U.S. patent application number 15/092903 was filed with the patent office on 2017-03-02 for carm1 inhibitors and uses thereof.
This patent application is currently assigned to Epizyme, Inc.. The applicant listed for this patent is Epizyme, Inc.. Invention is credited to Robert E. Babine, Richard Chesworth, Lei Jin, Oscar Miguel Moradei, Gideon Shapiro.
Application Number | 20170056409 15/092903 |
Document ID | / |
Family ID | 51569592 |
Filed Date | 2017-03-02 |
United States Patent
Application |
20170056409 |
Kind Code |
A1 |
Chesworth; Richard ; et
al. |
March 2, 2017 |
CARM1 INHIBITORS AND USES THEREOF
Abstract
Provided herein are compounds of Formula (I): ##STR00001## and
pharmaceutically acceptable salts thereof, and pharmaceutical
compositions thereof; wherein X, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.2c, R.sup.2d, are as defined herein, and Ring HET is a
6-membered monocyclic heteroaryl ring system of formula:
##STR00002## wherein L.sup.2, R.sup.13, G.sub.8, G.sub.10,
G.sub.11, and G.sub.12 are as defined herein. Compounds of the
present invention are useful for inhibiting CARM1 activity. Methods
of using the compounds for treating CARM1-mediated disorders are
also described.
Inventors: |
Chesworth; Richard;
(Concord, MA) ; Moradei; Oscar Miguel;
(Burlington, MA) ; Shapiro; Gideon; (Gainesville,
FL) ; Jin; Lei; (Wellesley, MA) ; Babine;
Robert E.; (Carlsbad, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Epizyme, Inc. |
Cambridge |
MA |
US |
|
|
Assignee: |
Epizyme, Inc.
Cambridge
MA
|
Family ID: |
51569592 |
Appl. No.: |
15/092903 |
Filed: |
April 7, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14210672 |
Mar 14, 2014 |
9346802 |
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15092903 |
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61794442 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 403/04 20130101;
C07D 413/04 20130101; C07D 239/48 20130101; C07D 471/04 20130101;
A61K 31/506 20130101; C07D 405/14 20130101; A61K 31/5377 20130101;
C07D 405/12 20130101; C07D 239/42 20130101; C07D 401/04 20130101;
C07D 405/04 20130101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/506 20060101 A61K031/506 |
Claims
1-25. (canceled)
26. A method of treating a CARM1-mediated disorder, comprising
administering to a subject in need thereof an effective amount of a
compound of Formula (I): ##STR00131## or a pharmaceutically
acceptable salt thereof: wherein: X is --O--, --S--, or
--CH.sub.2--; R.sup.1 is hydrogen or optionally substituted
C.sub.1-4 aliphatic; each of R.sup.2a, R.sup.2b, R.sup.2c, and
R.sup.2d is independently hydrogen, halogen, --CN, --NO.sub.2,
--C(.dbd.O)R.sup.A2, --C(.dbd.O)OR.sup.A2,
--C(.dbd.O)N(R.sup.A2).sub.2, --OR.sup.A2, --SR.sup.A,
--N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A2,
--S(.dbd.O).sub.2R.sup.A2, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, or optionally substituted heterocyclyl,
wherein each instance of R.sup.A2 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.A2 groups
attached to the same nitrogen atom are joined to form an optionally
substituted heterocyclyl or optionally substituted heteroaryl ring;
Ring HET is a 6-membered monocyclic heteroaryl ring system of the
formula: ##STR00132## each instance of R.sup.8, R.sup.10, R.sup.11,
and R.sup.12 is independently selected from the group consisting of
hydrogen, halo, --CN, --NO.sub.2, --C(.dbd.O)R', --C(.dbd.O)OR',
--C(.dbd.O)N(R').sub.2, optionally substituted alkyl, and
-L.sup.1-R.sup.3; each instance of R' is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R' groups attached to
the same nitrogen are joined to form an optionally substituted
heterocyclyl ring or optionally substituted heteroaryl ring; each
instance of L.sup.1 and L.sup.2 is independently a bond, --O--,
--N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L)--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.7--, --SO.sub.2N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--, an optionally substituted
C.sub.1-10 saturated or unsaturated hydrocarbon chain, wherein one
or more moieties selected from the group consisting of --O--,
--N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L)--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O)--, --S(O).sub.2O--, --SO.sub.2--, --N(R.sup.L)SO.sub.2--,
--SO.sub.2N(R.sup.L)--, and --N(R.sup.L)SO.sub.2N(R.sup.L)-- is
optionally and independently present between two carbon atoms of
the hydrocarbon chain, and optionally and independently present at
one or both ends of the hydrocarbon chain; each R.sup.L is
independently hydrogen, optionally substituted alkyl, or a nitrogen
protecting group, or R.sup.L and R.sup.3 taken together form an
optionally substituted heterocyclyl or optionally substituted
heteroaryl ring, or R.sup.L and R.sup.13 taken together form an
optionally substituted heterocyclyl or optionally substituted
heteroaryl ring; R.sup.3 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, or optionally
substituted heteroaryl, provided when R.sup.3 is hydrogen, then L
is not a bond; and R.sup.13 is optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl.
27. The method of claim 26, wherein the disorder is a proliferative
disorder.
28. The method of claim 26, wherein the disorder is cancer.
29. The method of claim 28, wherein the cancer is associated with
E2F1 upregulation.
30. The method of claim 28, wherein the cancer is associated with
aberrant CARM1 activity.
31. The method of claim 28, wherein the cancer is breast cancer,
prostate cancer, or colorectal cancer.
32. The method of claim 28, wherein the cancer is
ER.alpha.-dependent breast cancer.
33. The method of claim 28, wherein the cancer is
castration-resistant prostate cancer.
34. The method of claim 28, wherein the cancer is colorectal cancer
associated with dysregulated WNT/.beta.-catenin signaling.
35. The method of claim 26, wherein the disorder is a metabolic
disorder.
36. The method of claim 28, wherein the cancer is leukemia,
lymphoma, or multiple myeloma.
37. The method of claim 36, wherein the cancer is leukemia.
38. The method of claim 36, wherein the cancer is lymphoma.
39. The method of claim 36, wherein the cancer is multiple
myeloma.
40. A method of treating a CARM1-mediated disorder, comprising
administering to a subject in need thereof an effective amount of a
compound of Formula (I): ##STR00133## or a pharmaceutically
acceptable salt thereof; wherein: X is --O--, --S--, or
--CH.sub.2--; R.sup.1 is hydrogen or optionally substituted
C.sub.1-4 aliphatic; each of R.sup.2a, R.sup.2b, R.sup.2c, and
R.sup.2d is independently hydrogen, halogen, --CN, --NO.sub.2,
--C(.dbd.O)R.sup.A2, --C(.dbd.O)OR.sup.A2,
--C(.dbd.O)N(R.sup.A2).sub.2, --OR.sup.A2, --SR.sup.A2,
--N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A2,
--S(.dbd.O).sub.2R.sup.A2, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, or optionally substituted heterocyclyl,
wherein each instance of R.sup.A2 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.A2 groups
attached to the same nitrogen atom are joined to form an optionally
substituted heterocyclyl or optionally substituted heteroaryl ring;
Ring HET is a 6-membered monocyclic heteroaryl ring system of the
formula: ##STR00134## wherein: G.sub.8 is C--R.sup.8 or N; G.sub.10
is C--R.sup.10 or N; G.sub.11 is C--R.sup.11 or N; G.sub.12 is
C--R.sup.12 or N; provided at least one instance of G.sub.8,
G.sub.10, G.sub.11, or G.sub.12 is N; each instance of R.sup.8,
R.sup.10, R.sup.11, and R.sup.12 is independently selected from the
group consisting of hydrogen, halo, --CN, --NO.sub.2,
--C(.dbd.O)R', --C(.dbd.O)OR', --C(.dbd.O)N(R').sub.2, optionally
substituted alkyl, and -L.sup.1-R.sup.3; each instance of R' is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl,
or two R' groups attached to the same nitrogen are joined to form
an optionally substituted heterocyclyl ring or optionally
substituted heteroaryl ring; each instance of L.sup.1 and L.sup.2
is independently a bond, --O--, --N(R.sup.L)--, --S--, --C(O)--,
--C(O)O--, --C(O)S--, --C(O)N(R.sup.L)--,
--C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--, --OC(O)N(R.sup.L)--,
--NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L)--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.2--, --SO.sub.2N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--, an optionally substituted
C.sub.10 saturated or unsaturated hydrocarbon chain, wherein one or
more moieties selected from the group consisting of --O--,
--N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L)--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.2--, --SO.sub.2N(R.sup.L)--, and
--N(R.sup.L)SO.sub.2N(R.sup.L)-- is optionally and independently
present between two carbon atoms of the hydrocarbon chain, and
optionally and independently present at one or both ends of the
hydrocarbon chain; each R.sup.L is independently hydrogen,
optionally substituted alkyl, or a nitrogen protecting group, or
R.sup.L and R.sup.3 taken together form an optionally substituted
heterocyclyl or optionally substituted heteroaryl ring, or R.sup.L
and R.sup.13 taken together form an optionally substituted
heterocyclyl or optionally substituted heteroaryl ring; R.sup.3 is
hydrogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted heteroaryl, or aryl unsubstituted or substituted with
one or more substituents independently selected from the group
consisting of halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H,
SO.sub.3H, --OH, --OR.sup.aa, --N(R.sup.bb).sub.2, --SH,
--SR.sup.aa, --C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO,
--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,
C.sub.1 alkyl, C.sub.1 perhaloalkyl, C.sub.2-4 alkenyl, and
C.sub.2-4 alkynyl, provided when R.sup.3 is hydrogen, then L.sup.1
is not a bond; and R.sup.13 is optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted
heteroaryl, or aryl unsubstituted or substituted with one or more
substituents independently selected from the group consisting of
halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, SO.sub.3H, --OH,
--OR.sup.aa, --N(R.sup.bb).sub.2, --SH, --SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO, --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,
C.sub.1 alkyl, Ci perhaloalkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl; wherein: each instance of R.sup.aa is, independently, Ci
alkyl; and each instance of R.sup.bb is, independently, hydrogen or
Ci alkyl, or two R.sup.bb groups are joined to form a 3-6 membered
heterocyclyl or 5-6 membered heteroaryl ring.
41. The method of claim 40, wherein the disorder is a metabolic
disorder.
42. The method of claim 40, wherein the disorder is a proliferative
disorder.
43. The method of claim 40, wherein the disorder is cancer.
44. The method of claim 43, wherein the cancer is associated with
E2F1 upregulation.
45. The method of claim 43, wherein the cancer is associated with
aberrant CARM1 activity.
46. The method of claim 43, wherein the cancer is breast cancer,
prostate cancer, or colorectal cancer.
47. The method of claim 43, wherein the cancer is
ER.alpha.-dependent breast cancer.
48. The method of claim 43, wherein the cancer is
castration-resistant prostate cancer.
49. The method of claim 43, wherein the cancer is colorectal cancer
associated with dysregulated WNT/.beta.-catenin signaling.
50. The method of claim 43, wherein the cancer is leukemia,
lymphoma, or multiple myeloma.
51. The method of claim 50, wherein the cancer is leukemia.
52. The method of claim 50, wherein the cancer is lymphoma.
53. The method of claim 50, wherein the cancer is multiple myeloma.
Description
RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C.
.sctn.119(e) to U.S. Provisional Patent Application, U.S. Ser. No.
61/794,442, filed Mar. 15, 2013, the entire contents of which is
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Epigenetic regulation of gene expression is an important
biological determinant of protein production and cellular
differentiation and plays a significant pathogenic role in a number
of human diseases.
[0003] Epigenetic regulation involves heritable modification of
genetic material without changing its nucleotide sequence.
Typically, epigenetic regulation is mediated by selective and
reversible modification (e.g., methylation) of DNA and proteins
(e.g., histones) that control the conformational transition between
transcriptionally active and inactive states of chromatin. These
covalent modifications can be controlled by enzymes such as
methyltransferases (e.g., CARM1 (co-activator-associated arginine
methyltransferase 1; PRMT4)), many of which are associated with
specific genetic alterations that can cause human disease.
[0004] Disease-associated chromatin-modifying enzymes play a role
in diseases such as proliferative disorders, autoimmune disorders,
muscular disorders, and neurological disorders. Thus, there is a
need for the development of small molecules that are capable of
inhibiting the activity of CARM1.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0005] CARM1 is an attractive target for modulation given its role
in the regulation of diverse biological processes. It has now been
found that compounds described herein, and pharmaceutically
acceptable salts and compositions thereof, are effective as
inhibitors of CARM1. Such compounds have the general Formula
(I):
##STR00003##
and pharmaceutically acceptable salts thereof, and pharmaceutical
compositions thereof; wherein X, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.2c, R.sup.2d, are as defined herein, and wherein Ring HET is
a 6-membered monocyclic heteroaryl ring system of Formula:
##STR00004##
wherein L.sup.2, R.sup.13, G.sub.8, G.sub.10, G.sub.11, and
G.sub.12 are as defined herein.
[0006] In some embodiments, pharmaceutical compositions are
provided which comprise a compound described herein (e.g., a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof) and optionally a pharmaceutically acceptable
excipient.
[0007] In certain embodiments, compounds described herein inhibit
activity of CARM1. In certain embodiments, methods of inhibiting
CARM1 are provided which comprise contacting CARM1 with an
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof. The CARM1 may be purified
or crude, and may be present in a cell, tissue, or a subject. Thus,
such methods encompass inhibition of CARM1 activity both in vitro
and in vivo. In certain embodiments, the CARM1 is wild-type CARM1.
In certain embodiments, the CARM1 is overexpressed. In certain
embodiments, the CARM1 is a mutant. In certain embodiments, the
CARM1 is in a cell. In certain embodiments, the CARM1 is in an
animal, e.g., a human. In some embodiments, the CARM1 is expressed
at normal levels in a subject, but the subject would benefit from
CARM1 inhibition (e.g., because the subject has one or more
mutations in an CARM1 substrate that causes an increase in
methylation of the substrate with normal levels of CARM1). In some
embodiments, the CARM1 is in a subject known or identified as
having abnormal CARM1 activity (e.g., overexpression). In some
embodiments, a provided compound is selective for CARM1 over other
methyltransferases. In certain embodiments, a provided compound is
at least about 10-fold selective, at least about 20-fold selective,
at least about 30-fold selective, at least about 40-fold selective,
at least about 50-fold selective, at least about 60-fold selective,
at least about 70-fold selective, at least about 80-fold selective,
at least about 90-fold selective, or at least about 100-fold
selective relative to one or more other methyltransferases.
[0008] In certain embodiments, methods of modulating gene
expression or activity in a cell are provided which comprise
contacting a cell 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
cell in culture in vitro. In certain embodiments, cell is in an
animal, e.g., a human.
[0009] In certain embodiments, methods of modulating transcription
in a cell are provided which comprise contacting a cell 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 cell in culture in
vitro. In certain embodiments, the cell is in an animal, e.g., a
human.
[0010] In some embodiments, methods of treating a CARM1-mediated
disorder are provided which comprise administering to a subject
suffering from a CARM1-mediated disorder an effective amount of a
compound described herein (e.g., a compound of Formula (I), or a
pharmaceutically acceptable salt thereof), or a pharmaceutical
composition thereof. In certain embodiments, the CARM1-mediated
disorder is a proliferative disorder. In certain embodiments,
compounds described herein are useful for treating cancer. In
certain embodiments, compounds described herein are useful for
treating breast cancer or prostate cancer. In certain embodiments,
the CARM1-mediated disorder is a metabolic disorder.
[0011] Compounds described herein are also useful for the study of
CARM1 in biological and pathological phenomena, the study of
intracellular signal transduction pathways mediated by CARM1, and
the comparative evaluation of new CARM1 inhibitors.
[0012] This application refers to various issued patent, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference.
[0013] 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.
[0014] 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 present disclosure additionally encompasses compounds
described herein as individual isomers substantially free of other
isomers, and alternatively, as mixtures of various isomers.
[0015] Unless otherwise stated, structures depicted herein are also
meant to include compounds that differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structures except for the replacement of hydrogen by
deuterium or tritium, replacement of .sup.19F with .sup.18F, or the
replacement of a carbon by a .sup.13C- or .sup.14C-enriched carbon
are within the scope of the disclosure. Such compounds are useful,
for example, as analytical tools or probes in biological
assays.
[0016] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5,
and C.sub.5-6 alkyl.
[0017] "Aliphatic" refers to alkyl, alkenyl, alkynyl, and
carbocyclic groups.
[0018] "Alkyl" refers to a radical of a straight-chain or branched
saturated hydrocarbon group having from 1 to 20 carbon atoms
("C.sub.1-20 alkyl"). In some embodiments, an alkyl group has 1 to
10 carbon atoms ("C.sub.1-10 alkyl"). In some embodiments, an alkyl
group has 1 to 9 carbon atoms ("C.sub.1-9 alkyl"). In some
embodiments, an alkyl group has 1 to 8 carbon atoms ("C.sub.1-8
alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon
atoms ("C.sub.1-7 alkyl"). In some embodiments, an alkyl group has
1 to 6 carbon atoms ("C.sub.1-6 alkyl"). In some embodiments, an
alkyl group has 1 to 5 carbon atoms ("C.sub.1-5 alkyl"). In some
embodiments, an alkyl group has 1 to 4 carbon atoms ("C.sub.1-4
alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon
atoms ("C.sub.1-3 alkyl"). In some embodiments, an alkyl group has
1 to 2 carbon atoms ("C.sub.1-2 alkyl"). In some embodiments, an
alkyl group has 1 carbon atom ("C.sub.1 alkyl"). In some
embodiments, an alkyl group has 2 to 6 carbon atoms ("C.sub.2-6
alkyl"). Examples of C.sub.1-6 alkyl groups include methyl
(C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), and n-hexyl (C.sub.6).
Additional examples of alkyl groups include n-heptyl (C.sub.7),
n-octyl (C.sub.8) and the like. In certain embodiments, each
instance of an alkyl group is independently optionally substituted,
e.g., unsubstituted (an "unsubstituted alkyl") or substituted (a
"substituted alkyl") with one or more substituents. In certain
embodiments, the alkyl group is unsubstituted C.sub.1-10 alkyl
(e.g., --CH.sub.3). In certain embodiments, the alkyl group is
substituted C.sub.1-10 alkyl.
[0019] In some embodiments, an alkyl group is substituted with one
or more halogens. "Perhaloalkyl" is a substituted alkyl group as
defined herein wherein all of the hydrogen atoms are independently
replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In
some embodiments, the alkyl moiety has 1 to 8 carbon atoms
("C.sub.1-8 perhaloalkyl"). In some embodiments, the alkyl moiety
has 1 to 6 carbon atoms ("C.sub.1-6 perhaloalkyl"). In some
embodiments, the alkyl moiety has 1 to 4 carbon atoms ("C.sub.1-4
perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 3
carbon atoms ("C.sub.1-3 perhaloalkyl"). In some embodiments, the
alkyl moiety has 1 to 2 carbon atoms ("C.sub.1-2 perhaloalkyl"). In
some embodiments, all of the hydrogen atoms are replaced with
fluoro. In some embodiments, all of the hydrogen atoms are replaced
with chloro. Examples of perhaloalkyl groups include --CF.sub.3,
--CF.sub.2CF.sub.3, --CF.sub.2CF.sub.2CF.sub.3, --CCl.sub.3,
--CFCl.sub.2, --CF.sub.2Cl, and the like.
[0020] "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 (e.g., 1, 2, 3, or 4 double bonds),
and optionally one or more triple bonds (e.g., 1, 2, 3, or 4 triple
bonds) ("C.sub.2-20 alkenyl"). In certain embodiments, alkenyl does
not comprise triple bonds. In some embodiments, an alkenyl group
has 2 to 10 carbon atoms ("C.sub.2-20 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. In certain embodiments, each instance of
an alkenyl group is independently optionally substituted, e.g.,
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.
[0021] "Alkynyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms and one
or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple
bonds), and optionally one or more double bonds (e.g., 1, 2, 3, or
4 double bonds) ("C.sub.2-20 alkynyl"). In certain embodiments,
alkynyl does not comprise double bonds. 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. In certain embodiments, each instance of an alkynyl
group is independently optionally substituted, e.g., 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.
[0022] "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 7 ring carbon atoms
("C.sub.3-7 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 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") or tricyclic system ("tricyclic
carbocyclyl"), and can be saturated or can be partially
unsaturated. "Carbocyclyl" also includes ring systems wherein the
carbocyclyl ring, as defined above, is fused with one or more aryl
or heteroaryl groups wherein the point of attachment is on the
carbocyclyl ring, and in such instances, the number of carbons
continue to designate the number of carbons in the carbocyclic ring
system. In certain embodiments, each instance of a carbocyclyl
group is independently optionally substituted, e.g., unsubstituted
(an "unsubstituted carbocyclyl") or substituted (a "substituted
carbocyclyl") with one or more substituents. In certain
embodiments, the carbocyclyl group is unsubstituted C.sub.3-10
carbocyclyl. In certain embodiments, the carbocyclyl group is a
substituted C.sub.3-10 carbocyclyl.
[0023] 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). In certain embodiments, 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.
[0024] "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, and sulfur ("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") or tricyclic system ("tricyclic 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
heterocyclyl ring, as defined above, is fused with one or more
carbocyclyl groups wherein the point of attachment is either on the
carbocyclyl or heterocyclyl ring, or ring systems wherein the
heterocyclyl ring, as defined above, is fused with one or more aryl
or heteroaryl groups, wherein the point of attachment is on the
heterocyclyl ring, and in such instances, the number of ring
members continue to designate the number of ring members in the
heterocyclyl ring system. In certain embodiments, each instance of
heterocyclyl is independently optionally substituted, e.g.,
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.
[0025] In some embodiments, a heterocyclyl group is a 5-10 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In
some embodiments, a heterocyclyl group is a 5-8 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some
embodiments, a heterocyclyl group is a 5-6 membered non-aromatic
ring system having ring carbon atoms and 1-4 ring heteroatoms,
wherein each heteroatom is independently selected from nitrogen,
oxygen, and sulfur ("5-6 membered heterocyclyl"). In some
embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms
selected from nitrogen, oxygen, and sulfur. In some embodiments,
the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected
from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6
membered heterocyclyl has one ring heteroatom selected from
nitrogen, oxygen, and sulfur.
[0026] Exemplary 3-membered heterocyclyl groups containing one
heteroatom include, without limitation, azirdinyl, oxiranyl, and
thiorenyl. 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.
[0027] "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 t 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. In certain
embodiments, each instance of an aryl group is independently
optionally substituted, e.g., 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.
[0028] "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, e.g., either the ring bearing a
heteroatom (e.g., 2-indolyl) or the ring that does not contain a
heteroatom (e.g., 5-indolyl).
[0029] 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. In certain embodiments,
each instance of a heteroaryl group is independently optionally
substituted, e.g., unsubstituted ("unsubstituted heteroaryl") or
substituted ("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.
[0030] 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.
[0031] "Partially unsaturated" refers to a group that includes at
least one double or triple bond. The term "partially unsaturated"
is intended to encompass rings having multiple sites of
unsaturation, but is not intended to include aromatic groups (e.g.,
aryl or heteroaryl groups) as herein defined. Likewise, "saturated"
refers to a group that does not contain a double or triple bond,
i.e., contains all single bonds.
[0032] In some embodiments, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl groups, as defined herein, are
optionally substituted (e.g., "substituted" or "unsubstituted"
alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or
"unsubstituted" alkynyl, "substituted" or "unsubstituted"
carbocyclyl, "substituted" or "unsubstituted" heterocyclyl,
"substituted" or "unsubstituted" aryl or "substituted" or
"unsubstituted" heteroaryl group). In general, the term
"substituted", whether preceded by the term "optionally" or not,
means that at least one hydrogen present on a group (e.g., a carbon
or nitrogen atom) is replaced with a permissible substituent, e.g.,
a substituent which upon substitution results in a stable compound,
e.g., a compound which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
or other reaction. Unless otherwise indicated, a "substituted"
group has a substituent at one or more substitutable positions of
the group, and when more than one position in any given structure
is substituted, the substituent is either the same or different at
each position. The term "substituted" is contemplated to include
substitution with all permissible substituents of organic
compounds, including 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.
[0033] 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,
--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.sup.aa, --SO.sub.2OR,
--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).sub.2R.sup.aa, --OP(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
--OP(.dbd.O).sub.2N(R.sup.bb).sub.2, --P(.dbd.O)(NR.sup.bb).sub.2,
--OP(.dbd.O)(NR.sup.bb).sub.2,
--NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
--NR.sup.bbP(.dbd.O)(NR.sup.bb).sub.2, --P(R.sup.cc).sub.2,
--P(R.sup.cc).sub.3, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--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, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups;
[0034] 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;
[0035] 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, 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, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0036] each instance of R.sup.bb is, independently, selected from
hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, 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, 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, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0037] 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, 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, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0038] 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, --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, --NRCO.sub.2Re,
--NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2,
--C(.dbd.NR.sup.ff)OR.sup.ee, --OC(.dbd.NR.sup.ff)R.sup.ee,
OC(.dbd.NR.sup.ff)OR.sup.ee, --C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffSO.sub.2R.sup.ee, --SO.sub.2N(R.sup.ff).sub.2,
--SO.sub.2R.sup.ee, --SO.sub.2OR.sup.ee, --OSO.sub.2R.sup.ee,
--S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi(R.sup.ee).sub.3,
--C(.dbd.S)N(R.sup.ff).sub.2, --C(.dbd.O)SR.sup.ee,
--C(.dbd.S)SR.sup.ee, --SC(.dbd.S)SR.sup.ee,
--P(.dbd.O).sub.2R.sup.ee, --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.1-5 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, 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;
[0039] 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, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10
membered heterocyclyl, and 3-10 membered heteroaryl, wherein each
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups;
[0040] 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, 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 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0041] 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, --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).sub.2(C.sub.1-6 alkyl),
--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, 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 is a
counterion.
[0042] 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., methanesulfonate,
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).
[0043] "Halo" or "halogen" refers to fluorine (fluoro, --F),
chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine (iodo,
--I).
[0044] "Hydroxyl" or "hydroxy" refers to the group --OH.
"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, --OP(.dbd.O).sub.2R.sup.aa,
--OP(.dbd.O)(R.sup.aa).sub.2, --OP(.dbd.O)(OR.sup.cc).sub.2,
--OP(.dbd.O).sub.2N(R.sup.bb).sub.2, and
--OP(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein.
[0045] "Thiol" or "thio" refers to the group --SH. "Substituted
thiol" or "substituted thio," by extension, refers to a thiol group
wherein the sulfur atom directly attached to the parent molecule is
substituted with a group other than hydrogen, and includes groups
selected from --SR.sup.aa, --S.dbd.SR.sup.cc,
--SC(.dbd.S)SR.sup.aa, --SC(.dbd.O)SR.sup.aa,
--SC(.dbd.O)OR.sup.aa, and --SC(.dbd.O)R.sup.aa, wherein R.sup.aa
and R.sup.cc are as defined herein.
[0046] "Amino" refers to the group --NH.sub.2. "Substituted amino,"
by extension, refers to a monosubstituted amino, a disubstituted
amino, or a trisubstituted amino, as defined herein. In certain
embodiments, the "substituted amino" is a monosubstituted amino or
a disubstituted amino group.
[0047] "Monosubstituted amino" refers to an amino group wherein the
nitrogen atom directly attached to the parent molecule is
substituted with one hydrogen and one group other than hydrogen,
and includes groups selected from --NH(R.sup.bb),
--NHC(.dbd.O)R.sup.aa, --NHCO.sub.2R.sup.aa,
--NHC(.dbd.O)N(R.sup.bb).sub.2,
--NHC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --NHSO.sub.2R.sup.aa,
--NHP(.dbd.O)(OR.sup.cc).sub.2, and --NHP(.dbd.O)(NR.sup.bb).sub.2,
wherein R.sup.aa, R.sup.bb and R.sup.cc are as defined herein, and
wherein R.sup.bb of the group --NH(R.sup.bb) is not hydrogen.
[0048] "Disubstituted amino" refers to an amino group wherein the
nitrogen atom directly attached to the parent molecule is
substituted with two groups other than hydrogen, and includes
groups selected from --N(R.sup.bb).sub.2, --NR.sup.bb
C(.dbd.O)R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
and --NR.sup.bbP(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa,
R.sup.bb, and R.sup.cc are as defined herein, with the proviso that
the nitrogen atom directly attached to the parent molecule is not
substituted with hydrogen.
[0049] "Trisubstituted amino" refers to an amino group wherein the
nitrogen atom directly attached to the parent molecule is
substituted with three groups, and includes groups selected from
--N(R.sup.bb).sub.3 and --N(R.sup.bb).sub.3.sup.+X, wherein
R.sup.bb and X are as defined herein.
[0050] "Sulfonyl" refers to a group selected from
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa, and
--SO.sub.2OR.sup.aa wherein R.sup.aa and R.sup.bb are as defined
herein.
[0051] "Sulfinyl" refers to the group --S(.dbd.O)R.sup.aa, wherein
R.sup.aa is as defined herein.
[0052] "Carbonyl" refers a group wherein the carbon directly
attached to the parent molecule is sp.sup.2 hybridized, and is
substituted with an oxygen, nitrogen or sulfur atom, e.g., a group
selected from ketones (--C(.dbd.O)R.sup.aa), carboxylic acids
(--CO.sub.2H), aldehydes (--CHO), esters (--CO.sub.2R.sup.aa,
--C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa), amides
(--C(.dbd.O)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa,
--C(.dbd.S)N(R.sup.bb).sub.2), and imines
(--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), wherein R.sup.aa and
R.sup.bb are as defined herein.
[0053] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quarternary nitrogen atoms. Exemplary nitrogen atom substitutents
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).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, 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, or two
R.sup.cc groups attached to a nitrogen atom are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, 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.
[0054] 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.
[0055] Amide nitrogen protecting groups (e.g., --C(.dbd.O)R.sup.aa)
include, but are not limited to, formamide, acetamide,
chloroacetamide, trichloroacetamide, trifluoroacetamide,
phenylacetamide, 3-phenylpropanamide, picolinamide,
3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,
p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,
acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide,
3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,
2-methyl-2-(o-nitrophenoxy)propanamide,
2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,
3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine,
o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.
[0056] Carbamate nitrogen protecting groups (e.g.,
--C(.dbd.O)OR.sup.aa) include, but are not limited to, methyl
carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc),
9-(2-sulfo)fluorenylmethyl carbamate,
9-(2,7-dibromo)fluoroenylmethyl carbamate,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl
carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),
2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl
carbamate (Teoc), 2-phenylethyl carbamate (hZ),
1-(1-adamantyl)-1-methylethyl carbamate (Adpoc),
1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl
carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),
1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'-
and 4'-pyridyl)ethyl carbamate (Pyoc),
2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate
(BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl
carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl
carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl
carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate,
benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),
p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl
carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl
carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl
carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl
carbamate, 2-(p-toluenesulfonyl)ethyl carbamate,
[2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl
carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc),
2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl
carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate,
m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl
carbamate, 5-benzisoxazolylmethyl carbamate,
2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc),
m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate,
o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate,
phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl
thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate,
cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl
carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl
carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,
1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,
2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl
carbamate, isobutyl carbamate, isonicotinyl carbamate,
p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl
carbamate, 1-methylcyclohexyl carbamate,
1-methyl-1-cyclopropylmethyl carbamate,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,
1-methyl-1-(p-phenylazophenyl)ethyl carbamate,
1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl
carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate,
2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl
carbamate, and 2,4,6-trimethylbenzyl carbamate.
[0057] Sulfonamide nitrogen protecting 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), P-trimethylsilylethanesulfonamide (SES),
9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide.
[0058] 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).
[0059] In certain embodiments, the substituent present on an oxygen
atom is an oxygen protecting group (also referred to as a 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)N(R.sup.bb2,
--C(.dbd.NR.sup.bb)R.sup.aa, --C(.dbd.NR.sup.bbOR,
--C(.dbd.NR.sup.bbN(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. 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.
[0060] Exemplary oxygen protecting groups include, but are not
limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM),
t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM),
benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM),
(4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM),
t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl,
2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),
tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,
tetrahydrothiopyranyl, 1-methoxycyclohexyl,
4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl,
4-methoxytetrahydrothiopyranyl S,S-dioxide,
1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP),
1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,
1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl,
4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
o-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), methyl carbonate,
9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, t-butyl
carbonate (Boc), 2,2,2-trichloroethyl carbonate (Troc),
2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl
carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),
isobutyl carbonate, vinyl carbonate, allyl carbonate, p-nitrophenyl
carbonate, benzyl carbonate, p-methoxybenzyl carbonate,
3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate,
p-nitrobenzyl carbonate, S-benzyl thiocarbonate,
4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate,
2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate,
o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate,
2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate,
2-(methylthiomethoxymethyl)benzoate,
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,
o-(methoxyacyl)benzoate, co-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,
borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,
sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate
(Ts).
[0061] 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,
--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. 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.
[0062] These and other exemplary substituents are described in more
detail in the Detailed Description, Examples, and claims. The
present disclosure is not intended to be limited in any manner by
the above exemplary listing of substituents.
[0063] "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 other 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.
Pharmaceutically acceptable salts of the compounds describe 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 used 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.1-4alkyl).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,
quaternary salts.
[0064] A "subject" to which administration is contemplated
includes, but is not limited to, humans (e.g., a male or female of
any age group, e.g., a pediatric subject (e.g, infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult
or senior adult)) and/or other non-human animals, for example,
non-human mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus
monkeys); commercially relevant mammals such as cattle, pigs,
horses, sheep, goats, cats, and/or dogs), birds (e.g., commercially
relevant birds such as chickens, ducks, geese, and/or turkeys),
rodents (e.g., rats and/or mice), reptiles, amphibians, and fish.
In certain embodiments, the non-human animal is a mammal. The
non-human animal may be a male or female at any stage of
development. A non-human animal may be a transgenic animal.
[0065] "Condition," "disease," and "disorder" are used
interchangeably herein.
[0066] "Treat," "treating" and "treatment" encompasses an action
that occurs while a subject is suffering from a condition which
reduces the severity of the condition or retards or slows the
progression of the condition ("therapeutic treatment"). "Treat,"
"treating" and "treatment" also encompasses an action that occurs
before a subject begins to suffer from the condition and which
inhibits or reduces the severity of the condition ("prophylactic
treatment").
[0067] An "effective amount" of a compound refers to an amount
sufficient to elicit the desired biological response, e.g., treat
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.
An effective amount encompasses therapeutic and prophylactic
treatment.
[0068] A "therapeutically effective amount" of a compound is an
amount sufficient to provide a therapeutic benefit in the treatment
of a condition or to delay or minimize one or more symptoms
associated with the condition. A therapeutically effective amount
of a compound means an amount of therapeutic agent, alone or in
combination with other therapies, which provides a therapeutic
benefit in the treatment of the condition. The term
"therapeutically effective amount" can encompass an amount that
improves overall therapy, reduces or avoids symptoms or causes of
the condition, or enhances the therapeutic efficacy of another
therapeutic agent.
[0069] A "prophylactically effective amount" of a compound 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.
[0070] As used herein, the term "methyltransferase" represents
transferase class enzymes that are able to transfer a methyl group
from a donor molecule to an acceptor molecule, e.g., an amino acid
residue of a protein or a nucleic base of a DNA molecule.
Methytransferases typically use a reactive methyl group bound to
sulfur in S-adenosyl methionine (SAM) as the methyl donor. In some
embodiments, a methyltransferase described herein is a protein
methyltransferase. In some embodiments, a methyltransferase
described herein is a histone methyltransferase. Histone
methyltransferases (HMT) are histone-modifying enzymes, (including
histone-lysine N-methyltransferase and histone-arginine
N-methyltransferase), that catalyze the transfer of one or more
methyl groups to lysine and arginine residues of histone proteins.
In certain embodiments, a methyltransferase described herein is a
histone-arginine N-methyltransferase.
[0071] As generally described above, provided herein are compounds
useful as CARM1 inhibitors. In some embodiments, the present
disclosure provides a compound of Formula (I):
##STR00005##
or a pharmaceutically acceptable salt thereof; wherein:
[0072] X is --O--, --S--, or --CH.sub.2--;
[0073] R.sup.1 is hydrogen or optionally substituted C.sub.1-4
aliphatic;
[0074] each of R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d is
independently hydrogen, halogen, --CN, --NO.sub.2,
--C(.dbd.O)R.sup.A2, --C(.dbd.O)OR.sup.A2,
--C(.dbd.O)N(R.sup.A2).sub.2, --OR.sup.A2, --SR.sup.A2,
--N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A2,
--S(.dbd.O).sub.2R.sup.A2, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
wherein each instance of R.sup.A2 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.A2 groups
attached to the same nitrogen atom are joined to form an optionally
substituted heterocyclyl or optionally substituted heteroaryl
ring;
[0075] Ring HET is a 6-membered monocyclic heteroaryl ring system
of the formula:
##STR00006##
wherein:
[0076] G.sub.8 is C--R.sup.8 or N;
[0077] G.sub.10 is C--R.sup.10 or N;
[0078] G.sub.11 is C--R.sup.11 or N;
[0079] G.sub.12 is C--R.sup.12 or N;
[0080] provided at least one instance of G.sub.8, G.sub.10,
G.sub.11, or G.sub.12 is N;
[0081] each instance of R.sup.8, R.sup.10, R.sup.11, and R.sup.12
is independently selected from the group consisting of hydrogen,
halo, --CN, --NO.sub.2, --C(.dbd.O)R', --C(.dbd.O)OR',
--C(.dbd.O)N(R').sub.2, optionally substituted alkyl, and
-L.sup.1-R.sup.3;
[0082] each instance of R' is independently hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl, or two R' groups attached to the
same nitrogen are joined to form an optionally substituted
heterocyclyl ring or optionally substituted heteroaryl ring;
[0083] each instance of L.sup.1 and L.sup.2 is independently a
bond, --O--, --N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.2--, --SO.sub.2N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--, an optionally substituted
C.sub.1-10 saturated or unsaturated hydrocarbon chain, wherein one
or more moieties selected from the group consisting of --O--,
--N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L)--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.2--, --SO.sub.2N(R.sup.L)--, and
--N(R.sup.L)SO.sub.2N(R.sup.L)-- is optionally and independently
present between two carbon atoms of the hydrocarbon chain, and
optionally and independently present at one or both ends of the
hydrocarbon chain;
[0084] each R.sup.L is independently hydrogen, optionally
substituted alkyl, or a nitrogen protecting group, or R.sup.L and
R.sup.3 taken together form an optionally substituted heterocyclyl
or optionally substituted heteroaryl ring, or R.sup.L and R.sup.13
taken together form an optionally substituted heterocyclyl or
optionally substituted heteroaryl ring;
[0085] R.sup.3 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, or optionally
substituted heteroaryl, provided when R.sup.3 is hydrogen, then
L.sup.1 is not a bond; and
[0086] R.sup.13 is optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl.
[0087] It is generally understood that compounds of Formula (I), as
described herein, comprises one or more asymmetric centers, and
thus can exist in various isomeric forms, e.g., enantiomeric and/or
diastereomeric forms. In certain embodiments, the compound of
Formula (I) has the following stereochemistry (I-a) or (I-b):
##STR00007##
[0088] As generally defined herein, X is --O--, --S--, or
--CH.sub.2--. In certain embodiments, X is --O--. In certain
embodiments, X is --S--. In certain embodiments, X is --O--.
[0089] As generally defined herein, R.sup.1 is hydrogen or
optionally substituted C.sub.1-4 aliphatic. In certain embodiments,
R.sup.1 is hydrogen. In certain embodiments, R.sup.1 is optionally
substituted C.sub.1-4 aliphatic, e.g., optionally substituted
C.sub.1 aliphatic, optionally substituted C.sub.2 aliphatic,
optionally substituted C.sub.3 aliphatic, or optionally substituted
C.sub.4 aliphatic. It is understood that aliphatic, as used herein,
encompasses alkyl, alkenyl, alkynyl, and carbocyclic groups. In
certain embodiments, R.sup.1 is optionally substituted C.sub.1-4
alkyl, e.g., optionally substituted C.sub.1-2alkyl, optionally
substituted C.sub.2-3alkyl, optionally substituted C.sub.3-4alkyl,
optionally substituted C.sub.1alkyl, optionally substituted
C.sub.2alkyl, optionally substituted C.sub.3alkyl, or optionally
substituted C.sub.4alkyl. Exemplary R.sup.1 C.sub.1-4 alkyl groups
include, but are not limited to, methyl (C.sub.1), ethyl (C.sub.2),
n-propyl (C.sub.3), isopropyl (C.sub.3), n-butyl (C.sub.4),
tert-butyl (C.sub.4), sec-butyl (C.sub.4), or iso-butyl (C.sub.4),
each of which may be substituted or unsubstituted. In certain
embodiments, R.sup.1 is optionally substituted C.sub.2-4 alkenyl,
e.g., optionally substituted C.sub.2-3alkenyl, optionally
substituted C.sub.3-alkenyl, optionally substituted C.sub.2alkenyl,
optionally substituted C.sub.3alkenyl, or optionally substituted
C.sub.4alkenyl. In certain embodiments, R.sup.1 is optionally
substituted C.sub.2-4 alkynyl, e.g., optionally substituted
C.sub.2-3alkynyl, optionally substituted C.sub.3-alkynyl,
optionally substituted C.sub.2alkynyl, optionally substituted
C.sub.3alkynyl, or optionally substituted C.sub.4alkynyl. In
certain embodiments, R.sup.1 is optionally substituted
C.sub.3carbocyclyl, e.g., optionally substituted cyclopropyl. In
certain embodiments, R.sup.1 is hydrogen or an unsubstituted
C.sub.1-4 aliphatic group, e.g., for example, in certain
embodiments, R.sup.1 is hydrogen, methyl, ethyl, n-propyl,
isopropyl, or cyclopropyl.
[0090] As generally defined herein, each of R.sup.2a, R.sup.2b,
R.sup.2c, and R.sup.2d is independently hydrogen, halo, --CN,
--NO.sub.2, --C(.dbd.O)R.sup.A2, --C(.dbd.O)OR.sup.A2,
--C(.dbd.O)N(R.sup.A2).sub.2, --OR.sup.A2, --SR.sup.A2,
--N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A2,
--S(.dbd.O).sub.2R.sup.A2, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
wherein each instance of R.sup.A2 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.A2 groups
attached to the same nitrogen atom are joined to form an optionally
substituted heterocyclyl or optionally substituted heteroaryl
ring.
[0091] In certain embodiments, at least one of (e.g., one, two,
three, each of) R.sup.2a, R.sup.2b, R.sup.2c and R.sup.2d is
hydrogen. In certain embodiments, at least one of R.sup.2a,
R.sup.2b, R.sup.2c, and R.sup.2d is halo, e.g., fluoro, chloro,
bromo, or iodo. In certain embodiments, at least one of R.sup.2a,
R.sup.2b, R.sup.2c, and R.sup.2d is chloro. In certain embodiments,
at least one of R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d is --CN.
In certain embodiments, at least one of R.sup.2a, R.sup.2b,
R.sup.2c, and R.sup.2d is --NO.sub.2. In certain embodiments, at
least one of R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d is
--C(.dbd.O)R.sup.A2, e.g., wherein R.sup.A2 is hydrogen or
optionally substituted alkyl (e.g., methyl). In certain
embodiments, at least one of R.sup.2a, R.sup.2b, R.sup.2c, and
R.sup.2d is --C(.dbd.O)OR.sup.A2, e.g., wherein R.sup.A2 is
hydrogen or optionally substituted alkyl (e.g., methyl). In certain
embodiments, at least one of R.sup.2a, R.sup.2b, R.sup.2c, and
R.sup.2d is --C(.dbd.O)N(R.sup.A2).sub.2, e.g., wherein each
instance of R.sup.A2 is hydrogen or optionally substituted alkyl
(e.g., methyl), or two R.sup.A2 groups attached to the same
nitrogen atom are joined to form an optionally substituted
heterocyclyl or optionally substituted heteroaryl ring. In certain
embodiments, at least one of R.sup.2a, R.sup.2b, R.sup.2c, and
R.sup.2d is optionally substituted alkyl, e.g., optionally
substituted C.sub.1-4 alkyl, optionally substituted C.sub.1-2alkyl,
optionally substituted C.sub.2-3alkyl, optionally substituted
C.sub.3-4alkyl, optionally substituted C.sub.1alkyl, optionally
substituted C.sub.2alkyl, optionally substituted C.sub.3alkyl, or
optionally substituted C.sub.4alkyl. Exemplary R.sup.2a, R.sup.2b,
R.sup.2c, and R.sup.2d C.sub.1-4alkyl groups include, but are not
limited to, methyl (C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3),
isopropyl (C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4),
sec-butyl (C.sub.4), and iso-butyl (C.sub.4), each of which may be
substituted or unsubstituted. In certain embodiments, at least one
of R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d is alkyl substituted
with hydroxy or substituted hydroxy, e.g., --(CH.sub.2).sub.aOH or
--(CH.sub.2).sub.aOCH.sub.3, wherein a is 1, 2, 3, 4, 5, or 6. In
certain embodiments, at least one of R.sup.2a, R.sup.2b, R.sup.2c,
and R.sup.2d is alkyl substituted with halogen (e.g., fluoro),
e.g., at least one of R.sup.2aR.sup.2b, R.sup.2c, and R.sup.2d is
--CF.sub.3. In certain embodiments, at least one of R.sup.2a,
R.sup.2b, R.sup.2c, and R.sup.2d is optionally substituted alkenyl,
e.g., optionally substituted C.sub.2-4 alkenyl, optionally
substituted C.sub.2-3alkenyl, optionally substituted
C.sub.3-alkenyl, optionally substituted C.sub.2alkenyl, optionally
substituted C.sub.3alkenyl, or optionally substituted
C.sub.4alkenyl. In certain embodiments, at least one of R.sup.2a,
R.sup.2b, R.sup.2c, and R.sup.2d is optionally substituted
C.sub.2alkenyl or optionally substituted C.sub.3alkenyl, e.g.,
vinyl or allyl. In certain embodiments, at least one of R.sup.2a,
R.sup.2b, R.sup.2c, and R.sup.2d is optionally substituted alkynyl,
e.g., optionally substituted C.sub.2-4 alkynyl, optionally
substituted C.sub.2-3alkynyl, optionally substituted
C.sub.3-alkynyl, optionally substituted C.sub.2alkynyl, optionally
substituted C.sub.3alkynyl, or optionally substituted
C.sub.4alkynyl. In certain embodiments, at least one of R.sup.2a,
R.sup.2b, R.sup.2c, and R.sup.2d is optionally substituted
C.sub.2alkynyl, e.g., acetylene. In certain embodiments, at least
one of R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d is optionally
substituted carbocyclyl, e.g., optionally substituted C.sub.3-5
carbocyclyl, optionally substituted C.sub.3-carbocyclyl, optionally
substituted C.sub.4-5 carbocyclyl, optionally substituted
C.sub.3carbocyclyl, optionally substituted C.sub.4carbocyclyl, or
optionally substituted C.sub.5carbocyclyl. In certain embodiments,
at least one of R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d is
optionally substituted C.sub.3carbocyclyl, e.g., cyclopropyl. In
certain embodiments, at least one of R.sup.2a, R.sup.2b, R.sup.2c,
and R.sup.2d is optionally substituted heterocyclyl, e.g.,
optionally substituted 3- to 5-membered heterocyclyl, optionally
substituted 3- to 4-membered heterocyclyl, optionally substituted
4- to 5-membered heterocyclyl, optionally substituted 3-membered
heterocyclyl, optionally substituted 4-membered heterocyclyl, or
optionally substituted 5-membered heterocyclyl. In certain
embodiments, at least one of R.sup.2a, R.sup.2b, R.sup.2c, and
R.sup.2d is --OR.sup.A2, --SR.sup.A2, or --N(R.sup.A2).sub.2,
wherein R.sup.A2 is as defined herein. In certain embodiments, at
least one of R.sup.2a, R.sup.2b, R.sup.2c and R.sup.2d is
--S(.dbd.O)R.sup.A2 or --S(.dbd.O).sub.2R.sup.A2, wherein R.sup.A2
is as defined herein. In certain embodiments, at least one R.sup.A2
is hydrogen, e.g., for example, to provide at least one of
R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d as --OH, --SH,
--NH.sub.2, or --NHR.sup.A2. In certain embodiments, at least one
of R.sup.A2 is optionally substituted alkyl, e.g., optionally
substituted C.sub.1-4 alkyl, optionally substituted C.sub.1-2alkyl,
optionally substituted C.sub.2-3alkyl, optionally substituted
C.sub.3-alkyl, optionally substituted C.sub.1alkyl, optionally
substituted C.sub.2alkyl, optionally substituted C.sub.3alkyl, or
optionally substituted C.sub.4alkyl, e.g., for example, at least
one of R.sup.A2 is methyl to provide a group R.sup.2a, R.sup.2b,
R.sup.2c, and R.sup.2d of formula --OCH.sub.3, --SCH.sub.3,
--NHCH.sub.3, --N(CH.sub.3).sub.2, or --NCH.sub.3R.sup.A2. In
certain embodiments, at least one of R.sup.A2 is alkyl substituted
with halogen (e.g., fluoro), e.g., to provide a group R.sup.2a,
R.sup.2b, R.sup.2c and R.sup.2d of formula --OCF.sub.3,
--SCF.sub.3, --NHCF.sub.3, --N(CF.sub.3).sub.2, or
--NCF.sub.3R.sup.A2. In certain embodiments, at least one of
R.sup.A2 is a group of formula --CH.sub.2CH(OH)CH.sub.2NHR.sup.1,
wherein R.sup.1 is as defined herein, e.g., to provide a group
R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d of formula
--OCH.sub.2CH(OH)CH.sub.2NHR.sup.1,
--SCH.sub.2CH(OH)CH.sub.2NHR.sup.1,
--NHCH.sub.2CH(OH)CH.sub.2NHR.sup.1, or
--N(R.sup.A2)CH.sub.2CH(OH)CH.sub.2NHR.sup.1. In certain
embodiments, at least one of R.sup.A2 is alkyl substituted with an
optionally substituted aryl (e.g., optionally substituted phenyl)
or optionally substituted heteroaryl (e.g., optionally substituted
pyridinyl), e.g., to provide a group R.sup.2a, R.sup.2b, R.sup.2c,
and R.sup.2d of formula --O(CH.sub.2).sub.aAr,
--S(CH.sub.2).sub.aAr, --NH(CH.sub.2).sub.aAr, or
--N(R.sup.A2)(CH.sub.2).sub.aAr, wherein a is 1, 2, 3, 4, 5, or 6,
and Ar is optionally substituted aryl (e.g., optionally substituted
phenyl) or optionally substituted heteroaryl (e.g., optionally
substituted pyridinyl). In certain embodiments, at least one of
R.sup.A2 is optionally substituted alkenyl, e.g., optionally
substituted C.sub.2-4 alkenyl, optionally substituted
C.sub.2-3alkenyl, optionally substituted C.sub.3-alkenyl,
optionally substituted C.sub.2alkenyl, optionally substituted
C.sub.3alkenyl, or optionally substituted C.sub.4alkenyl. In
certain embodiments, at least one of R.sup.A2 is optionally
substituted alkynyl, e.g., optionally substituted C.sub.2-4
alkynyl, optionally substituted C.sub.2-3alkynyl, optionally
substituted C.sub.3-alkynyl, optionally substituted C.sub.2alkynyl,
optionally substituted C.sub.3alkynyl, or optionally substituted
C.sub.4alkynyl. In certain embodiments, at least one of R.sup.A2 is
optionally substituted carbocyclyl, e.g., optionally substituted
C.sub.3-5carbocyclyl, optionally substituted C.sub.3-carbocyclyl,
optionally substituted C.sub.4-5 carbocyclyl, optionally
substituted C.sub.3carbocyclyl, optionally substituted
C.sub.4carbocyclyl, or optionally substituted C.sub.5carbocyclyl.
In certain embodiments, at least one of R.sup.A2 is optionally
substituted heterocyclyl, e.g., optionally substituted 3- to
5-membered heterocyclyl, optionally substituted 3- to 4-membered
heterocyclyl, optionally substituted 4- to 5-membered heterocyclyl,
optionally substituted 3-membered heterocyclyl, optionally
substituted 4-membered heterocyclyl, or optionally substituted
5-membered heterocyclyl. In certain embodiments, at least one of
R.sup.A2 is optionally substituted aryl (e.g., optionally
substituted phenyl) or optionally substituted heteroaryl (e.g.,
optionally substituted pyridinyl). In certain embodiments, two
R.sup.A2 groups, e.g., of --N(R.sup.A2).sub.2, are joined to form
an optionally substituted heterocyclyl or optionally substituted
heteroaryl ring.
[0092] In certain embodiments, at least one of R.sup.2a, R.sup.2b,
R.sup.2c, and R.sup.2d is hydrogen. In certain embodiments, at
least two of R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d is
hydrogen. In certain embodiments, at least three of R.sup.2a,
R.sup.2b, R.sup.2c, and R.sup.2d is hydrogen. In certain
embodiments, each of R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are
hydrogen, e.g., to provide a compound of Formula (I-c):
##STR00008##
or a pharmaceutically acceptable salt thereof.
[0093] However, in certain embodiments, at least one of R.sup.2a,
R.sup.2b, R.sup.2c, and R.sup.2d is a non-hydrogen group. For
example, in certain embodiments, R.sup.2a is a non-hydrogen group.
In certain embodiments, R.sup.2a is a non-hydrogen group, and each
of R.sup.2b, R.sup.2c, and R.sup.2d is hydrogen, e.g., to provide a
compound of Formula (I-d):
##STR00009##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, R.sup.2a is a non-hydrogen group selected from the
group consisting of halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.A2, --OR.sup.A2, --SR.sup.A2, --N(R.sup.A2).sub.2,
optionally substituted cyclopropyl, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.2-4alkenyl, and
optionally substituted C.sub.2-4alkynyl, wherein R.sup.A2 is
optionally substituted alkyl.
[0094] In certain embodiments, R.sup.2b is a non-hydrogen group. In
certain embodiments, R.sup.2b is a non-hydrogen group, and each of
R.sup.2a, R.sup.2c, and R.sup.2d is hydrogen, e.g., to provide a
compound of Formula (I-e):
##STR00010##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, R.sup.2b is a non-hydrogen group selected from the
group consisting of halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.A2, --OR, --SR.sup.A2, --N(R.sup.A2).sub.2,
optionally substituted cyclopropyl, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.2-4alkenyl, and
optionally substituted C.sub.2-4alkynyl, wherein R.sup.A2 is
optionally substituted alkyl.
[0095] In certain embodiments, R.sup.2c is a non-hydrogen group. In
certain embodiments, R.sup.2c is a non-hydrogen group, and each of
R.sup.2a, R.sup.2b, and R.sup.2d is hydrogen, e.g., to provide a
compound of Formula (I-f):
##STR00011##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, R.sup.2c is a non-hydrogen group selected from the
group consisting of halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.A2, --OR, --SR.sup.A2, --N(R.sup.A2).sub.2,
optionally substituted cyclopropyl, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.2-4alkenyl, and
optionally substituted C.sub.2-4alkynyl, wherein R.sup.A2 is
optionally substituted alkyl.
[0096] In certain embodiments, R.sup.2d is a non-hydrogen group. In
certain embodiments, R.sup.2d is a non-hydrogen group, and each of
R.sup.2a, R.sup.2b, and R.sup.2c is hydrogen, e.g., to provide a
compound of Formula (I-g):
##STR00012##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, R.sup.2d is a non-hydrogen group selected from the
group consisting of halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.A2, --OR.sup.A2, --SR, --N(R.sup.A2).sub.2,
optionally substituted cyclopropyl, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.2-4alkenyl, and
optionally substituted C.sub.2-4alkynyl, wherein R.sup.A2 is
optionally substituted alkyl.
[0097] As generally understood from the present disclosure, Ring
HET is a 6-membered monocyclic heteroaryl ring system of
Formula:
##STR00013##
i.e., to provide a compound of Formula (I-h):
##STR00014##
or pharmaceutically acceptable salt thereof, wherein at least one
instance of G.sub.8, G.sub.10, G.sub.11, or G.sub.12 is N, e.g., at
least one, two, or three instances of G.sub.8, G.sub.10, G.sub.11,
or G.sub.12 is N. In certain embodiments, G.sub.8 is N. In certain
embodiments, G.sub.10 is N. In certain embodiments, G.sub.11 is N.
In certain embodiments, G.sub.12 is N. In certain embodiments, two
instances of G.sub.8, G.sub.10, G.sub.11, or G.sub.12 are N. In
certain embodiments, G.sub.8 and G.sub.10 are both N. In certain
embodiments, G.sub.8 and G.sub.11 are both N. In certain
embodiments, G.sub.8 and G.sub.12 are both N. In certain
embodiments, G.sub.10 and G.sub.12 are both N. In certain
embodiments, three instances of G.sub.8, G.sub.10, G.sub.11, or
G.sub.12 are N. In certain embodiments, G.sub.8, G.sub.10, and
G.sub.12 are each N.
[0098] Exemplary Ring HET groups of the formula (i), (ii), or
(iii), include, but are not limited to, any one of the following
ring systems, wherein one, two, or three instances of G.sub.8,
G.sub.10, G.sub.11, and G.sub.12 are N:
##STR00015##
[0099] Furthermore, as generally defined above, each instance of
R.sup.8, R.sup.10, R.sup.11, and R.sup.12 is independently selected
from the group consisting of hydrogen, halo, --CN, --NO.sub.2,
--C(.dbd.O)R', --C(.dbd.O)OR', --C(.dbd.O)N(R').sub.2, optionally
substituted alkyl, or -L.sup.1-R.sup.3; wherein L.sup.1, R.sup.3,
and R' are as defined herein. In certain embodiments, one of
R.sup.8, R.sup.10, R.sup.11, and R.sup.12 is -L.sup.1-R.sup.3.
Alternatively, neither R.sup.8, R.sup.10, R.sup.11, and R.sup.12 is
-L.sup.1-R.sup.3. In certain embodiments, R.sup.8 is
-L.sup.1-R.sup.3. In certain embodiments, R.sup.10 is
-L.sup.1-R.sup.3. In certain embodiments, R.sup.11 is
-L.sup.1-R.sup.3. In certain embodiments, R.sup.12 is
-L.sup.1-R.sup.3. In certain embodiments, one instance of R.sup.8,
R.sup.10, R.sup.11, and R.sup.12 is a -L.sup.1-R.sup.3 and the
other instances (i.e., one or two instances) are a hydrogen or
non-hydrogen moiety selected from the group consisting of halo,
--CN, --NO.sub.2, --C(.dbd.O)R', --C(.dbd.O)OR',
--C(.dbd.O)N(R').sub.2, or optionally substituted alkyl. For
example, in certain embodiments, at least one instance of R.sup.8,
R.sup.10, R.sup.11, and R.sup.12 is halo, e.g., fluoro, chloro,
bromo, or iodo. In certain embodiments, at least one instance of
R.sup.8, R.sup.10, R.sup.11, and R.sup.12 is --CN. In certain
embodiments, at least one instance of R.sup.8, R.sup.10, R.sup.11,
and R.sup.12 is --NO.sub.2. In certain embodiments, at least one
instance of R.sup.8, R.sup.10, R.sup.11, and R.sup.12 is
--C(.dbd.O)R', --C(.dbd.O)OR', or --C(.dbd.O)N(R').sub.2, wherein
R' is as defined herein. In certain embodiments, at least one
instance of R.sup.8, R.sup.10, R.sup.11, and R.sup.12 is optionally
substituted alkyl, e.g., optionally substituted C.sub.1-4 alkyl,
optionally substituted C.sub.1-2alkyl, optionally substituted
C.sub.2-3alkyl, optionally substituted C.sub.3-alkyl, optionally
substituted C.sub.1alkyl, optionally substituted C.sub.2alkyl,
optionally substituted C.sub.3alkyl, or optionally substituted
C.sub.4alkyl. In certain embodiments, at least one instance of
R.sup.8, R.sup.10, R.sup.11, and R.sup.12 is methyl. In certain
embodiments, each instance of R.sup.8, R.sup.10, R.sup.11, and
R.sup.12 is hydrogen. In certain embodiments, at least one instance
of R.sup.8, R.sup.10, R.sup.11, and R.sup.12 is hydrogen or
methyl.
[0100] As understood from the present disclosure, Ring HET
optionally comprises a group -L.sup.1-R.sup.3 attached thereto. In
certain embodiments, Ring HET does not comprise a group of formula
-L.sup.1-R.sup.3 attached thereto, but in other embodiments, Ring
HET does comprise a group of formula -L.sup.1-R.sup.3 attached
thereto. In certain embodiments, -L.sup.1-R.sup.3 is meta to the
point of attachment of Ring HET to the parent moiety. In certain
embodiments, -L.sup.1-R.sup.3 is meta to -L.sup.2-R.sup.13. In
certain embodiments, R.sup.3 is an acyclic moiety selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, or optionally substituted alkynyl.
In certain embodiments, R.sup.3 is a cyclic moiety selected from
the group consisting of optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
and optionally substituted heteroaryl. In certain embodiments,
R.sup.3 is directly attached to the Ring HET, i.e., wherein L.sup.1
is a bond, provided that R.sup.3 is not also hydrogen. In other
embodiments, R.sup.3 is indirectly attached to Ring HET, i.e.,
wherein L.sup.1 is a linking group.
[0101] As generally defined herein, L.sup.1 is a bond, --O--,
--N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L)--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.2--, --SO.sub.2N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--, or an optionally substituted
C.sub.1-10 saturated or unsaturated hydrocarbon chain, wherein one
or more moieties selected from the group consisting of --O--,
--N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L)--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.2--, --SO.sub.2N(R.sup.L)--, and
--N(R.sup.L)SO.sub.2N(R.sup.L)-- is optionally and independently
present between two carbon atoms of the hydrocarbon chain, and
optionally and independently present at one or both ends of the
hydrocarbon chain. It is understood that the linker joining R.sup.3
to Ring HET may comprise one or more of the above recited moieties
in combination to form the group L.sup.1.
[0102] In certain embodiments, L.sup.1 is a bond. In certain
embodiments, L.sup.1 is a bond, and R.sup.3 is optionally
substituted alkyl, optionally substituted alkenyl, or optionally
substituted alkynyl. In certain embodiments, L.sup.1 is a bond, and
R.sup.3 is optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, and
optionally substituted heteroaryl.
[0103] In certain embodiments, L.sup.1 is --O--. In certain
embodiments, L.sup.1 is --N(R.sup.L)--. In certain embodiments,
L.sup.1 is --S--. In certain embodiments, L.sup.1 is --C(O)--. In
certain embodiments, L.sup.1 is --C(O)O--. In certain embodiments,
L.sup.1 is --C(O)S--. In certain embodiments, L.sup.1 is
--C(O)N(R.sup.L)--. In certain embodiments, L.sup.1 is
--C(O)N(R.sup.L)N(R.sup.L)--. In certain embodiments, L.sup.1 is
--OC(O)--. In certain embodiments, L.sup.1 is --OC(O)N(R.sup.L)--.
In certain embodiments, L.sup.1 is --NR.sup.LC(O)--. In certain
embodiments, L.sup.1 is --NR.sup.LC(O)N(R.sup.L)--. In certain
embodiments, L.sup.1 is --NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--. In
certain embodiments, L.sup.1 is --NR.sup.LC(O)O--. In certain
embodiments, L.sup.1 is --SC(O)--. In certain embodiments, L.sup.1
is --C(.dbd.NR.sup.L)--. In certain embodiments, L.sup.1 is
--C(.dbd.NNR.sup.L)--. In certain embodiments, L.sup.1 is
--C(.dbd.NOR.sup.L)--. In certain embodiments, L.sup.1 is
--C(.dbd.NR.sup.L)N(R.sup.L)--. In certain embodiments, L.sup.1 is
--NR.sup.LC(.dbd.NR.sup.L)--. In certain embodiments, L.sup.1 is
--C(S)--. In certain embodiments, L.sup.1 is --C(S)N(R.sup.L)--. In
certain embodiments, L.sup.1 is --NR.sup.LC(S)--. In certain
embodiments, L.sup.1 is --S(O)--. In certain embodiments, L.sup.1
is --OS(O).sub.2--. In certain embodiments, L.sup.1 is
--S(O).sub.2O--. In certain embodiments, L.sup.1 is --SO.sub.2--.
In certain embodiments, L.sup.1 is --N(R.sup.L)SO.sub.2--. In
certain embodiments, L.sup.1 is --SO.sub.2N(R.sup.L)--. In certain
embodiments, L.sup.1 is --N(R.sup.L)SO.sub.2N(R.sup.L)--.
[0104] In certain embodiments, L.sup.1 is an optionally substituted
C.sub.1-10 saturated or unsaturated hydrocarbon chain, e.g., in
certain embodiments, L.sup.1 is an optionally substituted C.sub.10
alkyl chain, L.sup.1 is an optionally substituted C.sub.2-10
alkenyl chain, or L.sup.1 is an optionally substituted C.sub.2-10
alkynyl chain. In certain embodiments, L.sup.1 is an optionally
substituted C.sub.1-10 alkyl chain, e.g., an optionally substituted
C.sub.1-8 alkyl chain, optionally substituted C.sub.1-6 alkyl
chain, optionally substituted C.sub.1-4 alkyl chain, optionally
substituted C.sub.1-3 alkyl chain, or optionally substituted
C.sub.1-2 alkyl chain. In certain embodiments, L.sup.1 is an
unsubstituted C.sub.1-10 n-alkyl chain of the formula
--(CH.sub.2).sub.x--, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10. In certain embodiments, L.sup.1 is an optionally substituted
C.sub.2-10 alkenyl chain, e.g., an optionally substituted C.sub.2-8
alkenyl chain, optionally substituted C.sub.2-6 alkenyl chain,
optionally substituted C.sub.2-4 alkenyl chain, optionally
substituted C.sub.2-3 alkenyl chain, or optionally substituted
C.sub.2 alkenyl chain. In certain embodiments, L.sup.1 is an
optionally substituted C.sub.2-10 alkynyl chain, e.g., an
optionally substituted C.sub.2-8 alkynyl chain, optionally
substituted C.sub.2-6 alkynyl chain, optionally substituted
C.sub.2-4 alkynyl chain, optionally substituted C.sub.2-3 alkynyl
chain, or optionally substituted C.sub.2 alkynyl chain.
[0105] In certain embodiments, L.sup.1 is an optionally substituted
C.sub.1-10 saturated or unsaturated hydrocarbon chain, wherein one
or more moieties selected from the group consisting of --O--,
--N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L)--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.2--, --SO.sub.2N(R.sup.L)--, or
--N(R.sup.L)SO.sub.2N(R.sup.L)-- independently present between two
carbon atoms of the hydrocarbon chain, or present at one or both
ends of the hydrocarbon chain. In this instance, in certain
embodiments, L.sup.1 is a chain of at least 2 atoms, e.g., L.sup.1
is a chain comprising 1 to 10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6,
7, 8, 9, or 10 carbon atoms), and 1 or more of the above recited
moieties (e.g., 1, 2, 3, or more), to provide a chain of between 2
and 20 atoms, inclusive, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, or 20 chain atoms. In certain
embodiments, a moiety is present between two carbon atoms of the
hydrocarbon chain. In certain embodiments, a moiety is present at
one end of the hydrocarbon chain. In certain embodiments, a moiety
is independently present at each end of the hydrocarbon chain. In
certain embodiments, L.sup.1 is an optionally substituted
C.sub.1-10 alkyl chain, L.sup.1 is an optionally substituted
C.sub.2-10 alkenyl chain, or L.sup.1 is an optionally substituted
C.sub.2-10 alkynyl chain comprising one or more of the above
recited moieties independently present between two carbon atoms of
the hydrocarbon chain, or present at one or both ends of the
hydrocarbon chain. In certain embodiments, L.sup.1 is an optionally
substituted C.sub.1-10 alkyl chain, e.g., an optionally substituted
C.sub.1-8 alkyl chain, optionally substituted C.sub.1-6 alkyl
chain, optionally substituted C.sub.1-4 alkyl chain, optionally
substituted C.sub.1-3 alkyl chain, or optionally substituted
C.sub.1-2 alkyl chain, comprising one or more of the above recited
moieties independently present between two carbon atoms of the
hydrocarbon chain, or present at one or both ends of the
hydrocarbon chain. In certain embodiments, L.sup.1 is an
unsubstituted C.sub.1-10 n-alkyl chain of the formula
--(CH.sub.2).sub.x--, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10, comprising one or more of the above recited moieties
independently present between two carbon atoms of the hydrocarbon
chain, or present at one or both ends of the hydrocarbon chain. In
certain embodiments, L.sup.1 is an optionally substituted
C.sub.2-10 alkenyl chain, e.g., an optionally substituted C.sub.2-8
alkenyl chain, optionally substituted C.sub.2-6 alkenyl chain,
optionally substituted C.sub.2-4 alkenyl chain, optionally
substituted C.sub.2-3 alkenyl chain, or optionally substituted
C.sub.2 alkenyl chain, comprising one or more of the above recited
moieties independently present between two carbon atoms of the
hydrocarbon chain, or present at one or both ends of the
hydrocarbon chain. In certain embodiments, L.sup.1 is an optionally
substituted C.sub.2-10 alkynyl chain, e.g., an optionally
substituted C.sub.2-8 alkynyl chain, optionally substituted
C.sub.2-6 alkynyl chain, optionally substituted C.sub.2-4 alkynyl
chain, optionally substituted C.sub.2-3 alkynyl chain, or
optionally substituted C.sub.2 alkynyl chain, comprising one or
more of the above recited moieties independently present between
two carbon atoms of the hydrocarbon chain, or present at one or
both ends of the hydrocarbon chain.
[0106] As described above, in certain embodiments, L.sup.1 is an
unsubstituted C.sub.1-10 n-alkyl chain of the formula
--(CH.sub.2).sub.x--, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10, comprising one or more of the above recited moieties
independently present between two carbon atoms of the hydrocarbon
chain, or present at one or both ends of the hydrocarbon chain. In
certain embodiments, L.sup.1 is --O--(CH.sub.2).sub.x--,
--(CH.sub.2).sub.x--O--, or --O--(CH.sub.2).sub.x--O--. In certain
embodiments, L.sup.1 is --N(R.sup.L)--(CH.sub.2).sub.x--,
--(CH.sub.2).sub.x--N(R.sup.L)--,
--N(R.sup.L)--(CH.sub.2).sub.x--N(R.sup.L)--,
--O--(CH.sub.2).sub.x--N(R.sup.L)--,
--N(R.sup.L)--(CH.sub.2).sub.x--O--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--, or
--OC(O)--(CH.sub.2).sub.x--N(R.sup.L)--. In certain embodiments,
L.sup.1 is --S--(CH.sub.2).sub.x-- or --(CH.sub.2).sub.x--S--. In
certain embodiments, L.sup.1 is --C(O)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(O)--. In certain embodiments, L.sup.1 is
--C(O)O--(CH.sub.2).sub.x-- or --(CH.sub.2).sub.x--C(O)O--. In
certain embodiments, L.sup.1 is --C(O)S--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(O)S--. In certain embodiments, L.sup.1 is
--C(O)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(O)N(R.sup.L)--. In certain embodiments,
L.sup.1 is --C(O)N(R.sup.L)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(O)N(R.sup.L)N(R.sup.L)--. In certain
embodiments, L.sup.1 is --OC(O)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--OC(O)--. In certain embodiments, L.sup.1 is
--OC(O)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--OC(O)N(R.sup.L)--. In certain embodiments,
L.sup.1 is --NR.sup.LC(O)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(O)--. In certain embodiments, L.sup.1
is --NR.sup.LC(O)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(O)N(R.sup.L)--. In certain
embodiments, L.sup.1 is
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--. In certain
embodiments, L.sup.1 is --NR.sup.LC(O)O--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(O)O--. In certain embodiments,
L.sup.1 is --SC(O)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--SC(O)--. In certain embodiments, L.sup.1 is
--C(.dbd.NR.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.xC(.dbd.NR.sup.L)--. In certain embodiments,
L.sup.1 is --C(.dbd.NNR.sup.L)--(CH.sub.2)-- or
--(CH.sub.2).sub.x--C(.dbd.NNR.sup.L)--. In certain embodiments,
L.sup.1 is --C(.dbd.NOR.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2)--C(.dbd.NOR.sup.L)--. In certain embodiments, L.sup.1
is --C(.dbd.NR.sup.L)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(.dbd.NR.sup.L)N(R.sup.L)--. In certain
embodiments, L.sup.1 is
--NR.sup.LC(.dbd.NR.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(.dbd.NR.sup.L)--. In certain
embodiments, L.sup.1 is --C(S)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(S)--. In certain embodiments, L.sup.1 is
--C(S)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2)--C(S)N(R.sup.L)--. In certain embodiments, L.sup.1 is
--NR.sup.LC(S)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(S)--. In certain embodiments, L.sup.1
is --S(O)--(CH.sub.2).sub.x-- or --(CH.sub.2).sub.x--S(O)--. In
certain embodiments, L.sup.1 is --OS(O).sub.2--(CH.sub.2).sub.x--
or --(CH.sub.2).sub.x--OS(O).sub.2--. In certain embodiments,
L.sup.1 is --S(O).sub.2O--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--S(O).sub.2O--. In certain embodiments, L.sup.1
is --SO.sub.2--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--SO.sub.2--. In certain embodiments, L.sup.1 is
--N(R.sup.L)SO.sub.2--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--N(R.sup.L)SO.sub.2--. In certain embodiments,
L.sup.1 is --SO.sub.2N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--SO.sub.2N(R.sup.L)--. In certain embodiments,
L.sup.1 is --N(R.sup.L)SO.sub.2N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--N(R.sup.L)SO.sub.2N(R.sup.L)--. In certain
embodiments, L.sup.1 is a bond, --N(R.sup.L)--, --NR.sup.LC(O)O--,
--NR.sup.LC(O)N(R.sup.L)--, --N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--, --NR.sup.L,
--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2)--,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--.
[0107] In certain embodiments, R.sup.3 is an acyclic moiety
selected from the group consisting of hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, and optionally
substituted alkynyl. In certain embodiments, R.sup.3 is hydrogen,
e.g., for example, when L.sup.1 is --N(R.sup.L)-- or
--NR.sup.L--(CH.sub.2).sub.x--NR.sup.L--. In certain embodiments,
R.sup.3 is optionally substituted alkyl, e.g., for example, when
L.sup.1 is --NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--,
--N(R.sup.L)--, --N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2)--C(O)O--, or
--NR.sup.L--(CH.sub.2).sub.x--O--. In certain embodiments, R.sup.3
is optionally substituted C.sub.1-6 alkyl, e.g., optionally
substituted C.sub.1-5 alkyl, optionally substituted C.sub.1-4alkyl,
optionally substituted C.sub.1-2alkyl, optionally substituted
C.sub.2-3alkyl, optionally substituted C.sub.3-alkyl, optionally
substituted C.sub.1alkyl, optionally substituted C.sub.2alkyl,
optionally substituted C.sub.3alkyl, optionally substituted
C.sub.4alkyl, optionally substituted C.sub.5alkyl, or optionally
substituted C.sub.6alkyl. Exemplary R.sup.3 C.sub.1-6alkyl groups
include, but are not limited to, methyl (C.sub.1), ethyl (C.sub.2),
n-propyl (C.sub.3), isopropyl (C.sub.3), n-butyl (C.sub.4),
tert-butyl (C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4),
n-pentyl (C.sub.5), 3-pentanyl (C.sub.5), amyl (C.sub.5), neopentyl
(C.sub.5), 3-methyl-2-butanyl (C.sub.5), tertiary amyl (C.sub.5),
and n-hexyl (C.sub.6). In certain embodiments, R.sup.3 is alkyl
substituted with --CN, e.g., --(CH.sub.2).sub.yCN, wherein y is 1,
2, 3, 4, 5, or 6. In certain embodiments, R.sup.3 is alkyl
substituted with hydroxy or substituted hydroxy, e.g.,
--(CH.sub.2).sub.yOCH.sub.3, wherein y is 1, 2, 3, 4, 5, or 6. In
certain embodiments, R.sup.3 is alkyl substituted with amino or
substituted substituted amino, e.g., --(CH.sub.2).sub.yNH.sub.2,
wherein y is 1, 2, 3, 4, 5, or 6. In certain embodiments, R.sup.3
is optionally substituted alkenyl, e.g., for example, when L.sup.1
is a bond. In certain embodiments, R.sup.3 is optionally
substituted C.sub.2-4 alkenyl, e.g., optionally substituted
C.sub.2-3alkenyl, optionally substituted C.sub.3-alkenyl,
optionally substituted C.sub.2alkenyl, optionally substituted
C.sub.3alkenyl, or optionally substituted C.sub.4alkenyl. In
certain embodiments, R.sup.3 is optionally substituted
C.sub.2alkenyl or C.sub.3alkenyl, e.g., optionally substituted
vinyl or optionally substituted allyl. In certain embodiments,
R.sup.3 is optionally substituted alkynyl, e.g., for example, when
L.sup.1 is a bond. In certain embodiments, R.sup.3 is optionally
substituted C.sub.2-4 alkynyl, e.g., optionally substituted
C.sub.2-3alkynyl, optionally substituted C.sub.3-alkynyl,
optionally substituted C.sub.2alkynyl, optionally substituted
C.sub.3alkynyl, or optionally substituted C.sub.4alkynyl. In
certain embodiments, R.sup.3 is optionally substituted
C.sub.2alkynyl, e.g., optionally substituted acetylene.
[0108] Alternatively, in certain embodiments, R.sup.3 is a cyclic
moiety selected from the group consisting of optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, and optionally substituted heteroaryl. It is
understood that the R.sup.3 cyclic moiety may be monocyclic or
polycyclic (e.g., bicyclic or tricyclic). In certain embodiments,
R.sup.3 is a monocyclic optionally substituted carbocyclyl,
monocyclic optionally substituted heterocyclyl, monocyclic
optionally substituted aryl, or monocyclic optionally substituted
heteroaryl. In certain embodiments, R.sup.3 is a bicyclic
optionally substituted carbocyclyl, bicyclic optionally substituted
heterocyclyl, bicyclic optionally substituted aryl, or bicyclic
optionally substituted heteroaryl.
[0109] In certain embodiments, R.sup.3 is an optionally substituted
monocyclic or bicyclic carbocyclyl, e.g., an optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted C.sub.3-9
carbocyclyl, optionally substituted C.sub.3-8 carbocyclyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted C.sub.3-6 carbocyclyl, optionally substituted
C.sub.3-4carbocyclyl, optionally substituted C.sub.5-10
carbocyclyl, optionally substituted C.sub.3 carbocyclyl, optionally
substituted C.sub.4 carbocyclyl, optionally substituted C.sub.5
carbocyclyl, optionally substituted C.sub.6 carbocyclyl, optionally
substituted C.sub.7 carbocyclyl, optionally substituted C.sub.8
carbocyclyl, optionally substituted C.sub.9 carbocyclyl, or
optionally substituted C.sub.10 carbocyclyl. In certain
embodiments, R.sup.3 is an optionally substituted 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), 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),
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), or spiro[4.5]decanyl
(C.sub.10) ring.
[0110] In certain embodiments, R.sup.3 is an optionally substituted
monocyclic or bicyclic heterocyclyl, e.g., an optionally
substituted 3- to 10-membered heterocyclyl, 3- to 8-membered
heterocyclyl, 3- to 6-membered heterocyclyl, 3- to 5-membered
heterocyclyl, 3- to 4-membered heterocyclyl, 3-membered
heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl,
6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered
heterocyclyl, 9-membered heterocyclyl, or 10-membered heterocyclyl.
In certain embodiments, R.sup.3 is an optionally substituted
azirdinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, thietanyl,
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolidin-2-one,
pyrrolyl-2,5-dione, dioxolanyl, oxasulfuranyl, disulfuranyl,
oxazolidin-2-one, triazolinyl, oxadiazolinyl, thiadiazolinyl,
piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl,
piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinanyl,
azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl,
indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzoxazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
furo[2,3-b]furanyl, 2,3-dihydro-1,4-dioxinyl,
3-oxa-8-azabicyclo[3.2.1]octanyl, or
8-oxa-3-azabicyclo[3.2.1]octanyl ring.
[0111] In certain embodiments, R.sup.3 is an optionally substituted
monocyclic or bicyclic aryl, e.g., an optionally substituted
phenyl, or optionally substituted naphthyl ring.
[0112] In certain embodiments, R.sup.3 is an optionally substituted
monocyclic or bicyclic heteroaryl, e.g., an optionally substituted
5- to 10-membered heteroaryl, optionally substituted 5- to
8-membered heteroaryl, optionally substituted 5- to 6-membered
heteroaryl, optionally substituted 5-membered heteroaryl, or
optionally substituted 6-membered heteroaryl. In certain
embodiments, R.sup.3 is an optionally substituted pyrrolyl,
furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, tetrazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl,
thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl,
purinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, or quinazolinyl ring.
[0113] In certain embodiments, R.sup.3 is a cyclic moiety selected
from the group consisting of
##STR00016## ##STR00017## ##STR00018## ##STR00019##
wherein:
[0114] each instance of independently represents a single or double
bond;
[0115] n is 0, 1, 2, or 3;
[0116] each instance of R.sup.3A is independently hydroxyl,
substituted hydroxyl, thiol, substituted thiol, amino, substituted
amino, carbonyl, sulfonyl, sulfinyl, --CN, --NO.sub.2, halogen,
optionally substituted alkyl, or two R.sup.3A groups are joined to
form an optionally substituted carbocyclic, optionally substituted
heterocyclic, optionally substituted aryl, or optionally
substituted heteroaryl ring, or R.sup.3A and R.sup.3B groups are
joined to form an optionally substituted carbocyclic, optionally
substituted heterocyclic, optionally substituted aryl, or
optionally substituted heteroaryl ring; and
[0117] R.sup.3B is hydrogen, optionally substituted alkyl, or a
nitrogen protecting group.
[0118] In certain embodiments, n is 0. In certain embodiments, n is
1. In certain embodiments, n is 2. In certain embodiments, n is 3.
In certain embodiments, each instance of R.sup.3A is independently
hydroxyl, --OCH.sub.3, optionally substituted C.sub.1-4alkyl (e.g.,
methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, isobutyl,
secbutyl, tertbutyl), --CN, or sulfonyl (e.g.,
--S(O).sub.2CH.sub.3).
[0119] As generally defined herein, L.sup.2 is a bond, --O--,
--N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.2--, --SO.sub.2N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--, or an optionally substituted
C.sub.10 saturated or unsaturated hydrocarbon chain, wherein one or
more moieties selected from the group consisting of --O--,
--N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L)--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.2--, --SO.sub.2N(R.sup.L)--, and
--N(R.sup.L)SO.sub.2N(R.sup.L)-- is optionally and independently
present between two carbon atoms of the hydrocarbon chain, and
optionally and independently present at one or both ends of the
hydrocarbon chain. It is understood that the linker joining
R.sup.13 to Ring HET may comprise one or more of the above recited
moieties in combination to form the group L.sup.2.
[0120] In certain embodiments, L.sup.2 is a bond. In certain
embodiments, L.sup.2 is --O--. In certain embodiments, L.sup.2 is
--N(R.sup.L)--. In certain embodiments, L.sup.2 is --S--. In
certain embodiments, L.sup.2 is --C(O)--. In certain embodiments,
L.sup.2 is --C(O)O--. In certain embodiments, L.sup.2 is --C(O)S--.
In certain embodiments, L.sup.2 is --C(O)N(R.sup.L)--. In certain
embodiments, L.sup.2 is --C(O)N(R.sup.L)N(R.sup.L)--. In certain
embodiments, L is --OC(O)--. In certain embodiments, L.sup.1 is
--OC(O)N(R.sup.L)--. In certain embodiments, L.sup.2 is
--NR.sup.LC(O)--. In certain embodiments, L.sup.2 is
--NR.sup.LC(O)N(R.sup.L)--. In certain embodiments, L.sup.1 is
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--. In certain embodiments,
L.sup.2 is --NR.sup.LC(O)O--. In certain embodiments, L.sup.2 is
--SC(O)--. In certain embodiments, L.sup.2 is --C(.dbd.NR.sup.L)--.
In certain embodiments, L.sup.2 is --C(.dbd.NNR.sup.L)--. In
certain embodiments, L.sup.2 is --C(.dbd.NOR.sup.L)--. In certain
embodiments, L.sup.2 is --C(.dbd.NR.sup.L)N(R.sup.L)--. In certain
embodiments, L.sup.2 is --NR.sup.LC(.dbd.NR.sup.L)--. In certain
embodiments, L.sup.2 is --C(S)--. In certain embodiments, L.sup.2
is --C(S)N(R.sup.L)--. In certain embodiments, L.sup.2 is
--NR.sup.LC(S)--. In certain embodiments, L.sup.2 is --S(O)--. In
certain embodiments, L.sup.2 is --OS(O).sub.2--. In certain
embodiments, L.sup.1 is --S(O).sub.2O--. In certain embodiments,
L.sup.1 is --SO.sub.2--. In certain embodiments, L.sup.1 is
--N(R.sup.L)SO.sub.2--. In certain embodiments, L.sup.2 is
--SO.sub.2N(R.sup.L)--. In certain embodiments, L.sup.2 is
--N(R.sup.L)SO.sub.2N(R.sup.L)--.
[0121] In certain embodiments, L.sup.2 is an optionally substituted
C.sub.1-10 saturated or unsaturated hydrocarbon chain, e.g., in
embodiments, L.sup.2 is an optionally substituted C.sub.1-10 alkyl
chain, L.sup.2 is an optionally substituted C.sub.2-10 alkenyl
chain, or L.sup.2 is an optionally substituted C.sub.2-10 alkynyl
chain. In certain embodiments, L.sup.2 is an optionally substituted
C.sub.1-10 alkyl chain, e.g., an optionally substituted C.sub.1-8
alkyl chain, optionally substituted C.sub.1-6 alkyl chain,
optionally substituted C.sub.1-4 alkyl chain, optionally
substituted C.sub.1-3 alkyl chain, or optionally substituted
C.sub.1-2 alkyl chain. In certain embodiments, L.sup.2 is an
unsubstituted C.sub.1-10 n-alkyl chain of the formula
--(CH.sub.2).sub.x--, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10. In certain embodiments, L.sup.2 is an optionally substituted
C.sub.2-10 alkenyl chain, e.g., an optionally substituted C.sub.2-8
alkenyl chain, optionally substituted C.sub.2-6 alkenyl chain,
optionally substituted C.sub.2-4 alkenyl chain, optionally
substituted C.sub.2-3 alkenyl chain, or optionally substituted
C.sub.2 alkenyl chain. In certain embodiments, L.sup.2 is an
optionally substituted C.sub.2-10 alkynyl chain, e.g., an
optionally substituted C.sub.2 s alkynyl chain, optionally
substituted C.sub.2-6 alkynyl chain, optionally substituted
C.sub.2-4 alkynyl chain, optionally substituted C.sub.2-3 alkynyl
chain, or optionally substituted C.sub.2 alkynyl chain.
[0122] In certain embodiments, L.sup.2 is an optionally substituted
C.sub.1-10 saturated or unsaturated hydrocarbon chain, wherein one
or more moieties selected from the group consisting of --O--,
--N(R.sup.L)--, --S--, --C(O)--, --C(O)O--, --C(O)S--,
--C(O)N(R.sup.L)--, --C(O)N(R.sup.L)N(R.sup.L)--, --OC(O)--,
--OC(O)N(R.sup.L)--, --NR.sup.LC(O)--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--, --NR.sup.LC(O)O--, --SC(O)--,
--C(.dbd.NR.sup.L)--, --C(.dbd.NNR.sup.L)--, --C(.dbd.NOR.sup.L)--,
--C(.dbd.NR.sup.L)N(R.sup.L)--, --NR.sup.LC(.dbd.NR.sup.L)--,
--C(S)--, --C(S)N(R.sup.L)--, --NR.sup.LC(S)--, --S(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --SO.sub.2--,
--N(R.sup.L)SO.sub.2--, --SO.sub.2N(R.sup.L)--, or
--N(R.sup.L)SO.sub.2N(R.sup.L)-- independently present between two
carbon atoms of the hydrocarbon chain, or present at one or both
ends of the hydrocarbon chain. In this instance, in certain
embodiments, L.sup.2 is a chain of at least 2 atoms, e.g., L.sup.2
is a chain comprising 1 to 10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6,
7, 8, 9, or 10 carbon atoms), and 1 or more of the above recited
moieties (e.g., 1, 2, 3, or more), to provide a chain of between 2
and 20 atoms, inclusive, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, or 20 chain atoms. In certain
embodiments, a moiety is present between two carbon atoms of the
hydrocarbon chain. In certain embodiments, a moiety is present at
one end of the hydrocarbon chain. In certain embodiments, a moiety
is independently present at each end of the hydrocarbon chain. In
certain embodiments, L.sup.2 is an optionally substituted
C.sub.1-10 alkyl chain, L.sup.2 is an optionally substituted
C.sub.2-10 alkenyl chain, or L.sup.2 is an optionally substituted
C.sub.2-10 alkynyl chain comprising one or more of the above
recited moieties independently present between two carbon atoms of
the hydrocarbon chain, or present at one or both ends of the
hydrocarbon chain. In certain embodiments, L.sup.2 is an optionally
substituted C.sub.10 alkyl chain, e.g., an optionally substituted
C.sub.1-8 alkyl chain, optionally substituted C.sub.1-6 alkyl
chain, optionally substituted C.sub.1-4 alkyl chain, optionally
substituted C.sub.1-3 alkyl chain, or optionally substituted
C.sub.1-2 alkyl chain, comprising one or more of the above recited
moieties independently present between two carbon atoms of the
hydrocarbon chain, or present at one or both ends of the
hydrocarbon chain. In certain embodiments, L.sup.2 is an
unsubstituted C.sub.1-10 n-alkyl chain of the formula
--(CH.sub.2).sub.x--, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10, comprising one or more of the above recited moieties
independently present between two carbon atoms of the hydrocarbon
chain, or present at one or both ends of the hydrocarbon chain. In
certain embodiments, L.sup.2 is an optionally substituted
C.sub.2-10 alkenyl chain, e.g., an optionally substituted C.sub.2-8
alkenyl chain, optionally substituted C.sub.2-6 alkenyl chain,
optionally substituted C.sub.2-4 alkenyl chain, optionally
substituted C.sub.2-3 alkenyl chain, or optionally substituted
C.sub.2 alkenyl chain, comprising one or more of the above recited
moieties independently present between two carbon atoms of the
hydrocarbon chain, or present at one or both ends of the
hydrocarbon chain. In certain embodiments, L.sup.2 is an optionally
substituted C.sub.2-10 alkynyl chain, e.g., an optionally
substituted C.sub.2-8 alkynyl chain, optionally substituted
C.sub.2-6 alkynyl chain, optionally substituted C.sub.2-4 alkynyl
chain, optionally substituted C.sub.2-3 alkynyl chain, or
optionally substituted C.sub.2 alkynyl chain, comprising one or
more of the above recited moieties independently present between
two carbon atoms of the hydrocarbon chain, or present at one or
both ends of the hydrocarbon chain.
[0123] As described above, in certain embodiments, L.sup.2 is an
unsubstituted C.sub.1-10 n-alkyl chain of the formula
--(CH.sub.2).sub.x--, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10, comprising one or more of the above recited moieties
independently present between two carbon atoms of the hydrocarbon
chain, or present at one or both ends of the hydrocarbon chain. In
certain embodiments, L.sup.2 is --O--(CH.sub.2).sub.x--,
--(CH.sub.2).sub.x--O--, or --O--(CH.sub.2).sub.x--O--. In certain
embodiments, L.sup.2 is --N(R.sup.L)--(CH.sub.2).sub.x--,
--(CH.sub.2).sub.x--N(R.sup.L)--,
--N(R.sup.L)--(CH.sub.2).sub.x--N(R.sup.L)--,
--O--(CH.sub.2).sub.x--N(R.sup.L)--,
--N(R.sup.L)--(CH.sub.2).sub.x--O--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--, or
--OC(O)--(CH.sub.2).sub.x--N(R.sup.L)--. In certain embodiments,
L.sup.2 is --S--(CH.sub.2).sub.x-- or --(CH.sub.2).sub.x--S--. In
certain embodiments, L.sup.2 is --C(O)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(O)--. In certain embodiments, L.sup.2 is
--C(O)O--(CH.sub.2).sub.x-- or --(CH.sub.2).sub.x--C(O)O--. In
certain embodiments, L.sup.2 is --C(O)S--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(O)S--. In certain embodiments, L.sup.2 is
--C(O)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(O)N(R.sup.L)--. In certain embodiments,
L.sup.2 is --C(O)N(R.sup.L)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.xC(O)N(R.sup.L)N(R.sup.L)--. In certain
embodiments, L.sup.2 is --OC(O)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--OC(O)--. In certain embodiments, L.sup.2 is
--OC(O)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--OC(O)N(R.sup.L)--. In certain embodiments,
L.sup.2 is --NR.sup.LC(O)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(O)--. In certain embodiments, L.sup.2
is --NR.sup.LC(O)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(O)N(R.sup.L)--. In certain
embodiments, L.sup.2 is
--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(O)N(R.sup.L)N(R.sup.L)--. In certain
embodiments, L.sup.2 is --NR.sup.LC(O)O--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(O)O--. In certain embodiments,
L.sup.2 is --SC(O)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--SC(O)--. In certain embodiments, L.sup.2 is
--C(.dbd.NR.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.xC(.dbd.NR.sup.L)--. In certain embodiments,
L.sup.2 is --C(.dbd.NNR.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(.dbd.NNR.sup.L)--. In certain embodiments,
L.sup.2 is --C(.dbd.NOR.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(.dbd.NOR.sup.L)--. In certain embodiments,
L.sup.2 is --C(.dbd.NR.sup.L)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(.dbd.NR.sup.L)N(R.sup.L)--. In certain
embodiments, L.sup.2 is
--NR.sup.LC(.dbd.NR.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(.dbd.NR.sup.L)--. In certain
embodiments, L.sup.2 is --C(S)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(S)--. In certain embodiments, L.sup.2 is
--C(S)N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--C(S)N(R.sup.L)--. In certain embodiments,
L.sup.2 is --NR.sup.LC(S)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--NR.sup.LC(S)--. In certain embodiments, L.sup.2
is --S(O)--(CH.sub.2).sub.x-- or --(CH.sub.2).sub.x--S(O)--. In
certain embodiments, L.sup.2 is --OS(O).sub.2--(CH.sub.2).sub.x--
or --(CH.sub.2).sub.x--OS(O).sub.2--. In certain embodiments,
L.sup.2 is --S(O).sub.2O--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--S(O).sub.2O--. In certain embodiments, L.sup.2
is --SO.sub.2--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--SO.sub.2--. In certain embodiments, L.sup.2 is
--N(R.sup.L)SO.sub.2--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--N(R.sup.L)SO.sub.2--. In certain embodiments,
L.sup.2 is --SO.sub.2N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--SO.sub.2N(R.sup.L)--. In certain embodiments,
L.sup.2 is --N(R.sup.L)SO.sub.2N(R.sup.L)--(CH.sub.2).sub.x-- or
--(CH.sub.2).sub.x--N(R.sup.L)SO.sub.2N(R.sup.L)--. In certain
embodiments, L.sup.2 is a bond, --N(R.sup.L)--, --NR.sup.LC(O)O--,
--NR.sup.LC(O)N(R.sup.L)--, --N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L-(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2).sub.x--,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--.
[0124] As generally defined herein, R.sup.13 attached directly
(wherein L.sup.2 is a bond) or indirectly (wherein L.sup.2 is a
linking group) to Ring HET is a cyclic moiety selected from the
group consisting of optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, and
optionally substituted heteroaryl. It is understood that the
R.sup.13 cyclic moiety may be monocyclic or polycyclic (e.g.,
bicyclic or tricyclic). In certain embodiments, R.sup.13 is a
monocyclic optionally substituted carbocyclyl, monocyclic
optionally substituted heterocyclyl, monocyclic optionally
substituted aryl, or monocyclic optionally substituted heteroaryl.
In certain embodiments, R.sup.13 is a bicyclic optionally
substituted carbocyclyl, bicyclic optionally substituted
heterocyclyl, bicyclic optionally substituted aryl, or bicyclic
optionally substituted heteroaryl.
[0125] In certain embodiments, R.sup.13 is an optionally
substituted monocyclic or bicyclic carbocyclyl, e.g., an optionally
substituted C.sub.3-10 carbocyclyl, optionally substituted
C.sub.3-9 carbocyclyl, optionally substituted C.sub.3-8
carbocyclyl, optionally substituted C.sub.3-7 carbocyclyl,
optionally substituted C.sub.3-6 carbocyclyl, optionally
substituted C.sub.3-carbocyclyl, optionally substituted C.sub.5-10
carbocyclyl, optionally substituted C.sub.3 carbocyclyl, optionally
substituted C.sub.4 carbocyclyl, optionally substituted C.sub.5
carbocyclyl, optionally substituted C.sub.6 carbocyclyl, optionally
substituted C.sub.7 carbocyclyl, optionally substituted C.sub.8
carbocyclyl, optionally substituted C.sub.9 carbocyclyl, or
optionally substituted C.sub.10 carbocyclyl. In certain
embodiments, R.sup.13 is an optionally substituted 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), 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),
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), or spiro[4.5]decanyl
(C.sub.10) ring.
[0126] In certain embodiments, R.sup.13 is an optionally
substituted monocyclic or bicyclic heterocyclyl, e.g., an
optionally substituted 3- to 10-membered heterocyclyl, 3- to
8-membered heterocyclyl, 3- to 6-membered heterocyclyl, 3- to
5-membered heterocyclyl, 3- to 4-membered heterocyclyl, 3-membered
heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl,
6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered
heterocyclyl, 9-membered heterocyclyl, or 10-membered heterocyclyl.
In certain embodiments, R.sup.3 is an optionally substituted
azirdinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, thietanyl,
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolidin-2-one,
pyrrolyl-2,5-dione, dioxolanyl, oxasulfuranyl, disulfuranyl,
oxazolidin-2-one, triazolinyl, oxadiazolinyl, thiadiazolinyl,
piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl,
piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinanyl,
azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl,
indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzoxazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
furo[2,3-b]furanyl, 2,3-dihydro-1,4-dioxinyl,
3-oxa-8-azabicyclo[3.2.1]octanyl, or
8-oxa-3-azabicyclo[3.2.1]octanyl ring.
[0127] In certain embodiments, R.sup.13 is an optionally
substituted monocyclic or bicyclic aryl, e.g., an optionally
substituted phenyl, or optionally substituted naphthyl ring.
[0128] In certain embodiments, R.sup.13 is an optionally
substituted monocyclic or bicyclic heteroaryl, e.g., an optionally
substituted 5- to 10-membered heteroaryl, optionally substituted 5-
to 8-membered heteroaryl, optionally substituted 5- to 6-membered
heteroaryl, optionally substituted 5-membered heteroaryl, or
optionally substituted 6-membered heteroaryl. In certain
embodiments, R.sup.13 is an optionally substituted pyrrolyl,
furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, tetrazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl,
thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl,
purinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, or quinazolinyl ring.
[0129] In certain embodiments, R.sup.13 is a cyclic moiety selected
from the group consisting of:
##STR00020## ##STR00021## ##STR00022## ##STR00023##
wherein:
[0130] each instance of independently represents a single or double
bond;
[0131] m is 0, 1, 2, or 3;
[0132] each instance of R.sup.13A is independently hydroxyl,
substituted hydroxyl, thiol, substituted thiol, amino, substituted
amino, carbonyl, sulfonyl, sulfinyl, --CN, --NO.sub.2, halogen,
optionally substituted alkyl, or two R.sup.13A groups are joined to
form an optionally substituted carbocyclic, optionally substituted
heterocyclic, optionally substituted aryl, or optionally
substituted heteroaryl ring, or R.sup.13A and R.sup.13B group are
joined to form an optionally substituted carbocyclic, optionally
substituted heterocyclic, optionally substituted aryl, or
optionally substituted heteroaryl ring; and
[0133] R.sup.13B is hydrogen, optionally substituted alkyl, or a
nitrogen protecting group.
[0134] In certain embodiments, m is 0. In certain embodiments, m is
1. In certain embodiments, m is 2. In certain embodiments, m is 3.
In certain embodiments, each instance of R.sup.13A is independently
hydroxyl, --OCH.sub.3, optionally substituted C.sub.1-4alkyl (e.g.,
methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, isobutyl,
secbutyl, tertbutyl), --CN, or sulfonyl (e.g.,
--S(O).sub.2CH.sub.3).
[0135] As generally defined herein, each R.sup.L provided in
L.sup.1 and L.sup.2 is independently hydrogen, optionally
substituted alkyl, or a nitrogen protecting group, or R.sup.L and
R.sup.3 taken together form an optionally substituted heterocyclyl
or optionally substituted heteroaryl ring, or R.sup.L and R.sup.13
taken together form an optionally substituted heterocyclyl or
optionally substituted heteroaryl ring. In certain embodiments, at
least one instance of R.sup.L is hydrogen. In certain embodiments,
each instance of R.sup.L is hydrogen. In certain embodiments, at
least one instance of R.sup.L is optionally substituted alkyl,
e.g., optionally substituted C.sub.1-6 alkyl, optionally
substituted C.sub.1-5alkyl, optionally substituted C.sub.1-4alkyl,
optionally substituted C.sub.1-2alkyl, optionally substituted
C.sub.2-3alkyl, optionally substituted C.sub.3-4alkyl, optionally
substituted C.sub.1alkyl, optionally substituted C.sub.2alkyl,
optionally substituted C.sub.3alkyl, optionally substituted
C.sub.4alkyl, optionally substituted C.sub.5alkyl, or optionally
substituted C.sub.6alkyl. Exemplary R.sup.L C.sub.1-6alkyl groups
include, but are not limited to, methyl (C.sub.1), ethyl (C.sub.2),
n-propyl (C.sub.3), isopropyl (C.sub.3), n-butyl (C.sub.4),
tert-butyl (C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4),
n-pentyl (C.sub.5), 3-pentanyl (C), amyl (C.sub.5), neopentyl
(C.sub.5), 3-methyl-2-butanyl (C.sub.5), tertiary amyl (C.sub.5),
and n-hexyl (C.sub.6). In certain embodiments, R.sup.L is alkyl
substituted with --CN, e.g., --(CH.sub.2).sub.zCN, wherein z is 1,
2, 3, 4, 5, or 6. In certain embodiments, R.sup.L is alkyl
substituted with hydroxy or substituted hydroxy, e.g.,
--(CH.sub.2).sub.zOCH.sub.3, wherein z is 1, 2, 3, 4, 5, or 6. In
certain embodiments, R.sup.L is alkyl substituted with amino or
substituted substituted amino, e.g., --(CH.sub.2).sub.zNH.sub.2,
wherein z is 1, 2, 3, 4, 5, or 6. In certain embodiments, at least
one instance of R.sup.L is a nitrogen protecting group. In certain
embodiments, R.sup.L and R.sup.3 taken together form an optionally
substituted heterocyclyl ring, e.g., an optionally substituted 3-
to 10-membered heterocyclyl, 3- to 8-membered heterocyclyl, 3- to
6-membered heterocyclyl, 3- to 5-membered heterocyclyl, 3- to
4-membered heterocyclyl, 3-membered heterocyclyl, 4-membered
heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl,
7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered
heterocyclyl, or 10-membered heterocyclyl ring. In certain
embodiments, R.sup.L and R.sup.3 taken together form an optionally
substituted heteroaryl ring, e.g., an optionally substituted 5- to
10-membered heteroaryl, optionally substituted 5- to 8-membered
heteroaryl, optionally substituted 5- to 6-membered heteroaryl,
optionally substituted 5-membered heteroaryl, or optionally
substituted 6-membered heteroaryl. In certain embodiments, R.sup.L
and R.sup.13 taken together form an optionally substituted
heterocyclyl ring, e.g., an optionally substituted 3- to
10-membered heterocyclyl, 3- to 8-membered heterocyclyl, 3- to
6-membered heterocyclyl, 3- to 5-membered heterocyclyl, 3- to
4-membered heterocyclyl, 3-membered heterocyclyl, 4-membered
heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl,
7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered
heterocyclyl, or 10-membered heterocyclyl ring. In certain
embodiments, R.sup.L and R.sup.13 taken together form an optionally
substituted heteroaryl ring, e.g., an optionally substituted 5- to
10-membered heteroaryl, optionally substituted 5- to 8-membered
heteroaryl, optionally substituted 5- to 6-membered heteroaryl,
optionally substituted 5-membered heteroaryl, or optionally
substituted 6-membered heteroaryl.
[0136] Various combination of the above described embodiments are
further contemplated herein. For example, in certain embodiments of
Formula (I-h), wherein G.sub.8 and G.sub.12 are both N, provided is
a compound of Formula (I-i):
##STR00024##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, X is --O--. In certain embodiments, R.sup.1 is
hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl. In
certain embodiments, R.sup.2a, R.sup.2c, and R.sup.2d are hydrogen.
In certain embodiments, R.sup.2b is halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.A2, --OR.sup.A2, --SR.sup.A2, --N(R.sup.A2).sub.2,
optionally substituted cyclopropyl, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.2-4alkenyl, optionally
substituted C.sub.2-4alkynyl, wherein R.sup.A2 is optionally
substituted alkyl. In certain embodiments, L.sup.2 is a bond,
--N(R.sup.L)--, --NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--,
--N(R.sup.L)--, --N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2).sub.x,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--. In certain embodiments,
R.sup.13 is optionally substituted heterocyclyl or optionally
substituted heteroaryl.
[0137] In certain embodiments of Formula (I-h), wherein G.sub.8 and
G.sub.12 are both N, and G.sub.11 is a group of formula
C--R.sup.11, provided is a compound of Formula (I-j):
##STR00025##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, X is --O--. In certain embodiments, R.sup.1 is
hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl. In
certain embodiments, R.sup.2a, R.sup.2c, and R.sup.2d are hydrogen.
In certain embodiments, R.sup.2b is halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.A2, --OR, --SR, --N(R.sup.A2).sub.2, optionally
substituted cyclopropyl, optionally substituted C.sub.1-4alkyl,
optionally substituted C.sub.2-4alkenyl, optionally substituted
C.sub.2-4alkynyl, wherein R.sup.A2 is optionally substituted alkyl.
In certain embodiments, L.sup.2 is a bond, --N(R.sup.L)--,
--NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--, --N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2).sub.x,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--. In certain embodiments,
R.sup.13 is optionally substituted heterocyclyl or optionally
substituted heteroaryl. In certain embodiments, R.sup.11 is
hydrogen or a group -L.sup.1-R.sup.3.
[0138] In certain embodiments of Formula (I-h), wherein G.sub.8 and
G.sub.12 are both N, G.sub.11 is C--R.sup.11, and G.sub.10 is
C--R.sup.10, provided is a compound of Formula (I-k):
##STR00026##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, X is --O--. In certain embodiments, R.sup.1 is
hydrogen, methyl, or ethyl. In certain embodiments, R.sup.2a,
R.sup.2c, and R.sup.2d are hydrogen In certain embodiments,
R.sup.2b is halogen (e.g., chloro), --CN, --C(.dbd.O)R, --OR,
--SR.sup.A2, --N(R.sup.A2).sub.2, optionally substituted
cyclopropyl, optionally substituted C.sub.1-4alkyl, optionally
substituted C.sub.2-4alkenyl, optionally substituted
C.sub.2-4alkynyl, wherein R.sup.A2 is optionally substituted alkyl.
In certain embodiments, L.sup.2 is a bond, --N(R.sup.L)--,
--NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--, --N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L-(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2).sub.x--,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--. In certain embodiments,
R.sup.13 is optionally substituted heterocyclyl or optionally
substituted heteroaryl. In certain embodiments, R.sup.11 is
hydrogen or a group -L.sup.1-R.sup.3. In certain embodiments,
R.sup.10 is hydrogen or methyl.
[0139] In certain embodiments of Formula (I-h), wherein G.sub.8 and
G.sub.12 are both N, G.sub.11 is C--R.sup.11, R.sup.11 is
-L.sup.1-R.sup.3, and G.sub.10 is C--R.sup.10, provided is a
compound of Formula (I-l):
##STR00027##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, X is --O--. In certain embodiments, R.sup.1 is
hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl. In
certain embodiments, R.sup.2a, R.sup.2c, and R.sup.2d are hydrogen.
In certain embodiments, R.sup.2b is halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.A2, --OR.sup.A2, --SR.sup.A2, --N(R.sup.A2).sub.2,
optionally substituted cyclopropyl, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.2-4alkenyl, optionally
substituted C.sub.2-4alkynyl, wherein R.sup.A2 is optionally
substituted alkyl. In certain embodiments, L.sup.2 is a bond,
--N(R.sup.L)--, --NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--,
--N(R.sup.L)--, --N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2).sub.x,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--. In certain embodiments,
R.sup.13 is optionally substituted heterocyclyl or optionally
substituted heteroaryl. In certain embodiments, L.sup.1 is a bond,
--N(R.sup.L)--, --NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--,
--N(R.sup.L)--, --N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2).sub.x--,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--. In certain embodiments,
R.sup.3 is an acyclic moiety. In certain embodiments, R.sup.3 is a
cyclic moiety. In certain embodiments, R.sup.10 is hydrogen or
methyl.
[0140] In other embodiments of Formula (I-h), wherein G.sub.8 and
G.sub.10 are both N, provided is a compound of Formula (I-m):
##STR00028##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, X is --O--. In certain embodiments, R.sup.1 is
hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl. In
certain embodiments, R.sup.2a, R.sup.2c, and R.sup.2d are hydrogen.
In certain embodiments, R.sup.2b is halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.A2, --OR, --SR, --N(R.sup.A2).sub.2, optionally
substituted cyclopropyl, optionally substituted C.sub.1-4alkyl,
optionally substituted C.sub.2-4alkenyl, optionally substituted
C.sub.2-4alkynyl, wherein R.sup.A2 is optionally substituted alkyl.
In certain embodiments, L.sup.2 is a bond, --N(R.sup.L)--,
--NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--, --N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2).sub.x,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--. In certain embodiments,
R.sup.13 is optionally substituted heterocycyl or optionally
substituted heteroaryl.
[0141] In certain embodiments of Formula (I-h), wherein G.sub.8 and
G.sub.12 are both N, and G.sub.11 is C--R.sup.11, provided is a
compound of Formula (I-n):
##STR00029##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, X is --O--. In certain embodiments, R.sup.1 is
hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl. In
certain embodiments, R.sup.2a, R.sup.2c, and R.sup.2d are hydrogen.
In certain embodiments, R.sup.2b is halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.A2, --OR, --SR, --N(R.sup.A2).sub.2, optionally
substituted cyclopropyl, optionally substituted C.sub.1-4alkyl,
optionally substituted C.sub.2-4alkenyl, optionally substituted
C.sub.2-4 alkynyl, wherein R.sup.A2 is optionally substituted
alkyl. In certain embodiments, L.sup.2 is a bond, --N(R.sup.L)--,
--NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--, --N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2),
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--. In certain embodiments,
R.sup.13 is optionally substituted heterocyclyl or optionally
substituted heteroaryl. In certain embodiments, R.sup.11 is
hydrogen or a group -L.sup.1-R.sup.3.
[0142] In certain embodiments of Formula (I-h), wherein G.sub.8 and
G.sub.12 are both N, G.sub.11 is C--R.sup.11, and G.sub.12 is
C--R.sup.12, provided is a compound of Formula (I-o):
##STR00030##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, X is --O--. In certain embodiments, R.sup.1 is
hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl. In
certain embodiments, R.sup.2a, R.sup.2c, and R.sup.2d are hydrogen.
In certain embodiments, R.sup.2b is halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.A2, --OR.sup.A2, --SR.sup.A2, --N(R.sup.A2).sub.2,
optionally substituted cyclopropyl, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.2-4alkenyl, optionally
substituted C.sub.2-4alkynyl, wherein R.sup.A2 is optionally
substituted alkyl. In certain embodiments, L.sup.2 is a bond,
--N(R.sup.L)--, --NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--,
--N(R.sup.L)--, --N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2).sub.x,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--. In certain embodiments,
R.sup.13 is optionally substituted heterocyclyl or optionally
substituted heteroaryl. In certain embodiments, R.sup.11 is
hydrogen or a group -L.sup.1-R.sup.3. In certain embodiments,
R.sup.12 is hydrogen or methyl.
[0143] In certain embodiments of Formula (I-h), wherein G.sub.8 and
G.sub.12 are both N, G.sub.11 is C--R.sup.11, R.sup.11 is a group
of formula -L.sup.1-R.sup.3, and G.sub.12 is C--R.sup.12, provided
is a compound of Formula (I-p):
##STR00031##
or a pharmaceutically acceptable salt thereof. In certain
embodiments, X is --O--. In certain embodiments, R.sup.1 is
hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl. In
certain embodiments, R.sup.2a, R.sup.2c, and R.sup.2d are hydrogen.
In certain embodiments, R.sup.2b is halogen (e.g., chloro), --CN,
--C(.dbd.O)R.sup.2, --OR, --SR, --N(R.sup.A2).sub.2, optionally
substituted cyclopropyl, optionally substituted C.sub.1-4alkyl,
optionally substituted C.sub.2-4alkenyl, optionally substituted
C.sub.2-4alkynyl, wherein R.sup.A2 is optionally substituted alkyl.
In certain embodiments, L.sup.2 is a bond, --N(R.sup.L)--,
--NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--, --N(R.sup.L)--,
--N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2).sub.x,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--. In certain embodiments,
R.sup.13 is optionally substituted heterocyclyl or optionally
substituted heteroaryl. In certain embodiments, L.sup.1 is a bond,
--N(R.sup.L)--, --NR.sup.LC(O)O--, --NR.sup.LC(O)N(R.sup.L)--,
--N(R.sup.L)--, --N(R.sup.L)SO.sub.2N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--C(O)O--,
--NR.sup.L--(CH.sub.2).sub.x--O--, --NR.sup.LC(O)N(R.sup.L)--,
--NR.sup.L--(CH.sub.2).sub.x--, --(CH.sub.2).sub.x--NR.sup.L--,
--NR.sup.LC(O)O(CH.sub.2).sub.x--,
--NR.sup.LC(O)NR.sup.L(CH.sub.2).sub.x--, or
--NR.sup.L(CH.sub.2).sub.xNR.sup.LC(O)--. In certain embodiments,
R.sup.3 is an acyclic moiety. In certain embodiments, R.sup.3 is a
cyclic moiety. In certain embodiments, R.sup.12 is hydrogen or
methyl.
[0144] In certain embodiments, a compound of Formula (I) is
selected from any one of the compounds provided in Tables 1 and 2,
or a pharmaceutically acceptable salt thereof.
TABLE-US-00001 TABLE 1 Exemplary Compounds LC-MS m/z # Structure (M
+ H) 1-1 ##STR00032## 450.3 2-1 ##STR00033## 450.3 3-1 ##STR00034##
444.3 4-1 ##STR00035## 359.2 5-1 ##STR00036## 383.2 6-1
##STR00037## 387.2 7-1 ##STR00038## 397.2 8-1 ##STR00039## 403.3
9-1 ##STR00040## 408.1 10-1 ##STR00041## 413.3 11-1 ##STR00042##
413.3 12-1 ##STR00043## 414.2 13-1 ##STR00044## 415.3 14-1
##STR00045## 416.3 15-1 ##STR00046## 416.3 16-1 ##STR00047## 416.3
17-1 ##STR00048## 419.2 18-1 ##STR00049## 420.1 19-1 ##STR00050##
427.2 20-1 ##STR00051## 428.3 21-1 ##STR00052## 429.3 22-1
##STR00053## 430.3 23-1 ##STR00054## 434.2 24-1 ##STR00055## 443.2
25-1 ##STR00056## 443.3 26-1 ##STR00057## 444.3 27-1 ##STR00058##
444.4 28-1 ##STR00059## 447.3 29-1 ##STR00060## 449.2 30-1
##STR00061## 449.2 31-1 ##STR00062## 449.2 32-1 ##STR00063## 450.2
33-1 ##STR00064## 454.3 34-1 ##STR00065## 455.3 35-1 ##STR00066##
458.2 36-1 ##STR00067## 458.4 37-1 ##STR00068## 458.3 38-1
##STR00069## 460.2 39-1 ##STR00070## 460.2 40-1 ##STR00071## 464.3
41-1 ##STR00072## 464.2 42-1 ##STR00073## 466.1 43-1 ##STR00074##
469.0 44-1 ##STR00075## 469.2 45-1 ##STR00076## 470.3 46-1
##STR00077## 475.2 47-1 ##STR00078## 475.2 48-1 ##STR00079## 476.0
49-1 ##STR00080## 478.2 50-1 ##STR00081## 478.1 51-1 ##STR00082##
481.3 52-1 ##STR00083## 486.3 53-1 ##STR00084## 486.2 54-1
##STR00085## 487.1 55-1 ##STR00086## 489.3 56-1 ##STR00087## 496.3
57-1 ##STR00088## 498.1 58-1 ##STR00089## 498.2 59-1 ##STR00090##
507.1 60-1 ##STR00091## 507.2 61-1 ##STR00092## 509.2 62-1
##STR00093## 525.0 63-1 ##STR00094## 526.2 64-1 ##STR00095## 527.2
65-1 ##STR00096## 532.2 66-1 ##STR00097## 534.2 67-1 ##STR00098##
536.3 68-1 ##STR00099## 536.3 69-1 ##STR00100## 537.3 70-1
##STR00101## 538.3 71-1 ##STR00102## 545.2 72-1 ##STR00103## 545.2
73-1 ##STR00104## 554.2 74-1 ##STR00105## 559.2 75-1 ##STR00106##
561.0
TABLE-US-00002 TABLE 2 Exemplary Compounds # Structure LC-MS m/z (M
+ H) 1-2 ##STR00107## 387.2 2-2 ##STR00108## 401.3 3-2 ##STR00109##
402.2 4-2 ##STR00110## 413.2 5-2 ##STR00111## 413.3 6-2
##STR00112## 415.3 7-2 ##STR00113## 416.3 8-2 ##STR00114## 416.3
9-2 ##STR00115## 416.3 10-2 ##STR00116## 429.3 11-2 ##STR00117##
436.3 12-2 ##STR00118## 444.3 13-2 ##STR00119## 444.2 14-2
##STR00120## 450.2 15-2 ##STR00121## 458.2 16-2 ##STR00122##
489.2
[0145] In certain embodiments, a provided compound inhibits CARM1.
In certain embodiments, a provided compound inhibits wild-type
CARM1. In certain embodiments, a provided compound inhibits a
mutant CARM1. In certain embodiments, a provided compound inhibits
CARM1, e.g., as measured in an assay described herein. In certain
embodiments, the CARM1 is from a human. In certain embodiments, a
provided compound inhibits CARM1 at an IC.sub.50 less than or equal
to 10 .mu.M. In certain embodiments, a provided compound inhibits
CARM1 at an IC.sub.50 less than or equal to 1 .mu.M. In certain
embodiments, a provided compound inhibits CARM1 at an IC.sub.50
less than or equal to 0.1 .mu.M. In certain embodiments, a provided
compound inhibits CARM1 in a cell at an EC.sub.50 less than or
equal to 10 .mu.M. In certain embodiments, a provided compound
inhibits CARM1 in a cell at an EC.sub.50 less than or equal to 1
.mu.M. In certain embodiments, a provided compound inhibits CARM1
in a cell at an EC.sub.50 less than or equal to 0.1 .mu.M. In
certain embodiments, a provided compound inhibits cell
proliferation at an EC.sub.50 less than or equal to 10 .mu.M. In
certain embodiments, a provided compound inhibits cell
proliferation at an EC.sub.50 less than or equal to 1 .mu.M. In
certain embodiments, a provided compound inhibits cell
proliferation at an EC.sub.50 less than or equal to 0.1 .mu.M. In
some embodiments, a provided compound is selective for CARM1 over
other methyltransferases. In certain embodiments, a provided
compound is at least about 10-fold selective, at least about
20-fold selective, at least about 30-fold selective, at least about
40-fold selective, at least about 50-fold selective, at least about
60-fold selective, at least about 70-fold selective, at least about
80-fold selective, at least about 90-fold selective, or at least
about 100-fold selective for PRMT1 relative to one or more other
methyltransferases.
[0146] It will be understood by one of ordinary skill in the art
that the CARM1 can be wild-type CARM1, or any mutant or variant of
CARM1.
[0147] The present disclosure provides pharmaceutical compositions
comprising a compound described herein, e.g., a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, as described
herein, and optionally a pharmaceutically acceptable excipient. It
will be understood by one of ordinary skill in the art that the
compounds described herein, or salts thereof, may be present in
various forms, such as amorphous, hydrates, solvates, or
polymorphs. In certain embodiments, a provided composition
comprises two or more compounds described herein. In certain
embodiments, a compound described herein, or a pharmaceutically
acceptable salt 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 an amount effective for
inhibiting CARM1. In certain embodiments, the effective amount is
an amount effective for treating a CARM1-mediated disorder. In
certain embodiments, the effective amount is a prophylactically
effective amount. In certain embodiments, the effective amount is
an amount effective to prevent a CARM1-mediated disorder.
[0148] Pharmaceutically acceptable excipients include any and all
solvents, diluents, or other liquid vehicles, dispersions,
suspension aids, surface active agents, isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants,
and the like, as suited to the particular dosage form desired.
General considerations in formulation and/or manufacture of
pharmaceutical compositions agents can be found, for example, in
Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.
Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The
Science and Practice of Pharmacy, 21st Edition (Lippincott Williams
& Wilkins, 2005).
[0149] 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 a compound
described herein (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.
[0150] Pharmaceutical compositions can be prepared, packaged,
and/or sold in bulk, as a single unit dose, and/or as a plurality
of single unit doses. As used herein, a "unit dose" is 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.
[0151] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition of the present
disclosure 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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 F68, Poloxamer 188, cetrimonium
bromide, cetylpyridinium chloride, benzalkonium chloride, docusate
sodium, and/or mixtures thereof.
[0156] 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.
[0157] Exemplary preservatives include antioxidants, chelating
agents, antimicrobial preservatives, antifungal preservatives,
alcohol preservatives, acidic preservatives, and other
preservatives.
[0158] Exemplary antioxidants include alpha tocopherol, ascorbic
acid, acorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite,
sodium metabisulfite, and sodium sulfite.
[0159] 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.
[0160] 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.
[0161] Exemplary alcohol preservatives include ethanol,
polyethylene glycol, phenol, phenolic compounds, bisphenol,
chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. 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.
[0162] 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. In certain embodiments,
the preservative is an anti-oxidant. In other embodiments, the
preservative is a chelating agent.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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 compounds
described herein are mixed with solubilizing agents such as
Cremophor.TM., alcohols, oils, modified oils, glycols,
polysorbates, cyclodextrins, polymers, and mixtures thereof.
[0167] 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.
[0168] 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.
[0169] 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.
[0170] Compositions for rectal or vaginal administration are
typically suppositories which can be prepared by mixing the
compounds described herein with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active ingredient.
[0171] 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 comprise buffering agents.
[0172] 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 pharmaceutical formulating art. 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.
[0173] The active ingredient can be in micro-encapsulated form with
one or more excipients as noted above. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active 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.
[0174] Dosage forms for topical and/or transdermal administration
of a provided compound 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
desired preservatives and/or buffers as can be required.
Additionally, the present disclosure encompasses 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.
[0175] 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.
[0176] A provided pharmaceutical composition 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.
[0177] 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).
[0178] Pharmaceutical compositions 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.
[0179] Formulations described herein as being useful for pulmonary
delivery are useful for intranasal delivery of a pharmaceutical
composition. 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.
[0180] Formulations for nasal administration may, for example,
comprise from about as little as 0.1% (w/w) and as much as 100%
(w/w) of the active ingredient, and may comprise one or more of the
additional ingredients described herein. A provided pharmaceutical
composition 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.
[0181] A provided pharmaceutical composition 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 disclosure.
[0182] 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.
[0183] 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 provided
compositions 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, disorder,
or condition 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.
[0184] 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).
[0185] 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).
[0186] 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.
[0187] In certain embodiments, a compound described herein may be
administered at dosage levels sufficient to deliver from about
0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about
mg/kg, from about 0.1 mg/kg to about 40 mg/kg, 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, or 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.
[0188] In some embodiments, a compound described herein is
administered one or more times per day, for multiple days. In some
embodiments, the dosing regimen is continued for days, weeks,
months, or years.
[0189] 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.
[0190] It will be also appreciated that a compound or composition,
as described herein, can be administered in combination with one or
more additional therapeutically active agents. In certain
embodiments, a compound or composition provided herein is
administered in combination with one or more additional
therapeutically active agents that improve its bioavailability,
reduce and/or modify its metabolism, inhibit its excretion, and/or
modify its 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.
[0191] The compound or composition can be administered concurrently
with, prior to, or subsequent to, one or more additional
therapeutically active agents. In certain embodiments, the
additional therapeutically active agent is a compound of Formula
(I). In certain embodiments, the additional therapeutically active
agent is not a compound of Formula (I). In general, each agent will
be administered at a dose and/or on a time schedule determined for
that agent. In will further be appreciated that the additional
therapeutically active agent utilized in this combination can be
administered together in a single composition or administered
separately in different compositions. The particular combination to
employ in a regimen will take into account compatibility of a
provided compound with the additional therapeutically active agent
and/or the desired therapeutic effect to be achieved. In general,
it is expected that additional therapeutically active agents
utilized 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.
[0192] Exemplary additional therapeutically active agents include,
but are not limited to, 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.
[0193] Also encompassed by the present disclosure are kits (e.g.,
pharmaceutical packs). The kits provided may comprise a provided
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 a provided
pharmaceutical composition or compound. In some embodiments, a
provided pharmaceutical composition or compound provided in the
container and the second container are combined to form one unit
dosage form. In some embodiments, a provided kits further includes
instructions for use.
[0194] Compounds and compositions described herein are generally
useful for the inhibition of CARM1. In some embodiments, methods of
treating CARM1-mediated disorder in a subject are provided which
comprise administering an effective amount of a compound described
herein (e.g., a compound of Formula (I), or a pharmaceutically
acceptable salt thereof), to a subject in need of treatment. In
certain embodiments, the effective amount is a therapeutically
effective amount. In certain embodiments, the effective amount is a
prophylactically effective amount. In certain embodiments, the
subject is suffering from a CARM1-mediated disorder. In certain
embodiments, the subject is susceptible to a CARM1-mediated
disorder.
[0195] As used herein, the term "CARM1-mediated disorder" means any
disease, disorder, or other pathological condition in which CARM1
is known to play a role. Accordingly, in some embodiments, the
present disclosure relates to treating or lessening the severity of
one or more diseases in which CARM1 is known to play a role.
[0196] In some embodiments, the present disclosure provides a
method of inhibiting CARM1 comprising contacting CARM1 with an
effective amount of a compound described herein, e.g., a compound
of Formula (I), or a pharmaceutically acceptable salt thereof. The
CARM1 may be purified or crude, and may be present in a cell,
tissue, or subject. Thus, such methods encompass both inhibition of
in vitro and in vivo CARM1 activity. In certain embodiments, the
method is an in vitro method, e.g., such as an assay method. It
will be understood by one of ordinary skill in the art that
inhibition of CARM1 does not necessarily require that all of the
CARM1 be occupied by an inhibitor at once. Exemplary levels of
inhibition of CARM1 include at least 10% inhibition, about 10% to
about 25% inhibition, about 25% to about 50% inhibition, about 50%
to about 75% inhibition, at least 50% inhibition, at least 75%
inhibition, about 80% inhibition, about 90% inhibition, and greater
than 90% inhibition.
[0197] In some embodiments, provided is a method of inhibiting
CARM1 activity in a subject in need thereof comprising
administering to the subject an effective amount of a compound
described herein (e.g., a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition thereof.
[0198] In certain embodiments, provided is a method of modulating
gene expression or activity in a cell which comprises contacting a
cell with an effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof. In certain embodiments,
the cell in culture in vitro. In certain embodiments, the cell is
in an animal, e.g., a human. In certain embodiments, the cell is in
a subject in need of treatment.
[0199] In certain embodiments, provided is a method of modulating
transcription in a cell which comprises contacting a cell with an
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof. In certain embodiments,
the cell in culture in vitro. In certain embodiments, the cell is
in an animal, e.g., a human. In certain embodiments, the cell is in
a subject in need of treatment.
[0200] In certain embodiments, a method is provided of selecting a
therapy for a subject having a disease associated with
CARM1-mediated disorder or mutation comprising the steps of
determining the presence of CARM1-mediated disorder or gene
mutation in the CARM1 gene or and selecting, based on the presence
of CARM1-mediated disorder a gene mutation in the CARM1 gene a
therapy that includes the administration of a provided compound. In
certain embodiments, the disease is cancer.
[0201] In certain embodiments, a method of treatment is provided
for a subject in need thereof comprising the steps of determining
the presence of CARM1-mediated disorder or a gene mutation in the
CARM1 gene and treating the subject in need thereof, based on the
presence of a CARM1-mediated disorder or gene mutation in the CARM1
gene with a therapy that includes the administration of a provided
compound. In certain embodiments, the subject is a cancer
patient.
[0202] In some embodiments, a compound provided herein is useful in
treating a proliferative disorder, such as cancer. For example,
while not being bound to any particular mechanism, protein arginine
methylation by CARM1 is a modification that has been implicated in
signal transduction, gene transcription, DNA repair and mRNA
splicing, among others; and overexpression of CARM1 within these
pathways is often associated with various cancers. Thus, compounds
which inhibit the action of PRMTs, and specifically CARM1, as
provided herein, are effective in the treatment of cancer.
[0203] In some embodiments, compounds provided herein are effective
in treating cancer through the inhibition of CARM1. For example,
CARM1 levels have been shown to be elevated in castration-resistant
prostate cancer (CRPC), as well as in aggressive breast tumors
(Hong et al., Cancer 2004 101, 83-89; El Messaoudi et al., Proc.
Natl. Acad. Sci. U.S.A 2006, 103, 13351-13356; Majumder et al.,
Prostate 2006 66, 1292-1301). Thus, in some embodiments, inhibitors
of CARM1, as described herein, are useful in treating cancers
associated with aberrant CARM1 activity, e.g., CARM1 overexpression
or aberrant protein methylation. CARM1 has also been shown to
affect ER.alpha.-dependent breast cancer cell differentiation and
proliferation (Al-Dhaheri et al., Cancer Res. 2011 71, 2118-2128),
thus in some aspects CARM1 inhibitors, as described herein, are
useful in treating ER.alpha.-dependent breast cancer by inhibiting
cell differentiation and proliferation. In another example, CARM1
has been shown to be recruited to the promoter of E2F1 (which
encodes a cell cycle regulator) as a transcriptional co-activator
(Frietze et al., Cancer Res. 2008 68, 301-306). Thus,
CARM1-mediated upregulation of E2F1 expression may contribute to
cancer progression and chemoresistance as increased abundance of
E2F1 triggers invasion and metastasis by activating growth receptor
signaling pathways, which in turn promote an antiapoptotic tumor
environment (Engelmann and Putzer, Cancer Res 2012 72; 571).
Accordingly, in some embodiments, the inhibition of CARM1, e.g., by
compounds provided herein, is useful in treating cancers associated
with E2F1 upregulation. Thus, without being bound by any particular
mechanism, the inhibition of CARM1, e.g., by compounds described
herein, is beneficial in the treatment of cancer. CARM1
overexpression has also been demonstrated to be elevated in 75% of
colorectal cancers (Kim et al., BMC Cancer, 10, 197). It has been
additionally been determined that depletion of CARM1 in
WNT/.beta.-catenin dysregulated colorectal cancer suppressed
anchorage independent growth (Ou et al., Mol. Cancer. Res., 2011 9,
660-670). This, in some embodiments, the inhibition of CARM1, e.g.
by compounds provided herein, is useful in colorectal cancer
associated with elevated CARM1 expression or dysregulated
WNT/.beta.-catenin signaling.
[0204] In some embodiments, compounds described herein are useful
for treating a cancer including, but not limited to, acoustic
neuroma, adenocarcinoma, adrenal gland cancer, anal cancer,
angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma,
hemangiosarcoma), appendix cancer, benign monoclonal gammopathy,
biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast
cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of
the breast, mammary cancer, medullary carcinoma of the breast),
brain cancer (e.g., meningioma; 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),
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 adenocarinoma),
Ewing sarcoma, eye cancer (e.g., intraocular melanoma,
retinoblastoma), familiar hypereosinophilia, gall bladder cancer,
gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal
stromal tumor (GIST), head and neck cancer (e.g., head and neck
squamous cell carcinoma, oral cancer (e.g., oral squamous cell
carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal
cancer, nasopharyngeal cancer, oropharyngeal cancer)),
hematopoietic cancers (e.g., leukemia such as acute lymphocytic
leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic
leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic
leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic
lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphoma
such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and
non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large
cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)),
follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic
lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone
B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT)
lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal
zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt
lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenstrom's
macroglobulinemia"), hairy cell leukemia (HCL), immunoblastic large
cell lymphoma, precursor B-lymphoblastic lymphoma and primary
central nervous system (CNS) lymphoma; and T-cell NHL such as
precursor T-lymphoblastic lymphomalleukemia, peripheral T-cell
lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,
mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell
lymphoma, extranodal natural killer T-cell lymphoma, enteropathy
type T-cell lymphoma, subcutaneous panniculitis-like T-cell
lymphoma, anaplastic large cell lymphoma); a mixture of one or more
leukemiallymphoma as described above; and multiple myeloma (MM)),
heavy chain disease (e.g., alpha chain disease, gamma chain
disease, mu chain disease), hemangioblastoma, 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), 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 neuroendoctrine tumor (GEP-NET), carcinoid
tumor), osteosarcoma, 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), 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, 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).
[0205] CARM1 is also the most abundant PRMT expressed in skeletal
muscle cells, and has been found to selectively control the
pathways modulating glycogen metabolism, and associated AMPK
(AMP-activated protein kinase) and p38 MAPK (mitogen-activated
protein kinase) expression. See, e.g., Wang et al., Biochem (2012)
444:323-331. Thus, in some embodiments, inhibitors of CARM1, as
described herein, are useful in treating metabolic disorders, e.g.,
for example skeletal muscle metabolic disorders, e.g., glycogen and
glucose metabolic disorders. Exemplary skeletal muscle metabolic
disorders include, but are not limited to, Acid Maltase Deficiency
(Glycogenosis type 2; Pompe disease), Debrancher deficiency
(Glycogenosis type 3), Phosphorylase deficiency (McArdle's; GSD 5),
X-linked syndrome (GSD9D), Autosomal recessive syndrome (GSD9B),
Tarui's disease (Glycogen storage disease VII; GSD 7),
Phosphoglycerate Mutase deficiency (Glycogen storage disease X;
GSDX; GSD 10), Lactate dehydrogenase A deficiency (GSD 11),
Branching enzyme deficiency (GSD 4), Aldolase A (muscle)
deficiency, .beta.-Enolase deficiency, Triosephosphate isomerase
(TIM) deficiency, Lafora's disease (Progressive myoclonic epilepsy
2), Glycogen storage disease (Muscle, Type 0, Phosphoglucomutase 1
Deficiency (GSD 14)), and Glycogenin Deficiency (GSD 15).
[0206] Scheme 1 shows a general synthesis route to compounds of
Formula I-(ii) wherein R.sup.3' is the same as R.sup.3 as defined
above or is a suitable precursor that may be converted to R.sup.3.
This method is based on Suzuki coupling reactions of heteroaryl
chloride intermediates of general Formula XI-(ii) with pinacol
borane intermediates of general Formula X. In a first step, Suzuki
coupling reaction of these intermediates is typically conducted in
the presence of a palladium catalyst (e.g. PdCl.sub.2(dppf)) and a
base (e.g. potassium carbonate) in an organic solvent (e.g.
toluene) at elevated temperature. In a second optional set of steps
the R.sup.3' group as well as other groups in the molecule may be
converted to the defined final substituents in Formula I-(ii). In a
final deprotection step the N-Boc protecting is removed by for
example using an acid (e.g. HCl) in a suitable organic solvent
(e.g. ethanol) to give certain corresponding embodiments of
compounds of Formula I-(ii).
##STR00123##
[0207] Compounds of general Formula XI-(ii) can be prepared from
heteroaryl dichlorides of general Formula XX-(ii) as depicted in
Scheme 2. In certain embodiments when L is --N(R.sup.L)--,
--C(O)N(R.sup.L)--, or --OC(O)N(R.sup.L)--,
--NR.sup.LC(O)N(R.sup.L)--, Buchwald coupling of XX-(ii)
respectively with active amines R.sup.3'N(R.sup.L)H, amides
R.sup.3'C(O)N(R.sup.L)H, carbamates --OC(O)N(R.sup.L)H, or ureas
--NR.sup.LC(O)N(R.sup.L)H, may be implemented in the first step. In
certain embodiments when L.sup.1 is a bond, and the monocyclic
heterocycle core structure is directly attached to R.sup.3' by a
carbon-carbon bond, Suzuki coupling of XXI-(i) with boronic acids
or ester intermediates R.sup.3'B(OH).sub.2 may be implemented to
yield the corresponding certain embodiments of XI-(ii). In certain
embodiments the formation of compounds of Formula XI-(ii) using the
methods described above can be accompanied by formation of the
regioisomeric intermediate compounds of Formula XI-(ii)-a. In
certain embodiments when a mixture of XI-(ii) and
XI-(ii)-regioisomers is formed they may be separated by
chromatography. Intermediates of Formula XI-(ii)-a may in turn be
implemented to prepare compounds of the invention using the same
general method described in Scheme 1.
##STR00124##
[0208] In certain embodiments wherein X in general Formulas I-(ii)
is O, pinacol borane intermediates of general Formula X can be
prepared using standard methods as depicted in Scheme 3. Thus, in a
first step 3-bromophenols of general structure XXX are treated with
epibromohydrin to give epoxides XXXI. Opening of the epoxide group
of intermediates XXXI in with amines of Formula R.sup.1NH.sub.2 in
an organic solvent with heating as necessary followed by protection
of the resulting amine with Boc-anhydride gives intermediates
XXXII. TBS protection of the alcohol group in the next step using
t-butyldimethylsilyltriflate gives intermediate bromides XXXIII. In
a final step the Br group is converted to the pinacol borane
function to give intermediates XX under standard Suzuki-Miyura
conditions.
##STR00125##
[0209] Certain heteroaryl dichlorides of general Formula XX-(ii)
are commercially available. Certain embodiments of general
structure XX-(ii) may be prepared by known methods. For example
embodiments of intermediates of general structure XX-(ii)-x may be
prepared from trichloropyrimidine intermediates L-(ii)-x as
depicted in Scheme 4. In certain embodiments Suzuki coupling of
L-(ii)-x with aryl or heteroaryl boronates gives intermediate
compounds of Formula L-(ii)-x a wherein R.sup.11 is aryl or
heteroaryl. In certain embodiments Buchwald coupling of L-(ii)-x
with primary or secondary cyclic (e.g. morpholine) or acyclic
amines gives intermediate compounds of Formula L-(ii)-x a wherein
R.sup.1 is an acyclic or cyclic amino group.
##STR00126##
EXAMPLES
[0210] In order that the invention described herein may be more
fully understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
Synthetic Methods
[0211] The synthesis of an exemplary set of compounds of Formula
(I) is provided below. These compounds are also listed in Tables 1
and 2, infra. Compounds provided in Tables 1 and 2 have been
prepared following Examples 1-3.
Example 1
Preparation of
1-(3-(4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-6-(pyridine-4-yl)pyrimidi-
n-2-yl)phenoxy)-3-(methylamino)propan-2-ol
##STR00127## ##STR00128##
[0212] Step 1: Synthesis of
(2,6-dichloro-pyrimidin-4-yl)-methyl-(tetrahydro-pyran-4-yl)-amine
[0213] To a solution of 2,4,6-trichloro-pyrimidine (9.2 g, 50 mmol)
and triethylamine (10.1 g, 100 mmol) in EtOH (100 mL) was added
N-methyltetrahydro-2H-pyran-4-amine (5.17 g, 45 mmol) dropwise at
-40.degree. C. The mixture was warmed up to room temperature then
stirred for 14 h., quenched with H.sub.2O (25 mL), concentrated and
the residue was extracted with EtOAc (100 mL.times.3). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by chromatographic column on
silica gel (petroleum ether/EtOAc=30/1 to 2/1) to give
(2,6-dichloro-pyrimidin-4-yl)-methyl-(tetrahydro-pyran-4-yl)amine
as white solid (7.8 g, 60% yield). ESI-LCMS (m/z): 263.14
[M+1].sup.+;
Step 2: Synthesis of
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-chloro-6-[methyl-(tetrahydro--
pyran-4-yl)-amino]-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester and
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{2-chloro-6-[methyl-(tetrahydro--
pyran-4-yl)-amino]-pyrimidin-4-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester
[0214] To a solution of
(2,6-dichloro-pyrimidin-4-yl)-methyl-(tetrahydro-pyran-4-yl)amine
(0.4 g, 1.5 mmol) in degassed dioxane and H.sub.2O (4/1, 25 mL) was
added Na.sub.2CO.sub.3 (315 mg, 3.0 mmol); Pd(PPh.sub.3).sub.4 (86
mg, 0.075 mmol) and
{2-(tert-Butyl-dimethyl-silanyloxy)-3-[3-(4,4,5,5-tetramethyl-[-
1,3,2]dioxaborolan-2-yl)-phenoxy]-propyl}-methyl-carbamic acid
tert-butyl ester (703 mg, 1.35 mmol). The system was purged with
N.sub.2 stream and the mixture was stirred at 100.degree. C. for 2
h., cooled to room temperature, diluted with water (50 mL) and
extracted with EtOAc (50 mL.times.2). The organic layers were
combined, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by preparative HPLC to give
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-chloro-6-[methyl-(tetrahydro--
pyran-4-yl)-amino]-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester (373 mg, 40% yield) as major product.
ESI-LCMS (m/z): 411.2 [M+1].sup.+ along with the minor product
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{2-chloro-6-[methyl-(tetrahydro--
pyran-4-yl)-amino]-pyrimidin-4-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester (140 mg, 15% yield). ESI-LCMS (m/z): 411.2
[M+1].sup.+.
Step 3: Synthesis of
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-y-
l)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester
[0215] To a solution of
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-chloro-6-[methyl-(tetrahydro--
pyran-4-yl)-amino]-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester (160 mg, 0.26 mmol) in degassed dioxane and
H.sub.2O (4/1, 25 mL) was added Na.sub.2CO.sub.3 (83 mg, 0.78
mmol); Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) and
pyridin-4-ylboronic acid (64 mg, 0.52 mmol). The system was purged
with N.sub.2 stream and the mixture was stirred 100.degree. C. for
2 h., cooled down to room temperature, diluted with water (25 mL)
and extracted with EtOAc (25 mL.times.2). The organic layers were
combined, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by chromatographic column on silica gel
(petroleum ether/EtOAc=10/1 to 1/1) to give
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-y-
l)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester (128 mg, 75% yield). ESI-LCMS (m/z): 664.4
[M+1].sup.+.
Step 4: Synthesis of
1-methylamino-3-(3-{4-[methyl-(tetrahydro-pyran-4-yl)-amino]-6-pyridin-4--
yl-pyrimidin-2-yl}-phenoxy)-propan-2-ol
[0216] A solution of
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-y-
l)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester (135 mg, 0.20 mmol) was treated with a 2.5 N
HCl solution in methanol (10 mL) and the mixture was stirred at
room temperature for 4 h., concentrated under vacuum and the
residue was purified by preparative HPLC to give
1-methylamino-3-(3-{4-[methyl-(tetrahydro-pyran-4-yl)-amino]-6-pyridin-4--
yl-pyrimidin-2-yl}-phenoxy)-propan-2-ol as white solid (49 mg, 56%
yield). .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm: 8.72-8.70
(m, 2H), 8.23 (brs, 2H), 8.14-8.10 (m, 2H), 7.43 (t, J=8.5 Hz, 1H),
7.16-7.10 (m, 2H), 4.24-4.18 (m, 1H), 4.15-4.08 (m, 4H), 3.72-3.65
(m, 2H), 3.14 (s, 3H), 3.00-2.85 (m, 2H), 2.56 (s, 3H), 2.09-1.98
(m, 2H), 1.79-1.72 (m, 2H). ESI-LCMS: 450.5 (M+1).sup.+.
Example 2
Preparation of
1-Methylamino-3-(3-{6-[methyl-(tetrahydro-pyran-4-yl)-amino]-2-pyridin-4--
yl-pyrimidin-4-yl}-phenoxy)-propan-2-ol
##STR00129##
[0217] Step 5: Synthesis of
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-y-
l)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester
[0218] To a solution of
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{2-chloro-6-[methyl-(tetrahydro--
pyran-4-yl)-amino]-pyrimidin-4-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester (160 mg, 0.26 mmol) in degassed dioxane and
H.sub.2O (4/1, 25 mL) was added Na.sub.2CO.sub.3 (83 mg, 0.78
mmol); Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) and
pyridin-4-ylboronic acid (64 mg, 0.52 mmol). The system purged with
N.sub.2 stream and the mixture was stirred to 100.degree. C. for 2
h., cooled down to room temperature, diluted with water (25 mL) and
extracted with EtOAc (25 mL.times.2). The organic layers were
combined, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by chromatographic column on silica gel
(petroleum ether/EtOAc=10/1 to 2/3) to give
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-y-
l)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester (135 mg, 79% yield). ESI-LCMS (m/z): 664.4
[M+1].sup.+.
Step 6: Synthesis of
1-Methylamino-3-(3-{6-[methyl-(tetrahydro-pyran-4-yl)-amino]-2-pyridin-4--
yl-pyrimidin-4-yl}-phenoxy)-propan-2-ol
[0219] A solution of
[2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-y-
l)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic
acid tert-butyl ester (128 mg, 0.19 mmol) was treated with a 2.5 N
HCl solution in methanol, (10 mL), and the mixture was stirred at
room temperature for 4 h., concentrated under vacuum and the
residue was purified by preparative HPLC to give
1-methylamino-3-(3-{6-[methyl-(tetrahydro-pyran-4-yl)-amino]-2-pyridin-4--
yl-pyrimidin-4-yl}-phenoxy)-propan-2-ol as white solid (52 mg, 57%
yield). .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm: 8.71 (d,
J=5.5 Hz, 2H), 8.47 (d, J=5.0 Hz, 2H), 7.84 (s, 1H), 7.79 (d, J=8.0
Hz, 1H), 7.47-7.43 (m, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.09 (s, 1H),
4.22-4.17 (m, 1H), 4.15-4.09 (m, 4H), 3.74-3.66 (m, 2H), 3.15 (s,
3H), 2.96-2.82 (m, 2H), 2.53 (s, 3H), 2.07-1.97 (m, 2H), 1.78-1.73
(m, 2H); LCMS: 450.3 (M+H).sup.+;
Example 3
Preparation of
1-(3-(5-methyl-4-morpholino-6-((R)-tetrahydrofuran-3-ylamino)pyrimidin-2--
yl)phenoxy)-3-(methylamino)propan-2-ol
##STR00130##
[0220] Step 1: Synthesis of
(R)-2,6-dichloro-5-methyl-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine
[0221] A mixture of 2,4,6-trichloro-5-methylpyrimidine (2 g, 10.2
mmol), (R)-tetrahydro-furan-3-amine hydrochloride (1.12 g, 9.2
mmol) and Et.sub.3N (2.1 g, 20.3 mmol) in EtOH (20 mL) was stirred
at room temperature for 14 h., concentrated under vacuum and the
residue was purified by chromatographic column on silica gel
(EtOAc/petroleum ether, gradient elution, from 1/10 to 2/1) to give
the
(R)-2,6-dichloro-5-methyl-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine
(1.25 g, 53% yield) as a white solid. ESI-LCMS (m/z): 248.1
[M+1].sup.+.
Step 2: Synthesis of
(R)-3-(4-chloro-5-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)phen-
ol
[0222] To a solution of of
(R)-2,6-dichloro-5-methyl-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine
(1.8 g, 7.3 mmol) in degassed dioxane and H.sub.2O (4/1, 21 mL) was
added Na.sub.2CO.sub.3 (1.5 g, 14.5 mmol); Pd(PPh.sub.3).sub.4 (296
mg, 0.36 mmol) and 3-hydroxy-phenylboronic acid (1.21 g, 8.8 mmol).
The system was purged with nitrogen stream and then stirred at
100.degree. C. for 14 h., cooled down to room temperature, diluted
with water (30 mL) and the resulting mixture extracted with EtOAc
(30 mL.times.2). The combined organic layer were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by chromatographic column on silica gel (EtOAc/petroleum
ether, gradient elution, from 1/10 to 2:1) to give
(R)-3-(4-chloro-5-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl-
) phenol (2.4 g, 33%) as a white solid. ESI-LCMS (m/z): 306.1
[M+1].sup.+.
Step 3: Synthesis of
(R)-3-(5-methyl-4-morpholino-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)-
phenol
[0223] A mixture of
(R)-3-(4-chloro-5-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)
phenol (800 mg, 2.6 mmol); neat morpholine (274 mg, 3.1 mmol) and
Na.sub.2CO.sub.3 (556 mg, 5.2 mmol) in EtOH (12 mL) was stirred at
80.degree. C. in a sealed vial for 14 h. The mixture was filtered
and the filtrate was concentrated. The residue was purified by
chromatographic column on silica gel (EtOAc/petroleum ether,
gradient elution, from 1/2 to 2/1) to give the
(R)-3-(5-methyl-4-morpholino-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)-
phenol (120 mg, 13% yield) as a light yellow solid. ESI-LCMS (m/z):
357.1 [M+1].sup.+.
Step 4: Synthesis of
5-methyl-6-morpholino-2-(3-(oxiran-2-ylmethoxy)phenyl)-N--((R)-tetrahydro-
furan-3-yl)pyrimidin-4-amine
[0224] A mixture of
(R)-3-(5-methyl-4-morpholino-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)-
phenol (50 mg, 0.14 mmol); 2-(chloromethyl)oxirane (16 mg, 0.17
mmol) and K.sub.2CO.sub.3 (39 mg, 0.28 mmol) in MeCN (10 mL) was
heated at 80.degree. C. in a sealed vial for 14 h. The mixture was
filtered and the filtrate was concentrated. The residue was
purified by chromatographic column on silica gel (EtOAc/petroleum
ether, gradient elution, from 1/5 to 4:1) to give the
5-methyl-6-morpholino-2-(3-(oxiran-2-ylmethoxy)phenyl)-N--((R)-tetrahydro-
furan-3-yl)pyrimidin-4-amine (20 mg, 34% yield) as a light yellow
solid. ESI-LCMS (m/z): 413.2 [M+1].sup.+.
Step 5: Synthesis of
1-(3-(5-methyl-4-morpholino-6-((R)-tetrahydrofuran-3-ylamino)pyrimidin-2--
yl)phenoxy)-3-(methylamino)propan-2-ol
[0225]
5-Methyl-6-morpholino-2-(3-(oxiran-2-ylmethoxy)phenyl)-N--((R)-tetr-
a-hydrofuran-3-yl)pyrimidin-4-amine (20 mg, 0.05 mmol) was
dissolved in a 2N MeNH.sub.2 solution in methanol, (10 mL) and the
mixture was stirred at room temperature for 14 h., concentrated
under vacuum and the residue was purified by preparative HPLC to
obtain the
1-(3-(5-methyl-4-morpholino-6-((R)-tetrahydrofuran-3-ylamino)pyrimidin-2--
yl)phenoxy)-3-(methyl-amino)propan-2-ol (8 mg, 37% yield) as a
white solid. 1H NMR (500 MHz, CD.sub.3OD) .delta. ppm:8.02-7.96 (m,
2H), 7.34 (t, J=8.0 Hz, 1H), 7.05-7.00 (m, 1H), 4.85-4.80 (m, 1H),
4.20-4.14 (m, 2H), 4.07-4.01 (m, 3H), 3.93-3.84 (m, 5H), 3.78-3.74
(m, 1H), 2.96-2.92 (m, 1H), 2.88-2.82 (m, 1H), 2.53 (s, 3H),
2.42-2.35 (m, 1H), 2.11-2.04 (m, 4H); ESI-LCMS (m/z): 444.3
[M+1].sup.+.
Biological Assays
General Materials
[0226] S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH),
bicine, Tween20, dimethylsulfoxide (DMSO), bovine skin gelatin
(BSG), sodium butyrate and Tris(2-carboxyethyl)phosphine
hydrochloride solution (TCEP) were purchased from Sigma-Aldrich at
the highest level of purity possible. .sup.3H-SAM was purchase from
American Radiolabeled Chemicals with a specific activity of 80
Ci/mmol. 384-well streptavidin Flashplates were purchased from
PerkinElmer.
Substrates
[0227] Peptide representative of human histone H3 residues 16-30
was synthesized with an N-terminal linker-affinity tag motif and a
C-terminal amide cap by 21.sup.st Century Biochemicals. The peptide
was purified by high-performance liquid chromatography (HPLC) to
greater than 95% purity and confirmed by liquid chromatography mass
spectrometry (LC-MS). The sequence was
Biot-Ahx-PRKQLATKAARKSAP-amide and contained a monomethylated
arginine at position 26 (SEQ ID NO.:1).
Molecular Biology
[0228] Human CARM1 (PRMT4) (NM_199141.1) transcript clone was
amplified from an HEK 293 cDNA library, incorporating a flanking 5'
sequence encoding a FLAG tag (MDYKDDDDK) (SEQ ID NO.:2) fused
directly to Ala 2 of CARM1 and 3' sequence encoding a hexa His
sequence (EGHHHHHH) (SEQ ID NO.:3) fused directly to Ser 608. The
gene sequence encoding isoforml containing a deletion of amino
acids 539-561 was amplified subsequently and subcloned into
pFastBacMam (Viva Biotech).
Protein Expression
[0229] Recombinant baculovirus were generated according to
Bac-to-Bac kit instructions (Life Technologies). Protein
over-expression was accomplished by infecting exponentially growing
HEK 293F cell culture at 1.3.times.10.sup.6 cell/ml with virus
(MOI=10) in the presence of 8 mM sodium butyrate. Infections were
carried out at 37.degree. C. for 48 hours, harvested by
centrifugation, and stored at -80.degree. C. for purification.
Protein Purification
[0230] Expressed full-length human Flag- and His-tagged CARM1
protein was purified from cell paste by anti-flag M2 affinity
chromatography with resin equilibrated with buffer containing 20 mM
Tris, 150 mM NaCl, 5% glycerol, pH 7.8. Column was washed with 500
mM NaCl in buffer A and Flag-CARM1-His was eluted with 200 ug/ml
FLAG peptide in buffer A. Pooled fractions were dialyzed in 20 mM
Tris, 150 mM NaCl, 5% glycerol and 1 mM DTT, pH 7.8. The purity of
recovered protein was 94.
Predicted Translations
TABLE-US-00003 [0231] Flag-CARM1-His (SEQ ID NO.: 4)
MDYKDDDDKAAAAAAVGPGAGGAGSAVPGGAGPCATVSVFPGARLL
TIGDANGEIQRHAEQQALRLEVRAGPDSAGIALYSHEDVCVFKCSV
SRETECSRVGKQSFIITLGCNSVLIQFATPNDFCSFYNILKTCRGH
TLERSVFSERTEESSAVQYFQFYGYLSQQQNMMQDYVRTGTYQRAI
LQNHTDFKDKIVLDVGCGSGILSFFAAQAGARKIYAVEASTMAQHA
EVLVKSNNLTDRIVVIPGKVEEVSLPEQVDIIISEPMGYMLFNERM
LESYLHAKKYLKPSGNMFPTIGDVHLAPFTDEQLYMEQFTKANFWY
QPSFHGVDLSALRGAAVDEYFRQPVVDTFDIRILMAKSVKYTVNFL
EAKEGDLHRIEIPFKFHMLHSGLVHGLAFWFDVAFIGSIMTVWLST
APTEPLTHWYQVRCLFQSPLFAKAGDTLSGTCLLIANKRQSYDISI
VAQVDQTGSKSSNLLDLKNPFFRYTGTTPSPPPGSHYTSPSENMWN
TGSTYNLSSGMAVAGMPTAYDLSSVIASGSSVGHNNLIPLGSSGAQ
GSGGGSTSAHYAVNSQFTMGGPAISMASPMSIPTNTMHYGSEGHHH HHH
General Procedure for CARM1 Enzyme Assays on Peptide Substrates
[0232] The assays were all performed in a buffer consisting of 20
mM Bicine (pH=7.6), 1 mM TCEP, 0.005% BSG, and 0.002% Tween 20,
prepared on the day of use. Compounds in 100% DMSO (1 ul) were
spotted into a polypropylene 384-well V-bottom plates (Greiner)
using a Platemate Plus outfitted with a 384-channel head (Thermo
Scientific). DMSO (1 ul) was added to Columns 11, 12, 23, 24, rows
A-H for the maximum signal control and 1 ul of SAH, a known product
and inhibitor of CARM1, was added to columns 11, 12, 23, 24, rows
I-P for the minimum signal control. A cocktail (40 ul) containing
the CARM1 enzyme was added by Multidrop Combi (Thermo-Fisher). The
compounds were allowed to incubate with CARM1 for 30 min at room
temperature, then a cocktail (10 ul) containing .sup.3H-SAM and
peptide was added to initiate the reaction (final volume=51 ul).
The final concentrations of the components were as follows: CARM1
was 0.25 nM, .sup.3H-SAM was 30 nM, peptide was 250 nM, SAH in the
minimum signal control wells was 1 mM, and the DMSO concentration
was 2%. The assays were stopped by the addition of non-radiolabeled
SAM (10 ul) to a final concentration of 300 uM, which dilutes the
.sup.3H-SAM to a level where its incorporation into the peptide
substrate is no longer detectable. 50 ul of the reaction in the
384-well polypropylene plate was then transferred to a 384-well
Flashplate and the biotinylated peptides were allowed to bind to
the streptavidin surface for at least 1 hour before being washed
once with 0.1% Tween20 in a Biotek ELx405 plate washer. The plates
were then read in a PerkinElmer TopCount plate reader to measure
the quantity of .sup.3H-labeled peptide bound to the Flashplate
surface, measured as disintegrations per minute (dpm) or
alternatively, referred to as counts per minute (cpm).
% inhibition calculation ##EQU00001## % inh = 100 - ( dpm cmpd -
dpm min dpm max - dpm min ) .times. 100 ##EQU00001.2##
where dpm=disintegrations per minute, cmpd=signal in assay well,
and min and max are the respective minimum and maximum signal
controls.
parameter IC 50 fit ##EQU00002## Y = Bottom + ( Top - Bottom ) ( 1
+ ( X IC 50 ) Hill Coefficient ##EQU00002.2##
where top and bottom are the normally allowed to float, but may be
fixed at 100 or 0 respectively in a 3-parameter fit. The Hill
Coefficient normally allowed to float but may also be fixed at 1 in
a 3-parameter fit. Y is the % inhibition and X is the compound
concentration.
RKO Methylation Assay
[0233] RKO adherent cells were purchased from ATCC (American Type
Culture Collection), Manassas, Va., USA. DMEM/Glutamax medium,
penicillin-streptomycin, heat inactivated fetal bovine serum, 0.05%
trypsin and D-PBS were purchased from Life Technologies, Grand
Island, N.Y., USA. Odyssey blocking buffer, 800CW goat anti-rabbit
IgG (H+L) antibody, and Licor Odyssey infrared scanner were
purchased from Licor Biosciences, Lincoln, Nebr., USA. Asymmetric
di-methyl PABP1 antibody was purchased from Cell Signaling
Technology, Danvers, Mass., USA. Methanol was purchased from VWR,
Franklin, Mass., USA. 10% Tween 20 was purchased from KPL, Inc.,
Gaithersburg, Md., USA. Paraformaldehyde (PFA) was purchased from
EM Sciences. DRAQ5 was purchased from Biostatus Limited,
Leicestershire, UK.
[0234] RKO adherent cells were maintained in growth medium
(DMEM/Glutamax medium supplemented with 10% v/v heat inactivated
fetal bovine serum and 100 units/mL penicillin-streptomycin) and
cultured at 37.degree. C. under 5% CO.sub.2.
[0235] Cell treatment, In Cell Western (ICW) for detection of
asymmetric di-methyl PABP1 and DNA content: RKO cells were seeded
in assay medium at a concentration of 30,000 cells per mL to a
poly-D-lysine coated 384 well culture plate (BD Biosciences 356697)
with 50 aL per well. Compound (100 nL) from a 96-well source plate
was added directly to 384 well cell plate. Plates were incubated at
37.degree. C., 5% CO.sub.2 for 48 hours. After two days of
incubation, plates were brought to room temperature outside of the
incubator for ten minutes and blotted on paper towels to remove
cell media. Cells were fixed for 20 minutes at room temperature by
adding 50 ul of 8% PFA followed by aspiration of supernatant with
the Biotek EL406 plate washer. Cells were then permeabilized by
addition of 50 aL of ice cold 100% methanol directly to each well
and incubated for 30 min at room temperature. After 30 min, plates
were transferred to a Biotek EL406 plate washer and washed 2 times
with 100 aL per well of wash buffer (1.times.PBS). Next 60 aL per
well of Odyssey blocking buffer (Odyssey Buffer with 0.1% Tween 20
(v/v)) were added to each plate and incubated 1 hour at room
temperature. Blocking buffer was removed and 20 .mu.L per well of
primary antibody was added (asymmetric-methyl PABP1) diluted 1:400
in Odyssey buffer with 0.1% Tween 20 (v/v)) and plates were
incubated overnight (16 hours) at 4.degree. C. Plates were washed 5
times with 100 aL per well of wash buffer. Next 20 aL per well of
secondary antibody was added (1:800 800CW goat anti-rabbit IgG
(H+L) antibody, 1:2000 DRAQ5 in Odyssey buffer with 0.1% Tween 20
(v/v)) and incubated for 1 hour at room temperature. The plates
were washed 5 times with 100 .mu.L per well wash buffer then 2
times with 100 .mu.L per well of water. Plates were allowed to dry
at room temperature then imaged on the Licor Odyssey machine which
measures integrated intensity at 700 nm and 800 nm wavelengths.
Both 700 and 800 channels were scanned.
[0236] Calculations.
[0237] First, the ratio for each well was determined by:
( asymmetric di - methyl PABP 1 800 nm value DRAQ 5 700 nm value )
##EQU00003##
[0238] Each plate included fourteen control wells of DMSO only
treatment (minimum inhibition) as well as fourteen control wells
for maximum inhibition treated with 20 .mu.M of a reference
compound. The average of the ratio values for each control type was
calculated and used to determine the percent activation for each
test well in the plate. Reference compound was serially diluted
three-fold in DMSO for a total of nine test concentrations,
beginning at 20 .mu.M.
[0239] Percent inhibition was determined and IC.sub.50 curves were
generated using triplicate wells per concentration of compound.
Percent Inhibition = 100 - ( ( ( Minimum Inhibition Ratio ) - (
Individual Test Sample Ratio ) ( Minimum Inhibition Ratio ) - (
Maximum Inhibition Ratio ) ) * 100 ) ##EQU00004##
TABLE-US-00004 TABLE 3 Biochemical potencies Compound Biochem
IC.sub.50 1-1 A 2-1 A 3-1 A 4-1 E 5-1 D 6-1 B 7-1 B 8-1 B 9-1 A
10-1 A 11-1 A 12-1 B 13-1 A 14-1 A 15-1 A 16-1 B 17-1 C 18-1 A 19-1
A 20-1 A 21-1 B 22-1 A 23-1 B 24-1 A 25-1 A 26-1 A 27-1 B 28-1 B
29-1 A 30-1 B 31-1 B 32-1 A 33-1 A 34-1 A 35-1 B 36-1 A 37-1 A 38-1
B 39-1 B 40-1 B 41-1 A 42-1 A 43-1 B 44-1 B 45-1 A 46-1 A 47-1 B
48-1 A 49-1 A 50-1 A 51-1 B 52-1 B 53-1 A 54-1 B 55-1 A 56-1 A 57-1
A 58-1 B 59-1 A 60-1 A 61-1 C 62-1 A 63-1 B 64-1 A 65-1 B 66-1 B
67-1 B 68-1 B 69-1 B 70-1 A 71-1 A 72-1 B 73-1 B 74-1 B 75-1 B 1-2
B 2-2 A 3-2 B 4-2 A 5-2 A 6-2 A 7-2 B 8-2 A 9-2 B 10-2 B 11-2 B
12-2 B 13-2 B 14-2 A 15-2 A 16-2 A Classification codes for
biochemical potencies: A: IC.sub.50 <0.1 uM B: 0.1 uM .ltoreq.
IC.sub.50 < 1 uM C: 1 uM .ltoreq. IC.sub.50 < 3 uM D: 3 uM
.ltoreq. IC.sub.50 < 10 uM E: 10 uM < IC.sub.50
TABLE-US-00005 TABLE 4 Cellular potencies Compound Cellular
IC.sub.50 3-1 B 26-1 C 33-1 A 40-1 B 41-1 C 51-1 C 52-1 C 70-1 C
Classification codes for cellular potencies: A: IC.sub.50 <5 uM
B: 5 uM .ltoreq. IC.sub.50 < 10 uM C: 10 uM .ltoreq. IC.sub.50
< 20 uM
Other Embodiments
[0240] The foregoing has been a description of certain non-limiting
embodiments of the invention. 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
4116PRTArtificial SequenceSynthetic Polypeptide 1Xaa Pro Arg Lys
Gln Leu Ala Thr Lys Ala Ala Arg Lys Ser Ala Pro 1 5 10 15
29PRTArtificial SequenceSynthetic Polypeptide 2Met Asp Tyr Lys Asp
Asp Asp Asp Lys 1 5 38PRTArtificial SequenceSynthetic Polypeptide
3Glu Gly His His His His His His 1 5 4601PRTArtificial
SequenceSynthetic Polypeptide 4Met Asp Tyr Lys Asp Asp Asp Asp Lys
Ala Ala Ala Ala Ala Ala Val 1 5 10 15 Gly Pro Gly Ala Gly Gly Ala
Gly Ser Ala Val Pro Gly Gly Ala Gly 20 25 30 Pro Cys Ala Thr Val
Ser Val Phe Pro Gly Ala Arg Leu Leu Thr Ile 35 40 45 Gly Asp Ala
Asn Gly Glu Ile Gln Arg His Ala Glu Gln Gln Ala Leu 50 55 60 Arg
Leu Glu Val Arg Ala Gly Pro Asp Ser Ala Gly Ile Ala Leu Tyr 65 70
75 80 Ser His Glu Asp Val Cys Val Phe Lys Cys Ser Val Ser Arg Glu
Thr 85 90 95 Glu Cys Ser Arg Val Gly Lys Gln Ser Phe Ile Ile Thr
Leu Gly Cys 100 105 110 Asn Ser Val Leu Ile Gln Phe Ala Thr Pro Asn
Asp Phe Cys Ser Phe 115 120 125 Tyr Asn Ile Leu Lys Thr Cys Arg Gly
His Thr Leu Glu Arg Ser Val 130 135 140 Phe Ser Glu Arg Thr Glu Glu
Ser Ser Ala Val Gln Tyr Phe Gln Phe 145 150 155 160 Tyr Gly Tyr Leu
Ser Gln Gln Gln Asn Met Met Gln Asp Tyr Val Arg 165 170 175 Thr Gly
Thr Tyr Gln Arg Ala Ile Leu Gln Asn His Thr Asp Phe Lys 180 185 190
Asp Lys Ile Val Leu Asp Val Gly Cys Gly Ser Gly Ile Leu Ser Phe 195
200 205 Phe Ala Ala Gln Ala Gly Ala Arg Lys Ile Tyr Ala Val Glu Ala
Ser 210 215 220 Thr Met Ala Gln His Ala Glu Val Leu Val Lys Ser Asn
Asn Leu Thr 225 230 235 240 Asp Arg Ile Val Val Ile Pro Gly Lys Val
Glu Glu Val Ser Leu Pro 245 250 255 Glu Gln Val Asp Ile Ile Ile Ser
Glu Pro Met Gly Tyr Met Leu Phe 260 265 270 Asn Glu Arg Met Leu Glu
Ser Tyr Leu His Ala Lys Lys Tyr Leu Lys 275 280 285 Pro Ser Gly Asn
Met Phe Pro Thr Ile Gly Asp Val His Leu Ala Pro 290 295 300 Phe Thr
Asp Glu Gln Leu Tyr Met Glu Gln Phe Thr Lys Ala Asn Phe 305 310 315
320 Trp Tyr Gln Pro Ser Phe His Gly Val Asp Leu Ser Ala Leu Arg Gly
325 330 335 Ala Ala Val Asp Glu Tyr Phe Arg Gln Pro Val Val Asp Thr
Phe Asp 340 345 350 Ile Arg Ile Leu Met Ala Lys Ser Val Lys Tyr Thr
Val Asn Phe Leu 355 360 365 Glu Ala Lys Glu Gly Asp Leu His Arg Ile
Glu Ile Pro Phe Lys Phe 370 375 380 His Met Leu His Ser Gly Leu Val
His Gly Leu Ala Phe Trp Phe Asp 385 390 395 400 Val Ala Phe Ile Gly
Ser Ile Met Thr Val Trp Leu Ser Thr Ala Pro 405 410 415 Thr Glu Pro
Leu Thr His Trp Tyr Gln Val Arg Cys Leu Phe Gln Ser 420 425 430 Pro
Leu Phe Ala Lys Ala Gly Asp Thr Leu Ser Gly Thr Cys Leu Leu 435 440
445 Ile Ala Asn Lys Arg Gln Ser Tyr Asp Ile Ser Ile Val Ala Gln Val
450 455 460 Asp Gln Thr Gly Ser Lys Ser Ser Asn Leu Leu Asp Leu Lys
Asn Pro 465 470 475 480 Phe Phe Arg Tyr Thr Gly Thr Thr Pro Ser Pro
Pro Pro Gly Ser His 485 490 495 Tyr Thr Ser Pro Ser Glu Asn Met Trp
Asn Thr Gly Ser Thr Tyr Asn 500 505 510 Leu Ser Ser Gly Met Ala Val
Ala Gly Met Pro Thr Ala Tyr Asp Leu 515 520 525 Ser Ser Val Ile Ala
Ser Gly Ser Ser Val Gly His Asn Asn Leu Ile 530 535 540 Pro Leu Gly
Ser Ser Gly Ala Gln Gly Ser Gly Gly Gly Ser Thr Ser 545 550 555 560
Ala His Tyr Ala Val Asn Ser Gln Phe Thr Met Gly Gly Pro Ala Ile 565
570 575 Ser Met Ala Ser Pro Met Ser Ile Pro Thr Asn Thr Met His Tyr
Gly 580 585 590 Ser Glu Gly His His His His His His 595 600
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