWRRSRSPYS
PVLRRSGKSRSRSPYSSRHSRSRSRHRLSRSRSRHSSISPSTLTLKSSLA
AELNKNKKARAAEAARAAEAAKAAEATKAAEAAAKAAKASNTSTPTKGNT
ETSASASQTNHVKDVKKIKIEHAPSPSSGGTLKNDKAKTKPPLQVTKVEN
NLIVDKATKKAVIVGKESKSAATKEESVSLKEKTKPLTPSIGAKEKEQHV
ALVTSTLPPLPLPPMLPEDKEADSLRGNISVKAVKKEVEKKLRCLLADLP
LPPELPGGDDLSKSPEEKKTATQLHSKRRPKICGPRYGETKEKDIDWGKR
CVDKFDIIGIIGEGTYGQVYKARDKDTGEMVALKKVRLDNEKEGFPITAI
REIKILRQLTHQSIINMKEIVTDKEDALDFKKDKGAFYLVFEYMDHDLMG
LLESGLVHFNENHIKSFMRQLMEGLDYCHKKNFLHRDIKCSNILLNNRGQ
IKLADFGLARLYSSEESRPYTNKVITLWYRPPELLLGEERYTPAIDVWSC
GCILGELFTKKPIFQANQELAQLELISRICGSPCPAVWPDVIKLPYFNTM
KPKKQYRRKLREEFVFIPAAALDLFDYMLALDPSKRCTAEQALQCEFLRD
VEPSKMPPPDLPLWQDCHELWSKKRRRQKQMGMTDDVSTIKAPRKDLSLG
LDDSRTNTPQGVLPSSQLKSQGSSNVAPVKTGPGQHLNHSELAILLNLLQ
SKTSVNMADFVQVLNIKVNSETQQQLNKINLPAGILATGEKQTDPSTPQQ
ESSKPLGGIQPSSQTIQPKVETDAAQAAVQSAFAVLLTQLIKAQQSKQKD
VLLEERENGSGHEASLQLRPPPEPSTPVSGQDDLIQHQDMRILELTPEPD
RPRILPPDQRPPEPPEPPPVTEEDLDYRTENQHVPTTSSSLTDPHAGVKA
ALLQLLAQHQPQDDPKREGGIDYQAGDTYVSTSDYKDNFGSSSFSSAPYV
SNDGLGSSSAPPLERRSFIGNSDIQSLDNYSTASSHSGGPPQPSAFSESF
PSSVAGYGDIYLNAGPMLFSGDKDHRFEYSHGPIAVLANSSDPSTGPEST
HPLPAKMHNYNYGGNLQENPSGPSLMHGQTWTSPAQGPGYSQGYRGHIST STGRGRGRGLPY
[0104] The term "PIP kinases", also known as "PIPKs," refers to
phosphatidylinositol phosphate kinases or
phosphatidylinositol-5-phosphate 4-kinases, a class of enzymes that
catalyzes the chemical reaction: ATP+1-phosphatidyl-1D-myo-inositol
4-phosphate .revreaction.ADP+1-phosphatidyl-1D-myo-inositol
4,5-bisphosphate. PIP kinases are divided into two classes, type I
and type II. The type I and type II PIP kinases are 35% identical
at the kinase domain. Their sequences are significantly divergent
for a stretch of about 25 amino acids in the region of the kinase
domain that corresponds to the activation loop of protein kinases.
There are three isoforms of type II PIP4-kinase in mammalian cells,
namely .alpha. (PIP4K2A), .beta. (PIP4K2B), and .gamma. (PIP4K2C)
isoforms (Liu et al., Nat. Rev. Drug. Discov., 2009, 8(8):
627-644). At the protein level, the .alpha. and .beta. isoforms are
83% identical and the .gamma. isoform is about 60% identical to
either one of them. All isoforms are ubiquitously expressed, but
the .alpha. isoform is found predominantly in brain and platelets,
the .beta. isoform in brain and muscle, and the .gamma. isoform in
brain and kidney. Although the type II PIP4-kinase isoforms are
ubiquitously expressed, changes in protein levels may play a role
in the regulation of their cellular function. The type II
PIP4-kinase .beta. isoform gene, which localizes to the chromosome
17q11-12, was found to be amplified in primary breast cancer
samples with Heregulin 2 gene amplifications and in a subset of
breast cancer cell lines. These gene amplifications resulted in
increased protein expression, which correlated with increased
breast cancer cell proliferation and anchorage-independent growth
(Emerling et al., Cell, 2013, 155(4): 844-857). In certain
embodiments, the PIPK is PI5P4K.alpha. (i.e. PIP4K2A enzyme)
encoded by PIP4K2A gene. In certain embodiments, the PIPK is
PI5P4K.beta. (i.e. PIP4K2B enzyme) encoded by PIP4K2B gene. In
certain embodiments, the PIPK is PI5P4K.gamma. (i.e. PIP4K2C
enzyme) encoded by PIP4K2C gene. As used herein, type II PIP4Ks
enzymes are referred as follows: PI5P4K is interchangeable with
PIP4K; PI5P4K.alpha. is interchangeable with PIP4K.alpha., PIP4K2A,
PIP4K2A enzyme, and PIP4K2A protein; PI5P4K.beta. is
interchangeable with PIP4K.beta., PIP4K2B, PIP4K2B enzyme, and
PIP4K2B protein; PI5P4K.gamma. is interchangeable with
PIP4K.gamma., PIP4K2C, PIP4K2C enzyme, and PIP4K2C protein.
[0105] In certain embodiments, the PIP4K2A enzyme is
sp|P48426|PI42A_HUMAN Phosphatidylinositol 5-phosphate 4-kinase
type-2 alpha (OS.dbd.Homo sapiens, GN=PIP4K2A, PE=1, and SV=2) and
of the following sequence:
TABLE-US-00004 MATPGNLGSSVLASKTKTKKKHFVAQKVKLFRASDPLLSVLMWGVNHSIN
ELSHVQIPVMLMPDDFKAYSKIKVDNHLFNKENMPSHFKFKEYCPMVFRN
LRERFGIDDQDFQNSLTRSAPLPNDSQARSGARFHTSYDKRYIIKTITSE
DVAEMHNILKKYHQYIVECHGITLLPQFLGMYRLNVDGVEIYVIVTRNVF
SHRLSVYRKYDLKGSTVAREASDKEKAKELPTLKDNDFINEGQKIYIDDN
NKKVFLEKLKKDVEFLAQLKLMDYSLLVGIHDVERAEQEEVECEENDGEE
EGESDGTHPVGTPPDSPGNTLNSSPPLAPGEFDPNIDVYGIKCHENSPRK
EVYFMAIIDILTHYDAKKKAAHAAKTVKHGAGAEISTVNPEQYSKRFLDF IGHILT
[0106] In certain embodiments, the PIP4K2B enzyme is
sp|P78356|PI42B_HUMAN Phosphatidylinositol 5-phosphate 4-kinase
type-2 beta (OS.dbd.Homo sapiens, GN=PIP4K2B, PE=1, and SV=1) and
of the following sequence:
TABLE-US-00005 MSSNCTSTTAVAVAPLSASKTKTKKKHFVCQKVKLFRASEPILSVLMWGV
NHTINELSNVPVPVMLMPDDFKAYSKIKVDNHLFNKENLPSRFKFKEYCP
MVFRNLRERFGIDDQDYQNSVTRSAPINSDSQGRCGTRFLTTYDRRFVIK
TVSSEDVAEMHNILKKYHQFIVECHGNTLLPQFLGMYRLTVDGVETYMVV
TRNVFSHRLTVHRKYDLKGSTVAREASDKEKAKDLPTFKDNDFLNEGQKL
HVGEESKKNFLEKLKRDVEFLAQLKIMDYSLLVGIHDVDRAEQEEMEVEE
RAEDEECENDGVGGNLLCSYGTPPDSPGNLLSFPRFFGPGEFDPSVDVYA
MKSHESSPKKEVYFMAIIDILTPYDTKKKAAHAAKTVKHGAGAEISTVNP
EQYSKRFNEFMSNILT
[0107] In certain embodiments, the PIP4K2C enzyme is
sp|Q8TBX8|PI42C_HUMAN Phosphatidylinositol 5-phosphate 4-kinase
type-2 gamma (OS.dbd.Homo sapiens, GN=PIP4K2C, PE=1, and SV=3) and
of the following sequence:
TABLE-US-00006 MASSSVPPATVSAATAGPGPGFGFASKTKKKHFVQQKVKVFRAADPLVGV
FLWGVAHSINELSQVPPPVMLLPDDFKASSKIKVNNHLFHRENLPSHFKF
KEYCPQVFRNLRDRFGIDDQDYLVSLTRNPPSESEGSDGRFLISYDRTLV
IKEVSSEDIADMHSNLSNYHQYIVKCHGNTLLPQFLGMYRVSVDNEDSYM
LVMRNMFSHRLPVHRKYDLKGSLVSREASDKEKVKELPTLKDMDFLNKNQ
KVYIGEEEKKIFLEKLKRDVEFLVQLKIMDYSLLLGIHDIIRGSEPEEEA
PVREDESEVDGDCSLTGPPALVGSYGTSPEGIGGYIHSHRPLGPGEFESF
IDVYAIRSAEGAPQKEVYFMGLIDILTQYDAKKKAAHAAKTVKHGAGAEI
STVHPEQYAKRFLDFITNIFA
[0108] In certain embodiments, the PIP4K2A gene of Gene ID: 5305
and HGNC:8997 and has the cDNA sequence as follows:
TABLE-US-00007 ATGGCGACCCCCGGCAACCTAGGGTCCTCTGTCCTGGCGAGCAAGACCAA
GACCAAGAAGAAGCACTTCGTAGCGCAGAAAGTGAAGCTGTTTCGGGCCA
GCGACCCGCTGCTCAGCGTCCTCATGTGGGGGGTAAACCACTCGATCAAT
GAACTGAGCCATGTTCAAATCCCTGTTATGTTGATGCCAGATGACTTCAA
AGCCTATTCAAAAATAAAGGTGGACAATCACCTTTTTAACAAAGAAAACA
TGCCGAGCCATTTCAAGTTTAAGGAATACTGCCCGATGGTCTTCCGTAAC
CTGCGGGAGAGGTTTGGAATTGATGATCAAGATTTCCAGAATTCCCTGAC
CAGGAGCGCACCCCTCCCCAACGACTCCCAGGCCCGCAGTGGAGCTCGTT
TTCACACTTCCTACGACAAAAGATACATCATCAAGACTATTACCAGTGAA
GACGTGGCCGAAATGCACAACATCCTGAAGAAATACCACCAGTACATAGT
GGAATGTCATGGGATCACCCTTCTTCCCCAGTTCTTGGGCATGTACCGGC
TTAATGTTGATGGAGTTGAAATATATGTGATAGTTACAAGAAATGTATTC
AGCCACCGTTTGTCTGTGTATAGGAAATACGACTTAAAGGGCTCTACAGT
GGCTAGAGAAGCTAGTGACAAAGAAAAGGCCAAAGAACTGCCAACTCTGA
AAGATAATGATTTCATTAATGAGGGCCAAAAGATTTATATTGATGACAAC
AACAAGAAGGTCTTCCTGGAAAAACTAAAAAAGGATGTTGAGTTTCTGGC
CCAGCTGAAGCTCATGGACTACAGTCTGCTGGTGGGAATTCATGATGTGG
AGAGAGCCGAACAGGAGGAAGTGGAGTGTGAGGAGAACGATGGGGAGGAG
GAGGGCGAGAGCGATGGCACCCACCCGGTGGGAACCCCCCCAGATAGCCC
CGGGAATACACTGAACAGCTCACCACCCCTGGCTCCCGGGGAGTTCGATC
CGAACATCGACGTCTATGGAATTAAGTGCCATGAAAACTCGCCTAGGAAG
GAGGTGTACTTCATGGCAATTATTGACATCCTTACTCATTATGATGCAAA
AAAGAAAGCTGCCCATGCTGCAAAAACTGTTAAACATGGCGCTGGCGCGG
AGATCTCCACCGTGAACCCAGAACAGTATTCAAAGCGCTTTTTGGACTTT
ATTGGCCACATCTTGACGTAA
[0109] In certain embodiments, the PIP4K2B gene of Gene ID: 8396
and HGNC:8998, and has the cDNA sequence as follows:
TABLE-US-00008 ATGTCGTCCAACTGCACCAGCACCACGGCGGTGGCGGTGGCGCCGCTCAG
CGCCAGCAAGACCAAGACCAAGAAGAAGCATTTCGTGTGCCAGAAAGTGA
AGCTATTCCGGGCCAGCGAGCCGATCCTCAGCGTCCTGATGTGGGGGGTG
AACCACACGATCAATGAGCTGAGCAATGTTCCTGTTCCTGTCATGCTAAT
GCCAGATGACTTCAAAGCCTACAGCAAGATCAAGGTGGACAATCATCTCT
TCAATAAGGAGAACCTGCCCAGCCGCTTTAAGTTTAAGGAGTATTGCCCC
ATGGTGTTCCGAAACCTTCGGGAGAGGTTTGGAATTGATGATCAGGATTA
CCAGAATTCAGTGACGCGCAGCGCCCCCATCAACAGTGACAGCCAGGGTC
GGTGTGGCACGCGTTTCCTCACCACCTACGACCGGCGCTTTGTCATCAAG
ACTGTGTCCAGCGAGGACGTGGCGGAGATGCACAACATCTTAAAGAAATA
CCACCAGTTTATAGTGGAGTGTCATGGCAACACGCTTTTGCCACAGTTCC
TGGGCATGTACCGCCTGACCGTGGATGGTGTGGAAACCTACATGGTGGTT
ACCAGGAACGTGTTCAGCCATCGGCTCACTGTGCATCGCAAGTATGACCT
CAAGGGTTCTACGGTTGCCAGAGAAGCGAGCGACAAGGAGAAGGCCAAGG
ACTTGCCAACATTCAAAGACAATGACTTCCTCAATGAAGGGCAGAAGCTG
CATGTGGGAGAGGAGAGTAAAAAGAACTTCCTGGAGAAACTGAAGCGGGA
CGTTGAGTTCTTGGCACAGCTGAAGATCATGGACTACAGCCTGCTGGTGG
GCATCCACGACGTGGACCGGGCAGAGCAGGAGGAGATGGAGGTGGAGGAG
CGGGCAGAGGACGAGGAGTGTGAGAATGATGGGGTGGGTGGCAACCTACT
CTGCTCCTATGGCACACCTCCGGACAGCCCTGGCAACCTCCTCAGCTTTC
CTCGGTTCTTTGGTCCTGGGGAATTCGACCCCTCTGTTGACGTCTATGCC
ATGAAAAGCCATGAAAGTTCCCCCAAGAAGGAGGTGTATTTCATGGCCAT
CATTGATATCCTCACGCCATACGATACAAAGAAGAAAGCTGCACATGCTG
CCAAAACGGTGAAACACGGGGCAGGGGCCGAGATCTCGACTGTGAACCCT
GAGCAGTACTCCAAACGCTTCAACGAGTTTATGTCCAACATCCTGACGTA G
[0110] In certain embodiments, the PIP4K2C gene of Gene ID: 79837
and HGNC:23786, and has the cDNA sequence as follows:
TABLE-US-00009 ATGGCGTCCTCCTCGGTCCCACCAGCCACGGTATCGGCGGCGACAGCAGG
CCCCGGCCCAGGTTTCGGCTTCGCCTCCAAGACCAAGAAGAAGCATTTCG
TGCAGCAGAAGGTGAAGGTGTTCCGGGCGGCCGACCCGCTGGTGGGTGTG
TTCCTGTGGGGCGTAGCCCACTCGATCAATGAGCTCAGCCAGGTGCCTCC
CCCGGTGATGCTGCTGCCAGATGACTTTAAGGCCAGCTCCAAGATCAAGG
TCAACAATCACCTTTTCCACAGGGAAAATCTGCCCAGTCATTTCAAGTTC
AAGGAGTATTGTCCCCAGGTCTTCAGGAACCTCCGTGATCGATTTGGCAT
TGATGACCAAGATTACTTGGTGTCCCTTACCCGAAACCCCCCCAGCGAAA
GTGAAGGCAGTGATGGTCGCTTCCTTATCTCCTACGATCGGACTCTGGTC
ATCAAAGAAGTATCCAGTGAGGACATTGCTGACATGCATAGCAACCTCTC
CAACTATCACCAGTACATTGTGAAGTGCCATGGCAACACGCTTCTGCCCC
AGTTCCTGGGGATGTACCGAGTCAGTGTGGACAACGAAGACAGCTACATG
CTTGTGATGCGCAATATGTTTAGCCACCGTCTTCCTGTGCACAGGAAGTA
TGACCTCAAGGGTTCCCTAGTGTCCCGGGAAGCCAGCGATAAGGAAAAGG
TTAAAGAATTGCCCACCCTTAAGGATATGGACTTTCTCAACAAGAACCAG
AAAGTATATATTGGTGAAGAGGAGAAGAAAATATTTCTGGAGAAGCTGAA
GAGAGATGTGGAGTTTCTAGTGCAGCTGAAGATCATGGACTACAGCCTTC
TGCTAGGCATCCACGACATCATTCGGGGCTCTGAACCAGAGGAGGAAGCG
CCCGTGCGGGAGGATGAGTCAGAGGTGGATGGGGACTGCAGCCTGACTGG
ACCTCCTGCTCTGGTGGGCTCCTATGGCACCTCCCCAGAGGGTATCGGAG
GCTACATCCATTCCCATCGGCCCCTGGGCCCAGGAGAGTTTGAGTCCTTC
ATTGATGTCTATGCCATCCGGAGTGCTGAAGGAGCCCCCCAGAAGGAGGT
CTACTTCATGGGCCTCATTGATATCCTTACACAGTATGATGCTAAGAAGA
AAGCAGCTCATGCAGCCAAAACTGTCAAGCATGGGGCTGGGGCAGAGATC
TCTACTGTCCATCCGGAGCAGTATGCTAAGCGATTCCTGGATTTTATTAC
CAACATCTTTGCCTAA
BRIEF DESCRIPTION OF THE DRAWINGS
[0111] FIG. 1 shows that loss of PIP4K2.alpha./.beta. restricts
tumor death after p53 deletion. Kaplan-Meier plot analysis was
conducted for tumor free survival after p53 deletion. 15
TP53.sup.-/- PIP4K2A.sup.+/+PIP4K2B.sup.+/+ and 20
TP53.sup.-/-PIP4K2A.sup.-/-PIP4K2B.sup.+/- mice were tested.
*p<0.05 with two-tailed Student's t test.
TP53.sup.-/-PIP4K2A.sup.-/-PIP4K2B.sup.+/- mice had a great
increase of tumor free survival compared to
TP53.sup.-/-PIP4K2A.sup.+/+PIP4K2B.sup.+/+ mice. (Emerling et al.,
Cell, 2013, 155(4):844-57).
[0112] FIG. 2 shows an exemplary synthesis of Compound 7.
[0113] FIGS. 3A and 3B show the inhibition of PI5P4K.alpha./.beta.
by compound THZ-CE-A7. FIG. 3A: THZ-CE-A7 inhibited the kinase
activity of both PI5P4K.alpha. and PI5P4K.beta.. Radiometric kinase
assay was performed using C.sup.32P-ATP and PI5P. The radiolabeled
product, PI(4,5)P.sub.2, was measured after the separation by thin
layer chromatography. FIG. 3B: THZ-CE-A7 inhibited the
proliferation of TP53 mutant BT474 cells at 1 .mu.M (left panel).
The inhibition stayed effective after 6 hours of treatment and
washout (middle panel). THZ-CE-A7 did not inhibit TP53 wild type
MCF7 cells at 1 .mu.M (right panel).
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0114] Recent studies have shown that lipid kinases play an
essential role in inhibiting cancer cell growth when the TP53
function is absent. Depletion of two lipid kinases, PIP4K2A and
PIP4K2B, selectively inhibited the proliferation of TP53 mutant
breast cancer cell line (BT474 cells) while cells that were
wild-type for TP53 were unaffected (Emerling et al., Cell, 2013,
155: 844-857). Further research has shown that mice expressing one
allele of PIP4K2B and homozygous deletion of PIP4K2A and TP53 are
viable and exhibit a dramatic reduction in cancers and extended
lifespan compared to their littermates that were TP53 deleted with
wild type PIP4K2A. Therefore, small molecule inhibitors of lipid
kinases may hold promise as a therapeutic agent for treating
proliferative diseases.
[0115] The present invention provides compounds, which inhibit the
activity of a kinase, for the prevention and/or treatment of a
proliferative disease of a subject. In certain embodiments, the
inventive compounds inhibit the activity of a lipid kinase, such as
PIP4K. The present invention further provides methods of using the
compounds described herein, e.g., as biological probes to study the
modulation of the activity of a kinase (e.g., a lipid kinase such
as PIP4K), and as therapeutics, e.g., in the prevention and/or
treatment of diseases associated with the overexpression and/or
aberrant activity of the kinase (e.g., a lipid kinase such as
PIP4K). In certain embodiments, the disease being treated and/or
prevented is a proliferative disease. Exemplary proliferative
diseases include, but are not limited to, cancers (e.g., lung
cancer, breast cancer, leukemia, melanoma, multiple myeloma),
benign neoplasms, angiogenesis, inflammatory diseases,
autoinflammatory diseases, and autoimmune diseases. In certain
embodiments, the cancer is associated with the overexpression
and/or aberrant activity of a kinase (e.g., a lipid kinase such as
PIP4K).
Compounds
[0116] In one aspect of the present invention, provided are
compounds of Formula (I):
##STR00011##
or a pharmaceutically acceptable salt thereof, wherein:
[0117] Ring A is a substituted or unsubstituted, monocyclic or
bicyclic heteroaryl ring or a substituted or unsubstituted,
monocyclic heterocyclic ring;
[0118] each instance of R.sup.A is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0119] each instance of R.sup.a is independently hydrogen,
substituted or unsubstituted acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, a
nitrogen protecting group when attached to a nitrogen atom, an
oxygen protecting group when attached to an oxygen atom, or a
sulfur protecting group when attached to a sulfur atom, or two
instances of R.sup.a are joined to form a substituted or
unsubstituted, heterocyclic ring, or substituted or unsubstituted,
heteroaryl ring;
[0120] k is 0, 1, 2, 3, 4, 5, or 6;
[0121] M is NR.sup.M, O, or S;
[0122] R.sup.M is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, or a nitrogen protecting
group;
[0123] L.sup.1 is a bond, --C(R.sup.b).sub.2--, --C(.dbd.O)--,
--O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, or
--NR.sup.c--;
[0124] each instance of R.sup.b is independently hydrogen, halogen,
or substituted or unsubstituted C.sub.1-6 alkyl;
[0125] each instance of R.sup.c is independently hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group;
[0126] R.sup.B1 is hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0127] R.sup.B2 is hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0128] X is --C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--, --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
--NR.sup.cS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, or --NR.sup.cS(.dbd.O).sub.2--;
[0129] Ring C is a substituted or unsubstituted phenyl ring;
[0130] Ring D is a substituted or unsubstituted phenyl ring;
[0131] each instance of R.sup.C is independently halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0132] n is 0, 1, 2, 3, or 4;
[0133] L.sup.2 is --C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--,
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
--NR.sup.cS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, --NR.sup.cS(.dbd.O).sub.2--,
--OC(.dbd.O)O--, --NR.sup.cC(.dbd.O)O--, --OC(.dbd.O)NR.sup.c--,
--NR.sup.cC(.dbd.O)NR.sup.c--,
--C(R.sup.b).sub.2C(.dbd.O)C(R.sup.b).sub.2--,
--OC(.dbd.O)C(R.sup.b).sub.2--, --C(R.sup.b).sub.2C(.dbd.)O--,
--NR.sup.cC(.dbd.O)C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)NR.sup.c--, or a substituted or
unsubstituted 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--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, or --NR.sup.c--;
[0134] each instance of R.sup.D is independently halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0135] p is 0, 1, 2, 3, or 4;
[0136] R.sup.E is of the formula:
##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016##
##STR00017##
[0137] L.sup.3 is --C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--,
--S--, --S(O)--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
--NR.sup.cS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, --NR.sup.cS(.dbd.O).sub.2--,
--OC(.dbd.O)O--, --NR.sup.cC(.dbd.O)O--, --OC(.dbd.O)NR.sup.c--,
--NR.sup.cC(.dbd.O)NR.sup.c--,
--C(R.sup.b).sub.2C(.dbd.)C(R.sup.b).sub.2--,
--OC(.dbd.O)C(R.sup.b).sub.2--, --C(R.sup.b).sub.2C(.dbd.)O--,
--NR.sup.cC(.dbd.O)C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)NR.sup.c--, or a substituted or
unsubstituted 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--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, or --NR.sup.c--;
[0138] L.sup.4 is a bond or substituted or unsubstituted C.sub.1-6
hydrocarbon chain;
[0139] each of R.sup.E1, R.sup.E2, and R.sup.E3 is independently
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --CH.sub.2OR.sup.a,
--CH.sub.2N(R.sup.a).sub.2, --CH.sub.2SR.sup.a, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, or --Si(R.sup.a).sub.3; 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 a substituted or unsubstituted, carbocyclic
ring, or substituted or unsubstituted, heterocyclic ring;
[0140] R.sup.E4 is a leaving group;
[0141] R.sup.E5 is halogen;
[0142] R.sup.E6 is hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, or a nitrogen protecting group;
[0143] each instance of Y is independently O, S, or NR.sup.c;
[0144] a is 1 or 2; and
[0145] each instance of z is independently 0, 1, 2, 3, 4, 5, or
6.
[0146] In certain embodiments, the compound described herein is of
Formula (I), or a pharmaceutically acceptable salt thereof,
wherein:
[0147] Ring A is a substituted or unsubstituted, bicyclic
heteroaryl ring or a substituted or unsubstituted, monocyclic
heterocyclic ring;
[0148] each instance of R.sup.A is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0149] each instance of R.sup.a is independently hydrogen,
substituted or unsubstituted acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, a
nitrogen protecting group when attached to a nitrogen atom, an
oxygen protecting group when attached to an oxygen atom, or a
sulfur protecting group when attached to a sulfur atom, or two
instances of R.sup.a are joined to form a substituted or
unsubstituted, heterocyclic ring, or substituted or unsubstituted,
heteroaryl ring;
[0150] k is 0, 1, 2, 3, 4, 5, or 6;
[0151] M is NR.sup.M, O, or S;
[0152] R.sup.M is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, or a nitrogen protecting
group;
[0153] L.sup.1 is a bond, --C(R.sup.b).sub.2--, --C(.dbd.O)--,
--O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, or
--NR.sup.c--;
[0154] each instance of R.sup.b is independently hydrogen, halogen,
or substituted or unsubstituted C.sub.1-6 alkyl;
[0155] each instance of R.sup.c is independently hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group;
[0156] R.sup.B1 is hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0157] R.sup.B2 is hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0158] X is --C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--, --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
--NR.sup.cS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, or --NR.sup.cS(.dbd.O).sub.2--;
[0159] Ring C is a substituted or unsubstituted phenyl ring;
[0160] Ring D is a substituted or unsubstituted phenyl ring;
[0161] each instance of R.sup.C is independently halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0162] n is 0, 1, 2, 3, or 4;
[0163] L.sup.2 is --C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--,
--S--, --S(O)--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
NR.sup.cS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, --NR.sup.cS(.dbd.O).sub.2--,
--OC(.dbd.O)O--, --NR.sup.cC(.dbd.O)O--, --OC(.dbd.O)NR.sup.c--,
--NR.sup.cC(.dbd.O)NR.sup.c--,
--C(R.sup.b).sub.2C(.dbd.)C(R.sup.b).sub.2--,
--OC(.dbd.O)C(R.sup.b).sub.2--, --C(R.sup.b).sub.2C(.dbd.)O--,
--NR.sup.cC(.dbd.O)C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)NR.sup.c--, or a substituted or
unsubstituted 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--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, or --NR.sup.c--;
[0164] each instance of R.sup.D is independently halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0165] p is 0, 1, 2, 3, or 4;
[0166] R.sup.E is of the formula:
##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022##
##STR00023##
[0167] L.sup.3 is --C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--,
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
--NR.sup.cS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, --NR.sup.cS(.dbd.O).sub.2--,
--OC(.dbd.O)O--, --NR.sup.cC(.dbd.O)O--, --OC(.dbd.O)NR.sup.c--,
--NR.sup.cC(.dbd.O)NR.sup.c--,
--C(R.sup.b).sub.2C(.dbd.)C(R.sup.b).sub.2--,
--OC(.dbd.O)C(R.sup.b).sub.2--, --C(R.sup.b).sub.2C(.dbd.)O--,
--NR.sup.cC(.dbd.O)C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)NR.sup.c--, or a substituted or
unsubstituted 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--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, or --NR.sup.c--;
[0168] L.sup.4 is a bond or substituted or unsubstituted C.sub.1-6
hydrocarbon chain;
[0169] each of R.sup.E1, R.sup.E2, and R.sup.E3 is independently
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --CH.sub.2OR.sup.a,
--CH.sub.2N(R.sup.a).sub.2, --CH.sub.2SR.sup.a, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, or --Si(R.sup.a).sub.3; 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 a substituted or unsubstituted, carbocyclic
ring, or substituted or unsubstituted, heterocyclic ring;
[0170] R.sup.E4 is a leaving group;
[0171] R.sup.E5 is halogen;
[0172] R.sup.E6 is hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, or a nitrogen protecting group;
[0173] each instance of Y is independently O, S, or NR.sup.c;
[0174] a is 1 or 2; and
[0175] each instance of z is independently 0, 1, 2, 3, 4, 5, or
6.
[0176] As generally defined herein, M is NR.sup.M, O, or S. In
certain embodiments, M is NR.sup.M, wherein R.sup.M is as defined
herein. In certain embodiments, M is NR.sup.M, wherein R.sup.M is
hydrogen, substituted or unsubstituted alkenyl, or a nitrogen
protecting group. In certain embodiments, M is NH. In certain
embodiments, M is O. In certain embodiments, M is S.
[0177] Compounds of Formula (I) include Ring A attached to Ring B
through linker L.sup.1. In certain embodiments, Ring A is a
substituted or unsubstituted bicyclic heteroaryl ring. In certain
embodiments, Ring A is a substituted or unsubstituted, 9- or
10-membered, bicyclic heteroaryl ring, wherein one, two, three, or
four atoms in the heteroaryl ring system are independently oxygen,
nitrogen, or sulfur, as valency permits. In certain embodiments,
Ring A is a substituted or unsubstituted bicyclic heteroaryl ring
with one nitrogen. In certain embodiments, Ring A is a substituted
or unsubstituted bicyclic heteroaryl ring with two nitrogen. In
certain embodiments, Ring A is a substituted or unsubstituted
monocyclic heteroaryl ring fused with a substituted or
unsubstituted monocyclic aryl ring. In certain embodiments, Ring A
is a substituted or unsubstituted monocyclic heteroaryl ring fused
with another substituted or unsubstituted monocyclic heteroaryl
ring. Ring A may be a substituted or unsubstituted 6,5-membered
heteroaryl ring or a substituted or unsubstituted 5,6-membered
heteroaryl ring. In certain embodiments, Ring A is a substituted or
unsubstituted monocyclic 5-membered heteroaryl ring fused with a
substituted or unsubstituted monocyclic 6-membered aryl ring. In
certain embodiments, Ring A is a substituted or unsubstituted
monocyclic 5-membered heteroaryl ring fused with a substituted or
unsubstituted monocyclic 6-membered heteroaryl ring. The point of
attachment of Ring A to Ring B may be at any atom of Ring A, as
valency permits. In certain embodiments, Ring A is of Formula
(i-1):
##STR00024##
In certain embodiments, Ring A is of Formula (i-2):
##STR00025##
In certain embodiments, Ring A is of Formula (i-3)
##STR00026##
In certain embodiments, Ring A is of Formula (i-4):
##STR00027##
In compounds of Formula (I), V.sup.1, V.sup.2, V.sup.3, V.sup.4,
V.sup.5, V.sup.6, V.sup.7, V.sup.8, and V.sup.9 of Ring A may each
independently be O, S, N, NR.sup.A1, C, or CR.sup.A2, as valency
permits. In certain embodiments, V.sup.1 is O, S, N or NR.sup.A1.
In certain embodiments, V.sup.1 is N or NR.sup.A1. In certain
embodiments, Ring A is of the formula:
##STR00028##
In certain embodiments, Ring A is of the formula:
##STR00029##
In certain embodiments, Ring A is of the formula:
##STR00030##
In certain embodiments, Ring A is of the formula:
##STR00031##
In certain embodiments, Ring A is of the formula:
##STR00032##
In certain embodiments, Ring A is of the formula:
##STR00033##
In certain embodiments, Ring A is of the formula:
##STR00034##
[0178] In certain embodiments, only one of V.sup.1, V.sup.2,
V.sup.3, V.sup.4, V.sup.5, V.sup.6, V.sup.7, V.sup.8, and V.sup.9
is selected from the group consisting of O, S, N, and NR.sup.A1. In
certain embodiments, only one of V.sup.1, V.sup.2, V.sup.3,
V.sup.4, V.sup.5, V.sup.6, V.sup.7, V.sup.8, and V.sup.9 is
selected from the group consisting of N and NR.sup.A1. In certain
embodiments, V.sup.1 is N or NR.sup.A1; V.sup.2, V.sup.3, V.sup.4,
V.sup.5, V.sup.6, V.sup.7, V.sup.8, and V.sup.9 are each
independently C or CR.sup.A2; and therefore, Ring A is a
substituted or unsubstituted indole ring. In certain embodiments,
Ring A is of Formula (A-i):
##STR00035##
wherein R.sup.A1R.sup.A2, and k are as defined herein. In certain
embodiments, k is 0, 1, 2, 3, 4, or 5. In certain embodiments, Ring
A is of Formula (iii-1):
##STR00036##
In certain embodiments, Ring A is of Formula (iii-2):
##STR00037##
In certain embodiments, Ring A is of Formula (iii-3):
##STR00038##
In certain embodiments, Ring A is of the formula:
##STR00039##
In certain embodiments, Ring A is of the formula:
##STR00040##
In certain embodiments, Ring A is of Formula (iii-4):
##STR00041##
In certain embodiments, Ring A is of Formula (iii-5):
##STR00042##
In certain embodiments, Ring A is of Formula (iii-6):
##STR00043##
In certain embodiments, Ring A is of Formula (iii-7):
##STR00044##
[0179] In certain embodiments, only two of V.sup.1, V.sup.2,
V.sup.3, V.sup.4, V.sup.5, V.sup.6, V.sup.7, V.sup.8, and V.sup.9
are each independently selected from the group consisting of O, S,
N, and NR.sup.A1. In certain embodiments, only two of V.sup.1,
V.sup.2, V.sup.3, V.sup.4, V.sup.5, V.sup.6, V.sup.7, V.sup.8, and
V.sup.9 are each independently selected from the group consisting
of N and NR.sup.A1. In certain embodiments, V.sup.1 is N or
NR.sup.A1; and only one of V.sup.2, V.sup.3, V.sup.4, V.sup.5,
V.sup.6, V.sup.7, V.sup.8, and V.sup.9 is N or NR.sup.A1. In
certain embodiments, V and V.sup.2 are each independently N or
NR.sup.A1; V.sup.3, V.sup.4, V.sup.5, V.sup.6, V.sup.7, V.sup.8,
and V.sup.9 are each independently C or CR.sup.A2; and therefore,
Ring A is a substituted or unsubstituted indazole ring. In certain
embodiments, Ring A is of Formula (A-ii):
##STR00045##
wherein R.sup.A1, R.sup.A2, and k are as defined herein. In certain
embodiments, k is 0, 1, 2, 3, or 4. In certain embodiments, Ring A
is of the formula:
##STR00046##
In certain embodiments, Ring A is of the formula:
##STR00047##
In certain embodiments, Ring A is of the formula:
##STR00048##
In certain embodiments, Ring A is of the formula:
##STR00049##
In certain embodiments, Ring A is of the formula:
##STR00050##
In certain embodiments, Ring A is of the formula:
##STR00051##
In certain embodiments, Ring A is of Formula (A-iii):
##STR00052##
wherein R.sup.A1, R.sup.A2, and k are as defined herein. In certain
embodiments, k is 0, 1, 2, 3, or 4. In certain embodiments, Ring A
is of the formula:
##STR00053##
In certain embodiments, Ring A is of the formula:
##STR00054##
In certain embodiments, Ring A is of the formula:
##STR00055##
In certain embodiments, Ring A is of the formula:
##STR00056##
In certain embodiments, Ring A is of the formula:
##STR00057##
In certain embodiments, Ring A is of the formula:
##STR00058##
In certain embodiments, Ring A is of the formula:
##STR00059##
In certain embodiments, Ring A is of the formula:
##STR00060##
[0180] In certain embodiments, V.sup.1 and V.sup.3 are each
independently N or NR.sup.A1; V.sup.2, V.sup.4, V.sup.5, V.sup.6,
V.sup.7, V.sup.8, and V.sup.9 are each independently C or
CR.sup.A2; and therefore, Ring A is a substituted or unsubstituted
benzimidazole ring. In certain embodiments, Ring A is of Formula
(iv-1):
##STR00061##
In certain embodiments, Ring A is of Formula (iv-2):
##STR00062##
In certain embodiments, Ring A is of Formula (iv-3):
##STR00063##
In certain embodiments, Ring A is of Formula (iv-4):
##STR00064##
In certain embodiments, Ring A is of Formula (iv-5):
##STR00065##
In certain embodiments, Ring A is of Formula (iv-6):
##STR00066##
[0181] In certain embodiments, V.sup.1 and V.sup.4 are each
independently N or NR.sup.A1; V.sup.2, V.sup.3, V.sup.5, V.sup.6,
V.sup.7, V.sup.8, and V.sup.9 are each independently C or
CR.sup.A2; and therefore, Ring A is a substituted or unsubstituted
4-azaindazole ring. In certain embodiments, Ring A is of the
formula:
##STR00067##
In certain embodiments, Ring A is of the formula:
##STR00068##
In certain embodiments, Ring A is of the formula:
##STR00069##
In certain embodiments, Ring A is of the formula:
##STR00070##
In certain embodiments, Ring A is of the formula:
##STR00071##
In certain embodiments, Ring A is of the formula:
##STR00072##
[0182] In certain embodiments, V.sup.1 and V.sup.5 are each
independently N or NR.sup.A1; V.sup.2, V.sup.3, V.sup.4, V.sup.6,
V.sup.7, V.sup.8, and V.sup.9 are each independently C or
CR.sup.A2; and therefore, Ring A is a substituted or unsubstituted
5-azaindazole ring. In certain embodiments, Ring A is of the
formula:
##STR00073##
In certain embodiments, Ring A is of the formula:
##STR00074##
In certain embodiments, Ring A is of the formula:
##STR00075##
In certain embodiments, Ring A is of the formula:
##STR00076##
In certain embodiments, Ring A is of the formula:
##STR00077##
In certain embodiments, Ring A is of the formula:
##STR00078##
[0183] In certain embodiments, V.sup.1 and V.sup.6 are each
independently N or NR.sup.A1; V.sup.2, V.sup.3, V.sup.4, V.sup.5,
V.sup.7, V.sup.8, and V.sup.9 are each independently C or
CR.sup.A2; and therefore, Ring A is a substituted or unsubstituted
6-azaindole ring. In certain embodiments, Ring A is of the
formula:
##STR00079##
In certain embodiments, Ring A is of the formula:
##STR00080##
In certain embodiments, Ring A is of the formula:
##STR00081##
In certain embodiments, Ring A is of the formula:
##STR00082##
In certain embodiments, Ring A is of the formula:
##STR00083##
In certain embodiments, Ring A is of the formula:
##STR00084##
[0184] In certain embodiments, V.sup.1 and V.sup.7 are each
independently N or NR.sup.A1; V.sup.2, V.sup.3, V.sup.4, V.sup.5,
V.sup.6, V.sup.8, and V.sup.9 are each independently C or
CR.sup.A2; and therefore, Ring A is a substituted or unsubstituted
7-azaindole ring. In certain embodiments, Ring A is of Formula
(v-1):
##STR00085##
In certain embodiments, Ring A is of Formula (v-2):
##STR00086##
In certain embodiments, Ring A is of Formula (v-3):
##STR00087##
In certain embodiments, Ring A is of Formula (v-4):
##STR00088##
In certain embodiments, Ring A is of Formula (v-5):
##STR00089##
In certain embodiments, Ring A is of Formula (v-6):
##STR00090##
[0185] In certain embodiments, V.sup.1 and V.sup.a are each
independently N or NR.sup.A1, V.sup.2, V.sup.3, V.sup.4, V.sup.5,
V.sup.6, V.sup.7, and V.sup.9 are each independently C or
CR.sup.A2; and therefore, Ring A is a substituted or unsubstituted
8-azaindole ring. In certain embodiments, Ring A is of Formula
(vi-1):
##STR00091##
In certain embodiments, Ring A is of Formula (vi-2):
##STR00092##
In certain embodiments, Ring A is of Formula (vi-3):
##STR00093##
In certain embodiments, Ring A is of Formula (vi-4):
##STR00094##
In certain embodiments, Ring A is of Formula (vi-5):
##STR00095##
In certain embodiments, Ring A is of Formula (vi-6):
##STR00096##
[0186] In certain embodiments, V.sup.1 and V.sup.9 are each
independently N or NR.sup.A1; V.sup.2, V.sup.3, V.sup.4, V.sup.5,
V.sup.6, V.sup.7, and V.sup.8 are each independently C or
CR.sup.A2; and therefore, Ring A is a substituted or unsubstituted
9-azaindole ring. In certain embodiments, Ring A is of the
formula:
##STR00097##
In certain embodiments, Ring A is of the formula:
##STR00098##
In certain embodiments, Ring A is of the formula:
##STR00099##
In certain embodiments, Ring A is of the formula:
##STR00100##
In certain embodiments, Ring A is of the formula:
##STR00101##
In certain embodiments, Ring A is of the formula:
##STR00102##
[0187] In certain embodiments, only three of V.sup.1, V.sup.2,
V.sup.3, V.sup.4, V.sup.5, V.sup.6, V.sup.7, V.sup.8, and V.sup.9
are each independently selected from the group consisting of O, S,
N, and NR.sup.A1. In certain embodiments, only three of V.sup.1,
V.sup.2, V.sup.3, V.sup.4, V.sup.5, V.sup.6, V.sup.7, V.sup.8, and
V.sup.9 are each independently selected from the group consisting
of N and NR.sup.A1. In certain embodiments, V.sup.1 is N or
NR.sup.A1; and only two of V.sup.2, V.sup.3, V.sup.4, V.sup.5,
V.sup.6, V.sup.7, V.sup.8, and V.sup.9 are each independently N or
NR.sup.A1.
[0188] In compounds of Formula (I), Ring A may also be a
substituted or unsubstituted monocyclic heteroaryl ring. In certain
embodiments, Ring A is a substituted or unsubstituted, 5- or
6-membered, monocyclic heteroaryl ring, wherein one, two, three, or
four atoms in the heteroaryl ring system are independently oxygen,
nitrogen, or sulfur, as valency permits. In compounds of Formula
(I), Ring A may also be a substituted or unsubstituted 5-membered
heteroaryl ring. In certain embodiments, Ring A is of Formula
(i-5):
##STR00103##
[0189] In compounds of Formula (I), V.sup.10, V.sup.11, V.sup.12,
V.sup.13, and V.sup.14 of Ring A 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, Ring A is of the formula:
##STR00104##
[0190] In certain embodiments, Ring A is of the formula:
##STR00105##
[0191] In compounds of Formula (I), Ring A may also be a
substituted or unsubstituted monocyclic heteroaryl ring. In
compounds of Formula (I), Ring A may also be a substituted or
unsubstituted 5-membered heteroaryl ring. In certain embodiments,
Ring A is of Formula (i-5):
##STR00106##
[0192] 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, Ring A is of the formula:
##STR00107##
[0193] In certain embodiments, Ring A is of the formula:
##STR00108##
[0194] In certain embodiments, Ring A is of the formula:
##STR00109##
[0195] In certain embodiments, Ring A is of Formula (vii):
##STR00110##
In certain embodiments, Ring A is of the formula:
##STR00111##
In certain embodiments, Ring A is of the formula:
##STR00112##
In certain embodiments, Ring A is of the formula:
##STR00113##
[0196] 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, Ring A is of the formula:
##STR00114##
[0197] In certain embodiments, Ring A is of the formula:
##STR00115##
[0198] In certain embodiments, Ring A is of the formula:
##STR00116##
[0199] In certain embodiments, only four 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 N and NR.sup.A1. In certain
embodiments, Ring A is of the formula:
##STR00117##
[0200] In compounds of Formula (I), Ring A may also be a
substituted or unsubstituted 6-membered heteroaryl ring. In certain
embodiments, Ring A is of Formula (i-6):
##STR00118##
In compounds of Formula (I), V.sup.10, V.sup.11, V.sup.12,
V.sup.13, V.sup.14, and V.sup.15 of Ring A may each independently
be N, 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, V.sup.14, and
V.sup.15 is N. In certain embodiments, Ring A is of Formula
(A-v):
##STR00119##
wherein R.sup.A2 and k are as defined herein. In certain
embodiments, k is 0, 1, 2, 3, or 4. In certain embodiments, Ring A
is of the formula:
##STR00120##
[0201] In certain embodiments, only two 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, Ring A is of the formula:
##STR00121##
[0202] 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, Ring A is of the formula:
##STR00122##
[0203] In certain embodiments, Ring A is of the formula:
##STR00123##
[0204] In certain embodiments, Ring A is a substituted or
unsubstituted, monocyclic heterocyclic ring. In certain
embodiments, Ring A is a substituted or unsubstituted, 3- to
7-membered, monocyclic heterocyclic ring, wherein one, two, or
three atoms in the heterocyclic ring system are independently
oxygen, nitrogen, or sulfur, as valency permits. In certain
embodiments, Ring A is a substituted or unsubstituted 5-membered
heterocyclic ring. In certain embodiments, Ring A is a substituted
or unsubstituted 6-membered heterocyclic ring. In certain
embodiments, Ring A is of Formula (A-vi):
##STR00124##
wherein R.sup.A2 is as defined herein;
[0205] J is C(R.sup.CJ).sub.2 or NR.sup.NJ;
[0206] each instance of R.sup.CJ is independently hydrogen,
halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; and
[0207] R.sup.NJ is hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
optionally substituted acyl, or a nitrogen protecting group.
[0208] In certain embodiments, k is 0, 1, 2, 3, 4, 5, or 6. In
certain embodiments, Ring A is of the formula:
##STR00125##
In certain embodiments, at least one R.sup.CJ is hydrogen. In
certain embodiments, at least one R.sup.CJ is halogen. In certain
embodiments, at least one R.sup.CJ is halogen. In certain
embodiments, at least one R.sup.CJ is F. In certain embodiments, at
least one R.sup.CJ is Cl. In certain embodiments, at least one
R.sup.CJ is Br. In certain embodiments, at least one R.sup.CJ is I
(iodine). In certain embodiments, at least one R.sup.CJ is
substituted alkyl. In certain embodiments, at least one R.sup.CJ is
unsubstituted alkyl. In certain embodiments, at least one R.sup.CJ
is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.CJ
is methyl. In certain embodiments, at least one R.sup.CJ is ethyl.
In certain embodiments, at least one R.sup.CJ is propyl. In certain
embodiments, at least one R.sup.CJ is --OR.sup.a, wherein R.sup.a
is as defined herein. In certain embodiments, at least one R.sup.CJ
is --N(R.sup.a).sub.2, wherein R.sup.a is as defined herein. In
certain embodiments, at least one R.sup.CJ is --NHR.sup.a, wherein
R.sup.a is as defined herein. In certain embodiments, at least one
R.sup.CJ is --N(R.sup.a).sub.2, wherein two R.sup.a are joined with
the intervening nitrogen to form a substituted or unsubstituted
heterocyclic ring. In certain embodiments, both instances of
R.sup.CJ are hydrogen. In certain embodiments, one R.sup.CJ is
hydrogen and one R.sup.CJ is halogen. In certain embodiments, one
R.sup.CJ is hydrogen and one R.sup.CJ is halogen. In certain
embodiments, one R.sup.CJ is hydrogen and one R.sup.CJ is F. In
certain embodiments, one R.sup.CJ is hydrogen and one R.sup.CJ is
Cl. In certain embodiments, one R.sup.CJ is hydrogen and one
R.sup.CJ is Br. In certain embodiments, one R.sup.CJ is hydrogen
and one R.sup.CJ is I (iodine). In certain embodiments, one
R.sup.CJ is hydrogen and one R.sup.CJ is substituted alkyl. In
certain embodiments, one R.sup.CJ is hydrogen and one R.sup.CJ is
unsubstituted alkyl. In certain embodiments, one R.sup.CJ is
hydrogen and one R.sup.CJ is C.sub.1-6 alkyl. In certain
embodiments, one R.sup.CJ is hydrogen and one R.sup.CJ is methyl.
In certain embodiments, one R.sup.CJ is hydrogen and one R.sup.CJ
is ethyl. In certain embodiments, one R.sup.CJ is hydrogen and one
R.sup.CJ is propyl. In certain embodiments, one R.sup.CJ is
hydrogen and one R.sup.CJ is --N(R.sup.a).sub.2, wherein two
R.sup.a are joined with the intervening nitrogen to form a
substituted or unsubstituted 5-membered heterocyclic ring. In
certain embodiments, one R.sup.CJ is hydrogen and one R.sup.CJ is
--N(R.sup.a).sub.2, wherein two R.sup.a are joined with the
intervening nitrogen to form a substituted or unsubstituted
6-membered heterocyclic ring. In certain embodiments, one R.sup.CJ
is hydrogen and one R.sup.CJ is substituted or unsubstituted
morpholinyl. In certain embodiments, one R.sup.CJ is hydrogen and
one R.sup.CJ is substituted or unsubstituted piperazinyl. In
certain embodiments, one R.sup.CJ is hydrogen and one R.sup.CJ is
substituted or unsubstituted piperidinyl. In certain embodiments,
Ring A is of the formula:
##STR00126##
In certain embodiments, Ring A is of the formula:
##STR00127##
In certain embodiments, Ring A is of the formula:
##STR00128##
In certain embodiments, Ring A is of the formula:
##STR00129##
In certain embodiments, Ring A is of the formula:
##STR00130##
In certain embodiments, Ring A is of the formula:
##STR00131##
In certain embodiments, Ring A is of the formula:
##STR00132##
In certain embodiments, Ring A is of the formula:
##STR00133##
In certain embodiments, Ring A is of the formula:
##STR00134##
[0209] In certain embodiments, Ring A is of the formula:
##STR00135##
In certain embodiments, Ring A is of the formula:
##STR00136##
In certain embodiments, R.sup.NJ is hydrogen. In certain
embodiments, R.sup.NJ is substituted alkyl. In certain embodiments,
R.sup.NJ is unsubstituted alkyl. In certain embodiments, R.sup.NJ
is C.sub.1-6 alkyl. In certain embodiments, R.sup.NJ is methyl. In
certain embodiments, R.sup.NJ is ethyl. In certain embodiments,
R.sup.NJ is propyl. In certain embodiments, R.sup.NJ is ethyl. In
certain embodiments, R.sup.NJ is a nitrogen protecting group. In
certain embodiments, R.sup.NJ is ethyl. In certain embodiments,
R.sup.NJ is Boc.
[0210] In compounds of Formula (I), Ring A may be substituted with
one or more R.sup.A groups when the R.sup.A group is attached to a
carbon atom. In certain embodiments, at least one R.sup.A is
halogen. In certain embodiments, at least one R.sup.A is F. In
certain embodiments, at least one R.sup.A is Cl. In certain
embodiments, at least one R.sup.A is Br. In certain embodiments, at
least one R.sup.A is I (iodine). In certain embodiments, at least
one R.sup.A is substituted alkyl. In certain embodiments, at least
one R.sup.A is unsubstituted alkyl. In certain embodiments, at
least one R.sup.A is C.sub.1-6 alkyl. In certain embodiments, at
least one R.sup.A is methyl. In certain embodiments, at least one
R.sup.A is ethyl. In certain embodiments, at least one R.sup.A is
propyl. In certain embodiments, at least one R.sup.A is substituted
alkenyl. In certain embodiments, at least one R.sup.A is
unsubstituted alkenyl. In certain embodiments, at least one R.sup.A
is vinyl. In certain embodiments, at least one R.sup.A is
substituted alkynyl. In certain embodiments, at least one R.sup.A
is unsubstituted alkynyl. In certain embodiments, at least one
R.sup.A is ethynyl. In certain embodiments, at least one R.sup.A is
substituted carbocyclyl. In certain embodiments, at least one
R.sup.A is unsubstituted carbocyclyl. In certain embodiments, at
least one R.sup.A is substituted heterocyclyl. In certain
embodiments, at least one R.sup.A is unsubstituted heterocyclyl. In
certain embodiments, at least one R.sup.A is substituted aryl. In
certain embodiments, at least one R.sup.A is unsubstituted aryl. In
certain embodiments, at least one R.sup.A is substituted phenyl. In
certain embodiments, at least one R.sup.A is unsubstituted phenyl.
In certain embodiments, at least one R.sup.A is substituted
heteroaryl. In certain embodiments, at least one R.sup.A is
--OR.sup.a, wherein R.sup.a is as defined herein. In certain
embodiments, at least one R.sup.A is --OR.sup.a, wherein R.sup.Aa
is hydrogen. In certain embodiments, at least one R.sup.A is
--OR.sup.a, wherein R.sup.a is hydrogen or substituted or
unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one
R.sup.A is --OR.sup.a, wherein R.sup.a is unsubstituted C.sub.1-6
alkyl. In certain embodiments, at least one R.sup.A is --OCH.sub.3.
In certain embodiments, at least one R.sup.A is --N(R.sup.a).sub.2,
wherein R.sup.a is hydrogen or substituted or unsubstituted
C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.A is
--NHR.sup.a. In certain embodiments, at least one R.sup.A is
--SR.sup.a.
[0211] In compounds of Formula (I), Ring A may be substituted with
one or more R.sup.A groups as valency permits. In certain
embodiments, k is 0. In certain embodiments, k is 1. In certain
embodiments, k is 2. In certain embodiments, k is 3. In certain
embodiments, k is 5. In certain embodiments, k is 6.
[0212] In certain embodiments, at least one instance of R.sup.A1 is
H (hydrogen). In certain embodiments, at least one instance of
R.sup.A1 is halogen. In certain embodiments, at least one instance
of R.sup.A1 is F (fluorine). In certain embodiments, at least one
instance of R.sup.A1 is Cl (chlorine). In certain embodiments, at
least one instance of R.sup.A1 is Br (bromine). In certain
embodiments, at least one instance of R.sup.A1 is I (iodine). In
certain embodiments, at least one instance of R.sup.A1 is
substituted acyl. In certain embodiments, at least one instance of
R.sup.A1 is unsubstituted acyl. In certain embodiments, at least
one instance of R.sup.A1 is acetyl. In certain embodiments, at
least one instance of R.sup.A1 is substituted acetyl. In certain
embodiments, at least one instance of R.sup.A1 is substituted
alkyl. In certain embodiments, at least one instance of R.sup.A1 is
unsubstituted alkyl. In certain embodiments, at least one instance
of R.sup.A1 is C.sub.1-6 alkyl. In certain embodiments, at least
one instance of R.sup.A1 is methyl. In certain embodiments, at
least one instance of R.sup.A1 is ethyl. In certain embodiments, at
least one instance of R.sup.A1 is propyl. In certain embodiments,
at least one instance of R.sup.A1 is butyl. In certain embodiments,
at least one instance of R.sup.A1 is substituted alkenyl. In
certain embodiments, at least one instance of R.sup.A1 is
unsubstituted alkenyl. In certain embodiments, at least one
instance of R.sup.A1 is vinyl. In certain embodiments, at least one
instance of R.sup.A1 is substituted alkynyl. In certain
embodiments, at least one instance of R.sup.A1 is unsubstituted
alkynyl. In certain embodiments, at least one instance of R.sup.A1
is ethynyl. In certain embodiments, at least one instance of
R.sup.A1 is substituted carbocyclyl. In certain embodiments, at
least one instance of R.sup.A1 is unsubstituted carbocyclyl. In
certain embodiments, at least one instance of R.sup.A1 is
substituted heterocyclyl. In certain embodiments, at least one
instance of R.sup.A1 is unsubstituted heterocyclyl. In certain
embodiments, at least one instance of R.sup.A1 is substituted aryl.
In certain embodiments, at least one instance of R.sup.A1 is
unsubstituted aryl. In certain embodiments, at least one instance
of R.sup.A1 is substituted phenyl. In certain embodiments, at least
one instance of R.sup.A1 is unsubstituted phenyl. In certain
embodiments, at least one instance of R.sup.A1 is substituted
heteroaryl. In certain embodiments, at least one instance of
R.sup.A1 is unsubstituted heteroaryl. In certain embodiments, at
least one instance of R.sup.A1 is substituted pyridyl. In certain
embodiments, at least one instance of R.sup.A1 is unsubstituted
pyridyl. In certain embodiments, at least one instance of R.sup.A1
is a nitrogen protecting group. In certain embodiments, at least
one instance of R.sup.A1 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl,
triphenylmethyl, acetyl, or Ts.
[0213] In certain embodiments, at least one R.sup.A1 is hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group. In certain embodiments, all instances of R.sup.A1
are each independently hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, or a nitrogen protecting group. In certain
embodiments, all instances of R.sup.A1 are hydrogen.
[0214] In certain embodiments, at least one R.sup.A2 is H. In
certain embodiments, at least one R.sup.A2 is halogen. In certain
embodiments, at least one R.sup.A2 is F. In certain embodiments, at
least one R.sup.A2 is Cl. In certain embodiments, at least one
R.sup.A2 is Br. In certain embodiments, at least one R.sup.A2 is I
(iodine). In certain embodiments, at least one R.sup.A2 is
substituted acyl. In certain embodiments, at least one R.sup.A2 is
unsubstituted acyl. In certain embodiments, at least one R.sup.A2
is acetyl. In certain embodiments, at least one R.sup.A2 is
substituted acetyl. In certain embodiments, at least one R.sup.A2
is substituted alkyl. In certain embodiments, at least one R.sup.A2
is unsubstituted alkyl. In certain embodiments, at least one
R.sup.A2 is C.sub.1-6 alkyl. In certain embodiments, at least one
R.sup.A2 is methyl. In certain embodiments, at least one R.sup.A2
is ethyl. In certain embodiments, at least one R.sup.A2 is propyl.
In certain embodiments, at least one R.sup.A2 is butyl. In certain
embodiments, at least one R.sup.A2 is substituted alkenyl. In
certain embodiments, at least one R.sup.A2 is unsubstituted
alkenyl. In certain embodiments, at least one R.sup.A2 is vinyl. In
certain embodiments, at least one R.sup.A2 is substituted alkynyl.
In certain embodiments, at least one R.sup.A2 is unsubstituted
alkynyl. In certain embodiments, at least one R.sup.A2 is ethynyl.
In certain embodiments, at least one R.sup.A2 is substituted
carbocyclyl. In certain embodiments, at least one R.sup.A2 is
unsubstituted carbocyclyl. In certain embodiments, at least one
R.sup.A2 is substituted heterocyclyl. In certain embodiments, at
least one R.sup.A2 is unsubstituted heterocyclyl. In certain
embodiments, at least one R.sup.A2 is substituted aryl. In certain
embodiments, at least one R.sup.A2 is unsubstituted aryl. In
certain embodiments, at least one R.sup.A2 is substituted phenyl.
In certain embodiments, at least one R.sup.A2 is unsubstituted
phenyl. In certain embodiments, at least one R.sup.A2 is
substituted heteroaryl. In certain embodiments, at least one
R.sup.A2 is unsubstituted heteroaryl. In certain embodiments, at
least one R.sup.A2 is substituted pyridyl. In certain embodiments,
at least one R.sup.A2 is unsubstituted pyridyl. In certain
embodiments, at least one R.sup.A2 is --OR.sup.A2a, wherein
R.sup.A2a is as defined herein. In certain embodiments, at least
one R.sup.A2 is --OR.sup.A2a, wherein R.sup.A2a is hydrogen. In
certain embodiments, at least one R.sup.A2 is --OR.sup.A2a, wherein
R.sup.A2a is substituted or unsubstituted C.sub.1-6 alkyl. In
certain embodiments, at least one R.sup.A2 is --OR.sup.A2a, wherein
R.sup.A2a is unsubstituted C.sub.1-6 alkyl. In certain embodiments,
at least one R.sup.A2 is --OCH.sub.3. In certain embodiments, at
least one R.sup.A2 is --N(R.sup.A2a).sub.2. In certain embodiments,
at least one R.sup.A2 is --SR.sup.A2a. In certain embodiments, all
instances of R.sup.A2 are hydrogen.
[0215] In certain embodiments, all R.sup.A1 and R.sup.A2 are
hydrogen. In certain embodiments, R.sup.A1 is hydrogen; and at
least one R.sup.A2 is substituted or unsubstituted alkyl. In
certain embodiments, R.sup.A1 is hydrogen; and at least one
R.sup.A2 is unsubstituted alkyl. In certain embodiments, R.sup.A1
is hydrogen; and at least one R.sup.A2 is methyl, ethyl, or
n-propyl. In certain embodiments, R.sup.A1 is hydrogen; and at
least one R.sup.A2 is --OR.sup.A2a, wherein R.sup.A2a is as defined
herein. In certain embodiments, R.sup.A1 is hydrogen; and at least
one R.sup.A2 is --OR.sup.A2a, wherein R.sup.A2a is substituted or
unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A1 is
hydrogen; and at least one R.sup.A2 is --OR.sup.A2a, wherein
R.sup.A2a is unsubstituted C.sub.1-6 alkyl. In certain embodiments,
R.sup.A1 is hydrogen; and at least one R.sup.A2 is --OCH.sub.3.
[0216] In certain embodiments, R.sup.a is H. In certain
embodiments, R.sup.a is halogen. In certain embodiments, R.sup.a is
F. In certain embodiments, R.sup.a is Cl. In certain embodiments,
R.sup.a is Br. In certain embodiments, R.sup.a is I (iodine). In
certain embodiments, R.sup.a is substituted C.sub.1-6 alkyl. In
certain embodiments, R.sup.a is unsubstituted C.sub.1-6 alkyl. In
certain embodiments, R.sup.a is methyl. In certain embodiments,
R.sup.a is ethyl. In certain embodiments, at least one R.sup.a is
H. In certain embodiments, each R.sup.a is H. In certain
embodiments, at least one R.sup.a is halogen (e.g., F, Cl, Br, or I
(iodine)). In certain embodiments, at least one R.sup.a is
substituted or unsubstituted alkyl. In certain embodiments, at
least one R.sup.a is substituted C.sub.1-6 alkyl. In certain
embodiments, at least one R.sup.a is unsubstituted C.sub.1-6 alkyl.
In certain embodiments, at least one R.sup.a is Me. In certain
embodiments, at least one R.sup.a is substituted methyl (e.g.,
--CF.sub.3 or Bn), Et, substituted ethyl (e.g., fluorinated ethyl),
Pr, substituted propyl (e.g., fluorinated propyl), Bu, or
substituted butyl (e.g., fluorinated butyl). In certain
embodiments, at least one R.sup.a is substituted or unsubstituted
alkenyl or substituted or unsubstituted alkynyl. In certain
embodiments, at least one R.sup.a is substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
In certain embodiments, at least one R.sup.a is a nitrogen
protecting group when attached to a nitrogen atom, an oxygen
protecting group when attached to an oxygen atom, or a sulfur
protecting group when attached to a sulfur atom. In certain
embodiments, two instances of R.sup.a are joined to form a
substituted or unsubstituted, heterocyclic ring, or substituted or
unsubstituted, heteroaryl ring.
[0217] As generally defined herein, R.sup.B1 is hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2, wherein
R.sup.a is as defined herein. In certain embodiments, R.sup.B1 is
H. In certain embodiments, R.sup.B1 is halogen. In certain
embodiments, R.sup.B1 is F. In certain embodiments, R.sup.B1 is Cl.
In certain embodiments, R.sup.B1 is Br. In certain embodiments,
R.sup.B1 is I (iodine). In certain embodiments, R.sup.B1 is
substituted alkyl. In certain embodiments, R.sup.B1 is
unsubstituted alkyl. In certain embodiments, R.sup.B1 is C.sub.1-6
alkyl. In certain embodiments, R.sup.B1 is methyl. In certain
embodiments, R.sup.B1 is ethyl. In certain embodiments, R.sup.B1 is
propyl. In certain embodiments, R.sup.B1 is butyl. In certain
embodiments, R.sup.B1 is --OR.sup.B1a, wherein R.sup.B1a is
hydrogen or substituted or unsubstituted alkyl. In certain
embodiments, R.sup.B1 is --N(R.sup.B1a).sub.2, wherein each
instance of R.sup.B1a is independently H or substituted or
unsubstituted alkyl. In certain embodiments, R.sup.B1 is
--NHR.sup.B1a, wherein R.sup.B1a is independently H or substituted
or unsubstituted alkyl. In certain embodiments, R.sup.B1 is
--NH.sub.2,
[0218] As generally defined herein, R.sup.B2 is hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2, wherein
R.sup.a is as defined herein. In certain embodiments, R.sup.B2 is
H. In certain embodiments, R.sup.B2 is halogen. In certain
embodiments, R.sup.B2 is F. In certain embodiments, R.sup.B2 is Cl.
In certain embodiments, R.sup.B2 is Br. In certain embodiments,
R.sup.B2 is I (iodine). In certain embodiments, R.sup.B2 is
substituted alkyl. In certain embodiments, R.sup.B2 is
unsubstituted alkyl. In certain embodiments, R.sup.B2 is C.sub.1-6
alkyl. In certain embodiments, R.sup.B2 is methyl. In certain
embodiments, R.sup.B2 is ethyl. In certain embodiments, R.sup.B2 is
propyl.
[0219] In certain embodiments, R.sup.B1 and R.sup.B2 are the same.
In certain embodiments, R.sup.B1 and R.sup.B2 are different. In
certain embodiments, both R.sup.B1 and R.sup.B2 are hydrogen. In
certain embodiments, R.sup.B1 is hydrogen and R.sup.B2 is hydrogen,
halogen, substituted or unsubstituted alkyl, --OR.sup.a, or
--N(R.sup.a).sub.2, wherein each instance of R.sup.a is
independently hydrogen or substituted or unsubstituted alkyl. In
certain embodiments, R.sup.B1 is hydrogen and R.sup.B2 is halogen.
In certain embodiments, R.sup.B1 is hydrogen and R.sup.B2 is
substituted or unsubstituted alkyl. In certain embodiments,
R.sup.B1 is hydrogen and R.sup.B2 is unsubstituted alkyl. In
certain embodiments, R.sup.B1 is hydrogen and R.sup.B2 is methyl or
ethyl. In certain embodiments, R.sup.B2 is hydrogen and R.sup.B1 is
hydrogen, halogen, substituted or unsubstituted alkyl, --OR.sup.a,
or --N(R.sup.a).sub.2, wherein each instance of R.sup.a is
independently hydrogen, substituted or unsubstituted alkyl, an
oxygen protecting group when attached to oxygen, or a nitrogen
protecting group when attached to nitrogen. In certain embodiments,
R.sup.B2 is hydrogen and R.sup.B1 is halogen. In certain
embodiments, R.sup.B2 is hydrogen and R.sup.B1 is substituted or
unsubstituted alkyl. In certain embodiments, R.sup.B2 is hydrogen
and R.sup.B1 is unsubstituted alkyl. In certain embodiments,
R.sup.B2 is hydrogen and R.sup.B1 is methyl or ethyl. In certain
embodiments, R.sup.B2 is hydrogen and R.sup.B1 is --OR.sup.a,
wherein R.sup.a is independently hydrogen, substituted or
unsubstituted alkyl, or an oxygen protecting group. In certain
embodiments, R.sup.B2 is hydrogen and R.sup.B1 is --N(R.sup.a),
wherein each instance of R.sup.a is independently hydrogen,
substituted or unsubstituted alkyl, or a nitrogen protecting
group.
[0220] In compounds of Formula (I), L.sup.1 is a divalent linker
moiety connecting Ring A and Ring B. L.sup.1 may be a bond,
--C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, or --NR.sup.c--; wherein R.sup.b and R.sup.c
are as defined herein. In certain embodiments, L.sup.1 is a bond.
In certain embodiments, L.sup.1 is --O-- or --S--. In certain
embodiments, L.sup.1 is --O--. In certain embodiments, L.sup.1 is
--S--. In certain embodiments, L.sup.1 is --NR.sup.c--. In certain
embodiments, L.sup.1 is --NH--. In certain embodiments, L.sup.1 is
--C(R.sup.b).sub.2--. In certain embodiments, L.sup.1 is
--CH.sub.2--.
[0221] In certain embodiments, R.sup.b is H. In certain
embodiments, R.sup.b is halogen. In certain embodiments, R.sup.b is
F. In certain embodiments, R.sup.b is Cl. In certain embodiments,
R.sup.b is Br. In certain embodiments, R.sup.b is I (iodine). In
certain embodiments, R.sup.b is substituted C.sub.1-6 alkyl. In
certain embodiments, R.sup.b is unsubstituted C.sub.1-6 alkyl. In
certain embodiments, R.sup.b is methyl. In certain embodiments,
R.sup.b is ethyl. In certain embodiments, at least one R.sup.b is
H. In certain embodiments, each R.sup.b is H. In certain
embodiments, at least one R.sup.b is halogen (e.g., F, Cl, Br, or I
(iodine)). In certain embodiments, at least one R.sup.b is
substituted C.sub.1-6 alkyl. In certain embodiments, at least one
R.sup.b is unsubstituted C.sub.1-6 alkyl. In certain embodiments,
at least one R.sup.b is Me. In certain embodiments, at least one
R.sup.b is substituted methyl (e.g., --CF.sub.3 or Bn), Et,
substituted ethyl (e.g., fluorinated ethyl), Pr, substituted propyl
(e.g., fluorinated propyl), Bu, or substituted butyl (e.g.,
fluorinated butyl).
[0222] In certain embodiments, R.sup.c is H. In certain
embodiments, R.sup.c is substituted C.sub.1-6 alkyl. In certain
embodiments, R.sup.c is unsubstituted C.sub.1-6 alkyl. In certain
embodiments, R.sup.c is methyl. In certain embodiments, R.sup.c is
ethyl. In certain embodiments, R.sup.c is a nitrogen protecting
group. In certain embodiments, R.sup.c is BOC, acetyl, or Ts. In
certain embodiments, at least one R.sup.c is H. In certain
embodiments, each R.sup.c is H. In certain embodiments, at least
one R.sup.c is halogen (e.g., F, Cl, Br, or I (iodine)). In certain
embodiments, at least one R.sup.c is substituted C.sub.1-6 alkyl.
In certain embodiments, at least one R.sup.c is unsubstituted
C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.c is
Me. In certain embodiments, at least one R.sup.c is substituted
methyl (e.g., --CF.sub.3 or Bn), Et, substituted ethyl (e.g.,
fluorinated ethyl), Pr, substituted propyl (e.g., fluorinated
propyl), Bu, or substituted butyl (e.g., fluorinated butyl). In
certain embodiments, at least one R.sup.c is a nitrogen protecting
group.
[0223] In compounds of Formula (I), X is a divalent linker moiety
connecting Ring B and Ring C. As generally defined herein, X is
--C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
--NR.sup.cS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, or --NR.sup.cS(.dbd.O).sub.2--. In
certain embodiments, X is --O--. In certain embodiments, X is
--S--. In certain embodiments, X is --NR.sup.c--, wherein R.sup.c
is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group. In certain embodiments, X is --NH--. In
certain embodiments, X is --C(R.sup.b).sub.2--. In certain
embodiments, X is --CH.sub.2--.
[0224] In certain embodiments, L.sup.1 is a bond, --O--, --S--, or
--NR.sup.c--; and X is --C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--,
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, or --NR.sup.c--, wherein
R.sup.b and R.sup.c are as defined herein. In certain embodiments,
L.sup.1 is a bond and X is --C(R.sup.b).sub.2--, --C(.dbd.O)--,
--O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, or --NR.sup.c--,
wherein R.sup.b and R.sup.c are as defined herein. In certain
embodiments, L.sup.1 is a bond and X is --O--. In certain
embodiments, L.sup.1 is a bond and X is --S--. In certain
embodiments, L.sup.1 is a bond and X is --NR.sup.c--, wherein
R.sup.c is as defined herein. In certain embodiments, L.sup.1 is a
bond and X is --NH--. In certain embodiments, L.sup.1 is --O-- and
X is --C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--, --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, or --NR.sup.c--, wherein
R.sup.b and R.sup.c are as defined herein. In certain embodiments,
L.sup.1 is --O-- and X is --O--. In certain embodiments, L.sup.1 is
--O-- and X is --S--. In certain embodiments, L.sup.1 is --O-- and
X is --NR.sup.c--, wherein R.sup.c is as defined herein. In certain
embodiments, L.sup.1 is --O-- and X is-NH--. In certain
embodiments, L.sup.1 is --NR.sup.c-- and X is --O--. In certain
embodiments, L.sup.1 is --NR.sup.c-- and X is --S--. In certain
embodiments, L.sup.1 is --NR.sup.c-- and X is independently
--NR.sup.c--, wherein R.sup.c is as defined herein. In certain
embodiments, L.sup.1 and X are --NH--.
[0225] In compounds of Formula (I), L.sup.2 is a divalent linker
moiety connecting Ring C and Ring D. L.sup.2 may be
--C(R.sup.b).sub.2--, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NR.sup.c--,
--C(R.sup.b).sub.2C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)--, --C(.dbd.O)C(R.sup.b).sub.2--,
(E)-CR.sup.b.dbd.CR.sup.b--, (Z)--CR.sup.b.dbd.CR.sup.b--,
--C.ident.C--, --OC(.dbd.O)--, --C(.dbd.O)O--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--,
--OC(R.sup.b).sub.2--, --C(R.sup.b).sub.2O--,
--SC(R.sup.b).sub.2--, --C(R.sup.b).sub.2S--,
--NR.sup.cC(R.sup.b).sub.2--, --C(R.sup.b).sub.2NR.sup.c--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.c--,
--NR.sup.cS(.dbd.O)--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.c--, --NR.sup.cS(.dbd.O).sub.2--,
--OC(.dbd.O)O--, --NR.sup.cC(.dbd.O)O--, --OC(.dbd.O)NR.sup.c--,
--NR.sup.cC(.dbd.O)NR.sup.c--,
--C(R.sup.b).sub.2C(.dbd.O)C(R.sup.b).sub.2--,
--OC(.dbd.O)C(R.sup.b).sub.2--, --C(R.sup.b).sub.2C(.dbd.O)O--,
--NR.sup.cC(.dbd.O)C(R.sup.b).sub.2--,
--C(R.sup.b).sub.2C(.dbd.O)NR.sup.c--, or a substituted or
unsubstituted 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--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, or --NR.sup.c--, wherein R.sup.b and R.sup.c
are as defined herein. In certain embodiments, L.sup.2 is
--NR.sup.cC(.dbd.O)--, --C(.dbd.O)NR.sup.c--, --C(.dbd.O)--,
--C(R.sup.b).sub.2--, --C(R.sup.b).sub.2C(.dbd.O)--, or
--C(R.sup.b).sub.2C(.dbd.O)NR.sup.c--, wherein each instance of
R.sup.b is independently hydrogen, halogen, or substituted or
unsubstituted C.sub.1-6 alkyl; and each instance of R.sup.c is
independently hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, or a nitrogen protecting group. In certain embodiments,
L.sup.2 is --C(.dbd.O)--. In certain embodiments, L.sup.2 is
--C(R.sup.b).sub.2--. In certain embodiments, L.sup.2 is
--CH.sub.2--. In certain embodiments, L.sup.2 is --NR.sup.c--. In
certain embodiments, L.sup.2 is --NH--. In certain embodiments,
L.sup.2 is --NR.sup.cC(.dbd.O)-- or --C(.dbd.O)NR.sup.c--. In
certain embodiments, L.sup.2 is --NHC(.dbd.O)-- or --C(.dbd.O)NH--.
In certain embodiments, L.sup.2 is of the formula:
--C(.dbd.O)NR.sup.c--. In certain embodiments, L.sup.2 is of the
formula: --C(.dbd.O)NH--. In certain embodiments, L.sup.2 is of the
formula: --NR.sup.cC(.dbd.O)--. In certain embodiments, L.sup.2 is
of the formula: --NHC(.dbd.O)--. In certain embodiments, L.sup.2 is
of the formula: --C(.dbd.O)NH-- or --NH(.dbd.O)--. In certain
embodiments, L.sup.2 is of the formula:
--C(R.sup.b).sub.2C(.dbd.O)--. In certain embodiments, L.sup.2 is
of the formula: --CH.sub.2C(.dbd.O)--. In certain embodiments,
L.sup.2 is of the formula: --C(R.sup.b).sub.2C(.dbd.O)NR.sup.c--.
In certain embodiments, L.sup.2 is of the formula:
--CH.sub.2C(.dbd.O)NR.sup.c--. In certain embodiments, L.sup.2 is
of the formula: --CH.sub.2C(.dbd.O)NH--.
[0226] As generally defined herein, Ring C is a substituted or
unsubstituted phenyl ring. In certain embodiments, Ring C is a
substituted phenyl ring. In certain embodiments, Ring C is an
unsubstituted phenyl ring. In certain embodiments, Ring C is a
substituted or unsubstituted 1,2-phenylene moiety. In certain
embodiments, Ring C is a substituted or unsubstituted 1,3-phenylene
moiety. In certain embodiments, Ring C is a substituted or
unsubstituted 1,4-phenylene moiety. Ring C may be unsubstituted or
may be substituted with one or more R.sup.C groups. In certain
embodiments, at least one R.sup.C is halogen. In certain
embodiments, at least one R.sup.C is F. In certain embodiments, at
least one R.sup.C is Cl. In certain embodiments, at least one
R.sup.C is Br. In certain embodiments, at least one R.sup.C is I
(iodine). In certain embodiments, at least one R.sup.c is
substituted alkyl. In certain embodiments, at least one R.sup.C is
unsubstituted alkyl. In certain embodiments, at least one R.sup.C
is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.C is
methyl. In certain embodiments, at least one R.sup.C is ethyl. In
certain embodiments, at least one R.sup.C is propyl. In certain
embodiments, at least one R.sup.C is substituted alkenyl. In
certain embodiments, at least one R.sup.C is unsubstituted alkenyl.
In certain embodiments, at least one R.sup.C is vinyl. In certain
embodiments, at least one R.sup.C is substituted alkynyl. In
certain embodiments, at least one R.sup.C is unsubstituted alkynyl.
In certain embodiments, at least one R.sup.C is ethynyl. In certain
embodiments, at least one R.sup.C is substituted carbocyclyl. In
certain embodiments, at least one R.sup.C is unsubstituted
carbocyclyl. In certain embodiments, at least one R.sup.C is
substituted heterocyclyl. In certain embodiments, at least one
R.sup.C is unsubstituted heterocyclyl. In certain embodiments, at
least one R.sup.C is substituted aryl. In certain embodiments, at
least one R.sup.C is unsubstituted aryl. In certain embodiments, at
least one R.sup.C is substituted phenyl. In certain embodiments, at
least one R.sup.C is unsubstituted phenyl. In certain embodiments,
at least one R.sup.C is substituted heteroaryl. In certain
embodiments, at least one R.sup.C is unsubstituted heteroaryl. In
certain embodiments, each instance of R.sup.C is independently
halogen, substituted or unsubstituted C.sub.1-6 alkyl, or
--OR.sup.a(e.g., --OH or --O(substituted or unsubstituted C.sub.1-6
alkyl)).
[0227] In certain embodiments, Ring C is a substituted phenyl ring
and at least one R.sup.C is independently halogen or substituted or
unsubstituted C.sub.1-6 alkyl. In certain embodiments, Ring C is a
substituted phenyl ring and at least one R.sup.C is independently
halogen. In certain embodiments, Ring C is a substituted phenyl
ring and at least one R.sup.C is substituted or unsubstituted
C.sub.1-6 alkyl. In certain embodiments, Ring C is a substituted
phenyl ring and one R.sup.C is substituted or unsubstituted
C.sub.1-6 alkyl. In certain embodiments, Ring C is a substituted
phenyl ring and one R.sup.C is unsubstituted C.sub.1-6 alkyl (e.g.
methyl or ethyl).
[0228] Ring C may be unsubstituted or substituted with one or more
R.sup.C groups as valency permits. In certain embodiments, Ring C
is a substituted or unsubstituted phenyl ring and n is 0, 1, 2, 3,
or 4. In certain embodiments, Ring C is unsubstituted, and thus n
is 0. In certain embodiments, n is 1. In certain embodiments, n is
2. In certain embodiments, n is 3. In certain embodiments, n is
4.
[0229] As generally defined herein, Ring D is a substituted or
unsubstituted phenyl ring. In certain embodiments, Ring D is a
substituted phenyl ring. In certain embodiments, Ring D is an
unsubstituted phenyl ring. In certain embodiments, Ring D is a
substituted or unsubstituted 1,2-phenylene moiety. In certain
embodiments, Ring D is a substituted or unsubstituted 1,3-phenylene
moiety. In certain embodiments, Ring D is a substituted or
unsubstituted 1,4-phenylene moiety.
[0230] In certain embodiments, Ring C is an unsubstituted phenyl
ring and Ring D is a substituted or unsubstituted phenyl ring. In
certain embodiments, Ring C is an unsubstituted phenyl ring and
Ring D is an unsubstituted phenyl ring. In certain embodiments,
Ring C is an unsubstituted phenyl ring and Ring D is a substituted
phenyl ring. In certain embodiments, Ring C is a substituted phenyl
ring and Ring D is a substituted phenyl ring. In certain
embodiments, Ring C is a substituted phenyl ring and Ring D is an
unsubstituted phenyl ring.
[0231] In compounds of Formula (I), Ring D is substituted with
R.sup.E and may also be substituted with one or more R.sup.D
groups. In certain embodiments, at least one R.sup.D is H. In
certain embodiments, at least one R.sup.D is halogen. In certain
embodiments, at least one R.sup.D is F. In certain embodiments, at
least one R.sup.D is Cl. In certain embodiments, at least one
R.sup.D is Br. In certain embodiments, at least one R.sup.D is I
(iodine). In certain embodiments, at least one R.sup.D is
substituted alkyl. In certain embodiments, at least one R.sup.D is
unsubstituted alkyl. In certain embodiments, at least one R.sup.D
is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.D is
methyl. In certain embodiments, at least one R.sup.D is ethyl. In
certain embodiments, at least one R.sup.D is propyl. In certain
embodiments, each instance of R.sup.c is independently halogen,
substituted or unsubstituted C.sub.1-6 alkyl, or --OR.sup.a (e.g.,
--OH or --O(substituted or unsubstituted C.sub.1-6 alkyl)).
[0232] Ring D may be unsubstituted or substituted with one or more
R.sup.D groups. In certain embodiments, Ring D is unsubstituted,
and thus 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.
[0233] In certain embodiments, R.sup.D is halogen; and p is 1. In
certain embodiments, R.sup.D is F; and p is 1. In certain
embodiments, R.sup.D is Cl; and p is 1. In certain embodiments,
R.sup.D is Br; and p is 1. In certain embodiments, R.sup.D is I
(iodine); and p is 1. In certain embodiments, R.sup.D is
substituted alkyl; and p is 1. In certain embodiments, R.sup.D is
unsubstituted alkyl; and p is 1. In certain embodiments, R.sup.D is
C.sub.1-6 alkyl; and p is 1. In certain embodiments, R.sup.D is
methyl; and p is 1. In certain embodiments, R.sup.D is ethyl,
propyl, or butyl; and p is 1. In certain embodiments, each instance
of R.sup.D is independently halogen or substituted or unsubstituted
alkyl; and p is 2. In certain embodiments, each instance of R.sup.D
is independently halogen or C.sub.1-6 alkyl; and p is 2.
[0234] In compounds of Formula (I), Ring D also includes a
substituent R.sup.E. In certain embodiments, R.sup.E comprises a
Michael acceptor moiety. This Michael acceptor moiety may react
with a cysteine residue of a kinase (e.g., PIP4K) to allow covalent
attachment of the compound to the kinase. In certain embodiments,
the covalent attachment is irreversible. In other embodiments, the
covalent attachment is reversible.
[0235] As generally defined herein in Formula (I), R.sup.E may be
any one of Formulae (i-1)-(i-41). In certain embodiments, R.sup.E
is of Formula (i-1):
##STR00137##
In certain embodiments, R.sup.E is of Formula (i-2):
##STR00138##
In certain embodiments, R.sup.E is of Formula (i-3):
##STR00139##
In certain embodiments, R.sup.E is of Formula (i-4):
##STR00140##
4). In certain embodiments, R.sup.E is of Formula (i-5):
##STR00141##
In certain embodiments, R.sup.E is of Formula (i-6):
##STR00142##
In certain embodiments, R.sup.E is of Formula (i-7):
##STR00143##
In certain embodiments, R.sup.E is of Formula (i-8):
##STR00144##
In certain embodiments, R.sup.E is of Formula (i-9):
##STR00145##
In certain embodiments, R.sup.E is of Formula (i-10):
##STR00146##
In certain embodiments, R.sup.E is of Formula (i-11):
##STR00147##
In certain embodiments, R.sup.E is of Formula (i-12):
##STR00148##
In certain embodiments, R.sup.E is of Formula (i-13):
##STR00149##
In certain embodiments, R.sup.E is of Formula (i-14):
##STR00150##
In certain embodiments, R.sup.E Is of Formula (i-15):
##STR00151##
In certain embodiments, R is of Formula (i-16):
##STR00152##
certain embodiments, R.sup.E is of Formula (i-17):
##STR00153##
In certain embodiments, R.sup.E is of Formula (i-18):
##STR00154##
In certain embodiments, R.sup.E is of Formula (i-19):
##STR00155##
In certain embodiments, R.sup.E is of Formula (i-20):
##STR00156##
In certain embodiments, R.sup.E is of Formula (i-21):
##STR00157##
In certain embodiments, R.sup.E is of Formula (i-22):
##STR00158##
In certain embodiments, R.sup.E is of Formula (i-23):
##STR00159##
In certain embodiments, R.sup.E is of Formula (i-24):
##STR00160##
In certain embodiments, R.sup.E is of Formula (i-25):
##STR00161##
In certain embodiments, R.sup.E is of Formula (i-26):
##STR00162##
In certain embodiments, R.sup.E is of Formula (i-27):
##STR00163##
In certain embodiments, R.sup.E is of Formula (i-28):
##STR00164##
In certain embodiments, R.sup.E is of Formula (i-29):
##STR00165##
In certain embodiments, R.sup.E is of Formula (i-30):
##STR00166##
In certain embodiments, R.sup.E is of Formula (i-31):
##STR00167##
In certain embodiments, R.sup.E is of Formula (i-32):
##STR00168##
In certain embodiments, R.sup.E is of Formula (i-33):
##STR00169##
In certain embodiments, R.sup.E is of Formula (i-34):
##STR00170##
certain embodiments, R.sup.E is of Formula (i-3):
##STR00171##
In certain embodiments, R.sup.E is of Formula (i-36):
##STR00172##
In certain embodiments, R.sup.E is of Formula (i-37):
##STR00173##
In certain embodiments, R.sup.E is of Formula (i-38):
##STR00174##
In certain embodiments, R.sup.E is of Formula (i-39):
##STR00175##
In certain embodiments, R.sup.E is of Formula (i-40):
##STR00176##
In certain embodiments, R.sup.E is of Formula (i-41):
##STR00177##
[0236] In certain embodiments, R.sup.E is of Formula (i-1a):
##STR00178##
In certain embodiments, R.sup.E is of Formula (i-1b):
##STR00179##
In certain embodiments, R.sup.E is of Formula (i-1c):
##STR00180##
In certain embodiments, R.sup.E is of Formula (i-1d):
##STR00181##
In certain embodiments, R.sup.E is of Formula (i-1e):
##STR00182##
In certain embodiments, R.sup.E s of Formula (i-1f):
##STR00183##
In certain embodiments, R.sup.E is of Formula (i-1g):
##STR00184##
In certain embodiments, R.sup.E is
##STR00185##
In certain embodiments, R.sup.E is of the formula:
##STR00186##
In certain embodiments, R.sup.E is of Formula (i-1h):
##STR00187##
In certain embodiments, R.sup.E is
##STR00188##
[0237] In certain embodiments, R.sup.E is of Formula (i-1a):
##STR00189##
In certain embodiments, R.sup.E is of Formula (i-1b):
##STR00190##
In certain embodiments, R.sup.E is of Formula (i-1c):
##STR00191##
[0238] In certain embodiments, R.sup.E is of Formula (i-18a):
##STR00192##
In certain embodiments, R.sup.E is of Formula (i-18b):
##STR00193##
In certain embodiments, R.sup.E is of Formula (i-18c):
##STR00194##
[0239] In certain embodiments, R.sup.E is of Formula (i-15a):
##STR00195##
In certain embodiments, R.sup.E is of Formula (i-15b):
##STR00196##
In certain embodiments, R.sup.E is of Formula (i-15c):
##STR00197##
[0240] In certain embodiment, X and L.sup.2 are para or meta to
each other. In certain embodiment, X and L.sup.2 are para to each
other. In certain embodiments, X and L.sup.2 are meta to each
other. In certain embodiment, R.sup.E and L.sup.2 are para or meta
to each other. In certain embodiments, R.sup.E and L.sup.2 are para
to each other. In certain embodiments, R.sup.E and L.sup.2 are meta
to each other. In certain embodiments, Ring D is of the
formula:
##STR00198##
In certain embodiments, Ring D is of the formula:
##STR00199##
In certain embodiments, Ring D is of the formula:
##STR00200##
In certain embodiments, Ring D is of the formula:
##STR00201##
In certain embodiments, Ring D is of the formula:
##STR00202##
In certain embodiments, Ring D is of the formula:
##STR00203##
In certain embodiments, Ring D is of the formula:
##STR00204##
In certain embodiments, Ring D is of the formula:
##STR00205##
[0241] In certain embodiments, R.sup.E and L.sup.2 are para to each
other. In certain embodiments, Ring D is of the formula:
##STR00206##
In certain embodiments, Ring D is of the formula:
##STR00207##
In certain embodiments, Ring D is of the formula:
##STR00208##
In certain embodiments, Ring D is of the formula:
##STR00209##
In certain embodiments, Ring D is of the formula:
##STR00210##
In certain embodiments, Ring D is of the formula:
##STR00211##
[0242] In compounds of Formula (I), L.sup.3 is a divalent linker
moiety. L.sup.3 may contain 0-4 carbon or hetero atoms in the
backbone of L.sup.3. L.sup.3 may be saturated or unsaturated.
L.sup.3 may be substituted or unsubstituted. L.sup.3 may be
branched or unbranched. In certain embodiments, L.sup.3 is a bond.
In certain embodiments, L.sup.3 is --O--. In certain embodiments,
L.sup.3 is --S--. In certain embodiments, L.sup.3 is
--NR.sup.L3a--. In certain embodiments, L.sup.3 is --NH--. In
certain embodiments, L.sup.3 is a substituted C.sub.1-4 hydrocarbon
chain. In certain embodiments, L.sup.3 is an unsubstituted
C.sub.1-4 hydrocarbon chain. In certain embodiments, L.sup.3 is
--C(R.sup.L3b).sub.2--. In certain embodiments, L.sup.3 is
--CHR.sup.L3b--. In certain embodiments, L.sup.3 is --CH.sub.2--.
In certain embodiments, L.sup.3 is a substituted C.sub.2
hydrocarbon chain. In certain embodiments, L.sup.3 is an
unsubstituted C.sub.2 hydrocarbon chain. In certain embodiments,
L.sup.3 is --C(R.sup.L3b).sub.2C(R.sup.L3b).sub.2--. In certain
embodiments, L.sup.3 is --CH.sub.2CH.sub.2--. In certain
embodiments, L.sup.3 is trans-CR.sup.L3b.dbd.CR.sup.L3b--. In
certain embodiments, L.sup.3 is trans-CH.dbd.CH--. In certain
embodiments, L.sup.3 is cis-CR.sup.L3b.dbd.CR.sup.L3b--. In certain
embodiments, L.sup.3 is cis-CH.dbd.CH--. In certain embodiments,
L.sup.3 is --C.ident.C--. In certain embodiments, L.sup.3 is a
substituted C.sub.3 hydrocarbon chain. In certain embodiments,
L.sup.3 is an unsubstituted C.sub.3 hydrocarbon chain. In certain
embodiments, L.sup.3 is --(CH.sub.2).sub.3--. In certain
embodiments, L.sup.3 is --CH.dbd.CH--CH.sub.2--, wherein CH.dbd.CH
is trans or cis. In certain embodiments, L.sup.3 is
--CH.sub.2--CH.dbd.CH--, wherein CH.dbd.CH is trans or cis. In
certain embodiments, L.sup.3 is --C.ident.C--CH.sub.2--. In certain
embodiments, L.sup.3 is --CH.sub.2--C.ident.C--. In certain
embodiments, L.sup.3 is a substituted C.sub.4 hydrocarbon chain. In
certain embodiments, L.sup.3 is an unsubstituted C.sub.4
hydrocarbon chain. In certain embodiments, L.sup.3 is
--(CH.sub.2).sub.4--. In certain embodiments, L.sup.3 is
--CH.dbd.CH--CH.dbd.CH--, wherein each instance of CH.dbd.CH is
independently trans or cis. In certain embodiments, L.sup.3 is
--CH.dbd.CH--C.ident.C--, wherein CH.dbd.CH is trans or cis. In
certain embodiments, L.sup.3 is --C.ident.C--CH.dbd.CH--, wherein
CH.dbd.CH is trans or cis. In certain embodiments, L.sup.3 is
--C.ident.C--C.ident.C--. In certain embodiments, L.sup.3 is a
substituted or unsubstituted C.sub.1-4 hydrocarbon chain, wherein
one or more carbon units of the hydrocarbon chain is replaced with
--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).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.L3a--, or
--NR.sup.L3aS(.dbd.O).sub.2--.
[0243] In certain embodiments, R.sup.L3a is H. In certain
embodiments, R.sup.L3a is substituted alkyl. In certain
embodiments, R.sup.L3a is unsubstituted alkyl. In certain
embodiments, R.sup.L3a is C.sup.1-6 alkyl. In certain embodiments,
R.sup.L3a is methyl. In certain embodiments, R.sup.L3a is ethyl. In
certain embodiments, R.sup.L3a is propyl. In certain embodiments,
R.sup.L3a is butyl. In certain embodiments, R.sup.L3a is a nitrogen
protecting group. In certain embodiments, R.sup.L3a is Bn, BOC,
Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
[0244] In certain embodiments, at least one R.sup.L3b is H. In
certain embodiments, at least one R.sup.L3b is halogen. In certain
embodiments, at least one R.sup.L3b is F. In certain embodiments,
at least one R.sup.L3b is Cl. In certain embodiments, at least one
R.sup.L3b is Br. In certain embodiments, at least one R.sup.L3b is
I (iodine). In certain embodiments, at least one R.sup.L3b is
substituted alkyl. In certain embodiments, at least one R.sup.L3b
is unsubstituted alkyl. In certain embodiments, at least one
R.sup.L3b is C.sub.1-6 alkyl. In certain embodiments, at least one
R.sup.L3b is methyl. In certain embodiments, at least one R.sup.L3b
is ethyl. In certain embodiments, at least one R.sup.L3b is propyl.
In certain embodiments, at least one R.sup.L3b is butyl. In certain
embodiments, at least one R.sup.L3b is substituted alkenyl. In
certain embodiments, at least one R.sup.L3b is unsubstituted
alkenyl. In certain embodiments, at least one R.sup.L3b is vinyl.
In certain embodiments, at least one R.sup.L3b is substituted
alkynyl. In certain embodiments, at least one R.sup.L3b is
unsubstituted alkynyl. In certain embodiments, at least one
R.sup.L3b is ethynyl. In certain embodiments, at least one
R.sup.L3b is substituted carbocyclyl. In certain embodiments, at
least one R.sup.L3b is unsubstituted carbocyclyl. In certain
embodiments, at least one R.sup.L3b is substituted heterocyclyl. In
certain embodiments, at least one R.sup.L3b is unsubstituted
heterocyclyl. In certain embodiments, at least one R.sup.L3b is
substituted aryl. In certain embodiments, at least one R.sup.L3b is
unsubstituted aryl. In certain embodiments, at least one R.sup.L3b
is substituted phenyl. In certain embodiments, at least one
R.sup.L3b is unsubstituted phenyl. In certain embodiments, at least
one R.sup.L3b is substituted heteroaryl. In certain embodiments, at
least one R.sup.L3b is unsubstituted heteroaryl. In certain
embodiments, at least one R.sup.L3b is substituted pyridyl. In
certain embodiments, at least one R.sup.L3b is unsubstituted
pyridyl. In certain embodiments, two R.sup.L3b groups are joined to
form a substituted carbocyclic ring. In certain embodiments, two
R.sup.L3b groups are joined to form an unsubstituted carbocyclic
ring. In certain embodiments, two R.sup.L3b groups are joined to
form a substituted heterocyclic ring. In certain embodiments, two
R.sup.L3b groups are joined to form an unsubstituted heterocyclic
ring.
[0245] In compounds of Formula (I), L.sup.4 is a divalent linker
moiety. L.sup.4 may contain 0-4 carbon or hetero atoms in the
backbone of L.sup.4. L.sup.4 may be saturated or unsaturated.
L.sup.4 may be substituted or unsubstituted. L.sup.4 may be
branched or unbranched. In certain embodiments, L.sup.4 is a bond.
In certain embodiments, L.sup.4 is a substituted C.sub.1
hydrocarbon chain. In certain embodiments, L.sup.4 is an
unsubstituted C.sub.1-4 hydrocarbon chain. In certain embodiments,
L.sup.4 is --C(R.sup.L4b).sub.2--. In certain embodiments, L.sup.4
is --CHR.sup.L4b--. In certain embodiments, L.sup.4 is
--CH.sub.2--. In certain embodiments, L.sup.4 is a substituted
C.sub.2 hydrocarbon chain. In certain embodiments, L.sup.4 is a
unsubstituted C.sub.2 hydrocarbon chain. In certain embodiments,
L.sup.4 is --C(R.sup.L4b).sub.2C(R.sup.L4b).sub.2--. In certain
embodiments, L.sup.4 is --CH.sub.2CH.sub.2--. In certain
embodiments, L.sup.4 is trans-CR.sup.L4b.dbd.CR.sup.L4b--. In
certain embodiments, L.sup.4 is trans-CH.dbd.CH--. In certain
embodiments, L.sup.4 is cis-CR.sup.L4b.dbd.CR.sup.L4b--. In certain
embodiments, L.sup.4 is cis-CH.dbd.CH--. In certain embodiments,
L.sup.4 is --C.ident.C--. In certain embodiments, L.sup.4 is a
substituted C.sub.3 hydrocarbon chain. In certain embodiments,
L.sup.4 is an unsubstituted C.sub.3 hydrocarbon chain. In certain
embodiments, L.sup.4 is --(CH.sub.2).sub.3--. In certain
embodiments, L.sup.4 is --CH.dbd.CH--CH.sub.2--, wherein CH.dbd.CH
is trans or cis. In certain embodiments, L.sup.4 is
--CH.sub.2--CH.dbd.CH--, wherein CH.dbd.CH is trans or cis. In
certain embodiments, L.sup.4 is --C.ident.C--CH.sub.2--. In certain
embodiments, L.sup.4 is --CH.sub.2--C.ident.C--. In certain
embodiments, L.sup.4 is a substituted C.sub.4 hydrocarbon chain. In
certain embodiments, L.sup.4 is an unsubstituted C.sub.4
hydrocarbon chain. In certain embodiments, L.sup.4 is
--(CH.sub.2).sub.4--. In certain embodiments, L.sup.4 is
--CH.dbd.CH--CH.dbd.CH--, wherein each instance of CH.dbd.CH is
independently trans or cis. In certain embodiments, L.sup.4 is
--CH.dbd.CH--C.ident.C--, wherein CH.dbd.CH is trans or cis. In
certain embodiments, L.sup.4 is --C.ident.C--CH.dbd.CH--, wherein
CH.dbd.CH is trans or cis. In certain embodiments, L.sup.4 is
--C.ident.C--C.ident.C--.
[0246] In compounds of Formula (I), R.sup.E may include a
substituent R.sup.E1. In certain embodiments, R.sup.E1 is H. In
certain embodiments, R.sup.E1 is halogen. In certain embodiments,
R.sup.E1 is F. In certain embodiments, R.sup.E1 is Cl. In certain
embodiments, R.sup.E1 is Br. In certain embodiments, R.sup.E1 is I
(iodine). In certain embodiments, R.sup.E1 is substituted acyl. In
certain embodiments, R.sup.E1 is unsubstituted acyl. In certain
embodiments, R.sup.E1 is acetyl. In certain embodiments, R.sup.E1
is substituted acetyl. In certain embodiments, R.sup.E1 is
substituted alkyl. In certain embodiments, R.sup.E1 is
unsubstituted alkyl. In certain embodiments, R.sup.E1 is C.sub.1-6
alkyl. In certain embodiments, R.sup.E1 is methyl. In certain
embodiments, R.sup.E1 is ethyl. In certain embodiments, R.sup.E1 is
propyl. In certain embodiments, R.sup.E1 is butyl. In certain
embodiments, R.sup.E1 is substituted alkenyl. In certain
embodiments, R.sup.E1 is unsubstituted alkenyl. In certain
embodiments, R.sup.E1 is vinyl. In certain embodiments, R.sup.E1 is
substituted alkynyl. In certain embodiments, R.sup.E1 is
unsubstituted alkynyl. In certain embodiments, R.sup.E1 is ethynyl.
In certain embodiments, R.sup.E1 is substituted carbocyclyl. In
certain embodiments, R.sup.E1 is unsubstituted carbocyclyl. In
certain embodiments, R.sup.E1 is substituted heterocyclyl. In
certain embodiments, R.sup.E1 is unsubstituted heterocyclyl. In
certain embodiments, R.sup.E1 is substituted aryl. In certain
embodiments, R.sup.E1 is unsubstituted aryl. In certain
embodiments, R.sup.E1 is substituted phenyl. In certain
embodiments, R.sup.E1 is unsubstituted phenyl. In certain
embodiments, R.sup.E1 is substituted heteroaryl. In certain
embodiments, R.sup.E1 is unsubstituted heteroaryl. In certain
embodiments, R.sup.E1 is substituted pyridyl. In certain
embodiments, R.sup.E1 is unsubstituted pyridyl. In certain
embodiments, R.sup.E1 is --CN. In certain embodiments, R.sup.E1 is
--OR.sup.E1a. In certain embodiments, R.sup.E1 is
--N(R.sup.E1a).sub.2. In certain embodiments, R.sup.E1 is
--SR.sup.E1a. In certain embodiments, R.sup.E1 is
--CH.sub.2OR.sup.E1a. In certain embodiments, R.sup.E1 is
--CH.sub.2N(R.sup.E1a).sub.2. In certain embodiments, R.sup.E1 is
--CH.sub.2SR.sup.E1a.
[0247] In certain embodiments, when R.sup.E1 is --OR.sup.E1a,
--N(R.sup.E1a).sub.2, --SR.sup.E1a, --CH.sub.2OR.sup.E1a,
--CH.sub.2N(R.sup.E1a).sub.2, or --CH.sub.2SR.sup.E1a, R.sup.E1a is
H. In certain embodiments, R.sup.E1 is --Si(R.sup.E1a).sub.3,
optionally wherein each instance of R.sup.E1a is independently
unsubstituted C.sub.1-6 alkyl or unsubstituted phenyl. In certain
embodiments, R.sup.E1 is --Si(Me).sub.3). In certain embodiments,
R.sup.E1a is substituted acyl. In certain embodiments, R.sup.E1a is
unsubstituted acyl. In certain embodiments, R.sup.E1a is acetyl. In
certain embodiments, R.sup.E1a is substituted acetyl. In certain
embodiments, R.sup.E1a is substituted alkyl. In certain
embodiments, R.sup.E1a is unsubstituted alkyl. In certain
embodiments, R.sup.E1a is C.sub.1-6 alkyl. In certain embodiments,
R.sup.E1a is methyl. In certain embodiments, R.sup.E1a is ethyl. In
certain embodiments, R.sup.E1a is propyl. In certain embodiments,
R.sup.E1a is butyl. In certain embodiments, R.sup.E1a is
substituted alkenyl. In certain embodiments, R.sup.E1a is
unsubstituted alkenyl. In certain embodiments, R.sup.E1a is vinyl.
In certain embodiments, R.sup.E1a is substituted alkynyl. In
certain embodiments, R.sup.E1a is unsubstituted alkynyl. In certain
embodiments, R.sup.E1a is ethynyl. In certain embodiments,
R.sup.E1a is substituted carbocyclyl. In certain embodiments,
R.sup.E1a is unsubstituted carbocyclyl. In certain embodiments,
R.sup.E1a is substituted heterocyclyl. In certain embodiments,
R.sup.E1a is unsubstituted heterocyclyl. In certain embodiments,
R.sup.E1a is substituted aryl. In certain embodiments, R.sup.E1a is
unsubstituted aryl. In certain embodiments, R.sup.E1a is
substituted phenyl. In certain embodiments, R.sup.E1a is
unsubstituted phenyl. In certain embodiments, R.sup.E1a is
substituted heteroaryl. In certain embodiments, R.sup.E1a is
unsubstituted heteroaryl. In certain embodiments, R.sup.E1a is
substituted pyridyl. In certain embodiments, R.sup.E1a is
unsubstituted pyridyl. In certain embodiments, R.sup.E1a is a
nitrogen protecting group when attached to a nitrogen atom. In
certain embodiments, R.sup.E1a is Bn, BOC, Cbz, Fmoc,
trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a
nitrogen atom. In certain embodiments, R.sup.E1a is an oxygen
protecting group when attached to an oxygen atom. In certain
embodiments, R.sup.E1a is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM,
THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to
an oxygen atom. In certain embodiments, R.sup.E1a is a sulfur
protecting group when attached to a sulfur atom. In certain
embodiments, R.sup.E1a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine
sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to
a sulfur atom. In certain embodiments, two R.sup.E1a groups are
joined to form a substituted heterocyclic ring. In certain
embodiments, two R.sup.E1a groups are joined to form an
unsubstituted heterocyclic ring.
[0248] In compounds of Formula (I), R.sup.E may include a
substituent R.sup.E2. In certain embodiments, R.sup.E2 is H. In
certain embodiments, R.sup.E2 is halogen. In certain embodiments,
R.sup.E2 is F. In certain embodiments, R.sup.E2 is Cl. In certain
embodiments, R.sup.E2 is Br. In certain embodiments, R.sup.E2 is I
(iodine). In certain embodiments, R.sup.E2 is substituted acyl. In
certain embodiments, R.sup.E2 is unsubstituted acyl. In certain
embodiments, R.sup.E2 is acetyl. In certain embodiments, R.sup.E2
is substituted acetyl. In certain embodiments, R.sup.E2 is
substituted alkyl. In certain embodiments, R.sup.E2 is
unsubstituted alkyl. In certain embodiments, R.sup.E2 is C.sub.1-6
alkyl. In certain embodiments, R.sup.E2 is methyl. In certain
embodiments, R.sup.E2 is ethyl. In certain embodiments, R.sup.E2 is
propyl. In certain embodiments, R.sup.E2 is butyl. In certain
embodiments, R.sup.E2 is substituted alkenyl. In certain
embodiments, R.sup.E2 is unsubstituted alkenyl. In certain
embodiments, R.sup.E2 is vinyl. In certain embodiments, R.sup.E2 is
substituted alkynyl. In certain embodiments, R.sup.E2 is
unsubstituted alkynyl. In certain embodiments, R.sup.E2 is ethynyl.
In certain embodiments, R.sup.E2 is substituted carbocyclyl. In
certain embodiments, R.sup.E2 is unsubstituted carbocyclyl. In
certain embodiments, R.sup.E2 is substituted heterocyclyl. In
certain embodiments, R.sup.E2 is unsubstituted heterocyclyl. In
certain embodiments, R.sup.E2 is substituted aryl. In certain
embodiments, R.sup.E2 is unsubstituted aryl. In certain
embodiments, R.sup.E2 is substituted phenyl. In certain
embodiments, R.sup.E2 is unsubstituted phenyl. In certain
embodiments, R.sup.E2 is substituted heteroaryl. In certain
embodiments, R.sup.E2 is unsubstituted heteroaryl. In certain
embodiments, R.sup.E2 is substituted pyridyl. In certain
embodiments, R.sup.E2 is unsubstituted pyridyl. In certain
embodiments, R.sup.E2 is --CN. In certain embodiments, R.sup.E2 is
--OR.sup.E2a. In certain embodiments, R.sup.E2 is
--N(R.sup.E2a).sub.2. In certain embodiments, R.sup.E2 is
--SR.sup.E2a. In certain embodiments, R.sup.E2 is
--CH.sub.2OR.sup.E2a. In certain embodiments, R.sup.E2 is
--CH.sub.2N(R.sup.E2a).sub.2. In certain embodiments, R.sup.E2 is
--CH.sub.2SR.sup.E2a.
[0249] In certain embodiments, when R.sup.E2 is --OR.sup.E2a,
--N(R.sup.E2a).sub.2, --SR.sup.E2a, --CH.sub.2OR.sup.E2a,
--CH.sub.2N(R.sup.E2a).sub.2, or --CH.sub.2SR.sup.E2a, R.sup.E2a is
H. In certain embodiments, R.sup.E2a is substituted acyl. In
certain embodiments, R.sup.E2a is unsubstituted acyl. In certain
embodiments, R.sup.E2a is acetyl. In certain embodiments, R.sup.E2a
is substituted acetyl. In certain embodiments, R.sup.E2a is
substituted alkyl. In certain embodiments, R.sup.E2a is
unsubstituted alkyl. In certain embodiments, R.sup.E2a is C.sub.1-6
alkyl. In certain embodiments, R.sup.E2a is methyl. In certain
embodiments, R.sup.E2a is ethyl. In certain embodiments, R.sup.E2a
is propyl. In certain embodiments, R.sup.E2a is butyl. In certain
embodiments, R.sup.E2a is substituted alkenyl. In certain
embodiments, R.sup.E2a is unsubstituted alkenyl. In certain
embodiments, R.sup.E2a is vinyl. In certain embodiments, R.sup.E2a
is substituted alkynyl. In certain embodiments, R.sup.E2a is
unsubstituted alkynyl. In certain embodiments, R.sup.E2a is
ethynyl. In certain embodiments, R.sup.E2a is unsubstituted
carbocyclyl. In certain embodiments, R.sup.E2a is unsubstituted
carbocyclyl. In certain embodiments, R.sup.E2a is substituted
heterocyclyl. In certain embodiments, R.sup.E2a is unsubstituted
heterocyclyl. In certain embodiments, R.sup.E2a is substituted
aryl. In certain embodiments, R.sup.E2a is unsubstituted aryl. In
certain embodiments, R.sup.E2a is substituted phenyl. In certain
embodiments, R.sup.E2a is unsubstituted phenyl. In certain
embodiments, R.sup.E2a is substituted heteroaryl. In certain
embodiments, R.sup.E2a is unsubstituted heteroaryl. In certain
embodiments, R.sup.E2a is substituted pyridyl. In certain
embodiments, R.sup.E2a is unsubstituted pyridyl. In certain
embodiments, R.sup.E2a is a nitrogen protecting group when attached
to a nitrogen atom. In certain embodiments, R.sup.E2a is Bn, BOC,
Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when
attached to a nitrogen atom. In certain embodiments, R.sup.E2a is
an oxygen protecting group when attached to an oxygen atom. In
certain embodiments, R.sup.E2a is silyl, TBDPS, TBDMS, TIPS, TES,
TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when
attached to an oxygen atom. In certain embodiments, R.sup.E2a is a
sulfur protecting group when attached to a sulfur atom. In certain
embodiments, R.sup.E2a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine
sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to
a sulfur atom. In certain embodiments, two R.sup.E2a groups are
joined to form a substituted heterocyclic ring. In certain
embodiments, two R.sup.E2a groups are joined to form an
unsubstituted heterocyclic ring.
[0250] In compounds of Formula (I), R.sup.E may include a
substituent R.sup.E3. In certain embodiments, R.sup.E3 is H. In
certain embodiments, R.sup.E3 is halogen. In certain embodiments,
R.sup.E3 is F. In certain embodiments, R.sup.E3 is Cl. In certain
embodiments, R.sup.E3 is Br. In certain embodiments, R.sup.E3 is I
(iodine). In certain embodiments, R.sup.E3 is substituted acyl. In
certain embodiments, R.sup.E3 is unsubstituted acyl. In certain
embodiments, R.sup.E3 is acetyl. In certain embodiments, R.sup.E3
is substituted acetyl. In certain embodiments, R.sup.E3 is
substituted alkyl. In certain embodiments, R.sup.E3 is
unsubstituted alkyl. In certain embodiments, R.sup.E3 is C.sub.1-6
alkyl. In certain embodiments, R.sup.E3 is methyl. In certain
embodiments, R.sup.E3 is ethyl. In certain embodiments, R.sup.E3 is
propyl. In certain embodiments, R.sup.E3 is butyl. In certain
embodiments, R.sup.E3 is substituted alkenyl. In certain
embodiments, R.sup.E3 is unsubstituted alkenyl. In certain
embodiments, R.sup.E3 is vinyl. In certain embodiments, R.sup.E3 is
substituted alkynyl. In certain embodiments, R.sup.E3 is
unsubstituted alkynyl. In certain embodiments, R.sup.E3 is ethynyl.
In certain embodiments, R.sup.E3 is substituted carbocyclyl. In
certain embodiments, R.sup.E3 is unsubstituted carbocyclyl. In
certain embodiments, R.sup.E3 is substituted heterocyclyl. In
certain embodiments, R.sup.E3 is unsubstituted heterocyclyl. In
certain embodiments, R.sup.E3 is substituted aryl. In certain
embodiments, R.sup.E3 is unsubstituted aryl. In certain
embodiments, R.sup.E3 is substituted phenyl. In certain
embodiments, R.sup.E3 is unsubstituted phenyl. In certain
embodiments, R.sup.E3 is substituted heteroaryl. In certain
embodiments, R.sup.E3 is unsubstituted heteroaryl. In certain
embodiments, R.sup.E3 is substituted pyridyl. In certain
embodiments, R.sup.E3 is unsubstituted pyridyl. In certain
embodiments, R.sup.E3 is --CN. In certain embodiments, R.sup.E3 is
--OR.sup.E3a. In certain embodiments, R.sup.E3 is
--N(R.sup.E3a).sub.2. In certain embodiments, R.sup.E3 is
--SR.sup.E3a. In certain embodiments, R.sup.E3 is
--CH.sub.2OR.sup.E3a. In certain embodiments, R.sup.E3 is
--CH.sub.2N(R.sup.E3a).sub.2. In certain embodiments, R.sup.E3 is
--CH.sub.2SR.sup.E3a.
[0251] In certain embodiments, when R.sup.E3 is --OR.sup.E3a,
--N(R.sup.E3a).sub.2, --SR.sup.E3a, --CH.sub.2OR.sup.E3a,
--CH.sub.2N(R.sup.E3a).sub.2, or --CH.sub.2SR.sup.E3a, R.sup.E3a is
H. In certain embodiments, R.sup.E3a is substituted acyl. In
certain embodiments, R.sup.E3a is unsubstituted acyl. In certain
embodiments, R.sup.E3a is acetyl. In certain embodiments, R.sup.E3a
is substituted acetyl. In certain embodiments, R.sup.E3a is
substituted alkyl. In certain embodiments, R.sup.E3a is
unsubstituted alkyl. In certain embodiments, R.sup.E3a is C.sub.1-6
alkyl. In certain embodiments, R.sup.E3a is methyl. In certain
embodiments, R.sup.E3a is ethyl. In certain embodiments, R.sup.E3a
is propyl. In certain embodiments, R.sup.E3a is butyl. In certain
embodiments, R.sup.E3a is substituted alkenyl. In certain
embodiments, R.sup.E3a is unsubstituted alkenyl. In certain
embodiments, R.sup.E3a is vinyl. In certain embodiments, R.sup.E3a
is substituted alkynyl. In certain embodiments, R.sup.E3a is
unsubstituted alkynyl. In certain embodiments, R.sup.E3a is
ethynyl. In certain embodiments, R.sup.E3a is substituted
carbocyclyl. In certain embodiments, R.sup.E3a is unsubstituted
carbocyclyl. In certain embodiments, R.sup.E3a is substituted
heterocyclyl. In certain embodiments, R.sup.E3a is unsubstituted
heterocyclyl. In certain embodiments, R.sup.E3a is substituted
substituted aryl. In certain embodiments, R.sup.E3a is
unsubstituted aryl. In certain embodiments, R.sup.E3a is
substituted phenyl. In certain embodiments, R.sup.E3a is
unsubstituted phenyl. In certain embodiments, R.sup.E3a is
substituted heteroaryl. In certain embodiments, R.sup.E3a is
unsubstituted heteroaryl. In certain embodiments, R.sup.E3a is
substituted pyridyl. In certain embodiments, R.sup.E3a is
unsubstituted pyridyl. In certain embodiments, R.sup.E3a is a
nitrogen aryl. In deprotecting group when attached to a nitrogen
atom. In certain embodiments, R.sup.E3a is Bn, BOC, Cbz, Fmoc,
trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a
nitrogen atom. In certain embodiments, R.sup.E3a is an oxygen
protecting group when attached to an oxygen atom. In certain
embodiments, R.sup.E3a is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM,
THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to
an oxygen atom. In certain embodiments, R.sup.E3a is a sulfur
protecting group when attached to a sulfur atom. In certain
embodiments, R.sup.E3a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine
sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to
a sulfur atom. In certain embodiments, two R.sup.E3a groups are
joined to form a substituted heterocyclic ring. In certain
embodiments, two R.sup.E3a groups are joined to form an
unsubstituted heterocyclic ring.
[0252] In compounds of Formula (I), R.sup.E1 and R.sup.E3, or
R.sup.E2 and R.sup.E3, or R.sup.E1 and R.sup.E2 may be joined to
form a substituted or unsubstituted carbocyclic or substituted or
unsubstituted heterocyclic ring. In certain embodiments, R.sup.E1
and R.sup.E3 are joined to form a substituted or unsubstituted
carbocyclic ring. In certain embodiments, R.sup.E1 and R.sup.E3 are
joined to form a substituted or unsubstituted heterocyclic ring. In
certain embodiments, R.sup.E2 and R.sup.E3 are joined to form a
substituted or unsubstituted carbocyclic ring. In certain
embodiments, R.sup.E2 and R.sup.E3 are joined to form a substituted
or unsubstituted heterocyclic ring. In certain embodiments,
R.sup.E1 and R.sup.E2 are joined to form a substituted or
unsubstituted carbocyclic ring. In certain embodiments, R.sup.E1
and R.sup.E2 are joined to form a substituted or unsubstituted
heterocyclic ring.
[0253] In compounds of Formula (I), R.sup.E may include a
substituent R.sup.E4. In certain embodiments, R.sup.E4 is a leaving
group. In certain embodiments, R.sup.E4 is halogen. In certain
embodiments, R.sup.E4 is F. In certain embodiments, R.sup.E4 is Cl.
In certain embodiments, R.sup.E4 is Br. In certain embodiments,
R.sup.E4 is I (iodine). In certain embodiments, R.sup.E is
--OS(.dbd.O).sub.wR.sup.E4a. In certain embodiments, w is 1. In
certain embodiments, w is 2. In certain embodiments, R.sup.E is
--OMs. In certain embodiments, R.sup.E4 is --OTf. In certain
embodiments, R.sup.E4 is --OTs. In certain embodiments, R.sup.E4 is
--OBs. In certain embodiments, R.sup.E4 is
2-nitrobenzenesulfonyloxy. In certain embodiments, R.sup.E4 is
--OR.sup.E4a. In certain embodiments, R.sup.E4 is --OMe. In certain
embodiments, R.sup.E4 is --OCF.sub.3. In certain embodiments,
R.sup.E4 is --OPh. In certain embodiments, R.sup.E4 is
--OC(.dbd.)R.sup.E4a. In certain embodiments, R.sup.E4 is
--OC(.dbd.O)Me. In certain embodiments, R.sup.E4 is
--OC(.dbd.O)CF.sub.3. In certain embodiments, R.sup.E4 is
--OC(.dbd.O)Ph. In certain embodiments, R.sup.E4 is --OC(.dbd.O)Cl.
In certain embodiments, R.sup.E4 is --OC(.dbd.O)OR.sup.E4a. In
certain embodiments, R.sup.E4 is --OC(.dbd.O)OMe. In certain
embodiments, R.sup.E4 is --OC(.dbd.O)O(t-Bu).
[0254] In certain embodiments, R.sup.E4a is substituted alkyl. In
certain embodiments, R.sup.E4a is unsubstituted alkyl. In certain
embodiments, R.sup.E4a is C.sub.1-6 alkyl. In certain embodiments,
R.sup.E4a is methyl. In certain embodiments, R.sup.E4a is ethyl. In
certain embodiments, R.sup.E4a is propyl. In certain embodiments,
R.sup.E4a is butyl. In certain embodiments, R.sup.E4a is
substituted alkenyl. In certain embodiments, R.sup.E4a is
unsubstituted alkenyl. In certain embodiments, R.sup.E4a is vinyl.
In certain embodiments, R.sup.E4a is substituted alkynyl. In
certain embodiments, R.sup.E4a vinyl. In unsubstituted alkynyl. In
certain embodiments, R.sup.E4a is ethynyl. In certain embodiments,
R.sup.E4a is substituted carbocyclyl. In certain embodiments,
R.sup.E4a is unsubstituted carbocyclyl. In certain embodiments,
R.sup.E4a is substituted heterocyclyl. In certain embodiments,
R.sup.E4a is unsubstituted heterocyclyl. In certain embodiments,
R.sup.E4a is substituted aryl. In certain embodiments, R.sup.E4a is
unsubstituted aryl. In certain embodiments, R.sup.E4a is
substituted phenyl. In certain embodiments, R.sup.E4a is
unsubstituted phenyl. In certain embodiments, R.sup.E4a is
substituted heteroaryl. In certain embodiments, R.sup.E4a is
unsubstituted heteroaryl. In certain embodiments, R.sup.E4a is
substituted pyridyl. In certain embodiments, R.sup.E4a is
unsubstituted pyridyl.
[0255] In compounds of Formula (I), R.sup.E may include a Y group.
In certain embodiments, Y is .dbd.O. In certain embodiments, Y is
--O--. In certain embodiments, Y is .dbd.S. In certain embodiments,
Y is --S--. In certain embodiments, Y is .dbd.NR.sup.E6. In certain
embodiments, Y is --NR.sup.E6--. In certain embodiments, Y is
.dbd.NH. In certain embodiments, Y is --NH--. 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., --CH.sub.3). In
certain embodiments, R.sup.E6 is a nitrogen protecting group (e.g.,
Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or
Ts).
[0256] In compounds of Formula (I), R.sup.E may include a
substituent R.sup.E5, which is halogen. In certain embodiments,
R.sup.E5 is F, Cl, Br, or I (iodine).
[0257] In certain embodiments, a is 1. In certain embodiments, a is
2.
[0258] In certain embodiments, z is 0. In certain embodiments, z is
1. In certain embodiments, z is 2. In certain embodiments, z is 3.
In certain embodiments, z is 4. In certain embodiments, z is 5. In
certain embodiments, z is 6.
[0259] In certain embodiments, R.sup.E is of Formula (i-1); and
R.sup.E1 is hydrogen. In certain embodiments, R.sup.E is of Formula
(i-1); and R.sup.E2 is hydrogen. In certain embodiments, R.sup.E is
of Formula (i-1); and R.sup.E3 is hydrogen. In certain embodiments,
R.sup.E is of Formula (i-1); and R.sup.E2 and R.sup.E3 are each
hydrogen. In certain embodiments, R.sup.E is of Formula (i-1); and
R.sup.E1, R.sup.E2 and R.sup.E3 are each hydrogen. In certain
embodiments, R.sup.E is of Formula (i-1); and R.sup.E1 is
--CH.sub.2N(R.sup.E1a). In certain embodiments, R.sup.E is of
Formula (i-1); R.sup.E1 is --CH.sub.2N(R.sup.E1a); and R.sup.E1a is
C.sub.1-6 alkyl. In certain embodiments, R.sup.E is of Formula
(i-1); R.sup.E1 is --CH.sub.2N(R.sup.E1a); and R.sup.E1a is methyl.
In certain embodiments, R.sup.E is of Formula (i-1); and R.sup.E2
is --CH.sub.2N(R.sup.E2a). In certain embodiments, R.sup.E is of
Formula (i-1); R.sup.E2 is --CH.sub.2N(R.sup.E2a); and R.sup.E2a is
C.sub.1-6 alkyl. In certain embodiments, R.sup.E is of Formula
(i-1); R.sup.E2 is --CH.sub.2N(R.sup.E2a); and R.sup.E2a is methyl.
In certain embodiments, R.sup.E is of Formula (i-1); and R.sup.E3
is --CH.sub.2N(R.sup.E3a). In certain embodiments, R.sup.E is of
Formula (i-1); R.sup.E3 is --CH.sub.2N(R.sup.E3a); and R.sup.E3a is
C.sub.1-6 alkyl. In certain embodiments, R.sup.E is of Formula
(i-1); R.sup.E3 is --CH.sub.2N(R.sup.E3a); and R.sup.E3a is methyl.
In certain embodiments, R.sup.E is of Formula (i-1); and Y is
.dbd.O. In certain embodiments, R.sup.E is of Formula (i-1); and
L.sup.3 is --NR.sup.L3a--. In certain embodiments, R.sup.E is of
Formula (i-1); and L.sup.3 is --NH--. In certain embodiments,
R.sup.E is of the formula:
##STR00212##
In certain embodiments, R.sup.E is of the formula:
##STR00213##
In certain embodiments, R.sup.E is of the formula:
##STR00214##
In certain embodiments, R.sup.E is of the formula:
##STR00215##
In certain embodiments, R.sup.E is of the formula:
##STR00216##
In certain embodiments, R.sup.E is of the formula:
##STR00217##
In certain embodiments, R.sup.E is of the formula:
##STR00218##
In certain embodiments, R.sup.E is of the formula:
##STR00219##
In certain embodiments, R.sup.E is of the formula:
##STR00220##
In certain embodiments, R.sup.E is of the formula:
##STR00221##
In certain embodiments, R.sup.E is of the formula:
##STR00222##
In certain embodiments, R.sup.E is of the formula:
##STR00223##
In certain embodiments, R.sup.E is of the formula:
##STR00224##
In certain embodiments, R.sup.E is of the formula:
##STR00225##
In certain embodiments, R.sup.E is of the formula:
##STR00226## ##STR00227##
[0260] In certain embodiments, R.sup.E is of Formula (i-3); and
R.sup.E1 is hydrogen. In certain embodiments, R.sup.E is of Formula
(i-3); and R.sup.E1 is --CH.sub.2N(R.sup.E1a). In certain
embodiments, R.sup.E is of Formula (i-3); and R.sup.E1 is
--Si(R.sup.E1a).sub.3 (e.g., --Si(Me).sub.3). In certain
embodiments, R.sup.E is of Formula (i-3); R.sup.E1 is
--CH.sub.2N(R.sup.E1a); and R.sup.E1a is C.sub.1-6 alkyl. In
certain embodiments, R.sup.E is of Formula (i-3); R.sup.E1 is
--CH.sub.2N(R.sup.E1a); and R.sup.E1a is methyl. In certain
embodiments, R.sup.E is of Formula (i-3); and Y is .dbd.O. In
certain embodiments, R.sup.E is of Formula (i-3); and L.sup.3 is
--NR.sup.L3a--. In certain embodiments, R.sup.E is of Formula
(i-3); and L.sup.3 is --NH--.
[0261] In certain embodiments, R.sup.E is of the formula:
##STR00228##
In certain embodiments, R.sup.E is of the formula:
##STR00229##
[0262] In certain embodiments, R.sup.E is not of the formula:
##STR00230##
[0263] In certain embodiments, R.sup.E is of the formula:
[0264] (i-36), (i-37), or (i-38).
[0265] In certain embodiments, R.sup.E is of the formula:
##STR00231##
[0266] In certain embodiments, R.sup.E is of the formula:
##STR00232##
In certain embodiments, R.sup.E is of the formula:
##STR00233##
[0267] In certain embodiments, the compound of Formula (I) is of
Formula (I-a):
##STR00234##
or a pharmaceutically acceptable salt thereof.
[0268] In certain embodiments, the compound of Formula (I) is of
Formula (I-a-i):
##STR00235##
or a pharmaceutically acceptable salt thereof.
[0269] In certain embodiments, the compound of Formula (I) is of
Formula (I-a-ii):
##STR00236##
or a pharmaceutically acceptable salt thereof.
[0270] In certain embodiments, the compound of Formula (I) is of
Formula (I-a-iii):
##STR00237##
or a pharmaceutically acceptable salt thereof.
[0271] In certain embodiments, the compound of Formula (I) is of
Formula (I-a-iv):
##STR00238##
or a pharmaceutically acceptable salt thereof.
[0272] In certain embodiments, the compound of Formula (I) is of
Formula (I-b):
##STR00239##
or a pharmaceutically acceptable salt thereof.
[0273] In certain embodiments, the compound of Formula (I) is of
Formula (I-b-i):
##STR00240##
or a pharmaceutically acceptable salt thereof.
[0274] In certain embodiments, the compound of Formula (I) is of
Formula (I-b-ii):
##STR00241##
or a pharmaceutically acceptable salt thereof.
[0275] In certain embodiments, the compound of Formula (I) is of
Formula (I-b-iii):
##STR00242##
or a pharmaceutically acceptable salt thereof.
[0276] In certain embodiments, the compound of Formula (I) is of
Formula (I-b-iv):
##STR00243##
or a pharmaceutically acceptable salt thereof.
[0277] In certain embodiments of Formulae (I), and (I-a)-(I-c),
R.sup.E is of Formula (i-1); and L.sup.3 is --NR.sup.L3a--. In
certain embodiments of Formulae (I)-(VI), R.sup.E is of Formula
(i-1); and L.sup.3 is --NH--. In certain embodiments of Formulae
(I)-(VI), R.sup.E is of the formula:
##STR00244##
In certain embodiments of Formulae (I)-(VI), R.sup.E is of the
formula:
##STR00245##
In certain embodiments, R.sup.E is of the formula:
##STR00246##
[0278] In certain embodiments, the compound of Formula (I) is of
the formula:
##STR00247## ##STR00248## ##STR00249## ##STR00250##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0279] In certain embodiments, the compound of Formula (I) is of
the formula:
##STR00251##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0280] In certain embodiments, the compound of Formula (I) is of
the formula:
##STR00252##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0281] In certain embodiments, a compound of Formula (I) is
substantially pure. In certain embodiments, a compound of Formula
(I) is a substantially pure stereoisomer. In certain embodiments,
the compounds of the present invention are compounds of Formula
(I), and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof. In certain embodiments,
the compounds of the present invention are compounds of Formula
(I), and pharmaceutically acceptable salts and stereoisomers
thereof. In certain embodiments, the compounds of the present
invention are compounds of Formula (I), and pharmaceutically
acceptable salts thereof. In certain embodiments, the compounds of
the present invention are a stereoisomeric mixture of compounds of
Formula (I), and pharmaceutically acceptable salts thereof. In
certain embodiments, the compounds of the present invention are a
racemic stereoisomeric mixture of compounds of Formula (I), and
pharmaceutically acceptable salts thereof.
[0282] The compounds of the present invention may bear multiple
binding motifs for binding to a kinase. The compounds of the
present invention may also inhibit a kinase. In certain
embodiments, the kinase is a protein kinase. In certain
embodiments, the protein kinase is a CDK (e.g., CDK7, CDK12, and/or
CDK13). In certain embodiments, the kinase is a lipid kinase. In
certain embodiments, the protein kinase is a PIP4K. In certain
embodiments, the PIP4K is a PIP4K2. In certain embodiments, the
PIP4K2 is PIP4K2A protein. In certain embodiments, the PIP4K2 is
PIP4K2B protein. In certain embodiments, the PIP4K2 is PIPK2C
protein. Ring A of the inventive compounds may be accommodated by a
hydrophobic pocket in the ATP-binding site of the kinase (e.g., a
lipid kinase such as PIP4K2 enzyme). Functionalities on Rings A and
B may bind to residues of the kinase (e.g., a lipid kinase such as
PIP4K2 enzyme). For example, Ring A may form a hydrogen bond with a
Cys residue of PIP4K (e.g. Cys293 of PIP4K2A enzyme or Cys307
and/or Cys318 of PIP4K2B enzyme). Functional groups of R.sup.E may
form one or more hydrogen bonds with the kinase (e.g., a lipid
kinase such as PIP4K2 enzyme). Moreover, the Michael acceptor
moiety of R.sup.E may react with a cysteine residue of the kinase
(e.g., a lipid kinase such as PIP4K2 enzyme) to allow covalent
attachment of the compound to the kinase (e.g., a lipid kinase such
as a PIP4K2 enzyme).
[0283] In certain embodiments, the provided compound is capable of
covalently modifying Cys293 of PI5P4K.alpha.. In certain
embodiments, the provided compound is capable of covalently
modifying Cys307 and/or Cys318 of PI5P4K.beta.. In certain
embodiments, the provided compound is capable of covalently
modifying Cys313 of PI5P4K.gamma. while Cys313 is based on the
sequence alignment.
[0284] The compounds of the present invention are thought to be
kinase inhibitors. In certain embodiments, the inventive compounds
are inhibitors of protein kinases. In certain embodiments, the
inventive compounds are CDK inhibitors. In certain embodiments, the
inventive compounds are CDK7 inhibitors. In certain embodiments,
the inventive compounds are CDK12 inhibitors. In certain
embodiments, the inventive compounds are CDK13 inhibitors. In
certain embodiments, the inventive compounds are inhibitors of
lipid kinases. In certain embodiments, the inventive compounds are
PIPK inhibitors. In certain embodiments, the inventive compounds
are PIP4K2 inhibitors. In certain embodiments, the inventive
compounds are PIP4K2A inhibitors. In certain embodiments, the
inventive compounds are PIP4K2B inhibitors. In certain embodiments,
the inventive compounds are PIP4K2C inhibitors. In certain
embodiments, the inventive compounds are selective CDK inhibitors
(e.g., being more active in inhibiting a CDK than a non-CDK
kinase). In certain embodiments, the inventive compounds are
selective CDK7 inhibitors (e.g., being more active in inhibiting
CDK7 than a non-CDK7 kinase). In certain embodiments, the inventive
compounds are selective CDK12 inhibitors. In certain embodiments,
the inventive compounds are selective CDK13 inhibitors. In certain
embodiments, the inventive compounds are selective PIPK inhibitors
(e.g., being more active in inhibiting a PIPK than a non-PIPK
kinase). In certain embodiments, the inventive compounds are
selective PIP4K2 inhibitors (e.g., being more active in inhibiting
PIP4K2 than a non-PIP4K2 kinase). In certain embodiments, the
inventive compounds are selective PIP4K2A inhibitors. In certain
embodiments, the inventive compounds are selective PIP4K2B
inhibitors. In certain embodiments, the inventive compounds are
selective PIP4K2C inhibitors.
[0285] The selectivity of an inventive compound for a first kinase
(e.g., lipid kinase) over a second kinase (e.g., a non-lipid
kinase) may be measured by the quotient of the IC.sub.50 (half
maximal inhibitory concentration) value of the inventive compound
in inhibiting the activity of the second kinase over the IC.sub.50
value of the inventive compound in inhibiting the activity of the
first kinase. The selectivity of an inventive compound for a first
kinase over a second kinase may also be measured by the quotient of
the K.sub.d (dissociation constant) value of an adduct (covalent or
non-covalent) of the inventive compound and the second kinase over
the K.sub.d value of an adduct of the inventive compound and the
first kinase. In certain embodiments, the selectivity is at least
about 1-fold, at least about 2-fold, at least about 5-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. In certain
embodiments, IC.sub.50 values are measured by a functional
antagonist assay. In certain embodiments, IC.sub.50 values are
measured by a competition binding assay. In certain embodiments,
IC.sub.50 values are measured by a method described herein. In
certain embodiments, K.sub.d values are measured by a nuclear
magnetic resonance method (e.g., a linearization method and a curve
fitting method). In certain embodiments, K.sub.d values are
measured by a mass spectrometry method (e.g., a one-ligand
one-binding-site ESI-MS method).
Pharmaceutical Compositions, Kits, and Administration
[0286] The present invention provides pharmaceutical compositions
comprising a compound of Formula (I), e.g., a compound of Formula
(I), or a pharmaceutically acceptable salt, solvate, hydrate,
polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof, as described herein, and optionally
a pharmaceutically acceptable excipient. In certain embodiments,
the pharmaceutical composition of the invention comprises a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, and optionally a pharmaceutically acceptable excipient. In
certain embodiments, the compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof, 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.
[0287] Pharmaceutical compositions described herein can be prepared
by any method known in the art of pharmacology. In general, such
preparatory methods include the steps of bringing the compound of
Formula (I) (the "active ingredient") into association with a
carrier and/or one or more other accessory ingredients, and then,
if necessary and/or desirable, shaping and/or packaging the product
into a desired single- or multi-dose unit.
[0288] 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, for example, one-half or one-third of such a
dosage.
[0289] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition of the invention will
vary, depending upon the identity, size, and/or condition of the
subject treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[0290] 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.
[0291] 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.
[0292] 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.
[0293] Exemplary surface active agents and/or emulsifiers include
natural emulsifiers (e.g. acacia, agar, alginic acid, sodium
alginate, tragacanth, chondrux, cholesterol, xanthan, pectin,
gelatin, egg yolk, casein, wool fat, cholesterol, wax, and
lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and
Veegum (magnesium aluminum silicate)), long chain amino acid
derivatives, high molecular weight alcohols (e.g. stearyl alcohol,
cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene
glycol distearate, glyceryl monostearate, and propylene glycol
monostearate, polyvinyl alcohol), carbomers (e.g. carboxy
polymethylene, polyacrylic acid, acrylic acid polymer, and
carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.
carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene
sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween
60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan
monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan
tristearate (Span 65), glyceryl monooleate, sorbitan monooleate
(Span 80)), polyoxyethylene esters (e.g. polyoxyethylene
monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil,
polyethoxylated castor oil, polyoxymethylene stearate, and
Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid
esters (e.g. Cremophor.TM.), polyoxyethylene ethers, (e.g.
polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone),
diethylene glycol monolaurate, triethanolamine oleate, sodium
oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate,
sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, cetrimonium
bromide, cetylpyridinium chloride, benzalkonium chloride, docusate
sodium, and/or mixtures thereof.
[0294] Exemplary binding agents include starch (e.g. cornstarch and
starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose,
dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and
synthetic gums (e.g. acacia, sodium alginate, extract of Irish
moss, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, ethylcellulose,
hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, microcrystalline cellulose, cellulose acetate,
poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and
larch arabogalactan), alginates, polyethylene oxide, polyethylene
glycol, inorganic calcium salts, silicic acid, polymethacrylates,
waxes, water, alcohol, and/or mixtures thereof.
[0295] Exemplary preservatives include antioxidants, chelating
agents, antimicrobial preservatives, antifungal preservatives,
alcohol preservatives, acidic preservatives, and other
preservatives. In certain embodiments, the preservative is an
antioxidant. In other embodiments, the preservative is a chelating
agent.
[0296] Exemplary antioxidants include alpha tocopherol, ascorbic
acid, ascorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite,
sodium metabisulfite, and sodium sulfite.
[0297] 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.
[0298] 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.
[0299] Exemplary alcohol preservatives include ethanol,
polyethylene glycol, phenol, phenolic compounds, bisphenol,
chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
[0300] 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.
[0301] Other preservatives include tocopherol, tocopherol acetate,
deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA),
butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl
sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium
bisulfite, sodium metabisulfite, potassium sulfite, potassium
metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115,
Germaben II, Neolone, Kathon, and Euxyl.
[0302] 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.
[0303] 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.
[0304] 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.
[0305] 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
of the invention are mixed with solubilizing agents such as
Cremophor.TM., alcohols, oils, modified oils, glycols,
polysorbates, cyclodextrins, polymers, and mixtures thereof.
[0306] 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 diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0307] 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.
[0308] 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 is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0309] Compositions for rectal or vaginal administration are
typically suppositories which can be prepared by mixing the
conjugates of this invention 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.
[0310] 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.
[0311] 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 embedding 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 polyethylene glycols and the
like.
[0312] 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
embedding compositions which can be used include polymeric
substances and waxes.
[0313] Dosage forms for topical and/or transdermal administration
of a compound of this invention 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 and/or any
needed preservatives and/or buffers as can be required.
Additionally, the present invention 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.
[0314] 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. Jet injection devices which deliver liquid vaccines 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.
Alternatively or additionally, conventional syringes can be used in
the classical mantoux method of intradermal administration.
[0315] 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.
[0316] A pharmaceutical composition of the invention 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.
[0317] 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).
[0318] Pharmaceutical compositions of the invention 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.
[0319] Formulations described herein as being useful for pulmonary
delivery are useful for intranasal delivery of a pharmaceutical
composition of the invention. 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.
[0320] 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 of the invention 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.
[0321] A pharmaceutical composition of the invention 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. 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 contemplated as being within the scope
of this invention.
[0322] 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.
[0323] 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 of the present invention will be decided by the
attending 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.
[0324] 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).
[0325] 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(s), mode of administration, and the like. The
desired dosage can be delivered three times a day, two times a day,
once a day, every other day, every third day, every week, every two
weeks, every three weeks, or every four weeks. In certain
embodiments, the desired dosage can be delivered using multiple
administrations (e.g., two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, or more
administrations).
[0326] 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 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 tissue
or cell, the frequency of administering the multiple doses to the
subject or applying the multiple doses to the 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
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 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
tissue or cell is three doses per day. In certain embodiments, when
multiple doses are administered to a subject or applied to a 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.
[0327] In certain embodiments, a dose described herein is a dose to
an adult human whose body weight is 70 kg. In certain embodiments,
an effective amount of a compound for administration one or more
times a day to a 70 kg adult human may comprise about 0.0001 mg to
about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to
about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to
about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about
1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg,
or about 100 mg to about 1000 mg, of a compound per unit dosage
form.
[0328] In certain embodiments, the compounds of Formula (I) may be
at dosage levels sufficient to deliver from about 0.001 mg/kg to
about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg,
preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from
about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about
10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more
preferably from about 1 mg/kg to about 25 mg/kg, of subject body
weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0329] It will be appreciated that 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.
[0330] It will be also appreciated that a compound or composition,
as described herein, can be administered in combination with one or
more additional pharmaceutical agents. The compounds or
compositions can be administered in combination with additional
pharmaceutical agents that improve their bioavailability, reduce
and/or modify their metabolism, inhibit their excretion, and/or
modify their distribution within the body. 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.
[0331] 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. 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 inventive
compound with the additional pharmaceutical agents and/or the
desired therapeutic and/or prophylactic effect to be achieved. In
general, it is expected that the additional pharmaceutical agents
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.
[0332] Exemplary additional pharmaceutical agents include, but are
not limited to, anti-proliferative agents, anti-cancer agents,
anti-diabetic agents, anti-inflammatory agents, immunosuppressant
agents, and a pain-relieving agent. Pharmaceutical agents include
small organic molecules such as drug compounds (e.g., compounds
approved 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 selected from the group consisting of
cytotoxic agents, 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.
[0333] Also encompassed by the invention are kits (e.g.,
pharmaceutical packs). The inventive kits may be useful for
preventing and/or treating a proliferative disease (e.g., cancer
(e.g., leukemia, lymphoma, melanoma, multiple myeloma, breast
cancer, Ewing's sarcoma, osteosarcoma, brain cancer, neuroblastoma,
lung cancer), benign neoplasm, angiogenesis, inflammatory disease,
autoinflammatory disease, or autoimmune disease). The kits provided
may comprise an inventive pharmaceutical composition or compound
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 an inventive pharmaceutical composition or compound.
In some embodiments, the inventive pharmaceutical composition or
compound provided in the container and the second container are
combined to form one unit dosage form.
[0334] Thus, in one aspect, provided are kits including a first
container comprising a compound described herein, or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, and prodrug thereof, or a pharmaceutical composition
thereof. In certain embodiments, the kit of the invention includes
a first container comprising a compound described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition thereof. In certain embodiments, the kits are useful in
preventing and/or treating a proliferative disease in a subject. In
certain embodiments, the kits further include instructions for
administering the compound, or a pharmaceutically acceptable salt,
solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,
isotopically labeled derivative, and prodrug thereof, or a
pharmaceutical composition thereof, to a subject to prevent and/or
treat a proliferative disease.
Methods of Treatment and Uses
[0335] The present invention also provides methods for the
treatment or prevention of a proliferative disease (e.g., cancer,
benign neoplasm, angiogenesis, inflammatory disease,
autoinflammatory disease, or autoimmune disease) or an infectious
disease (e.g., a viral disease) in a subject.
[0336] 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.
[0337] The proliferative disease to be treated or prevented using
the compounds of Formula (I) may be associated with overexpression
of a kinase. The proliferative disease to be treated or prevented
using the compounds of Formula (I) may be associated with aberrant
activity of a kinase. In certain embodiments, the kinase is a lipid
kinase. In certain embodiments, the lipid kinase is a PIP kinase.
In certain embodiments, the PIPK is PIP4K, catalyzing
phosphorylation of lipid phosphatidylinositol-5-phosphate (PI-5-P)
at the 4-position to generate phosphatidylinositol-4,5-bisphosphate
(PI-4,5-P.sub.2). In some embodiments, the PIP4K is class I PIP4K,
i.e. PIP4K1. In some embodiments, the PIP4K is class II PIP4K, i.e.
PIP4K2. In some embodiments, the PIP4K2 is PIP4K2A protein. In some
embodiments, the PIP4K2 is PIP4K2B protein. In some embodiments,
the PIP4K2 is PIP4K2C protein.
[0338] In certain embodiments, the kinase is a protein kinase. In
certain embodiments, the protein kinase is a cyclin-dependent
kinase (CDK). The process of eukaryotic cell division may be
broadly divided into a series of sequential phases termed G1, S,
G2, and M. Correct progression through the various phases of the
cell cycle has been shown to be critically dependent upon the
spatial and temporal regulation of a family of proteins known as
cyclin dependent kinases (CDKs) and a diverse set of their cognate
protein partners termed cyclins. CDKs are CDC2 (also known as CDK1)
homologous serine-threonine kinase proteins that are able to
utilize ATP as a substrate in the phosphorylation of diverse
polypeptides in a sequence-dependent context. Cyclins are a family
of proteins characterized by a homology region, containing
approximately 100 amino acids, termed the "cyclin box" which is
used in binding to, and defining selectivity for, specific CDK
partner proteins. In certain embodiments, the CDK is CDK7. In
certain embodiments, the CDK is CDK12. In certain embodiments, the
CDK is CDK13.
[0339] In certain embodiments, a proliferative disease may be
associated with aberrant activity of a CDK (e.g., CDK7). Aberrant
activity of a CDK (e.g., CDK7) may be an elevated and/or an
inappropriate activity of the CDK. Deregulation of cell cycle
progression is a characteristic of a proliferative disease, and a
majority of proliferative diseases have abnormalities in some
component of CDK (e.g., CDK7) activity, frequently through elevated
and/or inappropriate CDK activation. Inhibition of the catalytic
activity of CDK7 would be expected to inhibit cell cycle
progression by blocking the phosphorylation of cell cycle CDKs, and
would additionally inhibit transcription of effectors of cell
division. In certain embodiments, CDK7 is not overexpressed, and
the activity of CDK7 is elevated and/or inappropriate. In certain
other embodiments, CDK7 is overexpressed, and the activity of CDK7
is elevated and/or inappropriate. 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 CDK7 and be useful in treating and/or preventing
proliferative diseases.
[0340] In other embodiments, the proliferative disease to be
treated or prevented using the compounds of Formula (I) will
typically be associated with aberrant activity of CDK12. Aberrant
activity of CDK12 may be an elevated and/or an inappropriate (e.g.,
abnormal) activity of CDK12. In certain embodiments, CDK12 is not
overexpressed, and the activity of CDK12 is elevated and/or
inappropriate. In certain other embodiments, CDK12 is
overexpressed, and the activity of CDK12 is elevated and/or
inappropriate. The compounds of Formula (I), and pharmaceutically
acceptable salts, solvates, hydrates, tautomers, stereoisomers,
isotopically labeled derivatives, and compositions thereof, may
inhibit the activity of CDK12 and be useful in treating and/or
preventing proliferative diseases.
[0341] In other embodiments, the proliferative disease to be
treated or prevented using the compounds of Formula (I) will
typically be associated with aberrant activity of CDK13. Aberrant
activity of CDK13 may be an elevated and/or an inappropriate (e.g.,
abnormal) activity of CDK13. In certain embodiments, CDK13 is not
overexpressed, and the activity of CDK13 is elevated and/or
inappropriate. In certain other embodiments, CDK13 is
overexpressed, and the activity of CDK13 is elevated and/or
inappropriate. The compounds of Formula (I), and pharmaceutically
acceptable salts, solvates, hydrates, tautomers, stereoisomers,
isotopically labeled derivatives, and compositions thereof, may
inhibit the activity of CDK13 and be useful in treating and/or
preventing proliferative diseases.
[0342] In certain embodiments, the proliferative disease to be
treated or prevented using the compounds of Formula (I) is cancer.
All types of cancers disclosed herein or known in the art are
contemplated as being within the scope of the invention. In some
embodiments, the cancer has one or more mutations. In certain
embodiments, the cancer has EGFR mutation. In certain embodiments,
the cancer has TP53 mutation. In certain embodiments, the cancer
has loss of TP53 mutation. In certain embodiments, the cancer has
KRAS mutation. In certain embodiments, the cancer has ALK mutation.
In certain embodiments, the proliferative disease is a cancer
associated with dependence on BCL-2 anti-apoptotic proteins (e.g.,
MCL-1 and/or XIAP). In certain embodiments, the proliferative
disease is a cancer associated with overexpression of MYC (a gene
that codes for a transcription factor). 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 myelogenous
leukemia (AML). In certain embodiments, the proliferative disease
is acute monocytic leukemia (AMoL). In certain embodiments, the
proliferative disease is 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
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
lung cancer has one or more mutations. In certain embodiments, the
lung cancer has EGFR mutation. In certain embodiments, the lung
cancer has TP53 mutation. In certain embodiments, the lung cancer
has loss of TP53 mutation. In certain embodiments, the lung cancer
has KRAS mutation. In certain embodiments, the lung cancer has ALK
mutation. 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. 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.
[0343] In certain embodiments, the infectious disease to be treated
or prevented using the compounds of Formula (I) is a viral disease.
Such viral infections are described in U.S. Provisional patent
application, U.S. Ser. No. 61/622,828, filed Apr. 11, 2012, and
international PCT application, PCT/US2013/032488, filed Mar. 15,
2013 and published on Oct. 17, 2011, each of which is incorporated
herein in its entirety by reference.
[0344] The cell described herein may be an abnormal cell. The cell
may be in vitro or in vivo. In certain embodiments, the cell is a
proliferative cell. In certain embodiments, the cell is a blood
cell. In certain embodiments, the cell is a lymphocyte. In certain
embodiments, the cell is a B-cell. In certain embodiments, the cell
is a T-cell. In certain embodiments, the cell is a cancer cell. In
certain embodiments, the cell is a leukemia cell. In certain
embodiments, the cell is a CLL cell. In certain embodiments, the
cell is a melanoma cell. In certain embodiments, the cell is a
multiple myeloma cell. In certain embodiments, the cell is a benign
neoplastic cell. In certain embodiments, the cell is an endothelial
cell. In certain embodiments, the cell is an immune cell.
[0345] In another aspect, the present invention provides methods of
modulating the activity of a kinase (e.g. a lipid kinase such as
PIPK (e.g. PIP4K2A, PIP4K2B, or PIP4K2C protein) enzyme or a
protein kinase such as CDK (e.g., CDK7, CDK1, CDK2, CDK5, CDK8,
CDK9, CDK12, CDK13) enzyme) in a biological sample or subject. In
certain embodiments, the activity of the kinase is aberrant
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 of Formula (I) to the
kinase.
[0346] Also provided in the present invention are methods of
inhibiting transcription in a biological sample or subject.
[0347] The present invention also provides methods of inhibiting
cell growth in a biological sample or subject.
[0348] In certain embodiments, the methods described herein include
administering to a subject or contacting a biological sample with
an effective amount of a compound of Formula (I), 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 of Formula (I), 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.
[0349] 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. 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 an anti-myelodysplasia agent. In certain
embodiments, the additional pharmaceutical agent is REVLIMID
(lenalidomide), DACOGEN (decitabine), VIDAZA (azacitidine),
CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin), CERUBIDINE
(daunorubicin), or a combination thereof.
[0350] In certain embodiments, the additional pharmaceutical agent
is an anti-macroglobulinemia agent.
[0351] In certain embodiments, the additional pharmaceutical agent
is 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), or a
combination thereof. In certain embodiments, the additional
pharmaceutical agent is a histone deacetylase inhibitor. In certain
embodiments, the histone deacetylase inhibitor is a hydroxamic acid
such as Vorinostat (SAHA), ITF2357, or PXD-101, a cyclic peptide
such as depsipeptide, a benzamide such as MS-275, or an aliphatic
acid such as valproic acid or AN-9.
[0352] In certain embodiments, the additional pharmaceutical agent
is an inhibitor of a lipid kinase. In certain embodiments, the
additional pharmaceutical agent is an inhibitor of a PIP4K. In
certain embodiments, the additional pharmaceutical agent is an
inhibitor of a PIP4K2. In certain embodiments, the additional
pharmaceutical agent is an inhibitor of a PIP4K2A. In certain
embodiments, the additional pharmaceutical agent is an inhibitor of
a PIP4K2B. In certain embodiments, the additional pharmaceutical
agent is an inhibitor of a PIP4K2C. In certain embodiments, the
additional pharmaceutical agent is an inhibitor of a protein
kinase. In certain embodiments, the additional pharmaceutical agent
is an inhibitor of a CDK. In certain embodiments, the additional
pharmaceutical agent is an inhibitor of CDK7. In certain
embodiments, the additional pharmaceutical agent is an inhibitor of
CDK12. In certain embodiments, the additional pharmaceutical agent
is an inhibitor of CDK13. 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 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. In certain embodiments, the additional
pharmaceutical agent is an inhibitor of one or more protein kinases
selected from the group consisting of IRAK1, IRAK4, BMX, and PI3K.
In certain embodiments, the additional pharmaceutical agent is an
inhibitor of one or more protein kinases selected from the group
consisting of BUB1B, CDK2, CDK9, CHEK2, FGR, HIPK4, PRKCQ, RET,
SRC, or MELK. In certain embodiments, the additional pharmaceutical
agent is an inhibitor of one or more protein kinases selected from
the group consisting of ABL, ARG, BLK, CSK, EphB1, EphB2, FGR, FRK,
FYN, SRC, YES, LCK, LYN, MAP2K5, NLK, p38a, SNRK, and TEC. In
certain embodiments, the additional pharmaceutical agent is an
inhibitor of one or more protein kinases selected from the group
consisting of ABL1(H396P)-phosphorylated, ABL1-phosphorylated, BLK,
EPHA4, EPHB2, EPHB3, EPHB4, FGR, JAK3(JH1 domain-catalytic), KIT,
KIT(L576P), KIT(V559D), PDGFRB, SRC, YES,
ABL1(H396P)-nonphosphorylated, ABL1(Y253F)-phosphorylated,
ABL1-nonphosphorylated, FRK, LYN, ABL1(Q252H)-nonphosphorylated,
DDR1, EPHB1, ERBB4, p38-alpha, ABL2, ABL1(Q252H)-phosphorylated,
SIK, EPHA8, MEK5, ABL1(E255K)-phosphorylated,
ABL1(F317L)-nonphosphorylated, FYN, LCK, EPHA2,
ABL(M351T)-phosphorylated, TXK, EGFR(L858R), EGFR(L861Q), ERBB2,
ERBB3, EPHA5, ABL1(F317I)-nonphosphorylated, EGFR(L747-E749de1,
A750P), CSK, EPHA1, ABL1(F317L)-phosphorylated, BRAF(V600E), EGFR,
KIT-autoinhibited, and EGFR(E746-A750de1). In certain embodiments,
the additional pharmaceutical agent is an inhibitor of one or more
protein kinases selected from the group consisting of
ABL1(F317L)-nonphosphorylated, AB L1(H396P)-nonphosphorylated, AB
L1(H396P)-phosphorylated, ABL1-phosphorylated, BLK, EPHA4, EPHB2,
EPHB3, EPHB4, JAK3(JH1domain-catalytic), KIT, KIT(L576P),
KIT(V559D), LYN, PDGFRB, SRC, YES, ABL1-nonphosphorylated,
ABL1(Y253F)-phosphorylated, ERBB3, FGR, FRK, p38-alpha,
ABL1(F317I)-nonphosphorylated, DDR1, EPHA2,
ABL1(Q252H)-phosphorylated, MEK5, ABL1(Q252H)-nonphosphorylated,
ABL2, FYN, EPHB1, ABL1(E255K)-phosphorylated,
ABL1(F317L)-phosphorylated, EPHA1, ABL1(M351T)-phosphorylated,
ERBB4, TXK, LCK, EPHA8, SIK, EPHA5, EGFR(L861Q),
CSF1R-autoinhibited, BRAF(V600E), BRK, CSK, KIT(D816V),
KIT-autoinhibited, EGFR(L747-T751de1,Sins), EGFR(L858R),
EGFR(L747-E749de1, A750P), and CSF1R. In certain embodiments, the
additional pharmaceutical agent is an anti-angiogenesis agent,
anti-inflammatory agent, immunosuppressant, anti-bacterial agent,
anti-viral agent, cardiovascular agent, cholesterol-lowering agent,
anti-diabetic agent, anti-allergic agent, pain-relieving agent, or
a combination thereof. 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, transplantation (e.g., bone marrow transplantation,
stem cell transplantation), surgery, radiation therapy,
immunotherapy, and chemotherapy.
[0353] Another aspect of the invention relates to methods of
screening a library of compounds to identify one or more compounds
that are useful in the treatment of a proliferative disease, in
inhibiting a kinase (e.g., PIPK or CDK (e.g CDK7, CDK12, CDK13)
enzyme), in inhibiting cell growth. In certain embodiments, the
library of compounds is a library of compounds of Formula (I). The
methods of screening a library include providing at least two
different compounds of Formula (I), or pharmaceutically acceptable
salts, solvates, hydrates, polymorphs, co-crystals, tautomers,
stereoisomers, isotopically labeled derivatives, or prodrugs
thereof, or pharmaceutical compositions thereof; and performing at
least one assay using the different compounds of Formula (I), or
pharmaceutically acceptable salts, solvates, hydrates, polymorphs,
co-crystals, tautomers, stereoisomers, isotopically labeled
derivatives, or prodrugs thereof, or pharmaceutical compositions
thereof, to detect one or more characteristics associated with the
proliferative disease. In certain embodiments, the methods of
screening a library include providing at least two different
compounds of Formula (I), or pharmaceutically acceptable salts
thereof, or pharmaceutical compositions thereof; and performing at
least one assay using the different compounds of Formula (I), or
pharmaceutically acceptable salts thereof, or pharmaceutical
compositions thereof, to detect one or more characteristics
associated with the proliferative disease. The characteristic to be
detected may be a desired characteristic associated with the
proliferative disease. In certain embodiments, the desired
characteristic is anti-proliferation. In certain embodiments, the
desired characteristic is anti-cancer. In certain embodiments, the
desired characteristic is inhibition of a kinase. In certain
embodiments, the desired characteristic is inhibition of a lipid
kinase. In certain embodiments, the desired characteristic is
inhibition of PIPK. In certain embodiments, the desired
characteristic is inhibition of PIP4K. In certain embodiments, the
desired characteristic is inhibition of class II PIP4K, i.e.
PIP4K2. In certain embodiments, the desired characteristic is
inhibition of PIP4K2A. In certain embodiments, the desired
characteristic is inhibition of PIP4K2B. In certain embodiments,
the desired characteristic is inhibition of PIP4K2C. In certain
embodiments, the desired characteristic is inhibition of a protein
kinase. In certain embodiments, the desired characteristic is
inhibition of CDK. In certain embodiments, the desired
characteristic is inhibition of CDK7. In certain embodiments, the
desired characteristic is inhibition of CDK12. In certain
embodiments, the desired characteristic is inhibition of CDK13. In
certain embodiments, the desired characteristic is down-regulation
of a kinase such as PIPK or CDK.
EXAMPLES
[0354] 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.
Synthesis of the Compounds
[0355] The compounds provided herein can be prepared from readily
available starting materials using the following general methods
and procedures. See, e.g., Scheme 1 below. It will be appreciated
that 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.
[0356] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in Greene et al., Protecting Groups in Organic Synthesis,
Second Edition, Wiley, New York, 1991, and references cited
therein.
Example 1. Synthesis of Compound 7 (FIG. 2)
2-chloro-4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]-
pyrimidine (Compound 2)
[0357] To a solution of 1 (1.0 g, 2.6 mmol) in MeCN and H.sub.2O(20
mL, 4/1, v/v) was added 2,4-dichlorothieno[3,2-d]pyrimidine (0.53
g, 2.6 mmol), NaHCO.sub.3(0.21 g, 2.6 mmol) and
Pd(PPh.sub.3).sub.2Cl.sub.2(91 mg, 0.013 mmol). The reaction
mixture was heated to 80.degree. C. for 12 h. Then the mixture was
diluted with EtOAc (100 mL) at room temperature, washed with water
and brine, dried (Na.sub.2SO.sub.4), and concentrated. The residue
was purified by a silica gel column to afford the title compound
2(0.83 g, 75%). MS(ESI): m/z 427.15 (M+H).sup.+.
N1-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrim-
idin-2-yl)benzene-1,3-diamine (Compound 3)
[0358] To a solution of 2 (0.83 g, 1.95 mmol) in 2-BuOH (5.0 mL)
was added benzene-1,3-diamine (0.21 g, 1.95 mmol) and PTSA (0.33
mg, 1.95 mmol). The reaction mixture was heated to 120.degree. C.
for 12 h. Then the resulting mixture was diluted with EtOAc (150
mL) at room temperature, washed with water and brine, dried
(Na.sub.2SO.sub.4), and concentrated. The residue was purified by a
silica gel column to afford the title compound 3 (0.31 g, 32%).
MS(ESI): m/z 499.21 (M+H).sup.+.
4-nitro-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3-
,2-d]pyrimidin-2-ylamino)phenyl)benzamide (Compound 4)
[0359] To a solution of 3 (0.31 g, 0.62 mmol) in DCM (5.0 mL) was
added 4-nitrobenzoyl chloride (0.47 g, 0.93 mmol) and DIPEA (0.20
mL). The reaction mixture was stirred at room temperature for 2 h.
Then the resulting mixture was concentrated and purified by a
silica gel column to afford the title compound 4 (0.32 g, 81%).
MS(ESI): m/z 648.30 (M+H).sup.+.
4-amino-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3-
,2-d]pyrimidin-2-ylamino)phenyl)benzamide (Compound 5)
[0360] To a solution of 4 (0.32 g, 0.5 mmol) in MeOH (8.0 mL) was
added 10% Pd/C (120 mg) and protected by a balloon of H.sub.2. The
reaction mixture was stirred at 25.degree. C. for 12 h. Then the
resulting mixture was filtered through a pad of celite. The crude
product was purified by a silica gel column to afford the title
compound 5 (0.25 g, 80%). MS(ESI): m/z 618.24 (M+H).sup.+.
(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrr-
olo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-2-ylamino)phenyl)benzamide
(Compound 6)
[0361] To a solution of 5 (0.25 g, 0.4 mmol) in CH.sub.3CN (8.0 mL)
was added (E)-4-bromobut-2-enoyl chloride (0.10 g, 0.6 mmol) and
DIPEA (0.12 mL). The reaction mixture was stirred at 0.degree. C.
for 0.5 h. Then 1 mL of 2.0 M dimethylamine (in THF) was added. The
resulting mixture was concentrated and purified by a silica gel
column to afford the title compound 6 (0.12 g, 42%). MS(ESI): m/z
729.11 (M+H).sup.+.
(E)-N-(4-(5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-ylamino)ph-
enyl)-3-(4-(dimethylamino)but-2-enamido)benzamide (Compound 7)
[0362] To a solution of 6 (100 mg, 0.13 mmol) in dioxane (4.0 mL)
was IM NaOH (1 mL). The reaction mixture was stirred at room
temperature for 2 h. Then resulting mixture was concentrated and
purified by a silica gel column to afford the title compound 7
(18.4 mg). MS m/z 589.18 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.00 (s, 1H), 10.69 (s, 1H), 10.13 (s, 1H),
9.73 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 8.37 (s, 2H), 7.96 (d,
J=7.8 Hz, 2H), 7.80 (d, J=7.8 Hz, 2H), 7.55-7.43 (m, 2H), 7.42 (s,
1H), 7.28-7.00 (m, 2H), 6.81-6.77 (m, 1H), 6.48 (d, J=15.2 Hz, 1H),
3.86 (d, J=15.2 Hz, 2H), 2.71 (s, 6H).
Example 2. Synthesis of Compound MFH-2-25-1
##STR00253## ##STR00254## ##STR00255##
[0363] 5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine
(MFH-2-6-1)
[0364] A mixture of 5-nitro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.84
mmol) and benzenesulfonyl chloride (812 mg, 4.6 mmol) in pyridine
(3 mL) was refluxed for 6 hours. Then the reaction mixture was
concentrated under reduced pressure, and the residue was purified
by silica gel (PE/EA=0-50%) to obtain MFH-2-6-1 (530 mg, yield
95%). LCMS (m/z): 304 [M+H].sup.+.
1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (MFH-2-7-1)
[0365] A mixture of MFH-2-6-1 (530 mg, 1.75 mmol) and 10% Pd/C (50
mg) in MeOH (20 mL) was stirred overnight at room temperature with
an H.sub.2 balloon. The mixture was filtered through CELITE, and
solvent was removed to give MFH-2-7-1 (230 mg, yield 48%). LCMS
(m/z): 274 [M+H].sup.+.
2-chloro-N-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]-
pyrimidin-4-amine (MFH-2-8-1)
[0366] A solution of MFH-2-7-1 (230 mg, 0.84 mmol),
2,4-dichlorothieno[3,2-d]pyrimidine (173 mg, 0.84 mmol) and DIEA
(163 mg, 1.26 mmol) in NMP (1 mL) was stirred at 100.degree. C. for
10 hours. The mixture was then extracted with chloroform and
iso-propanol (4:1). The organic phase was washed with brine (50
mL.times.2) and dried over Na.sub.2SO.sub.4. The removal of the
solvent to provide the residue which was purified by silica gel
(MeOH/DCM=0-20%) to give MFH-2-8-1 (259 mg, yield 70%). LCMS (m/z):
442 [M+H].sup.+.
tert-butyl3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-ylamino)thie-
no[3,2-d]pyrimidin-2-ylamino)phenylcarbamate (MFH-2-11-1)
[0367] A mixture of MFH-2-8-1 (259 mg, 0.57 mmol), tert-butyl
3-aminophenylcarbamate (147 mg, 0.7 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (48 mg, 0.1
mmol), K.sub.2CO.sub.3 (118 mg, 0.86 mmol), and Pd.sub.2(dba).sub.3
(91 mg, 0.1 mmol) in tert-Butanol (8 mL) was refluxed for 5 hours
under N.sub.2 atmosphere. After cooling down to room temperature,
the reaction mixture was diluted with water (20 mL) and extracted
with chloroform and iso-propanol (4:1). The organic phase was
washed with brine (50 mL.times.2), dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (MeOH/DCM, 0-20%) to
give MFH-2-11-1 (170 mg, yield 49%). LCMS (m/z): 614
[M+H].sup.+.
N2-(3-aminophenyl)-N4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)th-
ieno[3,2-d]pyrimidine-2,4-diamine (MFH-2-14-1)
[0368] To a mixture of compound MFH-2-11-1 (170 mg, 0.28 mmol) in
methanol (5 mL) was added 4 N HCl/dioxane (6 mL) and the resulted
solution was stirred for 3 hours. The mixture was concentrated
under reduced pressure to provide the crude which was directly used
in the next step. LCMS (m/z): 514 [M+H].sup.+.
4-nitro-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-ylamino)thi-
eno[3,2-d]pyrimidin-2-ylamino)phenyl)benzamide (MFH-2-16-1)
[0369] A mixture of MFH-2-14-1 (140 mg, 0.27 mmol) and
4-nitrobenzoyl chloride (61 mg, 0.33 mmol) in pyridine (2 mL) was
refluxed overnight. Then the reaction mixture was concentrated
under reduced pressure, and the residue was directly used in the
next step. LCMS (m/z): 663 [M+H].sup.+.
4-amino-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-ylamino)thi-
eno[3,2-d]pyrimidin-2-ylamino)phenyl)benzamide (MFH-2-20-1)
[0370] To a solution of MFH-2-16-1 (179 mg, 0.27 mmol) in ethyl
acetate and methanol (1:1) were added Tin(II) chloride dehydrate
(183 mg, 0.81 mmol) and cone. HCl (0.1 mL). After stirring for 3
hours at 80.degree. C., the reaction mixture was diluted with
chloroform and iso-propanol (4:1), neutralized with saturated
NaHCO.sub.3, and filtered. The filtrate was extracted with
chloroform and iso-propanol (4:1) and concentrated under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (MeOH/DCM=0-20%) to give MFH-2-20-1 (90 mg,
yield 53%). LCMS (m/z): 633 [M+H].sup.+.
(E)-4-(4-bromobut-2-enamido)-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]-
pyridin-5-ylamino)thieno[3,2-d]pyrimidin-2-ylamino)phenyl)benzamide
(MFH-2-23-1)
[0371] A solution of (E)-4-bromobut-2-enoic acid (12 mg, 0.07 mmol)
in SOCl.sub.2 (0.2 mL) was stirred at 70.degree. C. for 1 hour
under N.sub.2 atmosphere. The mixture was cooled to room
temperature and then was concentrated under reduced pressure. The
residue was diluted with dichloromethane, and the resulted solution
was added dropwise to a solution of MFH-2-20-1 (30 mg, 0.05 mmol)
and DIPEA (0.2 mL) in CH.sub.3CN (2 mL) at 0.degree. C. After
stirring for 1 hour at 0.degree. C., a solution of dimethylamine in
THF (2 mol/L, 0.05 ml, 0.1 mmol) was added, and the reaction
mixture was stirred at room temperature for 1 hour. The removal of
the solvent under reduced pressure provided the residue which was
purified by HPLC (MeOH/H.sub.2O, 0.05% TFA) to obtain MFH-2-23-1
(30 mg, yield 86%). LCMS (m/z): 744 [M+H].sup.+.
(E)-N-(3-(4-(1H-pyrrolo[2,3-b]pyridin-5-ylamino)thieno[3,2-d]pyrimidin-2-y-
lamino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide
(MFH-2-25-1)
[0372] A solution of MFH-2-23-1 (30 mg, 0.04 mmol) in 1 M NaOH (5
ml) and dioxane (5 mL) was stirred at room temperature for 2 hours.
The solution was then neutralized (1 M HCl) and concentrated under
reduced pressure. The residue was purified by prep-HPLC
(MeOH/H.sub.2O, 0.05% TFA) to obtain MFH-2-25-1 (off-white solid,
6.8 mg, yield 28%). LCMS (m/z): 604 [M+H]; .sup.1H NMR (500 MHz,
DMSO-d6) .delta. 11.78 (s, 1H), 10.77 (s, 1H), 10.64 (s, 1H), 10.32
(s, 1H), 10.22 (s, 1H), 10.05 (s, 1H), 8.37 (s, 1H), 8.27 (s, 2H),
7.93 (t, J=10.6 Hz, 3H), 7.80 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.3 Hz,
2H), 7.40 (s, 1H), 7.31 (d, J=5.2 Hz, 1H), 7.19 (s, 1H), 6.84-6.73
(m, 1H), 6.50 (d, J=15.3 Hz, 1H), 6.46 (s, 1H), 3.18 (d, 2H) 2.81
(s, 6H).
Example 3. Synthesis of Compound MFH-2-40-1
##STR00256## ##STR00257##
[0373]
4-(1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl)morpholine
(MFH-2-29-1)
[0374] To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (300
mg, 1.46 mmol) and DIPEA (227 mg, 1.76 mmol) in DCM (5 mL) was
added 4-(piperidin-4-yl)morpholine (274 mg, 1.61 mmol) in DCM (3
mL) dropwise at room temperature. The mixture was stirred at room
temperature for 3 hours and then was concentrated under reduced
pressure. The residue was purified by silica gel
(NH3/MeOH(1.75N)/DCM=0-20%) to obtain MFH-2-29-1 (496 mg, yield
100%). LCMS (m/z): 339 [M+H].sup.+.
tert-butyl3-(4-(4-morpholinopiperidin-1-yl)thieno[3,2-d]pyrimidin-2-ylamin-
o)phenylcarbamate (MFH-2-32-1)
[0375] A solution of MFH-2-29-1 (496 mg, 1.46 mmol), tert-butyl
3-aminophenylcarbamate (335 mg, 1.61 mmol),
2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (105 mg, 0.22
mmol), K.sub.2CO.sub.3 (243 mg, 1.76 mmol), and Pd.sub.2(dba).sub.3
(201 mg, 0.22 mmol) in tert-Butanol (10 mL) was refluxed for 5
hours under N.sub.2 atmosphere. The mixture was cooled to room
temperature, diluted with water (20 mL), and extracted with
chloroform and iso-propanol (4:1). The organic phase was washed
with brine (50 mL.times.2), dried over Na.sub.2SO.sub.4, and
filtered, and the solvent was removed under reduced pressure. The
residue was purified by silica gel column chromatography
(NH.sub.3/MeOH (1.75N)/DCM 20%) to give MFH-2-32-1 (700 mg, yield
94%). LCMS (m/z): 511 [M+H].sup.+.
N1-(4-(4-morpholinopiperidin-1-yl)thieno[3,2-d]pyrimidin-2-yl)benzene-1,3--
diamine (MFH-2-33-1)
[0376] To a mixture of compound MFH-2-32-1 (700 mg, 1.37 mmol) in
methanol (6 mL) was added 4 N HCl/dioxane (12 mL), and the reaction
was stirred for 3 hours at room temperature. The solution was
concentrated under reduced pressure, and the residue was used
directly in the next step. LCMS (m/z): 411 [M+H].sup.+.
N-(3-(4-(4-morpholinopiperidin-1-yl)thieno[3,2-d]pyrimidin-2-ylamino)pheny-
l)-4-nitrobenzamide (MFH-2-35-1)
[0377] A mixture of MFH-2-33-1 (570 mg, 1.39 mmol), 4-nitrobenzoyl
chloride (322 mg, 1.74 mmol), and pyridine (3 mL) was refluxed
overnight. Then the reaction mixture was concentrated under reduced
pressure, and the residue was directly used in the next step. LCMS
(m/z): 560 [M+H].sup.+.
4-amino-N-(3-(4-(4-morpholinopiperidin-1-yl)thieno[3,2-d]pyrimidin-2-ylami-
no)phenyl)benzamide (MFH-2-38-1)
[0378] To a solution of MFH-2-35-1 (430 mg, 0.77 mmol) in ethyl
acetate and methanol (1:1) were added Tin(II) chloride dehydrate
(522 mg, 2.31 mmol) and cone. HCl (0.2 mL). After stirring for 3
hours at 80.degree. C., the reaction mixture was diluted with
chloroform and iso-propanol (4:1) and neutralized with saturated
NaHCO.sub.3. The solution was then filtered, and the filtrate was
extracted with chloroform and iso-propanol (4:1). Concentration
under reduced pressure provided the crude which was purified by
silica gel column chromatography (NH.sub.3/MeOH (1.75N)/DCM=0-20%)
to give MFH-2-38-1 (200 mg, yield 49%). LCMS (m/z): 530
[M+H].sup.+.
4-acrylamido-N-(3-(4-(4-morpholinopiperidin-1-yl)thieno[3,2-d]pyrimidin-2--
ylamino)phenyl)benzamide (MFH-2-40-1)
[0379] To a solution of MFH-2-38-1 (50 mg, 0.09 mmol) in sat.
NaHCO.sub.3 (3 mL) and THF (3 mL) was added acryloyl chloride (11
mg, 0.12 mmol) in DCM (0.5 mL) dropwise at 0.degree. C. The mixture
was stirred for 1 hour and then was concentrated under reduced
pressure. The residue was purified by prep-HPLC (MeOH/H.sub.2O,
0.05% TFA) to obtain MFH-2-40-1 (off-white solid, 14 mg, yield
25%). LCMS (m/z): 584 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 10.47 (s, 1H), 10.13 (s, 1H), 9.95 (s, 1H), 9.46 (s, 1H),
8.32 (s, 1H), 8.17 (d, J=5.4 Hz, 1H), 7.98 (d, J=8.7 Hz, 2H), 7.82
(d, J=8.8 Hz, 2H), 7.39 (d, J=7.3 Hz, 1H), 7.28 (s, 1H), 7.26 (d,
J=1.0 Hz, 1H), 7.24 (s, 1H), 6.49 (dd, J=17.0, 10.2 Hz, 1H), 6.32
(dd, J=17.0, 1.9 Hz, 1H), 5.82 (dd, J=10.1, 1.9 Hz, 1H), 3.97 (s,
4H), 3.08 (s, 4H), 3.03 (s, 1H), 2.21 (d, J=10.8 Hz, 4H), 1.71 (d,
J=9.1 Hz, 4H).
Example 4. Synthesis of Compound MFH-2-44-1
##STR00258## ##STR00259##
[0380] 5-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine
(MFH-2-10-1)
[0381] A mixture of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (800 mg,
5.4 mmol) and benzenesulfonyl chloride (1.9 g, 10.8 mmol) in
pyridine (8 mL) was refluxed overnight. Then the reaction mixture
was concentrated under reduced pressure, and the residue was
purified by silica gel (PE/EA=0-50%) to obtain MFH-2-10-1 (646 mg,
yield 42%). LCMS (m/z): 289 [M+H].sup.+.
1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (MFH-2-13-1)
[0382] To a solution of MFH-2-10-1 (646 mg, 2.25 mmol) in DCM (20
mL) was added boron trichloride in hexane (1 mol/L, 22.5 ml, 22.5
mmol) dropwise at -15.degree. C. The mixture was warmed to room
temperature and the mixture was stirred overnight. After
completion, water (50 ml) was added at 0.degree. C. and the aqueous
layer was extracted with DCM. The combined organic layers was
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography (PE/EA=0-50%) to give MFH-2-13-1 (353 mg, yield
57%). LCMS (m/z): 275 [M+H].sup.+.
2-chloro-4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy)thieno[3,2-
-d]pyrimidine (MFH-2-18-1)
[0383] A mixture of MFH-2-13-1 (353 mg, 1.29 mmol),
2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1.00 mmol), and DIEA
(259 mg, 2.00 mmol) in NMP (2 mL) was stirred at 130.degree. C. for
10 hours. The residue was extracted with chloroform and
iso-propanol (4:1). The organic phase was washed with brine (50
mL.times.2) and dried over Na.sub.2SO.sub.4. After removal of the
solvent, the residue was purified by silica gel (MeOH/DCM=0-20%) to
obtain MFH-2-18-1 (290 mg, yield 51%). LCMS (m/z): 443
[M+H].sup.+.
tert-butyl3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy)thieno-
[3,2-d]pyrimidin-2-ylamino)phenylcarbamate (MFH-2-21-1)
[0384] A mixture of MFH-2-18-1 (290 mg, 0.66 mmol), tert-butyl
3-aminophenylcarbamate (164 mg, 0.79 mmol),
2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (63 mg, 0.13
mmol), K.sub.2CO.sub.3 (109 mg, 0.79 mmol), and Pd.sub.2(dba).sub.3
(120 mg, 0.13 mmol) in tert-Butanol (8 mL). The mixture was stirred
at reflux for 5 hours under N.sub.2 atmosphere. The mixture was
cooled to room temperature and diluted with water (20 ml) and
extracted with chloroform and iso-propanol (4:1). The organic phase
was washed with brine (50 mL.times.2). The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated to give the crude
which was purified by silica gel column chromatography
(MeOH/DCM=0-20%) to give MFH-2-21-1 (400 mg, yield 99%). LCMS
(m/z): 615 [M+H].sup.+.
N1-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy)thieno[3,2-d]py-
rimidin-2-yl)benzene-1,3-diamine (MFH-2-22-1)
[0385] To a solution of MFH-2-21-1 (400 mg, 0.65 mmol) in methanol
(5 mL) was added 4 N HCl/dioxane (12 mL). The solution was then
stirred for 3 hours at room temperature, and the solvent was
removed under reduced pressure to provide a crude which was
directly used in the next step. LCMS (m/z): 515 [M+H].sup.+.
4-nitro-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy)thien-
o[3,2-d]pyrimidin-2-ylamino)phenyl)benzamide (MFH-2-37-1)
[0386] The mixture of MFH-2-22-1 (200.0 mg, 0.39 mmol) and
4-nitrobenzoyl chloride (72.0 mg, 0.39 mmol) in pyridine (3.0 mL)
was refluxed overnight. Then the reaction mixture was concentrated
under reduced pressure, and the residue was directly used in the
next step. LCMS (m/z): 664 [M+H].sup.+.
4-amino-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy)thien-
o[3,2-d]pyrimidin-2-ylamino)phenyl)benzamide (MFH-2-39-1)
[0387] To a solution of MFH-2-37-1 (258 mg, 0.39 mmol) in ethyl
acetate and methanol (1:1) was added Tin(II) chloride dehydrate
(271 mg, 1.2 mmol). After stirring for 3 hours at 80.degree. C.,
the reaction mixture was diluted with chloroform and iso-propanol
(4:1) and neutralized with saturated NaHCO.sub.3. The mixture was
then filtered, and the filtrate was extracted with chloroform and
iso-propanol (4:1). The solvent was then removed under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (MeOH/DCM=0-20%) to give MFH-2-39-1 (120 mg,
yield 48%). LCMS (m/z): 634 [M+H].sup.+.
4-acrylamido-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-
thieno[3,2-d]pyrimidin-2-ylamino)phenyl)benzamide (MFH-2-43-1)
[0388] To a solution of MFH-2-39-1 (25 mg, 0.04 mmol) and DIPEA
(0.2 mL) in CH.sub.3CN (2 mL) was added acryloyl chloride (5 mg,
0.05 mmol) in DCM (0.2 mL) dropwise. The mixture was then stirred
at 0.degree. C. for 1 hour. The solution was then concentrated
under reduced pressure, and the residue was purified by prep-HPLC
(MeOH/H.sub.2O, 0.05% TFA) to provide MFH-2-43-1 (22 mg, yield
80%). LCMS (m/z): 688 [M+H].sup.+.
N-(3-(4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)thieno[3,2-d]pyrimidin-2-ylamino-
)phenyl)-4-acrylamidobenzamide (MFH-2-44-1)
[0389] To a solution of MFH-2-43-1 (22 mg, 0.03 mmol) in IM NaOH (3
ml) and dioxane (3 mL) was stirred at room temperature for 2 hours.
The solution was neutralized (1 M HCl) and concentrated under
reduced pressure. The residue was purified by prep-HPLC
(MeOH/H.sub.2O, 0.05% TFA) to obtain MFH-2-44-1 (3.8 mg, yield
22%). LCMS (m/z): 548 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 11.82 (s, 1H), 10.44 (d, J=10.0 Hz, 1H), 10.05 (s, 1H),
9.44 (s, 1H), 8.30 (d, J=5.4 Hz, 1H), 8.26 (d, J=2.5 Hz, 1H), 8.03
(t, J=4.9 Hz, 1H), 7.99 (d, J=7.0 Hz, 1H), 7.97-7.91 (m, 2H), 7.80
(d, J=8.8 Hz, 2H), 7.61-7.55 (m, 1H), 7.38 (dd, J=13.7, 6.8 Hz,
2H), 7.28-7.19 (m, 1H), 6.93 (t, J=8.1 Hz, 1H), 6.51 (dd, J=3.4,
1.8 Hz, 1H), 6.49-6.43 (m, 1H), 6.31 (dd, J=17.0, 1.9 Hz, 1H), 5.81
(dd, J=10.1, 1.9 Hz, 1H).
Example 5. Synthesis of Compound MFH-2-60-1
##STR00260## ##STR00261##
[0390]
2-chloro-4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3-
,2-d]pyrimidine (MFH-2-48-1)
[0391] A mixture of 2,4-dichlorofuro[3,2-d]pyrimidine (300 mg, 1.59
mmol),
1-(phenylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyr-
rolo[2,3-b]pyridine (640 mg, 1.67 mmol), Sat. Na.sub.2CO.sub.3 (3
mL), and Pd(PPh.sub.3).sub.2Cl.sub.2 (167 mg, 0.24 mmol) in dioxane
(6 mL) was stirred at 80.degree. C. for 2 hours under N.sub.2
atmosphere. The mixture was then cooled to room temperature and
diluted with water (30 mL). The residue was extracted with
chloroform and iso-propanol (4:1), and the organic phase was washed
with brine (50 mL.times.2) and dried with Na.sub.2SO.sub.4. The
solvent was then removed, and the residue was purified by silica
gel (MeOH/DCM=0-10%) to obtain MFH-2-48-1 (520 mg, yield 79%). LCMS
(m/z): 411 [M+H].sup.+.
tert-butyl3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2--
d]pyrimidin-2-ylamino)phenylcarbamate (MFH-2-49-1)
[0392] A mixture of MFH-2-48-1 (520 mg, 1.27 mmol), tert-butyl
3-aminophenylcarbamate (277 mg, 1.33 mmol),
2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (91 mg, 0.19
mmol) K.sub.2CO.sub.3 (210 mg, 1.52 mmol), and Pd.sub.2(dba).sub.3
(174 mg, 0.19 mmol) in tert-Butanol (8 mL) was refluxed for 5 hours
under N.sub.2 atmosphere. The mixture was cooled to room
temperature and diluted with water (20 mL) and extracted with
chloroform and iso-propanol (4:1). The organic phase was washed
with brine (50 mL.times.2) and dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (MeOH/DCM=0-20%) to
give MFH-2-49-1 (310 mg, yield 42%). LCMS (m/z): 583
[M+H].sup.+.
N1-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-d]pyrimid-
in-2-yl)benzene-1,3-diamine (MFH-2-52-1)
[0393] To a mixture of compound MFH-2-49-1 (310 mg, 0.53 mmol) in
methanol (5 mL) was added 4 N HCl/dioxane (8 mL). The mixture was
stirred for 3 hours at room temperature and then was concentrated
under reduced pressure to give a crude which was used directly in
the next step. LCMS (m/z): 483 [M+H].sup.+.
4-nitro-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-
-d]pyrimidin-2-ylamino)phenyl)benzamide (MFH-2-54-1)
[0394] A mixture of MFH-2-52-1 (220 mg, 0.46 mmol), 4-nitrobenzoyl
chloride (101 mg, 0.55 mmol), and pyridine (2 mL) was refluxed for
overnight. Then the reaction mixture was concentrated under reduced
pressure, and the residue was used directly in the next step. LCMS
(m/z): 632 [M+H].sup.+.
4-amino-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-
-d]pyrimidin-2-ylamino)phenyl)benzamide (MFH-2-57-1)
[0395] To a solution of MFH-2-54-1 (290 mg, 0.46 mmol) in ethyl
acetate and methanol (1:1) were added tin(II) chloride dehydrate
(312 mg, 1.38 mmol) and cone. HCl (0.1 mL). After stirring for 3
hours at 80.degree. C., the reaction mixture was diluted with
chloroform and iso-propanol (4:1), neutralized with saturated
NaHCO.sub.3, and filtered. The filtrate was extracted with
chloroform and iso-propanol (4:1) and concentrated under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (MeOH/DCM=0-20%) to give MFH-2-57-1 (140 mg,
yield 51%). LCMS (m/z): 602 [M+H].sup.+.
4-acrylamido-N-(3-(4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)fur-
o[3,2-d]pyrimidin-2-ylamino)phenyl)benzamide (MFH-2-59-1)
[0396] To a solution of MFH-2-57-1 (40 mg, 0.07 mmol) and DIPEA
(0.2 mL) in CH.sub.3CN (2 mL) was added acryloyl chloride (8 mg,
0.09 mmol) in DCM (0.2 mL) dropwise. The mixture was then stirred
at 0.degree. C. for 1 hour and then was concentrated under reduced
pressure. The residue was purified by prep-HPLC (C18 column,
MeOH/H.sub.2O, containing 0.05% TFA) to obtain MFH-2-59-1
(off-white solid, 40 mg, yield 87%). LCMS (m/z): 656
[M+H].sup.+.
N-(3-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)furo[3,2-d]pyrimidin-2-ylamino)phen-
yl)-4-acrylamidobenzamide (MFH-2-60-1)
[0397] To a solution of MFH-2-59-1 (40 mg, 0.06 mmol) in 1 M NaOH
(4 mL) and dioxane (4 mL) was stirred at room temperature for 2
hours. The reaction solution was neutralized (1 M HCl),
concentrated under reduced pressure. The residue was purified by
prep-HPLC (C.sub.18 column, MeOH/H.sub.2O, containing 0.05% TFA) to
obtain MFH-2-60-1 (off-white solid, 6.8 mg, yield 22%), LCMS (m/z):
516 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6) .delta. 12.02 (s,
1H), 10.44 (s, 1H), 10.14 (d, J=15.8 Hz, 1H), 9.61 (s, 1H), 9.35
(s, 1H), 9.09 (d, J=1.7 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H), 8.43 (s,
1H), 7.99 (dd, J=18.6, 8.6 Hz, 2H), 7.82 (t, J=12.7 Hz, 2H),
7.62-7.59 (m, 1H), 7.58-7.55 (m, 1H), 7.33-7.26 (m, 2H), 7.06 (d,
J=2.2 Hz, 1H), 6.62 (dd, J=3.3, 1.7 Hz, 1H), 6.49 (dd, J=16.9, 10.1
Hz, 1H), 6.33 (dd, J=17.0, 1.8 Hz, 1H), 5.83 (dd, J=10.1, 1.8 Hz,
1H).
Example 6. Synthesis of Compound FMF-3-27-1
##STR00262##
[0398]
N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-2-yl-
)amino)phenyl)-4-(2-chloroacetamido)benzamide
[0399]
N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-2-yl-
)amino)phenyl)-4-aminobenzamide (30 mg, 0.06 mmol) was dissolved in
5 mL THF and 5 mL saturated aqueous solution of NaHCO.sub.3. The
reaction mixture was cooled to 0.degree. C. A 1.3 mM solution of
2-chloroacetyl chloride in THF was added drop-wise until the
reaction was complete as analyzed by LC/MS. The reaction mixture
was diluted with water and extracted with dichloromethane
(3.times.20 mL), dried over MgSO.sub.4, concentrated, and purified
by HPLC to give the title compound (10 mg, 0.02 mmol) as a TFA
salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.04 (s, 1H),
10.60 (s, 1H), 10.17 (s, 1H), 9.77 (s, 1H), 9.07 (d, J=2.0 Hz, 1H),
8.82 (d, J=2.0 Hz, 1H), 8.48-8.29 (m, 2H), 8.01 (d, J=8.7 Hz, 2H),
7.75 (d, J=8.7 Hz, 2H), 7.66-7.58 (m, 2H), 7.47 (d, J=5.5 Hz, 1H),
7.34 (d, J=8.4 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 6.64 (dd, J=3.4,
1.8 Hz, 1H), 4.32 (s, 2H). MS (ESI) m/z: 555 Da (M+H).sup.+.
Biological Evaluation
Example 7. Kinase Assay
[0400] PIP4K in vitro kinase assay was carried out as described in
Rameh et al (Nature, 1997). Briefly, 0.1 ug of GST-PI5P4Ka or 0.4
ug of GST-PI5P4Ka resuspended in 70 uL of kinase buffer containing
20 mM HEPES pH 7.4, 100 mM NaCl, 0.5 mM EGTA was stabilized at room
temperature for 10 minutes and incubated with 1 uM of DMSO or
indicated compound for 30 minutes. Then the kinase reaction was
carried out in a total volume of 100 ul for 10 minutes by adding 20
uL of lipid substrates (4 ug of phosphatidylserine and 2 ug of
PI5P) in buffer containing 30 mM HEPES pH7.4 and 1 mM EGTA, and 10
uL of ATP mix (500 uM non-radiolabeled ATP, 10 uCi
[g-.sup.32P]-ATP, 65 mM HEPES pH7.4 and 100 mM MgCl.sub.2). The
reaction was terminated by adding 50 uL of HCl. Phosphoinositides
were extracted by adding 100 uL methanol/chloroform (1:1, vol:vol)
mix and subjected to thin layer chromatography separation using
heat-activated 1% potassium oxalate-coated silica gel 60 plates
(EMD Chemicals Inc., Billerica, Mass., USA) and a 1-propanol/2 M
acetic acid (65:35, vol:vol) solvent system. The radiolabeled
PI(4,5)P.sub.2 was quantified with a Phosphorimager (Molecular
Dynamics, STORM840, GE Healthcare, Waukesha, Wis., USA).
Example 8. Cell Proliferation Assay
[0401] To determine cell proliferation, cells were plated at
2.times.10 cells per well of 96-well plate. Cells were incubated
and assayed at indicated times using Cell Titer-Glo Luminescent
Cell Viability assay (Promega). Cells were allowed to equilibrate
to room temperature for 15 minutes, then an equal volume of the
Cell Titer-Glo reagent was added to wells and incubated for 15
minutes on an orbital shaker. Luminescence was recorded according
to the manufacturer's protocol.
EQUIVALENTS AND SCOPE
[0402] 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.
[0403] 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.
[0404] 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.
[0405] 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.
Sequence CWU 1
1
91346PRTHomo sapiens 1Met Ala Leu Asp Val Lys Ser Arg Ala Lys Arg
Tyr Glu Lys Leu Asp 1 5 10 15 Phe Leu Gly Glu Gly Gln Phe Ala Thr
Val Tyr Lys Ala Arg Asp Lys 20 25 30 Asn Thr Asn Gln Ile Val Ala
Ile Lys Lys Ile Lys Leu Gly His Arg 35 40 45 Ser Glu Ala Lys Asp
Gly Ile Asn Arg Thr Ala Leu Arg Glu Ile Lys 50 55 60 Leu Leu Gln
Glu Leu Ser His Pro Asn Ile Ile Gly Leu Leu Asp Ala 65 70 75 80 Phe
Gly His Lys Ser Asn Ile Ser Leu Val Phe Asp Phe Met Glu Thr 85 90
95 Asp Leu Glu Val Ile Ile Lys Asp Asn Ser Leu Val Leu Thr Pro Ser
100 105 110 His Ile Lys Ala Tyr Met Leu Met Thr Leu Gln Gly Leu Glu
Tyr Leu 115 120 125 His Gln His Trp Ile Leu His Arg Asp Leu Lys Pro
Asn Asn Leu Leu 130 135 140 Leu Asp Glu Asn Gly Val Leu Lys Leu Ala
Asp Phe Gly Leu Ala Lys 145 150 155 160 Ser Phe Gly Ser Pro Asn Arg
Ala Tyr Thr His Gln Val Val Thr Arg 165 170 175 Trp Tyr Arg Ala Pro
Glu Leu Leu Phe Gly Ala Arg Met Tyr Gly Val 180 185 190 Gly Val Asp
Met Trp Ala Val Gly Cys Ile Leu Ala Glu Leu Leu Leu 195 200 205 Arg
Val Pro Phe Leu Pro Gly Asp Ser Asp Leu Asp Gln Leu Thr Arg 210 215
220 Ile Phe Glu Thr Leu Gly Thr Pro Thr Glu Glu Gln Trp Pro Asp Met
225 230 235 240 Cys Ser Leu Pro Asp Tyr Val Thr Phe Lys Ser Phe Pro
Gly Ile Pro 245 250 255 Leu His His Ile Phe Ser Ala Ala Gly Asp Asp
Leu Leu Asp Leu Ile 260 265 270 Gln Gly Leu Phe Leu Phe Asn Pro Cys
Ala Arg Ile Thr Ala Thr Gln 275 280 285 Ala Leu Lys Met Lys Tyr Phe
Ser Asn Arg Pro Gly Pro Thr Pro Gly 290 295 300 Cys Gln Leu Pro Arg
Pro Asn Cys Pro Val Glu Thr Leu Lys Glu Gln 305 310 315 320 Ser Asn
Pro Ala Leu Ala Ile Lys Arg Lys Arg Thr Glu Ala Leu Glu 325 330 335
Gln Gly Gly Leu Pro Lys Lys Leu Ile Phe 340 345 21490PRTHomo
sapiens 2Met Pro Asn Ser Glu Arg His Gly Gly Lys Lys Asp Gly Ser
Gly Gly 1 5 10 15 Ala Ser Gly Thr Leu Gln Pro Ser Ser Gly Gly Gly
Ser Ser Asn Ser 20 25 30 Arg Glu Arg His Arg Leu Val Ser Lys His
Lys Arg His Lys Ser Lys 35 40 45 His Ser Lys Asp Met Gly Leu Val
Thr Pro Glu Ala Ala Ser Leu Gly 50 55 60 Thr Val Ile Lys Pro Leu
Val Glu Tyr Asp Asp Ile Ser Ser Asp Ser 65 70 75 80 Asp Thr Phe Ser
Asp Asp Met Ala Phe Lys Leu Asp Arg Arg Glu Asn 85 90 95 Asp Glu
Arg Arg Gly Ser Asp Arg Ser Asp Arg Leu His Lys His Arg 100 105 110
His His Gln His Arg Arg Ser Arg Asp Leu Leu Lys Ala Lys Gln Thr 115
120 125 Glu Lys Glu Lys Ser Gln Glu Val Ser Ser Lys Ser Gly Ser Met
Lys 130 135 140 Asp Arg Ile Ser Gly Ser Ser Lys Arg Ser Asn Glu Glu
Thr Asp Asp 145 150 155 160 Tyr Gly Lys Ala Gln Val Ala Lys Ser Ser
Ser Lys Glu Ser Arg Ser 165 170 175 Ser Lys Leu His Lys Glu Lys Thr
Arg Lys Glu Arg Glu Leu Lys Ser 180 185 190 Gly His Lys Asp Arg Ser
Lys Ser His Arg Lys Arg Glu Thr Pro Lys 195 200 205 Ser Tyr Lys Thr
Val Asp Ser Pro Lys Arg Arg Ser Arg Ser Pro His 210 215 220 Arg Lys
Trp Ser Asp Ser Ser Lys Gln Asp Asp Ser Pro Ser Gly Ala 225 230 235
240 Ser Tyr Gly Gln Asp Tyr Asp Leu Ser Pro Ser Arg Ser His Thr Ser
245 250 255 Ser Asn Tyr Asp Ser Tyr Lys Lys Ser Pro Gly Ser Thr Ser
Arg Arg 260 265 270 Gln Ser Val Ser Pro Pro Tyr Lys Glu Pro Ser Ala
Tyr Gln Ser Ser 275 280 285 Thr Arg Ser Pro Ser Pro Tyr Ser Arg Arg
Gln Arg Ser Val Ser Pro 290 295 300 Tyr Ser Arg Arg Arg Ser Ser Ser
Tyr Glu Arg Ser Gly Ser Tyr Ser 305 310 315 320 Gly Arg Ser Pro Ser
Pro Tyr Gly Arg Arg Arg Ser Ser Ser Pro Phe 325 330 335 Leu Ser Lys
Arg Ser Leu Ser Arg Ser Pro Leu Pro Ser Arg Lys Ser 340 345 350 Met
Lys Ser Arg Ser Arg Ser Pro Ala Tyr Ser Arg His Ser Ser Ser 355 360
365 His Ser Lys Lys Lys Arg Ser Ser Ser Arg Ser Arg His Ser Ser Ile
370 375 380 Ser Pro Val Arg Leu Pro Leu Asn Ser Ser Leu Gly Ala Glu
Leu Ser 385 390 395 400 Arg Lys Lys Lys Glu Arg Ala Ala Ala Ala Ala
Ala Ala Lys Met Asp 405 410 415 Gly Lys Glu Ser Lys Gly Ser Pro Val
Phe Leu Pro Arg Lys Glu Asn 420 425 430 Ser Ser Val Glu Ala Lys Asp
Ser Gly Leu Glu Ser Lys Lys Leu Pro 435 440 445 Arg Ser Val Lys Leu
Glu Lys Ser Ala Pro Asp Thr Glu Leu Val Asn 450 455 460 Val Thr His
Leu Asn Thr Glu Val Lys Asn Ser Ser Asp Thr Gly Lys 465 470 475 480
Val Lys Leu Asp Glu Asn Ser Glu Lys His Leu Val Lys Asp Leu Lys 485
490 495 Ala Gln Gly Thr Arg Asp Ser Lys Pro Ile Ala Leu Lys Glu Glu
Ile 500 505 510 Val Thr Pro Lys Glu Thr Glu Thr Ser Glu Lys Glu Thr
Pro Pro Pro 515 520 525 Leu Pro Thr Ile Ala Ser Pro Pro Pro Pro Leu
Pro Thr Thr Thr Pro 530 535 540 Pro Pro Gln Thr Pro Pro Leu Pro Pro
Leu Pro Pro Ile Pro Ala Leu 545 550 555 560 Pro Gln Gln Pro Pro Leu
Pro Pro Ser Gln Pro Ala Phe Ser Gln Val 565 570 575 Pro Ala Ser Ser
Thr Ser Thr Leu Pro Pro Ser Thr His Ser Lys Thr 580 585 590 Ser Ala
Val Ser Ser Gln Ala Asn Ser Gln Pro Pro Val Gln Val Ser 595 600 605
Val Lys Thr Gln Val Ser Val Thr Ala Ala Ile Pro His Leu Lys Thr 610
615 620 Ser Thr Leu Pro Pro Leu Pro Leu Pro Pro Leu Leu Pro Gly Asp
Asp 625 630 635 640 Asp Met Asp Ser Pro Lys Glu Thr Leu Pro Ser Lys
Pro Val Lys Lys 645 650 655 Glu Lys Glu Gln Arg Thr Arg His Leu Leu
Thr Asp Leu Pro Leu Pro 660 665 670 Pro Glu Leu Pro Gly Gly Asp Leu
Ser Pro Pro Asp Ser Pro Glu Pro 675 680 685 Lys Ala Ile Thr Pro Pro
Gln Gln Pro Tyr Lys Lys Arg Pro Lys Ile 690 695 700 Cys Cys Pro Arg
Tyr Gly Glu Arg Arg Gln Thr Glu Ser Asp Trp Gly 705 710 715 720 Lys
Arg Cys Val Asp Lys Phe Asp Ile Ile Gly Ile Ile Gly Glu Gly 725 730
735 Thr Tyr Gly Gln Val Tyr Lys Ala Lys Asp Lys Asp Thr Gly Glu Leu
740 745 750 Val Ala Leu Lys Lys Val Arg Leu Asp Asn Glu Lys Glu Gly
Phe Pro 755 760 765 Ile Thr Ala Ile Arg Glu Ile Lys Ile Leu Arg Gln
Leu Ile His Arg 770 775 780 Ser Val Val Asn Met Lys Glu Ile Val Thr
Asp Lys Gln Asp Ala Leu 785 790 795 800 Asp Phe Lys Lys Asp Lys Gly
Ala Phe Tyr Leu Val Phe Glu Tyr Met 805 810 815 Asp His Asp Leu Met
Gly Leu Leu Glu Ser Gly Leu Val His Phe Ser 820 825 830 Glu Asp His
Ile Lys Ser Phe Met Lys Gln Leu Met Glu Gly Leu Glu 835 840 845 Tyr
Cys His Lys Lys Asn Phe Leu His Arg Asp Ile Lys Cys Ser Asn 850 855
860 Ile Leu Leu Asn Asn Ser Gly Gln Ile Lys Leu Ala Asp Phe Gly Leu
865 870 875 880 Ala Arg Leu Tyr Asn Ser Glu Glu Ser Arg Pro Tyr Thr
Asn Lys Val 885 890 895 Ile Thr Leu Trp Tyr Arg Pro Pro Glu Leu Leu
Leu Gly Glu Glu Arg 900 905 910 Tyr Thr Pro Ala Ile Asp Val Trp Ser
Cys Gly Cys Ile Leu Gly Glu 915 920 925 Leu Phe Thr Lys Lys Pro Ile
Phe Gln Ala Asn Leu Glu Leu Ala Gln 930 935 940 Leu Glu Leu Ile Ser
Arg Leu Cys Gly Ser Pro Cys Pro Ala Val Trp 945 950 955 960 Pro Asp
Val Ile Lys Leu Pro Tyr Phe Asn Thr Met Lys Pro Lys Lys 965 970 975
Gln Tyr Arg Arg Arg Leu Arg Glu Glu Phe Ser Phe Ile Pro Ser Ala 980
985 990 Ala Leu Asp Leu Leu Asp His Met Leu Thr Leu Asp Pro Ser Lys
Arg 995 1000 1005 Cys Thr Ala Glu Gln Thr Leu Gln Ser Asp Phe Leu
Lys Asp Val 1010 1015 1020 Glu Leu Ser Lys Met Ala Pro Pro Asp Leu
Pro His Trp Gln Asp 1025 1030 1035 Cys His Glu Leu Trp Ser Lys Lys
Arg Arg Arg Gln Arg Gln Ser 1040 1045 1050 Gly Val Val Val Glu Glu
Pro Pro Pro Ser Lys Thr Ser Arg Lys 1055 1060 1065 Glu Thr Thr Ser
Gly Thr Ser Thr Glu Pro Val Lys Asn Ser Ser 1070 1075 1080 Pro Ala
Pro Pro Gln Pro Ala Pro Gly Lys Val Glu Ser Gly Ala 1085 1090 1095
Gly Asp Ala Ile Gly Leu Ala Asp Ile Thr Gln Gln Leu Asn Gln 1100
1105 1110 Ser Glu Leu Ala Val Leu Leu Asn Leu Leu Gln Ser Gln Thr
Asp 1115 1120 1125 Leu Ser Ile Pro Gln Met Ala Gln Leu Leu Asn Ile
His Ser Asn 1130 1135 1140 Pro Glu Met Gln Gln Gln Leu Glu Ala Leu
Asn Gln Ser Ile Ser 1145 1150 1155 Ala Leu Thr Glu Ala Thr Ser Gln
Gln Gln Asp Ser Glu Thr Met 1160 1165 1170 Ala Pro Glu Glu Ser Leu
Lys Glu Ala Pro Ser Ala Pro Val Ile 1175 1180 1185 Leu Pro Ser Ala
Glu Gln Thr Thr Leu Glu Ala Ser Ser Thr Pro 1190 1195 1200 Ala Asp
Met Gln Asn Ile Leu Ala Val Leu Leu Ser Gln Leu Met 1205 1210 1215
Lys Thr Gln Glu Pro Ala Gly Ser Leu Glu Glu Asn Asn Ser Asp 1220
1225 1230 Lys Asn Ser Gly Pro Gln Gly Pro Arg Arg Thr Pro Thr Met
Pro 1235 1240 1245 Gln Glu Glu Ala Ala Ala Cys Pro Pro His Ile Leu
Pro Pro Glu 1250 1255 1260 Lys Arg Pro Pro Glu Pro Pro Gly Pro Pro
Pro Pro Pro Pro Pro 1265 1270 1275 Pro Pro Leu Val Glu Gly Asp Leu
Ser Ser Ala Pro Gln Glu Leu 1280 1285 1290 Asn Pro Ala Val Thr Ala
Ala Leu Leu Gln Leu Leu Ser Gln Pro 1295 1300 1305 Glu Ala Glu Pro
Pro Gly His Leu Pro His Glu His Gln Ala Leu 1310 1315 1320 Arg Pro
Met Glu Tyr Ser Thr Arg Pro Arg Pro Asn Arg Thr Tyr 1325 1330 1335
Gly Asn Thr Asp Gly Pro Glu Thr Gly Phe Ser Ala Ile Asp Thr 1340
1345 1350 Asp Glu Arg Asn Ser Gly Pro Ala Leu Thr Glu Ser Leu Val
Gln 1355 1360 1365 Thr Leu Val Lys Asn Arg Thr Phe Ser Gly Ser Leu
Ser His Leu 1370 1375 1380 Gly Glu Ser Ser Ser Tyr Gln Gly Thr Gly
Ser Val Gln Phe Pro 1385 1390 1395 Gly Asp Gln Asp Leu Arg Phe Ala
Arg Val Pro Leu Ala Leu His 1400 1405 1410 Pro Val Val Gly Gln Pro
Phe Leu Lys Ala Glu Gly Ser Ser Asn 1415 1420 1425 Ser Val Val His
Ala Glu Thr Lys Leu Gln Asn Tyr Gly Glu Leu 1430 1435 1440 Gly Pro
Gly Thr Thr Gly Ala Ser Ser Ser Gly Ala Gly Leu His 1445 1450 1455
Trp Gly Gly Pro Thr Gln Ser Ser Ala Tyr Gly Lys Leu Tyr Arg 1460
1465 1470 Gly Pro Thr Arg Val Pro Pro Arg Gly Gly Arg Gly Arg Gly
Val 1475 1480 1485 Pro Tyr 1490 31512PRTHomo sapiens 3Met Pro Ser
Ser Ser Asp Thr Ala Leu Gly Gly Gly Gly Gly Leu Ser 1 5 10 15 Trp
Ala Glu Lys Lys Leu Glu Glu Arg Arg Lys Arg Arg Arg Phe Leu 20 25
30 Ser Pro Gln Gln Pro Pro Leu Leu Leu Pro Leu Leu Gln Pro Gln Leu
35 40 45 Leu Gln Pro Pro Pro Pro Pro Pro Pro Leu Leu Phe Leu Ala
Ala Pro 50 55 60 Gly Thr Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala
Ser Ser Ser Cys 65 70 75 80 Phe Ser Pro Gly Pro Pro Leu Glu Val Lys
Arg Leu Ala Arg Gly Lys 85 90 95 Arg Arg Ala Gly Gly Arg Gln Lys
Arg Arg Arg Gly Pro Arg Ala Gly 100 105 110 Gln Glu Ala Glu Lys Arg
Arg Val Phe Ser Leu Pro Gln Pro Gln Gln 115 120 125 Asp Gly Gly Gly
Gly Ala Ser Ser Gly Gly Gly Val Thr Pro Leu Val 130 135 140 Glu Tyr
Glu Asp Val Ser Ser Gln Ser Glu Gln Gly Leu Leu Leu Gly 145 150 155
160 Gly Ala Ser Ala Ala Thr Ala Ala Thr Ala Ala Gly Gly Thr Gly Gly
165 170 175 Ser Gly Gly Ser Pro Ala Ser Ser Ser Gly Thr Gln Arg Arg
Gly Glu 180 185 190 Gly Ser Glu Arg Arg Pro Arg Arg Asp Arg Arg Ser
Ser Ser Gly Arg 195 200 205 Ser Lys Glu Arg His Arg Glu His Arg Arg
Arg Asp Gly Gln Arg Gly 210 215 220 Gly Ser Glu Ala Ser Lys Ser Arg
Ser Arg His Ser His Ser Gly Glu 225 230 235 240 Glu Arg Ala Glu Val
Ala Lys Ser Gly Ser Ser Ser Ser Ser Gly Gly 245 250 255 Arg Arg Lys
Ser Ala Ser Ala Thr Ser Ser Ser Ser Ser Ser Arg Lys 260 265 270 Asp
Arg Asp Ser Lys Ala His Arg Ser Arg Thr Lys Ser Ser Lys Glu 275 280
285 Pro Pro Ser Ala Tyr Lys Glu Pro Pro Lys Ala Tyr Arg Glu Asp Lys
290 295 300 Thr Glu Pro Lys Ala Tyr Arg Arg Arg Arg Ser Leu Ser Pro
Leu Gly 305 310 315 320 Gly Arg Asp Asp Ser Pro Val Ser His Arg Ala
Ser Gln Ser Leu Arg 325 330 335 Ser Arg Lys Ser Pro Ser Pro Ala Gly
Gly Gly Ser Ser Pro Tyr Ser 340 345 350 Arg Arg Leu Pro Arg Ser Pro
Ser Pro Tyr Ser Arg Arg Arg Ser Pro 355 360 365 Ser Tyr Ser Arg His
Ser Ser Tyr Glu Arg Gly Gly Asp Val Ser Pro 370 375 380 Ser Pro Tyr
Ser Ser Ser Ser Trp Arg Arg Ser Arg Ser Pro Tyr Ser 385 390 395 400
Pro Val Leu Arg Arg Ser Gly Lys Ser Arg Ser Arg Ser Pro Tyr Ser 405
410 415 Ser Arg His Ser Arg Ser Arg Ser Arg His Arg Leu Ser Arg Ser
Arg 420 425 430 Ser Arg His Ser Ser Ile Ser Pro Ser Thr Leu Thr
Leu
Lys Ser Ser 435 440 445 Leu Ala Ala Glu Leu Asn Lys Asn Lys Lys Ala
Arg Ala Ala Glu Ala 450 455 460 Ala Arg Ala Ala Glu Ala Ala Lys Ala
Ala Glu Ala Thr Lys Ala Ala 465 470 475 480 Glu Ala Ala Ala Lys Ala
Ala Lys Ala Ser Asn Thr Ser Thr Pro Thr 485 490 495 Lys Gly Asn Thr
Glu Thr Ser Ala Ser Ala Ser Gln Thr Asn His Val 500 505 510 Lys Asp
Val Lys Lys Ile Lys Ile Glu His Ala Pro Ser Pro Ser Ser 515 520 525
Gly Gly Thr Leu Lys Asn Asp Lys Ala Lys Thr Lys Pro Pro Leu Gln 530
535 540 Val Thr Lys Val Glu Asn Asn Leu Ile Val Asp Lys Ala Thr Lys
Lys 545 550 555 560 Ala Val Ile Val Gly Lys Glu Ser Lys Ser Ala Ala
Thr Lys Glu Glu 565 570 575 Ser Val Ser Leu Lys Glu Lys Thr Lys Pro
Leu Thr Pro Ser Ile Gly 580 585 590 Ala Lys Glu Lys Glu Gln His Val
Ala Leu Val Thr Ser Thr Leu Pro 595 600 605 Pro Leu Pro Leu Pro Pro
Met Leu Pro Glu Asp Lys Glu Ala Asp Ser 610 615 620 Leu Arg Gly Asn
Ile Ser Val Lys Ala Val Lys Lys Glu Val Glu Lys 625 630 635 640 Lys
Leu Arg Cys Leu Leu Ala Asp Leu Pro Leu Pro Pro Glu Leu Pro 645 650
655 Gly Gly Asp Asp Leu Ser Lys Ser Pro Glu Glu Lys Lys Thr Ala Thr
660 665 670 Gln Leu His Ser Lys Arg Arg Pro Lys Ile Cys Gly Pro Arg
Tyr Gly 675 680 685 Glu Thr Lys Glu Lys Asp Ile Asp Trp Gly Lys Arg
Cys Val Asp Lys 690 695 700 Phe Asp Ile Ile Gly Ile Ile Gly Glu Gly
Thr Tyr Gly Gln Val Tyr 705 710 715 720 Lys Ala Arg Asp Lys Asp Thr
Gly Glu Met Val Ala Leu Lys Lys Val 725 730 735 Arg Leu Asp Asn Glu
Lys Glu Gly Phe Pro Ile Thr Ala Ile Arg Glu 740 745 750 Ile Lys Ile
Leu Arg Gln Leu Thr His Gln Ser Ile Ile Asn Met Lys 755 760 765 Glu
Ile Val Thr Asp Lys Glu Asp Ala Leu Asp Phe Lys Lys Asp Lys 770 775
780 Gly Ala Phe Tyr Leu Val Phe Glu Tyr Met Asp His Asp Leu Met Gly
785 790 795 800 Leu Leu Glu Ser Gly Leu Val His Phe Asn Glu Asn His
Ile Lys Ser 805 810 815 Phe Met Arg Gln Leu Met Glu Gly Leu Asp Tyr
Cys His Lys Lys Asn 820 825 830 Phe Leu His Arg Asp Ile Lys Cys Ser
Asn Ile Leu Leu Asn Asn Arg 835 840 845 Gly Gln Ile Lys Leu Ala Asp
Phe Gly Leu Ala Arg Leu Tyr Ser Ser 850 855 860 Glu Glu Ser Arg Pro
Tyr Thr Asn Lys Val Ile Thr Leu Trp Tyr Arg 865 870 875 880 Pro Pro
Glu Leu Leu Leu Gly Glu Glu Arg Tyr Thr Pro Ala Ile Asp 885 890 895
Val Trp Ser Cys Gly Cys Ile Leu Gly Glu Leu Phe Thr Lys Lys Pro 900
905 910 Ile Phe Gln Ala Asn Gln Glu Leu Ala Gln Leu Glu Leu Ile Ser
Arg 915 920 925 Ile Cys Gly Ser Pro Cys Pro Ala Val Trp Pro Asp Val
Ile Lys Leu 930 935 940 Pro Tyr Phe Asn Thr Met Lys Pro Lys Lys Gln
Tyr Arg Arg Lys Leu 945 950 955 960 Arg Glu Glu Phe Val Phe Ile Pro
Ala Ala Ala Leu Asp Leu Phe Asp 965 970 975 Tyr Met Leu Ala Leu Asp
Pro Ser Lys Arg Cys Thr Ala Glu Gln Ala 980 985 990 Leu Gln Cys Glu
Phe Leu Arg Asp Val Glu Pro Ser Lys Met Pro Pro 995 1000 1005 Pro
Asp Leu Pro Leu Trp Gln Asp Cys His Glu Leu Trp Ser Lys 1010 1015
1020 Lys Arg Arg Arg Gln Lys Gln Met Gly Met Thr Asp Asp Val Ser
1025 1030 1035 Thr Ile Lys Ala Pro Arg Lys Asp Leu Ser Leu Gly Leu
Asp Asp 1040 1045 1050 Ser Arg Thr Asn Thr Pro Gln Gly Val Leu Pro
Ser Ser Gln Leu 1055 1060 1065 Lys Ser Gln Gly Ser Ser Asn Val Ala
Pro Val Lys Thr Gly Pro 1070 1075 1080 Gly Gln His Leu Asn His Ser
Glu Leu Ala Ile Leu Leu Asn Leu 1085 1090 1095 Leu Gln Ser Lys Thr
Ser Val Asn Met Ala Asp Phe Val Gln Val 1100 1105 1110 Leu Asn Ile
Lys Val Asn Ser Glu Thr Gln Gln Gln Leu Asn Lys 1115 1120 1125 Ile
Asn Leu Pro Ala Gly Ile Leu Ala Thr Gly Glu Lys Gln Thr 1130 1135
1140 Asp Pro Ser Thr Pro Gln Gln Glu Ser Ser Lys Pro Leu Gly Gly
1145 1150 1155 Ile Gln Pro Ser Ser Gln Thr Ile Gln Pro Lys Val Glu
Thr Asp 1160 1165 1170 Ala Ala Gln Ala Ala Val Gln Ser Ala Phe Ala
Val Leu Leu Thr 1175 1180 1185 Gln Leu Ile Lys Ala Gln Gln Ser Lys
Gln Lys Asp Val Leu Leu 1190 1195 1200 Glu Glu Arg Glu Asn Gly Ser
Gly His Glu Ala Ser Leu Gln Leu 1205 1210 1215 Arg Pro Pro Pro Glu
Pro Ser Thr Pro Val Ser Gly Gln Asp Asp 1220 1225 1230 Leu Ile Gln
His Gln Asp Met Arg Ile Leu Glu Leu Thr Pro Glu 1235 1240 1245 Pro
Asp Arg Pro Arg Ile Leu Pro Pro Asp Gln Arg Pro Pro Glu 1250 1255
1260 Pro Pro Glu Pro Pro Pro Val Thr Glu Glu Asp Leu Asp Tyr Arg
1265 1270 1275 Thr Glu Asn Gln His Val Pro Thr Thr Ser Ser Ser Leu
Thr Asp 1280 1285 1290 Pro His Ala Gly Val Lys Ala Ala Leu Leu Gln
Leu Leu Ala Gln 1295 1300 1305 His Gln Pro Gln Asp Asp Pro Lys Arg
Glu Gly Gly Ile Asp Tyr 1310 1315 1320 Gln Ala Gly Asp Thr Tyr Val
Ser Thr Ser Asp Tyr Lys Asp Asn 1325 1330 1335 Phe Gly Ser Ser Ser
Phe Ser Ser Ala Pro Tyr Val Ser Asn Asp 1340 1345 1350 Gly Leu Gly
Ser Ser Ser Ala Pro Pro Leu Glu Arg Arg Ser Phe 1355 1360 1365 Ile
Gly Asn Ser Asp Ile Gln Ser Leu Asp Asn Tyr Ser Thr Ala 1370 1375
1380 Ser Ser His Ser Gly Gly Pro Pro Gln Pro Ser Ala Phe Ser Glu
1385 1390 1395 Ser Phe Pro Ser Ser Val Ala Gly Tyr Gly Asp Ile Tyr
Leu Asn 1400 1405 1410 Ala Gly Pro Met Leu Phe Ser Gly Asp Lys Asp
His Arg Phe Glu 1415 1420 1425 Tyr Ser His Gly Pro Ile Ala Val Leu
Ala Asn Ser Ser Asp Pro 1430 1435 1440 Ser Thr Gly Pro Glu Ser Thr
His Pro Leu Pro Ala Lys Met His 1445 1450 1455 Asn Tyr Asn Tyr Gly
Gly Asn Leu Gln Glu Asn Pro Ser Gly Pro 1460 1465 1470 Ser Leu Met
His Gly Gln Thr Trp Thr Ser Pro Ala Gln Gly Pro 1475 1480 1485 Gly
Tyr Ser Gln Gly Tyr Arg Gly His Ile Ser Thr Ser Thr Gly 1490 1495
1500 Arg Gly Arg Gly Arg Gly Leu Pro Tyr 1505 1510 4406PRTHomo
sapiens 4Met Ala Thr Pro Gly Asn Leu Gly Ser Ser Val Leu Ala Ser
Lys Thr 1 5 10 15 Lys Thr Lys Lys Lys His Phe Val Ala Gln Lys Val
Lys Leu Phe Arg 20 25 30 Ala Ser Asp Pro Leu Leu Ser Val Leu Met
Trp Gly Val Asn His Ser 35 40 45 Ile Asn Glu Leu Ser His Val Gln
Ile Pro Val Met Leu Met Pro Asp 50 55 60 Asp Phe Lys Ala Tyr Ser
Lys Ile Lys Val Asp Asn His Leu Phe Asn 65 70 75 80 Lys Glu Asn Met
Pro Ser His Phe Lys Phe Lys Glu Tyr Cys Pro Met 85 90 95 Val Phe
Arg Asn Leu Arg Glu Arg Phe Gly Ile Asp Asp Gln Asp Phe 100 105 110
Gln Asn Ser Leu Thr Arg Ser Ala Pro Leu Pro Asn Asp Ser Gln Ala 115
120 125 Arg Ser Gly Ala Arg Phe His Thr Ser Tyr Asp Lys Arg Tyr Ile
Ile 130 135 140 Lys Thr Ile Thr Ser Glu Asp Val Ala Glu Met His Asn
Ile Leu Lys 145 150 155 160 Lys Tyr His Gln Tyr Ile Val Glu Cys His
Gly Ile Thr Leu Leu Pro 165 170 175 Gln Phe Leu Gly Met Tyr Arg Leu
Asn Val Asp Gly Val Glu Ile Tyr 180 185 190 Val Ile Val Thr Arg Asn
Val Phe Ser His Arg Leu Ser Val Tyr Arg 195 200 205 Lys Tyr Asp Leu
Lys Gly Ser Thr Val Ala Arg Glu Ala Ser Asp Lys 210 215 220 Glu Lys
Ala Lys Glu Leu Pro Thr Leu Lys Asp Asn Asp Phe Ile Asn 225 230 235
240 Glu Gly Gln Lys Ile Tyr Ile Asp Asp Asn Asn Lys Lys Val Phe Leu
245 250 255 Glu Lys Leu Lys Lys Asp Val Glu Phe Leu Ala Gln Leu Lys
Leu Met 260 265 270 Asp Tyr Ser Leu Leu Val Gly Ile His Asp Val Glu
Arg Ala Glu Gln 275 280 285 Glu Glu Val Glu Cys Glu Glu Asn Asp Gly
Glu Glu Glu Gly Glu Ser 290 295 300 Asp Gly Thr His Pro Val Gly Thr
Pro Pro Asp Ser Pro Gly Asn Thr 305 310 315 320 Leu Asn Ser Ser Pro
Pro Leu Ala Pro Gly Glu Phe Asp Pro Asn Ile 325 330 335 Asp Val Tyr
Gly Ile Lys Cys His Glu Asn Ser Pro Arg Lys Glu Val 340 345 350 Tyr
Phe Met Ala Ile Ile Asp Ile Leu Thr His Tyr Asp Ala Lys Lys 355 360
365 Lys Ala Ala His Ala Ala Lys Thr Val Lys His Gly Ala Gly Ala Glu
370 375 380 Ile Ser Thr Val Asn Pro Glu Gln Tyr Ser Lys Arg Phe Leu
Asp Phe 385 390 395 400 Ile Gly His Ile Leu Thr 405 5416PRTHomo
sapiens 5Met Ser Ser Asn Cys Thr Ser Thr Thr Ala Val Ala Val Ala
Pro Leu 1 5 10 15 Ser Ala Ser Lys Thr Lys Thr Lys Lys Lys His Phe
Val Cys Gln Lys 20 25 30 Val Lys Leu Phe Arg Ala Ser Glu Pro Ile
Leu Ser Val Leu Met Trp 35 40 45 Gly Val Asn His Thr Ile Asn Glu
Leu Ser Asn Val Pro Val Pro Val 50 55 60 Met Leu Met Pro Asp Asp
Phe Lys Ala Tyr Ser Lys Ile Lys Val Asp 65 70 75 80 Asn His Leu Phe
Asn Lys Glu Asn Leu Pro Ser Arg Phe Lys Phe Lys 85 90 95 Glu Tyr
Cys Pro Met Val Phe Arg Asn Leu Arg Glu Arg Phe Gly Ile 100 105 110
Asp Asp Gln Asp Tyr Gln Asn Ser Val Thr Arg Ser Ala Pro Ile Asn 115
120 125 Ser Asp Ser Gln Gly Arg Cys Gly Thr Arg Phe Leu Thr Thr Tyr
Asp 130 135 140 Arg Arg Phe Val Ile Lys Thr Val Ser Ser Glu Asp Val
Ala Glu Met 145 150 155 160 His Asn Ile Leu Lys Lys Tyr His Gln Phe
Ile Val Glu Cys His Gly 165 170 175 Asn Thr Leu Leu Pro Gln Phe Leu
Gly Met Tyr Arg Leu Thr Val Asp 180 185 190 Gly Val Glu Thr Tyr Met
Val Val Thr Arg Asn Val Phe Ser His Arg 195 200 205 Leu Thr Val His
Arg Lys Tyr Asp Leu Lys Gly Ser Thr Val Ala Arg 210 215 220 Glu Ala
Ser Asp Lys Glu Lys Ala Lys Asp Leu Pro Thr Phe Lys Asp 225 230 235
240 Asn Asp Phe Leu Asn Glu Gly Gln Lys Leu His Val Gly Glu Glu Ser
245 250 255 Lys Lys Asn Phe Leu Glu Lys Leu Lys Arg Asp Val Glu Phe
Leu Ala 260 265 270 Gln Leu Lys Ile Met Asp Tyr Ser Leu Leu Val Gly
Ile His Asp Val 275 280 285 Asp Arg Ala Glu Gln Glu Glu Met Glu Val
Glu Glu Arg Ala Glu Asp 290 295 300 Glu Glu Cys Glu Asn Asp Gly Val
Gly Gly Asn Leu Leu Cys Ser Tyr 305 310 315 320 Gly Thr Pro Pro Asp
Ser Pro Gly Asn Leu Leu Ser Phe Pro Arg Phe 325 330 335 Phe Gly Pro
Gly Glu Phe Asp Pro Ser Val Asp Val Tyr Ala Met Lys 340 345 350 Ser
His Glu Ser Ser Pro Lys Lys Glu Val Tyr Phe Met Ala Ile Ile 355 360
365 Asp Ile Leu Thr Pro Tyr Asp Thr Lys Lys Lys Ala Ala His Ala Ala
370 375 380 Lys Thr Val Lys His Gly Ala Gly Ala Glu Ile Ser Thr Val
Asn Pro 385 390 395 400 Glu Gln Tyr Ser Lys Arg Phe Asn Glu Phe Met
Ser Asn Ile Leu Thr 405 410 415 6421PRTHomo sapiens 6Met Ala Ser
Ser Ser Val Pro Pro Ala Thr Val Ser Ala Ala Thr Ala 1 5 10 15 Gly
Pro Gly Pro Gly Phe Gly Phe Ala Ser Lys Thr Lys Lys Lys His 20 25
30 Phe Val Gln Gln Lys Val Lys Val Phe Arg Ala Ala Asp Pro Leu Val
35 40 45 Gly Val Phe Leu Trp Gly Val Ala His Ser Ile Asn Glu Leu
Ser Gln 50 55 60 Val Pro Pro Pro Val Met Leu Leu Pro Asp Asp Phe
Lys Ala Ser Ser 65 70 75 80 Lys Ile Lys Val Asn Asn His Leu Phe His
Arg Glu Asn Leu Pro Ser 85 90 95 His Phe Lys Phe Lys Glu Tyr Cys
Pro Gln Val Phe Arg Asn Leu Arg 100 105 110 Asp Arg Phe Gly Ile Asp
Asp Gln Asp Tyr Leu Val Ser Leu Thr Arg 115 120 125 Asn Pro Pro Ser
Glu Ser Glu Gly Ser Asp Gly Arg Phe Leu Ile Ser 130 135 140 Tyr Asp
Arg Thr Leu Val Ile Lys Glu Val Ser Ser Glu Asp Ile Ala 145 150 155
160 Asp Met His Ser Asn Leu Ser Asn Tyr His Gln Tyr Ile Val Lys Cys
165 170 175 His Gly Asn Thr Leu Leu Pro Gln Phe Leu Gly Met Tyr Arg
Val Ser 180 185 190 Val Asp Asn Glu Asp Ser Tyr Met Leu Val Met Arg
Asn Met Phe Ser 195 200 205 His Arg Leu Pro Val His Arg Lys Tyr Asp
Leu Lys Gly Ser Leu Val 210 215 220 Ser Arg Glu Ala Ser Asp Lys Glu
Lys Val Lys Glu Leu Pro Thr Leu 225 230 235 240 Lys Asp Met Asp Phe
Leu Asn Lys Asn Gln Lys Val Tyr Ile Gly Glu 245 250 255 Glu Glu Lys
Lys Ile Phe Leu Glu Lys Leu Lys Arg Asp Val Glu Phe 260 265 270 Leu
Val Gln Leu Lys Ile Met Asp Tyr Ser Leu Leu Leu Gly Ile His 275 280
285 Asp Ile Ile Arg Gly Ser Glu Pro Glu Glu Glu Ala Pro Val Arg Glu
290 295 300 Asp Glu Ser Glu Val Asp Gly Asp Cys Ser Leu Thr Gly Pro
Pro Ala 305 310 315 320 Leu Val Gly Ser Tyr Gly Thr Ser Pro Glu Gly
Ile Gly Gly Tyr Ile 325 330 335 His Ser His Arg Pro Leu Gly Pro Gly
Glu Phe Glu Ser Phe Ile Asp 340 345 350 Val Tyr Ala Ile Arg Ser Ala
Glu Gly Ala Pro Gln Lys Glu Val Tyr 355 360 365 Phe Met Gly Leu Ile
Asp Ile Leu Thr Gln Tyr Asp Ala
Lys Lys Lys 370 375 380 Ala Ala His Ala Ala Lys Thr Val Lys His Gly
Ala Gly Ala Glu Ile 385 390 395 400 Ser Thr Val His Pro Glu Gln Tyr
Ala Lys Arg Phe Leu Asp Phe Ile 405 410 415 Thr Asn Ile Phe Ala 420
71221DNAHomo sapiens 7atggcgaccc ccggcaacct agggtcctct gtcctggcga
gcaagaccaa gaccaagaag 60aagcacttcg tagcgcagaa agtgaagctg tttcgggcca
gcgacccgct gctcagcgtc 120ctcatgtggg gggtaaacca ctcgatcaat
gaactgagcc atgttcaaat ccctgttatg 180ttgatgccag atgacttcaa
agcctattca aaaataaagg tggacaatca cctttttaac 240aaagaaaaca
tgccgagcca tttcaagttt aaggaatact gcccgatggt cttccgtaac
300ctgcgggaga ggtttggaat tgatgatcaa gatttccaga attccctgac
caggagcgca 360cccctcccca acgactccca ggcccgcagt ggagctcgtt
ttcacacttc ctacgacaaa 420agatacatca tcaagactat taccagtgaa
gacgtggccg aaatgcacaa catcctgaag 480aaataccacc agtacatagt
ggaatgtcat gggatcaccc ttcttcccca gttcttgggc 540atgtaccggc
ttaatgttga tggagttgaa atatatgtga tagttacaag aaatgtattc
600agccaccgtt tgtctgtgta taggaaatac gacttaaagg gctctacagt
ggctagagaa 660gctagtgaca aagaaaaggc caaagaactg ccaactctga
aagataatga tttcattaat 720gagggccaaa agatttatat tgatgacaac
aacaagaagg tcttcctgga aaaactaaaa 780aaggatgttg agtttctggc
ccagctgaag ctcatggact acagtctgct ggtgggaatt 840catgatgtgg
agagagccga acaggaggaa gtggagtgtg aggagaacga tggggaggag
900gagggcgaga gcgatggcac ccacccggtg ggaacccccc cagatagccc
cgggaataca 960ctgaacagct caccacccct ggctcccggg gagttcgatc
cgaacatcga cgtctatgga 1020attaagtgcc atgaaaactc gcctaggaag
gaggtgtact tcatggcaat tattgacatc 1080cttactcatt atgatgcaaa
aaagaaagct gcccatgctg caaaaactgt taaacatggc 1140gctggcgcgg
agatctccac cgtgaaccca gaacagtatt caaagcgctt tttggacttt
1200attggccaca tcttgacgta a 122181251DNAHomo sapiens 8atgtcgtcca
actgcaccag caccacggcg gtggcggtgg cgccgctcag cgccagcaag 60accaagacca
agaagaagca tttcgtgtgc cagaaagtga agctattccg ggccagcgag
120ccgatcctca gcgtcctgat gtggggggtg aaccacacga tcaatgagct
gagcaatgtt 180cctgttcctg tcatgctaat gccagatgac ttcaaagcct
acagcaagat caaggtggac 240aatcatctct tcaataagga gaacctgccc
agccgcttta agtttaagga gtattgcccc 300atggtgttcc gaaaccttcg
ggagaggttt ggaattgatg atcaggatta ccagaattca 360gtgacgcgca
gcgcccccat caacagtgac agccagggtc ggtgtggcac gcgtttcctc
420accacctacg accggcgctt tgtcatcaag actgtgtcca gcgaggacgt
ggcggagatg 480cacaacatct taaagaaata ccaccagttt atagtggagt
gtcatggcaa cacgcttttg 540ccacagttcc tgggcatgta ccgcctgacc
gtggatggtg tggaaaccta catggtggtt 600accaggaacg tgttcagcca
tcggctcact gtgcatcgca agtatgacct caagggttct 660acggttgcca
gagaagcgag cgacaaggag aaggccaagg acttgccaac attcaaagac
720aatgacttcc tcaatgaagg gcagaagctg catgtgggag aggagagtaa
aaagaacttc 780ctggagaaac tgaagcggga cgttgagttc ttggcacagc
tgaagatcat ggactacagc 840ctgctggtgg gcatccacga cgtggaccgg
gcagagcagg aggagatgga ggtggaggag 900cgggcagagg acgaggagtg
tgagaatgat ggggtgggtg gcaacctact ctgctcctat 960ggcacacctc
cggacagccc tggcaacctc ctcagctttc ctcggttctt tggtcctggg
1020gaattcgacc cctctgttga cgtctatgcc atgaaaagcc atgaaagttc
ccccaagaag 1080gaggtgtatt tcatggccat cattgatatc ctcacgccat
acgatacaaa gaagaaagct 1140gcacatgctg ccaaaacggt gaaacacggg
gcaggggccg agatctcgac tgtgaaccct 1200gagcagtact ccaaacgctt
caacgagttt atgtccaaca tcctgacgta g 125191266DNAHomo sapiens
9atggcgtcct cctcggtccc accagccacg gtatcggcgg cgacagcagg ccccggccca
60ggtttcggct tcgcctccaa gaccaagaag aagcatttcg tgcagcagaa ggtgaaggtg
120ttccgggcgg ccgacccgct ggtgggtgtg ttcctgtggg gcgtagccca
ctcgatcaat 180gagctcagcc aggtgcctcc cccggtgatg ctgctgccag
atgactttaa ggccagctcc 240aagatcaagg tcaacaatca ccttttccac
agggaaaatc tgcccagtca tttcaagttc 300aaggagtatt gtccccaggt
cttcaggaac ctccgtgatc gatttggcat tgatgaccaa 360gattacttgg
tgtcccttac ccgaaacccc cccagcgaaa gtgaaggcag tgatggtcgc
420ttccttatct cctacgatcg gactctggtc atcaaagaag tatccagtga
ggacattgct 480gacatgcata gcaacctctc caactatcac cagtacattg
tgaagtgcca tggcaacacg 540cttctgcccc agttcctggg gatgtaccga
gtcagtgtgg acaacgaaga cagctacatg 600cttgtgatgc gcaatatgtt
tagccaccgt cttcctgtgc acaggaagta tgacctcaag 660ggttccctag
tgtcccggga agccagcgat aaggaaaagg ttaaagaatt gcccaccctt
720aaggatatgg actttctcaa caagaaccag aaagtatata ttggtgaaga
ggagaagaaa 780atatttctgg agaagctgaa gagagatgtg gagtttctag
tgcagctgaa gatcatggac 840tacagccttc tgctaggcat ccacgacatc
attcggggct ctgaaccaga ggaggaagcg 900cccgtgcggg aggatgagtc
agaggtggat ggggactgca gcctgactgg acctcctgct 960ctggtgggct
cctatggcac ctccccagag ggtatcggag gctacatcca ttcccatcgg
1020cccctgggcc caggagagtt tgagtccttc attgatgtct atgccatccg
gagtgctgaa 1080ggagcccccc agaaggaggt ctacttcatg ggcctcattg
atatccttac acagtatgat 1140gctaagaaga aagcagctca tgcagccaaa
actgtcaagc atggggctgg ggcagagatc 1200tctactgtcc atccggagca
gtatgctaag cgattcctgg attttattac caacatcttt 1260gcctaa 1266
* * * * *