U.S. patent application number 16/412721 was filed with the patent office on 2019-10-31 for inhibitors of cyclin-dependent kinase 7 (cdk7).
The applicant listed for this patent is Syros Pharmaceuticals, Inc.. Invention is credited to Jason J. Marineau, Darby Schmidt, Kevin Sprott.
Application Number | 20190330218 16/412721 |
Document ID | / |
Family ID | 52998238 |
Filed Date | 2019-10-31 |
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United States Patent
Application |
20190330218 |
Kind Code |
A1 |
Marineau; Jason J. ; et
al. |
October 31, 2019 |
INHIBITORS OF CYCLIN-DEPENDENT KINASE 7 (CDK7)
Abstract
The present invention provides novel compounds described herein,
such as of Formula (I), and pharmaceutically acceptable salts,
solvates, hydrates, tautomers, stereoisomers, isotopically labeled
derivatives, and compositions thereof. Also provided are methods
and kits involving the compounds or compositions for treating or
preventing proliferative diseases (e.g., cancers (e.g., leukemia,
melanoma, multiple myeloma), benign neoplasms, angiogenesis,
inflammatory diseases, autoinflammatory diseases, and autoimmune
diseases) in a subject. Treatment of a subject with a proliferative
disease using a compound or composition of the invention may
inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7),
and therefore, induce cellular apoptosis and/or inhibit
transcription in the subject. ##STR00001##
Inventors: |
Marineau; Jason J.;
(Franklin, MA) ; Sprott; Kevin; (Needham, MA)
; Schmidt; Darby; (Arlington, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Syros Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
52998238 |
Appl. No.: |
16/412721 |
Filed: |
May 15, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15301819 |
Oct 4, 2016 |
10336760 |
|
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PCT/US2015/024336 |
Apr 3, 2015 |
|
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16412721 |
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61975773 |
Apr 5, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4545 20130101;
A61K 31/53 20130101; A61P 35/00 20180101; A61K 45/06 20130101; A61K
31/454 20130101; A61K 31/519 20130101; C07D 487/04 20130101; C07D
417/14 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61K 45/06 20060101 A61K045/06; A61K 31/53 20060101
A61K031/53; C07D 417/14 20060101 C07D417/14; A61K 31/4545 20060101
A61K031/4545; A61K 31/454 20060101 A61K031/454; A61K 31/519
20060101 A61K031/519 |
Claims
1.-47. (canceled)
48. A compound having the structural formula (IVa): ##STR00112## or
a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or
stereoisomer thereof, wherein: R.sup.b and R.sup.c are each
C.sub.1-C.sub.6 alkyl; W is --NR.sup.bR.sup.c, wherein R.sup.b is
hydrogen and R.sup.c is optionally substituted C.sub.1-C.sub.6
alkyl; R.sup.2 is a bond; Q is a bond; R.sup.3 is --C(O)-- or
--CH.sub.2--; Z is an unsubstituted, monocyclic aryl; and R.sup.4
is Formula (ii-1): ##STR00113## wherein L.sup.3 is --N(R.sup.6)--,
wherein R.sup.6 is hydrogen, Y is O, and each of R.sup.E1,
R.sup.E2, and R.sup.E3 is hydrogen or optionally substituted
alkyl.
49. The compound of claim 48, or a pharmaceutically acceptable
salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
R.sup.b and R.sup.c are each methyl; W is --NR.sup.bR.sup.c,
wherein R.sup.b is hydrogen and R.sup.c is optionally substituted
C.sub.2 alkyl; R.sup.3 is --C(O)--; and R.sup.4 is
--NH--C(O)--CH.dbd.CH--CH.sub.2--N(CH.sub.3).sub.2 or
--NH--C(O)--CH.dbd.CH.sub.2.
50. The compound of claim 49, or a pharmaceutically acceptable
salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
R.sup.1 is --NR.sup.bR.sup.c, wherein R.sup.b is hydrogen and
R.sup.c is a C.sub.2 alkyl substituted with phenyl and with
--N(R.sup..smallcircle.).sub.2, wherein each R.sup..smallcircle. is
methyl; and R.sup.4 is --NH--C(O)--CH.dbd.CH.sub.2.
51. The compound of claim 50, or the pharmaceutically acceptable
salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein
Z is ##STR00114## wherein "1" represents a portion of Z bound to
R.sup.3, "2" represents a portion of Z bound to R.sup.4, and m is
zero (0).
52. The compound of claim 51, wherein Z is ##STR00115##
53. The compound of claim 50 in the form of the pharmaceutically
acceptable salt.
54. A pharmaceutical composition comprising the compound of claim
50, or a pharmaceutically acceptable salt, solvate, hydrate,
tautomer, or stereoisomer thereof, and a pharmaceutically
acceptable excipient.
55. The pharmaceutical composition of claim 54, wherein the
composition comprises a pharmaceutically acceptable salt of the
compound of claim 50.
56. The pharmaceutical composition of claim 54, wherein the
composition is formulated for oral administration.
57. The pharmaceutical composition of claim 54, wherein the
composition is formulated for intravenous administration.
58. The pharmaceutical composition of claim 57, wherein the
composition is an injectable solution or suspension and the
excipient is a non-toxic, parenterally acceptable diluent or
solvent.
59. The pharmaceutical composition of claim 54, wherein the
composition is packaged as a single unit dose or a plurality of
single unit doses.
60. A kit comprising the compound of claim 50, or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer, or
stereoisomer thereof, and instructions for administering the
compound, or the pharmaceutically acceptable salt, solvate,
hydrate, tautomer, or stereoisomer thereof, to a subject having a
proliferative disease.
61. A method of treating a subject suffering from a proliferative
disease associated with aberrant activity of cyclin-dependent
kinase 7 (CDK7), the method comprising administering to the subject
the pharmaceutical composition of claim 54, wherein the compound of
claim 48 or the pharmaceutically acceptable salt, solvate, hydrate,
tautomer, or stereoisomer thereof is provided therein in a
therapeutically effective amount.
62. The method of claim 61, wherein the proliferative disease is
cancer or a benign neoplasm.
63. The method of claim 62, wherein the cancer is a blood cancer,
melanoma, a bone cancer, a breast cancer, a brain cancer, a lung
cancer, or ovarian cancer.
64. The method of claim 63, wherein the blood cancer is chronic
lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL),
acute myelocytic leukemia (AML), chronic myelogenous leukemia
(CML), acute myelogenous leukemia (AML), a lymphoma, or multiple
myeloma.
65. The method of claim 63, wherein the breast cancer is
triple-negative breast cancer (TNBC).
66. The method of claim 63, wherein the brain cancer is a glioma or
medulloblastoma.
67. The method of claim 63, wherein the lung cancer is small cell
lung cancer.
68. The method of claim 61, wherein the proliferative disease is
myelodysplastic syndrome (MDS).
Description
CLAIM OF PRIORITY
[0001] The present application is a continuation of U.S.
application Ser. No. 15/301,819, filed Oct. 4, 2016, which is a
U.S. National Stage Application under 35 U.S.C. .sctn. 371 of
International Application No. PCT/US2015/024336, filed Apr. 3,
2015, which claims priority under 35 U.S.C. .sctn. 119(e) to U.S.
Provisional Application No. 61/975,773, filed Apr. 5, 2014. The
entire contents of each of the foregoing applications are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The members of the cyclin-dependent kinase (CDK) family play
critical regulatory roles in proliferation. Unique among the
mammalian CDKs, CDK7 has consolidated kinase activities, regulating
both the cell cycle and transcription. In the cytosol, CDK7 exists
as a heterotrimeric complex and is believed to function as a
CDK1/2-activating kinase (CAK), whereby phosphorylation of
conserved residues in CDK1/2 by CDK7 is required for full catalytic
CDK activity and cell cycle progression. In the nucleus, CDK7 forms
the kinase core of the RNA polymerase (RNAP) II general
transcription factor complex and is charged with phosphorylating
the C-terminal domain (CTD) of RNAP II, a requisite step in gene
transcriptional initiation Together, the two functions of CDK7,
i.e., CAK and CTD phosphorylation, support critical facets of
cellular proliferation, cell cycling, and transcription.
[0003] Disruption of RNAP II CTD phosphorylation has been shown to
preferentially affect proteins with short half-lives, including
those of the anti-apoptotic BCL-2 family. Cancer cells have
demonstrated ability to circumvent pro-cell death signaling through
upregulation of BCL-2 family members. Therefore, inhibition of
human CDK7 kinase activity is likely to result in
anti-proliferative activity.
[0004] The discovery of selective inhibitors of CDK7 has been
hampered by the high sequence and structural similarities of the
kinase domain of CDK family members. Therefore, there is a need for
the discovery and development of selective CDK7 inhibitors. Such
CKD7 inhibitors hold promise as a therapeutic agent for the
treatment of CLL and other cancers.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] FIGS. 1A-1C are a table of exemplary compounds of the
invention.
SUMMARY OF THE INVENTION
[0006] The present invention provides inhibitors of one or more of
the family of CDK proteins. The present invention further provides
CDK7 inhibitors, in particular selective CDK7 inhibitors of Formula
(I), and pharmaceutically acceptable salts, solvates, hydrates,
tautomers, stereoisomers, isotopically labeled derivatives, and
compositions thereof. The present invention further provides
methods of using the compounds of the invention, and
pharmaceutically acceptable salts, solvates, hydrates, tautomers,
stereoisomers, isotopically labeled derivatives, and compositions
thereof, to study the inhibition of CDK7 and CDK12 and/or CDK13 as
therapeutics for the prevention and/or treatment of diseases
associated with overexpression and/or aberrant activity of CDK7
and/or CDK12 and/or CDK13. In certain embodiments, the inventive
compounds are used for the prevention and/or treatment of
proliferative diseases (e.g., cancers (e.g., leukemia, melanoma,
multiple myeloma), benign neoplasms, angiogenesis, inflammatory
diseases, autoinflammatory diseases, and autoimmune diseases) in a
subject.
[0007] In one aspect, the present invention provides a compound
described herein, such as of Formula (I):
##STR00002##
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer,
or stereoisomer thereof, wherein G, R.sup.2, Q, R.sup.3, Z, and
R.sup.4 and subvariables thereof are as defined herein.
[0008] In another aspect, the present invention provides
pharmaceutical compositions comprising a compound described herein,
such as of Formula (I), or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, stereoisomer, or isotopically labeled
derivative thereof, and optionally a pharmaceutically acceptable
excipient. In certain embodiments, the pharmaceutical compositions
described herein include a therapeutically effective amount of a
compound described herein, such as of Formula (I), or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, or isotopically labeled derivative thereof. The
pharmaceutical composition may be useful for treating and/or
preventing a proliferative or infectious disease.
[0009] In another aspect, the present invention provides methods
for treating and/or preventing proliferative diseases. Exemplary
proliferative diseases include cancer (e.g., leukemia, melanoma,
multiple myeloma), benign neoplasm, angiogenesis, inflammatory
diseases, autoinflammatory diseases, and autoimmune diseases. In
other embodiments, the present invention provides methods for
treating and/or preventing an infectious disease (e.g., a viral
infection).
[0010] In still another aspect, the present invention provides
methods of down-regulating the expression of CDK7 in a biological
sample or subject.
[0011] Another aspect of the invention relates to methods of
inhibiting the activity of CDK7 in a biological sample or
subject.
[0012] The present invention also provides methods of inhibiting
cell growth in a biological sample or subject.
[0013] In still another aspect, the present invention provides
methods of inducing apoptosis of a cell in a biological sample or a
subject.
[0014] In yet another aspect, the present invention provides
compounds described herein, such as of Formula (I), and
pharmaceutically acceptable salts, solvates, hydrates, tautomers,
stereoisomers, isotopically labeled derivatives, and compositions
thereof, for use in the treatment of a proliferative disease in a
subject.
[0015] In yet another aspect, the present invention provides
compounds described herein, such as of Formula (I), and
pharmaceutically acceptable salts, solvates, hydrates, tautomers,
stereoisomers, isotopically labeled derivatives, and compositions
thereof, for use in the treatment or prevention of an infectious
disease in a subject. In certain embodiments, the infectious
disease is a viral infection.
[0016] Another aspect of the present invention relates to kits
comprising a container with a compound described herein, such as of
Formula (I), or a pharmaceutically acceptable salt, solvate,
hydrate, tautomer, stereoisomer, or isotopically labeled derivative
thereof, or a pharmaceutical composition thereof. In certain
embodiments, the kits described herein further include instructions
for administering the compound described herein, such as of Formula
(I), or the pharmaceutically acceptable salt, solvate, hydrate,
tautomer, stereoisomer, or isotopically labeled derivative thereof,
or the pharmaceutical composition thereof.
[0017] In still another aspect, the present invention provides
methods of inhibiting other CDKs, specifically CDK12 and/or CDK13,
with a compound described herein, such as of Formula (I), or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer, or
stereoisomer, or a pharmaceutical composition thereof.
[0018] The details of one or more embodiments of the invention are
set forth herein. Other features, objects, and advantages of the
invention will be apparent from the Detailed Description, the
Figures, the Examples, and the Claims.
Definitions
[0019] 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.
[0020] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, Z
and E double bond isomers, and Z and E conformational isomers.
Therefore, single stereochemical isomers as well as enantiomeric,
diastereomeric, and geometric (or conformational) mixtures of the
present compounds are within the scope of the invention. Unless
otherwise stated, all tautomeric forms of the compounds of the
invention are within the scope of the invention. Additionally,
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 including the replacement of hydrogen by
deuterium or tritium, or the replacement of a carbon by a .sup.13C-
or .sup.14C-enriched carbon are within the scope of this invention.
Such compounds are useful, for example, as analytical tools, as
probes in biological assays, or as therapeutic agents in accordance
with the present invention.
[0021] Where a particular enantiomer is preferred, it may, in some
embodiments be provided substantially free of the corresponding
enantiomer, and may also be referred to as "optically enriched."
"Optically enriched," as used herein, means that the compound is
made up of a significantly greater proportion of one enantiomer. In
certain embodiments the compound is made up of at least about 90%
by weight of a preferred enantiomer. In other embodiments the
compound is made up of at least about 95%, 98%, or 99% by weight of
a preferred enantiomer. Preferred enantiomers may be isolated from
racemic mixtures by any method known to those skilled in the art,
including chiral high pressure liquid chromatography (HPLC) and the
formation and crystallization of chiral salts or prepared by
asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E.
L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962);
Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p.
268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972).
[0022] The term "aliphatic" or "aliphatic group", as used herein,
denotes a hydrocarbon moiety that may be straight-chain (i.e.,
unbranched), branched, or cyclic (including fused, bridging, and
spiro-fused polycyclic) and may be completely saturated or may
contain one or more units of unsaturation, but which is not
aromatic. Unless otherwise specified, aliphatic groups contain 1-6
carbon atoms. In some embodiments, aliphatic groups contain 1-4
carbon atoms, and in yet other embodiments aliphatic groups contain
1-3 carbon atoms. Suitable aliphatic groups include, but are not
limited to, linear or branched, alkyl, alkenyl, and alkynyl groups,
and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl
or (cycloalkyl)alkenyl. Aliphatic groups may be optionally
substituted, e.g., as described herein.
[0023] The term "alkyl," as used herein, refers to a monovalent
saturated, straight- or branched-chain hydrocarbon such as a
straight or branched group of 1-12, 1-10, or 1-6 carbon atoms,
referred to herein as C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.10
alkyl, and C.sub.1-C.sub.6 alkyl, respectively. Alkyl groups may be
optionally substituted, e.g., as described herein. Examples of
alkyl groups include, but are not limited to, methyl, ethyl,
n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl,
iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl,
and the like. An alkyl may be optionally substituted, e.g., as
described herein.
[0024] The terms "alkenyl" and "alkynyl" are art-recognized and
refer to unsaturated aliphatic groups analogous in length and
possible substitution to the alkyls described above, but that
contain at least one double or triple bond, respectively. Exemplary
alkenyl groups include, but are not limited to, --CH.dbd.CH.sub.2
and --CH.sub.2CH.dbd.CH.sub.2.
[0025] The term "alkylene" refers to the diradical of an alkyl
group.
[0026] The terms "alkenylene" and "alkynylene" refer to the
diradicals of an alkenyl and an alkynyl group, respectively.
[0027] The term "methylene unit" refers to a divalent --CH.sub.2--
group present in an alkyl, alkenyl, alkynyl, alkylene, alkenylene,
or alkynylene moiety.
[0028] The term "carbocyclic ring system", as used herein, means a
monocyclic, or fused, spiro-fused, and/or bridged bicyclic or
polycyclic hydrocarbon ring system, wherein each ring is either
completely saturated or contains one or more units of unsaturation,
but where no ring is aromatic.
[0029] The term "carbocyclyl" refers to a radical of a carbocyclic
ring system. Representative carbocyclyl groups include cycloalkyl
groups (e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and
the like), and cycloalkenyl groups (e.g., cyclopentenyl,
cyclohexenyl, cyclopentadienyl, and the like). A carbocyclyl may be
optionally substituted, e.g., as described herein.
[0030] The term "aromatic ring system" is art-recognized and refers
to a monocyclic, bicyclic or polycyclic hydrocarbon ring system,
wherein at least one ring is aromatic.
[0031] The term "aryl" refers to a radical of an aromatic ring
system. Representative aryl groups include fully aromatic ring
systems, such as phenyl, naphthyl, and anthracenyl, and ring
systems where an aromatic carbon ring is fused to one or more
non-aromatic carbon rings, such as indanyl, phthalimidyl,
naphthimidyl, or tetrahydronaphthyl, and the like. An aryl may be
optionally substituted, e.g., as described herein.
[0032] The term "heteroaromatic ring system" is art-recognized and
refers to monocyclic, bicyclic or polycyclic ring system wherein at
least one ring is both aromatic and comprises a heteroatom; and
wherein no other rings are heterocyclyl (as defined below). In
certain instances, a ring which is aromatic and comprises a
heteroatom contains 1, 2, 3, or 4 independently selected ring
heteroatoms in such ring.
[0033] The term "heteroaryl" refers to a radical of a
heteroaromatic ring system. Representative heteroaryl groups
include ring systems where (i) each ring comprises a heteroatom and
is aromatic, e.g., imidazolyl, oxazolyl, thiazolyl, triazolyl,
pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl,
pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and
pteridinyl; (ii) each ring is aromatic or carbocyclyl, at least one
aromatic ring comprises a heteroatom and at least one other ring is
a hydrocarbon ring or e.g., indolyl, isoindolyl, benzothienyl,
benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,
benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one,
5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl;
and (iii) each ring is aromatic or carbocyclyl, and at least one
aromatic ring shares a bridgehead heteroatom with another aromatic
ring, e.g., 4H-quinolizinyl. In certain embodiments, the heteroaryl
is a monocyclic or bicyclic ring, wherein each of said rings
contains 5 or 6 ring atoms where 1, 2, 3, or 4 of said ring atoms
are a heteroatom independently selected from N, O, and S. A
heteroaryl may be optionally substituted, e.g., as described
herein.
[0034] The term "heterocyclic ring system" refers to monocyclic, or
fused, spiro-fused, and/or bridged bicyclic and polycyclic ring
systems where at least one ring is saturated or partially
unsaturated (but not aromatic) and comprises a heteroatom. A
heterocyclic ring system can be attached to its pendant group at
any heteroatom or carbon atom that results in a stable structure
and any of the ring atoms can be optionally substituted.
[0035] The term "heterocyclyl" refers to a radical of a
heterocyclic ring system. Representative heterocyclyls include ring
systems in which (i) every ring is non-aromatic and at least one
ring comprises a heteroatom, e.g., tetrahydrofuranyl,
tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,
pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,
dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl,
morpholinyl, and quinuclidinyl; (ii) at least one ring is
non-aromatic and comprises a heteroatom and at least one other ring
is an aromatic carbon ring, e.g., 1,2,3,4-tetrahydroquinolinyl,
1,2,3,4-tetrahydroisoquinolinyl; and (iii) at least one ring is
non-aromatic and comprises a heteroatom and at least one other ring
is aromatic and comprises a heteroatom, e.g.,
3,4-dihydro-1H-pyrano[4,3-c]pyridine, and
1,2,3,4-tetrahydro-2,6-naphthyridine. In certain embodiments, the
heterocyclyl is a monocyclic or bicyclic ring, wherein each of said
rings contains 3-7 ring atoms where 1, 2, 3, or 4 of said ring
atoms are a heteroatom independently selected from N, O, and S. A
heterocyclyl may be optionally substituted, e.g., as described
herein.
[0036] The term "saturated heterocyclyl" refers to a radical of
heterocyclic ring system wherein every ring is saturated, e.g.,
tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine and
piperazine.
[0037] "Partially unsaturated" refers to a group that includes at
least one double or triple bond. A "partially unsaturated" ring
system is further intended to encompass rings having multiple sites
of unsaturation, but is not intended to include aromatic groups
(e.g., aryl or heteroaryl groups) as herein defined. Likewise,
"saturated" refers to a group that does not contain a double or
triple bond, i.e., contains all single bonds.
[0038] As described herein, compounds of the invention may contain
"optionally substituted" moieties. In general, the term
"substituted", whether preceded by the term "optionally" or not,
means that one or more hydrogens of the designated moiety are
replaced with a suitable substituent. Unless otherwise indicated,
an "optionally substituted" group may have a suitable substituent
at each substitutable position of the group, and when more than one
position in any given structure may be substituted with more than
one substituent selected from a specified group, the substituent
may be either the same or different at each position. Combinations
of substituents envisioned under this invention are preferably
those that result in the formation of stable or chemically feasible
compounds. The term "stable", as used herein, refers to compounds
that are not substantially altered when subjected to conditions to
allow for their production, detection, and, in certain embodiments,
their recovery, purification, and use for one or more of the
purposes disclosed herein.
[0039] Suitable monovalent substituents on a substitutable carbon
atom of an "optionally substituted" group (such as an alkyl,
alkenyl, alkynyl, alkylene, alkenylene, alkynylene or the carbon
atom of a carbocyclyl, aryl, heterocyclyl or heteroaryl) are
independently deuterium; halogen;
--(CH.sub.2).sub.0-4R.sup..smallcircle.;
--(CH.sub.2).sub.0-4OR.sup..smallcircle.;
--O--(CH.sub.2).sub.0-4C(O)OR.sup..smallcircle.;
--(CH.sub.2).sub.0-4CH(OR.sup..smallcircle.).sub.2;
--(CH.sub.2).sub.0-4SR.sup..smallcircle.; --(CH.sub.2).sub.0-4Ph
(where "Ph" is phenyl), which may be substituted with
R.sup..smallcircle.; --(CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1Ph
which may be substituted with R.sup..smallcircle.; --CH.dbd.CHPh,
which may be substituted with --R.sup..smallcircle.; --NO.sub.2;
--CN; --N.sub.3; --(CH.sub.2).sub.0-4N(R.sup..smallcircle.).sub.2;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.)C(O)R.sup..smallcircle.;
--N(R.sup..smallcircle.)C(S)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.)C(O)NR.sup..smallcircle..sub.2;
--N(R.sup..smallcircle.)C(S)NR.sup..smallcircle..sub.2;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.)C(O)OR.sup..smallcircle.;
--N(R.sup..smallcircle.)N(R.sup..smallcircle.)C(O)R.sup..smallcircle.;
--N(R.sup..smallcircle.)N(R.sup..smallcircle.)C(O)NR.sup..smallcircle..su-
b.2;
--N(R.sup..smallcircle.)N(R.sup..smallcircle.)C(O)OR.sup..smallcircle-
.; --(CH.sub.2).sub.0-4C(O)R.sup..smallcircle.;
--C(S)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)OR.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)SR.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)OSiR.sup..smallcircle..sub.3;
--(CH.sub.2).sub.0-4--C(O)--N(R.sup..smallcircle.)--S(O).sub.2--R.sup..sm-
allcircle., --(CH.sub.2).sub.0-4OC(O)R.sup..smallcircle.;
--OC(O)(CH.sub.2).sub.0-4SR.sup..smallcircle.--,
--SC(S)SR.sup..smallcircle.;
--(CH.sub.2).sub.0-4SC(O)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)NR.sup..smallcircle..sub.2;
--C(S)NR.sup..smallcircle..sub.2; --C(S)SR.sup..smallcircle.;
--(CH.sub.2).sub.0-4OC(O)NR.sup..smallcircle..sub.2;
--C(O)N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(O)C(O)R.sup..smallcircle.;
--C(O)CH.sub.2C(O)R.sup..smallcircle.;
--C(NOR.sup..smallcircle.)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4SSR.sup..smallcircle.;
--(CH.sub.2).sub.0-4S(O).sub.2R.sup..smallcircle.;
--(CH.sub.2).sub.0-4S(O).sub.2OR.sup..smallcircle.;
--(CH.sub.2).sub.0-4OS(O).sub.2R.sup..smallcircle.;
--S(O).sub.2NR.sup..smallcircle..sub.2;
--(CH.sub.2).sub.0-4S(O)R.sup..smallcircle.;
--N(R.sup..smallcircle.)S(O).sub.2NR.sup..smallcircle..sub.2;
--N(R.sup..smallcircle.)S(O).sub.2R.sup..smallcircle.;
--N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(NH)NR.sup..smallcircle..sub.2; --P(O).sub.2R.sup..smallcircle.;
--P(O)R.sup..smallcircle..sub.2; --OP(O)R.sup..smallcircle..sub.2;
--OP(O)(OR.sup..smallcircle.).sub.2; --SiR.sup..smallcircle..sub.3;
--(C.sub.1-4 straight or
branched)alkylene)O--N(R.sup..smallcircle.).sub.2; or --(C.sub.1-4
straight or branched)alkylene)C(O)O--N(R.sup..smallcircle.).sub.2,
wherein each R.sup..smallcircle. may be substituted as defined
below and is independently hydrogen, deuterium, C.sub.1-6
aliphatic, --CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or a 5-6-membered
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or, notwithstanding the definition above, two independent
occurrences of R.sup..smallcircle., taken together with their
intervening atom(s), form a 3-12-membered saturated, partially
unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, which may
be substituted as defined below.
[0040] Suitable monovalent substituents on R.sup..smallcircle. (or
the ring formed by taking two independent occurrences of
R.sup..smallcircle. together with their intervening atoms), are
independently deuterium, halogen,
--(CH.sub.2).sub.0-2R.sup..circle-solid.,
-(haloR.sup..circle-solid.), --(CH.sub.2).sub.0-2OH,
--(CH.sub.2).sub.0-2OR.sup..circle-solid.,
--(CH.sub.2).sub.0-2CH(OR.sup..circle-solid.).sub.2;
--O(haloR.sup..circle-solid.), --CN, --N.sub.3,
--(CH.sub.2).sub.0-2C(O)R.sup..circle-solid.,
--(CH.sub.2).sub.0-2C(O)OH,
--(CH.sub.2).sub.0-2C(O)OR.sup..circle-solid.,
--(CH.sub.2).sub.0-2SR.sup..circle-solid., --(CH.sub.2).sub.0-2SH,
--(CH.sub.2).sub.0-2NH.sub.2,
--(CH.sub.2).sub.0-2NHR.sup..circle-solid.,
--(CH.sub.2).sub.0-2NR.sup..circle-solid..sub.2, --NO.sub.2,
--SiR.sup..circle-solid..sub.3, --OSiR.sup..circle-solid..sub.3,
--C(O)SR.sup..circle-solid., --(C.sub.1-4 straight or branched
alkylene)C(O)OR.sup..circle-solid., or --SSR.sup..circle-solid.
wherein each R.sup..circle-solid. is unsubstituted or where
preceded by "halo" is substituted only with one or more halogens,
and is independently selected from C.sub.1-4 aliphatic,
--CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or a 5-6-membered saturated,
partially unsaturated, or aryl ring having 0-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. Suitable
divalent substituents on a saturated carbon atom of
R.sup..smallcircle. include .dbd.O and .dbd.S.
[0041] Suitable divalent substituents on a saturated carbon atom of
an "optionally substituted" group include the following: .dbd.O,
.dbd.S, .dbd.NNR*.sub.2, .dbd.NNHC(O)R*, .dbd.NNHC(O)OR*,
.dbd.NNHS(O).sub.2R*, .dbd.NR*, .dbd.NOR*,
--O(C(R*.sub.2)).sub.2-3O--, or --S(C(R*.sub.2)).sub.2-3S--,
wherein each independent occurrence of R* is selected from
hydrogen, C.sub.1-6 aliphatic which may be substituted as defined
below, or an unsubstituted 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. Suitable divalent
substituents that are bound to vicinal substitutable carbons of an
"optionally substituted" group include: --O(CR*.sub.2).sub.2-3O--,
wherein each independent occurrence of R* is selected from
hydrogen, C.sub.1-6 aliphatic which may be substituted as defined
below, or an unsubstituted 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0042] Suitable substituents on the aliphatic group of R* include
deuterium, halogen, --R.sup..circle-solid.,
-(haloR.sup..circle-solid.), --OH, --OR.sup..circle-solid.,
--O(haloR.sup..circle-solid.), --CN, --C(O)OH,
--C(O)OR.sup..circle-solid., --NH.sub.2, --NHR.sup..circle-solid.,
--NR.sup..circle-solid..sub.2, or --NO.sub.2, wherein each
R.sup..circle-solid. is unsubstituted or where preceded by "halo"
is substituted only with one or more halogens, and is independently
C.sub.1-4 aliphatic, --CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or a
5-6-membered saturated, partially unsaturated, or aryl ring having
0-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0043] Suitable substituents on a substitutable nitrogen of an
"optionally substituted" group include --R.sup..dagger.,
--NR.sup..dagger..sub.2, --C(O)R.sup..dagger.,
--C(O)OR.sup..dagger., --C(O)C(O)R.sup..dagger.,
--C(O)CH.sub.2C(O)R.sup..dagger., --S(O).sub.2R.sup..dagger.,
--S(O).sub.2NR.sup..dagger..sub.2, --C(S)NR.sup..dagger..sub.2,
--C(NH)NR.sup..dagger..sub.2, or
--N(R.sup..dagger.)S(O).sub.2R.sup..dagger.; wherein each
R.sup..dagger. is independently hydrogen, C.sub.1-6 aliphatic which
may be substituted as defined below, unsubstituted --OPh, or an
unsubstituted 5-6-membered saturated, partially unsaturated, or
aryl ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or, notwithstanding the definition
above, two independent occurrences of R.sup..dagger., taken
together with their intervening atom(s) form an unsubstituted
3-12-membered saturated, partially unsaturated, or aryl mono- or
bicyclic ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
[0044] Suitable substituents on the aliphatic group of
R.sup..dagger. are independently deuterium, halogen,
--R.sup..circle-solid., -(haloR.sup..circle-solid.), --OH,
--OR.sup..circle-solid., --O(haloR.sup..circle-solid.), --CN,
--C(O)OH, --C(O)OR.sup..circle-solid., --NH.sub.2,
--NHR.sup..circle-solid., --NR.sup..circle-solid..sub.2, or
--NO.sub.2, wherein each R.sup..circle-solid. is unsubstituted or
where preceded by "halo" is substituted only with one or more
halogens, and is independently C.sub.1-4aliphatic, --CH.sub.2Ph,
--O(CH.sub.2).sub.04Ph, or a 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0045] "Halo" or "halogen" refers to fluorine (fluoro, --F),
chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine (iodo,
--I).
[0046] The term "one or more methylene units of the alkylene,
alkenylene or alkynylene is optionally replaced with --O--, --S--,
--S(.dbd.O).sub.2, or --NR.sup.X--" as used herein means that none,
one, more than one, or all of the methylene units present may be so
replaced. Thus, for example, the moieties, --O--, --S--, and
--NR.sup.X-- are included in this definition because in each case
they represent a C.sub.1 alkylene (i.e., methylene) replaced with
--O--, --S--, or --NR.sup.x--, respectively.
[0047] It should also be understood that reference to a variable or
subvariable in Formula I (e.g., R.sup.2, R.sup.3, or R.sup.4) being
"an optionally substituted C.sub.1-C.sub.4 alkylene, and an
optionally substituted C.sub.2-C.sub.4 alkenylene or alkynylene,
wherein: one or more methylene units of the alkylene, alkenylene or
alkynylene other than a methylene unit bound to a nitrogen atom is
optionally and independently replaced with --O, S, N(R.sup.6)--,
--NHC(O)--, --C(O)NH--, --C(O)--, or --S(.dbd.O).sub.2--" is only
intended to encompass chemically stable combinations of optionally
substitutions and replacements.
[0048] As used herein, the term "leaving group" is given its
ordinary meaning in the art of synthetic organic chemistry and
refers to an atom or a group capable of being displaced by a
nucleophile. Examples of suitable leaving groups include, but are
not limited to, halogen (such as F, Cl, Br, or I (iodine)),
alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy,
arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),
arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino,
pixyl, and haloformates. In some cases, the leaving group is a
sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs),
methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy
(brosylate, -OBs), or trifluoromethanesulfonate (triflate, -OTf).
In some cases, the leaving group is a brosylate, such as
p-bromobenzenesulfonyloxy. In some cases, the leaving group is a
nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments,
the leaving group is a sulfonate-containing group. In some
embodiments, the leaving group is a tosylate group. The leaving
group may also be a phosphineoxide (e.g., formed during a Mitsunobu
reaction) or an internal leaving group such as an epoxide or cyclic
sulfate. Other non-limiting examples of leaving groups are water,
ammonia, alcohols, ether moieties, thioether moieties, zinc
halides, magnesium moieties, diazonium salts, and copper
moieties.
[0049] These and other exemplary substituents are described in more
detail in the Detailed Description, Figures, Examples, and Claims.
The invention is not intended to be limited in any manner by the
above exemplary listing of substituents.
Other Definitions
[0050] The following definitions are more general terms used
throughout the present application:
[0051] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, Berge et al., describe
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 1977, 66, 1-19, incorporated herein by reference.
Pharmaceutically acceptable salts of the compounds of this
invention include those derived from suitable inorganic and organic
acids and bases. Examples of pharmaceutically acceptable, nontoxic
acid addition salts are salts of an amino group formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid, and perchloric acid or with organic
acids such as acetic acid, oxalic acid, maleic acid, tartaric acid,
citric acid, succinic acid, or malonic acid or by using other
methods known in the art such as ion exchange. Other
pharmaceutically acceptable salts include adipate, alginate,
ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4 alkyl).sub.4.sup.-
salts. Representative alkali or alkaline earth metal salts include
sodium, lithium, potassium, calcium, magnesium, and the like.
Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate,
and aryl sulfonate.
[0052] The term "solvate" refers to forms of the compound that are
associated with a solvent, usually by a solvolysis reaction. This
physical association may include hydrogen bonding. Conventional
solvents include water, methanol, ethanol, acetic acid, DMSO, THF,
diethyl ether, and the like. The compounds described herein, such
as of Formula (I) may be prepared, e.g., in crystalline form, and
may be solvated. Suitable solvates include pharmaceutically
acceptable solvates and further include both stoichiometric
solvates and non-stoichiometric solvates. In certain instances, the
solvate will be capable of isolation, for example, when one or more
solvent molecules are incorporated in the crystal lattice of a
crystalline solid. "Solvate" encompasses both solution-phase and
isolable solvates. Representative solvates include hydrates,
ethanolates, and methanolates.
[0053] The term "hydrate" refers to a compound which is associated
with water. Typically, the number of the water molecules contained
in a hydrate of a compound is in a definite ratio to the number of
the compound molecules in the hydrate. Therefore, a hydrate of a
compound may be represented, for example, by the general formula
R.x H.sub.2O, wherein R is the compound and wherein x is a number
greater than 0. A given compound may form more than one type of
hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x
is a number greater than 0 and smaller than 1, e.g., hemihydrates
(R.0.5H.sub.2O)), and polyhydrates (x is a number greater than 1,
e.g., dihydrates (R.2H.sub.2O) and hexahydrates (R.6H.sub.2O)).
[0054] The term "tautomers" refer to compounds that are
interchangeable forms of a particular compound structure, and that
vary in the displacement of hydrogen atoms and electrons. Thus, two
structures may be in equilibrium through the movement of .pi.
electrons and an atom (usually H). For example, enols and ketones
are tautomers because they are rapidly interconverted by treatment
with either acid or base. Another example of tautomerism is the
aci- and nitro-forms of phenylnitromethane, that are likewise
formed by treatment with acid or base.
[0055] Tautomeric forms may be relevant to the attainment of the
optimal chemical reactivity and biological activity of a compound
of interest.
[0056] It is also to be understood that compounds that have the
same molecular formula but differ in the nature or sequence of
bonding of their atoms or the arrangement of their atoms in space
are termed "isomers". Isomers that differ in the arrangement of
their atoms in space are termed "stereoisomers".
[0057] Stereoisomers that are not mirror images of one another are
termed "diastereomers" and those that are non-superimposable mirror
images of each other are termed "enantiomers". When a compound has
an asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0058] A "subject" to which administration is contemplated
includes, but is not limited to, humans (i.e., a male or female of
any age group, e.g., a pediatric subject (e.g., infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult,
or senior adult)) and/or other non-human animals, for example,
mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys);
commercially relevant mammals such as cattle, pigs, horses, sheep,
goats, cats, and/or dogs) and birds (e.g., commercially relevant
birds such as chickens, ducks, geese, and/or turkeys). In certain
embodiments, the animal is a mammal. The animal may be a male or
female and at any stage of development. A non-human animal may be a
transgenic animal.
[0059] The terms "administer," "administering," or
"administration," as used herein refers to implanting, absorbing,
ingesting, injecting, inhaling, or otherwise introducing an
inventive compound, or a pharmaceutical composition thereof.
[0060] As used herein, the terms "treatment," "treat," and
"treating" refer to reversing, alleviating, delaying the onset of,
or inhibiting the progress of a "pathological condition" (e.g., a
disease, disorder, or condition, or one or more signs or symptoms
thereof) described herein. In some embodiments, "treatment,"
"treat," and "treating" require that signs or symptoms of the
disease disorder or condition have developed or have been observed.
In other embodiments, treatment may be administered in the absence
of signs or symptoms of the disease or condition. For example,
treatment may be administered to a susceptible individual prior to
the onset of symptoms (e.g., in light of a history of symptoms
and/or in light of genetic or other susceptibility factors).
Treatment may also be continued after symptoms have resolved, for
example, to delay or prevent recurrence.
[0061] As used herein, the terms "condition," "disease," and
"disorder" are used interchangeably.
[0062] An "effective amount" of a compound described herein, such
as of Formula (I) refers to an amount sufficient to elicit the
desired biological response, i.e., treating the condition. As will
be appreciated by those of ordinary skill in this art, the
effective amount of a compound described herein, such as of Formula
(I) may vary depending on such factors as the desired biological
endpoint, the pharmacokinetics of the compound, the condition being
treated, the mode of administration, and the age and health of the
subject. An effective amount encompasses therapeutic and
prophylactic treatment. For example, in treating cancer, an
effective amount of an inventive compound may reduce the tumor
burden or stop the growth or spread of a tumor.
[0063] A "therapeutically effective amount" of a compound described
herein, such as of Formula (I) is an amount sufficient to provide a
therapeutic benefit in the treatment of a condition or to delay or
minimize one or more symptoms associated with the condition. In
some embodiments, a therapeutically effective amount is an amount
sufficient to provide a therapeutic benefit in the treatment of a
condition or to 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.
[0064] A "prophylactically effective amount" of a compound
described herein, such as of Formula (I) is an amount sufficient to
prevent a condition, or one or more symptoms associated with the
condition or prevent its recurrence. A prophylactically effective
amount of a compound means an amount of a therapeutic agent, alone
or in combination with other agents, which provides a prophylactic
benefit in the prevention of the condition. The term
"prophylactically effective amount" can encompass an amount that
improves overall prophylaxis or enhances the prophylactic efficacy
of another prophylactic agent.
[0065] A "proliferative disease" refers to a disease that occurs
due to abnormal growth or extension by the multiplication of cells
(Walker, Cambridge Dictionary of Biology; Cambridge University
Press: Cambridge, UK, 1990). A proliferative disease may be
associated with: 1) the pathological proliferation of normally
quiescent cells; 2) the pathological migration of cells from their
normal location (e.g., metastasis of neoplastic cells); 3) the
pathological expression of proteolytic enzymes such as the matrix
metalloproteinases (e.g., collagenases, gelatinases, and
elastases); or 4) the pathological angiogenesis as in proliferative
retinopathy and tumor metastasis. Exemplary proliferative diseases
include cancers (i.e., "malignant neoplasms"), benign neoplasms,
angiogenesis, inflammatory diseases, autoinflammatory diseases, and
autoimmune diseases.
[0066] The terms "neoplasm" and "tumor" are used herein
interchangeably and refer to an abnormal mass of tissue wherein the
growth of the mass surpasses and is not coordinated with the growth
of a normal tissue. A neoplasm or tumor may be "benign" or
"malignant," depending on the following characteristics: degree of
cellular differentiation (including morphology and functionality),
rate of growth, local invasion, and metastasis. A "benign neoplasm"
is generally well differentiated, has characteristically slower
growth than a malignant neoplasm, and remains localized to the site
of origin. In addition, a benign neoplasm does not have the
capacity to infiltrate, invade, or metastasize to distant sites.
Exemplary benign neoplasms include, but are not limited to, lipoma,
chondroma, adenomas, acrochordon, senile angiomas, seborrheic
keratoses, lentigos, and sebaceous hyperplasias. In some cases,
certain "benign" tumors may later give rise to malignant neoplasms,
which may result from additional genetic changes in a subpopulation
of the tumor's neoplastic cells, and these tumors are referred to
as "pre-malignant neoplasms." An exemplary pre-malignant neoplasm
is a teratoma. In contrast, a "malignant neoplasm" is generally
poorly differentiated (anaplasia) and has characteristically rapid
growth accompanied by progressive infiltration, invasion, and
destruction of the surrounding tissue. Furthermore, a malignant
neoplasm generally has the capacity to metastasize to distant
sites.
[0067] As used herein, the term "cancer" refers to a malignant
neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.;
Williams & Wilkins: Philadelphia, 1990). Exemplary cancers
include, but are not limited to, acoustic neuroma; adenocarcinoma;
adrenal gland cancer; anal cancer; angiosarcoma (e.g.,
lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma);
appendix cancer; benign monoclonal gammopathy; biliary cancer
(e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g.,
adenocarcinoma of the breast, papillary carcinoma of the breast,
mammary cancer, medullary carcinoma of the breast); brain cancer
(e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma,
oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid
tumor; cervical cancer (e.g., cervical adenocarcinoma);
choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer
(e.g., colon cancer, rectal cancer, colorectal adenocarcinoma);
connective tissue cancer; epithelial carcinoma; ependymoma;
endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic
hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer,
uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the
esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer
(e.g., intraocular melanoma, retinoblastoma); familiar
hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,
stomach adenocarcinoma); gastrointestinal stromal tumor (GIST);
germ cell cancer; head and neck cancer (e.g., head and neck
squamous cell carcinoma, oral cancer (e.g., oral squamous cell
carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal
cancer, nasopharyngeal cancer, oropharyngeal cancer));
hematopoietic cancers (e.g., leukemia such as acute lymphocytic
leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic
leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic
leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic
lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));
lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL)
and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse
large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma),
follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic
lymphoma (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 lymphoma/leukemia, peripheral T-cell
lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,
mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell
lymphoma, extranodal natural killer T-cell lymphoma, enteropathy
type T-cell lymphoma, subcutaneous panniculitis-like T-cell
lymphoma, and anaplastic large cell lymphoma); a mixture of one or
more leukemia/lymphoma as described above; and multiple myeloma
(MM)), heavy chain disease (e.g., alpha chain disease, gamma chain
disease, mu chain disease); hemangioblastoma; hypopharynx cancer;
inflammatory myofibroblastic tumors; immunocytic amyloidosis;
kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell
carcinoma); liver cancer (e.g., hepatocellular cancer (HCC),
malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma,
small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC),
adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis
(e.g., systemic mastocytosis); muscle cancer; myelodysplastic
syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD)
(e.g., polycythemia vera (PV), essential thrombocytosis (ET),
agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),
chronic idiopathic myelofibrosis, chronic myelocytic leukemia
(CML), chronic neutrophilic leukemia (CNL), hypereosinophilic
syndrome (HES)); neuroblastoma; neurofibroma (e.g.,
neurofibromatosis (NF) type 1 or type 2, schwannomatosis);
neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine
tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone
cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian
embryonal carcinoma, ovarian adenocarcinoma); papillary
adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma,
intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors);
penile cancer (e.g., Paget's disease of the penis and scrotum);
pinealoma; primitive neuroectodermal tumor (PNT); plasma cell
neoplasia; paraneoplastic syndromes; intraepithelial neoplasms;
prostate cancer (e.g., prostate adenocarcinoma); rectal cancer;
rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g.,
squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma,
basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix
cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma
(MFH), liposarcoma, malignant peripheral nerve sheath tumor
(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous
gland carcinoma; small intestine cancer; sweat gland carcinoma;
synovioma; testicular cancer (e.g., seminoma, testicular embryonal
carcinoma); thyroid cancer (e.g., papillary carcinoma of the
thyroid, papillary thyroid carcinoma (PTC), medullary thyroid
cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g.,
Paget's disease of the vulva).
[0068] The term "angiogenesis" refers to the formation and the
growth of new blood vessels. Normal angiogenesis occurs in the
healthy body of a subject for healing wounds and for restoring
blood flow to tissues after injury. The healthy body controls
angiogenesis through a number of means, e.g.,
angiogenesis-stimulating growth factors and angiogenesis
inhibitors. Many disease states, such as cancer, diabetic
blindness, age-related macular degeneration, rheumatoid arthritis,
and psoriasis, are characterized by abnormal (i.e., increased or
excessive) angiogenesis. Abnormal angiogenesis refers to
angiogenesis greater than that in a normal body, especially
angiogenesis in an adult not related to normal angiogenesis (e.g.,
menstruation or wound healing). Abnormal angiogenesis can provide
new blood vessels that feed diseased tissues and/or destroy normal
tissues, and in the case of cancer, the new vessels can allow tumor
cells to escape into the circulation and lodge in other organs
(tumor metastases).
[0069] As used herein, an "inflammatory disease" refers to a
disease caused by, resulting from, or resulting in inflammation.
The term "inflammatory disease" may also refer to a dysregulated
inflammatory reaction that causes an exaggerated response by
macrophages, granulocytes, and/or T-lymphocytes leading to abnormal
tissue damage and/or cell death. An inflammatory disease can be
either an acute or chronic inflammatory condition and can result
from infections or non-infectious causes Inflammatory diseases
include, without limitation, atherosclerosis, arteriosclerosis,
autoimmune disorders, multiple sclerosis, systemic lupus
erythematosus, polymyalgia rheumatica (PMR), gouty arthritis,
degenerative arthritis, tendonitis, bursitis, psoriasis, cystic
fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory
arthritis, Sjogren's syndrome, giant cell arteritis, progressive
systemic sclerosis (scleroderma), ankylosing spondylitis,
polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes
(e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis, Graves'
disease, Goodpasture's disease, mixed connective tissue disease,
sclerosing cholangitis, inflammatory bowel disease, Crohn's
disease, ulcerative colitis, pernicious anemia, inflammatory
dermatoses, usual interstitial pneumonitis (UIP), asbestosis,
silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis,
sarcoidosis, desquamative interstitial pneumonia, lymphoid
interstitial pneumonia, giant cell interstitial pneumonia, cellular
interstitial pneumonia, extrinsic allergic alveolitis, Wegener's
granulomatosis and related forms of angiitis (temporal arteritis
and polyarteritis nodosa), inflammatory dermatoses, hepatitis,
delayed-type hypersensitivity reactions (e.g., poison ivy
dermatitis), pneumonia, respiratory tract inflammation, Adult
Respiratory Distress Syndrome (ARDS), encephalitis, immediate
hypersensitivity reactions, asthma, hayfever, allergies, acute
anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,
cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic
injury), reperfusion injury, allograft rejection, host-versus-graft
rejection, appendicitis, arteritis, blepharitis, bronchiolitis,
bronchitis, cervicitis, cholangitis, chorioamnionitis,
conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis,
endometritis, enteritis, enterocolitis, epicondylitis,
epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,
gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis,
nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,
pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis,
phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,
salpingitis, sinusitis, stomatitis, synovitis, testitis,
tonsillitis, urethritis, urocystitis, uveitis, vaginitis,
vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis,
osteomyelitis, optic neuritis, temporal arteritis, transverse
myelitis, necrotizing fasciitis, and necrotizing enterocolitis.
[0070] As used herein, an "autoimmune disease" refers to a disease
arising from an inappropriate immune response of the body of a
subject against substances and tissues normally present in the
body. In other words, the immune system mistakes some part of the
body as a pathogen and attacks its own cells. This may be
restricted to certain organs (e.g., in autoimmune thyroiditis) or
involve a particular tissue in different places (e.g.,
Goodpasture's disease which may affect the basement membrane in
both the lung and kidney). The treatment of autoimmune diseases is
typically with immunosuppression, e.g., medications which decrease
the immune response. Exemplary autoimmune diseases include, but are
not limited to, glomerulonephritis, Goodpasture's syndrome,
necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa,
systemic lupus erythematosis, rheumatoid, arthritis, psoriatic
arthritis, systemic lupus erythematosis, psoriasis, ulcerative
colitis, systemic sclerosis, dermatomyositis/polymyositis,
anti-phospholipid antibody syndrome, scleroderma, pemphigus
vulgaris, ANCA-associated vasculitis (e.g., Wegener's
granulomatosis, microscopic polyangiitis), uveitis, Sjogren's
syndrome, Crohn's disease, Reiter's syndrome, ankylosing
spondylitis, Lyme arthritis, Guillain-Barre syndrome, Hashimoto's
thyroiditis, and cardiomyopathy.
[0071] The term "autoinflammatory disease" refers to a category of
diseases that are similar but different from autoimmune diseases.
Autoinflammatory and autoimmune diseases share common
characteristics in that both groups of disorders result from the
immune system attacking a subject's own tissues and result in
increased inflammation. In autoinflammatory diseases, a subject's
innate immune system causes inflammation for unknown reasons. The
innate immune system reacts even though it has never encountered
autoantibodies or antigens in the subject. Autoinflammatory
disorders are characterized by intense episodes of inflammation
that result in such symptoms as fever, rash, or joint swelling.
These diseases also carry the risk of amyloidosis, a potentially
fatal buildup of a blood protein in vital organs. Autoinflammatory
diseases include, but are not limited to, familial Mediterranean
fever (FMF), neonatal onset multisystem inflammatory disease
(NOMID), tumor necrosis factor (TNF) receptor-associated periodic
syndrome (TRAPS), deficiency of the interleukin-1 receptor
antagonist (DIRA), and Behcet's disease.
[0072] The term "biological sample" refers to any sample including
tissue samples (such as tissue sections and needle biopsies of a
tissue); cell samples (e.g., cytological smears (such as Pap or
blood smears) or samples of cells obtained by microdissection);
samples of whole organisms (such as samples of yeasts or bacteria);
or cell fractions, fragments or organelles (such as obtained by
lysing cells and separating the components thereof by
centrifugation or otherwise). Other examples of biological samples
include blood, serum, urine, semen, fecal matter, cerebrospinal
fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied
tissue (e.g., obtained by a surgical biopsy or needle biopsy),
nipple aspirates, milk, vaginal fluid, saliva, swabs (such as
buccal swabs), or any material containing biomolecules that is
derived from a first biological sample. Biological samples also
include those biological samples that are transgenic, such as
transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor
cell, or cell nucleus.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
Compounds
[0073] In one aspect of the present invention, provided are
compounds described herein, such as of Formula (I): compound having
the structural Formula (I):
##STR00003##
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer,
or stereoisomer thereof, wherein G is selected from:
##STR00004## ##STR00005##
wherein a hydrogen on G is replaced by a bond to R.sup.2, and each
R.sup.1 is independently selected from hydrogen, halogen,
heterocyclyl, aryl, heteroaryl, optionally substituted
C.sub.1-C.sub.6 alkyl, carbocyclyl, --OR.sup.a, --NR.sup.bR.sup.c,
--C(O)R.sup.a, --C(O)NR.sup.bR.sup.c, --S(O).sub.xR.sup.a, and
--S(O)--NR.sup.bR.sup.c; R.sup.A6 is hydrogen, halogen,
heterocyclyl, C.sub.1-C.sub.6 alkyl, carbocyclyl, --OR.sup.a,
--NR.sup.bR.sup.c, --C(O)R.sup.a, --C(O)NR.sup.bR.sup.c,
--S(O).sub.xR.sup.a, or --S(O).sub.xNR.sup.bR.sup.c; R.sup.A7 is
hydrogen, halogen, heterocyclyl, C.sub.1-C.sub.6 alkyl,
carbocyclyl, --OR.sup.a, --NR.sup.bR.sup.c, --C(O)R.sup.a,
--C(O)NR.sup.bR.sup.c, --S(O).sub.xR.sup.a, or
--S(O).sub.xNR.sup.bR.sup.c; each R.sup.a is independently selected
from hydrogen, C.sub.1-C.sub.6 alkyl, optionally substituted aryl,
optionally substituted heteroaryl, and optionally substituted
heterocyclyl; each R.sup.b and R.sup.c is independently selected
from hydrogen and --C.sub.1-C.sub.6 alkyl, or R.sup.b and R.sup.c
taken together with the atom to which they are attached form a
3-7-membered ring; Y is N or CH; K is bond, aryl, heteroaryl,
carbocyclyl, or heterocyclyl; J is --NH-- or --O--; T is a
5-membered aryl or heteroaryl; p is 0, 1, 2, 3, 4, or 5; x is 0, 1,
or 2; R.sup.2 is a bond, an optionally substituted C.sub.1-C.sub.4
alkylene or an optionally substituted C.sub.2-C.sub.4 alkenylene or
alkynylene, wherein one or more methylene units of the alkylene,
alkenylene or alkynylene are optionally and independently replaced
with --O--, --S--, --C(O)--, or --N(R.sup.6)--, wherein R.sup.6 is
hydrogen or a C.sub.1-C.sub.6 alkyl chain, and AIk.sup.1 is an
optionally substituted divalent hydrocarbyl chain containing from 1
to 6 carbon atoms in length and optionally unsaturated bonds
between at least two carbon atoms of AIk.sup.1 when AIk.sup.1
contains at least two carbon atoms; Q is selected from a bond, an
optionally substituted divalent carbocyclyl, an optionally
substituted divalent heterocyclyl, an optionally substituted
divalent aryl, and an optionally substituted divalent heteroaryl;
R.sup.3 is selected from a bond, an optionally substituted
C.sub.1-C.sub.4 alkylene, and an optionally substituted
C.sub.2-C.sub.4 alkenylene or alkynylene, wherein one or more
methylene units of the alkylene, alkenylene or alkynylene is
optionally and independently replaced with --O--, --S--,
--N(R.sup.6)--, --NHC(O)--, --C(O)NH--, --C(O)--, or
--S(.dbd.O).sub.2--; each R.sup.6 is independently selected from
hydrogen and optionally substituted --C.sub.1-C.sub.6 alkyl; Z is
selected from a bond; a monocyclic or bicyclic aryl, carbocyclyl,
heterocyclyl or heteroaryl, wherein when Z is other than a bond, Z
is optionally substituted; R.sup.4 is any one of the Formulae
(ii-0)-(ii-19):
##STR00006## ##STR00007## ##STR00008##
wherein: L.sup.3 is a bond, an optionally substituted
C.sub.1-C.sub.7 alkylene, or an optionally substituted
C.sub.2-C.sub.7 alkenylene or alkynylene, wherein one or more
methylene units of the alkylene, alkenylene or alkynylene are
optionally and independently replaced with --O--, --S--, --S(O)--,
--S(O).sub.2, --N--, or --N(R.sup.6)--; L.sup.4 is a bond, an
optionally substituted C.sub.1-C.sub.4 alkylene, or an optionally
substituted C.sub.2-C.sub.4 alkenylene or alkynylene; each of
R.sup.E1, R.sup.E2 and R.sup.E3 is independently selected from
hydrogen, deuterium, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --CH.sub.2OR.sup.9, --CH.sub.2N(R.sup.9).sub.2,
--CH.sub.2SR.sup.9, --CN, --OR.sup.9, --N(R.sup.9).sub.2, and
--SR.sup.9, wherein each occurrence of R.sup.9 is independently
selected from hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, and optionally substituted heteroaryl,
or R.sup.E1 and R.sup.E3, or R.sup.E2 and R.sup.E3, or R.sup.E1 and
R.sup.E2 are joined to form an optionally substituted carbocyclic
or optionally substituted heterocyclic ring; R.sup.E4 is a leaving
group; Y is O, S, or N(R); and z is 0, 1, 2, 3, 4, 5, or 6; when Q
is phenyl, Z is other than a bond; and except in the case wherein
R.sup.4 is (ii-0), no more than one of Q, R.sup.3, and Z is a
bond.
[0074] In some embodiments, the compound of formula (I) is a
compound having the structural formula (IIb):
##STR00009##
[0075] In some aspects of these embodiments, the compound of
formula (IIb) is the compound:
##STR00010##
[0076] In some embodiments, the compound of formula (I) is a
compound having the structural formula (IIc):
##STR00011##
[0077] In some embodiments, the compound of formula (I) is a
compound having the structural formula (IId):
##STR00012##
wherein V is hydrogen, halogen, heterocyclyl, aryl, heteroaryl,
C.sub.1-C.sub.6 alkyl, carbocyclyl, --OR.sup.a, --NR.sup.bR.sup.c,
--S(O).sub.xR.sup.a, --S(O)--NR.sup.bR.sup.c; and W is hydrogen,
halogen, heterocyclyl, aryl, heteroaryl, C.sub.1-C.sub.6 alkyl,
carbocyclyl, --OR.sup.a, --NR.sup.bR.sup.c, --S(O).sub.xR.sup.a,
--S(O).sub.xNR.sup.bR.sup.c.
[0078] In some aspects of these embodiments, the compound of
formula (IId) is a compound having the structural formula
(IIe):
##STR00013##
[0079] In some aspects of these embodiments, the compound of
formula (IId) is a compound having the structural formula
(IIf):
##STR00014##
[0080] In some embodiments, the compound of formula (I) is a
compound having the structural formula (IIg):
##STR00015##
[0081] In some aspects of these embodiments, the compound of
formula (IIg) is a compound having the structural formula
(IIh):
##STR00016##
[0082] In some aspects of these embodiments, the compound of
formula (IIh) is a compound having the structural formula
(IIi):
##STR00017##
[0083] wherein A is optionally substituted aryl, optionally
substituted heterocyclyl, or optionally substituted heteroaryl;
R.sup.B is C.sub.1-C.sub.6 alkyl or halogen; and q is 0, 1, 2, or
3.
[0084] In some aspects of these embodiments, the compound of
formula (IIi) is a compound having the structural formula
(IIj):
##STR00018##
[0085] wherein R.sup.2B is a bond or optionally substituted
--CH.sub.2; and B is optionally substituted divalent aryl,
optionally substituted divalent heteroaryl, or optionally
substituted divalent heterocyclyl.
[0086] In some aspects of these embodiments, the compound of
formula (IIj) is the compound
##STR00019##
[0087] In some aspects of these embodiments, the compound of
formula (IIj) is a compound having the structural formula
(IIk):
##STR00020##
[0088] wherein A is optionally substituted aryl, optionally
substituted heterocyclyl, or optionally substituted heteroaryl; C
is optionally substituted monocyclic aryl, optionally substituted
monocyclic heteroaryl, or optionally substituted monocyclic
heterocyclyl; R.sup.B is C.sub.1-C.sub.6 alkyl or halogen; R.sup.3B
is a bond, optionally substituted --NHC(O)--, optionally
substituted --CH.sub.2--, optionally substituted --NH--, optionally
substituted --NHCH.sub.2--, or optionally substituted
--CH.sub.2NH--; each of R.sup.E1B and R.sup.E2B is independently
selected from hydrogen or --CH.sub.2N(CH.sub.3).sub.2; and q is 0,
1, 2, or 3.
[0089] In some aspects of these embodiments, the compound of
formula (IIk) is a compound having the structural formula
(IIm):
##STR00021##
[0090] wherein C is optionally substituted monocyclic aryl,
optionally substituted monocyclic heteroaryl, or optionally
substituted monocyclic heterocyclyl; R.sup.3B is a bond, optionally
substituted --NHC(O)--, optionally substituted --CH.sub.2--,
optionally substituted --NH--, optionally substituted
--NHCH.sub.2--, or optionally substituted --CH.sub.2NH--; and each
of R.sup.E1B and R.sup.E2B is independently selected from hydrogen
or --CH.sub.2N(CH.sub.3).sub.2.
[0091] In some aspects of these embodiments, the compound of
formula (IIm) is the compound:
##STR00022##
[0092] In some embodiments, the compound of formula (I) is a
compound having the structural formula (IIIa):
##STR00023##
[0093] In some aspects of these embodiments, the compound of
formula (IIIa) is a compound having the structural formula
(IIIb):
##STR00024##
[0094] In some aspects of these embodiments, the compound of
formula (IIIb) is a compound having the structural formula
(IIIc):
##STR00025##
[0095] In some aspects of these embodiments, the compound of
formula (IIIc) is the compound:
##STR00026##
[0096] In some aspects of these embodiments, the compound of
formula (IIIc) is a compound having the structural formula
(IIId):
##STR00027##
wherein R.sup.3C is a bond, optionally substituted --CH.sub.2--,
optionally substituted --NH--, --C(O), --N(CH.sub.3)--, or
optionally substituted --CH(CH.sub.3)--; and D is optionally
substituted monocyclic or bicyclic aryl or heteroaryl.
[0097] In some aspects of these embodiments, the compound of
formula (IIId) is the compound:
##STR00028##
[0098] In some aspects of these embodiments, the compound of
formula (IIId) is a compound having the structural formula
(IIIe):
##STR00029##
wherein each of R.sup.E1C and R.sup.E2C is independently selected
from hydrogen or --CH.sub.2N(CH.sub.3).sub.2.
[0099] In some aspects of these embodiments, the compound of
formula (IIIe) is the compound:
##STR00030##
[0100] In some embodiments, the compound of formula (I) is a
compound having the structural formula (IVa):
##STR00031##
[0101] In some aspects of these embodiments, the compound of
formula (IVa) is a compound having the structural formula
(IVb):
##STR00032##
[0102] In some embodiments, the compound of formula (I) is a
compound having the structural formula (Va):
##STR00033##
[0103] In some aspects of these embodiments, the compound of
formula (Va) is a compound having the structural formula (VIa):
##STR00034##
[0104] In some embodiments, the compound of formula (I) is a
compound having the structural formula (VIIa):
##STR00035##
[0105] In some embodiments, the compound of formula (I) is a
compound having the structural formula (VIIIa):
##STR00036##
[0106] In some embodiments, the compound of formula (I) is a
compound having the structural formula (IXa):
##STR00037##
[0107] In some embodiments, R.sup.2 is a bond, an optionally
substituted C.sub.1-C.sub.4 alkylene or an optionally substituted
C.sub.2-C.sub.4 alkenylene or alkynylene, wherein one or more
methylene units of the alkylene, alkenylene or alkynylene are
optionally and independently replaced with --O--, --S--, --C(O)--,
or --N(R.sup.6)--, wherein R.sup.6 is hydrogen or a C.sub.1-C.sub.6
alkyl chain. In some embodiments, R.sup.6 does not comprise
AIk.sup.1.
[0108] In some embodiments, R.sup.2 is selected from a bond,
.dagger.--NH--, .dagger.--C(O), .dagger.--CH.sub.2--, and
.dagger.--NHC(O)--, wherein ".dagger." represents a portion of
R.sup.2 bound to G. In some embodiments,
[0109] In some embodiments, Q is selected from a bond, divalent
1,3,4-oxadiazole; divalent 1-oxa-3-azaspiro[4.5]dec-2-ene; divalent
cyclohexyl; divalent 4-thia-1,2-diazaspiro[4.5]dec-2-ene; divalent
oxazole; divalent phenyl; divalent piperidine and divalent
pyrrolidine, wherein Q is optionally substituted with up to three
independently selected substituents.
[0110] In some aspects of these embodiments, Q is selected from
1,3,4-oxadiazol-2,5-diyl; 1-oxa-3-azaspiro[4.5]dec-2-en-7,2-diyl;
4-fluorocyclohex-1,4-diyl; 4-hydroxycyclohex-1,4-diyl;
4-thia-1,2-diazaspiro[4.5]dec-2-en-7,3-diyl; cyclohex-1,3-diyl;
cyclohex-1,4-diyl; oxazol-2,5-diyl; benzene-1,2-diyl;
benzene-1,3-diyl; benzene-1,2,3-triyl; piperidin-1,3-diyl;
piperidin-1,3-diyl; piperidin-4,1-diyl; piperidin-1,4-diyl; and
pyrrolidin-3,1-diyl.
[0111] In some embodiments, R.sup.3 is selected from a bond,
.dagger.--C(O)--(CH.sub.2).sub.3--,
.dagger.--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
.dagger.--C(O)--, .dagger.--C(O)--NH--, .dagger.--NH--C(O)--,
.dagger.--NH--C(O)--CF.sub.2--CH.sub.2--, .dagger.--CH.sub.2--,
.dagger.--NH--, .dagger.--NH--CH.sub.2--, .dagger.--CH.sub.2--NH--,
.dagger.--NH--C(O)--CH(CF.sub.3)--,
.dagger.--N(CH.sub.3)--CH.sub.2--,
.dagger.--NH--C(O)--CH.sub.2--CH.sub.2--, .dagger.--CH(CH.sub.3)--,
.dagger.--N(CH.sub.3)--, and
.dagger.--NH--CH.sub.2--CH(CF.sub.3)--, wherein ".dagger."
represents a portion of R.sup.3 bound to Q.
[0112] In some embodiments, Z is selected from a bond,
##STR00038## ##STR00039## ##STR00040##
wherein: "1" represents a portion of Z bound to R.sup.3; "2"
represents a portion of Z bound to R.sup.4; each instance of
R.sup.5, if present, is independently selected from deuterium,
halogen, optionally substituted acyl, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.D1, --N(R.sup.D1).sub.2, and --SR.sup.D1,
wherein each occurrence of R.sup.D1 is independently selected from
hydrogen, optionally substituted acyl, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted carbocyclyl, optionally substituted
heterocyclyl, and optionally substituted aryl, optionally
substituted heteroaryl; and m is 0, 1, 2, 3 or 4.
[0113] In some aspects of these embodiments, Z is selected from a
bond,
##STR00041## ##STR00042##
[0114] In some aspects of these embodiments, Z is selected from a
bond, cyclohex-1,4-diyl, piperidin-3,1-diyl, piperidin-4,1-diyl,
piperidin-1,2-diyl, piperidin-2,1-diyl, pyridin-2,5-diyl,
pyridin-2,4-diyl, bicyclo[1.1.1]pent-1,3-diyl, pyrimidin-2,5-diyl,
pyrazol-1,4-diyl, pyrrolidin-2,1-diyl,
4,4-difluoropyrrolidin-2,1-diyl, isoindolin-2,5-diyl,
6-azaspiro[2.5]octan-6,1-diyl, 2,8-diazaspiro[4.5]decan-2,8-diyl,
pyrrolidin-3,1-diyl,
5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-3,6-diyl,
1,1-dioxobenzo[d]isothiazol-3,6-diyl, piperazin-1,4-diyl,
pyrrolidin-1,3-diyl, piperidin-1,4-diyl, pyrrolidin-2,4-diyl,
2,2-difluorocyclopent-1,1-diyl, 3-fluoroazetidin-3,1-diyl,
3,3-difluoropiperidin-4,1-diyl, benzene-1,2-diyl, benzene-1,3-diyl,
benzene-1,4-diyl, and 4-hydroxypyrrolidin-3,1-diyl.
[0115] In some embodiments, R.sup.4 is
##STR00043##
In some aspects of these embodiments, L.sup.3 is selected from a
bond, --NH--, --CH.sub.2--NH--**, --S(O).sub.2--NH--**, and
--NH--S(O).sub.2--NH--**, wherein "**" represents a portion of
L.sup.3 bound to --C(.dbd.Y)--. In some embodiments, Y is O. In
some aspects of these embodiments, R.sup.4 is selected from:
--CH.sub.2--NH--C(O)--CH.dbd.CH--CH.sub.2--N(CH.sub.3).sub.2,
--NH--C(O)--CH.dbd.CH--CH.sub.2--N(CH.sub.3).sub.2,
--C(O)--CH.dbd.CH--CH.sub.2--N(CH.sub.3).sub.2,
--NH--C(O)--CH.dbd.CH.sub.2, --C(O)--CH.dbd.CH.sub.2,
--C(O)--CH.dbd.CH--N(CH.sub.3).sub.2,
--S(O).sub.2--NH--C(O)--CH.dbd.CH.sub.2, and
--NH--S(O).sub.2--NH--C(O)--CH.dbd.CH.sub.2--NH--C(O)--CH.dbd.CH.sub.2.
[0116] In some embodiments, R.sup.4 is
##STR00044##
In some aspects of these embodiments, R.sup.4 is
--CH.dbd.CH.sub.2.
[0117] In some embodiments, R.sup.4 is
##STR00045##
In some aspects of these embodiments, L.sup.3 is --N--. In some
aspects of these embodiments, R.sup.4 is
--N(C(O)--CH.dbd.CH.sub.2).sub.2.
[0118] In some embodiments, the compound of Formula (I) is selected
from the group consisting of any one of the compounds in the table
of FIGS. 1A-1C and any pharmaceutically acceptable salts, solvates,
hydrates, tautomers, stereoisomers, and isotopically labeled
derivatives thereof.
[0119] Although, as indicated above, various embodiments and
aspects thereof for a variable in Formula (I) may be selected from
a group of chemical moieties, the invention also encompasses as
further embodiments and aspects thereof situations where such
variable is: a) selected from any subset of chemical moieties in
such a group; and b) any single member of such group.
[0120] Although various embodiments and aspects thereof are set
forth (or implied, as discussed in the preceding paragraph)
individually for each variable in Formula (I) above, the invention
encompasses all possible combinations of the different embodiments
and aspects for each of the variables in Formula (I).
Pharmaceutical Compositions, Kits, and Administration
[0121] The present invention provides pharmaceutical compositions
comprising a compound described herein, such as of Formula (I), or
a pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, or isotopically labeled derivative thereof, as
described herein, and optionally a pharmaceutically acceptable
excipient. In certain embodiments, the pharmaceutical composition
of the invention comprises a compound described herein, such as of
Formula (I), or a pharmaceutically acceptable salt thereof, and
optionally a pharmaceutically acceptable excipient. In certain
embodiments, the compound described herein, such as of Formula (I),
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, or isotopically labeled derivative thereof, is
provided in an effective amount in the pharmaceutical composition.
In certain embodiments, the effective amount is a therapeutically
effective amount. In certain embodiments, the effective amount is a
prophylactically effective amount.
[0122] Pharmaceutical compositions described herein can be prepared
by any method known in the art of pharmacology. In general, such
preparatory methods include the steps of bringing the compound
described herein, such as of Formula (I) (the "active ingredient")
into association with a carrier and/or one or more other accessory
ingredients, and then, if necessary and/or desirable, shaping
and/or packaging the product into a desired single- or multi-dose
unit.
[0123] Pharmaceutical compositions can be prepared, packaged,
and/or sold in bulk, as a single unit dose, and/or as a plurality
of single unit doses. As used herein, a "unit dose" is a discrete
amount of the pharmaceutical composition comprising a predetermined
amount of the active ingredient. The amount of the active
ingredient is generally equal to the dosage of the active
ingredient which would be administered to a subject and/or a
convenient fraction of such a dosage such as, for example, one-half
or one-third of such a dosage.
[0124] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition of the invention will
vary, depending upon the identity, size, and/or condition of the
subject treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[0125] The term "pharmaceutically acceptable excipient" refers to a
non-toxic carrier, adjuvant, diluent, or vehicle that does not
destroy the pharmacological activity of the compound with which it
is formulated. Pharmaceutically acceptable excipients useful in the
manufacture of the pharmaceutical compositions of the invention are
any of those that are well known in the art of pharmaceutical
formulation and 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. Pharmaceutically
acceptable excipients useful in the manufacture of the
pharmaceutical compositions of the invention include, but are not
limited to, ion exchangers, alumina, aluminum stearate, lecithin,
serum proteins, such as human serum albumin, buffer substances such
as phosphates, glycine, sorbic acid, potassium sorbate, partial
glyceride mixtures of saturated vegetable fatty acids, water, salts
or electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, cellulose-based substances, polyethylene glycol,
sodium carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, polyethylene glycol
and wool fat.
[0126] Compositions of the present invention may be administered
orally, parenterally (including subcutaneous, intramuscular,
intravenous and intradermal), by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. In some embodiments, provided compounds or compositions
are administrable intravenously and/or orally.
[0127] The term "parenteral" as used herein includes subcutaneous,
intravenous, intramuscular, intraocular, intravitreal,
intra-articular, intra-synovial, intrasternal, intrathecal,
intrahepatic, intraperitoneal intralesional and intracranial
injection or infusion techniques. Preferably, the compositions are
administered orally, subcutaneously, intraperitoneally or
intravenously. Sterile injectable forms of the compositions of this
invention may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium.
[0128] Pharmaceutically acceptable compositions of this invention
may be orally administered in any orally acceptable dosage form
including, but not limited to, capsules, tablets, aqueous
suspensions or solutions. In the case of tablets for oral use,
carriers commonly used include lactose and corn starch. Lubricating
agents, such as magnesium stearate, are also typically added. For
oral administration in a capsule form, useful diluents include
lactose and dried cornstarch. When aqueous suspensions are required
for oral use, the active ingredient is combined with emulsifying
and suspending agents. If desired, certain sweetening, flavoring or
coloring agents may also be added. In some embodiments, a provided
oral formulation is formulated for immediate release or
sustained/delayed release. In some embodiments, the composition is
suitable for buccal or sublingual administration, including
tablets, lozenges and pastilles. A provided compound can also be in
micro-encapsulated form.
[0129] Alternatively, pharmaceutically acceptable compositions of
this invention may be administered in the form of suppositories for
rectal administration. Pharmaceutically acceptable compositions of
this invention may also be administered topically, especially when
the target of treatment includes areas or organs readily accessible
by topical application, including diseases of the eye, the skin, or
the lower intestinal tract. Suitable topical formulations are
readily prepared for each of these areas or organs.
[0130] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0131] For ophthalmic use, provided pharmaceutically acceptable
compositions may be formulated as micronized suspensions or in an
ointment such as petrolatum.
[0132] Pharmaceutically acceptable compositions of this invention
may also be administered by nasal aerosol or inhalation.
[0133] 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.
[0134] 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.
[0135] Compounds provided herein are typically formulated in dosage
unit form, e.g., single unit dosage form, for ease of
administration and uniformity of dosage. It will be understood,
however, that the total daily usage of the compositions of the
present invention will be decided by the attending physician within
the scope of sound medical judgment. The specific therapeutically
effective dose level for any particular subject or organism will
depend upon a variety of factors including the disease being
treated and the severity of the disorder; the activity of the
specific active ingredient employed; the specific composition
employed; the age, body weight, general health, sex and diet of the
subject; the time of administration, route of administration, and
rate of excretion of the specific active ingredient employed; the
duration of the treatment; drugs used in combination or
coincidental with the specific active ingredient employed; and like
factors well known in the medical arts.
[0136] 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).
[0137] 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.
[0138] In certain embodiments, the compounds described herein, such
as of Formula (I) may be at dosage levels sufficient to deliver
from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to
about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg,
preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01
mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg,
and more preferably from about 1 mg/kg to about 25 mg/kg, of
subject body weight per day, one or more times a day, to obtain the
desired therapeutic effect.
[0139] 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.
[0140] It will be also appreciated that a compound or composition,
as described herein, can be administered in combination with one or
more additional pharmaceutical agents. The compounds or
compositions can be administered in combination with additional
pharmaceutical agents that improve their bioavailability, reduce
and/or modify their metabolism, inhibit their excretion, and/or
modify their distribution within the body. It will also be
appreciated that the therapy employed may achieve a desired effect
for the same disorder, and/or it may achieve different effects.
[0141] The compound or composition can be administered concurrently
with, prior to, or subsequent to, one or more additional
pharmaceutical agents, which may be useful as, e.g., combination
therapies. Pharmaceutical agents include therapeutically active
agents. Pharmaceutical agents also include prophylactically active
agents. Each additional pharmaceutical agent may be administered at
a dose and/or on a time schedule determined for that pharmaceutical
agent. The additional pharmaceutical agents may also be
administered together with each other and/or with the compound or
composition described herein in a single dose or administered
separately in different doses. The particular combination to employ
in a regimen will take into account compatibility of the inventive
compound with the additional pharmaceutical agents and/or the
desired therapeutic and/or prophylactic effect to be achieved. In
general, it is expected that the additional pharmaceutical agents
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.
[0142] Exemplary additional pharmaceutical agents include, but are
not limited to, anti-proliferative agents, anti-cancer agents,
anti-diabetic agents, anti-inflammatory agents, immunosuppressant
agents, and a pain-relieving agent. Pharmaceutical agents include
small organic molecules such as drug compounds (e.g., compounds
approved by the U.S. Food and Drug Administration as provided in
the Code of Federal Regulations (CFR)), peptides, proteins,
carbohydrates, monosaccharides, oligosaccharides, polysaccharides,
nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides
or proteins, small molecules linked to proteins, glycoproteins,
steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides,
oligonucleotides, antisense oligonucleotides, lipids, hormones,
vitamins, and cells.
[0143] Also encompassed by the invention are kits (e.g.,
pharmaceutical packs). The inventive kits may be useful for
preventing and/or treating a proliferative disease (e.g., cancer
(e.g., leukemia, melanoma, multiple myeloma), benign neoplasm,
angiogenesis, inflammatory disease, autoinflammatory disease, or
autoimmune disease). The kits provided may comprise an inventive
pharmaceutical composition or compound and a container (e.g., a
vial, ampule, bottle, syringe, and/or dispenser package, or other
suitable container). In some embodiments, provided kits may
optionally further include a second container comprising a
pharmaceutical excipient for dilution or suspension of an inventive
pharmaceutical composition or compound. In some embodiments, the
inventive pharmaceutical composition or compound provided in the
container and the second container are combined to form one unit
dosage form.
[0144] Thus, in one aspect, provided are kits including a first
container comprising a compound described herein, or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, and isotopically labeled derivative, or a
pharmaceutical composition thereof. In certain embodiments, the kit
of the invention includes a first container comprising a compound
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition thereof. In certain embodiments, the
kits are useful in preventing and/or treating a proliferative
disease in a subject. In certain embodiments, the kits further
include instructions for administering the compound, or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, isotopically and labeled derivative thereof, or a
pharmaceutical composition thereof, to a subject to prevent and/or
treat a proliferative disease.
Methods of Treatment and Uses
[0145] The present invention also provides methods for the
treatment or prevention of a proliferative disease (e.g., cancer,
benign neoplasm, angiogenesis, inflammatory disease,
autoinflammatory disease, or autoimmune disease) or an infectious
disease (e.g., a viral disease) in a subject. Such methods comprise
the step of administering to the subject in need thereof an
effective amount of a compound described herein, such as of Formula
(I), or a pharmaceutically acceptable salt, solvate, hydrate,
tautomer, stereoisomer, or isotopically labeled derivative thereof,
or a pharmaceutical composition thereof. In certain embodiments,
the methods described herein include administering to a subject an
effective amount of a compound described herein, such as of Formula
(I), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition thereof.
[0146] In one aspect of the present invention, provided is a method
of treating a subject suffering from a disease or condition
associated with aberrant activity of CDK7 comprising the step of
administering to the subject in need thereof with a composition
described herein, e.g., a composition comprising a compound as
described herein, e.g., a compound of formula (I). In some
embodiments, the disease or condition is selected from cancer,
benign neoplasm, angiogenesis, inflammatory disease,
autoinflammatory disease, autoimmune disease, or an infectious
disease. In some embodiments, the subject is a mammal. In some
embodiments, the disease is cancer. In some embodiments, the cancer
is selected from a blood cancer, melanoma, a bone cancer, a breast
cancer, a brain cancer, or a lung cancer. In some embodiments, the
cancer is a blood cancer selected from chronic lymphocytic leukemia
(CLL), acute lymphoblastic leukemia (ALL), T-cell acute
lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML),
acute myelogenous leukemia (AML), lymphoma, and multiple myeloma.
In some embodiments, the disease is a bone cancer selected from
osteosarcoma and Ewing's sarcoma. In some embodiments, the disease
is triple-negative breast cancer (TNBC). In some embodiments, the
disease is neuroblastoma. In some embodiments, the disease is small
cell lung cancer (SCLC). In some embodiments, the method comprises
the additional step of administering to the subject in need thereof
one or more additional agents independently selected from
anti-proliferative agents, anti-cancer agents, immunosuppressant
agents, and pain-relieving agents.
[0147] In certain embodiments, the subject being treated is a
mammal. In certain embodiments, the subject is a human. In certain
embodiments, the subject is a domesticated animal, such as a dog,
cat, cow, pig, horse, sheep, or goat. In certain embodiments, the
subject is a companion animal such as a dog or cat. In certain
embodiments, the subject is a livestock animal such as a cow, pig,
horse, sheep, or goat. In certain embodiments, the subject is a zoo
animal. In another embodiment, the subject is a research animal
such as a rodent, dog, or non-human primate. In certain
embodiments, the subject is a non-human transgenic animal such as a
transgenic mouse or transgenic pig.
[0148] The proliferative disease to be treated or prevented using
the compounds described herein, such as of Formula (I) will
typically be associated with aberrant activity of CDK7. Aberrant
activity of CDK7 may be an elevated and/or an inappropriate (e.g.,
abnormal) activity of CDK7. In certain embodiments, CDK7 is not
overexpressed, and the activity of CDK7 is elevated and/or
inappropriate. In certain other embodiments, CDK7 is overexpressed,
and the activity of CDK7 is elevated and/or inappropriate. The
compounds described herein, such as of Formula (I), and
pharmaceutically acceptable salts, solvates, hydrates, tautomers,
stereoisomers, isotopically labeled derivatives, and compositions
thereof, may inhibit the activity of CDK7 and be useful in treating
and/or preventing proliferative diseases.
[0149] In other embodiments, the proliferative disease to be
treated or prevented using the compounds described herein, such as
of Formula (I), will typically be associated with aberrant activity
of CDK12 and/or CDK13. Aberrant activity of CDK12 and/or CDK13 may
be an elevated and/or an inappropriate (e.g., abnormal) activity of
CDK12 and/or CDK13. In certain embodiments, CDK12 and/or CDK13 is
not overexpressed, and the activity of CDK12 and/or CDK13 is
elevated and/or inappropriate. In certain other embodiments, CDK12
and/or CDK13 is overexpressed, and the activity of CDK12 and/or
CDK13 is elevated and/or inappropriate. The compounds described
herein, such as of Formula (I), and pharmaceutically acceptable
salts, solvates, hydrates, tautomers, stereoisomers, isotopically
labeled derivatives, and compositions thereof, may inhibit the
activity of CDK12 and/or CDK13 and be useful in treating and/or
preventing proliferative diseases.
[0150] A proliferative disease may also be associated with
inhibition of apoptosis of a cell in a biological sample or
subject. All types of biological samples described herein or known
in the art are contemplated as being within the scope of the
invention. Inhibition of the activity of CDK7 is expected to cause
cytotoxicity via induction of apoptosis. The compounds described
herein, such as of Formula (I), and pharmaceutically acceptable
salts, solvates, hydrates, tautomers, stereoisomers, isotopically
labeled derivatives, and compositions thereof, may induce
apoptosis, and therefore, be useful in treating and/or preventing
proliferative diseases.
[0151] In certain embodiments, the proliferative disease to be
treated or prevented using the compounds described herein, such as
of Formula (I), is cancer. All types of cancers disclosed herein or
known in the art are contemplated as being within the scope of the
invention. In certain embodiments, the proliferative disease is a
cancer associated with dependence on BCL-2 anti-apoptotic proteins
(e.g., MCL-1 and/or XIAP). In certain embodiments, the
proliferative disease is a cancer associated with overexpression of
MYC (a gene that codes for a transcription factor). In certain
embodiments, the proliferative disease is a hematological
malignancy. In certain embodiments, the proliferative disease is a
blood cancer. In certain embodiments, the proliferative disease is
leukemia. In certain embodiments, the proliferative disease is
chronic lymphocytic leukemia (CLL). In certain embodiments, the
proliferative disease is acute lymphoblastic leukemia (ALL). In
certain embodiments, the proliferative disease is T-cell acute
lymphoblastic leukemia (T-ALL). In certain embodiments, the
proliferative disease is chronic myelogenous leukemia (CML). In
certain embodiments, the proliferative disease is acute myelogenous
leukemia (AML). In certain embodiments, the proliferative disease
is lymphoma. In certain embodiments, the proliferative disease is
melanoma. In certain embodiments, the proliferative disease is
multiple myeloma. In certain embodiments, the proliferative disease
is a bone cancer. In certain embodiments, the proliferative disease
is osteosarcoma. In some embodiments, the proliferative disease is
Ewing's sarcoma. In some embodiments, the proliferative disease is
triple-negative breast cancer (TNBC). In some embodiments, the
proliferative disease is a brain cancer. In some embodiments, the
proliferative disease is neuroblastoma. In some embodiments, the
proliferative disease is a lung cancer. In some embodiments, the
proliferative disease is small cell lung cancer (SCLC). In some
embodiments, the proliferative disease is large cell lung cancer.
In some embodiments, the proliferative disease is a benign
neoplasm. All types of benign neoplasms disclosed herein or known
in the art are contemplated as being within the scope of the
invention.
[0152] In some embodiments, the proliferative disease is associated
with angiogenesis. All types of angiogenesis disclosed herein or
known in the art are contemplated as being within the scope of the
invention.
[0153] In certain embodiments, the proliferative disease is an
inflammatory disease. All types of inflammatory diseases disclosed
herein or known in the art are contemplated as being within the
scope of the invention. In certain embodiments, the inflammatory
disease is rheumatoid arthritis. In some embodiments, the
proliferative disease is an autoinflammatory disease. All types of
autoinflammatory diseases disclosed herein or known in the art are
contemplated as being within the scope of the invention. In some
embodiments, the proliferative disease is an autoimmune disease.
All types of autoimmune diseases disclosed herein or known in the
art are contemplated as being within the scope of the
invention.
[0154] The cell described herein may be an abnormal cell. The cell
may be in vitro or in vivo. In certain embodiments, the cell is a
proliferative cell. In certain embodiments, the cell is a blood
cell. In certain embodiments, the cell is a lymphocyte. In certain
embodiments, the cell is a cancer cell. In certain embodiments, the
cell is a leukemia cell. In certain embodiments, the cell is a CLL
cell. In certain embodiments, the cell is a melanoma cell. In
certain embodiments, the cell is a multiple myeloma cell. In
certain embodiments, the cell is a benign neoplastic cell. In
certain embodiments, the cell is an endothelial cell. In certain
embodiments, the cell is an immune cell.
[0155] In another aspect, the present invention provides methods of
down-regulating the expression of CDK7 in a biological sample or
subject.
[0156] In certain embodiments, the methods described herein
comprise the additional step of administering one or more
additional pharmaceutical agents in combination with the compound
described herein, such as of Formula (I), a pharmaceutically
acceptable salt thereof, or compositions comprising such compound
or pharmaceutically acceptable salt thereof. Such additional
pharmaceutical agents include, but are not limited to,
anti-proliferative agents, anti-cancer agents, anti-diabetic
agents, anti-inflammatory agents, immunosuppressant agents, and a
pain-relieving agent. The additional pharmaceutical agent(s) may
synergistically augment inhibition of CDK7 induced by the inventive
compounds or compositions of this invention in the biological
sample or subject. Thus, the combination of the inventive compounds
or compositions and the additional pharmaceutical agent(s) may be
useful in treating proliferative diseases resistant to a treatment
using the additional pharmaceutical agent(s) without the inventive
compounds or compositions.
[0157] In yet another aspect, the present invention provides the
compounds described herein, such as of Formula (I), and
pharmaceutically acceptable salts, solvates, hydrates, tautomers,
stereoisomers, isotopically labeled derivatives, and compositions
thereof, for use in the treatment of a proliferative disease in a
subject. In certain embodiments, provided by the invention are the
compounds described herein, and pharmaceutically acceptable salts
and compositions thereof, for use in the treatment of a
proliferative disease in a subject. In certain embodiments,
provided by the invention are the compounds described herein, and
pharmaceutically acceptable salts and compositions thereof, for use
in inhibiting cell growth. In certain embodiments, provided by the
invention are the compounds described herein, and pharmaceutically
acceptable salts and compositions thereof, for use in inducing
apoptosis in a cell. In certain embodiments, provided by the
invention are the compounds described herein, and pharmaceutically
acceptable salts and compositions thereof, for use in inhibiting
transcription.
EXAMPLES
[0158] In order that the invention described herein may be more
fully understood, the following examples are set forth. The
synthetic and biological examples described in this application are
offered to illustrate the compounds, pharmaceutical compositions,
and methods provided herein and are not to be construed in any way
as limiting their scope.
[0159] The compounds provided herein can be prepared from readily
available starting materials using modifications to the specific
synthesis protocols set forth below that would be well known to
those of skill in the art. It will be appreciated that where
typical or preferred process conditions (i.e., reaction
temperatures, times, mole ratios of reactants, solvents, pressures,
etc.) are given, other process conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvents used, but such conditions can be
determined by those skilled in the art by routine optimization
procedures.
[0160] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in Greene et al., Protecting Groups in Organic Synthesis,
Second Edition, Wiley, New York, 1991, and references cited
therein.
TABLE-US-00001 Abbreviations Abbreviation Name Ac acetyl ACN
acetonitrile aq. aqueous atm atmospheres Boc tert-butoxy carbonyl
Boc.sub.2O Di-t-butyl dicarbonate CDI 1,1'-Carbonyldiimidazole DCC
N,N'-Dicyclohexylcarbodiimide DCM Dichloromethane DIPEA
N,N-Diisopropyl ethylamine DMF Dimethylformamide DMSO
Dimethylsulfoxide EDTA Ethylenediamine tetraacetic acid eq(s).
equivalent(s) EtOAc Ethyl acetate Et Ethyl EtOH Ethanol Et.sub.3N
Triethylamine g gram(s) h hour(s) HATU
(Dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-
b]pyridin-3-yloxy)methaniminium hexafluorophosphate HBTU
O-Benzotriazole-N,N,N',N'-tetramethyl-uronium- hexafluoro-phosphate
Hex Hexanes HOBt 1 -Hydroxybenzotriazole HPLC High pressure liquid
chromatography IPA Isopropanol LCMS; LC-MS liquid chromatography
mass spectrometry MeOH Methanol mg milligram(s) min Minute(s) mL;
ml milliliter(s) MS mass spectrometry mW megawatt NMe N-methyl NMP
N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance Ph phenyl
POCl.sub.3 Phosphoryl Chloride Py Pyridine r.t.; rt; RT Room
temperature S., sat. saturated TEA Triethylamine TFA
Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer
chromatography
Example 1: Synthesis of
(E)-4-(Dimethylamino)-N-(4-(4-((8-isopropyl-2-((1-methylpiperidin-4-yl)ox-
y)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carbonyl)phenyl)bu-
t-2-enamide (Compound 102)
##STR00046##
[0161]
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)-4-(1H-1,2,4-triazol-1-y-
l)pyrazolo[1,5-a][1,3,5]triazine
##STR00047##
[0163] To a solution of 1H-1,2,4-triazole (1.07 g, 15.48 mmol) in
Py (10 mL) was added POCl.sub.3 (791 mg, 5.16 mmol). The mixture
was stirred at room temperature for 2 h, followed by addition of
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin--
4-ol (500 mg, 1.72 mmol). After stirring at room temperature for 4
h, LC-MS showed complete conversion to the desired product. The
solution was used directly in the next step. The mixture was
stirred at room temperature for 4 h. LCMS: (M+H.sup.+): 343.
tert-butyl
4-((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][-
1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate
##STR00048##
[0165] To a solution of
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin--
4-ol (587.6 mg, 1.72 mmol) in Py (10 mL) was added tert-butyl
4-aminopiperidine-1-carboxylate (1.03 g, 5.16 mmol), and the
mixture was stirred at room temperature for 12 h, after which LCMS
showed the reaction was completed. The mixture was concentrated
under vacuum, and the residue was purified by preparative HPLC to
afford tert-butyl
4-((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]tria-
zin-4-yl)amino)piperidine-1-carboxylate (200 mg, 24% yield).
.sup.1H NMR: (CDCl.sub.3; 400 MHz) .delta. 12.48 (s, 1H), 7.77 (s,
1H), 5.39 (s, 2H), 4.48 (s, 1H), 3.80 (s, 1H), 3.37-3.30 (m, 6H),
3.14-3.11 (m, 1H), 2.81 (d, J=4.80 Hz, 3H), 2.73-2.66 (m, 2H), 2.28
(d, J=14.80 Hz, 2H), 2.14 (d, J=10.40 Hz, 2H), 1.52 (d, J=11.20 Hz,
2H), 1.46 (s, 9H), 1.29-1.27 (m, 6H). LCMS: (M+H.sup.+): 474.
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)-N-(piperidin-4-yl)pyrazolo[1,5-
-a][1,3,5]triazin-4-amine
##STR00049##
[0167] To a solution of tert-butyl
4-((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]tria-
zin-4-yl)amino)piperidine-1-carboxylate (170 mg, 0.36 mmol) in
EtOAc (1 mL) was added HCl/EtOAc (10 mL). The mixture was stirred
at room temperature for 2 h, after which LCMS showed the reaction
was completed. The mixture was concentrated in vacuo to afford
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)-N-(piperidin-4-yl)pyrazolo[1,-
5-a][1,3,5]triazin-4-amine (135 mg, 100% yield). LCMS: (M+H.sup.+):
374
(E)-4-(Dimethylamino)-N-(4-(4-((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy-
)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carbonyl)phenyl)but-
-2-enamide (Compound 102)
##STR00050##
[0169] To a solution of
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)-N-(piperidin-4-yl)pyrazolo[1,-
5-a][1,3,5]triazin-4-amine (135 mg, 0.36 mmol) in DMF (2 mL) was
added (E)-4-(4-(dimethylamino)but-2-enamido)benzoic acid (99 mg,
0.39 mmol), TEA (110 mg, 1.08 mmol), and HATU (151 mg, 0.39 mmol).
The mixture was stirred at room temperature for 12 h, after which
LCMS showed the reaction was completed. The mixture was then
concentrated in vacuo, and the residue was purified by preparative
HPLC to afford
(E)-4-(dimethylamino)-N-(4-(4-((8-isopropyl-2-((1-methylpiperidin-4-yl)ox-
y)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carbonyl)phenyl)bu-
t-2-enamide (30 mg, 14% yield). .sup.1H NMR: (DMSO; 400 MHz)
.delta. 10.28 (s, 1H), 8.18 (d, J=7.60 Hz, 1H), 7.93 (s, 1H), 7.81
(d, J=8.80 Hz, 2H), 7.71 (d, J=8.80 Hz, 2H), 6.78-6.72 (m, 1H),
6.29 (d, J=15.60 Hz, 1H), 5.25 (s, 1H), 4.95 (s, 1H), 4.16 (s, 1H),
3.42-3.36 (m, 4H), 3.11 (d, J=5.60 Hz, 2H), 2.99-2.98 (m, 1H), 2.83
(s, 2H), 2.54 (s, 1H), 2.36 (s, 3H), 2.21 (s, 6H), 2.04-1.95 (m,
4H), 1.79 (s, 2H), 1.65 (d, J=11.20 Hz, 2H), 1.25 (d, J=6.80 Hz,
6H). LCMS: (M+H.sup.+): 604
Example 2: Synthesis of
(E)-4-(4-(dimethylamino)but-2-enamido)-N-(2-(((8-isopropyl-2-((1-methylpi-
peridin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)be-
nzamide (Compound 103)
##STR00051##
[0170]
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)-4-(1H-1,2,4-triazol-1-y-
l)pyrazolo[1,5-a][1,3,5]triazine
##STR00052##
[0172] To a solution of 1H-1,2,4-triazole (1.07 g, 15.45 mmol) in
Py (15 mL) was added POCl.sub.3 (789 mg, 5.15 mmol). After stirring
at room temperature for 1.5 h,
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin--
4-ol (500 mg, 1.72 mmol) was then added and the mixture was stirred
at room temperature for an additional 7.5 h. LCMS analysis
indicated the reaction was complete, and the solution was used
directly in next step. LCMS: (M+H.sup.+): 343
N-(2-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]t-
riazin-4-yl)amino)methyl)phenyl)-4-nitrobenzamide
##STR00053##
[0174] To a solution of
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)-4-(1H-1,2,4-triazol-1-yl)pyra-
zolo[1,5-a][1,3,5]triazine (587.6 mg, 1.72 mmol) in Py (10 mL) was
added 2-(aminomethyl)-N-(4-nitrobenzyl)aniline (1.40 g, 5.15 mmol).
The mixture was stirred at room temperature for 9 h, after which
LCMS analysis indicated the reaction was complete. The mixture was
concentrated in vacuo, and the residue was purified by preparative
HPLC to afford
N-(2-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]-
triazin-4-yl)amino)methyl)phenyl)-4-nitrobenzamide (330 mg, 35%
yield) as light yellow solid. .sup.1H NMR: (MeOD; 400 MHz) .delta.
8.35-8.30 (m, 2H), 8.18 (d, J=7.60 Hz, 1H), 8.10 (d, J=8.00 Hz,
1H), 7.86 (s, 1H), 7.53-7.35 (m, 5H), 4.85 (s, 2H), 4.82 (s, 1H),
3.49 (s, 1H), 3.19-3.13 (m, 2H), 3.04-3.01 (m, 1H), 2.88-2.86 (m,
3H), 2.23-2.05 (m, 3H), 1.73 (s, 1H), 1.30 (d, J=6.80 Hz, 6H).
LCMS: (M+H.sup.+): 545.
4-amino-N-(2-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a]-
[1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide
##STR00054##
[0176] To a solution of
N-(2-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]-
triazin-4-yl)amino)methyl)phenyl)-4-nitrobenzamide (230 mg, 0.42
mmol) in MeOH (3 mL) was added Raney Ni (500 mg) under H.sub.2 at
15 psi. The mixture was stirred at room temperature for 6 h, after
which LCMS showed the reaction was complete. The mixture was then
concentrated in vacuo to afford
4-amino-N-(2-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazol-
o[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide (215 mg,
100% yield) as light yellow solid. .sup.1H NMR: (MeOD; 400 MHz)
.delta. 7.79 (s, 1H), 7.75 (d, J=8.40 Hz, 2H), 7.45-7.44 (m, 2H),
7.32-7.22 (m, 2H), 6.65 (d, J=8.40 Hz, 2H), 4.72 (s, 2H), 3.27 (s,
3H), 3.21-3.01 (m, 2H), 3.00-2.95 (m, 1H), 2.82-2.74 (m, 4H),
2.11-1.96 (m, 3H), 1.25 (d, J=6.80 Hz, 6H). LCMS: (M+H.sup.+):
515
(E)-4-(4-(dimethylamino)but-2-enamido)-N-(2-(((8-isopropyl-2-((1-methylpip-
eridin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)ben-
zamide (Compound 103)
##STR00055##
[0178] To a solution of
4-amino-N-(2-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a-
][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide (140 mg, 0.27
mmol) in DMF (8 mL) was added (E)-4-(dimethylamino)but-2-enoic acid
(53 mg, 0.41 mmol), TEA (110 mg, 1.09 mmol), and HATU (155 mg, 0.41
mmol). The mixture was stirred at room temperature for 12 h, after
which LCMS showed the reaction was completed. The mixture was then
concentrated in vacuo, and the residue was purified by preparative
HPLC to afford Compound 103 (30 mg, 16% yield) as a brown solid.
.sup.1H NMR: (MeOD; 400 MHz) .delta. 8.19 (d, J=6.40 Hz, 2H), 8.12
(s, 1H), 7.85 (d, J=8.40 Hz, 2H), 7.61 (d, J=6.80 Hz, 1H),
7.38-7.33 (m, 2H), 7.24-7.22 (m, 1H), 6.78-6.71 (m, 1H), 6.38 (d,
J=15.20 Hz, 1H), 5.43 (s, 1H), 4.45 (d, J=10.80 Hz, 2H), 3.90 (s,
2H), 3.61-3.45 (m, 2H), 3.14-3.09 (m, 2H), 2.90 (s, 3H), 2.86 (s,
1H), 2.83 (s, 6H), 2.47-2.11 (m, 4H), 1.25 (d, J=6.80 Hz, 6H).
LCMS: (M+H.sup.+)/2: 313, (M+H.sup.+): 626
N-(2-(aminomethyl)phenyl)-4-nitrobenzamide
##STR00056##
[0180] To a solution of 2-(aminomethyl)aniline (10.00 g, 81.85
mmol) in ACN (100 mL) was added Boc.sub.2O (17.86 g, 81.85 mmol) in
portions. The mixture was stirred at room temperature for 4 h,
after which TLC showed the reaction was complete. The mixture was
concentrated in vacuo, and the residue was washed with PE/MTBE
(50/1), filtered, and filter cake was concentrated in vacuo to
afford tert-butyl 2-aminobenzylcarbamate (14.50 g, 79.7%) as a
white solid. .sup.1H NMR: (DMSO; 400 MHz) .delta. 7.27-7.24 (m,
1H), 6.97-6.94 (m, 2H), 6.63 (d, J=8.00 Hz, 1H), 6.53-6.49 (m, 1H),
5.01 (s, 2H), 3.99 (d, J=6.00 Hz, 2H), 1.41 (s, 9H). LCMS:
(M+H.sup.+): 223.
N-(2-(aminomethyl)phenyl)-4-nitrobenzamide
##STR00057##
[0182] To a mixture of tert-butyl 2-aminobenzylcarbamate (2.00 g,
9.00 mmol) and TEA (1.82 g, 18.00 mmol) in DCM (50 mL) under
N.sub.2 was added a solution of 4-nitrobenzoyl chloride (1.84 g,
9.90 mmol) in DCM (10 mL) dropwise. The mixture was stirred at room
temperature for 4 h, after which LCMS showed the reaction was
completed. The mixture was concentrated in vacuo, and the residue
was washed with PE/DCM (50/1), filtered, and filter cake was
concentrated in vacuo to afford tert-butyl
2-(4-nitrobenzamido)benzylcarbamate (4.6 g, crude) as pale white
solid. .sup.1H NMR: (DMSO; 400 MHz) .delta. 10.51 (s, 1H), 8.37 (d,
J=8.40 Hz, 2H), 8.25 (d, J=8.80 Hz, 2H), 7.47-7.46 (m, 2H),
7.36-7.26 (m, 3H), 4.17 (d, J=6.00 Hz, 2H), 1.36 (s, 9H). LCMS:
(M+Na.sup.+): 394.
N-(2-(aminomethyl)phenyl)-4-nitrobenzamide
##STR00058##
[0184] To a solution of tert-butyl
2-(4-nitrobenzamido)benzylcarbamate (crude 3.60 g, 9.69 mmol) in
DCM (10 mL) was added HCl/EA (50 mL), and the mixture was stirred
at room temperature for 4 h. Once LCMS showed the reaction was
complete, the mixture was concentrated in vacuo to afford
N-(2-(aminomethyl)phenyl)-4-nitrobenzamide (1.65 g, 63% yield) as
pale white solid. .sup.1H NMR: (MeOH; 400 MHz) .delta. 8.41 (d,
J=8.80 Hz, 2H), 8.26 (d, J=8.40 Hz, 2H), 7.62 (d, J=7.20 Hz, 1H),
7.54-7.46 (m, 2H), 7.40 (d, J=7.60 Hz, 1H), 4.12 (s, 2H). LCMS:
(M+H.sup.+): 272.
Example 3: Synthesis of
(E)-4-(dimethylamino)-N-(4-(4-(((8-isopropyl-2-((1-methylpiperidin-4-yl)o-
xy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)amino)methyl)phe-
nyl)but-2-enamide (Compound 104)
##STR00059##
[0185] N-(4-aminobenzyl)-2-(aminomethyl)aniline
##STR00060##
[0186] tert-butyl
2-((4-((tert-butyl)amino)benzyl)amino)benzylcarbamate
[0187] To a solution of tert-butyl 2-aminobenzylcarbamate (2.00 g,
9.00 mmol) in MeOH (20 mL) was added tert-butyl
(4-formylphenyl)carbamate (2.09 g, 9.45 mmol) and AcOH (351 mg,
5.85 mmol). After stirring at room temperature for 1 h,
NaBH.sub.3CN (1.13 g, 18.00 mmol) was added in portions. The
mixture was stirred at room temperature for 12 h until TLC showed
the reaction was complete. The mixture was concentrated in vacuo,
and the residue was purified by column chromatography on silica gel
to afford N-(4-aminobenzyl)-2-(aminomethyl)aniline (2.15 g, 56%) as
a white solid. .sup.1H NMR: (DMSO; 400 MHz) .delta. 9.23 (s, 1H),
7.37-7.35 (m, 3H), 7.21 (d, J=8.80 Hz, 2H), 6.98-6.93 (m, 2H),
6.52-6.50 (m, 1H), 6.42 (d, J=8.00 Hz, 1H), 5.77 (s, 1H), 4.25 (d,
J=5.60 Hz, 2H), 4.05 (d, J=6.00 Hz, 2H), 1.46 (s, 9H), 1.38 (s,
9H). LCMS: (M+H.sup.+): 428.
N-(4-aminobenzyl)-2-(aminomethyl)aniline
[0188] To a solution of tert-butyl
2-((4-((tert-butyl)amino)benzyl)amino)benzylcarbamate (2.15 g, 5.03
mmol) in EA (10 mL) was added HCl/EA (50 mL). The mixture was
stirred at room temperature for 4 h until TLC showed the reaction
was complete. The mixture was concentrated in vacuo to afford
N-(4-aminobenzyl)-2-(aminomethyl)aniline (1.90 g, crude) as red
brown solid. .sup.1H NMR: (MeOH; 400 MHz) .delta. 7.69 (d, J=9.20
Hz, 1H), 7.61-7.58 (m, 2H), 7.53-7.51 (m, 3H), 7.40 (d, J=8.40 Hz,
2H), 4.50 (s, 2H), 4.33 (s, 2H).
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)-4-(1H-1,2,4-triazol-1-yl)pyraz-
olo[1,5-a][1,3,5]triazine
##STR00061##
[0190] To a solution of 1H-1,2,4-triazole (1.07 g, 15.45 mmol) in
Py (10 mL) was added POCl.sub.3 (789 mg, 5.15 mmol). After stirring
at room temperature for 1 h,
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin--
4-ol (500 mg, 1.72 mmol) was added, and the mixture was stirred at
room temperature for 11 h. LCMS showed the reaction was complete
and only the desired product was formed. The solution was used
directly in next step without further purification. LCMS:
(M+H.sup.+): 343.
N-(2-((4-aminobenzyl)amino)benzyl)-8-isopropyl-2-((1-methylpiperidin-4-yl)-
oxy)pyrazolo[1,5-a][1,3,5]triazin-4-amine
##STR00062##
[0192] To a solution of
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)-4-(1H-1,2,4-triazol-1-yl)pyra-
zolo[1,5-a][1,3,5]triazine (587.6 mg, 1.72 mmol) in Py (10 mL) was
added N-(4-aminobenzyl)-2-(aminomethyl)aniline (1.17 g, 5.16 mmol).
The mixture was stirred at room temperature for 5 h, after which
LCMS showed the reaction was complete. The mixture was concentrated
in vacuo to afford
N-(2-((4-aminobenzyl)amino)benzyl)-8-isopropyl-2-((1-methylpiperidin-4-yl-
)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-amine (2.00 g, Crude) as a
brown oil. LCMS: (M+H.sup.+): 501.
(E)-4-(dimethylamino)-N-(4-(((2-(((8-isopropyl-2-((1-methylpiperidin-4-yl)-
oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)amino)methyl)ph-
enyl)but-2-enamide
##STR00063##
[0194] To a solution of
N-(2-((4-aminobenzyl)amino)benzyl)-8-isopropyl-2-((1-methylpiperidin-4-yl-
)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-amine (2.00 g, 3.99 mmol) in
DMF (15 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (774
mg, 5.99 mmol), TEA (1.21 g, 11.98 mmol) and HATU (2.28 g, 5.99
mmol). The mixture was stirred at room temperature for 12 h, after
which LCMS showed the reaction was complete. The mixture was
concentrated in vacuo. The residue was purified by preparative HPLC
to afford Compound 104 (25 mg, 1% yield) as a yellow solid. .sup.1H
NMR: (DMSO; 400 MHz) .delta. 8.29 (s, 1H), 7.96 (s, 1H), 7.70 (d,
J=8.40 Hz, 2H), 7.37 (d, J=8.40 Hz, 2H), 7.08-7.00 (m, 2H),
6.67-6.63 (m, 1H), 6.57-6.53 (m, 2H), 6.12 (d, J=14.80 Hz, 1H),
5.91 (s, 1H), 5.68 (s, 1H), 4.96 (s, 1H), 4.36-4.32 (m, 4H), 3.07
(d, J=6.40 Hz, 2H), 2.81 (s, 2H), 2.39 (s, 2H), 2.33 (s, 3H), 2.21
(s, 6H), 2.05 (s, 3H), 1.82 (s, 2H), 1.32 (d, J=7.20 Hz, 6H). LCMS:
(M+H.sup.+): 612.
Example 4:
(E)-4-(Dimethylamino)-1-(4-(2-(((8-isopropyl-2-((1-methylpiperi-
din-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)pipera-
zin-1-yl)but-2-en-1-one (Compound 105)
##STR00064## ##STR00065##
[0195] 2-(Piperazin-1-yl)benzonitrile
##STR00066##
[0197] To the solution of 2-fluorobenzonitrile (5 g, 41.28 mmol) in
DMSO (250 mL) was added piperazine (27.02 g, 313.76 mmol) followed
by potassium carbonate (10.2 g, 73.9 mmol), and reaction was
stirred at room temperature for 16 h. The reaction progress was
monitored by TLC. The reaction mixture was diluted with water and
toluene, and the separated organic layer was washed with 1N NaOH,
dried over Na.sub.2SO.sub.4, and concentrated under vacuum to
afford the title compound (5.2 g, yield 67%) as a colorless sticky
solid which was used directly in the next step without further
purification. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.57 (dd,
J=1.40, 7.91 Hz, 1H), 7.44-7.52 (m, 1H), 6.96-7.05 (m, 2H),
3.16-3.23 (m, 4H), 3.04-3.13 (m, 4H), 1.75 (br. s, 1H).
tert-Butyl 4-(2-cyanophenyl)piperazine-1-carboxylate
##STR00067##
[0199] To a solution of 2-(piperazin-1-yl)benzonitrile (5 g, 26.69
mmol) in THF:H.sub.2O (1:1, 100 mL) was added potassium carbonate
(9.2 g, 66.7 mmol) and di-tert-butyl dicarbonate (6.4 g, 29.36
mmol) and the mixture was stirred at room temperature for 2 h. The
reaction progress was monitored by TLC. Upon completion, the
reaction mixture was diluted with ethyl acetate and separated. The
separated organic layer was washed with saturated NaHCO.sub.3
solution. The crude compound was dried over Na.sub.2SO.sub.4 and
concentrated under vacuum to afford the title compound (6.5 g,
yield 85%) as a colorless sticky solid. .sup.1H NMR (CDCl.sub.3,
400 MHz): .delta. 7.59 (d, J=7.34 Hz, 1H), 7.50 (t, J=7.83 Hz, 1H),
6.98-7.08 (m, 2H), 3.62-3.69 (m, 4H), 3.13-3.19 (m, 4H), 1.49 (s,
9H).
tert-Butyl 4-(2-(aminomethyl)phenyl)piperazine-1-carboxylate
##STR00068##
[0201] To a solution of tert-butyl
4-(2-cyanophenyl)piperazine-1-carboxylate (1.5 g, 5.22 mmol) in
methanol:THF (1:1, 25 mL) was added Raney nickel (.about.300 mg,
20% wt) and ammonium hydroxide (5 mL, 25% aq. solution). The
reaction mixture was stirred at room temperature at 100 psi under
hydrogen atmosphere in an autoclave for 2 weeks. The reaction
mixture was then filtered through a pad of celite and the filtrate
was concentrated in vacuo to afford 700 mg of the title compound as
light brown solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.
7.72 (d, J=7.45 Hz, 1H), 7.61 (t, J=7.89 Hz, 1H), 7.48 (br. s, 1H),
7.34 (br. s, 1H), 7.18 (d, J=8.33 Hz, 1H), 7.13 (t, J=7.45 Hz, 1H),
4.08 (br. s, 2H), 3.42-3.54 (m, 4H), 3.05-3.13 (m, 2H), 2.77-2.83
(m, 2H), 1.43 (s, 9H). LCMS-Condition-01: [M+H].sup.+=292.10;
R.sub.t=2.09 min
8-Isopropyl-2-((1-methylpiperidin-4-yl)oxy)-4-(1H-1,2,4-triazol-1-yl)pyraz-
olo[1,5-a][1,3,5]triazine
##STR00069##
[0203] To a solution of 1H-1,2,4-triazole (427 mg, 6.18 mmol) in
pyridine (1 mL) was added POCl.sub.3 (0.19 mL, 2.06 mmol) and the
mixture was stirred at room temperature for 1.5 h.
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]
triazin-4-ol (200 mg, 0.68 mmol) was then added and the mixture was
stirred at room temperature for 7.5 h. The reaction progress was
monitored by LCMS. The reaction mixture containing the title was
used directly in the next step without work-up. LCMS:
[M+H].sup.+=343.10; R.sub.t=1.85 min
tert-Butyl 4-(2-(((8-isopropyl-2-((1-methylpiperidin-4-yl)
oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)piperazine-1-c-
arboxylate
##STR00070##
[0205] To a solution of
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)-4-(1H-1,2,4-triazol-1-yl)pyra-
zolo[1,5-a][1,3,5]triazine (235 mg, 0.68 mmol) in pyridine (2 mL)
was added tert-butyl
4-(2-(aminomethyl)phenyl)piperazine-1-carboxylate (599 mg, 2.06
mmol) and stirred at room temperature for 12 h. The reaction
progress was monitored by TLC. The reaction mixture was
concentrated under vacuum to give in the crude compound, which was
purified by column chromatography on neutral silica gel using 5-10%
methanol in DCM to afford the title compound (250 mg, yield 64%) as
a light brown solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.
9.15 (br. s, 1H), 7.95 (s, 1H), 7.25 (d, J=7.34 Hz, 2H), 7.19 (d,
J=7.34 Hz, 1H), 7.07 (t, J=7.58 Hz, 1H), 5.00 (br. s, 1H), 4.78 (d,
J=5.38 Hz, 2H), 3.45-3.56 (m, 4H), 3.39 (d, J=6.36 Hz, 1H),
2.93-3.07 (m, 2H), 2.80-2.89 (m, 6H), 1.69-2.14 (m, 5H), 1.43 (s,
9H), 1.27 (m, 7H), 1.09 (t, J=7.09 Hz, 1H). LCMS:
[M+H].sup.+=565.25; R.sub.t=2.86 min
8-Isopropyl-2-((1-methylpiperidin-4-yl)oxy)-N-(2-(piperazin-1-yl)benzyl)py-
razolo[1,5-a][1,3,5]triazin-4-amine
##STR00071##
[0207] To the solution of tert-butyl
4-(2-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]-
triazin-4-yl)amino)methyl)phenyl)piperazine-1-carboxylate (250 mg,
0.44 mmol) in dioxane (2 mL) was added 4M HCl in dioxane (1 mL) and
the reaction was stirred at room temperature for 1 h. The reaction
was monitored by TLC, and once completed, was concentrated under
vacuum. The solid residue was triturated with ether and dried, then
dissolved in ethyl acetate and washed with saturated aqueous
NaHCO.sub.3 solution. The crude compound was dried over
Na.sub.2SO.sub.4 and concentrated under vacuum to afford the title
compound (150 mg, yield 73%) as a light brown solid. The crude
compound was used in the next step without further purification.
LCMS: [M+H].sup.+=465.20; R.sub.t=1.79
(E)-4-(Dimethylamino)-1-(4-(2-(((8-isopropyl-2-((1-methyl
piperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl-
)piperazin-1-yl)but-2-en-1-one (Compound 105)
##STR00072##
[0209] To a solution of
8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)-N-(2-(piperazin-1-yl)benzyl)p-
yrazolo[1,5-a][1,3,5]triazin-4-amine (100 mg, 0.32 mmol) and
(E)-4-(dimethylamino)but-2-enoic acid (53 mg, 0.32 mmol) in DCE (3
mL) was added triethylamine (0.13 mL, 0.96 mmol) followed by
T.sub.3P (0.75 mL, 1.17 mmol, 50% wt solution in ethyl acetate) at
0.degree. C. and stirred at room temperature for 30 min. The
reaction was monitored by TLC, and upon completion, was evaporated
under vacuum to dryness. The residue was triturated with ether and
dried to obtain crude material. The crude material was purified by
reverse phase Combiflash column chromatography to afford the title
compound (20 mg, yield 11%) as an off white solid. .sup.1H NMR
(CD.sub.3OD, 400 MHz): .delta. 7.85 (s, 1H), 7.23-7.36 m, 3H), 7.14
(t, J=6.85 Hz, 1H), 6.72-6.84 (m, 2H), 5.21 (br. s, 1H), 4.93 (s,
2H), 3.81-3.87 (m, 3H), 2.86-3.17 (m, 10H), 2.63 (s, 3H), 2.40 (s,
6H), 2.26 (s, 1H), 1.98-2.20 (m, 4H), 1.46-1.67 (m, 1H), 1.31 (d,
J=6.85 Hz, 6H). LCMS: [M+H].sup.+=576.25; R.sub.t=1.84 min
Example 5:
1-(3-Acrylamidobenzoyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methy-
l)thio)thiazol-2-yl)piperidine-4-carboxamide (Compound 117)
##STR00073##
[0210] 3-Acrylamidobenzoic Acid
##STR00074##
[0212] To the solution of 3-aminobenzoic acid (1 g, 7.29 mmol) and
pyridine (0.4 mL) in DMF (7 mL) at 0.degree. C. was added acryloyl
chloride (0.59 mL, 7.29 mmol), and the reaction was stirred at room
temperature for 2 h. The reaction progress was monitored by TLC.
The reaction mixture was poured in water (20 mL) and extracted with
ethyl acetate (3.times.20 mL). The combined organic solvents were
washed with water (20 mL), dried over Na.sub.2SO.sub.4 and
concentrated under vacuum to afford the title compound (821 mg,
yield 59%) as an off white solid which was used directly in the
next step without further purification. .sup.1H NMR (DMSO-d.sub.6,
400 MHz): .delta. 13.02 (br. s, 1H), 10.33 (s, 1H), 8.29 (s, 1H),
7.92 (d, J=8.31 Hz, 1H), 7.65 (d, J=7.83 Hz, 1H), 7.45 (t, J=7.83
Hz, 1H), 6.38-6.50 (m, 1H), 6.24-6.34 (m, 1H), 5.79 (dd, J=1.47,
10.27 Hz, 1H). LCMS: [M+H].sup.+=191.85; R.sub.t=0.49 min
1-(3-Acrylamidobenzoyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thia-
zol-2-yl)piperidine-4-carboxamide
##STR00075##
[0214] To a solution of 3-acrylamidobenzoic acid (70 mg, 0.36 mmol)
in DMF (1 mL) was added triethyl amine (0.15 mL, 1.09 mmol), EDCI
(105 mg, 0.54 mmol) and HOBt (74 mg, 0.54 mmol) and the reaction
was stirred at room temperature for 15 min. To the resulting
solution was added
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-c-
arboxamide (139 mg, 0.36 mmol) and the reaction was further stirred
at room temperature for 18 h. The reaction mixture was poured into
ice water and extracted with ethyl acetate (3.times.20 mL). The
combined organic solvents were dried over Na.sub.2SO.sub.4. After
removal of the solvent, the residue was purified by preparative
HPLC to afford the title compound (45 mg, yield 22%) as a white
solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 12.32 (br. s,
1H), 10.28 (s, 1H), 7.76 (s, 1H), 7.69 (d, J=8.21 Hz, 1H),
7.37-7.43 (m, 2H), 7.09 (d, J=7.54 Hz, 1H), 6.72 (s, 1H), 6.41 (d,
J=9.98 Hz, 1H), 6.30 (d, J=2.00 Hz, 1H), 5.76-5.81 (m, 1H), 4.46
(br. s, 1H), 4.06 (s, 2H), 3.67 (br. s, 1H), 3.06 (br. s, 1H),
2.74-2.86 (m, 2H), 1.71-1.97 (m, 2H), 1.53-1.62 (m, 2H), 1.18 (s,
9H). LCMS: [M+H].sup.+=554.15; R.sub.t=2.68 min.
Example 6: Synthesis of
1-acryloyl-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)pip-
eridine-4-carboxamide (Compound 116)
##STR00076##
[0216]
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidi-
ne-4-carboxamide (13 mg, 0.0342 mmol) was dissolved in
dichloromethane (0.7 mL), followed by the addition of triethylamine
(0.01 mL, 0.0683 mmol) and by acryloyl chloride (6 .mu.L, 0.0683
mmol). The reaction was stirred at room temperature for 16 h. At
completion, the reaction mixture was poured into sat. NaHCO.sub.3
(5 mL) and extracted with dichloromethane (5 mL.times.3). Combined
organics were dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude residue was purified by silica gel column
chromatography (0-100% EtOAc/Hexanes) to afford the title compound
(0.2 mg, yield 1.2%). LCMS: [M+H].sup.+=435.15; R.sub.t=2.3
min.
Example 7:
1-(3-Acrylamidobenzyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl-
)thio)thiazol-2-yl)piperidine-4-carboxamide (Compound 118)
##STR00077##
[0217]
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(3-ni-
trobenzyl)piperidine-4-carboxamide
##STR00078##
[0219] To a solution of 3-nitrobenzaldehyde (100 mg, 0.66 mmol) and
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-c-
arboxamide, (252 mg, 0.66 mmol) in DCE (20 mL) was added sodium
triacetoxyborohydride (420 mg, 1.98 mmol) portion wise and the
reaction was stirred at room temperature for 16 h. After TLC
indicated the reaction was complete, the mixture was diluted with
DCM (30 mL) and washed with water (2.times.20 mL). The combined
organic solvents were dried over Na.sub.2SO.sub.4 and concentrated
under vacuum to afford the title compound (175 mg, yield 51%) as a
yellow solid which was used directly in the next step without
further purification. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.
10.04 (br. s, 1H), 8.19 (d, J=8.48 Hz, 2H), 7.52 (d, J=8.48 Hz,
2H), 7.30-7.37 (m, 1H), 6.59 (s, 1H), 3.95 (s, 2H), 3.61 (s, 2H),
2.93 (d, J=11.47 Hz, 2H), 2.32-2.44 (m, 1H), 2.07-2.17 (m, 2H),
1.91 (d, J=3.49 Hz, 4H), 1.25 (s, 9H). LCMS-Condition 01:
[M+H].sup.+=516.10; R.sub.t=2.29 min.
1-(3-Aminobenzyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2--
yl)piperidine-4-carboxamide
##STR00079##
[0221] To a solution of
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(3-nitroben-
zyl)piperidine-4-carboxamide (170 mg, 0.33 mmol) in EtOH:H.sub.2O
(2:1, 7 mL) was added iron powder (147 mg, 2.64 mmol), and ammonium
chloride (18 mg, 0.33 mmol) at room temperature, and the mixture
was refluxed for 30 min. The reaction progress was monitored by
TLC. Upon completion, the reaction mixture was filtered through a
pad of celite, and the filtrate was concentrated under vacuum to
obtain a crude residue. The residue was dissolved in ethyl acetate
(20 mL) and washed with water (2.times.20 mL). The combined organic
solvents were dried over Na.sub.2SO.sub.4 and concentrated under
vacuum to afford the title compound (150 mg, yield 93%) as a yellow
solid which was used directly in the next step without further
purification. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 12.23
(br. s, 1H), 7.38 (s, 1H), 6.94-6.97 (m, 3H), 6.71 (s, 1H),
6.47-6.55 (m, 3H), 4.28 (d, J=5.72 Hz, 1H), 4.05 (s, 2H), 2.59-2.72
(m, 2H), 1.52-1.84 (m, 6H), 1.22-1.34 (m, 2H), 1.17 (s, 9H). LCMS:
[M+H].sup.+=486.15; R.sub.t=2.14 min
1-(3-Acrylamidobenzyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiaz-
ol-2-yl)piperidine-4-carboxamide
##STR00080##
[0223] To a solution of
1-(3-aminobenzyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-
-yl)piperidine-4-carboxamide (130 mg, 0.26 mmol) and acrylic acid
(19 mg, 0.26 mmol) in DCE (5 mL) was added triethylamine (0.11 mL,
0.80 mmol) and T.sub.3P (170 mg, 0.53 mmol), and the reaction was
stirred at room temperature for 1 h. The reaction progress was
monitored by TLC. The mixture was diluted with DCM (20 mL) and
washed with water (2.times.20 mL). The combined organic solvents
were dried over Na.sub.2SO.sub.4. After removal of solvent, the
residue was purified by preparative HPLC to afford title compound
(18 mg, yield 12%) as a white solid. .sup.1H NMR (CDCl.sub.3, 400
MHz): .delta. 8.32 (br. s, 1H), 7.50-7.74 (m, 3H), 7.29-7.35 (m,
2H), 7.10 (d, J=6.85 Hz, 1H), 6.59 (s, 1H), 6.39-6.49 (m, 1H),
6.22-6.32 (m, 1H), 5.78 (d, J=9.78 Hz, 1H), 3.95 (s, 2H), 3.68 (br.
s, 2H), 3.07 (d, J=11.25 Hz, 2H), 2.74-2.76 (m, 1H), 2.23-2.53 (m,
3H), 1.91-2.10 (m, 3H), 1.25 (s, 9H). LCMS: [M+H].sup.+=540.30;
R.sub.t=2.72 min.
Example 8:
1-(4-Acrylamidobenzyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl-
)thio)thiazol-2-yl)piperidine-4-carboxamide (Compound 119)
##STR00081##
[0224]
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(4-ni-
trobenzyl)piperidine-4-carboxamide
##STR00082##
[0226] To a solution of 4-nitrobenzaldehyde (100 mg, 0.66 mmol) and
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-c-
arboxamide (251 mg, 0.66 mmol) in DCE (5 mL) was added sodium
triacetoxyborohydride (420 mg, 1.98 mmol) portionwise and the
reaction was stirred at room temperature for 16 h. The reaction
progress was monitored by TLC. Upon completion, the reaction
mixture was diluted with DCM (30 mL) and washed with water
(2.times.20 mL). The combined organic solvents were dried over
Na.sub.2SO.sub.4 and concentrated under vacuum to afford the title
compound (250 mg, yield 73%) as an off white solid which was used
directly in the next step without further purification. LCMS:
[M+H].sup.+=516.10; R.sub.t=2.21 min
1-(4-Aminobenzyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)
thio)thiazol-2-yl)piperidine-4-carboxamide
##STR00083##
[0228] To a solution of
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(4-nitroben-
zyl)piperidine-4-carboxamide (250 mg, 0.48 mmol) in EtOH:H.sub.2O
(5:2, 7 mL) was added iron powder (217 mg, 3.88 mmol), ammonium
chloride (26 mg, 0.48 mmol) at room temperature and further
refluxed for 1 h. The reaction progress was monitored by TLC. The
reaction mixture was filtered through a pad of celite, the filtrate
obtained concentrated under vacuum to obtain crude residue. The
residue was dissolved in ethyl acetate (20 mL) and washed with
water (2.times.10 mL). The combined organic solvents were dried
over Na.sub.2SO.sub.4 and concentrated under vacuum to afford the
title compound (200 mg, yield 85%) as an off white solid which was
used directly in the next step without further purification.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 12.23 (br. s, 1H),
7.38 (s, 1H), 6.88-7.05 (m, 3H), 6.71 (s, 1H), 6.45-6.57 (m, 3H),
4.91 (br. s, 2H), 4.28 (d, J=5.72 Hz, 1H), 4.01-4.06 (m, 3H),
3.34-3.42 (m, 2H), 2.81 (br. s, 1H), 1.54-1.86 (m, 4H), 1.17 (s,
9H). LCMS: [M+H].sup.+=486.15; R.sub.t=2.18 min.
1-(4-Acrylamidobenzyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)
methyl)thio)thiazol-2-yl)piperidine-4-carboxamide
##STR00084##
[0230] To the solution of
1-(4-aminobenzyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-
-yl)piperidine-4-carboxamide (150 mg, 0.30 mmol) and acrylic acid
(22 mg, 0.30 mmol) in DCE (30 mL) was added triethylamine (0.12 mL,
0.92 mmol), 50% wt solution in ethyl acetate T.sub.3P (0.25 mL,
0.39 mmol) at 0.degree. C. and stirred at room temperature for 1 h.
The reaction progress was monitored by TLC. The reaction mixture
was diluted with DCM (20 mL) and washed with water (2.times.10 mL).
The combined organic solvents were dried over Na.sub.2SO.sub.4.
After removal of solvent, the residue was purified by preparative
HPLC to afford the title compound (15 mg, yield 9%) as an off white
solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 12.21 (br. s,
1H), 10.11 (br. s, 1H), 7.49-7.67 (m, 2H), 7.18-7.41 (m, 3H), 6.71
(s, 1H), 6.13-6.50 (m, 2H), 5.69-5.97 (m, 1H), 4.12-4.38 (m, 3H),
3.41 (br. s, 2H), 2.60-3.03 (m, 2H), 1.51-1.99 (m, 6H), 1.17 (s,
9H). LCMS: [M+H].sup.+=540.20; R.sub.t=2.86 min.
Example 9:
1-((1-Acryloylpiperidin-4-yl)methyl)-N-(5-(((5-(tert-butyl)oxaz-
ol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide (Compound
120)
##STR00085##
[0231]
tert-Butyl-(((4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazo-
l-2-yl)carbamoyl)piperidin-1-yl)methyl)piperidine-1-carboxylate
##STR00086##
[0233] To a solution of tert-butyl 4-formylpiperidine-1-carboxylate
(100 mg, 0.46 mmol) and
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-c-
arboxamide (178 mg, 0.46 mmol) in DCE (10 mL) was added sodium
triacetoxyborohydride (293 mg, 1.38 mmol) portion wise and the
reaction was stirred at room temperature for 16 h. The reaction
progress was monitored by TLC. The reaction mixture was diluted
with DCM (30 mL) and washed with water (2.times.20 mL). The
combined organic solvents were dried over Na.sub.2SO.sub.4 and
concentrated under vacuum to afford the title compound (200 mg,
yield 74%) as an off white solid which was used directly in the
next step without further purification. LCMS: [M+H].sup.+=578.20;
R.sub.t=2.29 min
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(piperidin-4-
-ylmethyl)piperidine-4-carboxamide
##STR00087##
[0235] A solution of tert-butyl
4-((4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl-
)piperidin-1-yl)methyl)piperidine-1-carboxylate (200 mg, 0.34 mmol)
in 4M HCl in dioxane (2 mL) was stirred at room temperature for 5
h. The reaction progress was monitored by TLC. The reaction mixture
was concentrated under vacuum to obtain crude residue which was
triturated with ethyl acetate (10 mL) and dried to afford the title
compound (160 mg, yield 96%) as off white solid which was used
directly in the next step without further purification. LCMS:
[M+H].sup.+=478.15; R.sub.t=1.82 min
1-((1-Acryloylpiperidin-4-yl)methyl)-N-(5-(((5-(tert-butyl)
oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide
##STR00088##
[0237] To a solution of
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(piperidin--
4-ylmethyl)piperidine-4-carboxamide (200 mg, 0.42 mmol) and acrylic
acid (30 mg, 0.42 mmol) in DCE (30 mL) was added triethyl amine
(0.17 mL, 1.26 mmol), T.sub.3P (0.2 mL, 0.31 mmol) at 0.degree. C.
and stirred at room temperature for 1 h. The reaction progress was
monitored by TLC. The reaction mixture was diluted with DCM (20 mL)
and washed with water (2.times.10 mL). The combined organic
solvents were dried over Na.sub.2SO.sub.4. After removal of
solvent, the residue was purified by preparative HPLC to afford the
title compound (15 mg, yield 7%) as off white solid. .sup.1H NMR
(CD.sub.3OD, 400 MHz): .delta. 7.32 (s, 1H), 6.76 (dd, J=10.71,
16.95 Hz, 1H), 6.67 (s, 1H), 6.17 (dd, J=1.56, 16.73 Hz, 1H), 5.72
(dd, J=1.78, 10.71 Hz, 1H), 4.56 (d, J=12.49 Hz, 1H), 4.12 (d,
J=13.38 Hz, 1H), 3.98 (s, 2H), 3.11-3.17 (m, 3H), 2.75 (t, J=11.82
Hz, 1H), 2.51-2.59 (m, 1H), 2.42 (d, J=6.25 Hz, 2H), 2.27-2.31 (m,
2H), 1.79-2.01 (m, 6H), 1.29-1.38 (m, 1H), 1.25 (s, 9H), 1.04-1.18
(m, 2H). LCMS: [M+H].sup.+=532.30; R.sub.t=2.57 min.
Example 10:
1-(1-(3-Acrylamidophenyl)ethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)-
thio)thiazol-2-yl)piperidine-4-carboxamide (Compound 121)
##STR00089##
[0238]
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(3-
-nitrophenyl)ethyl)piperidine-4-carboxamide
##STR00090##
[0240] To a solution of 1-(3-nitrophenyl)ethan-1-one (150 mg, 0.91
mmol) and
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-
-4-carboxamide (345 mg, 0.91 mmol) in DCE (15 mL) was added
titanium isopropoxide (294 mg, 1.03 mmol) and the reaction was
refluxed for 3 h. The mixture was then allowed to cool to room
temperature. To the resulting solution was added sodium
cyanoborohydride (65 mg, 1.03 mmol) and the mixture was stirred at
room temperature for 12 h. The reaction progress was monitored by
TLC. The reaction mixture was quenched with saturated NH.sub.4Cl
solution and extracted with ethyl acetate (2.times.20 mL). The
combined organic solvents were dried over Na.sub.2SO.sub.4 and
concentrated under vacuum. The crude compound was purified by
silica gel column chromatography eluting with 0-50% ethyl acetate
in n-hexane to afford the title compound (250 mg, yield 52%) as a
brown sticky oil. LCMS: [M+H].sup.+=530.10; R.sub.t=2.40 min
1-(1-(3-Aminophenyl)ethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)t-
hiazol-2-yl)piperidine-4-carboxamide
##STR00091##
[0242] To a solution of
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(1-(3-nitro-
phenyl)ethyl)piperidine-4-carboxamide (250 mg, 0.47 mmol) in
EtOH:H.sub.2O (5:2, 7 mL) was added iron powder (210 mg, 3.78
mmol), and ammonium chloride (25 mg, 0.47 mmol) at room
temperature, and the reaction was refluxed for 30 minutes. The
reaction progress was monitored by TLC. The reaction mixture was
filtered through a pad of celite and the filtrate was concentrated
under vacuum to obtain crude residue. The residue was dissolved in
ethyl acetate (20 mL) and washed with water (2.times.10 mL). The
combined organic solvents were dried over Na.sub.2SO.sub.4 and
concentrated under vacuum to afford the title compound (150 mg,
yield 64%) as a light brown solid which was used directly in the
next step without further purification. .sup.1H NMR (DMSO-d.sub.6,
400 MHz): .delta. 7.30-7.43 (m, 2H), 7.21 (br. s, 1H), 7.08 (br. s,
2H), 6.71 (br. s, 1H), 6.56-6.67 (m, 2H), 4.20-4.40 (m, 1H), 4.05
(br. s, 2H), 3.66-3.77 (m, 1H), 3.13-3.25 (m, 2H), 2.68-2.81 (m,
3H), 2.01-2.08 (m, 2H), 1.62 (d, J=6.17 Hz, 2H), 1.21-1.24 (m, 2H),
1.17 (s, 9H). LCMS: [M+H].sup.+=500.07; R.sub.t=2.27 min
1-(1-(3-Acrylamidophenyl)ethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)t-
hio)thiazol-2-yl)piperidine-4-carboxamide
##STR00092##
[0244] To a solution of
1-(1-(3-aminophenyl)ethyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)-
thiazol-2-yl)piperidine-4-carboxamide (150 mg, 0.30 mmol) and
acrylic acid (22 mg, 0.30 mmol) in DCE (3 mL) was added
triethylamine (0.12 mL, 0.90 mmol) followed by 50% wt T.sub.3P
solution in ethyl acetate (0.5 mL, 0.78 mmol) at 0.degree. C. The
reaction was stirred at room temperature for 1 h, and the reaction
progress was monitored by TLC. Upon completion of the reaction, the
mixture was diluted with DCM (20 mL) and washed with water
(2.times.10 mL). The combined organic solvents were dried over
Na.sub.2SO.sub.4 and concentrated. After removal of solvent, the
residue was purified by preparative HPLC to afford the title
compound (40 mg, yield 24%) as an off white solid. .sup.1H NMR
(CD.sub.3OD, 400 MHz): .delta. 7.53-7.65 (m, 2H), 7.27-7.36 (m,
2H), 7.09-7.15 (m, 1H), 6.67 (s, 1H), 6.31-6.49 (m, 2H), 5.76-5.78
(m, 1H), 3.98 (s, 2H), 3.52 (d, J=5.87 Hz, 1H), 3.18 (d, J=10.76
Hz, 1H), 2.95 (d, J=10.27 Hz, 1H), 2.76 (t, J=5.87 Hz, 1H),
1.96-2.17 (m, 2H), 1.74-1.93 (m, 4H), 1.43 (d, J=6.36 Hz, 3H), 1.23
(s, 9H). LCMS: [M+H].sup.+=554.29; R.sub.t=2.79 min
Example 11:
1-(4-Acrylamidobenzoyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thi-
azol-2-yl)piperidine-4-carboxamide (Compound 122)
##STR00093##
[0245] 4-Acrylamidobenzoic Acid
##STR00094##
[0247] To a solution of 4-aminobenzoic acid (3 g, 21.8 mmol) in DMF
(30 mL) was added pyridine (1.5 mL) followed by acryloyl chloride
(1.78 mL, 21.8 mmol) drop wise and stirred at room temperature for
3 h. The reaction progress was monitored by TLC. The reaction
mixture was diluted with ethyl acetate (30 mL) and washed with cold
water (2.times.20 mL). The combined organic solvents were dried
over Na.sub.2SO.sub.4 and concentrated under vacuum to afford the
title compound (2.31 g, yield 56%) as off white solid which was
used directly in the next step without further purification.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 12.72 (br. s, 1H),
10.44 (s, 1H), 7.87-7.99 (m, 2H), 7.71-7.83 (m, 2H), 6.41-6.56 (m,
1H), 6.19-6.33 (m, 1H), 5.81 (dd, J=1.85, 10.17 Hz, 1H). LCMS:
[M+H].sup.+=191.85; R.sub.t=0.45 min.
1-(4-Acrylamidobenzoyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thia-
zol-2-yl)piperidine-4-carboxamide
##STR00095##
[0249] To a solution of 4-acrylamidobenzoic acid (50 mg, 0.26 mmol)
in DMF (1 mL) was added triethylamine (0.1 mL, 0.78 mmol), EDCI (75
mg, 0.39 mmol) and HOBt (53 mg, 0.39 mmol). The reaction was
stirred at 0.degree. C. for 30 min, after which was added
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-c-
arboxamide (99 mg, 0.26 mmol). After stirring at room temperature
for 3 h, the mixture was diluted with water (10 mL) and extracted
with ethyl acetate (3.times.10 mL). The combined organic solvents
were dried over Na.sub.2SO.sub.4. After removal of the solvent, the
residue was purified by silica gel column chromatography eluting
with 0-4% methanol in DCM to afford the title compound (35 mg,
yield 24%) as a white solid. .sup.1H NMR (CDCl.sub.3, 400 MHz):
.delta. 10.56 (br. s, 1H), 7.83 (br. s, 1H), 7.60 (d, J=8.31 Hz,
2H), 7.38 (d, J=7.34 Hz, 2H), 7.31 (s, 1H), 6.59 (s, 1H), 6.42-6.52
(m, 1H), 6.23-6.35 (m, 1H), 5.80 (d, J=10.27 Hz, 1H), 3.98 (s, 2H),
3.03-3.07 (m, 2H), 2.65-2.67 (m, 1H), 1.78-2.04 (m, 4H), 1.26-1.31
(m, 11H). LCMS: [M+H].sup.+=554.05; R.sub.t=2.67 min
Example 12:
1-(1-Acryloylpiperidine-4-carbonyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)met-
hyl)thio)thiazol-2-yl)piperidine-4-carboxamide (Compound 123)
##STR00096##
[0250] Ethyl 1-acryloylpiperidine-4-carboxylate
##STR00097##
[0252] To a solution of ethyl piperidine-4-carboxylate (1 g, 6.36
mmol) in DCM (10 mL) at 0.degree. C. was added triethylamine (1.5
mL, 10.8 mmol) followed by acryloyl chloride (0.62 mL, 7.63 mmol)
and the reaction was stirred at room temperature for 3 h. The
reaction progress was monitored by TLC. The reaction mixture was
poured on ice and the solvent was concentrated under vacuum. The
slurry obtained was extracted with ethyl acetate (2.times.20 mL).
The combined organic solvents were washed with 1% HCl solution
followed by brine, dried over Na.sub.2SO.sub.4 and concentrated
under vacuum to afford the title compound (950 mg, yield 71%) as a
straw colored solid which was used directly in the next step
without further purification. .sup.1H NMR (CDCl.sub.3, 400 MHz):
.delta. 6.50-6.62 (m, 1H), 6.20-6.32 (m, 1H), 5.68 (dd, J=1.96,
10.76 Hz, 1H), 4.15 (q, J=7.17 Hz, 2H), 3.84-4.04 (m, 1H),
2.87-3.31 (m, 2H), 2.56 (tt, J=3.97, 10.70 Hz, 2H), 1.96 (dd,
J=2.93, 13.21 Hz, 2H), 1.62-1.81 (m, 2H), 1.18-1.33 (m, 3H). LCMS:
[M+H].sup.+=211.97; R.sub.t=2.20 min.
1-Acryloylpiperidine-4-carboxylic Acid
##STR00098##
[0254] To a solution of ethyl 1-acryloylpiperidine-4-carboxylate
(300 mg, 1.42 mmol) in MeOH:H.sub.2O (3:3 mL) was added solution of
lithium hydroxide (170 mg, 7.09 mmol) in water (2 mL) and stirred
at room temperature for 2 h. The reaction mixture was acidified
with 1N HCl and extracted with ethyl acetate (3.times.15 mL). The
combined organic solvents were dried over Na.sub.2SO.sub.4 and
concentrated under vacuum to afford the title compound (200 mg,
yield 77%) as an off white solid which was used directly in the
next step without further purification. .sup.1H NMR (CDCl.sub.3,
400 MHz): .delta. 6.57 (dd, J=10.52, 16.66 Hz, 1H), 6.27 (d,
J=16.66 Hz, 1H), 5.70 (d, J=10.52 Hz, 1H), 4.43-4.46 (m, 1H),
3.93-3.97 (m, 1H), 2.90-3.26 (m, 2H), 2.53-2.70 (m, 1H), 1.96-2.00
(m, 2H), 1.61-1.79 (m, 2H). LCMS: [M+H].sup.+=183.85; R.sub.t=2.32
min.
1-(1-Acryloylpiperidine-4-carbonyl)-N-(5-(((5-(tert-butyl)
oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide
##STR00099##
[0256] To a solution of 1-acryloylpiperidine-4-carboxylic acid (50
mg, 0.27 mmol) in DMF (2.5 mL) was added triethylamine (0.11 mL,
0.81 mmol), EDCI (78 mg, 0.41 mmol) and HOBt (55 mg, 0.41 mmol) and
the reaction was stirred at 0.degree. C. for 30 min. To the
resulting solution was added
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-c-
arboxamide (104 mg, 0.27 mmol) and the solution was stirred at room
temperature for 3 h. The reaction mixture was diluted with water
(10 mL) and extracted with ethyl acetate (3.times.20 mL). The
combined organic solvents were dried over Na.sub.2SO.sub.4. After
removal of solvent, the residue was purified by silica gel column
chromatography eluting with 0-4% methanol in DCM to afford the
title compound (40 mg, yield 27%) as a white solid. .sup.1H NMR
(CDCl.sub.3, 400 MHz): .delta. 10.82 (br. S, 1H), 7.31 (s, 1H),
6.54-6.63 (m, 2H), 6.26 (d, J=16.63 Hz, 1H), 5.69 (d, J=10.76 Hz,
1H), 4.54-4.61 (m, 2H), 3.85-4.16 (m, 4H), 3.14-3.20 (m, 2H),
2.62-2.82 (m, 4H), 1.96-2.01 (m, 2H), 1.72-1.85 (m, 6H), 1.26 (s,
9H). LCMS: [M+H].sup.+=546.15; R.sub.t=2.48 min
Example 13:
1-(3-Acrylamidobenzoyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thi-
azol-2-yl)piperidine-4-carboxamide (Compound 124)
##STR00100##
[0257] 3-Acrylamidobenzoic Acid
##STR00101##
[0259] To a solution of 3-aminobenzoic acid (1 g, 7.29 mmol) and
pyridine (0.4 mL) in DMF (7 mL) at 0.degree. C. was added acryloyl
chloride (0.59 mL, 7.29 mmol) and the reaction was stirred at room
temperature for 2 h. The reaction progress was monitored by TLC.
The reaction mixture was poured in water (20 mL) and extracted with
ethyl acetate (3.times.20 mL). The combined organic solvents was
washed with water (20 mL), dried over Na.sub.2SO.sub.4 and
concentrated under vacuum to afford the title compound (821 mg,
yield 59%) as an off white solid which was used directly in the
next step without further purification. .sup.1H NMR (DMSO-d.sub.6,
400 MHz): .delta. 13.02 (br. s, 1H), 10.33 (s, 1H), 8.29 (s, 1H),
7.92 (d, J=8.31 Hz, 1H), 7.65 (d, J=7.83 Hz, 1H), 7.45 (t, J=7.83
Hz, 1H), 6.38-6.50 (m, 1H), 6.24-6.34 (m, 1H), 5.79 (dd, J=1.47,
10.27 Hz, 1H). LCMS: [M+H].sup.+=191.85; R.sub.t=0.49 min.
1-(3-Acrylamidobenzoyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thia-
zol-2-yl)piperidine-4-carboxamide
##STR00102##
[0261] To a solution of 3-acrylamidobenzoic acid (70 mg, 0.36 mmol)
in DMF (1 mL) was added triethyl amine (0.15 mL, 1.09 mmol), EDCI
(105 mg, 0.54 mmol) and HOBt (74 mg, 0.54 mmol) and the reaction
was stirred at room temperature for 15 min. To the resulting
solution was added
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-c-
arboxamide (139 mg, 0.36 mmol) and the mixture was stirred at room
temperature for 18 h. The reaction mixture was poured into ice
water and extracted with ethyl acetate (3.times.20 mL). The
combined organic solvents were dried over Na.sub.2SO.sub.4. After
removal of the solvent, the residue was purified by preparative
HPLC to afford the title compound (45 mg, yield 22%) as a white
solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 12.32 (br. s,
1H), 10.28 (s, 1H), 7.76 (s, 1H), 7.69 (d, J=8.21 Hz, 1H),
7.37-7.43 (m, 2H), 7.09 (d, J=7.54 Hz, 1H), 6.72 (s, 1H), 6.41 (d,
J=9.98 Hz, 1H), 6.30 (d, J=2.00 Hz, 1H), 5.76-5.81 (m, 1H), 4.46
(br. s, 1H), 4.06 (s, 2H), 3.67 (br. s, 1H), 3.06 (br. s, 1H),
2.74-2.86 (m, 2H), 1.71-1.97 (m, 2H), 1.53-1.62 (m, 2H), 1.18 (s,
9H). LCMS: [M+H].sup.+=554.15; R.sub.t=2.68 min
Example 14:
1-((1-Acryloylpiperidin-3-yl)methyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)me-
thyl)thio)thiazol-2-yl)piperidine-4-carboxamide (Compound 125)
##STR00103##
[0262] tert-Butyl
3-((4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)
thiazol-2-yl)carbamoyl)piperidin-1-yl)methyl)piperidine-1-carboxylate
##STR00104##
[0264] To a solution of tert-butyl 3-formylpiperidine-1-carboxylate
(100 mg, 0.47 mmol) and
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-c-
arboxamide (178 mg, 0.47 mmol) in DCE (20 mL) was added sodium
triacetoxy borohydride (298 mg, 1.41 mmol) portion wise and the
mixture was stirred at room temperature for 16 h. The reaction
progress was monitored by TLC. The reaction mixture was diluted
with water and extracted with DCM (2.times.20 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4 and concentrated
under vacuum to afford the title compound (200 mg, yield 74%) as a
light brown sticky liquid. The crude compound was used in the next
step without further purification. .sup.1H NMR (DMSO-d.sub.6, 400
MHz): .delta. 12.22 (br. s, 1H), 7.39 (s, 1H), 6.72 (s, 1H), 4.05
(s, 2H), 3.88-3.92 (m, 1H), 3.76 (d, J=12.79 Hz, 1H), 3.17 (d,
J=4.85 Hz, 1H), 2.89 (s, 1H), 2.70-2.83 (m, 3H), 2.05-2.08 (m, 2H),
1.91 (s, 3H), 1.51-1.83 (m, 7H), 1.39 (s, 9H), 1.23-1.32 (m, 1H),
1.17 (s, 9H). LCMS: [M+H].sup.+=578.20; R.sub.t=2.40 min.
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(piperidin-3-
-ylmethyl)piperidine-4-carboxamide
##STR00105##
[0266] To a solution of tert-butyl
3-((4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)
thiazol-2-yl)carbamoyl)piperidin-1-yl)methyl)piperidine-1-carboxylate
(245 mg, 0.34 mmol) in dioxane (10 mL) was added 4M HCl in dioxane
(1 mL) at room temperature and stirred for 5 h. The completion of
the reaction was monitored by TLC. The reaction mixture was
concentrated under vacuum to obtain crude residue. The residue was
washed with ethyl acetate (20 mL) and dried to afford 200 mg of the
title compound as a light brown solid which was used directly in
the next step without further purification. .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 9.36 (br. s, 1H), 7.40 (s, 1H),
7.32 (br. s, 1H), 6.73 (s, 1H), 4.06 (s, 2H), 3.36-3.55 (m, 2H),
3.04-3.20 (m, 3H), 2.86-3.02 (m, 3H), 2.65-2.82 (m, 3H), 2.38 (br.
s, 1H), 1.96-2.15 (m, 4H), 1.66-1.92 (m, 4H), 1.23-1.28 (m, 1H),
1.18 (s, 9H). LCMS: [M+H].sup.+=478.25; R.sub.t=1.76 min
1-((1-Acryloylpiperidin-3-yl)methyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)met-
hyl)thio)thiazol-2-yl)piperidine-4-carboxamide
##STR00106##
[0268] To a solution of
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(piperidin--
3-ylmethyl)piperidine-4-carboxamide (200 mg, 0.42 mmol) and acrylic
acid (30 mg, 0.42 mmol) in DCE (19 mL) was added triethyl amine
(0.17 mL, 1.25 mmol), T.sub.3P (2 mL, 3.14 mmol, 50% wt solution in
ethyl acetate) and the mixture was stirred at room temperature for
1 h. The reaction progress was monitored by TLC. The reaction
mixture was diluted with DCM (20 mL) and washed with water
(2.times.20 mL). The combined organic solvents were dried over
Na.sub.2SO.sub.4. After removal of solvent, the residue was
purified by preparative HPLC to afford the title compound (70 mg,
yield 31%) as a white solid. .sup.1H NMR (CD.sub.3OD, 400 MHz):
.delta. 7.31 (s, 1H), 6.70-6.87 (m, 1H), 6.67 (s, 1H), 6.17 (d,
J=17.12 Hz, 1H), 5.73 (t, J=9.05 Hz, 1H), 4.48 (d, J=13.69 Hz, 1H),
3.92-4.09 (m, 4H), 3.09-3.23 (m, 2H), 2.84-3.05 (m, 2H), 2.53-2.62
(m, 1H), 2.46 (d, J=6.36 Hz, 1H), 2.06-2.36 (m, 3H), 1.68-2.00 (m,
8H), 1.24 (s, 9H). LCMS: [M+H].sup.+=532.40; R.sub.t=2.71 min.
Example 15:
(E)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(3-(4-(-
dimethylamino)but-2-enamido)benzyl)piperidine-4-carboxamide
(Compound 127)
##STR00107##
[0269]
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(3-ni-
trobenzyl)piperidine-4-carboxamide
##STR00108##
[0271] To a solution of 3-nitrobenzaldehyde (100 mg, 0.66 mmol) and
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-c-
arboxamide (252 mg, 0.66 mmol) in DCE (20 mL) was added sodium
triacetoxy borohydride (410 mg, 1.98 mmol) portion wise and stirred
at room temperature for 16 h. The reaction progress was monitored
by TLC. The reaction mixture was quenched with saturated NH.sub.4Cl
solution and extracted with ethyl acetate (2.times.20 mL). The
combined organic solvents were dried over Na.sub.2SO.sub.4 and
concentrated under vacuum to afford the title compound (250 mg,
yield 73%) as a brown sticky liquid. The crude compound was used in
the next step without further purification. .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 12.23 (s, 1H), 8.11-8.16 (m, 2H),
7.78 (d, J=7.63 Hz, 1H), 7.64 (t, J=7.87 Hz, 1H), 7.38 (s, 1H),
6.71 (s, 1H), 4.05 (s, 2H), 3.61 (s, 2H), 2.85 (d, J=11.44 Hz, 2H),
2.44-2.46 (m, 1H), 1.97-2.07 (m, 2H), 1.73-1.80 (m, 2H), 1.60-1.70
(m, 2H), 1.17 (s, 9H). LCMS: [M+H].sup.+=516.22; R.sub.t=3.24
min.
1-(3-Aminobenzyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2--
yl)piperidine-4-carboxamide
##STR00109##
[0273] To a solution of
N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(3-nitroben-
zyl)piperidine-4-carboxamide (245 mg, 0.47 mmol) in EtOH:H.sub.2O
(5:2, 7 mL) was added iron powder (213 mg, 3.80 mmol) and ammonium
chloride (25 mg, 0.47 mmol) at room temperature and the mixture was
refluxed for 30 min. The completion of the reaction was monitored
by TLC. The reaction mixture was filtered through a pad of celite,
and the filtrate was concentrated under vacuum to obtain crude
residue. The residue was dissolved in ethyl acetate (20 mL) and
washed with water (2.times.10 mL). The combined organic solvents
were dried over Na.sub.2SO.sub.4 and concentrated under vacuum to
afford the title compound (190 mg, yield 83%) as a light brown
solid which was used directly in the next step without further
purification. LCMS: [M+H].sup.+=486.25; R.sub.t=2.96 min
(E)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)-1-(3-(4-(d-
imethylamino)but-2-enamido)benzyl)piperidine-4-carboxamide
##STR00110##
[0275] To a solution of
1-(3-aminobenzyl)-N-(5-(((5-(tert-butyl)oxazol-2-yl)methyl)
thio)thiazol-2-yl)piperidine-4-carboxamide (190 mg, 0.39 mmol) and
(E)-4-(dimethylamino)but-2-enoic acid (50 mg, 0.39 mmol) in DCE (19
mL) was added triethyl amine (0.16 mL, 1.17 mmol) followed by 50%
wt T.sub.3P solution in ethyl acetate (1.9 mL, 2.98 mmol) at
0.degree. C. and the reaction mixture was stirred at room
temperature for 1 h. The reaction progress was monitored by TLC.
The reaction mixture was diluted with DCM (20 mL) and washed with
water (2.times.10 mL). The combined organic solvents were dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by preparative HPLC to afford the title
compound (11 mg, yield 5%) as an off white solid. .sup.1H NMR
(CD.sub.3OD, 400 MHz): .delta. 8.49 (br. s, 1H), 7.72 (br. s, 1H),
7.55 (d, J=7.34 Hz, 1H), 7.31-7.36 (m, 2H), 7.15 (d, J=7.34 Hz,
1H), 6.85-6.95 (m, 1H), 6.67 (s, 1H), 6.36 (d, J=15.16 Hz, 1H),
3.98 (s, 2H), 3.71 (s, 2H), 3.43 (d, J=6.36 Hz, 2H), 3.11 (d,
J=11.74 Hz, 2H), 2.49 (s, 6H), 2.54 (br. s, 1H), 2.32-2.36 (m, 2H),
1.90 (d, J=4.89 Hz, 4H), 1.24 (s, 9H). LCMS: [M+H].sup.+=597.21;
R.sub.t=2.99 min.
Example 16:
N-acryloyl-N-(6-((7-(benzylamino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-y-
l)amino)hexyl)acrylamide (Compound 100)
##STR00111##
[0277]
N5-(6-aminohexyl)-N7-benzyl-3-isopropylpyrazolo[1,5-a]pyrimidine-5,-
7-diamine (6 mg, 0.014 mmol) was dissolved in tetrahydrofuran (2.8
mL), followed by addition of triethylamine (63 .mu.L, 0.44 mmol)
and acryloyl chloride (0.14 .mu.L, 0.17 mmol). The reaction was
stirred at room temperature for 16 h. Upon completion, the reaction
mixture was poured into sat. NaHCO.sub.3 (10 mL) and extracted with
dichloromethane (10 mL.times.3). The combined organics were dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The crude
residue was purified by silica gel chromatography (0-15%
methanol/dichloromethane) to afford the title compound (0.6 mg,
yield 0.9%). LCMS: [M+H].sup.+=489.30; R.sub.t=2.74 min.
Example 17: CDK7 Kinase Activity
[0278] Compounds of the invention were assayed for CDK7 activity at
Life Technologies.TM. (Grand Island, N.Y.) using their commercially
available Adapta.RTM. kinase assay services. Test compounds were
tested at concentrations ranging from 10 .mu.M down to 0.514 nM in
a series of 3-fold serial dilutions. Details of this assay,
including substrates used, are available on the Life Technologies
web site
(http://www.lifetechnologies.com/us/en/home/life-science/drug-discovery/t-
arget-and-lead-identification-and-validation/kinasebiology/kinase-activity-
-assays.html). The results of the assay are shown below in Table 2,
where "A" represents a calculated IC.sub.50 of less than 100 nM;
"B" represents a calculated IC.sub.50 of between 100 nM and 1
.mu.M; and "C" represents a calculated IC.sub.50 of greater than 1
.mu.M.
TABLE-US-00002 TABLE 2 CDK7 Inhibitory Activity of Selected
Compounds of the Invention. Compound No. CDK7 Inhibition
(IC.sub.50) 100 C 102 C 103 B 104 A 105 A 116 B 117 C 118 B 119 B
120 C 121 B 122 C 123 C 124 C 125 B 127 B
Example 18: Inhibition of A637 Cell Proliferation
[0279] Representative compounds of the invention were tested at
different concentrations (from 4 .mu.M to 126.4 .mu.M; 0.5 log
serial dilutions) for their ability to inhibit the proliferation of
A673 cells. Known CDK inhibitors flavopiridol and triptolide were
used as positive controls. Cells were grown in Dulbecco's Modified
Eagle's Medium, +10% FBS+1 mM Sodium Pyruvate. The cells were
cultured at 37.degree. C. in a humidified chamber in the presence
of 5% CO.sub.2. Proliferation assays were conducted over a 72 hour
time period. CyQUANT.RTM. (Life Technologies, Chicago, Ill. USA)
was used to assess the anti-proliferative effects of the compounds
following manufacturer's directions and utilizing the reagents
supplied with the CyQUANT.RTM. kit. The results of the assay are
shown below in Table 3, where "A" represents an IC.sub.50 of less
than 500 nM; "B" an IC.sub.50 of between 500 nM and 5 .mu.M; and
"C" an IC.sub.50 of greater than 5 .mu.M.
TABLE-US-00003 TABLE 3 Inhibition of Proliferation of A673 Cells by
Compounds of the Invention. Compound No. A673 IC.sub.50 102 B 103 B
104 A 105 A 117 A 118 A 119 A 120 A 121 A 122 A 123 A 124 A 125 A
127 A
EQUIVALENTS AND SCOPE
[0280] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The invention includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0281] Furthermore, the invention encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should it be understood that, in general, where the invention,
or aspects of the invention, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
invention or aspects of the invention consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates
otherwise.
[0282] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present invention that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the invention can be excluded from any claim, for any
reason, whether or not related to the existence of prior art.
[0283] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
invention, as defined in the following claims.
* * * * *
References