U.S. patent application number 14/599192 was filed with the patent office on 2015-12-24 for inhibitors of fatty acid amide hydrolase.
This patent application is currently assigned to INFINITY PHARMACEUTICALS, INC.. The applicant listed for this patent is INFINITY PHARMACEUTICALS, INC.. Invention is credited to Mark L. BEHNKE, Alfredo C. CASTRO, Catherine A. EVANS, Louis GRENIER, Michael J. GROGAN, Tao LIU, Daniel A. SNYDER, Thomas T. TIBBITTS.
Application Number | 20150368278 14/599192 |
Document ID | / |
Family ID | 40912141 |
Filed Date | 2015-12-24 |
United States Patent
Application |
20150368278 |
Kind Code |
A1 |
BEHNKE; Mark L. ; et
al. |
December 24, 2015 |
INHIBITORS OF FATTY ACID AMIDE HYDROLASE
Abstract
The present invention provides compounds, and pharmaceutically
acceptable compositions thereof, encompassed by any of formulae
(I), (II), (III), (IV), (V), or (VI), or subgenera thereof. The
present invention also provides methods for treating an FAAH
mediated disease, disorder or condition by administering a
therapeutically effective amount of a compound or composition
comprising a compound of any of formulae (I), (II), (III), (IV),
(V), or (VI), or subgenera thereof, to a patient in need thereof.
Additionally, the present invention provides methods for inhibiting
FAAH by administering a therapeutically effective amount of a
compound or composition comprising a compound of any of formulae
(I), (II), (III), (IV), (V), or (VI), or subgenera thereof, to a
patient in need thereof. ##STR00001##
Inventors: |
BEHNKE; Mark L.;
(Somerville, MA) ; CASTRO; Alfredo C.; (Woburn,
MA) ; EVANS; Catherine A.; (Somerville, MA) ;
GRENIER; Louis; (Newton, MA) ; GROGAN; Michael
J.; (Winchester, MA) ; LIU; Tao; (Ashland,
MA) ; SNYDER; Daniel A.; (Somerville, MA) ;
TIBBITTS; Thomas T.; (Westford, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INFINITY PHARMACEUTICALS, INC. |
Cambridge |
MA |
US |
|
|
Assignee: |
INFINITY PHARMACEUTICALS,
INC.
Cambridge
MA
|
Family ID: |
40912141 |
Appl. No.: |
14/599192 |
Filed: |
January 16, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12901421 |
Oct 8, 2010 |
8957049 |
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14599192 |
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PCT/US09/39872 |
Apr 8, 2009 |
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12901421 |
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61043686 |
Apr 9, 2008 |
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Current U.S.
Class: |
514/64 ; 546/13;
548/110 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
25/22 20180101; A61P 5/14 20180101; A61P 1/02 20180101; A61P 17/06
20180101; A61P 1/12 20180101; A61P 25/24 20180101; A61P 19/10
20180101; A61P 13/12 20180101; A61P 21/04 20180101; A61K 31/69
20130101; A61P 19/02 20180101; A61P 25/28 20180101; A61P 25/00
20180101; A61P 17/04 20180101; A61P 17/02 20180101; A61P 27/02
20180101; A61P 25/20 20180101; C07F 5/02 20130101; C07F 5/025
20130101; A61P 9/10 20180101; A61P 3/10 20180101; A61P 1/00
20180101; A61P 17/00 20180101; A61P 37/02 20180101; A61P 29/00
20180101; A61P 21/00 20180101; A61P 25/06 20180101; A61P 9/00
20180101; A61P 25/16 20180101; A61P 11/06 20180101; A61P 37/06
20180101; A61P 27/06 20180101; A61P 25/04 20180101; A61P 7/06
20180101; A61P 43/00 20180101 |
International
Class: |
C07F 5/02 20060101
C07F005/02 |
Claims
1-67. (canceled)
68. A compound of formula ##STR00660## or a pharmaceutically
acceptable salt or prodrug thereof; wherein: (i) Z.sup.1 is --OH or
--OR.sup.3 and Z.sup.2 is --OH, --OR.sup.4, an optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl; (ii) Z.sup.1 and Z.sup.2 taken together with the boron
atom to which they are bound, form a 5- to 8-membered ring having
at least one O, S, N or NR.sup.5 atom directly bonded to the boron
atom; or (iii) Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring
A taken together form an optionally substituted 5- to 7-membered
ring; W.sup.3 is C, CR.sup.15, or N; X is a covalent bond, --O--,
--N.dbd.N--, --C.dbd.N--, --NR.sup.6--, --C(NR.sup.6)--, --S--,
--C(O)--, --S(O)--, --S(O).sub.2--, or optionally substituted
C.sub.1-6 alkylene, wherein one, two or three methylene units of
the C.sub.1-6 alkylene are optionally and independently replaced
with one or more groups selected from --O--, --N.dbd.N--,
--C.dbd.N--, --NR.sup.6--, --C(NR.sup.6)--, --S--, --C(O)--,
--S(O)--, and --S(O).sub.2--; each instance of R.sup.1 is,
independently, halogen, --OR.sup.8, --CF.sub.3, --CN, --NO.sub.2,
--SO.sub.2R.sup.8, --SOR.sup.8, --C(O)R.sup.8, --CO.sub.2R.sup.8,
--C(O)N(R).sub.2, --CHO, --N.sub.3, --N.sub.2R.sup.8,
--N(R.sup.8).sub.2, --B(OH.sub.2), optionally substituted C.sub.1-8
alkyl, optionally substituted C.sub.2-8 alkenyl, optionally
substituted C.sub.2-8 alkynyl, optionally substituted C.sub.1-8
heteroalkyl, optionally substituted C.sub.2-8 heteroalkenyl,
optionally substituted C.sub.2-8 heteroalkynyl, optionally
substituted C.sub.3-10 carbocyclyl, optionally substituted 3-10
membered heterocyclyl, optionally substituted C.sub.6-10 aryl, or
optionally substituted 5-10 membered heteroaryl; each instance of
R.sup.2 is, independently, halogen, --OR.sup.9, --CF.sub.3, --CN,
--NO.sub.2, --SO.sub.2R.sup.9, --SOR.sup.9, --C(O)R.sup.9,
--CO.sub.2R.sup.9, --C(O)N(R.sup.9).sub.2, --N.sub.3,
--N.sub.2R.sup.9, --N(R.sup.9).sub.2, optionally substituted
C.sub.1-8 alkyl, optionally substituted C.sub.2-8 alkenyl,
optionally substituted C.sub.2-8 alkynyl, optionally substituted
C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl; each instance of R.sup.3 and R.sup.4 is, independently,
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl; each instance of R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, and R.sup.10 is, independently,
hydrogen, --SO.sub.2R.sup.11, --SOR.sup.11, --C(O)R.sup.11,
--CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2, --C(O)NH(R.sup.11),
--C(O)NH.sub.2, optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl; each instance of R.sup.11 is,
independently, optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.2-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl; R.sup.15 is hydrogen, halogen,
--CF.sub.3, optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, or optionally substituted C.sub.2-8
alkynyl; n is 0, 1, 2 or 3 and m is 0, 1, 2, 3, 4, or 5 with the
proviso that the following compound is specifically excluded:
##STR00661##
69. (canceled)
70. The compound of claim 68, wherein W.sup.3 is C or CH.
71. The compound of claim 68, wherein W.sup.3 is N.
72. The compound of claim 68, wherein X is a covalent bond.
73. The compound of claim 68, wherein the compound is selected from
##STR00662## ##STR00663## ##STR00664## ##STR00665##
74. A compound of the following formula: ##STR00666## or a
pharmaceutically acceptable salt or prodrug thereof; wherein: (i)
Z.sup.1 is --OH or --OR.sup.3 and Z.sup.2 is --OH, or --OR.sup.4,
an optionally substituted C.sub.1-6 alkyl, optionally substituted
C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl,
optionally substituted C.sub.1-6 heteroalkyl, optionally
substituted C.sub.2-6 heteroalkenyl, optionally substituted
C.sub.2-6 heteroalkynyl, optionally substituted C.sub.6-10 aryl, or
optionally substituted 5-10 membered heteroaryl; or (ii) Z.sup.1 is
--OH or --OR.sup.3, and Z.sup.2 and ##STR00667## taken together
form an optionally substituted 5- to 7-membered ring, wherein the
ring is comprised of carbon atoms and optionally one or more
additional heteroatoms independently selected from the group
consisting of N, S and O; W.sup.3 is N; X is a covalent bond,
--O--, --N.dbd.N--, --C.dbd.N--, --NR.sup.6--, --C(NR.sup.6)--,
--S--, --C(O)--, --S(O)--, --S(O).sub.2--, or optionally
substituted C.sub.1-6 alkylene, wherein one, two or three methylene
units of the C.sub.1-6 alkylene are optionally and independently
replaced with one or more groups selected from --O--, --N.dbd.N--,
--C.dbd.N--, --NR.sup.6--, --C(NR.sup.6)--, --S--, --C(O)--,
--S(O)--, and --S(O).sub.2--; each instance of R.sup.1 is,
independently, halogen, --OR.sup.8, --CF.sub.3, --CN, --NO.sub.2,
--SO.sub.2R.sup.8, --SOR.sup.8, --C(O)R.sup.8, --CO.sub.2R.sup.8,
--C(O)N(R.sup.8).sub.2, --CHO, --N.sub.3, --N.sub.2R.sup.8,
--N(R.sup.8).sub.2, --B(OH).sub.2, optionally substituted C.sub.1-6
alkyl, optionally substituted C.sub.2-6 alkenyl, optionally
substituted C.sub.2-6 alkynyl; each instance of R.sup.2 is,
independently, --OR.sup.9, --N(R).sub.2, optionally substituted
alkyl, optionally substituted C.sub.2-6 alkenyl, or unsubstituted
C.sub.6-10 aryl; each instance of R.sup.3 and R.sup.4 is,
independently, optionally substituted C.sub.1-6 alkyl, optionally
substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6
alkynyl, optionally substituted C.sub.1-6 heteroalkyl, optionally
substituted C.sub.2-6 heteroalkenyl, optionally substituted
C.sub.2-6 heteroalkynyl, optionally substituted C.sub.6-10 aryl, or
optionally substituted 5-10 membered heteroaryl; each instance of
R.sup.6, R.sup.8 and R.sup.9 is, independently, hydrogen,
--SO.sub.2R.sup.11, --SOR.sup.1, --C(O)R.sup.11,
--CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2, --C(O)NH(R.sup.11),
--C(O)NH.sub.2, optionally substituted C.sub.1-6 alkyl, optionally
substituted C.sub.2-6 alkenyl, optionally substituted
C.sub.2-6alkynyl, optionally substituted C.sub.1-6 heteroalkyl,
optionally substituted C.sub.2-6 heteroalkenyl, optionally
substituted C.sub.2-6 heteroalkynyl, optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl; each instance of R.sup.11 is,
independently, optionally substituted C.sub.1-6alkyl, optionally
substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6
alkynyl, optionally substituted C.sub.1-6 heteroalkyl, optionally
substituted C.sub.2-6 heteroalkenyl, optionally substituted
C.sub.2-6 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl; R.sup.15 is hydrogen, halogen,
--CF.sub.3, optionally substituted C.sub.1-6 alkyl, optionally
substituted C.sub.2-6 alkenyl, or optionally substituted C.sub.2-6
alkynyl; and n is, 1, 2 or 3.
75. The compound of claim 74, wherein X is a covalent bond, --O--,
or --(CH.sub.2)--.
76. The compound of claim 74, wherein Z.sup.1 and Z.sup.2 are both
OH.
77. The compound of claim 74, wherein n is 0.
78. The compound of claim 74, wherein R.sup.2 is optionally
substituted C.sub.1-6 alkyl.
79. The compound of claim 74, wherein R.sup.2 is unsubstituted
C.sub.6-10 aryl.
80. The compound of claim 74, which is: ##STR00668##
81. A compound of the following formula: ##STR00669## or a
pharmaceutically acceptable salt or prodrug thereof; wherein: (i)
Z.sup.1 is --OH or --OR.sup.3 and Z.sup.2 is --OH, or --OR.sup.4,
an optionally substituted C.sub.1-6 alkyl, optionally substituted
C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl,
optionally substituted C.sub.1-6 heteroalkyl, optionally
substituted C.sub.2-6 heteroalkenyl, optionally substituted
C.sub.2-6 heteroalkynyl, optionally substituted C.sub.6-10 aryl, or
optionally substituted 5-10 membered heteroaryl; or (ii) Z.sup.1 is
--OH or --OR.sup.3, and Z.sup.2 and ##STR00670## taken together
form an optionally substituted 5- to 7-membered ring, wherein the
ring is comprised of carbon atoms and optionally one or more
additional heteroatoms independently selected from the group
consisting of N, S and O; W.sup.3 is CR.sup.15; X is a covalent
bond, --O--, --N.dbd.N--, --C.dbd.N--, --NR.sup.6--,
--C(NR.sup.6)--, --S--, --C(O)--, --S(O)--, --S(O).sub.2--, or
optionally substituted C.sub.1-6 alkylene, wherein one, two or
three methylene units of the C.sub.1-6 alkylene are optionally and
independently replaced with one or more groups selected from --O--,
--N.dbd.N--, --C.dbd.N--, --NR.sup.6--, --C(NR.sup.6)--, --S--,
--C(O)--, --S(O)--, and --S(O).sub.2--; each instance of R.sup.1
is, independently, halogen, --OR.sup.8, --CF.sub.3, --CN,
--NO.sub.2, --SO.sub.2R.sup.8, --SOR.sup.8, --C(O)R.sup.8,
--CO.sub.2R.sup.8, --C(O)N(R.sup.8).sub.2, --CHO, --N.sub.3,
--N.sub.2R.sup.8, --N(R.sup.8).sub.2, --B(OH).sub.2, optionally
substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6
alkenyl, optionally substituted C.sub.2-6 alkynyl; each instance of
R.sup.2 is, independently, optionally substituted 5-10 membered
heteroaryl; each instance of R.sup.3 and R.sup.4 is, independently,
optionally substituted C.sub.1-6 alkyl, optionally substituted
C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl,
optionally substituted C.sub.1-6 heteroalkyl, optionally
substituted C.sub.2-6 heteroalkenyl, optionally substituted
C.sub.2-6 heteroalkynyl, optionally substituted C.sub.6-10 aryl, or
optionally substituted 5-10 membered heteroaryl; each instance of
R.sup.6 and R.sup.8 is, independently, hydrogen,
--SO.sub.2R.sup.11, --SOR.sup.11, --C(O)R.sup.11,
--CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2, --C(O)NH(R.sup.11),
--C(O)NH.sub.2, optionally substituted C.sub.1-6 alkyl, optionally
substituted C.sub.2-6 alkenyl, optionally substituted
C.sub.2-4alkynyl, optionally substituted C.sub.1 heteroalkyl,
optionally substituted C.sub.2-6 heteroalkenyl, optionally
substituted C.sub.2-6 heteroalkynyl, optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl; each instance of R.sup.11 is,
independently, optionally substituted C.sub.1-6alkyl, optionally
substituted C.sub.2-6 alkenyl, optionally substituted
C.sub.2-4alkynyl, optionally substituted C.sub.1-6 heteroalkyl,
optionally substituted C.sub.2-6 heteroalkenyl, optionally
substituted C.sub.2-6 heteroalkynyl, optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl; R.sup.15 is hydrogen,
halogen, --CF.sub.3, optionally substituted C.sub.1-6 alkyl,
optionally substituted C.sub.2-6 alkenyl, or optionally substituted
C.sub.2-6 alkynyl; and n is, 1, 2 or 3.
82. The compound of claim 81, wherein X is a covalent bond, --O--,
or --(CH.sub.2)--.
83. The compound of claim 81, wherein Z.sup.1 and Z.sup.2 are both
OH.
84. The compound of claim 81, wherein n is 0.
85. The compound of claim 81, which is: ##STR00671##
##STR00672##
86. A compound selected from: ##STR00673##
87. A method of treating a painful condition, disease or disorder
comprising administering to a patient in need thereof a
therapeutically effective amount of the composition of claim
68.
88. A method of treating an inflammatory disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of the composition of claim 68.
89. A method of treating a painful condition, disease or disorder
comprising administering to a patient in need thereof a
therapeutically effective amount of the composition of claim
74.
90. A method of treating an inflammatory disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of the composition of claim 74.
91. A method of treating a painful condition, disease or disorder
comprising administering to a patient in need thereof a
therapeutically effective amount of the composition of claim
81.
92. A method of treating an inflammatory disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of the composition of claim 81.
93. A method of treating a painful condition, disease or disorder
comprising administering to a patient in need thereof a
therapeutically effective amount of the composition of claim
86.
94. A method of treating an inflammatory disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of the composition of claim 86.
Description
BACKGROUND
[0001] Fatty acid amide hydrolase (FAAH), also referred to as
oleamide hydrolase and anandamide amidohydrolase, is an integral
membrane protein that degrades fatty acid primary amides and
ethanolamides, including oleamide and anandamide. FAAH degrades
neuromodulating fatty acid amides at their sites of action and is
intimately involved in their regulation.
[0002] FAAH has been demonstrated to be involved in a number of
biological processes and its inhibition has been shown to be
effective in treating a variety of conditions. For example,
inhibiting FAAH has been shown to be useful in treating chronic
pain, acute pain, neuropathic pain, anxiety, depression, feeding
behaviors, movement disorders, glaucoma, neuroprotection and
cardiovascular disease. However, current inhibitors of FAAH lack
the target selectivity, biological activity and/or bioavailability
needed for in vivo studies and therapeutic use. Thus, to date, the
therapeutic potential of FAAH inhibitors remains essentially
unexplored.
SUMMARY
[0003] Compounds described herein, and pharmaceutically acceptable
compositions thereof, are effective inhibitors of fatty acid amide
hydrolase (FAAH). Such compounds are encompassed by formula
(I):
##STR00002##
or pharmaceutically acceptable salts or prodrugs thereof, wherein
Z.sup.1, Z.sup.2, L.sup.1, X, Ring A, R.sup.1, R.sup.A and n are as
defined herein.
[0004] In certain embodiments, Ring A is a C.sub.3-10 carbocyclyl
or C.sub.6-10 aryl group. In some embodiments, Ring A is phenyl. In
other embodiments, Ring A is a 3-10 membered heterocyclyl group or
a 5-10 membered heteroaryl group. In some embodiments, Ring A is
monocyclic, while in other embodiments Ring A is bicyclic.
[0005] In certain embodiments, R.sup.A is Ring B, i.e., providing
compounds which are encompassed by formula (II):
##STR00003##
or pharmaceutically acceptable salts or prodrugs thereof, wherein
Z.sup.1, Z.sup.2, L.sup.1, X, Ring A, Ring B, R.sup.1, R.sup.2, n
and m are as defined herein. In certain embodiments, Ring B is a
3-10 membered heterocyclyl group or a 5-10 membered heteroaryl
group. In some embodiments, Ring B is monocyclic, while in other
embodiments Ring B is bicyclic.
[0006] Also provided are methods for treating conditions associated
with excessive FAAH activity by administering a therapeutically
effective amount of a compound provided herein, or a pharmaceutical
composition thereof, to a patient in need thereof.
[0007] Also provided are methods for inhibiting FAAH in a patient
by administering a therapeutically effective amount of a compound
provided herein, or a pharmaceutically acceptable composition
thereof, to a patient in need thereof.
Sequence Identification Numbers
TABLE-US-00001 [0008] SEQ ID NO. 1: Homo sapiens FAAH amino acid
sequence: MVQYELWAALPGASGVALACCFVAAAVALRWSGRRTARGAVVRARQRQRA
GLENMDRAAQRFRLQNPDLDSEALLALPLPQLVQKLHSRELAPEAVLFTY
VGKAWEVNKGTNCVTSYLADCETQLSQAPRQGLLYGVPVSLKECFTYKGQ
DSTLGLSLNEGVPAECDSVVVHVLKLQGAVPFVHTNVPQSMFSYDCSNPL
FGQTVNPWKSSKSPGGSSGGEGALIGSGGSPLGLGTDIGGSIRFPSSFCG
ICGLKPTGNRLSKSGLKGCVYGQEAVRLSVGPMARDVESLALCLRALLCE
DMFRLDPTVPPLPFREEVYTSSQPLRVGYYETDNYTMPSPAMRRAVLETK
QSLEAAGHTLVPFLPSNIPHALETLSTGGLFSDGGHTFLQNFKGDFVDPC
LGDLVSILKLPQWLKGLLAFLVKPLLPRLSAFLSNMKSRSAGKLWELQHE
IEVYRKTVIAQWRALDLDVVLTPMLAPALDLNAPGRATGAVSYTMLYNCL
DFPAGVVPVTTVTAEDEAQMEHYRGYFGDIWDKMLQKGMKKSVGLPVAVQ
CVALPWQEELCLRFMREVERLMTPEKQSS
DETAILED DESCRIPTION
1. General Description of Compounds
[0009] Provided are inhibitors of FAAH that contain at least one
Lewis acidic boron head group, such as, for example, a boronic
acid, boronic ester, borinic acid or borinic ester head group. Such
compounds include compounds of formula (I):
##STR00004##
or a pharmaceutically acceptable salt or prodrug thereof;
wherein:
[0010] (i) Z.sup.1 is --OH or --OR.sup.3; and Z.sup.2 is --OH,
--OR.sup.4, an optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl group;
[0011] (ii) Z.sup.1 and Z.sup.2 taken together with the boron atom
to which they are bound, form a 5- to 8-membered ring having at
least one O, S, N or NR.sup.5 atom directly bonded to the boron
atom;
[0012] (iii) Z.sup.1 is --OH or --OR.sup.3; and Z.sup.2 and Ring A
taken together form an optionally substituted 5- to 7-membered
ring;
[0013] L.sup.1 is a covalent bond, an optionally substituted
straight or branched C.sub.is alkylene, or an optionally
substituted straight or branched C.sub.2-6 alkenylene moiety;
[0014] Ring A is optionally substituted C.sub.3-10 carbocyclyl,
optionally substituted 3-10 membered heterocyclyl, optionally
substituted C.sub.6-10 aryl, or optionally substituted 5-10
membered heteroaryl;
[0015] X is a covalent bond, --O--, --N.dbd.N--, --C.dbd.N--,
--NR.sup.6--, --C(NR.sup.6)--, --S--, --C(O), --S(O)--,
--S(O).sub.2--, or optionally substituted C.sub.1-6 alkylene,
wherein one, two or three methylene units of the C.sub.1-6 alkylene
are optionally and independently replaced with one or more groups
selected from --O, --N.dbd.N--, --C.dbd.N--, --NR.sup.6,
--C(NR.sup.6)--, --S--, --C(O)--, --S(O)--, and --S(O).sub.2--;
[0016] R.sup.A is hydrogen, halogen, --OR.sup.7, --CF.sub.3, --CN,
--NO.sub.2, --SO.sub.2R.sup.7, --SOR.sup.7, --C(O)R.sup.7,
--CO.sub.2R.sup.7, --C(O)N(R.sup.7).sub.2, --N.sub.3,
--N.sub.2R.sup.7, --N(R.sup.7).sub.2, or Ring B having formula:
##STR00005##
[0017] wherein Ring B is optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0018] each instance of R.sup.1 is, independently, halogen,
--OR.sup.8, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.8,
--SOR.sup.8, --C(O)R.sup.8, --CO.sub.2R.sup.8,
--C(O)N(R.sup.8).sub.2, --N.sub.3, --N.sub.2R.sup.8,
--N(R.sup.8).sub.2, --B(OH.sub.2), optionally substituted C.sub.1-8
alkyl, optionally substituted C.sub.2-8 alkenyl, optionally
substituted C.sub.2-8 alkynyl, optionally substituted C.sub.1-8
heteroalkyl, optionally substituted C.sub.2-8 heteroalkenyl,
optionally substituted C.sub.2-8 heteroalkynyl, optionally
substituted C.sub.3-10 carbocyclyl, optionally substituted 3-10
membered heterocyclyl, optionally substituted C.sub.6-10 aryl, or
optionally substituted 5-10 membered heteroaryl;
[0019] each instance of R.sup.2 is, independently, halogen,
--OR.sup.9, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.9,
--SOR.sup.9, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)N(R.sup.9).sub.2, --N.sub.3, --N.sub.2R.sup.9,
--N(R.sup.9).sub.2, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, optionally substituted
C.sub.2-8 alkynyl, optionally substituted C.sub.1-8 heteroalkyl,
optionally substituted C.sub.2-8 heteroalkenyl, optionally
substituted C.sub.2-8 heteroalkynyl, optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl;
[0020] each instance of R.sup.3 and R.sup.4 is, independently,
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0021] each instance of R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, and R.sup.19 is, independently, hydrogen,
--SO.sub.2R.sup.11, --SOR.sup.11, --C(O)R.sup.11,
--CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2, --C(O)NH(R.sup.11),
--C(O)NH.sub.2, optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0022] each instance of R.sup.11 is, independently, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl;
[0023] n is 0, 1, 2 or 3; and
[0024] m is 0, 1, 2, 3, 4 or 5.
[0025] In certain embodiments, R.sup.A is Ring B, i.e., compounds
encompassed by formula (II):
##STR00006##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, L.sup.1, X, Ring A, Ring B, R.sup.1, R.sup.2, n
and m are as defined herein.
[0026] In certain embodiments, Ring A is a C.sub.3-10 carbocyclyl
or C.sub.6-10 aryl group. In some embodiments, Ring A is phenyl. In
other embodiments, Ring A is a 3-10 membered heterocyclyl group or
a 5-10 membered heteroaryl group. In some embodiments, Ring A is
monocyclic, while in other embodiments Ring A is bicyclic.
[0027] In certain embodiments, Ring B is a 3-10 membered
heterocyclyl group or a 5-10 membered heteroaryl group. In some
embodiments, Ring B is monocyclic, while in other embodiments Ring
B is bicyclic. For example, in certain embodiments, Ring B is a 5-6
membered monocyclic heteroaryl group, while in other embodiments,
Ring B is a 9-10 membered bicyclic heteroaryl group.
2. Compounds and Definitions
[0028] 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 Organic Chemistry, Thomas Sorrell, 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.
[0029] Certain compounds of the present invention can comprise one
or more asymmetric centers, and thus can exist in various isomeric
forms, e.g., stereoisomers and/or diastereomers. Thus, provided
compounds, and pharmaceutically acceptable compositions thereof,
may be in the form of an individual enantiomer, diastereomer or
geometric isomer, or may be in the form of a mixture of
stereoisomers. In certain embodiments, the compounds of the
invention are enantiopure compounds. In certain other embodiments,
mixtures of stereoisomers or diastereomers are provided.
[0030] Furthermore, certain compounds, as described herein may have
one or more double bonds that can exist as either the Z or E
isomer, unless otherwise indicated. The invention additionally
encompasses the compounds as individual isomers substantially free
of other isomers and, alternatively, as mixtures of various
isomers, e.g., racemic mixtures of stereoisomers.
[0031] 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."
"Opticallyenriched," 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, S. H., et al., Tetrahedron 33:2725 (1977);
Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY,
1962); and 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).
[0032] When a range of values is listed, it is intended to
encompass each value and subrange within the range. For example
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5,
and C.sub.5-6 alkyl.
[0033] As used herein a "direct bond" or "covalent bond" refers to
a single bond. As used herein, the term "boronic acid" refers to
any chemical compound comprising a B(OH).sub.2 moiety. Arylboronic
acid compounds readily form oligomeric anhydrides by dehydration of
the boronic acid moiety (see, for example, Snyder et al., J. Am.
Chem. Soc. (1958) 80: 3611). Thus, unless otherwise apparent from
context, the term "boronic acid" is expressly intended to encompass
free boronic acids, oligomeric anhydrides, including, but not
limited to, dimers, trimers, and tetramers, and mixtures
thereof.
[0034] The terms "boronic ester", "borinic acid" and "borinic
ester" are art understood terms referring to a --B(OR).sub.2
moiety, a --B(R)OH moiety and a --B(R)OR moiety, respectively,
wherein R is a group other than hydrogen (e.g., for example, an
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocycyl, optionally substituted 3-10 membered heterocycyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl group, or two R groups are joined to form
a 5- to 8-membered ring optionally containing 1 to 4 heteroatoms
selected from optionally substituted nitrogen, oxygen or
sulfur).
[0035] As used herein, alone or as part of another group, "halo"
and "halogen" refer to fluorine (fluoro, --F), chlorine (chloro,
--Cl), bromine (bromo, --Br), or iodine (iodo, --I).
[0036] As used herein, alone or as part of another group, "alkyl"
refers to a monoradical of a straightchain or branched saturated
hydrocarbon group having from 1 to 8 carbon atoms ("C.sub.1-8
alkyl"). In some embodiments, an alkyl group can have from 1 to 6
carbon atoms ("C.sub.1-6 alkyl"). In some embodiments, an alkyl
group can have from 1 to 4 carbon atoms ("C.sub.1-4 alkyl").
Examples of C.sub.1-4 alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, secbutyl and tert-butyl. Examples of
C.sub.1-6 alkyl groups include the aforementioned C.sub.1-4 alkyl
groups as well as pentyl, isopentyl, neopentyl, hexyl and the like.
Additional examples of alkyl groups include heptyl, octyl and the
like. Unless otherwise specified, each instance of an "optionally
substituted" alkyl group is independently unsubstituted or
substituted with 1-5 groups as described below.
[0037] As used herein, alone or as part of another group, "alkenyl"
refers to a monoradical of a straight-chain or branched hydrocarbon
group having from 2 to 8 carbon atoms and one or more carbon-carbon
double bonds ("C.sub.2-8 alkenyl"). In some embodiments, an alkenyl
group can have from 2 to 6 carbon atoms ("C.sub.2-6 alkenyl"). In
some embodiments, an alkenyl group can have from 2 to 4 carbon
atoms ("C.sub.2-4 alkenyl"). The one or more carbon-carbon double
bonds can be internal (such as in 2-butenyl) or terminal (such as
in 1-butenyl). Examples of C.sub.2-4 alkenyl groups include
ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl
and the like. Examples of C.sub.2-6 alkenyl groups include the
aforementioned C.sub.2-4 alkenyl groups as well as pentenyl,
pentadienyl, hexenyl and the like. Additional examples of alkenyl
include heptenyl, octenyl, octatrienyl and the like. Unless
otherwise specified, each instance of an "optionally substituted"
alkenyl group is independently unsubstituted or substituted with
1-5 groups as described below.
[0038] As used herein, alone or as part of another group, "alkynyl"
refers to a monoradical of a straight-chain or branched hydrocarbon
group having from 2 to 8 carbon atoms and one or more carbon-carbon
triple bonds ("C.sub.2-8 alkynyl"). In some embodiments, an alkynyl
group can have from 2 to 6 carbon atoms ("C.sub.2-6 alkynyl"). In
some embodiments, an alkynyl group can have from 2 to 4 carbon
atoms ("C.sub.2-4 alkynyl"). The one or more carbon-carbon triple
bonds can be internal (such as in 2-butynyl) or terminal (such as
in 1-butynyl). Examples of C.sub.2-4 alkynyl groups include
ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and the like.
Examples of C.sub.2-6 alkenyl groups include the aforementioned
C.sub.2-4 alkynyl groups as well as pentynyl, hexynyl and the like.
Additional examples of alkynyl include heptynyl, octynyl and the
like. Unless otherwise specified, each instance of an "optionally
substituted" alkynyl group is independently unsubstituted or
substituted with 1-5 groups as described below.
[0039] As used herein, alone or as part of another group,
"heteroalkyl" refers to an alkyl group, as defined herein, wherein
one or more carbon atoms are replaced with one or more heteroatoms
selected from optionally substituted nitrogen, oxygen and sulfur.
For example, "heteroalkyl" refers to a monoradical of a
straight-chain or branched hydrocarbon group having from 1 to 8
carbon atoms and one or more heteroatoms ("C.sub.1-8
heteroalkynyl"). Unless otherwise specified, each instance of an
"optionally substituted" heteroalkyl group is independently
unsubstituted or substituted with 1-5 groups as described
below.
[0040] As used herein, alone or as part of another group,
"heteroalkenyl" refers to an alkenyl group, as defined herein,
wherein one or more carbon atoms are replaced with one or more
heteroatoms selected from optionally substituted nitrogen, oxygen
and sulfur. For example, "heteroalkenyl" refers to a monoradical of
a straight-chain or branched hydrocarbon group having from 2 to 8
carbon atoms, one or more carbon-carbon double bonds, and one or
more heteroatoms ("C.sub.2-8 heteroalkenyl"). Unless otherwise
specified, each instance of an "optionally substituted"
heteroalkenyl group is independently unsubstituted or substituted
with 1-5 groups as described below.
[0041] As used herein, alone or as part of another group,
"heteroalkynyl" refers to an alkynyl group, as defined herein,
wherein one or more carbon atoms are replaced with one or more
heteroatoms selected from optionally substituted nitrogen, oxygen
and sulfur. For example, "heteroalkynyl" refers to a monoradical of
a straight-chain or branched hydrocarbon group having from 2 to 8
carbon atoms, one or more carbon-carbon triple bonds, and one or
more heteroatoms ("C.sub.2-8 heteroalkynyl"). Unless otherwise
specified, each instance of an "optionally substituted"
heteroalkynyl group is independently unsubstituted or substituted
with 1-5 groups as described below.
[0042] As used herein, alone or as part of another group,
"alkylene" refers to a diradical of a straight-chain or branched
saturated hydrocarbon group having from 1 to 6 carbon atoms
("C.sub.1-6 alkylene"). In some embodiments, an alkylene group can
have from 1 to 4 carbon atoms ("C.sub.1-4 alkylene"). In some
embodiments, an alkylene group can have from 1 to 2 carbon atoms
("C.sub.1-2 alkylene"). Examples of C.sub.1-2 alkylene groups
include methylene and ethylene. Examples of C.sub.1-4 alkylene
groups include the aforementioned C.sub.1-2 alkylene groups as well
as trimethylene (1,3-propanediyl), propylene (1,2-propanediyl),
tetramethylene (1,4-butanediyl), butylene (1,2-butanediyl),
1,3-butanediyl, 2-methyl-1,3-propanediyl and the like. Examples of
C.sub.1-6 alkylene groups include the aforementioned C.sub.1-4
alkylene groups as well as pentamethylene (1,5-pentanediyl),
pentylene (1,2-pentanediyl), hexamethylene (1,6-hexanediyl),
hexylene (1,2-hexanediyl), 2,3-dimethyl-1,4-butanediyl and the
like. In some embodiments, an alkylene group is an
.alpha.,.omega.-diradical. Examples of .alpha.,.omega.-diradical
alkylene groups include methylene, ethylene, trimethylene,
tetramethylene, pentamethylene and hexamethylene.
[0043] As used herein, alone or as part of another group,
"alkenylene" refers to a diradical of a straight-chain or branched
hydrocarbon group having from 2 to 6 carbon atoms and one or more
carbon-carbon double bonds ("C.sub.2-6 alkenylene"). In some
embodiments, an alkenylene group can have from 2 to 4 carbon atoms
("C.sub.2-4 alkenylene"). In some embodiments, an alkenylene group
can have 2 carbon atoms, i.e., ethenediyl. The one or more
carbon-carbon double bonds can be internal (such as in
1,4-but-2-enediyl) or terminal (such as in 1,4-but-1-enediyl).
Examples of C.sub.2-4 alkenylene groups include ethenediyl,
1,2-propenediyl, 1,3-propenediyl, 1,4-but-1-enediyl,
1,4-but-2-enediyl and the like. Examples of C.sub.2-6 alkenylene
groups include the aforementioned C.sub.2-4 alkenylene groups as
well as 1,5-pent-1-enediyl, 1,4-pent-2-enediyl, 1,6-hex-2-enediyl,
2,5-hex-3-enediyl, 2-methyl-1,4-pent-2-enediyl and the like. In
some embodiments, an alkenylene group is an
.alpha.,.omega.-diradical. Examples of .alpha.,.omega.-diradical
alkenylene groups include ethenediyl, 1,3-propenediyl,
1,4-but-2-enediyl, 1,5-pent-1-enediyl, 1,6-hex-3-enediyl and the
like.
[0044] As used herein, alone or as part of another group,
"alkynylene" refers to a diradical of a straight-chain or branched
hydrocarbon group having from 2 to 6 carbon atoms and one or more
carbon-carbon triple bonds ("C.sub.2-6 alkynylene"). In some
embodiments, an alkynylene group can have from 2 to 4 carbon atoms
("C.sub.2-4 alkynylene"). In some embodiments, an alkynylene group
can have 2 carbon atoms, i.e., ethynediyl. The one or more
carbon-carbon triple bonds can be internal (such as in
1,4-but-2-ynediyl) or terminal (such as in 1,4-but-1-ynediyl).
Examples of C.sub.2-4 alkynylene groups include ethynediyl,
propynediyl, 1,4-but-1-ynediyl, 1,4-but-2-ynediyl and the like.
Examples of C.sub.2-6 alkynylene groups include the aforementioned
C.sub.2-4 alkynylene groups as well as 1,5-pent-1-ynediyl,
1,4-pent-2-ynediyl, 1,6-hex-2-ynediyl, 2,5-hex-3-ynediyl,
3-methyl-1,5-hex-1-ynediyl and the like. In some embodiments, an
alkynylene group is an .alpha.,.omega.-diradical. Examples of
.alpha.,.omega.-diradical alkynylene groups include ethynediyl,
propynediyl, 1,4-but-2-ynediyl, 1,5-pent-1-ynediyl,
1,6-hex-3-ynediyl and the like.
[0045] As used herein, alone or as part of another group,
"perhaloalkyl" refers to an alkyl group having from 1 to 3 carbon
atoms, wherein all of the hydrogen atoms are each independently
replaced with fluoro or chloro. In some embodiments, all of the
hydrogen atoms are each replaced with fluoro. In some embodiments,
all of the hydrogen atoms are each replaced with chloro. Examples
of perhaloalkyl groups include --CF.sub.3, --CF.sub.2CF.sub.3,
--CF.sub.2CF.sub.2CF.sub.3, --CCl.sub.3, --CFCl.sub.2, --CF.sub.2Cl
and the like.
[0046] As used herein, alone or as part of another group, "alkoxy"
or "alkyloxy" refers to an --O-alkyl group having from 1 to 8
carbon atoms ("C.sub.1-8 alkoxy"). In some embodiments, an alkoxy
group can have from 1 to 6 carbon atoms ("C.sub.1-6 alkoxy"). In
some embodiments, an alkoxy group can have from 1 to 4 carbon atoms
("C.sub.1-4 alkoxy"). Examples of C.sub.1-4 alkoxy groups include
methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the
like. Examples of C.sub.1-6 alkoxy groups include the
aforementioned C.sub.1-4 alkoxy groups as well as pentyloxy,
isopentyloxy, neopentyloxy, hexyloxy and the like. Additional
examples of alkoxy groups include heptyloxy, octyloxy and the like.
Unless otherwise specified, each instance of an "optionally
substituted" alkoxy group is independently unsubstituted or
substituted with 1-5 groups as described below.
[0047] As used herein, alone or as part of another group,
"perhaloalkoxy" refers to an alkoxy group having from 1 to 3 carbon
atoms, wherein all of the hydrogen atoms are each independently
replaced with fluoro or chloro. In some embodiments, all of the
hydrogen atoms are each replaced with fluoro. In some embodiments,
all of the hydrogen atoms are each replaced with chloro. Examples
of perhaloalkoxy groups include --OCF.sub.3, --OCF.sub.2CF.sub.3,
--OCF.sub.2CF.sub.2CF.sub.3, --OCCl.sub.3, --OCFCl.sub.2,
--OCF.sub.2Cl and the like.
[0048] As used herein, alone or as part of another group,
"alkylthio" refers to an --S-alkyl group having from 1 to 8 carbon
atoms. In some embodiments, an alkylthio group can have from 1 to 6
carbon atoms. In some embodiments, an alkylthio group can have from
1 to 4 carbon atoms. Examples of C.sub.1-4 alkylthio groups include
methylthio, ethylthio, propylthio, isopropylthio, butylthio,
isobutylthio and the like. Examples of C.sub.1-6 alkylthio groups
include the aforementioned C.sub.1-4 alkylthio groups as well as
pentylthio, isopentylthio, hexylthio and the like. Additional
examples of alkylthio groups include heptylthio, octylthio and the
like. Unless otherwise specified, each instance of an "optionally
substituted" alkylthio group is independently unsubstituted or
substituted with 1-5 groups as described below.
[0049] As used herein, alone or as part of another group,
"carbocyclyl" or "carbocycle" refers to a radical of a non-aromatic
cyclic hydrocarbon group having from 3 to 10 ring carbon atoms
("C.sub.3-10 carbocyclyl"). In some embodiments, a carbocyclyl
group can have from 3 to 8 ring carbon atoms ("C.sub.3-8
carbocyclyl"). In some embodiments, a carbocyclyl group can have
from 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). Examples
of C.sub.3-6 carbocyclyl groups include cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,
cyclohexadienyl and the like. Examples of C.sub.3-8 carbocyclyl
groups include the aforementioned C.sub.3-6 carbocyclyl groups as
well as cycloheptyl, cycloheptadienyl, cycloheptatrienyl,
cyclooctyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl and the
like. Examples of C.sub.3-10 carbocyclyl groups include the
aforementioned C.sub.3-8 carbocyclyl groups as well as
octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and
the like. As the foregoing examples illustrate, in some embodiments
a carbocyclyl group can be monocyclic ("monocyclic carbocyclyl") or
bicyclic (e.g., containing a fused, bridged or spiro ring system),
and can be saturated or can contain one or more carbon-carbon
double or triple bonds. "Carbocyclyl" also refers to a phenyl group
(as defined below) fused to a monocyclic carbocyclyl group.
Examples of such carbocyclyl groups include
1,2,3,4-tetrahydronaphthalene (e.g.,
1,2,3,4-tetrahydronaphthalen-1-yl,
1,2,3,4-tetrahydronaphthalen-5-yl, and the like),
2,3-dihydro-1H-indene (e.g., 2,3-dihydro-1H-inden-1-yl,
2,3-dihydro-1H-inden-4-yl, and the like), indene (e.g.,
1H-inden-1-yl, 1H-inden-7-yl, and the like),
5,6,7,8-tetrahydroquinoline (e.g., 5,6,7,8-tetrahydroquinolin-5-yl,
5,6,7,8-tetrahydroquinolin-2-yl, and the like),
4,5,6,7-tetrahydro-1H-indole (e.g.,
4,5,6,7-tetrahydro-1H-indol-4-yl, 4,5,6,7-tetrahydro-1H-indol-3-yl,
and the like), 4,5,6,7-tetrahydrobenzofuran (e.g.,
4,5,6,7-tetrahydrobenzofuran-7-yl,
4,5,6,7-tetrahydrobenzofuran-2-yl, and the like) and the like.
Unless otherwise specified, each instance of an "optionally
substituted" carbocyclyl or carbocycle group is independently
unsubstituted or substituted with 1-5 groups as described
below.
[0050] In some embodiments, "carbocyclyl" or "carbocycle" can refer
to a monocyclic, saturated carbocyclyl group ("cycloalkyl") having
from 3 to 8 ring carbon atoms ("C.sub.3-8 cycloalkyl"). In some
embodiments, a cycloalkyl group can have from 3 to 6 ring carbon
atoms ("C.sub.3-6 cycloalkyl"). In some embodiments, a cycloalkyl
group can have from 5 to 6 ring carbon atoms ("C.sub.5-6
cycloalkyl"). Examples of C.sub.5-6 cycloalkyl groups include
cyclopentyl and cyclohexyl.
[0051] Examples of C.sub.3-6 cycloalkyl groups include the
aforementioned C.sub.5-6 cycloalkyl groups as well as cyclopropyl
and cyclobutyl. Examples of C.sub.3-8 cycloalkyl groups include the
aforementioned C.sub.3-6 cycloalkyl groups as well as cycloheptyl
and cyclooctyl. Unless otherwise specified, each instance of an
"optionally substituted" cycloalkyl group is independently
unsubstituted or substituted with 1-5 groups as described
below.
[0052] As used herein, alone or as part of another group,
"heterocyclyl" or "heterocycle" refers to a radical of a 3- to
10-membered non-aromatic ring system having ring carbon atoms and 1
to 4 ring heteroatoms, each heteroatom independently selected from
optionally substituted nitrogen, oxygen and sulfur. In some
embodiments, a heterocyclyl group can have from 3 to 7 ring atoms
selected from carbon atoms and 1 to 3 heteroatoms, each heteroatom
independently selected from optionally substituted nitrogen, oxygen
and sulfur. In some embodiments, a heterocyclyl group can have from
5 to 7 ring atoms selected from carbon atoms and 1 or 2
heteroatoms, each heteroatom independently selected from nitrogen,
oxygen and sulfur. In some embodiments, a heterocyclyl group can
have from 5 to 6 ring atoms selected from carbon atoms and 1 to 3
heteroatoms, each heteroatom independently selected from optionally
substituted nitrogen, oxygen and sulfur.
[0053] In heterocyclyl groups that contain one or more optionally
substituted nitrogen atoms, the point of attachment can be a carbon
or the optionally substituted nitrogen atom, as valency permits.
Examples of heterocyclyl groups with 1-2 ring heteroatoms include
oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidinyl,
dihydropyrrolyl, tetrahydrofuranyl, dihydrofuranyl,
dioxolanyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrazolidinyl,
imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,
piperidinyl, tetrahydropyridinyl, dihydropyridinyl, piperazinyl,
tetrahydropyranyl, dioxanyl, morpholinyl, azepanyl, diazepanyl,
diazepinyl, oxepanyl, dioxepanyl, oxazepanyl, oxazepinyl and the
like. Examples of heterocyclyl groups with 1-3 heteroatoms include
the aforementioned heterocyclyl groups as well as triazolidinyl,
oxadiazolidinyl, triazinanyl and the like. Heterocycyl groups can
be monocyclic (as in the aforementioned examples), bicyclic, or
tricyclic. Bicyclic heterocyclyl groups can include one or more
heteroatoms in one or both rings. Examples of such heterocyclyl
groups include tetrahydroindolyl, decahydroquinolinyl,
decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,
decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl,
octahydropyrrolo[3,2-b]pyrrole and the like.
[0054] "Heterocyclyl" or "heterocycle" also refers to a radical of
a 5- to 10-membered fused ring system having ring carbon atoms and
1 to 4 ring heteroatoms, each heteroatom independently selected
from nitrogen, oxygen and sulfur, wherein one ring is aromatic and
the other is non-aromatic. In some embodiments, at least one
heteroatom is present in either the aromatic or non-aromatic ring,
while in other embodiments, at least one heteroatom is present in
both rings. In heterocyclyl groups that contain one or more
optionally substituted nitrogen atoms, the point of attachment can
be a carbon or nitrogen atom, as valency permits. Examples of such
heterocyclyl groups include indolinyl (e.g., indolin-1-yl,
indolin-4-yl, and the like), isoindolinyl (e.g., isoindolin-1-yl,
isoindolin-4-yl, and the like), 4,5,6,7-tetrahydro-1H-indolyl
(e.g., tetrahydro-1H-indol-2-yl, 4,5,6,7-tetrahydro-1H-indol-4-yl,
and the like), dihydrobenzofuranyl (e.g., dihydrobenzofuran-3-yl,
dihydrobenzofuran-5-yl, and the like),
4,5,6,7-tetrahydrobenzofuranyl (e.g.,
4,5,6,7-tetrahydrobenzofuran-2-yl,
4,5,6,7-tetrahydrobenzofuran-5-yl, and the like),
dihydrobenzothienyl (e.g., dihydrobenzothien-2-yl,
dihydrobenzothien-4-yl, and the like),
4,5,6,7-tetrahydrobenzothiophenyl (e.g.,
4,5,6,7-tetra-hydrobenzothiophen-2-yl,
4,5,6,7-tetrahydrobenzothiophen-7-yl, and the like),
1,2,3,4-tetrahydroquinolinyl (e.g.,
1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroquinolin-7-yl,
and the like), chromanyl (e.g., chroman-2-yl, chroman-5-yl, and the
like), chromenyl (chromen-4-yl, chromen-8-yl, and the like),
thiochromanyl (e.g., thiochroman-3-yl, isochroman-7-yl, and the
like), 1H-benzo[e][1,4]diazepinyl (e.g.,
1H-benzo[e][1,4]diazepin-2-yl, 1H-benzo[e][1,4]diazepin-6-yl, and
the like), 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl (e.g.,
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl,
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl, and the like),
4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl (e.g.,
4,5,6,7-tetrahydro-1H-pyrrolo-[2,3-b]pyridin-2-yl,
4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridin-4-yl, and the like),
1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl (e.g.,
1,4,5,7-tetrahydropyrano[3,4-b]pyrrol-2-yl,
1,4,5,7-tetrahydropyrano[3,4-b]pyrrol-4-yl, and the like),
2,3-dihydrofuro[2,3-b]pyridinyl (e.g.,
2,3-dihydrofuro[2,3-b]pyridin-3-yl,
2,3-dihydrofuro[2,3-b]pyridin-5-yl, and the like),
4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl (e.g.,
4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl,
4,5,6,7-tetrahydrofuro[3,2-c]pyridin-5-yl, and the like),
4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl (e.g.,
4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl,
4,5,6,7-tetrahydrothieno[3,2-b]pyridin-7-yl, and the like),
5,6-dihydro-4H-furo[3,2-b]pyrrolyl (e.g.,
5,6-dihydro-4H-furo[3,2-b]pyrrol-6-yl,
5,6-dihydro-4H-furo[3,2-b]pyrrol-2-yl, and the like),
6,7-dihydro-5H-furo[3,2-b]pyranyl (e.g.,
6,7-dihydro-5H-furo[3,2-b]pyran-2-yl,
6,7-dihydro-5H-furo[3,2-b]pyran-6-yl, and the like),
5,7-dihydro-4H-thieno[2,3-c]pyranyl (e.g.,
5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl,
5,7-dihydro-4H-thieno[2,3-c]pyran-4-yl, and the like),
1,2,3,4-tetrahydro-1,6-naphthyridinyl (e.g.,
1,2,3,4-tetrahydro-1,6-naphthyridin-3-yl,
1,2,3,4-tetrahydro-1,6-naphthyridin-8-yl, and the like), and the
like.
[0055] Unless otherwise specified, each instance of an "optionally
substituted" heterocyclyl group is independently unsubstituted or
substituted with 1-5 groups as described below.
[0056] As used herein, alone or as part of another group, "aryl"
refers to a radical of an aromatic monocyclic or bicyclic ring
system having 6 or 10 ring carbon atoms. Examples of such aryl
groups include phenyl, 1-naphthyl and 2-naphthyl. Unless otherwise
specified, each instance of an "optionally substituted" aryl group
is independently unsubstituted or substituted with 1-5 groups as
described below.
[0057] The term "aralkyl" refers to an alkyl group substituted by
an aryl group, wherein the alkyl and aryl portions independently
are optionally substituted as described below.
[0058] As used herein, alone or as part of another group,
"heteroaryl" refers to a radical of a 5- to 10-membered aromatic
ring system having ring carbon atoms and 1 to 4 ring heteroatoms,
each heteroatom independently selected from optionally substituted
nitrogen, oxygen and sulfur. Examples of such heteroaryl groups
include pyrrolyl, furanyl (furyl), thiophenyl (thienyl), pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (pyridyl),
pyridazinyl, pyrimdinyl, pyrazinyl, triazinyl, indolyl,
benzofuranyl, benzothiophenyl (benzothienyl), indazolyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl,
phthalazinyl, naphthyridinyl and the like. As the foregoing
examples illustrate, in some embodiments a heteroaryl group can be
monocyclic ("monocyclic heteroaryl"), and in some embodiments a
heteroaryl group can be bicyclic ("bicyclic heteroaryl"). For
bicyclic heteroaryl groups wherein one ring does not contain a
heteroatom (e.g., indolyl, quinolinyl, and the like) the point of
attachment may be on either ring, i.e., either the ring bearing a
heteroatom (e.g., 2-indolyl) or the ring that does not contain a
heteroatom (e.g., 5-indolyl). Unless otherwise specified, each
instance of an "optionally substituted" heteroaryl group is
independently unsubstituted or substituted with 1-5 groups as
described below.
[0059] The term "heteroaralkyl" refers to an alkyl group
substituted by a heteroaryl group, wherein the alkyl and heteroaryl
portions independently are optionally substituted as described
below.
[0060] As used herein, the term "partially unsaturated" refers to a
ring moiety that includes at least one double or triple bond. The
term "partially unsaturated" is intended to encompass rings having
multiple sites of unsaturation, but is not intended to include aryl
or heteroaryl moieties, as herein defined.
[0061] 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 every position. Combinations
of substituents envisioned by 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.
[0062] Suitable monovalent substituents on a carbon atom of an
"optionally substituted" group are independently 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,
which may be substituted with one or more 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 one or more 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.0-4OC(O)R.sup..smallcircle.;
--OC(O)(CH.sub.2).sub.0-4SR, 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.;
--SC(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 alkylene)O--N(R).sub.2; or --(C.sub.1-4
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, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, C.sub.1-8 heteroalkyl, C.sub.2-8 heteroalkenyl,
C.sub.2-8 heteroalkynyl, --CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or
a 5- or 6-membered saturated, partially unsaturated, or aromatic
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
the atom(s) to which they are bound, form a 3- to 12-membered
saturated, partially unsaturated, or aromatic mono- or bicyclic
ring having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, which may be substituted as defined below.
[0063] Suitable monovalent substituents on R.sup..smallcircle. (or
the ring formed by two independent occurrences of
R.sup..smallcircle. together with the atoms to which they are
bound), are independently halogen,
--(CH.sub.2).sub.0-2R.sup..cndot., --(CH.sub.2).sub.0-2OH,
--(CH.sub.2).sub.0-2OR.sup..cndot.,
--(CH.sub.2).sub.0-2CH(OR.sup..cndot.).sub.2, --CN, --N.sub.3,
--(CH.sub.2).sub.0-2C(O)R.sup..cndot., --(CH.sub.2).sub.0-2C(O)OH,
--(CH.sub.2).sub.0-2C(O)OR.sup..cndot.,
--(CH.sub.2).sub.0-2SR.sup..cndot., --(CH.sub.2).sub.0-2SH,
--(CH.sub.2).sub.0-2NH.sub.2, --(CH.sub.2).sub.0-2NHR.sup..cndot.,
--(CH.sub.2).sub.0-2NR.sup..cndot..sub.2, --NO.sub.2,
--SiR.sup..cndot..sub.3, --OSiR.sup..cndot..sub.3,
--C(O)SR.sup..cndot., --(C.sub.1-4 alkylene)C(O)OR.sup..cndot., or
--SSR.sup..cndot. wherein each R.sup..cndot. is unsubstituted or
substituted with one or more halogens, and is independently
selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, --CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or a 5- or
6-membered saturated, partially unsaturated, or aromatic 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.
[0064] 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 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
each of which may be substituted as defined below; or an
unsubstituted 5- or 6-membered saturated, partially unsaturated, or
aromatic 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
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, each of which may be
substituted as defined below; or an unsubstituted 5- or 6-membered
saturated, partially unsaturated, or aromatic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0065] Suitable substituents on a C.sub.1-6 alkyl, C.sub.2-6
alkenyl, or C.sub.2-6 alkynyl R* group include halogen,
--R.sup..cndot., -(haloR.sup..cndot.), --OH, --OR.sup..cndot.,
--CN, --C(O)OH, --C(O)OR.sup..cndot., --NH.sub.2,
--NHR.sup..cndot., --NR.sup..cndot..sub.2, or --NO.sub.2, wherein
each R.sup..cndot. is unsubstituted or substituted with one or more
halogens, and is independently C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, --CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or a 5-
or 6-membered saturated, partially unsaturated, or aromatic ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
[0066] 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.1-4 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, each of which may be
substituted as defined below; unsubstituted --OPh; or an
unsubstituted 5- or 6-membered saturated, partially unsaturated, or
aromatic 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 the atom(s) to which they are bound form an
unsubstituted 3- to 12-membered saturated, partially unsaturated,
or aromatic mono- or bicyclic ring having 0-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0067] Suitable substituents on a C.sub.1-6 alkyl, C.sub.2-6
alkenyl, or C.sub.2-6 alkynyl R.sup..dagger. group are
independently halogen, --R.sup..cndot., --OH, --OR.sup..cndot.,
--CN, --C(O)OH, --C(O)OR.sup..cndot., --NH.sub.2,
--NHR.sup..cndot., --NR.sup..cndot..sub.2, or --NO.sub.2, wherein
each R.sup..cndot. is unsubstituted or substituted with one or more
halogens, and is independently C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, --CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or a 5-
or 6-membered saturated, partially unsaturated, or aromatic ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
[0068] 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, S. M. 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 used in the art such as ion exchange. Other
pharmaceutically acceptable salts include adipate, alginate,
ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0069] As used herein, the term "prodrug" refers to a derivative of
a parent compound that requires transformation within the body in
order to release the parent compound. In certain cases, a prodrug
has improved physical and/or delivery properties over the parent
compound. Prodrugs are typically designed to enhance
pharmaceutically and/or pharmacokinetically based properties
associated with the parent compound. The advantage of a prodrug can
lie in its physical properties, such as enhanced water solubility
for parenteral administration at physiological pH compared to the
parent compound, or it enhances absorption from the digestive
tract, or it may enhance drug stability for long-term storage. The
compounds of the invention readily undergo dehydration to form
oligomeric anhydrides by dehydration of the boronic acid moiety to
form dimers, trimers, and tetramers, and mixtures thereof. These
oligomeric species hydrolyze under physiological conditions to
reform the boronic acid. As such, the oligomeric anhydrides are
contemplated as a "prodrug" of the compounds described herein, and
may be used in the treatment of disorder and/or conditions a
wherein the inhibition of FAAH provides a therapeutic effect.
[0070] Exemplary prodrugs of the compounds described herein
include, but are not limited to, compounds wherein Z.sup.1 and
Z.sup.2 taken together form a 5- to 8-membered ring having at least
one heteroatom atom selected from optionally substituted nitrogen,
oxygen and sulfur directly attached to boron (B), wherein the ring
is comprised of carbon atoms and optionally one or more additional
heteroatoms independently selected from optionally substituted
nitrogen, oxygen and sulfur.
[0071] Other examples of prodrugs of the compounds described herein
are trifluoroborate prodrugs which hydrolyze to the boronic acid
(i.e., --BF.sub.3 hydrolyzing to --B(OH).sub.2) at acidic pH. Salt
forms of the boronic acid (e.g., Na.sup.+, Li.sup.+, Mg.sup.2+,
Ca.sup.2+, and the like) are also considered prodrugs. Amino acids
can be used to form prodrugs, such as, for example, serine and
cysteine protected boronic acids. 1,2 and 1,3 hydroxy sugars can be
used to form prodrugs, such as, for example, glycerol, erythritol,
threitol, ribitol, arabinitol, xylitol, allitol, altritol,
galactitol, sorbitol, mannitol, and iditol protected boronic acids.
Other sugars which are useful in the formation of prodrugs include,
but are not limited to, maltitol, lactitol, and isomalt; other
monosaccharides which include hexoses (e.g., allose, altrose,
glucose, mannose, gulose, idose, galactose, talose) and pentoses
(e.g., ribose, arabinaose, xylose, lyxose); pentaerythritols and
structural derivatives thereof, such as methylated, ethylated,
acetate, ethoxylate, and propoxylate derivatives; and phenolic
polyols such as 1,2,4 benzenetriol, 5-methyl benzene1,2,3-triol,
2,3,4-trihydroxybenzaldehyde, and 3,4,5-trihydroxybenzamide.
Prodrugs also include NMIDA-derivatives.
[0072] As used herein, the term "tautomer" includes two or more
interconvertable compounds resulting from at least one formal
migration of a hydrogen atom and at least one change in valency
(e.g., a single bond to a double bond, a triple bond to a single
bond, or vice versa). The exact ratio of the tautomers depends on
several factors, including temperature, solvent, and pH.
Tautomerizations (i.e., the reaction providing a tautomeric pair)
may catalyzed by acid or base. Exemplary tautomerizations include
keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine;
and enamine-to-(a different) enamine tautomerizations.
[0073] As used herein, the term "isomers" includes any and all
geometric isomers and stereoisomers. For example, "isomers" include
cis- and trans-isomers, E- and Z- isomers, R- and S-enantiomers,
diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof,
and other mixtures thereof, as falling within the scope of the
invention. For instance, an isomer/enantiomer 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 of the present invention 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, S. H., et al.,
Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon
Compounds (McGraw-Hill, NY, 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).
3. Description of Exemplary Compounds
(i) Z.sup.1 and Z.sup.2
[0074] As defined generally above, in certain embodiments, Z.sup.1
is --OH or --OR.sup.3 and Z.sup.2 is --OH, --OR.sup.4, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered heteroaryl
group.
[0075] In certain embodiments, Z.sup.1 is --OH and Z.sup.2 is
--OH.
[0076] In certain embodiments, Z.sup.1 is --OH and Z.sup.2 is
--OR.sup.4.
[0077] In certain embodiments, Z.sup.1 is --OR.sup.3 and Z.sup.2 is
--OR.sup.4.
[0078] In certain embodiments, Z.sup.1 is --OH or --OR.sup.3, and
Z.sup.2 is optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl or an optionally substituted C.sub.3-10 carbocyclyl.
[0079] In other embodiments, Z.sup.1 is --OH or --OR.sup.3, and
Z.sup.2 is optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, or an optionally substituted 3-10 membered
heterocyclyl.
[0080] In yet other embodiments, Z.sup.1 is --OH or --OR.sup.3, and
Z.sup.2 is an optionally substituted C.sub.6-10 aryl.
[0081] In yet other embodiments, Z.sup.1 is --OH or --OR.sup.3, and
Z.sup.2 is an optionally substituted 5-10 membered heteroaryl.
[0082] Alternatively, in certain embodiments, Z.sup.1 and Z.sup.2
taken together with the boron atom to which they are bound, form a
5- to 8-membered ring having at least one O, S, N or NR.sup.5 atom
directly attached to the boron atom,
[0083] wherein R.sup.5 is hydrogen, --SO.sub.2R.sup.11,
--SOR.sup.11, --C(O)R.sup.11, --CO.sub.2R.sup.11,
--C(O)N(R.sup.11).sub.2, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, optionally substituted
C.sub.2-8 alkynyl, optionally substituted C.sub.1-8 heteroalkyl,
optionally substituted C.sub.2-8 heteroalkenyl, optionally
substituted C.sub.2-8 heteroalkynyl, optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl, and
[0084] each instance of R.sup.11 is, independently, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl.
[0085] In certain embodiments, Z.sup.1 and Z.sup.2 taken together
with the boron atom to which they are bound, form a 5- to
8-membered ring having at least one O, S, N or NR.sup.5 atom
directly attached to the boron atom,
[0086] wherein the 5- to 8-membered ring is optionally substituted
with one or more hydrogen, --SO.sub.2R.sup.11, --SOR.sup.11,
--C(O)R, --CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2,
--C(O)NH(R.sup.11), optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, optionally substituted
C.sub.2-8 alkynyl, optionally substituted C.sub.1-8 heteroalkyl,
optionally substituted C.sub.2-8 heteroalkenyl, optionally
substituted C.sub.2-8 heteroalkynyl, optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl groups, or two groups present
on the ring are joined to form a 5- to 8-membered monocylic or
bicyclic ring optionally containing one or more heteroatoms
selected from O, S, N or NR.sup.5,
[0087] wherein each instance of R.sup.18 is independently,
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl.
[0088] In certain embodiments, the 5- to 8-membered ring is
optionally substituted with with one or more --C(.dbd.O)R.sup.18,
--C(.dbd.O)OR.sup.18, --C(.dbd.O)NH(R.sup.18),
--C(.dbd.O)N(R.sup.18).sub.2 and optionally substituted C.sub.1-8
alkyl groups.
[0089] For example, in certain embodiments, Z.sup.1 and Z.sup.2,
taken together with the boron atom to which they are bound, form a
5-membered ring having at least one O, S, N or NR.sup.5 atom
directly attached to the boron atom. Exemplary 5-membered rings
include, but are not limited to:
##STR00007##
wherein each R.sup.5 is as defined above and herein.
[0090] In other embodiments, Z.sup.1 and Z.sup.2, taken together
with the boron atom to which they are bound, form a 6-membered ring
having at least one O, S, N or NR.sup.5 atom directly attached to
the boron atom. Exemplary 6-membered rings include, but are not
limited to:
##STR00008##
[0091] In yet other embodiments, Z.sup.1 and Z.sup.2 form an
8-membered ring having at least one 0, S, N or NR.sup.5 atom
directly attached to the boron atom. Exemplary 8-membered ring
structures include, but are not limited to:
##STR00009##
wherein each R.sup.5 is as defined above and herein.
[0092] Furthermore, as generally defined above, in certain
embodiments, Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A
taken together form an optionally substituted 5- to 7-membered
ring.
[0093] For example, in certain embodiments, Z.sup.1 is --OH or
--OR.sup.3, and Z.sup.2 and Ring A taken together form an
optionally substituted 6-membered ring. Exemplary ring structures
include, but are not limited to:
##STR00010##
wherein Ring A is as defined above and herein.
(ii) L.sup.1
[0094] As defined generally above, in certain embodiments, L.sup.1
is a covalent bond, an optionally substituted straight or branched
C.sub.1-6 alkylene or an optionally substituted straight or
branched C.sub.2-6 alkenylene moiety.
[0095] In certain embodiments L.sup.1 is a covalent bond.
[0096] In some embodiments, L.sup.1 is an optionally substituted
C.sub.1-6 alkylene moiety. In some embodiments, L.sup.1 is an
optionally substituted C.sub.1-3 alkylene moiety. In other
embodiments, L.sup.1 is an optionally substituted C.sub.1-2
alkylene moiety. In certain embodiments, L.sup.1 is a --CH.sub.2--
group. In other embodiments, L.sup.1 is a --CH.sub.2CH.sub.2--
group. In yet other embodiments, L.sup.1 is a --CH.dbd.CH--
group.
(iii) Ring A
[0097] As defined generally above, Ring A is an optionally
substituted C.sub.3-10 carbocyclyl, optionally substituted 3-10
membered heterocyclyl, optionally substituted C.sub.6-10 aryl, or
optionally substituted 5-10 membered heteroaryl. Ring A is
monocyclic or bicyclic. In certain embodiments, Ring A is aromatic.
In certain embodiments, Ring A is saturated or partially
unsaturated.
[0098] In certain embodiments, Ring A is an optionally substituted
C.sub.6 or C.sub.8 monocyclic aryl group. Such monocyclic ring
systems include, but are not limited to:
##STR00011##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein.
[0099] In certain embodiments, Ring A is an optionally substituted
phenyl ring system of formula:
##STR00012##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein.
[0100] In certain embodiments, Ring A is phenyl and has at least
one fluorine substituent (i.e., n is at least one and R.sup.1 is
F). In certain embodiments, Ring A has at least two fluorine
substituents (i.e., n is at least 2 and each R.sup.1 is F). In
certain embodiments, Ring A has at least three fluorine
substituents (i.e., n is at least 3 and each R.sup.1 is F). In
certain embodiments, at least one R.sup.1 group is fluoro in the
ortho position relative to the boron atom. However, in certain
embodiments, compounds containing fluorine substituents on Ring A
are specifically excluded (i.e., when R.sup.1 is F). In certain
embodiments, compounds containing fluorine substituents ortho to
the boron atom on Ring A are specifically excluded (i.e., when
R.sup.1 is F at the ortho position of Ring A with respect to the
boron atom).
[0101] In certain embodiments, Ring A is an optionally substituted
phenyl ring system of any one of formulae:
##STR00013##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein.
[0102] In other embodiments, Ring A is an optionally substituted
phenyl ring system having an --XR.sup.A group para to the boron
atom, i.e., a phenyl ring of any one of formulae:
##STR00014##
wherein each of X, R.sup.A, and R.sup.1 is as defined above and
herein.
[0103] In yet other embodiments, Ring A is an optionally
substituted phenyl ring system having an --XR.sup.A group meta to
the boron atom, i.e., a phenyl ring of any one of formulae:
##STR00015##
wherein each of X, R.sup.A, and R.sup.1 is as defined above and
herein.
[0104] In yet other embodiments, Ring A is an optionally
substituted phenyl ring system having an --XR.sup.A group ortho to
the boron atom, i.e., a phenyl ring of any one of formulae:
##STR00016##
wherein each of X, R.sup.A, and R.sup.1 is as defined above and
herein.
[0105] In certain embodiments, Ring A is phenyl, X is a covalent
bond and R.sup.A is hydogen, i.e., Ring A is an optionally
substituted phenyl ring system of formula:
##STR00017##
wherein each of R.sup.1 and n is as defined above and herein.
Examples of such ring systems include:
##STR00018##
wherein each R.sup.1 is as defined above and herein.
[0106] In other embodiments, Ring A is an optionally substituted
saturated or partially unsaturated C.sub.3-10 or C.sub.3-8
monocyclic ring system. Such monocyclic ring systems include, but
are not limited to:
##STR00019##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein.
[0107] In certain embodiments, Ring A is an optionally substituted
5-8 membered or 5-6 membered monocyclic heteroaryl group. Such
aromatic monocyclic ring systems include, but are not limited to,
5-membered rings of any of following formulae:
##STR00020##
and 6-membered rings of the formulae:
##STR00021##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein,
[0108] R.sup.14 is hydrogen, --SO.sub.2R.sup.11, --SOR.sup.11,
--C(O)R.sup.1, --CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2,
--C(O)NH(R.sup.1), --C(O)NH.sub.2, optionally substituted C.sub.1-8
alkyl, optionally substituted C.sub.2-8 alkenyl, optionally
substituted C.sub.2-8 alkynyl, optionally substituted C.sub.1-8
heteroalkyl, optionally substituted C.sub.2-8 heteroalkenyl,
optionally substituted C.sub.2-8 heteroalkynyl, optionally
substituted C.sub.3-10 carbocyclyl, optionally substituted 3-10
membered heterocyclyl, optionally substituted C.sub.6 10 aryl, or
optionally substituted 5-10 membered heteroaryl, and
[0109] each instance of R.sup.11 is, independently, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl.
[0110] In certain embodiments, Ring A is an optionally substituted
furanyl group. In certain embodiments, Ring A is a furanyl group of
the formula:
##STR00022##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein.
[0111] In certain embodiments, Ring A is an optionally substituted
thiophenyl group. In certain embodiments, Ring A is a thiophenyl
group of the formula:
##STR00023##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein.
[0112] In certain embodiments, Ring A is an optionally substituted
pyridinyl group. In certain embodiments, Ring A is pyridinyl group
of the formula:
##STR00024##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein.
[0113] In other embodiments, Ring A is an optionally substituted
saturated or partially unsaturated 3-8 membered or 5-8-membered
monocyclic heterocyclyl group. Examples of such saturated or
partially unsaturated monocyclic ring systems include, but are not
limited to:
##STR00025##
[0114] wherein each of X, R.sup.A, R.sup.1, R.sup.14 and n is as
defined above and herein.
[0115] In certain embodiments, Ring A is an optionally substituted
bicyclic aryl group. Such bicyclic ring systems include, but are
not limited to:
##STR00026##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein. For example, in certain embodiments, Ring A is a bicyclic
group of any of formulae:
##STR00027##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein.
[0116] In other embodiments, Ring A is an optionally substituted
bicyclic C.sub.8-10 carbocyclyl group. In some embodiments, both
rings of the bicyclic C.sub.8-10 carbocyclyl group are saturated or
partially saturated. In other embodiments, one ring of the bicyclic
C.sub.8-10 carbocyclyl group is saturated or partially saturated
and the other ring is aromatic. Such bicyclic C.sub.8-10
carbocyclyl ring systems include, but are not limited to:
##STR00028##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein.
[0117] In certain embodiments, Ring A is an optionally substituted
6-10 membered bicyclic heteroaryl group. In certain embodiments,
Ring A is an optionally substituted 9-10 membered bicyclic
heteroaryl group. In certain embodiments, Ring A is an optionally
substituted 9 membered bicyclic heteroaryl group. In certain
embodiments, the optionally substituted 9-membered bicyclic
heteroaryl is a 6,5-fused heteroaryl ring. In certain embodiments,
the optionally substituted 10-membered bicyclic heteroaryl is a
6,6-fused heteroaryl ring.
[0118] For example, in certain embodiments, Ring A is a 6,5-fused
heteroaryl ring of any of formulae:
##STR00029##
wherein each of X, R.sup.A, R.sup.1, R.sup.14 and n is as defined
above and herein.
[0119] In certain embodiments, Ring A is a 6,6-fused heteroaryl
ring of any of formulae:
##STR00030##
wherein each of X, R.sup.A, R.sup.1 and n is as defined above and
herein.
[0120] In other embodiments, Ring A is an optionally substituted
bicyclic 6-10 membered heterocyclyl group. In some embodiments,
both rings of the bicyclic 6-10 membered heterocyclyl group are
saturated or partially saturated. In other embodiments, one ring of
the bicyclic 6-10 membered heterocyclyl group is saturated or
partially saturated and the other ring is aromatic. Such bicyclic
heterocyclyl ring systems include, but are not limited to:
##STR00031##
and wherein each of X, R.sup.A, R.sup.1, R.sup.14 and n is as
defined above and herein.
[0121] It will be appreciated that in any of the above drawings of
bicyclic Ring A having one or more floating substituents (e.g.,
--R.sup.1 and/or --X--R.sup.A) that the floating substituent may be
present on any substitutable carbon atom on either ring of the
fused ring system.
(iv) X
[0122] As is also defined generally above, X is a covalent bond,
--O--, --N.dbd.N--, --C.dbd.N--, --NR.sup.6--, C(NR.sup.6)--,
--S--, --C(O)--, --S(O)--, --S(O).sub.2--, optionally substituted
C.sub.1-6 alkylene, or optionally substituted C.sub.2-6 alkenylene,
wherein one, two or three methylene units of the C.sub.1-6 alkylene
or C.sub.2-6 alkenylene are optionally and independently replaced
with one or more --O--, --N.dbd.N--, --C.dbd.N--, --NR.sup.6--,
--C(NR')--, --S--, --C(O)--, --S(O)--, or --S(O).sub.2--.
[0123] In certain embodiments, X is a covalent bond.
[0124] In certain embodiments, X is --O--.
[0125] In certain embodiments, X is --NR.sup.6--.
[0126] In certain embodiments, X is --S--.
[0127] In certain embodiments, X is an optionally substituted
C.sub.1-6 alkylene. In other embodiments, X is an optionally
substituted C.sub.1-4 alkylene. In yet other embodiments, X is an
optionally substituted C.sub.1-2 alkylene. In certain embodiments,
X is --(CH.sub.2).sub.4--. In certain embodiments, X is
--(CH.sub.2).sub.3--. In certain embodiments, X is
--(CH.sub.2).sub.2--. In certain embodiments, X is
--CH.sub.2--.
[0128] In certain embodiments, X is an optionally substituted
C.sub.2-6 alkenylene. In other embodiments, X is an optionally
substituted C.sub.2-4 alkenylene. In yet other embodiments, X is an
optionally substituted C.sub.2 alkenylene. In certain embodiments,
X is --CH.dbd.CH--.
[0129] In certain embodiments, X is an optionally substituted
C.sub.1-6 alkylene, wherein one methylene unit is replaced with
--O--. In certain embodiments, X is --CH.sub.2O-- or
--OCH.sub.2--.
[0130] In certain embodiments, X is an optionally substituted
C.sub.1-6 alkylene, wherein one methylene unit is replaced with
--NR.sup.6--. In certain embodiments, X is --CH.sub.2NR.sup.6-- or
--NR.sup.6CH.sub.2--.
[0131] In certain embodiments, X is a covalent bond, C(O), --O--,
--CH.sub.2O--, --OCH.sub.2--, --NR.sup.6--, or
--CH.sub.2NR.sup.6--, or --NR.sup.6CH.sub.2--.
[0132] In certain embodiments, X is a covalent bond, --O--, or
optionally substituted C.sub.1-6 alkylene.
(v) R.sup.A
[0133] As is defined generally above, R.sup.A is hydrogen, halogen,
--OR.sup.7, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.7,
--SOR.sup.7, --C(O)R.sup.7, --CO.sub.2R.sup.7,
--C(O)N(R.sup.7).sub.2, --CHO, --N.sub.3, --N.sub.2R.sup.7,
--N(R.sup.7).sub.2, or Ring B having formula:
##STR00032##
[0134] wherein Ring B is optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl, and R.sup.2, R.sup.7 and m are as defined
herein.
[0135] In certain embodiments, R.sup.A is hydrogen.
[0136] In certain embodiments, R.sup.A is Ring B, as defined above
and herein.
(vi) Ring B
[0137] As described herein, Ring B is optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl. Ring B is monocyclic or
bicyclic. In certain embodiments, Ring B is aromatic.
[0138] In some embodiments, Ring B is an optionally substituted
C.sub.6 or C.sub.8 monocyclic aryl group. Such monocyclic aryl ring
systems include, but are not limited to:
##STR00033##
wherein each of R.sup.2 and m is as defined above and herein.
[0139] In certain embodiments, Ring B is an optionally substituted
phenyl ring of formula:
##STR00034##
wherein each of R.sup.2 and m is as defined above and herein.
[0140] In certain embodiments, Ring B is an optionally substituted
phenyl ring of any one of formulae:
##STR00035##
wherein R.sup.2 is as defined above and herein.
[0141] In certain embodiments, both of Ring B and Ring A are
phenyl.
[0142] In other embodiments, Ring B is an optionally substituted
saturated or partially unsaturated C.sub.3-10 or C.sub.5-8
monocyclic carbocyclyl group. Such monocyclic ring systems include,
but are not limited to:
##STR00036##
wherein each of R.sup.2 and m is as defined above and herein.
[0143] In certain embodiments, Ring B is an optionally substituted
5-8 membered or 5-6 membered monocyclic heteroaryl group.
[0144] In certain embodiments, Ring B is an optionally substituted
5-membered heteroaryl group. Such monocyclic heteroaryl systems
include, but are not limited to, any of formulae:
##STR00037##
wherein each of R.sup.2 and m is as defined above and herein,
[0145] R.sup.16 is hydrogen, --SO.sub.2R.sup.11, --SOR.sup.1,
--C(O)R.sup.11, --CO.sub.2R.sup.11, --C(O)NH.sub.2,
--C(O)NH(R.sup.11), --C(O)N(R.sup.11).sub.2, optionally substituted
C.sub.1-8 alkyl, optionally substituted C.sub.2-8 alkenyl,
optionally substituted C.sub.2-8 alkynyl, optionally substituted
C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl, and
[0146] each instance of R.sup.11 is, independently, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl.
[0147] In certain embodiments, Ring B is an optionally substituted
6-membered monocyclic heteroaryl group. Such monocyclic heteroaryl
systems include, but are not limited to, 6-membered rings of any of
formulae:
##STR00038##
wherein each of R.sup.2 and m is as defined above and herein.
[0148] In other embodiments, Ring B is an optionally substituted
saturated or partially unsaturated monocyclic 3 to 10 membered
heterocyclyl group. Such saturated or partially unsaturated
monocyclic heterocyclyl systems include, but are not limited
to:
##STR00039##
wherein each of R.sup.2, R.sup.16 and m is as defined above and
herein.
[0149] In certain embodiments, Ring B is an optionally substituted
C.sub.10 bicyclic aryl group (i.e., naphthyl) having the
formula:
##STR00040##
wherein each of R.sup.2 and m is as defined above and herein.
[0150] In other embodiments, Ring B is a bicyclic C.sub.8-10
carbocyclyl group. In some embodiments, both rings of the bicyclic
C.sub.8-10 carbocyclyl group are saturated or partially saturated.
In other embodiments, one ring of the bicyclic C.sub.8-10
carbocyclyl group is saturated or partially saturated and the other
ring is aromatic. Such bicyclic ring systems include, but are not
limited to:
##STR00041##
wherein each of R.sup.2 and m is as defined above and above and
described herein.
[0151] In certain embodiments, Ring B is an optionally substituted
6-10 membered bicyclic heteroaryl group. In certain embodiments,
Ring B is an optionally substituted 9-10 membered bicyclic
heteroaryl group. In certain embodiments, an optionally substituted
9-membered bicyclic heteroaryl group is a 6,5-fused bicyclic
heteroaryl group. In certain embodiments, an optionally substituted
10-membered bicyclic heteroaryl group is a 6,6-fused bicyclic
heteroaryl group.
[0152] Exemplary heteroaryl systems include, but are not limited
to, 6,5-fused ring systems of any of formulae:
##STR00042##
and 6,6-fused ring systems of any of formulae:
##STR00043##
wherein each of R.sup.2, R.sup.16 and m is as defined above and
herein.
[0153] In certain embodiments, Ring B is an optionally substituted
saturated or partially saturated 9-10 membered bicyclic
heterocyclyl group. Such bicyclic heterocyclyl systems include, but
are not limited to:
##STR00044##
wherein each of R.sup.2, R.sup.16 and m is as defined above and
herein.
[0154] It will be appreciated that in any of the above drawings of
bicyclic Ring B having one or more floating substituents (e.g.,
--R.sup.2) that the floating substituent may be present on any
substitutable carbon atom on either ring of the fused bicyclic ring
system.
(vii) R.sup.1 and n
[0155] As defined generally above, each instance of R.sup.1 is,
independently, halogen, --OR.sup.8, --CF.sub.3, --CN, --NO.sub.2,
--SO.sub.2R.sup.8, --SOR.sup.8, --C(O)R.sup.8, --CO.sub.2R.sup.8,
--C(O)N(R.sup.8).sub.2, --N.sub.3, --N.sub.2R.sup.8,
--N(R.sup.8).sub.2, --B(OH.sub.2), optionally substituted C.sub.1-8
alkyl, optionally substituted C.sub.2-8 alkenyl, optionally
substituted C.sub.2-8 alkynyl, optionally substituted C.sub.1-8
heteroalkyl, optionally substituted C.sub.2-8 heteroalkenyl,
optionally substituted C.sub.2-8 heteroalkynyl, optionally
substituted C.sub.3-10 carbocyclyl, optionally substituted 3-10
membered heterocyclyl, optionally substituted C.sub.6-10 aryl, or
an optionally substituted 5-10 membered heteroaryl group; and
wherein R.sup.8 is as described herein.
[0156] In certain embodiments, each instance of R.sup.1 is,
independently, halogen, --OR.sup.8, --CF.sub.3, --CN, --NO.sub.2,
--SO.sub.2R.sup.8, --SOR.sup.8, --C(O)R.sup.8, --CO.sub.2R.sup.8,
--C(O)N(R.sup.8).sub.2, --N.sub.3, --N.sub.2R.sup.8, or
--N(R).sub.2, optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, or optionally substituted C.sub.2-8
alkynyl.
[0157] In certain embodiments, each instance of R.sup.1 is,
independently, halogen, --OR.sup.8 or optionally substituted
C.sub.1-8 alkyl. In some embodiments, R.sup.1 is halogen. In other
embodiments, R.sup.1 is --F or --Cl. In certain embodiments,
R.sup.1 is --Cl. In other embodiments, R.sup.1 is --F.
[0158] In certain embodiments, at least one R.sup.1 is ortho to the
boron atom. In other embodiments, at least one R.sup.1 is meta to
the boron atom. In yet other embodiments, at least one R.sup.1 is
para to the boron atom.
[0159] In certain embodiments, at least one R.sup.1 is alpha to the
boron atom. In other embodiments, at least one R.sup.1 is beta to
the boron atom. In yet other embodiments, at least one R.sup.1 is
gamma to the boron atom.
[0160] In certain embodiments, n is 0, 1, 2 or 3. In some
embodiments, n is 0, 1 or 2. In other embodiments, n is 1 or 2. In
yet other embodiments, n is 3. In yet other embodiments, n is 2. In
still yet other embodiments, n is 1. In still yet other
embodiments, n is 0.
[0161] It is understood that when n is 0 then Ring A is not
substituted with an R.sup.1 group, but instead is substituted with
hydrogen. It is also understood that when n is 0, X is a covalent
bond and R.sup.A is hydrogen, then Ring A is unsubstituted.
(viii) R.sup.2 and m
[0162] As defined generally above, each instance of R.sup.2 is,
independently, halogen, --OR.sup.9, --CF.sub.3, --CN, --NO.sub.2,
--SO.sub.2R.sup.9, --SOR.sup.9, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)N(R.sup.9).sub.2, --N.sub.3, --N.sub.2R.sup.9,
--N(R.sup.9).sub.2, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, optionally substituted
C.sub.2-8 alkynyl, optionally substituted C.sub.1-8 heteroalkyl,
optionally substituted C.sub.2-8 heteroalkenyl, optionally
substituted C.sub.2-8 heteroalkynyl, optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl group; and wherein R.sup.9 is
as described herein.
[0163] In certain embodiments, each instance of R.sup.2 is,
independently, halogen, --OR.sup.9, --CF.sub.3, --CN, --NO.sub.2,
--SO.sub.2R.sup.9, --SOR.sup.9, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)N(R.sup.9).sub.2, --N.sub.3, --N.sub.2R.sup.9,
--N(R.sup.9).sub.2, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, or optionally substituted
C.sub.2-8 alkynyl.
[0164] In certain embodiments, each instance of R.sup.2 is,
independently, halogen or --OR.sup.9. In some embodiments, R.sup.2
is halogen. In other embodiments, R.sup.2 is --F or --Cl. In
certain embodiments, R.sup.2 is --Cl. In yet other embodiments,
R.sup.2 is --F.
[0165] In certain embodiments, at least one R.sup.2 is ortho to X.
In other embodiments, at least one R.sup.2 is meta to X. In yet
other embodiments, at least one R.sup.2 is para to X.
[0166] In certain embodiments, at least one R.sup.2 is alpha to X.
In other embodiments, at least one R.sup.2 is beta to X. In yet
other embodiments, at least one R.sup.2 is gamma to X.
[0167] In certain embodiments, m is 0, 1, 2, 3, 4 or 5. In some
embodiments, m is 0, 1, 2 or 3.
[0168] In some embodiments, m is 0, 1 or 2. In other embodiments, m
is 1 or 2. In yet other embodiments, m is 3. In still other
embodiments, m is 2. In still yet other embodiments, m is 1. In
still other embodiments, m is 0.
[0169] It is understood that when m is 0, then Ring B is not
substituted with an R.sup.2 group, but instead is substituted with
hydrogen.
(ix) Compounds of Formula (II) wherein Ring A is Bicyclic
[0170] In certain embodiments, the present invention provides
compounds of formula (I):
##STR00045##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, L.sup.1, X, R.sup.1, R.sup.A, and n are as
defined above and herein, and wherein Ring A is an optionally
substituted C.sub.10 bicyclic aryl or an optionally substituted
9-10 membered bicyclic heteroaryl.
[0171] In certain embodiments, Ring A is an optionally substituted
C.sub.10 bicyclic aryl group. In certain embodiments, Ring A is an
optionally substituted naphthyl group.
[0172] In certain embodiments, Ring A is an optionally substituted
9-10 membered bicyclic heteroaryl group.
[0173] In certain embodiments, Ring A is an optionally substituted
10-membered bicyclic heteroaryl group. In certain embodiments, Ring
A is a 6,6-fused bicyclic heteroaryl. In certain embodiments, Ring
A is a 6,6-fused bicyclic heteroaryl containing 1 to 2 N atoms. In
certain embodiments, Ring A is a 6,6-fused bicyclic heteroaryl
containing 1 N atom. In certain embodiments, Ring A is a 6,6-fused
bicyclic heteroaryl containing 2 N atoms.
[0174] In certain embodiments, Ring A is an optionally substituted
isoquinoline group. In certain embodiments, Ring A is an optionally
substituted quinolinyl group. In certain embodiments, Ring A is an
optionally substituted quinoxalinyl group.
[0175] In certain embodiments, the present invention provides
6,6-fused bicyclic compounds of formula (III):
##STR00046##
or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0176] (i) Z.sup.1 is --OH or --OR.sup.3 and Z.sup.2 is --OH,
--OR.sup.4, an optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0177] (ii) Z.sup.1 and Z.sup.2 taken together form a 5- to
8-membered ring having at least one O, S, N or NR.sup.5 directly
bonded to the boron atom; or
[0178] (iii) Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A
taken together form an optionally substituted 5- to 7-membered
ring;
[0179] W.sup.1 and W.sup.2 are independently selected from
CR.sup.12, C and N;
[0180] X is a covalent bond, --O--, --N.dbd.N--, --C.dbd.N--,
--NR.sup.6--, --C(NR.sup.6)--, --S--, --C(O)--, --S(O)--,
--S(O).sub.2--, or optionally substituted C.sub.1-6 alkylene,
wherein one, two or three methylene units of the C.sub.1-6 alkylene
are optionally and independently replaced with one or more groups
selected from --O--, --N.dbd.N--, --C.dbd.N--, --NR.sup.6--,
--C(NR.sup.6)--, --S--, --C(O)--, --S(O)--, and --S(O).sub.2--;
[0181] R.sup.A is hydrogen, halogen, --OR.sup.7, --CF.sub.3, --CN,
--NO.sub.2, --SO.sub.2R.sup.7, --SOR.sup.7, --C(O)R.sup.7,
--CO.sub.2R.sup.7, --C(O)N(R.sup.7).sub.2, --N.sub.3,
--N.sub.2R.sup.7, --N(R.sup.7).sub.2, or Ring B having formula:
##STR00047##
[0182] wherein Ring B is optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0183] each instance of R.sup.1 is, independently, halogen,
--OR.sup.8, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.8,
--SOR.sup.8, --C(O)R.sup.8, --CO.sub.2R.sup.8,
--C(O)N(R.sup.8).sub.2, --N.sub.3, --N.sub.2R.sup.8, --N(R).sub.2,
--B(OH.sub.2), optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.2-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0184] each instance of R.sup.2 is, independently, halogen,
--OR.sup.9, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.9,
--SOR.sup.9, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)N(R.sup.9).sub.2, --N.sub.3, --N.sub.2R.sup.9,
--N(R.sup.9).sub.2, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, optionally substituted
C.sub.2-8 alkynyl, optionally substituted C.sub.1-8 heteroalkyl,
optionally substituted C.sub.2-8 heteroalkenyl, optionally
substituted C.sub.2-8 heteroalkynyl, optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl;
[0185] each instance of R.sup.3 and R.sup.4 is, independently,
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0186] each instance of R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, and R.sup.10 is, independently, hydrogen, --C(O)R,
--SO.sub.2R.sup.11, --SOR.sup.11, --C(O)R.sup.11,
--CO.sub.2R.sup.11, --C(O)N(R.sup.1).sub.2, --C(O)NH(R.sup.11),
--C(O)NH.sub.2, optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0187] each instance of R.sup.11 is, independently, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl;
[0188] each instance of R.sup.12 is, independently, hydrogen,
halogen, --CF.sub.3, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, or optionally substituted
C.sub.2-8 alkynyl;
[0189] n is, independently, 0, 1, 2 or 3 and m is 0, 1, 2, 3, 4 or
5.
[0190] In certain embodiments, the present invention provides
6,6-fused bicyclic compounds of the formula (III-a), (III-b),
(III-c), (III-d) or (III-e):
##STR00048##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
W.sup.1, W.sup.2, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.A, and n are
as defined above and herein.
[0191] In certain embodiments, n is 0. In certain embodiments, n is
1 or 2. In certain embodiments, n is 1.
[0192] In certain embodiments, R.sup.1 is optionally substituted
C.sub.1-8 alkyl. In certain embodiments, R.sup.1 is --CH.sub.3.
[0193] In certain embodiments, X is a covalent bond, --(C.dbd.O)--,
--O--, --CH.sub.2O--, --OCH.sub.2--, --NH--, --N(R.sup.9)--,
--N(R.sup.9)CH.sub.2--, --CH.sub.2N(R.sup.9)-- or an optionally
substituted C.sub.1-6 alkylene. In certain embodiments, X is is a
covalent bond, --(C.dbd.O)--, --O--, --CH.sub.2O--, --OCH.sub.2--,
--NH--, --N(R.sup.9)--, --N(R.sup.9)CH.sub.2--,
--CH.sub.2N(R.sup.9)--, --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, or
--(CH.sub.2).sub.5--.
[0194] In certain embodiments, R.sup.A is hydrogen.
[0195] In certain embodiments, R.sup.A is Ring B. In certain
embodiments, Ring B is an optionally substituted aryl, optionally
substituted pyridinyl, optionally substituted pyrazinyl, optionally
substituted pyrimidinyl, optionally substituted
1,2,3,4-tetrahydroquinolinyl, optionally substituted cyclopentyl or
optionally substituted cyclohexyl.
[0196] In certain embodiments, m is 0. In certain embodiments, m is
1 or 2. In certain embodiments, m is 1.
[0197] In certain embodiments, R.sup.2 is halogen, --OR.sup.9,
--CN, --NO.sub.2, or --N(R.sup.9).sub.2. In certain embodiments,
R.sup.2 is --Cl, --CN, --NO.sub.2, --OH, --OCH.sub.3,
--OC.sub.4H.sub.9, or --N(CH.sub.3).sub.2.
[0198] In certain embodiments, at least one of W.sup.1 and W.sup.2
is N.
[0199] In certain embodiments, W.sup.1 is N and W.sup.2 is C or
CR.sup.12. In certain embodiments, W.sup.2 is N and W.sup.1 is C or
CR.sup.12. In some embodiments, W.sup.1 is N and W.sup.2 is CH. In
some embodiments, W.sup.2 is N and W.sup.1 is CH. In certain
embodiments, wherein W.sup.1 is N and W.sup.2 is C, CH or
CR.sup.12, or wherein W.sup.2 is N and W.sup.1 is C, CH or
CR.sup.12, the following compounds are specifically excluded:
[0200] (i) compounds wherein n is 0, X is a covalent bond and
R.sup.A is hydrogen;
[0201] (ii) compounds wherein n is 1, R.sup.1 is fluoro, X is
--CH.sub.2--, and R.sup.A is hydrogen; and/or
[0202] (iii) compounds wherein n is 1, R.sup.1 is chloro, X is a
covalent bond, and R.sup.A is hydrogen.
[0203] In certain embodiments, both W.sup.1 and W.sup.2 are N. In
certain embodiments, wherein both W.sup.1 and W.sup.2 are N, the
following compounds are specifically excluded:
[0204] (i) compounds wherein n is 0, X is a covalent bond and
R.sup.A is hydrogen.
[0205] In certain embodiments, both W.sup.1 and W.sup.2 are,
independently, C or CR.sup.12. In certain embodiments, both W.sup.1
and W.sup.2 are CH. In certain embodiments, wherein both W.sup.1
and W.sup.2 are C, CH or CR.sup.12, the following compounds are
specifically excluded: [0206] (i) compounds wherein n is 0, X is a
covalent bond and R.sup.A is hydrogen, --OH, --OCH.sub.3,
--OCH.sub.2CH.sub.3 or --OCH.sub.2C.sub.6H.sub.5; [0207] (ii)
compounds wherein n is 1, R.sup.1 is --CHO or
--CH.sub.2N(R.sup.9)C.sub.6H.sub.5, X is a covalent bond, and
R.sup.A is hydrogen; [0208] (iii) compounds wherein n is 0, X is a
covalent bond, and R.sup.A is an optionally substituted phenyl or
napthyl ring (Ring B); and/or [0209] (iv) compounds wherein n is 0
and X is --C.dbd.N--NH--(C.dbd.S)-- or
--C.dbd.N--NH--(C.dbd.O)--.
[0210] In certain embodiments, the following compounds are
specifically excluded:
##STR00049## ##STR00050##
or a pharmaceutically acceptable salt or prodrug thereof.
[0211] In certain embodiments, W.sup.1 is C or CH and W.sup.2 is N,
providing 6,6-fused bicyclic compounds of the formula (III-e):
##STR00051##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, L.sup.1, X, R.sup.1, R.sup.A, and n are as
defined above and herein. Examples of such compounds include
compounds of any of formulae (III-e1), (III-e2), (III-e3), (III-e4)
and (III-e5):
##STR00052##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.A, and n are as defined above
and herein.
[0212] In certain embodiments, both W.sup.1 and W.sup.2 are N,
providing 6,6-fused bicyclic compounds of the formula (III-f):
##STR00053##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, L.sup.1, X, R.sup.1, R.sup.A, and n are as
defined above and herein. Examples of such compounds include
compounds of any of formulae (III-f1), (III-f2), (III-f3) or
(III-f4):
##STR00054##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, L.sup.1, X, R.sup.1, R.sup.A, and n are as
defined above and herein.
[0213] In certain embodiments, both W.sup.1 and W.sup.2 are C or
CH, providing 6,6-fused bicyclic compounds of formula (III-g):
##STR00055##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, L.sup.1, X, R.sup.1, R.sup.A, and n are as
defined above and herein. Examples of such compounds include
compounds of any of formulae (III-g1), (III-g2), (III-g3),
(III-g4), (III-g5), (III-g6) or (III-g7):
##STR00056##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.A, and n are as defined above
and herein.
[0214] Exemplary 6,6-fused bicyclic compounds encompassed by
formulae (I), (III), and subgenera thereof, are provided below in
Tables 1-3.
TABLE-US-00002 TABLE 1 ##STR00057## 319 ##STR00058## 187
##STR00059## 190 ##STR00060## 189 ##STR00061## 192 ##STR00062## 191
##STR00063## 194 ##STR00064## 193 ##STR00065## 196 ##STR00066## 195
##STR00067## 198 ##STR00068## 197 ##STR00069## 200 ##STR00070## 199
##STR00071## 202 ##STR00072## 201 ##STR00073## 204 ##STR00074## 203
##STR00075## 206 ##STR00076## 205 ##STR00077## 210 ##STR00078## 207
##STR00079## 212 ##STR00080## 209 ##STR00081## 221 ##STR00082## 213
##STR00083## 215 ##STR00084## 188
TABLE-US-00003 TABLE 2 ##STR00085## 151 ##STR00086## 185
##STR00087## 186 ##STR00088## 208 ##STR00089## 216
TABLE-US-00004 TABLE 3 ##STR00090## 211
[0215] In certain embodiments, Ring A is an optionally substituted
9-membered bicyclic heteroaryl group. In certain embodiments, Ring
A is a 6,5-fused bicyclic heteroaryl group. In certain embodiments,
Ring A is a 6,5-fused bicyclic heteroaryl group containing 2-3
heteroatoms selected from O, S, N and NR.sup.14, wherein:
[0216] R.sup.14 is, independently, hydrogen, --SO.sub.2R.sup.11,
--SOR.sup.1, --C(O)R.sup.11, --CO.sub.2R.sup.11,
--C(O)N(R.sup.11).sub.2, C(O)NH(R.sup.11), --C(O)NH.sub.2,
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl; and
[0217] each instance of R.sup.11 is, independently, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl.
[0218] In certain embodiments, Ring A is a 6,5-fused bicyclic
heteroaryl group containing 2 heteroatoms selected from O, S, N and
NR.sup.14. In certain embodiments, Ring A is a 6,5-fused bicyclic
heteroaryl group containing 3 heteroatoms selected from O, S, N and
NR.sup.14.
[0219] In certain embodiments, Ring A is an optionally substituted
benzoxazolyl, optionally substituted benzthiazolyl, optionally
substituted benzimidazolyl, an optionally substituted indazolyl or
an optionally substituted imidazopyridinyl group.
[0220] In certain embodiments, the present invention provides
compounds of formula (IV):
##STR00091##
or pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0221] (i) Z.sup.1 is --OH or --OR.sup.3 and Z.sup.2 is --OH,
--OR.sup.4, an optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0222] (ii) Z.sup.1 and Z.sup.2 taken together form a 5- to
8-membered ring having at least one O, S, N or NR.sup.5 atom
directly bonded to the boron atom; or
[0223] (iii) Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A
taken together form an optionally substituted 5- to 7-membered
ring;
[0224] each of Y.sup.3, Y.sup.4 and Y.sup.5 is independently
selected from C, CR.sup.13, N, NR.sup.14, O and S, with the proviso
that at least one of Y.sup.3, Y.sup.4 or Y.sup.5 is a heteroatom
selected from N, NR.sup.14, O or S;
[0225] Y.sup.6 is C or N;
[0226] X is a covalent bond, --O--, --N.dbd.N--, --C.dbd.N--,
--NR.sup.6--, --C(NR.sup.6)--, --S--, --C(O)--, --S(O)--,
--S(O).sub.2--, or optionally substituted C.sub.1-6 alkylene,
wherein one, two or three methylene units of the C.sub.1-6 alkylene
are optionally and independently replaced with one or more groups
selected from --O--, --N.dbd.N--, --C.dbd.N--, --NR.sup.6--,
--C(NR.sup.6)--, --S--, --C(O)--, --S(O)--, and --S(O).sub.2--;
[0227] R.sup.A is hydrogen, halogen, --OR.sup.7, --CF.sub.3, --CN,
--NO.sub.2, --SO.sub.2R.sup.7, --SOR.sup.7, --C(O)R.sup.7,
--CO.sub.2R.sup.7, --C(O)N(R.sup.7).sub.2, --N.sub.3,
--N.sub.2R.sup.7, --N(R.sup.7).sub.2, or Ring B having formula:
##STR00092##
[0228] wherein Ring B is optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0229] each instance of R.sup.1 is, independently, halogen,
--OR.sup.8, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.8,
--SOR.sup.8, --C(O)R.sup.8, --CO.sub.2R.sup.8,
--C(O)N(R.sup.8).sub.2, --N.sub.3, --N.sub.2R.sup.8,
--N(R.sup.8).sub.2, --B(OH.sub.2), optionally substituted C.sub.1-8
alkyl, optionally substituted C.sub.2-8 alkenyl, optionally
substituted C.sub.2-8 alkynyl, optionally substituted C.sub.1-8
heteroalkyl, optionally substituted C.sub.2-8 heteroalkenyl,
optionally substituted C.sub.2-8 heteroalkynyl, optionally
substituted C.sub.3-10 carbocyclyl, optionally substituted 3-10
membered heterocyclyl, optionally substituted C.sub.6-10 aryl, or
optionally substituted 5-10 membered heteroaryl;
[0230] each instance of R.sup.2 is, independently, halogen,
--OR.sup.9, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.9,
--SOR.sup.9, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)N(R.sup.9).sub.2, --N.sub.3, --N.sub.2R.sup.9,
--N(R.sup.9).sub.2, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, optionally substituted
C.sub.2-8 alkynyl, optionally substituted C.sub.1-8 heteroalkyl,
optionally substituted C.sub.2-8 heteroalkenyl, optionally
substituted C.sub.2-8 heteroalkynyl, optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl;
[0231] each instance of R.sup.3 and R.sup.4 is, independently,
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl; each instance of R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.14 is,
independently, hydrogen, --SO.sub.2R.sup.11, --SOR.sup.11,
--C(O)R.sup.11, --CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2,
--C(O)NH(R.sup.11), --C(O)NH.sub.2, optionally substituted
C.sub.1-8 alkyl, optionally substituted C.sub.2-8 alkenyl,
optionally substituted C.sub.2-8 alkynyl, optionally substituted
C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl;
[0232] each instance of R.sup.11 is, independently, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl; each instance of R.sup.13 is, independently, hydrogen,
halogen, --CF.sub.3, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, or optionally substituted
C.sub.2-8 alkynyl;
[0233] n is 0, 1, 2 or 3; and
[0234] m is 0, 1, 2, 3, 4 or 5.
[0235] In certain embodiments, the present invention provides
compounds of any of formulae (IV-a), (IV-b), (IV-c), (IV-d) or
(IV-e):
##STR00093##
or pharmaceutically acceptable salts or prodrugs thereof, wherein
Y.sup.3, Y.sup.4, Y.sup.5, Y.sup.6, Z.sup.1, Z.sup.2, R.sup.1, X, n
and R.sup.A are as defined above and herein.
[0236] In certain embodiments, n is 0. In certain embodiments, n is
1 or 2. In certain embodiments, n is 1.
[0237] In certain embodiments, R.sup.1 is halogen. In certain
embodiments, R.sup.1 is --F. In certain embodiments, R.sup.1 is
--Br.
[0238] In certain embodiments, X is a covalent bond or an
optionally substituted C.sub.1-6 alkylene.
[0239] In certain embodiments, X is a covalent bond. In certain
embodiments, X is --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5-- or
--(CH.sub.2).sub.5(C.dbd.O)--.
[0240] In certain embodiments, R.sup.A is hydrogen. In certain
embodiments, R.sup.A is --CF.sub.3.
[0241] In certain embodiments, R.sup.A is Ring B. In certain
embodiments, Ring B is an optionally substituted phenyl, optionally
substituted pyrrolidinone or an optionally substituted
piperidinyl.
[0242] In certain embodiments, m is 0. In certain embodiments, m is
1 or 2. In certain embodiments, m is 1.
[0243] In certain embodiments, R.sup.2 is optionally substituted
C.sub.1-8 alkyl, optionally substituted C.sub.6-10 aryl,
--SO.sub.2R.sup.9, --SOR.sup.9, --C(O)R.sup.9, or
--CO.sub.2R.sup.9. In certain embodiments, R.sup.2 is
--C.sub.3H.sub.7, --CH.sub.2CH(CH.sub.3).sub.2, --CO.sub.2tBu,
--C(O)(CH.sub.2).sub.2C.sub.6H.sub.5, --C.sub.6H.sub.5,
--CH.sub.2C.sub.6H.sub.5, or --SO.sub.2C.sub.6H.sub.5.
[0244] In certain embodiments, two of Y.sup.3, Y.sup.4 and Y.sup.5
are, independently, heteroatoms selected from N, NR.sup.14, O or S,
and Y.sup.6 is C.
[0245] In certain embodiments, one of Y.sup.3, Y.sup.4, Y.sup.5 is
a heteroatom selected from N, NR.sup.14, O or S, and Y.sup.6 is C
or N.
[0246] In certain embodiments, one of Y.sup.3, Y.sup.4, Y.sup.5 is
a heteroatom selected from N, NR.sup.14, O or S, and Y.sup.6 is
N.
[0247] In certain embodiments, Y.sup.3 is O or S. In certain
embodiments, Y.sup.3 is O. In certain embodiments, Y.sup.3 is
S.
[0248] In certain embodiments, Y.sup.6 is C.
[0249] In certain embodiments, Y.sup.3 is O or S, Y.sup.4 is C,
Y.sup.5 is N and Y.sup.6 is C. In certain embodiments, wherein
Y.sup.3 is O or S; Y.sup.4 is C; Y.sup.5 is N and Y.sup.6 is C, the
following compounds are specifically excluded:
[0250] (i) compounds wherein n is 0, X is a covalent bond, and
R.sup.A is hydrogen; and/or
[0251] (ii) compounds wherein n is 0, X is --CH.sub.2--, and
R.sup.A is hydrogen.
[0252] In certain embodiments, Y.sup.3 is O or S, Y.sup.4 and
Y.sup.5 are, independently, C or CR.sup.13 and Y.sup.6 is C. In
certain embodiments, wherein Y.sup.3 is O or S, Y.sup.4 and Y.sup.5
are, independently, C or CR.sup.13 and Y.sup.6 is C, the following
compounds are specifically excluded: [0253] (i) compounds wherein n
is 0, X is a covalent bond or --CH.sub.2--, and R.sup.A is hydrogen
or chloro; [0254] (ii) compounds wherein n is 0, X is --CH.sub.2O--
or --OCH.sub.2-- and R.sup.A is --C.sub.6H.sub.5; and/or [0255]
(iii) compounds wherein n or is 0, X is --(C.dbd.O)--, and R.sup.A
is --C.sub.6H.sub.5.
[0256] In certain embodiments, Y.sup.3 and Y.sup.4 are,
independently, N or NR.sup.14, Y.sup.5 is C or CR.sup.13 and
Y.sup.6 is C. In certain embodiments, wherein Y.sup.3 and Y.sup.4
are, independently, N or NR.sup.14, Y.sup.5 is C or CR.sup.13 and
Y.sup.6 is C, the following compounds are specifically excluded:
[0257] (i) compounds wherein n is 0, X is a covalent bond, and
R.sup.A is hydrogen.
[0258] In certain embodiments, Y.sup.3 and Y.sup.5 are,
independently, N or NR.sup.14, Y.sup.4 is C or CR.sup.13, and
Y.sup.6 is C. In certain embodiments, wherein Y.sup.3 and Y.sup.5
are, independently, N or NR.sup.14, Y.sup.4 is C or CR.sup.13, and
Y.sup.6 is C, the following compounds are specifically
excluded:
[0259] (i) compounds wherein n is 0, X is a covalent bond, and
R.sup.A is hydrogen.
[0260] In certain embodiments, Y.sup.3 and Y.sup.6 are,
independently, N and Y.sup.4 and Y.sup.5 are, independently, C or
CR.sup.13. In certain embodiments, wherein Y.sup.3 and Y.sup.6 are,
independently, N and Y.sup.4 and Y.sup.5 are, independently, C or
CR.sup.13, the following compounds are specifically excluded:
[0261] (i) compounds wherein n is 0, X is a covalent bond, and
R.sup.A is hydrogen.
[0262] In certain embodiments, Y.sup.3 is N or NR.sup.14, and
Y.sup.4, Y.sup.5 and Y.sup.6 are, independently, C or CR.sup.13. In
certain embodiments, wherein Y.sup.3 is N or NR.sup.14, and
Y.sup.4, Y.sup.5 and Y.sup.6 are, independently, C or CR.sup.13,
the following compounds are specifically excluded: [0263] (i)
compounds wherein n is 0, X is a covalent bond, and R.sup.A is
hydrogen; [0264] (ii) compounds wherein n is 0, X is --OCH.sub.2--
or --CH.sub.2O--, and R.sup.A is --C.sub.6H.sub.5; and/or [0265]
(iii) compounds wherein n is 0, 1 or 2, R.sup.1 is --OH or
--OCH.sub.3, X is --(C.dbd.O)-- and R.sup.A is --OR.sup.7.
[0266] In certain embodiments, the following compounds are
specifically excluded:
##STR00094## ##STR00095## ##STR00096##
or pharmaceutically acceptable salts or prodrugs thereof.
[0267] In certain embodiments, the present invention provides
compounds of the formula (IV-f):
##STR00097##
[0268] or pharmaceutically acceptable salts or prodrugs thereof,
wherein Y.sup.3, Z.sup.1, Z.sup.2, R.sup.1, X, n and R.sup.A are as
defined above and herein. Examples of such compounds include
compounds of the formulae (IV-f1) and (IV-f2):
##STR00098##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Y.sup.3, Z.sup.1, Z.sup.2, R.sup.1, X, n and R.sup.A are as defined
above and herein.
[0269] In certain embodiments, the present invention provides
compounds of the formula (IV-g):
##STR00099##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Y.sup.3, Z.sup.1, Z.sup.2, R.sup.1, X, n and R.sup.A are as defined
above and herein. Examples of such compounds include compounds of
either of formulae (IV-g1) and (IV-g2):
##STR00100##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Y.sup.3, Z.sup.1, Z.sup.2, R.sup.1, X, n and R.sup.A are as defined
above and herein.
[0270] In certain embodiments, the present invention provides
compounds of formula (IV-h):
##STR00101##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, R.sup.1, X, n and R.sup.A are as defined above
and herein. Examples of such compounds include compounds of the
formulae (IV-h1) and (IV-h2):
##STR00102##
[0271] In certain embodiments, the present invention provides
compounds of either of formulae (IV-i) or (IV-k):
##STR00103##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, R.sup.1, X, n and R.sup.A are as defined above
and herein. Examples of such compounds include compounds of any of
formulae (IV-i1), (IV-i2), (IV-k1) and (IV-k2):
##STR00104##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, R.sup.1, X, n and R.sup.A are as defined above
and herein.
[0272] In certain embodiments, the present invention provides
compounds of the formulae (IV-m) or (IV-n):
##STR00105##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R.sup.14, Z.sup.1, Z.sup.2, R.sup.1, X, n and R.sup.A are as
defined above and herein.
[0273] Exemplary 6,5-fused bicyclic compounds encompassed by
formulae (I), (IV), and subgenera thereof, are provided below in
Tables 4-8.
TABLE-US-00005 TABLE 4 ##STR00106## 241 ##STR00107## 305
##STR00108## 243 ##STR00109## 244 ##STR00110## 245 ##STR00111## 246
##STR00112## 247 ##STR00113## 248 ##STR00114## 249 ##STR00115## 253
##STR00116## 299 ##STR00117## 306 ##STR00118## 301 ##STR00119## 302
##STR00120## 303 ##STR00121## 304 ##STR00122## 242
TABLE-US-00006 TABLE 5 ##STR00123## 214 ##STR00124## 278
##STR00125## 88
TABLE-US-00007 TABLE 6 ##STR00126## 313 ##STR00127## 217
##STR00128## 315 ##STR00129## 314 ##STR00130## 316
TABLE-US-00008 TABLE 7 ##STR00131## 291 ##STR00132## 293
TABLE-US-00009 TABLE 8 ##STR00133## 317
(x) Compounds of Formula II, Wherein Ring B is Het-B
[0274] In certain embodiments, the present invention provides
compounds of formula (II):
##STR00134##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z.sup.1, Z.sup.2, L.sup.1, X, Ring A, Ring B, R.sup.1, R.sup.2, n
and m are as defined above and herein.
[0275] In certain embodiments, Ring B is optionally substituted
3-10 membered heterocyclyl or optionally substituted 5-10 membered
heteroaryl (i.e., referred to as "Het-B"). Such ring systems are
depicted and described in detail above and herein.
[0276] For example, in certain embodiments, the present invention
provides compounds of formula (V):
##STR00135##
or a pharmaceutically acceptable salt or prodrug thereof;
wherein:
[0277] (i) Z.sup.1 is --OH or --OR.sup.3 and Z.sup.2 is --OH,
--OR.sup.4, an optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0278] (ii) Z.sup.1 and Z.sup.2 taken together form a 5- to
8-membered ring having at least one O, S, N or NR.sup.5 atom
directly bonded to the boron atom; or
[0279] (iii) Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A
taken together form an optionally substituted 5- to 7-membered
ring;
[0280] W.sup.3 is C, CR.sup.15, or N;
[0281] X is a covalent bond, --O--, --N.dbd.N--, --C.dbd.N--,
--NR.sup.6--, --C(NR.sup.6)--, --S--, --C(O)--, --S(O)--,
--S(O).sub.2--, or optionally substituted C.sub.1-6 alkylene,
wherein one, two or three methylene units of the C.sub.1-6 alkylene
are optionally and independently replaced with one or more groups
selected from --O--, --N.dbd.N--, --C.dbd.N--, --NR.sup.6--,
--C(NR.sup.6)--, --S--, --C(O)--, --S(O)--, and --S(O).sub.2--;
[0282] Het-B is an optionally substituted 3-10 membered
heterocyclyl or an optionally substituted 5-10 membered heteroaryl
ring;
[0283] each instance of R.sup.1 is, independently, halogen,
--OR.sup.8, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.8,
--SOR.sup.8, --C(O)R.sup.8, --CO.sub.2R.sup.8,
--C(O)N(R.sup.8).sub.2, --N.sub.3, --N.sub.2R.sup.8, --N(R).sub.2,
--B(OH.sub.2), optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0284] each instance of R.sup.2 is, independently, halogen,
--OR.sup.9, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.9,
--SOR.sup.9, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)N(R.sup.9).sub.2, --N.sub.3, --N.sub.2R.sup.9,
--N(R.sup.9).sub.2, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, optionally substituted
C.sub.2-8 alkynyl, optionally substituted C.sub.1-8 heteroalkyl,
optionally substituted C.sub.2-8 heteroalkenyl, optionally
substituted C.sub.2-8 heteroalkynyl, optionally substituted
C.sub.3-10 carbocyclyl, optionally substituted 3-10 membered
heterocyclyl, optionally substituted C.sub.6-10 aryl, or optionally
substituted 5-10 membered heteroaryl;
[0285] each instance of R.sup.3 and R.sup.4 is, independently,
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl; each instance of R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, and R.sup.10 is, independently,
hydrogen, --SO.sub.2R.sup.11, --SOR.sup.11, --C(O)R.sup.11,
--CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2, --C(O)NH(R.sup.11),
--C(O)NH.sub.2, optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0286] each instance of R.sup.11 is, independently, hydrogen,
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0287] R.sup.15 is hydrogen, halogen, --CF.sub.3, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, or optionally substituted C.sub.2-8 alkynyl;
[0288] n is 0, 1, 2 or 3; and
[0289] m is 0, 1, 2, 3, 4, or 5.
[0290] In certain embodiments, each n is 0. In certain embodiments,
each n is independently 1 or 2. In certain embodiments, each n is
1.
[0291] In certain embodiments, R.sup.1 is halogen, --OR.sup.8,
--CF.sub.3, optionally substituted C.sub.1-8 alkyl or optionally
substituted 5-membered heteroaryl. In certain embodiments, R.sup.1
is --Cl, --F, --OCH.sub.3, --OCH.sub.2CH.sub.2C.sub.6H.sub.5,
--O(CH.sub.2).sub.3CH.sub.3, --CH.sub.2C(CH.sub.3).sub.2, or an
optionally substituted oxadiazolyl.
[0292] In certain embodiments, X is a covalent bond or an
optionally substituted C.sub.1-6 alkylene. In certain embodiments,
X is a covalent bond. In certain embodiments, X is --CH.sub.2-- or
--CH.dbd.CH--.
[0293] In certain embodiments, each m is 0. In certain embodiments,
each m is independently 1 or 2. In certain embodiments, each m is
1.
[0294] In certain embodiments, R.sup.2 is selected from --OR.sup.9,
--N(R.sup.9).sub.2, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, optionally substituted
C.sub.1-8 heteroalkyl, optionally substituted C.sub.6-10 aryl, or
optionally substituted 5-10 membered heteroaryl. In certain
embodiments, R.sup.2 is selected from optionally substituted
C.sub.1-8 alkyl, optionally substituted C.sub.6-10 aryl, or
optionally substituted 5-10 membered heteroaryl.
[0295] In certain embodiments, R.sup.2 is selected from --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2C(CH.sub.3).sub.2,
--(CH.sub.2).sub.2CH.sub.3, --C(CH.sub.3).sub.3,
--(CH.sub.2).sub.3CH.sub.3, --CH.sub.2C(CH.sub.3).sub.2,
--(CH.sub.2).sub.4CH.sub.3, --(CH.sub.2).sub.5CH.sub.3,
--(CH.sub.2).sub.3C(CH.sub.3).sub.2, --(CH.sub.2).sub.6CH.sub.3,
--(CH.sub.2).sub.4CH.sub.3, --CH.sub.2CH.sub.2CF.sub.3,
--CH(CH.sub.3)(CH.sub.2).sub.3CH.sub.3,
--CH.dbd.CH(CH.sub.2).sub.2CH.sub.3,
--(CH.sub.2).sub.2CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.2CF.sub.3, --C(OH)(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2(C.dbd.O)-(oxadiazole), optionally
substituted pyridinyl, --C.sub.6H.sub.5, optionally substituted
phenyl, optionally substituted benzyl, --CH.sub.2CH.sub.2Ph,
optionally substituted furanyl, optionally substituted imidazolyl,
optionally substituted thiazolyl, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2NHBoc,
--CH.sub.2CH.sub.2NHBoc, --CH.sub.2CH.sub.2NHAc,
--CH.sub.2CH.sub.2NH(C.dbd.O)OCH.sub.3, --N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2N(--C.dbd.OCH.sub.2CH.sub.2CH.sub.2--),
--CH.sub.2CH.sub.2(C.dbd.O)N(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2---
), --CH.sub.2C.sub.5H.sub.9, --CH.sub.2C.sub.6H.sub.1,
--CH.sub.2CH.sub.2C.sub.5H.sub.9, --CH.sub.2CH.sub.2C.sub.6H.sub.1,
--CH.sub.2(furanyl), --CH.sub.2(thiophenyl), and
--CH.sub.2(indanyl). In certain embodiments, R.sup.2 is selected
from --(CH.sub.2).sub.4CH.sub.3,
--CH.sub.2CH.sub.2CF.sub.2CF.sub.3, optionally substituted
pyridinyl and optionally substituted phenyl. In certain
embodiments, R.sup.2 is selected from --(CH.sub.2).sub.4CH.sub.3,
--CH.sub.2CH.sub.2CF.sub.2CF.sub.3, -pyridinyl or
--C.sub.6H.sub.5.
[0296] In certain embodiments, W.sup.3 is C or CR.sup.15. In
certain embodiments, W.sup.3 is C or CH. In certain embodiments,
W.sup.3 is CH. In certain embodiments, W.sup.3 is N.
[0297] In certain embodiments, the present invention provides
compounds of formula (V-a):
##STR00136##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
W.sup.3, Z.sup.1, Z.sup.2, X, Het-B, R.sup.1, R.sup.2, m and n are
as defined above and herein. Examples of such compounds, wherein
Ring A is substituted ortho, meta, or para to the boron atom with
the group X-HetB, are provided in compounds of any of formulae
(V-b), (V-c) or (V-d):
##STR00137##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
W.sup.3, Z.sup.1, Z.sup.2, X, Het-B, R.sup.1, R.sup.2, m and n are
as defined above and herein.
[0298] Exemplary Het-B rings include, but are not limited to,
##STR00138##
[0299] herein Y.sup.1, Y.sup.2, Y.sup.7, Y.sup.8, W.sup.4, W.sup.5,
W.sup.6, W.sup.7 and p are as defined below, and R.sup.2 and m are
as defined above and herein.
[0300] For example, in certain embodiments, the present invention
provides compounds of formula (V-e):
##STR00139##
[0301] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, Het-B, R.sup.1, R.sup.2, m
and n are as defined above and herein, and Y.sup.1 is O, S or
NR.sup.16.
[0302] In certain embodiments, Y.sup.1 is O or S. In certain
embodiments, Y.sup.1 is O. In certain embodiments, Y.sup.1 is S.
For example, in certain embodiments, the present invention provides
compounds of any of formulae (V-e1), (V-e2), (V-e3), (V-e4),
(V-e5), (V-e6), or (V-e7):
##STR00140##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
W.sup.3, Z.sup.1, Z.sup.2, X, Het-B, R.sup.1, R.sup.2, m and n are
as defined above and herein.
[0303] In certain embodiments, the present invention provides
compounds of formula (V-f):
##STR00141##
[0304] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m and n are
as defined above and herein. For example, in certain embodiments,
the present invention provides compounds of any of formulae (V-f1),
(V-f2), (V-f3) or (V-f4):
##STR00142##
[0305] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, Het-B, R.sup.1, R.sup.2, m
and n are as defined above and herein.
[0306] In certain embodiments, the present invention provides
compounds of formula (V-g):
##STR00143##
[0307] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, and m and n
are as defined above and herein. For example, in certain
embodiments, the present invention provides compounds of either of
formulae (V-g1) and (V-g2):
##STR00144##
[0308] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, R.sup.16, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m
and n are as defined above and herein.
[0309] In certain embodiments, the present invention provides
compounds of formula (V-h):
##STR00145##
[0310] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m and n are
as defined above and herein, and Y.sup.2 is O, S or NR.sup.16.
[0311] In certain embodiments, the present invention provides
compounds of formulae (V-h1) or (V-h2):
##STR00146##
[0312] or a pharmaceutically acceptable salt or prodrug thereof,
wherein Y.sup.2, W.sup.3, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m
and n are as defined above and herein.
[0313] In certain embodiments, Y.sup.2 is O or S. In certain
embodiments, Y.sup.2 is O. In certain embodiments, Y.sup.2 is S.
For example, in certain embodiments, the present invention provides
compounds of any of formulae (V-h3), (V-h4), (V-h5), (V-h6),
(V-h7), (V-h8), (V-h9) or (V-h10):
##STR00147##
[0314] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, R.sup.16, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m
and n are as defined above and herein.
[0315] In certain embodiments, the present invention provides
compounds of formula (V-i):
##STR00148##
[0316] or pharmaceutically acceptable salts or prodrugs thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m and n are
as defined above and herein,
[0317] Y.sup.7 and Y.sup.8 are independently selected from N,
NR.sup.16, O and S, and
[0318] W.sup.4 is C, CR.sup.17 or N, wherein R.sup.17 is hydrogen,
halogen, --CF.sub.3, optionally substituted C.sub.1-8 alkyl,
optionally substituted C.sub.2-8 alkenyl, or optionally substituted
C.sub.2-8 alkynyl.
[0319] In certain embodiments, Y.sup.7 is O or S and Y.sup.8 is N.
In certain embodiments, Y.sup.7 is O and Y.sup.8 is N. In certain
embodiments, Y.sup.7 is S and Y.sup.8 is N.
[0320] In certain embodiments, W.sup.4 is N.
[0321] In certain embodiments, W.sup.4 is C or CR.sup.17. In
certain embodiments, W.sup.4 is C or CH.
[0322] In certain embodiments, the present invention provides
compounds of formulae (V-i1):
##STR00149##
[0323] or pharmaceutically acceptable salts or prodrugs thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m, n,
W.sup.4, Y.sup.7 and Y.sup.8, are as defined above and herein.
[0324] In certain embodiments, the present invention provides
compounds of the formula (V-j):
##STR00150##
[0325] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m and n are
as defined above and herein, W.sup.5 is N or N.sup.16, and the
dashed line represents a single or double bond. In certain
embodiments, the dashed line is a single bond. In certain
embodiments, the dashed line is a double bond. For example, in
certain embodiments, the present invention provides compounds of
formulae (V-j1), (V-j2), (V-j3), (V-j4), (V-j5) or (V-j6):
##STR00151##
[0326] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, Z.sup.2, Z.sup.2, X, R.sup.1, R.sup.2, R.sup.16, m
and n are as defined above and herein.
[0327] In certain embodiments, the present invention provides
compounds of formula (V-k):
##STR00152##
[0328] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m and n are
as defined above and herein, and p is 1 or 2. For example, in
certain embodiments, the present invention provides compounds of
either of formulae (V-k1) or (V-k2):
##STR00153##
[0329] or a pharmaceutically acceptable salt or prodrug thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m and n are
as defined above and herein.
[0330] In certain embodiments, the present invention provides
compounds of formula (V-m):
##STR00154##
[0331] or pharmaceutically acceptable salts or prodrugs thereof,
wherein W.sup.3, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, R.sup.16,
m, and n, are as defined above and herein, and W and W.sup.7 are
selected from N or CH, with the proviso that one or both of W.sup.6
and W.sup.7 is N. For example, in certain embodiments, the present
invention provides compounds of either of formulae (V-m1), (V-m2)
or (V-m3):
##STR00155##
[0332] or pharmaceutically acceptable salts or prodrugs thereof,
wherein W.sup.3, W.sup.6, W.sup.7, Z.sup.1, Z.sup.2, X, R.sup.1,
R.sup.2, R.sup.16, m, and n, are as defined above and herein.
Additional Embodiments Wherein Het-B is an Optionally Substituted
3-10 Membered Heterocyclyl Ring
[0333] As generally defined above, in certain embodiments, Het-B is
an optionally substituted 3-10 membered heterocyclyl ring.
[0334] In certain embodiments, Het-B is an optionally substituted
3-10 membered heterocyclyl ring, wherein said heterocyclyl ring has
1 to 3 heteroatoms selected from N, NR.sup.16, O and S, and
R.sup.16 is, independently, hydrogen, --SO.sub.2R.sup.11,
--SOR.sup.11, --C(O)R.sup.11, --CO.sub.2R.sup.11,
--C(O)N(R.sup.11).sub.2, --C(O)NH(R.sup.11), --C(O)NH.sub.2,
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl.
[0335] In certain embodiments, Het-B is an optionally substituted
5-6 membered monocyclic heterocyclyl ring.
[0336] In certain embodiments, Het-B is an optionally substituted
5-membered monocyclic heterocyclyl ring. In certain embodiments,
Het-B is an optionally substituted 5-membered monocyclic
heterocyclyl ring containing 1 to 3 heteroatoms selected from N,
NR.sup.16, O and S. In certain embodiments, Het-B is an optionally
substituted 5-membered monocyclic heterocyclyl ring containing 1
heteroatom selected from N, NR.sup.16, O and S. In certain
embodiments, Het-B is an optionally substituted 5-membered
monocyclic heterocyclyl ring containing 2 heteroatoms selected from
N, NR.sup.16, O and S. In certain embodiments, Het-B is an
optionally substituted 5-membered monocyclic heterocyclyl ring
containing 3 heteroatoms selected from N, NR.sup.16, O and S. In
certain embodiments, Het-B is an an optionally substituted
5-membered monocyclic heterocyclyl ring selected from the group
consisting of optionally substituted 1,3-dioxolanyl, optionally
substituted 4,5-dihydroisoxazolyl, optionally substituted
isoxazolidinyl, optionally substituted oxazolidinyl, optionally
substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl
and optionally substituted pyrrolyl-2,5-dione.
[0337] In certain embodiments, wherein Het-B is an optionally
substituted pyrrolidinyl (i.e., containing 1 heteroatom selected
from N or NR.sup.16), the following compounds are specifically
excluded: [0338] (i) compounds wherein W.sup.3 is CH, n is 0, m is
0 and X is a covalent bond or --CH.sub.2OCH.sub.2--; [0339] (ii)
compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is CH.sub.2OH;
and/or [0340] (iii) compounds wherein Z.sup.1 is --OH or
--OR.sup.3, and Z.sup.2 and Ring A taken together form a 5-membered
ring containing 1 O atom.
[0341] In certain embodiments, Het-B is an optionally substituted
6-membered monocyclic heterocyclyl ring containing 1 to 3
heteroatoms selected from N, NR.sup.16, O and S. In certain
embodiments, Het-B is an optionally substituted 6-membered
monocyclic heterocyclyl ring containing 1 heteroatom selected from
N, NR.sup.16, O and S. In certain embodiments, Het-B is an
optionally substituted 6-membered monocyclic heterocyclyl ring
containing 2 heteroatoms selected from N, NR.sup.16, O and S. In
certain embodiments, Het-B is an optionally substituted 6-membered
monocyclic heterocyclyl ring containing 3 heteroatoms selected from
N, NR.sup.16, O and S. In certain embodiments, Het-B is an
optionally substituted 6-membered monocyclic heterocyclyl ring
selected from the group consisting of optionally substituted
1,3-dioxanyl, optionally substituted piperidinyl, optionally
substituted piperazinyl, optionally substituted morpholinyl, and
optionally substituted tetrahydropyranyl.
[0342] In certain embodiments, wherein Het-B is an optionally
substituted piperidinyl (i.e., containing 1 heteroatom selected
from N or NR.sup.16), the following compounds are specifically
excluded: [0343] (i) compounds wherein W.sup.3 is CH, n is 0, m is
0 and X is --(C.dbd.O)-- or a covalent bond; [0344] (ii) compounds
wherein W.sup.3 is CH, n is 1, R.sup.1 is fluoro, and X is
--OCH.sub.2CH.sub.2-- or --CH.sub.2CH.sub.2O--; [0345] (iii)
compounds wherein W.sup.3 is CH, n is 0 and X is --(C.dbd.O)--;
[0346] (iv) compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is
CH.sub.2OH; and/or [0347] (v) compounds wherein Z.sup.1 is --OH or
--OR.sup.3, and Z.sup.2 and Ring A taken together form a 5-membered
ring containing 10 atom.
[0348] In certain embodiments, wherein Het-B is an optionally
substituted piperazinyl (i.e., containing 2 heteroatoms selected
from N or NR.sup.16), the following compounds are specifically
excluded: [0349] (i) compounds wherein W.sup.3 is CH, n is 1, and X
is a covalent bond, --OCH.sub.2(C.dbd.O)-- or
--(C.dbd.O)CH.sub.2O--; [0350] (ii) compounds wherein W.sup.3 is N,
n is 1, R.sup.1 is --CH.sub.3 and X is a covalent bond; [0351]
(iii) compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is
CH.sub.2OH; and/or [0352] (iv) compounds wherein Z.sup.1 is --OH or
--OR.sup.3, and Z.sup.2 and Ring A taken together form a 5-membered
ring containing 10 atom.
[0353] In certain embodiments, wherein Het-B is an optionally
substituted morpholynyl (i.e., containing 1 heteroatom selected
from O and 1 heteroatom selected from N or NR.sup.16), the
following compounds are specifically excluded: [0354] (i) compounds
wherein W.sup.3 is CH, n is 0 or 1, m is 0 and X is --(C.dbd.O)--
or a covalent bond; [0355] (ii) compounds wherein W.sup.3 is N, n
is 1, R.sup.1 is --CH.sub.3 and X is a covalent bond; (iii)
compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is CH.sub.2OH;
and/or [0356] (iv) compounds wherein Z.sup.1 is --OH or --OR.sup.3,
and Z.sup.2 and Ring A taken together form a 5-membered ring
containing 1 O atom.
[0357] In certain embodiments, wherein Het-B is an optionally
substituted tetrahydropyranyl (i.e., containing 2 O heteroatoms),
the following compounds are specifically excluded: [0358] (i)
compounds wherein W.sup.3 is CH, n is 0, m is 0 and X is --O-- or
--CH.sub.2OCH.sub.2--; [0359] (ii) compounds wherein W.sup.3 is CH,
n is 1 and R.sup.1 is CH.sub.2OH; and/or [0360] (iii) compounds
wherein Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A taken
together form a 5-membered ring containing 10 atom.
[0361] In certain embodiments, Het-B is an optionally substituted
9-10 membered bicyclic heterocyclyl ring.
[0362] In certain embodiments, Het-B is an optionally substituted
9-membered bicyclic heterocyclyl ring containing 1 to 3 heteroatoms
selected from N, NR.sup.16, O and S. In certain embodiments, Het-B
is an optionally substituted 9-membered bicyclic heterocyclyl ring
containing 1 heteroatom selected from N, NR.sup.16, O and S. In
certain embodiments, Het-B is an optionally substituted 9-membered
bicyclic heterocyclyl ring containing 2 heteroatoms selected from
N, NR.sup.16, O and S. In certain embodiments, Het-B is an
optionally substituted 9-membered bicyclic heterocyclyl ring
containing 3 heteroatoms selected from N, NR.sup.16, O and S. In
certain embodiments, Het-B is an optionally substituted 9-membered
bicyclic heterocyclyl ring selected from the group consisting of
optionally substituted indolinyl, optionally substituted
isoindolinyl-1,3-dione, and optionally substituted
benzo[d][1,3]dioxolyl.
[0363] In certain embodiments, wherein Het-B is an optionally
substituted indolinyl (i.e., containing 1 heteroatom selected from
N or NR.sup.16), the following compounds are specifically excluded:
[0364] (i) compounds wherein W.sup.3 is CH, n is 0, m is 0, and X
is --CH.sub.2--; [0365] (ii) compounds wherein W.sup.3 is CH, n is
1, R.sup.1 is fluoro, m is 0, and X is --CH.sub.2--; [0366] (iii)
compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is CH.sub.2OH;
and/or [0367] (iv) compounds wherein Z.sup.1 is --OH or --OR.sup.3,
and Z.sup.2 and Ring A taken together form a 5-membered ring
containing 1 O atom.
[0368] In certain embodiments, wherein Het-B is an optionally
substituted isoindolinyl-1,3-dione (i.e., containing 1 heteroatom
selected from N or NR.sup.16), the following compounds are
specifically excluded: [0369] (i) compounds wherein W.sup.3 is CH,
n is 0, m is 0 and X is --CH.sub.2--; [0370] (ii) compounds wherein
W.sup.3 is CH, n is 1 and R.sup.1 is CH.sub.2OH; and/or [0371]
(iii) compounds wherein Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2
and Ring A taken together form a 5-membered ring containing 10
atom.
[0372] In certain embodiments, wherein Het-B is an optionally
substituted benzo[d][1,3]dioxolyl (i.e., containing 2 O
heteroatoms), the following compounds are specifically excluded:
[0373] (i) compounds wherein W.sup.3 is CH, n is 0, m is 0 and X is
--O--; [0374] (ii) compounds wherein W.sup.3 is CH, n is 1 and
R.sup.1 is CH.sub.2OH; and/or [0375] (iii) compounds wherein
Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A taken
together form a 5-membered ring containing 10 atom.
[0376] In certain embodiments, Het-B is an optionally substituted
10-membered bicyclic heterocyclyl ring containing 1 to 3
heteroatoms selected from N, NR.sup.16, O and S. In certain
embodiments, Het-B is an optionally substituted 10-membered
bicyclic heterocyclyl ring containing 1 heteroatom selected from N,
NR.sup.16, O and S. In certain embodiments, Het-B is an optionally
substituted 10-membered bicyclic heterocyclyl ring containing 2
heteroatoms selected from N, NR.sup.16, O and S. In certain
embodiments, Het-B is an optionally substituted 10-membered
bicyclic heterocyclyl ring containing 3 heteroatoms selected from
N, NR.sup.16, O and S. In certain embodiments, Het-B is an
optionally substituted 9-membered bicyclic heterocyclyl ring
selected from the group consisting of optionally substituted
1,2,3,4-tetrahydroquinolinyl.
[0377] In certain embodiments, wherein Het-B is an optionally
substituted 1,2,3,4-tetrahydroquinolinyl (i.e., containing 1
heteroatom selected from N or NR.sup.16), the following compounds
are specifically excluded: [0378] (iv) compounds wherein W.sup.3 is
CH, n is 0, m is 0 and X is --CH.sub.2--; [0379] (v) compounds
wherein W.sup.3 is CH, n is 1 and R.sup.1 is CH.sub.2OH; and/or
[0380] (vi) compounds wherein Z.sup.1 is --OH or --OR.sup.3, and
Z.sup.2 and Ring A taken together form a 5-membered ring containing
1 O atom.
Additional Embodiments Wherein Het-B is an Optionally Substituted
5-10 Membered Heteroaryl Ring
[0381] As generally defined above, in certain embodiments, Het-B is
an optionally substituted 5-10 membered heteroaryl ring.
[0382] In certain embodiments, Het-B is an optionally substituted
5-10 membered heteroaryl ring, wherein said heteroaryl ring has 1
to 3 heteroatoms selected from N, NR.sup.16, O and S, and R.sup.16
is, independently, hydrogen, --SO.sub.2R.sup.11, --SOR.sup.11,
--C(O)R.sup.11, --CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2,
--C(O)NH(R.sup.11), --C(O)NH.sub.2, optionally substituted
C.sub.1-8 alkyl, optionally substituted C.sub.2-8 alkenyl,
optionally substituted C.sub.2-8 alkynyl, optionally substituted
C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl.
[0383] In certain embodiments, Het-B is an optionally substituted
5-6 membered monocyclic heteroaryl ring.
[0384] In certain embodiments, Het-B is an optionally substituted
5-membered monocyclic heteroaryl ring containing 1 to 3 heteroatoms
selected from N, NR.sup.16, O and S. In certain embodiments, Het-B
is an optionally substituted 5-membered monocyclic heteroaryl ring
containing 1 heteroatom selected from N, NR.sup.16, O and S. In
certain embodiments, Het-B is an optionally substituted 5-membered
monocyclic heteroaryl ring containing 2 heteroatoms selected from
N, NR.sup.16, O and S. In certain embodiments, Het-B is an
optionally substituted 5-membered monocyclic heteroaryl ring
containing 3 heteroatoms selected from N, NR.sup.16, O and S. In
certain embodiments, Het-B is an optionally substituted 5-membered
monocyclic heteroaryl ring selected from the group consisting of
optionally substituted triazolyl, optionally substituted
oxadiazolyl, optionally substituted thiadiazolyl, optionally
substituted imidazolyl, optionally substituted pyrazolyl,
optionally substituted thiazolyl, optionally substituted
isothiazolyl, optionally substituted oxazolyl, optionally
substituted isoxazolyl, optionally substituted thiophenyl,
optionally substituted furanyl and optionally substituted
pyrrolyl.
[0385] In certain embodiments, wherein Het-B is an optionally
substituted oxadiazolyl group (i.e., containing one O and two N
atoms), the following compounds are specifically excluded: [0386]
(i) compounds wherein W.sup.3 is CH, X is a covalent bond, n is 0
and m is 0; [0387] (ii) compounds wherein W.sup.3 is CH, X is a
covalent bond, n is 0, m is 1 and R.sup.2 is an unsubstituted
furanyl group; [0388] (iii) compounds wherein W.sup.3 is CH, X is a
covalent bond, n is 0, m is 1 and R.sup.2 is --CH.sub.3; [0389]
(iv) compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is
CH.sub.2OH; and/or [0390] (v) compounds wherein Z.sup.1 is --OH or
--OR.sup.3, and Z.sup.2 and Ring A taken together form a 5-membered
ring containing 1 O atom.
[0391] In certain embodiments, wherein Het-B is an optionally
substituted thiadiazolyl group (i.e., containing one S and two N
atoms), the following compounds are specifically excluded: [0392]
(i) compounds wherein W.sup.3 is CH, X is a covalent bond, n is 0
and m is 0; [0393] (ii) compounds wherein W.sup.3 is CH, n is 1 and
R.sup.1 is CH.sub.2OH; and/or [0394] (iii) compounds wherein
Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A taken
together form a 5-membered ring containing 1 O atom.
[0395] In certain embodiments, wherein Het-B is an optionally
substituted triazolyl group (i.e., containing three heteroatoms
selected from N and NR.sup.16), the following compounds are
specifically excluded: [0396] (i) compounds wherein W.sup.3 is CH,
X is a covalent bond, n is 0 and m is 0; [0397] (ii) compounds
wherein W.sup.3 is CH, X is --OCH.sub.2-- or --CH.sub.2O--, n is 1,
R.sup.1 is fluoro, m is 1 and R.sup.2 is a cyclohexyl group; [0398]
(iii) compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is
CH.sub.2OH; and/or [0399] (iv) compounds wherein Z.sup.1 is --OH or
--OR.sup.3, and Z.sup.2 and Ring A taken together form a 5-membered
ring containing 1 O atom.
[0400] In certain embodiments, wherein Het-B is an optionally
substituted oxazolyl group (i.e., containing one N atom and one O
atom), the following compounds are specifically excluded: [0401]
(i) compounds wherein W.sup.3 is CH, X is a covalent bond, n is 0
and m is 0; [0402] (ii) compounds wherein W.sup.3 is CH, n is 1,
R.sup.1 is fluoro, X is --OCH.sub.2-- or --CH.sub.2O--, and m is 0;
[0403] (iii) compounds wherein W.sup.3 is CH, X is a covalent bond,
n is 0, m is 2 and each R.sup.2 is independently --CH.sub.3, an
optionally substituted C.sub.1-8 alkyl or C.sub.1-8 heteroalkyl
group; [0404] (iv) compounds wherein W.sup.3 is CH, n is 1 and
R.sup.1 is CH.sub.2OH; and/or [0405] (v) compounds wherein Z.sup.1
is --OH or --OR.sup.3, and Z.sup.2 and Ring A taken together form a
5-membered ring containing 10 atom.
[0406] In certain embodiments, wherein Het-B is an optionally
substituted thiazolyl group (i.e., containing one S atom and one N
atom), the following compounds are specifically excluded: [0407]
(i) compounds wherein W is CH, n is 0, X is a covalent bond, m is 1
and R.sup.2 is --CH.sub.3; [0408] (ii) compounds wherein W is CH, n
is 1, R.sup.1 is fluoro, X is --OCH.sub.2-- or --CH.sub.2O-- and m
is 0; [0409] (iii) compounds wherein W.sup.3 is CH, n is 1 and
R.sup.1 is CH.sub.2OH; and/or [0410] (iv) compounds wherein Z.sup.1
is --OH or --OR.sup.3, and Z.sup.2 and Ring A taken together form a
5-membered ring containing 1 O atom.
[0411] In certain embodiments, wherein Het-B is an optionally
substituted pyrazolyl group (i.e., containing two heteroatoms
selected from N or NR.sup.16), the following compounds are
specifically excluded: [0412] (i) compounds wherein W.sup.3 is CH,
n is 1, R.sup.1 is fluoro, X is --OCH.sub.2-- or --CH.sub.2O-- and
m is 0; [0413] (ii) compounds wherein W.sup.3 is CH, n is 0, X is
--OCH.sub.2CH.sub.2-- or --CH.sub.2CH.sub.2O-- and m is 0; [0414]
(iii) compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is
CH.sub.2OH; and/or [0415] (iv) compounds wherein Z.sup.1 is --OH or
--OR.sup.3, and Z.sup.2 and Ring A taken together form a 5-membered
ring containing 10 atom.
[0416] In certain embodiments, wherein Het-B is an optionally
substituted imidazolyl group (i.e., containing two heteroatoms
selected from N or NR.sup.16), the following compounds are
specifically excluded: [0417] (i) compounds wherein W.sup.3 is CH,
n is 1, R.sup.1 is fluoro, X is --OCH.sub.2-- or --CH.sub.2O--, and
m is 0; [0418] (ii) compounds wherein W.sup.3 is CH, n is 0, X is
--OCH.sub.2CH.sub.2-- or --CH.sub.2CH.sub.2O-- and m is 0; [0419]
(iii) compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is
CH.sub.2OH; and/or [0420] (iv) compounds wherein Z.sup.1 is --OH or
--OR.sup.3, and Z.sup.2 and Ring A taken together form a 5-membered
ring containing 1 O atom.
[0421] In certain embodiments, wherein Het-B is an optionally
substituted thiophenyl group (i.e., containing one S atom), the
following compounds are specifically excluded: [0422] (i) compounds
wherein W.sup.3 is CH, n is 0, m is 0 and X is a covalent bond;
[0423] (ii) compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is
CH.sub.2OH; and/or [0424] (iii) compounds wherein Z.sup.1 is --OH
or --OR.sup.3, and Z.sup.2 and Ring A taken together form a
5-membered ring containing 1 O atom.
[0425] In certain embodiments, wherein Het-B is an optionally
substituted furanyl group (i.e., containing one O atom), the
following compounds are specifically excluded: [0426] (i) compounds
wherein W.sup.3 is CH, n is 0, X is --(C.dbd.O)NHCH.sub.2-- or
--CH.sub.2NH(C.dbd.O)-- and m is 0; [0427] (ii) compounds wherein
W.sup.3 is CH, n is 0, m is 0 and X is a covalent bond; [0428]
(iii) compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is
CH.sub.2OH; and/or [0429] (iv) compounds wherein Z.sup.1 is --OH or
--OR.sup.3, and Z.sup.2 and Ring A taken together form a 5-membered
ring containing 1 O atom.
[0430] In certain embodiments, wherein Het-B is an optionally
substituted pyrrolyl group (i.e., containing one heteroatom
selected from N or NR.sup.16), the following compounds are
specifically excluded: [0431] (i) compounds wherein W.sup.3 is CH,
n is 0 and X is a covalent bond; [0432] (ii) compounds wherein
W.sup.3 is CH, n is 0 and X is --SO.sub.2--; [0433] (iii) compounds
wherein W.sup.3 is CH, n is 1 and R.sup.1 is CH.sub.2OH; and/or
[0434] (iv) compounds wherein Z.sup.1 is --OH or --OR.sup.3, and
Z.sup.2 and Ring A taken together form a 5-membered ring containing
1 O atom.
[0435] In certain embodiments, Het-B is an optionally substituted
6-membered monocyclic heteroaryl ring containing 1 to 3 heteroatoms
selected from N, NR.sup.16, O and S. In certain embodiments, Het-B
is an optionally substituted 6-membered monocyclic heteroaryl ring
containing 1 heteroatom selected from N, NR.sup.16, O and S. In
certain embodiments, Het-B is an optionally substituted 6-membered
monocyclic heteroaryl ring containing 2 heteroatoms selected from
N, NR.sup.16, O and S. In certain embodiments, Het-B is an
optionally substituted 6-membered monocyclic heteroaryl ring
containing 3 heteroatoms selected from N, NR.sup.16, O and S. In
certain embodiments, Het-B is an optionally substituted pyridinyl
group (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl).
[0436] However, in certain embodiments, Het-B is not an optionally
substituted 6-membered monocyclic heteroaryl ring. In certain
embodiments, Het-B is not an optionally substituted pyridinyl.
Alternatively, in certain embodiments, wherein Het-B is an
optionally substituted pyridinyl group, the following compounds are
specifically excluded: [0437] (i) 3-pyridinyl compounds wherein
W.sup.3 is CH, n is 1, R.sup.1 is a fluoro group ortho to the boron
atom, X is a covalent bond, --O--, --CH.sub.2--, --OCH.sub.2--,
--OCH.sub.2CH.sub.2-- or --CH.sub.2CH.sub.2O--, and m is 0; [0438]
(ii) 3-pyridinyl compounds wherein W.sup.3 is CH, n is 0, X is a
covalent bond and m is 0; [0439] (iii) 2-pyridinyl compounds
wherein W.sup.3 is CH, n is 1, R.sup.1 is fluoro ortho to the boron
atom, X is --OCH.sub.2CH.sub.2CH.sub.2O--, --CH.sub.2O--,
--OCH.sub.2--, --OCH.sub.2CH.sub.2-- or --CH.sub.2CH.sub.2O--, and
m is 0; [0440] (iv) 2-pyridinyl compounds wherein W.sup.3 is CH, n
is 0, X is --(C.dbd.O)NH-- or --NH(C.dbd.O)-- and m is 0; [0441]
(v) 4-pyridinyl compounds wherein W.sup.3 is CH, n is 1, R.sup.1 is
fluoro ortho to the boron atom, X is --CH.sub.2O-- or
--OCH.sub.2--, and m is 0; [0442] (vi) 4-pyridinyl compounds
wherein W.sup.3 is CH, n is 0, X is a covalent bond and m is 0;
[0443] (vii) compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is
CH.sub.2OH; and/or [0444] (viii) compounds wherein Z.sup.1 is --OH
or --OR.sup.3, and Z.sup.2 and Ring A taken together form a
5-membered ring containing 1 O atom.
[0445] In certain embodiments, Het-B is an optionally substituted
9-10 membered bicyclic heteroaryl ring.
[0446] In certain embodiments, Het-B is an optionally substituted
9-membered bicyclic heteroaryl ring containing 1 to 3 heteroatoms
selected from N, NR.sup.16, O and S (e.g., a 6-5 fused heteroaryl
ring). In certain embodiments, Het-B is an optionally substituted
9-membered bicyclic heteroaryl ring containing 1 heteroatom
selected from N, NR.sup.16, O and S. In certain embodiments, Het-B
is an optionally substituted 9-membered bicyclic heteroaryl ring
containing 2 heteroatoms selected from N, NR.sup.16, O and S. In
certain embodiments, Het-B is an optionally substituted 9-membered
bicyclic heteroaryl ring containing 3 heteroatoms selected from N,
NR.sup.16, O and S. In certain embodiments, Het-B is an optionally
substituted 9-membered bicyclic heteroaryl ring selected from the
group consisting of optionally substituted benzthiazolyl,
optionally substituted benzoxazolyl, optionally substituted
benzisoxazolyl, optionally substituted benzimidazolyl, optionally
substituted indazolyl, optionally substituted benzofuranyl,
optionally substituted benzothiophenyl and optionally substituted
indolyl.
[0447] In certain embodiments, wherein Het-B is an optionally
substituted benzoxazolyl group (i.e., containing one N atom and one
O atom), the following compounds are specifically excluded: [0448]
(i) compounds wherein W.sup.3 is CH, X is a covalent bond, n is 0
and m is 0; [0449] (ii) compounds wherein W.sup.3 is CH, n is 1 and
R.sup.1 is CH.sub.2OH; and/or [0450] (iii) compounds wherein
Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A taken
together form a 5-membered ring containing 1 O atom.
[0451] In certain embodiments, wherein Het-B is an optionally
substituted benzisoxazolyl group (i.e., containing one N atom and
one O atom), the following compounds are specifically excluded:
[0452] (i) compounds wherein W.sup.3 is CH, X is a covalent bond, n
is 0 and m is 0; [0453] (ii) compounds wherein W.sup.3 is CH, n is
1 and R.sup.1 is CH.sub.2OH; and/or [0454] (iii) compounds wherein
Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A taken
together form a 5-membered ring containing 1 O atom.
[0455] In certain embodiments, wherein Het-B is an optionally
substituted benzthiazolyl group (i.e., containing one N atom and
one S atom), the following compounds are specifically excluded:
[0456] (i) compounds wherein W.sup.3 is CH, X is a covalent bond, n
is 0 and m is 0; [0457] (ii) compounds wherein W.sup.3 is CH, n is
1 and R.sup.1 is CH.sub.2OH; and/or [0458] (iii) compounds wherein
Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A taken
together form a 5-membered ring containing 1 O atom.
[0459] In certain embodiments, wherein Het-B is an optionally
substituted benzimidazolyl group (i.e., containing two heteroatoms
selected from from N or NR.sup.16), the following compounds are
specifically excluded: [0460] (i) compounds wherein W.sup.3 is CH,
X is a covalent bond, n is 0 and m is 0; [0461] (ii) compounds
wherein W.sup.3 is CH, n is 1 and R.sup.1 is CH.sub.2OH; and/or
[0462] (iii) compounds wherein Z.sup.1 is --OH or --OR.sup.3, and
Z.sup.2 and Ring A taken together form a 5-membered ring containing
1 O atom.
[0463] In certain embodiments, wherein Het-B is an optionally
substituted indazolyl group (i.e., containing two heteroatoms
selected from from N or NR.sup.16), the following compounds are
specifically excluded: [0464] (i) compounds wherein W.sup.3 is CH,
X is a covalent bond, n is 0 and m is 0; [0465] (ii) compounds
wherein W.sup.3 is CH, n is 1 and R.sup.1 is CH.sub.2OH; and/or
[0466] (iii) compounds wherein Z.sup.1 is --OH or --OR.sup.3, and
Z.sup.2 and Ring A taken together form a 5-membered ring containing
10 atom.
[0467] In certain embodiments, wherein Het-B is an optionally
substituted indolyl group (i.e., containing one heteroatom selected
from from N or NR.sup.16), the following compounds are specifically
excluded: [0468] (i) compounds wherein W.sup.3 is CH, X is
--CH.sub.2--, n is 0 and m is 0; [0469] (ii) compounds wherein
W.sup.3 is CH, n is 1 and R.sup.1 is CH.sub.2OH; and/or [0470]
(iii) compounds wherein Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2
and Ring A taken together form a 5-membered ring containing 10
atom.
[0471] In certain embodiments, Het-B is an optionally substituted
10-membered bicyclic heteroaryl ring containing 1 to 3 heteroatoms
selected from N, NR.sup.16, O and S (e.g., a 6,6-fused heteroaryl
ring). In certain embodiments, Het-B is an optionally substituted
10-membered bicyclic heteroaryl ring containing 1 heteroatom
selected from N, NR.sup.16, O and S. In certain embodiments, Het-B
is an optionally substituted 10-membered bicyclic heteroaryl ring
containing 2 heteroatoms selected from N, NR.sup.16, O and S. In
certain embodiments, Het-B is an optionally substituted 10-membered
bicyclic heteroaryl ring containing 3 heteroatoms selected from N,
NR.sup.16, O and S. In certain embodiments, Het-B is an optionally
substituted 10-membered bicyclic heteroaryl ring selected from the
group consisting of optionally substituted quinolinyl, optionally
substituted isoquinolinyl or optionally substituted
quinoxalinyl.
[0472] In certain embodiments, wherein Het-B is an optionally
substituted quinolinyl group (i.e., containing one heteroatom
selected from from N), the following compounds are specifically
excluded: [0473] (iv) compounds wherein W.sup.3 is CH, X is a
covalent bond, n is 0, m is 1 and R.sup.2 is --CO.sub.2H; [0474]
(v) compounds wherein W.sup.3 is CH, n is 1 and R.sup.1 is
CH.sub.2OH; and/or [0475] (vi) compounds wherein Z.sup.1 is --OH or
--OR.sup.3, and Z.sup.2 and Ring A taken together form a 5-membered
ring containing 1 O atom.
[0476] In certain embodiments, the following compounds are
specifically excluded:
##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160##
##STR00161##
[0477] and pharmaceutically acceptable salts or prodrugs
thereof.
[0478] Exemplary compounds encompassed by formulae (II), (V), and
subgenera thereof, are provided below in Tables 9-20.
TABLE-US-00010 TABLE 9 ##STR00162## 126 ##STR00163## 127
##STR00164## 129 ##STR00165## 128 ##STR00166## 134 ##STR00167## 130
##STR00168## 137 ##STR00169## 138
TABLE-US-00011 TABLE 10 ##STR00170## 141 ##STR00171## 142
##STR00172## 143 ##STR00173## 144 ##STR00174## 131
TABLE-US-00012 TABLE 11 ##STR00175## 11 ##STR00176## 13
##STR00177## 18 ##STR00178## 17 ##STR00179## 19 ##STR00180## 22
##STR00181## 28 ##STR00182## 31 ##STR00183## 63 ##STR00184## 296
##STR00185## 281 ##STR00186## 286 ##STR00187## 282 ##STR00188## 283
##STR00189## 260 ##STR00190## 261 ##STR00191## 262 ##STR00192## 263
##STR00193## 264 ##STR00194## 265 ##STR00195## 268 ##STR00196## 269
##STR00197## 271 ##STR00198## 272 ##STR00199## 284 ##STR00200## 285
##STR00201## 9 ##STR00202## 12 ##STR00203## 10 ##STR00204## 20
##STR00205## 23 ##STR00206## 86 ##STR00207## 25 ##STR00208## 26
##STR00209## 57 ##STR00210## 21 ##STR00211## 29 ##STR00212## 30
##STR00213## 64 ##STR00214## 32 ##STR00215## 33 ##STR00216## 34
##STR00217## 35 ##STR00218## 36 ##STR00219## 37 ##STR00220## 38
##STR00221## 39 ##STR00222## 40 ##STR00223## 41 ##STR00224## 42
##STR00225## 43 ##STR00226## 44 ##STR00227## 45 ##STR00228## 46
##STR00229## 47 ##STR00230## 59 ##STR00231## 51 ##STR00232## 51
##STR00233## 53 ##STR00234## 54 ##STR00235## 65 ##STR00236## 66
##STR00237## 67 ##STR00238## 68 ##STR00239## 69 ##STR00240## 70
##STR00241## 71 ##STR00242## 239 ##STR00243## 73 ##STR00244## 74
##STR00245## 75 ##STR00246## 76 ##STR00247## 77 ##STR00248## 78
##STR00249## 79 ##STR00250## 80 ##STR00251## 81 ##STR00252## 82
##STR00253## 83 ##STR00254## 84 ##STR00255## 85
TABLE-US-00013 TABLE 12 ##STR00256## 48 ##STR00257## 62
##STR00258## 49 ##STR00259## 50 ##STR00260## 266
TABLE-US-00014 TABLE 13 ##STR00261## 272 ##STR00262## 273
##STR00263## 24
TABLE-US-00015 TABLE 14 ##STR00264## 7 ##STR00265##
TABLE-US-00016 TABLE 15 ##STR00266## 226 ##STR00267## 227
##STR00268## 222 ##STR00269## 232 ##STR00270## 92 ##STR00271##
231
TABLE-US-00017 TABLE 16 ##STR00272## 154 ##STR00273## 159
##STR00274## 161 ##STR00275## 162 ##STR00276## 163 ##STR00277## 164
##STR00278## 165 ##STR00279## 167 ##STR00280## 168 ##STR00281## 166
##STR00282## 160 ##STR00283## 156 ##STR00284## 148
TABLE-US-00018 TABLE 17 ##STR00285## 276 ##STR00286## 225
##STR00287## 3 ##STR00288## 8 ##STR00289## 89 ##STR00290## 1
##STR00291## 2 ##STR00292## 90
TABLE-US-00019 TABLE 18 ##STR00293## 173 ##STR00294## 174
##STR00295## 175 ##STR00296## 179 ##STR00297## 180 ##STR00298## 181
##STR00299## 182 ##STR00300## 182
TABLE-US-00020 TABLE 19 ##STR00301## 224 ##STR00302## 223
##STR00303## 259 ##STR00304## 87
TABLE-US-00021 TABLE 20 ##STR00305## 233 ##STR00306## 236
##STR00307## 279 ##STR00308## 280 ##STR00309## 318 ##STR00310##
329
[0479] Additionally, in certain embodiments, the present invention
provides compounds of formula (VI):
##STR00311##
[0480] or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0481] (i) Z.sup.1 is --OH or --OR.sup.3 and Z.sup.2 is --OH,
--OR.sup.4, an optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0482] (ii) Z.sup.1 and Z.sup.2 taken together form a 5- to
8-membered ring having at least one O, S, N or NR.sup.5 atom
directly bonded to the boron atom; or
[0483] (iii) Z.sup.1 is --OH or --OR.sup.3, and Z.sup.2 and Ring A
taken together form an optionally substituted 5- to 7-membered
ring;
[0484] Y.sup.9 is an S or O;
[0485] X is a covalent bond, --O--, --N.dbd.N--, --C.dbd.N--,
--NR.sup.6--, --C(NR.sup.6)--, --S--, --C(O)--, --S(O)--,
--S(O).sub.2--, or optionally substituted C.sub.1-6 alkylene,
wherein one, two or three methylene units of the C.sub.1-6 alkylene
are optionally and independently replaced with one or more groups
selected from --O--, --N.dbd.N--, --C.dbd.N--, --NR.sup.6--,
--C(NR.sup.6)--, --S--, --C(O)--, --S(O)--, and --S(O).sub.2--;
[0486] Het-B is an optionally substituted 3-10 membered
heterocyclyl or an optionally substituted 5-10 membered heteroaryl
ring;
[0487] each instance of R.sup.1 is, independently, halogen,
--OR.sup.8, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.8,
--SOR.sup.8, --C(O)R, --CO.sub.2R, --C(O)N(R).sub.2, --N.sub.3,
--N.sub.2R, --N(R).sub.2, --B(OH.sub.2), optionally substituted
C.sub.1-8 alkyl, optionally substituted C.sub.2-8 alkenyl,
optionally substituted C.sub.2-8 alkynyl, optionally substituted
C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl;
[0488] each instance of R.sup.2 is, independently, halogen,
--OR.sup.9, --CF.sub.3, --CN, --NO.sub.2, --SO.sub.2R.sup.9,
--SOR.sup.9, --C(O)R.sup.9, --CO.sub.2R.sup.9, --C(O)N(R).sub.2,
--N.sub.3, --N.sub.2R.sup.9, --N(R.sup.9).sub.2, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.3-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl;
[0489] each instance of R.sup.3 and R.sup.4 is, independently,
optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.2-8 alkenyl, optionally substituted C.sub.2-8 alkynyl,
optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0490] each instance of R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, and R.sup.10 is, independently, hydrogen,
--SO.sub.2R.sup.11, --SOR.sup.11, --C(O)R.sup.11,
--CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2, --C(O)NH(R.sup.11),
--C(O)NH.sub.2, optionally substituted C.sub.1-8 alkyl, optionally
substituted C.sub.2-8 alkenyl, optionally substituted C.sub.2-8
alkynyl, optionally substituted C.sub.1-8 heteroalkyl, optionally
substituted C.sub.2-8 heteroalkenyl, optionally substituted
C.sub.2-8 heteroalkynyl, optionally substituted C.sub.3-10
carbocyclyl, optionally substituted 3-10 membered heterocyclyl,
optionally substituted C.sub.6-10 aryl, or optionally substituted
5-10 membered heteroaryl;
[0491] each instance of R.sup.11 is, independently, optionally
substituted C.sub.1-8 alkyl, optionally substituted C.sub.2-8
alkenyl, optionally substituted C.sub.2-8 alkynyl, optionally
substituted C.sub.1-8 heteroalkyl, optionally substituted C.sub.2-8
heteroalkenyl, optionally substituted C.sub.2-8 heteroalkynyl,
optionally substituted C.sub.1-10 carbocyclyl, optionally
substituted 3-10 membered heterocyclyl, optionally substituted
C.sub.6-10 aryl, or optionally substituted 5-10 membered
heteroaryl;
[0492] n is 0, 1, 2 or 3 and m is 0, 1, 2, 3, 4, or 5.
[0493] In certain embodiments, the present invention provides
compounds of any of formulae (VI-a), (VI-b), (VI-c), (VI-d) or
(VI-e):
##STR00312##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Y.sup.9, Z.sup.1, Z.sup.2, Het-B, X, R.sup.1, R.sup.2, m and n are
as defined above and herein.
[0494] Exemplary Het-B rings include, but are not limited to,
##STR00313##
[0495] wherein Y.sup.1, Y.sup.2, Y.sup.7, Y.sup.8, W.sup.4,
W.sup.8, W.sup.6, W.sup.7, p, R.sup.2 and m are as defined above
and herein.
[0496] In certain embodiments, Het-B of formula (VI), and subgenera
thereof, is selected from
##STR00314##
[0497] In certain embodiments, Het-B of formula (VI), and subgenera
thereof, is selected from
##STR00315##
[0498] For example, in certain embodiments, the present invention
provides compounds of formula (VI-e):
##STR00316##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Y.sup.9, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m and n are as
defined above and herein. For example, in certain embodiments, the
present invention provides compounds of any of formulae (VI-e1),
(VI-e2), (VI-e3), (VI-e4) or (VI-e5):
##STR00317##
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Y.sup.9, Z.sup.1, Z.sup.2, X, R.sup.1, R.sup.2, m and n are as
defined above and herein.
[0499] In certain embodiments, n is 0.
[0500] In certain embodiments, X is a covalent bond.
[0501] In certain embodiments, m is 1. In certain embodiments,
R.sup.2 is selected from optionally substituted C.sub.1-8 alkyl or
optionally substituted C.sub.6-10 aryl. In certain embodiments,
R.sup.2 is selected from --CH.sub.3, --CH.sub.2CH.sub.3,
--(CH.sub.2).sub.2CH.sub.3, --(CH.sub.2).sub.3CH.sub.3,
--(CH.sub.2).sub.4CH.sub.3, optionally substituted phenyl,
optionally substituted benzyl, and
--(CH.sub.2).sub.2C.sub.6H.sub.5.
[0502] In certain embodiments, Y.sup.9 is a S atom. In certain
embodiments, Y.sup.9 is an O atom.
[0503] In certain embodiments, Het-B is an optionally substituted
3-10 membered heterocyclyl ring having 2 to 3 heteroatoms selected
from N, NR.sup.16, O and S. In certain embodiments, Het-B is an
optionally substituted 5-10 membered heteroaryl ring having 2 to 3
heteroatoms selected from N, NR.sup.16, O and S. In certain
embodiments, Het-B is an optionally substituted 5-membered
heteroaryl ring having 2 to 3 heteroatoms selected from N,
NR.sup.16, O and S.
[0504] In certain embodiments, Het-B is an optionally substituted
5-membered monocyclic heteroaryl ring selected from the group
consisting of an optionally substituted triazolyl, optionally
substituted oxadiazolyl, optionally substituted thiadiazolyl,
optionally substituted imidazolyl, optionally substituted
pyrazolyl, optionally substituted thiazolyl, optionally substituted
isothiazolyl, optionally substituted oxazolyl and optionally
substituted isoxazolyl.
[0505] In certain embodiments, compounds of formula (VI) or
subgenera thereof, wherein Y.sup.9 is S, X is a covalent bond, n is
0, m is 0 and Het-B is C.sub.6H.sub.5 or unsubstituted thiophenyl,
are specifically excluded.
[0506] In certain embodiments, the following compounds are
specifically excluded:
##STR00318##
[0507] or a pharmaceutically acceptable salt or prodrug
thereof.
[0508] Exemplary compounds encompassed by formulae (II), (VI), and
subgenera thereof, are provided below in Table 21.
TABLE-US-00022 TABLE 21 ##STR00319## 72 ##STR00320## 72
##STR00321## 61 ##STR00322## 60 ##STR00323## 55 ##STR00324## 58
##STR00325## 27 ##STR00326## 56 ##STR00327## 240
4. Pharmaceutically Acceptable Compositions and Formulations
[0509] In certain embodiments, the present invention provides a
pharmaceutically acceptable composition comprising a compound of
any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera
thereof, or a pharmaceutically acceptable salt or prodrug thereof,
and a pharmaceutically acceptable excipient, medium, or
carrier.
[0510] In some embodiments, the present invention provides a
pharmaceutically acceptable composition comprising a compound of
any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera
thereof, or a pharmaceutically acceptable salt or prodrug thereof,
as provided in any of Tables 1 through 20, and a pharmaceutically
acceptable excipient, medium, or carrier.
[0511] In some embodiments, the present invention provides a
pharmaceutically acceptable composition comprising a compound of
any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera
thereof, or a pharmaceutically acceptable salt or prodrug thereof,
as provided in the Examples, and a pharmaceutically acceptable
excipient, medium, or carrier.
[0512] In other embodiments, the present invention provides a
pharmaceutically acceptable composition comprising a compound of
any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera
thereof, or a pharmaceutically acceptable salt or prodrug thereof,
as provided in the Examples having a K.sub.i of less than or equal
to 0.01 microM or having a K.sub.i of between 0.01 microM and 0.1
microM (i.e., compounds with activities designated "A" and "B"),
and a pharmaceutically acceptable excipient, medium, or
carrier.
[0513] In yet other embodiments, the present invention provides a
pharmaceutically acceptable composition comprising a compound of
any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera
thereof, or a pharmaceutically acceptable salt or prodrug thereof,
as provided in the Examples having a K of less than or equal to
0.01 microM (i.e., compounds with activities designated "A") and a
pharmaceutically acceptable excipient, medium, or carrier.
[0514] In still yet other embodiments, the present invention
provides a pharmaceutically acceptable composition comprising a
compound of any of formulae (I), (II), (III), (IV), (V), or (VI),
or subgenera thereof, or a pharmaceutically acceptable salt or
prodrug thereof, and a pharmaceutically acceptable excipient,
medium, or carrier, wherein said compound is selected from the any
compound depicted in the Examples.
[0515] As described above, pharmaceutically acceptable compositions
of the present invention additionally comprise a pharmaceutically
acceptable excipient, which, as used herein, includes any and all
solvents, diluents, or other liquid vehicle, dispersion or
suspension aids, surface active agents, isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants and
the like, as suited to the particular dosage form desired.
Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.
Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various
carriers used in formulating pharmaceutically acceptable
compositions and known techniques for the preparation thereof.
Except insofar as any conventional carrier medium is incompatible
with the compounds of the invention, such as by producing any
undesirable biological effect or otherwise interacting in a
deleterious manner with any other component(s) of the
pharmaceutically acceptable composition, its use is contemplated to
be within the scope of this invention.
[0516] Some examples of materials which can serve as
pharmaceutically acceptable carriers 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, or 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, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water, isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0517] Provided formulations of pharmaceutically acceptable
compositions described herein may be prepared by any method known
or hereafter developed in the art of pharmacology. In general, such
preparatory methods include the step of bringing 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.
[0518] A pharmaceutically acceptable composition of the invention
may be prepared, packaged, and/or sold in bulk, as a single unit
dose, and/or as a plurality of single unit doses. As used herein, a
"unit dose" is discrete amount of the pharmaceutically acceptable
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.
[0519] Relative amounts of the active ingredient, the
pharmaceutically acceptable carrier, and/or any additional
ingredients in a pharmaceutically acceptable 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.
[0520] In some embodiments, the pharmaceutically acceptable
excipient is at least 95%, 96%, 97%, 98%, 99%, or 100% pure. In
some embodiments, the excipient is approved for use in humans and
for veterinary use. In some embodiments, the excipient is approved
by United States Food and Drug Administration. In some embodiments,
the excipient is pharmaceutical grade. In some embodiments, the
excipient meets the standards of the United States Pharmacopoeia
(USP), the European Pharmacopoeia (EP), the British Pharmacopoeia,
and/or the International Pharmacopoeia.
[0521] Pharmaceutically acceptable excipients used in the
manufacture of provided pharmaceutically acceptable compositions
include, but are not limited to, 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. Such excipients may
optionally be included in the inventive formulations. Excipients
such as cocoa butter and suppository waxes, coloring agents,
coating agents, sweetening, flavoring, and perfuming agents can be
present in the composition, according to the judgment of the
formulator.
[0522] Exemplary diluents include, but are not limited to, calcium
carbonate, sodium carbonate, calcium phosphate, dicalcium
phosphate, calcium sulfate, calcium hydrogen phosphate, sodium
phosphate lactose, sucrose, cellulose, microcrystalline cellulose,
kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch,
cornstarch, powdered sugar, etc., and combinations thereof.
[0523] Exemplary granulating and/or dispersing agents include, but
are not limited to, potato starch, corn starch, tapioca starch,
sodium starch glycolate, clays, alginic acid, guar gum, citrus
pulp, agar, bentonite, cellulose and wood products, natural sponge,
cation-exchange resins, calcium carbonate, silicates, sodium
carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone),
sodium carboxymethyl starch (sodium starch glycolate),
carboxymethyl cellulose, cross-linked sodium carboxymethyl
cellulose (croscarmellose), methylcellulose, pregelatinized starch
(starch 1500), microcrystalline starch, water insoluble starch,
calcium carboxymethyl cellulose, magnesium aluminum silicate
(Veegum), sodium lauryl sulfate, quaternary ammonium compounds,
etc., and combinations thereof.
[0524] Exemplary surface active agents and/or emulsifiers include,
but are not limited to, natural emulsifiers (e.g. acacia, agar,
alginic acid, sodium alginate, tragacanth, chondrux, cholesterol,
xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol,
wax, and lecithin), colloidal clays (e.g. bentonite [aluminum
silicate] and Veegum [magnesium aluminum silicate]), long chain
amino acid derivatives, high molecular weight alcohols (e.g.
stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin
monostearate, ethylene glycol distearate, glyceryl monostearate,
and propylene glycol monostearate, polyvinyl alcohol), carbomers
(e.g. carboxy polymethylene, polyacrylic acid, acrylic acid
polymer, and carboxyvinyl polymer), carrageenan, cellulosic
derivatives (e.g. carboxymethylcellulose sodium, powdered
cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty
acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20],
polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan
monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan
monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl
monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters
(e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene
hydrogenated castor oil, polyethoxylated castor oil,
polyoxymethylene stearate, and Solutol), sucrose fatty acid esters,
polyethylene glycol fatty acid esters (e.g. Cremophor),
polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij
30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate,
triethanolamine oleate, sodium oleate, potassium oleate, ethyl
oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic
F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride,
benzalkonium chloride, docusate sodium, etc. and/or combinations
thereof.
[0525] Exemplary binding agents include, but are not limited to,
starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g.
sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol,
mannitol, etc.); natural and synthetic gums (e.g. acacia, sodium
alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage
of isapol husks, carboxymethylcellulose, methylcellulose,
ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, microcrystalline cellulose,
cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum
silicate (Veegum), and larch arabogalactan); alginates;
polyethylene oxide; polyethylene glycol; inorganic calcium salts;
silicic acid; polymethacrylates; waxes; water, alcohol; etc.; and
combinations thereof.
[0526] Exemplary preservatives may include antioxidants, chelating
agents, antimicrobial preservatives, antifungal preservatives,
alcohol preservatives, acidic preservatives, and other
preservatives.
[0527] Exemplary antioxidants include, but are not limited to,
alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated
hydroxyanisole, butylated hydroxytoluene, monothioglycerol,
potassium metabisulfite, propionic acid, propyl gallate, sodium
ascorbate, sodium bisulfite, sodium metabisulfite, and sodium
sulfite.
[0528] Exemplary chelating agents include
ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate,
disodium edetate, dipotassium edetate, edetic acid, fumaric acid,
malic acid, phosphoric acid, sodium edetate, tartaric acid, and
trisodium edetate. Exemplary antimicrobial preservatives include,
but are not limited to, benzalkonium chloride, benzethonium
chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium
chloride, chlorhexidine, chlorobutanol, chlorocresol,
chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine,
imidurea, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric nitrate, propylene glycol, and thimerosal.
[0529] Exemplary antifungal preservatives include, but are not
limited to, butyl paraben, methyl paraben, ethyl paraben, propyl
paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate,
potassium sorbate, sodium benzoate, sodium propionate, and sorbic
acid.
[0530] Exemplary alcohol preservatives include, but are not limited
to, ethanol, polyethylene glycol, phenol, phenolic compounds,
bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl
alcohol.
[0531] Exemplary acidic preservatives include, but are not limited
to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid,
acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and
phytic acid.
[0532] Other preservatives include, but are not limited to,
tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide,
butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether
sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium
sulfite, potassium metabisulfite, Glydant Plus, Phenonip,
methylparaben, Germall 115, Germaben II, Neolone, Kathon, and
Euxyl. In certain embodiments, the preservative is an anti-oxidant.
In other embodiments, the preservative is a chelating agent.
[0533] Exemplary buffering agents include, but are not limited to,
citrate buffer solutions, acetate buffer solutions, phosphate
buffer solutions, ammonium chloride, calcium carbonate, calcium
chloride, calcium citrate, calcium glubionate, calcium gluceptate,
calcium gluconate, D-gluconic acid, calcium glycerophosphate,
calcium lactate, propanoic acid, calcium levulinate, pentanoic
acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium
phosphate, calcium hydroxide phosphate, potassium acetate,
potassium chloride, potassium gluconate, potassium mixtures,
dibasic potassium phosphate, monobasic potassium phosphate,
potassium phosphate mixtures, sodium acetate, sodium bicarbonate,
sodium chloride, sodium citrate, sodium lactate, dibasic sodium
phosphate, monobasic sodium phosphate, sodium phosphate mixtures,
tromethamine, magnesium hydroxide, aluminum hydroxide, alginic
acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl
alcohol, etc., and combinations thereof.
[0534] Exemplary lubricating agents include, but are not limited
to, magnesium stearate, calcium stearate, stearic acid, silica,
talc, malt, glyceryl behanate, hydrogenated vegetable oils,
polyethylene glycol, sodium benzoate, sodium acetate, sodium
chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate,
etc., and combinations thereof.
[0535] Exemplary oils include, but are not limited to, almond,
apricot kernel, avocado, babassu, bergamot, black current seed,
borage, cade, camomile, canola, caraway, carnauba, castor,
cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton
seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol,
gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba,
kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut,
mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,
orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,
pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,
sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,
soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut,
and wheat germ oils. Exemplary oils include, but are not limited
to, butyl stearate, caprylic triglyceride, capric triglyceride,
cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl
myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone
oil, and combinations thereof.
[0536] Liquid dosage forms for oral and parenteral administration
include, but are not limited to, pharmaceutically acceptable
emulsions, microemulsions, solutions, suspensions, syrups and
elixirs. In addition to the active ingredients, the liquid dosage
forms may comprise inert diluents commonly used in the art such as,
for example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can include adjuvants
such as wetting agents, emulsifying and suspending agents,
sweetening, flavoring, and perfuming agents. In certain embodiments
for parenteral administration, the conjugates of the invention are
mixed with solubilizing agents such as Cremophor, alcohols, oils,
modified oils, glycols, polysorbates, cyclodextrins, polymers, and
combinations thereof.
[0537] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0538] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0539] 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 may 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.
[0540] Compositions for rectal or vaginal administration are
typically suppositories which can be prepared by mixing the
conjugates of this invention with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or
a suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active ingredient.
[0541] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active ingredient is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may comprise buffering agents.
[0542] Solid compositions of a similar type may be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally comprise opacifying agents and can be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes. Solid compositions of a
similar type may be employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as
well as high molecular weight polethylene glycols and the like.
[0543] The active ingredients can be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active ingredient may be admixed with at least one inert diluent
such as sucrose, lactose or starch. Such dosage forms may comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may comprise
buffering agents. They may optionally comprise opacifying agents
and can be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions which can be used include polymeric
substances and waxes.
[0544] Dosage forms for topical and/or transdermal administration
of a compound of this invention may include ointments, pastes,
creams, lotions, gels, powders, solutions, sprays, inhalants and/or
patches. Generally, the active ingredient is admixed under sterile
conditions with a pharmaceutically acceptable carrier and/or any
needed preservatives and/or buffers as may be required.
Additionally, the present invention contemplates the use of
transdermal patches, which often have the added advantage of
providing controlled delivery of an active ingredient to the body.
Such dosage forms may be prepared, for example, by dissolving
and/or dispensing the active ingredient in the proper medium.
Alternatively or additionally, the rate may be controlled by either
providing a rate controlling membrane and/or by dispersing the
active ingredient in a polymer matrix and/or gel.
[0545] Suitable devices for use in delivering intradermal
pharmaceutically acceptable compositions described herein include
short needle devices such as those described in U.S. Pat. Nos.
4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235;
5,141,496; and 5,417,662. Intradermal compositions may be
administered by devices which limit the effective penetration
length of a needle into the skin, such as those described in PCT
publication WO 99/34850 and functional equivalents thereof. Jet
injection devices which deliver liquid vaccines to the dermis via a
liquid jet injector and/or via a needle which pierces the stratum
corneum and produces a jet which reaches the dermis are suitable.
Jet injection devices are described, for example, in U.S. Pat. Nos.
5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;
5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;
5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;
4,940,460; and PCT publications WO 97/37705 and WO 97/13537.
Ballistic powder/particle delivery devices which use compressed gas
to accelerate vaccine in powder form through the outer layers of
the skin to the dermis are suitable. Alternatively or additionally,
conventional syringes may be used in the classical mantoux method
of intradermal administration.
[0546] Formulations suitable for topical administration include,
but are not limited to, liquid and/or semi liquid preparations such
as liniments, lotions, oil in water and/or water in oil emulsions
such as creams, ointments and/or pastes, and/or solutions and/or
suspensions. Topically-administrable formulations may, for example,
comprise from about 1% to about 10% (w/w) active ingredient,
although the concentration of the active ingredient may be as high
as the solubility limit of the active ingredient in the solvent.
Formulations for topical administration may further comprise one or
more of the additional ingredients described herein.
[0547] A pharmaceutically acceptable composition of the invention
may be prepared, packaged, and/or sold in a formulation suitable
for pulmonary administration via the buccal cavity. Such a
formulation may comprise dry particles which comprise the active
ingredient and which have a diameter in the range from about 0.5 to
about 7 nanometers or from about 1 to about 6 nanometers. Such
compositions are conveniently in the form of dry powders for
administration using a device comprising a dry powder reservoir to
which a stream of propellant may be directed to disperse the powder
and/or using a self propelling solvent/powder dispensing container
such as a device comprising the active ingredient dissolved and/or
suspended in a low-boiling propellant in a sealed container. Such
powders comprise particles wherein at least 98% of the particles by
weight have a diameter greater than 0.5 nanometers and at least 95%
of the particles by number have a diameter less than 7 nanometers.
Alternatively, at least 95% of the particles by weight have a
diameter greater than 1 nanometer and at least 90% of the particles
by number have a diameter less than 6 nanometers. Dry powder
compositions may include a solid fine powder diluent such as sugar
and are conveniently provided in a unit dose form.
[0548] Low boiling propellants generally include liquid propellants
having a boiling point of below 65.degree. F. at atmospheric
pressure. Generally the propellant may constitute 50 to 99.9% (w/w)
of the composition, and the active ingredient may constitute 0.1 to
20% (w/w) of the composition. The propellant may further comprise
additional ingredients such as a liquid non-ionic and/or solid
anionic surfactant and/or a solid diluent (which may have a
particle size of the same order as particles comprising the active
ingredient).
[0549] Pharmaceutically acceptable compositions of the invention
formulated for pulmonary delivery may provide the active ingredient
in the form of droplets of a solution and/or suspension. Such
formulations may be prepared, packaged, and/or sold as aqueous
and/or dilute alcoholic solutions and/or suspensions, optionally
sterile, comprising the active ingredient, and may conveniently be
administered using any nebulization and/or atomization device. Such
formulations may further comprise one or more additional
ingredients including, but not limited to, a flavoring agent such
as saccharin sodium, a volatile oil, a buffering agent, a surface
active agent, and/or a preservative such as methylhydroxybenzoate.
The droplets provided by this route of administration may have an
average diameter in the range from about 0.1 to about 200
nanometers.
[0550] The formulations described herein as being useful for
pulmonary delivery are useful for intranasal delivery of a
pharmaceutically acceptable composition of the invention. Another
formulation suitable for intranasal administration is a coarse
powder comprising the active ingredient and having an average
particle from about 0.2 to 500 micrometers. Such a formulation is
administered in the manner in which snuff is taken, i.e. by rapid
inhalation through the nasal passage from a container of the powder
held close to the nares.
[0551] Formulations suitable for nasal administration may, for
example, comprise from about as little as 0.1% (w/w) and as much as
100% (w/w) of the active ingredient, and may comprise one or more
of the additional ingredients described herein. A pharmaceutically
acceptable composition of the invention may be prepared, packaged,
and/or sold in a formulation suitable for buccal administration.
Such formulations may, for example, be in the form of tablets
and/or lozenges made using conventional methods, and may, for
example, 0.1 to 20% (w/w) active ingredient, the balance comprising
an orally dissolvable and/or degradable composition and,
optionally, one or more of the additional ingredients described
herein. Alternately, formulations suitable for buccal
administration may comprise a powder and/or an aerosolized and/or
atomized solution and/or suspension comprising the active
ingredient. Such powdered, aerosolized, and/or aerosolized
formulations, when dispersed, may have an average particle and/or
droplet size in the range from about 0.1 to about 200 nanometers,
and may further comprise one or more of the additional ingredients
described herein.
[0552] A pharmaceutically acceptable composition of the invention
may be prepared, packaged, and/or sold in a formulation suitable
for ophthalmic administration. Such formulations may, for example,
be in the form of eye drops including, for example, a 0.1/1.0%
(w/w) solution and/or suspension of the active ingredient in an
aqueous or oily liquid carrier. Such drops may further comprise
buffering agents, salts, and/or one or more other of the additional
ingredients described herein. Other opthalmically-administrable
formulations which are useful include those which comprise the
active ingredient in microcrystalline form and/or in a liposomal
preparation. Ear drops and/or eye drops are contemplated as being
within the scope of this invention.
[0553] General considerations in the formulation and/or manufacture
of pharmaceutical agents may be found, for example, in Remington:
The Science and Practice of Pharmacy 21.sup.st ed., Lippincott
Williams & Wilkins, 2005.
[0554] Although the descriptions of pharmaceutically acceptable
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 pharmaceutically acceptable
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
merely ordinary, if any, experimentation.
5. Kits
[0555] Still further encompassed by the invention are kits
comprising one or more compounds of the invention (or
pharmaceutically acceptable salts or prodrugs thereof), and/or one
or more pharmaceutically acceptable compositions as described
herein. Kits are typically provided in a suitable container (e.g.,
for example, a foil, plastic, or cardboard package).
[0556] In certain embodiments, an inventive kit may include one or
more pharmaceutical excipients, pharmaceutical additives,
therapeutically active agents, and the like, as described herein.
In certain embodiments, an inventive kit may include means for
proper administration, such as, for example, graduated cups,
syringes, needles, cleaning aids, and the like. In certain
embodiments, an inventive kit may include instructions for proper
administration and/or preparation for proper administration.
6. Methods of Treatment
[0557] The present invention also provides methods for treating an
FAAH-mediated disease, disorder or condition by administering a
therapeutically effective amount of a compound of any of formulae
(I), (II), (III), (IV), (V), or (VI), or subgenera thereof, or a
pharmaceutically acceptable composition thereof, to a patient in
need thereof.
[0558] Additionally, the present invention provides methods for
inhibiting FAAH in a patient by administering a therapeutically
effective amount of a compound of any of formulae (I), (II), (III),
(IV), (V), or (VI), or subgenera thereof, or a pharmaceutically
acceptable composition thereof, to a patient in need thereof.
[0559] A patient to which administration is contemplated includes,
but is not limited to, humans (e.g., male, female, infant, child,
adolescant, adult, elderly, etc.) and/or other primates; mammals,
including commercially relevant mammals such as cattle, pigs,
horses, sheep, cats, and/or dogs; and/or birds, including
commercially relevant birds such as chickens, ducks, geese, and/or
turkeys.
[0560] "Treating," as used herein, refers to partially or
completely inhibiting or reducing the condition from which the
patient is suffering.
[0561] "Therapeutically effective amount," as used herein, refers
to the minimal amount or concentration of an inventive compound, or
pharmaceutically acceptable composition thereof, that, when
administered, is sufficient in treating the patient. Treating may
be via prophylactic or therapeutic therapy.
[0562] In other embodiments, the present invention provides a
method for inhibiting FAAH in a biological sample comprising the
step of contacting said sample with a compound of any of formulae
(I), (II), (III), (IV), (V), or (VI), or subgenera thereof, or with
a compound set forth in the Examples.
[0563] FAAH-mediated diseases, disorders or conditions include, but
are not limited to, painful conditions, inflammatory disorders,
immune disorders, depression, anxiety, anxiety-related disorders,
sleep disorders, feeding behaviors, movement disorders, glaucoma,
neuroprotection and cardiovascular disease.
[0564] In certain embodiments, the FAAH-mediated disease, disorder
or condition is a painful condition, disease or disorder. As used
herein, a "painful condition, disease or disorder" includes, but is
not limited to, neuropathic pain (e.g., peripheral neuropathic
pain), central pain, deafferentiation pain, chronic pain (e.g.,
chronic nociceptive pain, and other forms of chronic pain such as
post-operative pain), stimulus of nociceptive receptors, acute pain
(e.g., phantom and transient acute pain), non-inflammatory pain,
inflammatory pain, pain associated with cancer, wound pain, burn
pain, post-operative pain, pain associated with medical procedures,
arthritic pain (e.g., pain associated with rheumatoid arthritis,
osteoarthritis), lumbosacral pain, musculo-skeletal pain, headache,
migraine, muscle ache, lower back and neck pain, toothache and the
like.
[0565] In certain embodiments, the painful condition, disease or
disorder is neuropathic pain. The term "neuropathic pain" refers to
pain resulting from injury to a nerve. Neuropathic pain is
distinguished from nociceptive pain, which is the pain caused by
acute tissue injury involving small cutaneous nerves or small
nerves in muscle or connective tissue. Neuropathic pain typically
is long-lasting or chronic and often develops days or months
following an initial acute tissue injury. Neuropathic pain can
involve persistent, spontaneous pain as well as allodynia, which is
a painful response to a stimulus that normally is not painful.
Neuropathic pain also can be characterized by hyperalgesia, in
which there is an accentuated response to a painful stimulus that
usually is trivial, such as a pin prick. Neuropathic pain
conditions can develop following neuronal injury and the resulting
pain may persist for months or years, even after the original
injury has healed. Neuronal injury may occur in the peripheral
nerves, dorsal roots, spinal cord or certain regions in the brain.
Neuropathic pain conditions include: diabetic neuropathy; sciatica;
non-specific lower back pain; multiple sclerosis pain;
fibromyalgia; HIV-related neuropathy; neuralgia, such as
post-herpetic neuralgia and trigeminal neuralgia; and pain
resulting from physical trauma, amputation, cancer,
chemotherapy-induced pain, chemotherapy, surgery, invasive medical
procedures, toxins burns, infection, or chronic inflammatory
conditions. Neuropathic pain can result from a peripheral nerve
disorder such as neuroma; nerve compression; nerve crush, nerve
stretch or incomplete nerve transsection; mononeuropathy or
polyneuropathy. Neuropathic pain can also result from a disorder
such as dorsal root ganglion compression; inflammation of the
spinal cord; contusion, tumor or hemisection of the spinal cord;
tumors of the brainstem, thalamus or cortex; or trauma to the
brainstem, thalamus or cortex.
[0566] The symptoms of neuropathic pain are heterogeneous and are
often described as spontaneous shooting and lancinating pain, or
ongoing, burning pain. In addition, there is pain associated with
normally non-painful sensations such as "pins and needles"
(paraesthesias and dysesthesias), increased sensitivity to touch
(hyperesthesia), painful sensation following innocuous stimulation
(dynamic, static or thermal allodynia), increased sensitivity to
noxious stimuli (thermal, cold, mechanical hyperalgesia),
continuing pain sensation after removal of the stimulation
(hyperpathia) or an absence of or deficit in selective sensory
pathways (hypoalgesia).
[0567] In certain embodiments, the painful condition, disease or
disorder is non-inflammatory pain and/or inflammatory pain. The
types of non-inflammatory pain include, without limitation,
peripheral neuropathic pain (e.g., pain caused by a lesion or
dysfunction in the peripheral nervous system), central pain (e.g.,
pain caused by a lesion or dysfunction of the central nervous
system), deafferentation pain (e.g., pain due to loss of sensory
input to the central nervous system), chronic nociceptive pain
(e.g., certain types of cancer pain), noxious stimulus of
nociceptive receptors (e.g., pain felt in response to tissue damage
or impending tissue damage), phantom pain (e.g., pain felt in a
part of the body that no longer exists, such as a limb that has
been amputated), pain felt by psychiatric patients (e.g., pain
where no physical cause may exist), and wandering pain (e.g.,
wherein the pain repeatedly changes location in the body). In
certain embodiments, non-inflammatory pain and/or inflammatory pain
are associated with disorders such as inflammatory diseases (e.g.,
autoimmune disease).
[0568] In certain embodiments, the FAAH-mediated disease, disorder
or condition is an inflammatory disorder. The term "inflammatory
disorders" refers to those diseases or conditions that are
characterized by signs of pain (dolor, from the generation of
noxious substances and the stimulation of nerves), heat (calor,
from vasodilatation), redness (rubor, from vasodilatation and
increased blood flow), swelling (tumor, from excessive inflow or
restricted outflow of fluid), and/or loss of function (functio
laesa, which may be partial or complete, temporary or permanent).
Inflammatory disorders include, without limitation, those affecting
the blood vessels (e.g., polyarteritis, temporal arteritis); joints
(e.g, arthritis: crystalline, osteo-, psoriatic, reactive,
rheumatoid, Reiter's syndrome); gastrointestinal tract (e.g,
Crohn's disease, ulcerative colitis); skin (e.g, dermatitis); or
multiple organs and tissues (e.g, systemic lupus erythematosus).
Inflammatory disorders include, but are not limited to,
inflammation associated with vascular diseases, migraine headaches,
tension headaches, arteritis, thyroiditis, aplastic anemia,
Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes,
myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's
syndrome, polymyositis, gingivitis, hypersensitivity,
conjunctivitis, multiple sclerosis, and ischemia (e.g., myocardial
ischemia), and the like. The compounds and compositions may be
useful for treating neuroinflammation associated with brain
disorders (e.g., Parkinson's disease and Alzheimer's disease) and
chronic inflammation associated with cranial radiation injury. The
compounds may be useful for treating acute inflammatory conditions
(e.g., conditions resulting from infection) and chronic
inflammatory conditions (e.g., conditions resulting from asthma,
arthritis and inflammatory bowel disease). The compounds may also
be useful in treating inflammation associated with trauma and
non-inflammatory myalgia. Inflammation takes on many forms and
includes, but is not limited to, acute, adhesive, atrophic,
catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative,
fibrinous, fibrosing, focal, granulomatous, hyperplastic,
hypertrophic, interstitial, metastatic, necrotic, obliterative,
parenchymatous, plastic, productive, proliferous, pseudomembranous,
purulent, sclerosing, seroplastic, serous, simple, specific,
subacute, suppurative, toxic, traumatic, and/or ulcerative
inflammation.
[0569] In certain embodiments, the FAAH-mediated disease, disorder
or condition is an immune disorder. Immune disorders, such as
auto-immune disorders, include, but are not limited to, arthritis
(including rheumatoid arthritis, spondyloarthopathies, gouty
arthritis, degenerative joint diseases such as osteoarthritis,
systemic lupus erythematosus, Sjogren's syndrome, ankylosing
spondylitis, undifferentiated spondylitis, Behcet's disease,
haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic
lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and
juvenile arthritis), asthma, atherosclerosis, osteoporosis,
bronchitis, tendonitis, bursitis, skin inflammation disorders
(e.g., psoriasis, eczema, burns, dermatitis), enuresis,
eosinophilic disease, gastrointestinal disorders (e.g.,
inflammatory bowel disease (IBD), peptic ulcers, regional
enteritis, diverticulitis, gastrointestinal bleeding, Crohn's
disease, gastritis, diarrhoea, irritable bowel syndrome and
ulcerative colitis), and disorders ameliorated by a
gastroprokinetic agent (e.g., ileus, postoperative ileus and ileus
during sepsis; gastroesophageal reflux disease (GORD, or its
synonym GERD); eosinophilic esophagitis, gastroparesis such as
diabetic gastroparesis; food intolerances and food allergies and
other functional bowel disorders, such as non-ulcerative dyspepsia
(NUD) and non-cardiac chest pain (NCCP, including
costo-chondritis)).
[0570] In certain embodiments, the immune disorder is a
gastrointestinal disorder. In some embodiments, the immune disorder
is inflammatory bowel disease (e.g., Crohn's disease and/or
ulcerative colitis), peptic ulcers, regional enteritis,
diverticulitis, gastrointestinal bleeding, Crohn's disease,
gastritis, diarrhea, irritable bowel syndrome and ulcerative
colitis. In other embodiments, the immune disorder is inflammatory
bowel disease (IBD).
[0571] In certain embodiments, the FAAH-mediated disease, disorder
or condition is a skin disorder. In some embodiments, the skin
disorder is pruritus (itch), psoriasis, eczema, burns or
dermatitis. In certain embodiments, the the skin disorder is
psoriasis. In certain embodiments, the the skin disorder is
pruritis.
[0572] In certain embodiments, the FAAH-mediated disease, disorder
or condition is anxiety. "Anxiety," as used herein, includes, but
is not limited to anxiety and anxiety disorders or conditions, such
as, for example, clinical anxiety, panic disorder, agoraphobia,
generalized anxiety disorder, specific phobia, social phobia,
obsessive-compulsive disorder, acute stress disorder, and
post-traumatic stress disorder; and adjustment disorders with
anxious features, anxiety disorders associated with depression,
anxiety disorders due to general medical conditions, and
substance-induced anxiety disorders. This treatment may also be to
induce or promote sleep in a patient (e.g., for example, a patient
with anxiety).
[0573] In certain embodiments, the FAAH-mediated disease, disorder
or condition is a sleep disorder. "Sleep disorders" include, but
are not limited to, insomia, sleep apnea, restless legs syndrome
(RLS), delayed sleep phase syndrome (DSPS), periodic limb movement
disorder (PLMD), hypopnea syndrome, rapid eye movement behavior
disorder (RBD), shift work sleep disorder (SWSD), and sleep
problems (e.g., parasomnias) such as nightmares, night terrors,
sleep talking, head banging, snoring, and clenched jaw and/or
grinding of teeth (bruxism).
[0574] In certain embodiments, the FAAH-mediated disease, disorder
or condition is depression. "Depression," as used herein, includes,
but is not limited to, depressive disorders or conditions, such as,
for example, major depressive disorders (unipolar depression),
dysthymic disorders (chronic, mild depression) and bipolar
disorders (manic-depression). The depression may be clinical or
subclinical depression.
[0575] In certain embodiments, the FAAH-mediated disease, disorder
or condition is feeding behavior. "Feeding behavior," as used
herein, includes but is not limited to, eating disorders (e.g.,
anorexias and cachexias of various natures, over-eating leading to
obesity), weight loss associated with cancer, weight loss
associated with other general medical conditions, weight loss
associated with failure to thrive, and other wasting conditions.
The compounds disclosed herein can also be used to reduce body fat
and for treating or preventing obesity in a mammal. The compounds
disclosed herein can also be used for preventing or treating the
diseases associated with these health conditions.
[0576] In certain embodiments, the FAAH-mediated disease, disorder
or condition is a movement disorder. In other embodiments, the
FAAH-mediated disease, disorder or condition is glaucoma. In yet
other embodiments, the FAAH-mediated disease, disorder or condition
is neuroprotection. In still yet other embodiments, the
FAAH-mediated disease, disorder or condition is cardiovascular
disease.
[0577] In certain embodiments, the above methods provide
administering a compound of any of formulae (I), (II), (III), (IV),
(V), or (VI), or subgenera thereof, or a pharmaceutically
acceptable salt or prodrug thereof, to a patient in need
thereof.
[0578] In some embodiments, the above methods provide administering
a compound of any of formulae (I), (II), (III), (IV), (V), or (VI),
or subgenera thereof, or a pharmaceutically acceptable salt or
prodrug thereof, as provided in the Examples.
[0579] In other embodiments, the above methods provide
administering a compound of any of formulae (I), (II), (III), (IV),
(V), or (VI), or subgenera thereof, or a pharmaceutically
acceptable salt or prodrug thereof, having a K.sub.i of less than
or equal to 0.01 microM or having a K.sub.i of between 0.01 microM
and 0.1 microM (i.e., compounds with activities designated "A" or
"B").
[0580] In yet other embodiments, the above methods provide
administering a compound of any of formulae (I), (II), (III), (IV),
(V), or (VI), or subgenera thereof, or a pharmaceutically
acceptable salt or prodrug thereof, having a K of less than or
equal to 0.01 microM (i.e., compounds with activities designated
"A").
7. Administration
[0581] Provided compounds may be administered using any amount and
any route of administration effective for treatment. The exact
amount required will vary from subject to subject, depending on the
species, age, and general condition of the subject, the severity of
the infection, the particular composition, its mode of
administration, its mode of activity, and the like.
[0582] Compounds of the present invention are typically formulated
in dosage unit form for ease of administration and uniformity of
dosage. It will be understood, however, that the total daily usage
of the compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
subject or organism will depend upon a variety of factors including
the disease, disorder, or condition being treated and the severity
of the disorder; the activity of the specific active ingredient
employed; the specific composition employed; the age, body weight,
general health, sex and diet of the subject; the time of
administration, route of administration, and rate of excretion of
the specific active ingredient employed; the duration of the
treatment; drugs used in combination or coincidental with the
specific active ingredient employed; and like factors well known in
the medical arts.
[0583] Provided compounds and compositions of the present invention
may be administered by any route. In some embodiments, provided
compounds and compositions are administered via a variety of
routes, including oral, intravenous, intramuscular, intra-arterial,
intramedullary, intrathecal, subcutaneous, intraventricular,
transdermal, interdermal, rectal, intravaginal, intraperitoneal,
topical (as by powders, ointments, creams, and/or drops), mucosal,
nasal, bucal, enteral, sublingual; by intratracheal instillation,
bronchial instillation, and/or inhalation; and/or as an oral spray,
nasal spray, and/or aerosol. Specifically contemplated routes are
systemic intravenous injection, regional administration via blood
and/or lymph supply, and/or direct administration to an affected
site. In general the most appropriate route of administration will
depend upon a variety of factors including the nature of the agent
(e.g., its stability in the environment of the gastrointestinal
tract), the condition of the subject (e.g., whether the subject is
able to tolerate oral administration), etc. At present the oral
and/or nasal spray and/or aerosol route is most commonly used to
deliver therapeutic agents directly to the lungs and/or respiratory
system. However, the invention encompasses the delivery of a
provided pharmaceutically acceptable composition by any appropriate
route taking into consideration likely advances in the sciences of
drug delivery.
[0584] The exact amount of a compound required to achieve a
therapeutically effective amount will vary from subject to subject,
depending 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 may 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 may be delivered using multiple
administrations (e.g., two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, or more
administrations).
[0585] In certain embodiments of the present invention, a
therapeutically effective amount of an inventive compound for
administration one or more times a day to a 70 kg adult human may
comprise about 0.0001 mg to about 1000 mg of an inventive compound
per unit dosage form. It will be appreciated that dose ranges as
described herein provide guidance for the administration of
provided pharmaceutically acceptable 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.
[0586] It will be also appreciated that an inventive compound or
composition, as described above and herein, can be administered in
combination with one or more additional therapeutically active
agents.
[0587] By "in combination with," it is not intended to imply that
the agents must be administered at the same time and/or formulated
for delivery together, although these methods of delivery are
certainly within the scope of the invention. The compositions can
be administered concurrently with, prior to, or subsequent to, one
or more other additional therapeutically active agents. In general,
each agent will be administered at a dose and/or on a time schedule
determined for that agent. In will further be appreciated that the
additional therapeutically active agent utilized in this
combination may be administered together in a single composition or
administered separately in different compositions. The particular
combination to employ in a regimen will take into account
compatibility of the inventive compound with the additional
therapeutically active agent and/or the desired therapeutic effect
to be achieved.
[0588] In general, it is expected that additional therapeutically
active agents utilized in combination be utilized at levels that do
not exceed the levels at which they are utilized individually. In
some embodiments, the levels utilized in combination will be lower
than those utilized individually.
[0589] By a "therapeutically active agent" or "active agent" refers
to any substance that is useful for therapy, including prophylactic
and therapeutic treatment.
[0590] The invention encompasses the delivery of provided
pharmaceutically acceptable compositions in combination with agents
that may 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
therapy employed may achieve a desired effect for the same disorder
(for example, an inventive compound may be administered in
combination with an anti-inflammatory, anti-anxiety and/or
anti-depressive agent, etc.), and/or they may achieve different
effects (e.g., control of any adverse side-effects).
[0591] Exemplary active agents include, but are not limited to,
anti-cancer agents, antibiotics, anti-viral agents, anesthetics,
anti-coagulants, inhibitors of an enzyme, steroidal agents,
steroidal or non-steroidal anti-inflammatory agents, antihistamine,
immunosuppressant agents, anti-neoplastic agents, antigens,
vaccines, antibodies, decongestant,s sedatives, opioids,
pain-relieving agents, analgesics, anti-pyretics, hormones,
prostaglandins, progestational agents, anti-glaucoma agents,
ophthalmic agents, anti-cholinergics, anti-depressants,
anti-psychotics, hypnotics, tranquilizers, anti-convulsants, muscle
relaxants, anti-spasmodics, muscle contractants, channel blockers,
miotic agents, anti-secretory agents, anti-thrombotic agents,
anticoagulants, anti-cholinergics, .beta.-adrenergic blocking
agents, diuretics, cardiovascular active agents, vasoactive agents,
vasodilating agents, anti-hypertensive agents, angiogenic agents,
modulators of cell-extracellular matrix interactions (e.g. cell
growth inhibitors and anti-adhesion molecules), or
inhibitors/intercalators of DNA, RNA, protein-protein interactions,
protein-receptor interactions, etc. Active agents include small
organic molecules such as drug compounds (e.g., compounds approved
by the Food and Drugs 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.
[0592] In certain embodiments, the additional therapeutically
active agent is a pain-relieving agent. In other embodiments, the
additional therapeutically active agent is an anti-inflammatory
agent.
8. Methods of Determining Biological Activity
[0593] Methods of determining the activity of compounds of the
present invention for various therapeutic uses are well known in
the art. These include, but are not limited to, high throughput
screening to identify compounds that bind to and/or modulate the
activity of isolated FAAH, as well as animal and cellular models of
therapies.
[0594] Assays for compounds described herein are amenable to high
throughput screening. Assays useful for screening the compounds of
the present invention may detect the binding of the inhibitor to
FAAH or the release of a reaction product (e.g., fatty acid amide
or ethanolamine) produced by the hydrolysis of a substrate such as
oleoylethanolamide or ananadamide. The substrate may be labeled to
facilitate detection of the released reaction products. U.S. Pat.
No. 5,559,410 discloses high throughput screening methods for
proteins, and U.S. Pat. Nos. 5,576,220 and 5,541,061 disclose high
throughput methods of screening for ligand/antibody binding.
[0595] Methods for screening FAAH inhibitors for an antinociceptive
effect are well known to one of ordinary skill in the art. For
instance, the test compounds can be administered to the subject
animals in the mouse hot-plate test and the mouse formalin test and
the nociceptive reactions to thermal or chemical tissue damage
measured (for example, see U.S. Pat. No. 6,326,156 which teaches
methods of screening for antinociceptive activity; see also Cravatt
et al. Proc. Natl. Acad. Sci. U.S.A. (2001) 98:9371-9376).
[0596] Two pharmacologically validated animal models of anxiety are
the elevated zero maze test, and the isolation-induced ultrasonic
emission test. The zero maze consists of an elevated annular
platform with two open and two closed quadrants and is based on the
conflict between an animal's instinct to explore its environment
and its fear of open spaces, where it may be attacked by predators
(see, for example, Bickerdike, M. J. et al., Eur. J. Pharmacol.,
(994) 271, 403-411; Shepherd, J. K. et al., Psychopharmacology,
(1994) 116, 56-64). Clinically used anxiolytic drugs, such as the
benzodiazepines, increase the proportion of time spent in, and the
number of entries made into, the open compartments.
[0597] A second test for an anti-anxiety compound is the ultrasonic
vocalization emission model, which measures the number of
stress-induced vocalizations emitted by rat pups removed from their
nest (see, for example, Insel, T. R. et al., Pharmacol. Biochem.
Behav., 24, 1263-1267 (1986); Miczek, K. A. et al.,
Psychopharmacology, 121, 38-56 (1995); Winslow, J. T. et al., Biol.
Psychiatry, 15, 745-757 (1991).
[0598] The effect of the compound of the invention in the treatment
of depression can be tested in the model of chronic mild stress
induced anhedonia in rats. This model is based on the observation
that chronic mild stress causes a gradual decrease in sensitivity
to rewards, for example consumption of sucrose, and that this
decrease is dose-dependently reversed by chronic treatment with
antidepressants. The method has previously been described and more
information with respect to the test appears from Willner, Paul,
Psychopharmacology, 1997, 134, 319-329.
[0599] Another test for antidepressant activity is the forced
swimming test (Nature 266, 730-732, 1977). In this test, animals
are administered an agent, preferably by the intraperitoneal route
or by the oral route, 30 or 60 minutes before the test. The animals
are placed in a crystallizing dish filled with water and the time
during which they remain immobile is clocked. The immobility time
is then compared with that of the control group treated with
distilled water. Imipramine 25 mg/kg. can be used as the positive
control. The antidepressant compounds decrease the immobility time
of the mice thus immersed.
[0600] Another test for antidepressant activity is the caudal
suspension test on the mouse (Psychopharmacology, 85, 367-370,
1985). In this test, animals are preferably treated with the study
compound by the intraperitoneal route or by the oral route 30 or 60
minutes before the test. The animals are then suspended by the tail
and their immobility time is automatically recorded by a computer
system. The immobility times are then compared with those of a
control group treated with distilled water. Imipramine 25 mg/kg can
be used as the positive control. Antidepressant compounds decrease
the immobility time of the mice.
[0601] Animal models are available to one of ordinary skill in the
art for studying anticonvulsant activity of test compounds. See for
instance, U.S. Pat. No. 6,309,406 and U.S. Pat. No. 6,326,156 which
describe methods for performing such tests.
[0602] Inhibition of FAAH has been reported to induce sleep in test
animals (U.S. Pat. No. 6,096,784). Methods for studying sleep
inducing compounds are well known to one of ordinary skill in the
art. In particular, methods for testing the ability of a FAAH
inhibitory compound to induce sleep or treat insomnia are disclosed
in U.S. Pat. No. 6,096,784 and U.S. Pat. No. 6,271,015. Most
obviously, the compounds can be administered to a test animal
(e.g., rat or mouse) or a human and the subsequent time (e.g.,
onset, duration) spent sleeping (e.g., eyes closed, motor
quiescence) can be monitored. See also WO 98/24396.
[0603] Methods for screening FAAH inhibitors which induce catalepsy
are also well known to one of ordinary skill in the art. See
Quistand et al. in Toxicology and Applied Pharmacology 173: 48-55
(2001). See Cravatt et al. Proc. Natl. Acad. Sci. U.S.A.
98:9371-9376 (2001).
[0604] Methods of assessing appetitive behavior are known to one of
ordinary skill in the art. For instance, Maruani et al. (U.S. Pat.
No. 6,344,474) teach two such assays. One method of assessing the
effect on appetite behavior is to administer a FAAH inhibitor to a
rat and assess its effect on the intake of a sucrose solution. This
method is taught in W. C. Lynch et al., Physiol. Behav., 1993, 54,
877-880.
9. Covalent Complex Formation between Serine-241 of FAAH and
Boronic Acid Inhibitors
[0605] Compounds provided herein can form reversible covalent
complexes with the nucleophilic side chain of Ser-241 FAAH.
[0606] Thus, compounds of any of formulae (I), (II), (III), (IV),
(V), or (VI), or subgenera thereof, as described above and herein,
associated with (e.g., complexed with) a serine residue of a
protein are also provided.
[0607] For example, in certain embodiments, compounds of any
offormulae (III), (IV), (V), or (VI), or subgenera thereof, as
described above and herein, are associated with a serine residue of
a protein:
##STR00328##
wherein Res.sub.1-Ser-Res.sub.2 is a protein having a length
between about 400 to about 600 residues.
[0608] By "Ser" is meant a serine residue. In certain embodiments,
Ser is Ser.sub.241 of FAAH protein. In some embodiments, the
protein is rat FAAH. In other embodiments, the protein is human
FAAH (SEQ ID NO. 1). In certain embodiments, the active site of the
protein has a Lys at 142; a Ser at 217; and a Ser at 241. In
certain embodiments, the compound binds at Ser.sub.241.
[0609] By Res.sub.1 is meant the residue(s) closer to the
N-terminus than Ser. By Res.sub.2 is meant the residue(s) closer to
the C-terminus than Ser. In certain embodiments, Res.sub.1 has a
serine residue that is 24 amino acids closer to the N terminus than
(Ser) and a lysine residue that is 99 amino acids closer to the N
terminus than (Ser).
[0610] In certain embodiments, Z.sup.1 and Z.sup.2 are both --OH.
Thus, in certain embodiments, the compound is a boronic acid
compound.
10. Methods of Synthesis
[0611] A number of methods are known in the art to synthesize the
compounds provided herein. A recognized method of synthesizing
boronate esters is the reaction of an organometallic species with
an organic borate, such as trimethyl borate. Suitable
organometallic species include, but are not limited to, alkyl
lithium and Grignard reagents. Other methods for the synthesis of
boronates are employed when the boronate contains sensitive
functionality that may not tolerate alkyl lithium reagents or
Grignard reagents. These methods include palladium coupling
reactions of aryl or akenyl halides and diboronates or dialkoxy
boranes and hydroboration of alkenes or alkynes. Using these
methods a diverse collection of boronates can be synthesized.
Boronates can be readily transformed in to boronic acids by
hydrolyzing the boronate under aqueous acidic conditions using a
suitable acid. Suitable acids include, but are not limited to HCl,
H.sub.2SO.sub.4, and HBr. Another method of hydrolyzing boronates
is an oxidative hydrolysis employing an oxidizing agent, such as
NaIO.sub.4, as exemplified in Example 5. The boronic acid compounds
of the present invention readily form boronic esters when exposed
to alcohols. The resulting boronic esters may also be used in the
methods provided herein. Cyclic boronates are formed when certain
diols (e.g., 1,2- and 1,3-diols) are used. Boronic acid compounds
provided herein readily form oligomeric anhydrides by dehydration
of the boronic acid moiety to form dimers, trimers, and tetramers,
and mixtures thereof. These species in the presence of water and
under physiological conditions convert back to the boronic acid by
hydrolysis.
EXEMPLIFICATION
[0612] The invention now being generally described, it will be more
readily understood by reference to the following examples, which
are included merely for purposes of illustration of certain aspects
and embodiments of the present invention, and are not intended to
limit the invention.
[0613] Exemplary compounds are set forth in the Examples provided
below. Compounds were assayed as inhibitors of human FAAH using the
method described in detail in Example 286.
[0614] Activity of exemplified compounds are provided in the
Examples, wherein activity designated as "A" refers to compounds
having a K.sub.i of less than or equal to 0.01 microM, "B" refers
to compounds having a K.sub.i of between 0.01 microM and 0.1
microM, "C" refers to compounds having a K.sub.i of between 0.1
microM and 1 microM, and "D" refers to compounds having a K.sub.i
of greater than 1 microM.
General Synthetic Methods
Preparation of Boronic Acids:
##STR00329##
[0615] Method 1
[0616] General conditions for the preparation of boronic acids:
under an argon atmosphere, 0.1 M aryl bromide (1.0 equiv) dissolved
in 4:1 toluene/tetrahydrofuran was cooled to -78.degree. C.
Triisopropylborate (1.3 equiv) was added, and the mixture was
treated dropwise with nBuLi in hexanes (1.2 equiv). After stirring
for 30 min, the mixture was warmed to 0.degree. C. and stirred for
an additional 30 min. The mixture was quenched with 2N aqueous HCl
(10 equiv) and stirred for 1 h at 23.degree. C. The mixture was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine and then dried over sodium sulfate. The
residue upon concentration was purified either by
recrystallization/trituration (heptanes, acetonitrile, or other) or
by flash silica gel chromatography (1.fwdarw.10%
methanol/dichloromethane) to generally produce a white solid.
Method 2
[0617] General conditions for the preparation of boronic acids:
under an argon atmosphere, 0.1 M aryl bromide (1.0 equiv) dissolved
in 4:1 toluene/tetrahydrofuran was cooled to -78.degree. C. nBuLi
in hexanes (2.5M, 1.2 equiv) was added dropwise, and the mixture
was stirred for 60 min. Triisopropylborate (1.3 equiv) was then
added dropwise to the clear stirring solution. After 15 min, the
mixture was warmed to 0.degree. C. and stirred for an additional 30
min. The mixture was quenched with 2N aqueous HCl (10 equiv) and
stirred for h at 23.degree. C. The mixture was diluted with water
and extracted with ethyl acetate. The organic layer was washed with
brine and then dried over sodium sulfate. The residue upon
concentration was purified either by recrystallization/trituration
(heptanes, acetonitrile, or other) or by flash silica gel
chromatography (1.fwdarw.10% methanol/dichloromethane) to generally
produce a white solid.
Preparation of Boronic Acid Pinacol Esters:
##STR00330##
[0618] Method 3
[0619] General conditions for the preparation of boronic acid
pinacol esters: a dry flask under argon atmosphere was charged with
aryl bromide (1.0 equiv),
1,1''-Bis(diphenylphosphino)-ferrocenedichloropalladium(II) (0.05
equiv), potassium acetate (1.0 equiv), cesium carbonate (3 equiv),
and bis(pinacolato)diboron (2.0 equiv). The mixture was suspended
with dimethylsulfoxide (0.1 M with respect to aryl bromide) and
heated at 80.degree. C. for 2-8 h. Upon completion as judged by
thin layer chromatography analysis, the reaction was split between
water and ethyl acetate, and the organic layer was washed with
brine, dried over sodium sulfate, and concentrated in vacuo. The
concentrated reaction mixture was purified by flash silica gel
chromatography (ethyl acetate/hexanes) to provide boronic acid
pinacol ester.
Method 4
[0620] General conditions for the preparation of boronic acid
pinacol esters: a dry flask under argon atmosphere was charged with
aryl bromide (1.0 equiv), bis(triphenylphosphine)palladium(II)
dichloride (0.05 equiv), potassium acetate (2.0 equiv), and
bis(pinacolato)diboron (1.5 equiv). The mixture was suspended with
1,4-dioxane (0.1 M with respect to aryl bromide) and heated at
80.degree. C. for 2-8 h. Upon completion as judged by thin layer
chromatography analysis, the reaction was split between water and
ethyl acetate, and the organic layer was washed with brine, dried
over sodium sulfate, and concentrated in vacuo. The concentrated
reaction mixture was purified by flash silica gel chromatography
(ethyl acetate/hexanes) to provide boronic acid pinacol ester.
Conversion of Boronate Esters to Boronic Acids:
##STR00331##
[0621] Method 5
[0622] General conditions for the conversion of boronate esters to
boronic acids: the boronate ester (1.0 eq), sodium periodate (5.0
eq) and ammonium acetate (5.0 eq) were dissolved in acetone/water
2:1 (0.05 M boronate ester) and stirred for 12 h at 23.degree. C.
until TLC or LCMS indicated conversion to the boronic acid was
complete. One option for isolation is to precipitate the product by
dilution of the mixture with 1N aqueous HCl and collection by
filtration of the solid boronic acid. Alternately, the mixture was
split between water and ethyl acetate, and the organic layer was
washed with brine, dried over sodium sulfate, and concentrated in
vacuo. The residue was purified either by recrystallization and
trituration (heptane, acetonitrile, or other solvents) or by flash
silica gel chromatography (0.5%.fwdarw.10%
methanol/dichloromethane) to afford pure boronic acid.
Method 6
[0623] General conditions for the conversion of boronate esters to
boronic acids: the boronate ester was treated with concentrated
sulfuric acid (0.2 M final ester concentration) and stirred until
the mixture became a clear solution, about 10 min, at 23.degree. C.
The solution was diluted with water 15 fold, and the precipitated
boronic acid collected by filtration and washed with water.
Preparation of Oxadiazoles:
##STR00332##
[0624] Method 7
[0625] General conditions for the preparation of oxadiazoles: in a
microwave reactor tube, (hydrazinocarbonyl)arylboronic acid pinacol
ester (1.0 equiv) and carboxylic acid (1.0 equiv) were dissolved in
dry acetonitrile (0.1 M each). Polystyrene-supported
triphenylphosphine (3.0 equiv) and trichloroacetonitrile (2.0
equiv) were added, and the mixture was sealed and heated in a
microwave reactor at 130.degree. C. for 2 hours. The concentrated
reaction mixture was purified by flash silica gel chromatography
(hexanes/ethyl acetate) to provide oxadiazole-aryl boronic acid
pinacol ester.
Method 8
[0626] General conditions for the preparation of oxadiazoles: the
oxadiazole was formed as in Method 7, except that the reactants are
a carboxyarylboronic acid pinacol ester and either an alkyl or aryl
hydrazide.
Preparation of Thiadiazoles:
##STR00333##
[0627] Method 9
[0628] General conditions for the preparation of thiadiazoles:
(hydrazinocarbonyl)arylboronic acid pinacol ester (1.0 equiv) and
carboxylic acid (1 equiv) were dissolved in dry DCM (0.1 M each)
and treated with EDC (1.05 equiv) and DMAP (0.10 equiv). The
mixture was stirred for 6 h at 23.degree. C., and then diluted into
a separatory funnel with DCM and washed twice each with 0.5 M
aqueous citric acid and saturated aqueous sodium bicarbonate. The
organic layer was dried over magnesium sulfate and concentrated to
a clear oil.
[0629] This oil was dissolved in dry THF and 1.2 equiv Lawesson's
reagent added. The mixture was sealed in a tube and heated in a
microwave reactor at 115.degree. C. for 30 min. The concentrated
reaction mixture was purified by flash silica gel chromatography
(hexanes/ethyl acetate) to provide thiadiazole-aryl boronic acid
pinacol ester.
Method 10
[0630] General conditions for the preparation of thiadiazoles: the
thiadiazole was formed as in Method 9, except that the reactants
are a carboxyarylboronic acid pinacol ester and either an alkyl or
aryl hydrazide.
Preparation of Quinoline-2-Ethers:
##STR00334##
[0631] Method 11
[0632] Conditions for the preparation of quinoline-2-ethers:
substituted 2-chloroquinoline (1.0 eq.), alcohol (3.0 eq.), and
crushed NaOH (2.0 eq.) were suspended in NMP (0.3 M quinoline) and
subjected to microwave heating at a temperature of ca. 160.degree.
C. during 15 min. When done by lc/ms, the reaction mixture was
diluted into 0.1M NaOH and MTBE and separated. The organic phase
was washed with brine, dried on Na.sub.2SO.sub.4, and treated with
silica gel. After removal of the solvent, the residue was
chromatographed (2.fwdarw.10% EtOAc/hexanes) to give clean ether
product.
Preparation of Isoxazolines and Isoxazoles:
##STR00335##
[0633] Method 12
[0634] General conditions for the preparation of isoxazolines and
isoxazoles: Aldehyde (1.0 equiv.) was added to the solution of
hydroxylamine hydrochloride (1.0 equiv.) in 1:1 t-BuOH: H2O (0.1 M
aldehyde). To this was added NaOH to pH 5, and after being stirred
for 30 min at ambient temperature, TLC analysis indicated that
oxime formation was complete. Chloramine-T trihydrate (1.0 equiv.)
was added in small portions over 5 min, followed by CuSO.sub.4
(0.045 equiv.) and copper turnings (ca. 0.01 equiv.). Alkene or
alkyne (1.0 equiv.) was added, and the pH was adjusted to ca. 6 by
addition of a few drops of 1 M NaOH, and stirring was continued for
another 6 h. The reaction mixture was poured into ice/water, and
dilute NH.sub.4OH was added to remove all copper salts. The desired
product was collected by filtration and purified by flash silica
gel chromatography.
Preparation of Benzoxazoles:
##STR00336##
[0635] Method 13
[0636] General conditions for the preparation of benzoxazoles: in a
microwave reactor tube, aminophenol (1.0 equiv) and carboxylic acid
(1.0 equiv) were dissolved in dry acetonitrile (0.1 M each).
Polystyrene-supported triphenylphosphine (3.0 equiv) and
trichloroacetonitrile (2.0 equiv) were added, and the mixture was
sealed and heated in a microwave reactor at 150.degree. C. for 2
hours. The concentrated reaction mixture was purified by flash
silica gel chromatography (hexanes/ethyl acetate) to provide the
desired benzoxazole.
Method 14
[0637] General conditions for the preparation of benzoxazoles: in a
sealed tube, aminophenol (1.0 equiv) and carboxylic acid (1.0
equiv) were dissolved in dry acetonitrile (0.1 M each).
Polystyrene-supported triphenylphosphine (4.0 equiv) and
trichloroacetonitrile (2.0 equiv) were added, and the mixture was
sealed and heated at 100.degree. C. for 20-36 h. The concentrated
reaction mixture was purified by flash silica gel chromatography
(hexanes/ethyl acetate) to provide the desired benzoxazole.
Preparation of Boronic Acid Pinacol Esters from Aryl Chlorides:
##STR00337##
Method 15
[0638] General conditions for the preparation of boronic acid
pinacol esters from aryl chlorides: a dry flask under argon
atmosphere was charged with aryl chloride (1.0 equiv) and dissolved
in tetrahydrofuran (0.1 M with respect to aryl chloride).
Bis(pinacolato)diboron (2.5 equiv) was added followed by potassium
acetate (2.5 equiv), palladium diacetate (0.2 equiv) and
1,3-bis(2,6-di-iso-propylphenyl)imidazolium chloride (0.4 equiv).
The reaction was heated to 95.degree. C. in a sealed tube for 14-36
h. Upon completion as judged by thin layer chromatography analysis
the mixture was then filtered through a plug of celite with some
silica gel on top. The celite was washed with ethyl acetate. The
combined solution was concentrated in vacuo and purified by flash
silica gelchromatography (ethyl acetate/hexanes) to provide the
desired boronic acid pinacol ester.
Synthesis of Exemplary Compounds
Example 1
##STR00338##
[0640]
3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic
acid (470 mg, 1.77 mmol) and 2-aminoacetophenone hydrochloride (318
mg, 1.89 mmol) were dissolved in 10 mL anhydrous dichloromethane.
HOBt (286 mg, 2.12 mmol) and EDC (406 mg, 2.12 mmol) were added
followed by triethylamine (741 uL, 5.30 mmol). The reaction was
allowed to stir for 12 h at room temperature after which point it
was transferred to a separatory funnel with excess dichloromethane
and washed with 0.5 M citric acid (2.times.75 mL) and saturated
NaHCO.sub.3 (2.times.75 mL). The organic layer was then dried over
MgSO.sub.4, filtered and concentrated to provide the desired
ketoamide as a yellow solid in quantitative yield (680 mg) which
was used directly to form the oxazole the in the following
step.
[0641] The crude ketoamide (100 mg, 0.261 mmol) was dissolved in 2
mL concentrated H.sub.2SO.sub.4. The reaction solution first turns
bright orange, then a brown solid forms. The reaction was allowed
to stir at room temperature for 10 minutes after which it was
poured into 75 mL water at which point a white solid forms that was
isolated using vacuum filtration. The solid was washed with excess
water and dried under vacuum for 12 h to provide 45 mg of oxazole 1
in 61% yield. [M-H].sup.-=282.1 m/z. Activity: B
Example 2
##STR00339##
[0643] Oxazole 2 was prepared using conditions described for
example 1. [M-H].sup.-=264.1 m/z. Activity: B
Example 3
##STR00340##
[0645] The ketoamide that was used to prepare 2 (223 mg, 0.58 mmol)
was dissolved in 5 mL anhydrous tetrahydrofuran and Lawesson's
reagent (282 mg, 0.70 mmol) was then added. The reaction was heated
to 70.degree. C. for 14 h after which point it was loaded directly
onto silica gel and purified using silica gel chromatography using
a gradient of 20-70% ethyl acetate/hexanes to provide 200 mg of the
desired thiazole in 90% yield.
[0646] The resulting pinacol ester
(2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-phe-
nylthiazole) was then converted to thiazole 3 using Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=298.1 m/z. Activity: D
Example 4
##STR00341##
[0648] 6-Bromo-2-tetralone (4) was converted to its corresponding
pincol ester boronate (5) using Method 3. This ketone
(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydronaphthalen-2(-
1H)-one) (600 mg, 2.21 mmol) was dissolved in 10 mL 1:1 v/v
methanol/tetrahydrofuran and cooled to 0.degree. C. in an ice bath.
Sodium borohydride (250 mg, 6.63 mmol) was added portion wise and
the reaction was allowed to stir for 2 h after which point there
was no more starting material as indicated by TLC analysis.
Saturated NaCl (100 mL) was added to reaction and the mixture was
transferred to a separatory funnel with excess water and methylene
chloride. The water layer was washed with methylene chloride
(2.times.75 mL). The organic layers were combined, washed with
saturated NaCl (1.times.75 mL), dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to provide the corresponding
secondary alcohol in quantitative yield (600 mg).
[0649] This secondary alcohol (110 mg, 0.40 mmol) was dissolved in
2 mL anhydrous N,N-dimethylforamide and cooled to 0.degree. C. in
an ice bath. Sodium hydride (48 mg, 1.20 mmol, 60% in dispersion
oil) was added with some fizzing. After 10 min, benzyl bromide (95
.mu.L, 0.80 mmol) was added and the reaction was allowed to stir at
room temperature for 2 h. A large amount of starting material was
still remaining at this point so sodium hydride and benzyl bromide
was added in 3 additional portions and the reaction was allowed to
stir for an additional 48 h. After this point, the reaction was
quenched with saturated NH.sub.4Cl (75 mL) and transferred to a
separatory funnel with excess water and ethyl acetate. The water
layer was washed with ethyl acetate (2.times.75 mL). The combined
organic layers were washed with saturated NaCl (2.times.75 mL),
dried over MgSO.sub.4, concentrated directly onto silica gel and
purified by silica gel chromatography using a gradient of 5-10%
ethyl acetate/hexanes to provide the desired ether as an oil (57
mg) in 39% yield.
[0650] The resulting pinacol ester
(2-(6-(benzyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl--
1,3,2-dioxaborolane) was then converted to tetrahydronaphthalene 6
using Method 5 and was isolated after precipitation from the
reaction mixture. [M-H].sup.-=281.1 m/z. Activity: A
Example 5
##STR00342##
[0652] The ketoamide used to prepare 2 (100 mg, 0.26 mmol) and
ammonium acetate (1.00 g, 13.0 mmol) was added to a 5 mL microwave
reaction vial. Acetic acid (2 mL) is added and the reaction is
heated for 30 min at 175.degree. C. in a microwave reactor. Water
(100 mL) is added to the crude reaction mixture at which point a
small amount of solid crashes out which is isolated using vacuum
filtration and dried under vacuum overnight to provide 6 mg of
imidazole 7 in 8% yield. [M-H].sup.-=281.1 m/z. Activity: D
Example 6
##STR00343##
[0654] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid
(160 mg, 0.645 mmol) and 2-amino-1,4-diphenylbutan-1-one
hydrochloride (178 mg, 0.645 mmol) were dissolved in 10 mL
anhydrous dichloromethane. HOBt (105 mg, 0.774 mmol) and EDC (148
mg, 0.774 mmol) were added followed by triethylamine (270 uL, 1.94
mmol). The reaction was allowed to stir for 12 h at room
temperature after which point it was transferred to a separatory
funnel with excess dichloromethane and washed with 0.5 M citric
acid (2.times.75 mL) and saturated NaHCO.sub.3 (2.times.75 mL). The
organic layer was then dried over MgSO.sub.4, filtered and
concentrated to provide the desired ketoamide as a white solid in
93% yield (281 mg) which was used directly to form the thiazole in
the following step.
[0655] The ketoamide (140 mg, 0.298 mmol) was dissolved in 4 mL
anhydrous tetrahydrofuran and followed by the addition of
Lawesson's reagent (145 mg, 0.358 mmol). The reaction was heated to
115.degree. C. in a microwave reactor for 90 min after which point
the crude mixture was loaded directly onto silica gel and purified
using a gradient of 25-50% ethyl acetate/hexanes to isolate 90 mg
of the desired compound in 65% yield. The resulting pinacol ester
(4-phenethyl-5-phenyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)thiazole) was then converted to thiazole 8 by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=384.1 m/z. Activity: D
Example 7
##STR00344##
[0657] Oxadiazole 9 was prepared in 2 steps starting with
oxadiazole formation between 5-bromopicolic acid and hexanoic
hydrazide using Method 7 followed by the lithiation conditions of
Method 1. [M-H].sup.-=260.1 m/z. Activity: A
Example 8
##STR00345##
[0659] Oxadiazole 10 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
3-(2-oxo-pyrrolidin-1-yl)-propionic acid using Method 7 followed by
Method 5 and was isolated after precipitation from the reaction
mixture. [M-H].sup.-=300.1 m/z. Activity: C
Example 9
##STR00346##
[0661] Oxadiazole 11 was prepared in 2 steps starting with
oxadiazole formation between 2-bromo-5-(trifluoromethyl)benzoic
acid and acetic hydrazide using Method 7 followed by lithiation
using Method 1. [M-H].sup.-=271.0 m/z. Activity: C
Example 10
##STR00347##
[0663] Oxadiazole 12 was prepared in 2 steps starting with
oxadiazole formation between 5-bromopicolic acid and benzoic
hydrazide using Method 7 followed by lithiation using Method 1.
[M-H].sup.-=266.1 m/z. Activity: B
Example 11
##STR00348##
[0665] Oxadiazole 13 was prepared by Method 8 followed by Method 5.
[M-H].sup.-=231.1 m/z. Activity:
Example 12
##STR00349##
[0666] Part A
##STR00350##
[0668] 2-Bromo-5-hydroxybenzaldehyde 14 (1.0 g, 5 mmol. 1.0 equiv),
phenethyl bromide (2.76 g, 15 mmol, 3.0 equiv), and potassium
carbonate (2.75 g, 20 mmol, 4.0 equiv) were suspended in
dimethylformamide (15 ml) and heated at 80.degree. C. for 14 h. The
mixture was cooled and split between water (150 ml) and ethyl
acetate (150 ml), and the organic layer was washed with brine and
dried over sodium sulfate. The oil from concentration in vacuo was
purified by flash silica gel chromatography (1-30% ethyl
acetate/hexanes) to give phenethyl ether 15 as a clear oil (550
mg).
Part B
##STR00351##
[0670] Bromobenzaldehyde 15 (3.0 g, 9.83 mmol, 1.0 equiv) dissolved
in 2:1 tetrahydrofuran/water (75 ml) was treated with
2-methyl-2-butene (6.9 g, 98 mmol, 10 equiv), sodium phosphate
monobasic, dihydrate, (4.6 g, 29.5 mmol, 3.0 equiv), and sodium
chlorite (2.1 g, 24 mmol, 2.4 equiv). The mixture was stirred at
23.degree. C. for 6 h and was then split between ethyl acetate (200
ml) and 1N aqueous HCl (100 ml). The organic layer was washed with
brine (100 ml) and concentrated in vacuo. The resulting oil was
purified by flash silica gel chromatography (1.fwdarw.30% ethyl
acetate/hexanes) to give the carboxylic acid 16 (56% yield).
[0671] The acid 16 was converted to the oxadiazole-arylboronic acid
17 by Method 8 followed by Method 1. [M-H].sup.-=351.1 m/z.
Activity: A
Example 13
##STR00352##
[0673] Oxadiazole 18 was prepared in 2 steps starting with
oxadiazole formation between 2-bromo-5-phenethoxybenzoic acid 16
and furoic hydrazide using Method 7 followed by lithiation using
Method 1. [M-H].sup.-=375.1 m/z. Activity: A
Example 14
##STR00353##
[0675] Oxadiazole 19 was prepared in 2 steps starting with
oxadiazole formation between 2-bromo-5-phenethoxybenzoic acid 16
and acetic hydrazide using Method 7 followed by lithiation using
Method 1. [M-H].sup.-=323.1 m/z. Activity: A
Example 15
##STR00354##
[0677] Oxadiazole 20 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
4,4,5,5,5-pentafluoropentanoic acid using Method 7 followed by
Method 5 and was isolated after precipitation from the reaction
mixture. [M-H].sup.-=335.1 m/z. Activity: A
Example 16
##STR00355##
[0679] Oxadiazole 21 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
nicotinic hydrazide using Method 8 followed by Method 6.
[M-H].sup.-=266.1 m/z. Activity: A
Example 17
##STR00356##
[0681] Oxadiazole 22 was prepared in 2 steps by first forming the
oxadiazole from
4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic
acid and butyric hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture followed
by purification using flash silica gel chromatography.
[M-H].sup.-=249.1 m/z. Activity: D
Example 18
##STR00357##
[0683] Oxadiazole 23 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
(2-methyl-thiazol-4-yl)acetic acid hydrazide using Method 8
followed by Method 6. [M-H].sup.-=300.1 m/z. Activity: B
Example 19
##STR00358##
[0685] Oxadiazole 24 was prepared in 2 steps from the corresponding
aryl bromide using Method 3 followed by Method 5 and was isolated
after precipitation from the reaction mixture. [M-H].sup.-=231.1
m/z. Activity: A
Example 20
##STR00359##
[0687] Oxadiazole 25 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
2-hexenoic acid using Method 7 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=257.1 m/z. Activity: A
Example 21
##STR00360##
[0689] Oxadiazole 26 was prepared in 2 steps by first forming the
oxadiazole from
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic
acid and hexanoic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=279.1 m/z. Activity: A
Example 22
##STR00361##
[0691] Oxadiazole 27 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic
acid and hexanoic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=265.1 m/z. Activity: A
Example 23
##STR00362##
[0693] Oxadiazole 28 was prepared in 2 steps by first forming the
oxadiazole from
(E)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylic
acid and acetic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=229.1 m/z. Activity: C
Example 24
##STR00363##
[0695] Oxadiazole 29 was prepared in 2 steps by first forming the
oxadiazole from
3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic
acid and hexanoic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=293.1 m/z. Activity: A
Example 25
##STR00364##
[0697] Oxadiazole 30 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
hexanoic acid using Method 7 followed by Method 5 and was isolated
after precipitation from the reaction mixture. [M-H].sup.-=259.1
m/z. Activity: A
Example 26
##STR00365##
[0699] Oxadiazole 31 was prepared in 2 steps by first forming the
oxadiazole from
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
benzoic hydrazide using Method 8 followed by Method 5 and was
isolated after precipitation from the reaction mixture followed by
purification using flash silica gel chromatography.
[M-H].sup.-=265.1 m/z. Activity: D
Example 27
##STR00366##
[0701] Oxadiazole 32 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
4-methylhexanoic acid using Method 7 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=273.1 m/z. Activity: A
Example 28
##STR00367##
[0703] Oxadiazole 33 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
3-cyclopentylpropionic acid using Method 7 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=285.1 m/z. Activity: A
Example 29
##STR00368##
[0705] Oxadiazole 34 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
2-methylhexanoic acid using Method 7 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=273.1 m/z. Activity: A
Example 30
##STR00369##
[0707] Oxadiazole 35 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
cyclopentylacetic acid using Method 7 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=271.1 m/z. Activity: A
Example 31
##STR00370##
[0709] Oxadiazole 36 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
3-cyclohexylpropionic acid using Method 7 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=299.1 m/z. Activity: A
Example 32
##STR00371##
[0711] Oxadiazole 37 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
heptanoic acid using Method 7 followed by Method 5 and was isolated
after precipitation from the reaction mixture. [M-H].sup.-=273.1
m/z. Activity: A
Example 33
##STR00372##
[0713] Oxadiazole 38 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
5-methylhexanoic acid using Method 7 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=273.1 m/z. Activity: A
Example 34
##STR00373##
[0715] Oxadiazole 39 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
butyric hydrazide using Method 8 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=231.1 m/z. Activity: A
Example 35
##STR00374##
[0717] Oxadiazole 40 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
5,5,5-trifluoropentanoic acid using Method 7 followed by Method 5
and was isolated after precipitation from the reaction mixture.
[M-H].sup.-=299.1 m/z. Activity: A
Example 36
##STR00375##
[0719] Oxadiazole 41 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
5-fluoronicotinic acid using Method 7 followed by Method 6.
[M-H].sup.-=284.1 m/z. Activity: B
Example 37
##STR00376##
[0721] Oxadiazole 42 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
valeric hydrazide using Method 8 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=245.1 m/z. Activity: A
Example 38
##STR00377##
[0723] Oxadiazole 43 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
1,4-benzodioxan-5-carboxylic acid using Method 7 followed by Method
5 and was isolated after precipitation from the reaction mixture.
[M-H].sup.-=323.1 m/z. Activity: A
Example 39
##STR00378##
[0725] Oxadiazole 44 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
2,3-dimethoxybenzoic acid using Method 7 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=325.1 m/z. Activity: A
Example 40
##STR00379##
[0727] Oxadiazole 45 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
piperonylic acid using Method 7 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=309.0 m/z. Activity: A
Example 41
##STR00380##
[0729] Oxadiazole 46 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
2,3-dihydro-1-benzofuran-7-carboxylic acid using Method 7 followed
by Method 5 and was isolated after precipitation from the reaction
mixture. [M-H].sup.-=307.1 m/z. Activity: A
Example 42
##STR00381##
[0731] Oxadiazole 47 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
3-trifluoromethylbenzoic acid using Method 7 followed by Method 6.
[M-H].sup.-=333.0 m/z. Activity: A
Example 43
##STR00382##
[0733] Thiadiazole 48 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
3-trifluoromethylbenzoic acid using Method 9 followed by Method 6.
[M-H].sup.-=349.1 m/z. Activity: A
Example 44
##STR00383##
[0735] Thiadiazole 49 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
nicotinic hydrazide using Method 9 followed by Method 6.
[M-H].sup.-=282.1 m/z. Activity: A
Example 45
##STR00384##
[0737] Thiadiazole 50 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
3-trifluoromethylbenzoic acid using Method 9 followed by Method 5
and was isolated after precipitation from the reaction mixture.
[M-H].sup.-=325.1 m/z. Activity: A
Example 46
##STR00385##
[0739] Oxadiazole 51 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
1-methyl-1H-indole-4-carboxylic acid using Method 7 followed by
Method 5 and was isolated after precipitation from the reaction
mixture. [M-H].sup.-=318.1 m/z. Activity: A
Example 47
##STR00386##
[0741] Oxadiazole 52 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
2,2-difluoro-1,3-benzodioxole-4-carboxylic acid using Method 7
followed by Method 5 and was isolated after precipitation from the
reaction mixture. [M-H].sup.-=345.1 m/z. Activity: A
Example 48
##STR00387##
[0743] Oxadiazole 53 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
1,3-benzodioxole-4-carboxylic acid using Method 7 followed by
Method 5 and was isolated after precipitation from the reaction
mixture. [M-H].sup.-=309.1 m/z. Activity: A
Example 49
##STR00388##
[0745] Oxadiazole 54 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
1-methyl-1H-imidazole-5-carbohydrazide using Method 8 followed by
Method 6. [M-H].sup.-=269.1 m/z. Activity: B
Example 50
##STR00389##
[0747] Oxadiazole 55 was prepared in 2 steps by first forming the
oxadiazole from
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic
acid and phenylacetic hydrazide using Method 8 followed by Method 5
and was isolated after precipitation from the reaction mixture.
[M-H].sup.-=285.1 m/z. Activity: B
Example 51
##STR00390##
[0749] Oxadiazole 56 was prepared in 2 steps by first forming the
oxadiazole from
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic
acid and benzoic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=271.1 m/z. Activity: B
Example 52
##STR00391##
[0751] Oxadiazole 57 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
3-phenylpropionic acid hydrazide using Method 8 followed by Method
5 and was isolated after precipitation from the reaction mixture.
[M-H].sup.-=293.1 m/z. Activity: A
Example 53
##STR00392##
[0753] Oxadiazole 58 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic
acid and 3-phenylpropionic acid hydrazide using Method 8 followed
by Method 5 and was isolated after precipitation from the reaction
mixture. [M-H].sup.-=299.1 m/z. Activity: A
Example 54
##STR00393##
[0755] Oxadiazole 59 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
2-(3-thienyl)ethanohydrazide using Method 8 followed by Method 5
and was isolated after precipitation from the reaction mixture.
[M-H].sup.-=285.1 m/z. Activity: A
Example 55
##STR00394##
[0757] Oxadiazole 60 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic
acid and phenylacetic hydrazide using Method 8 followed by Method 5
and was isolated after precipitation from the reaction mixture.
[M-H].sup.-=285.1 m/z. Activity: A
Example 56
##STR00395##
[0759] Oxadiazole 61 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic
acid and benzoic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=271.1 m/z. Activity: B
Example 17
##STR00396##
[0761] Thiadiazole 62 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
benzoic acid using Method 9 followed by Method 5 and was isolated
after precipitation from the reaction mixture. [M-H].sup.-=281.1
m/z. Activity: A
Example 58
##STR00397##
[0763] Oxadiazole 63 was prepared in 2 steps by first forming the
oxadiazole from
3-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
benzoic hydrazide using Method 8 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=265.1 m/z. Activity: C
Example 59
##STR00398##
[0765] Oxadiazole 64 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)phenylacetic acid and
benzoic hydrazide using Method 8 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=279.1 m/z. Activity: B
##STR00399##
[0766] Oxadiazole 65 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
2-picolinyl hydrazide using Method 8 followed by Method 6.
[M-H].sup.-=266.1 m/z. Activity: B
Example 61
##STR00400##
[0768] Oxadiazole 66 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
3-methoxybenzoic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=295.1 m/z. Activity: A
Example 62
##STR00401##
[0770] Oxadiazole 67 was prepared in 2 steps by first forming the
oxadiazole from
2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic
acid and benzoic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=283.1 m/z. Activity: B
Example 63
##STR00402##
[0772] Oxadiazole 68 was prepared in 2 steps by first forming the
oxadiazole from
2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic
acid and benzoic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture. ESI-MS
[M+H].sup.+=301.2 m/z. Activity: A
Example 64
##STR00403##
[0774] Oxadiazole 69 was prepared in 2 steps by first forming the
oxadiazole from
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic
acid and phenylacetic hydrazide using Method 8 followed by Method 5
and was isolated after precipitation from the reaction mixture.
[M-H].sup.-=297.1 m/z. Activity: B
Example 65
##STR00404##
[0776] Oxadiazole 70 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
phenylacetic hydrazide using Method 8 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=279.0 m/z. Activity: A
Example 66
##STR00405##
[0778] Oxadiazole 71 was prepared in 2 steps by from the
corresponding aryl bromide using Method 1 followed by Method 6.
[M-H].sup.-=265.1 m/z. Activity: A
Example 67
##STR00406##
[0780] Oxadiazole 72 was prepared in 2 steps by first forming the
oxadiazole from
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carboxylic
acid and butyric hydrazide using Method 8 followed by Method 5.
[M-H].sup.-=237.1 m/z. Activity: D
Example 68
##STR00407##
[0782] Oxadiazole 73 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
2-hydroxyisobutryic hydrazide using Method 8 followed by Method 5.
[M-H].sup.-=247.1 m/z. Activity: B
Example 69
##STR00408##
[0784] Oxadiazole 74 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic hydrazide
and ethoxyacetic acid using Method 7 followed by Method 5.
[M-H].sup.-=247.1 m/z. Activity: B
Example 70
##STR00409##
[0786] Oxadiazole 75 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic hydrazide
and methoxyacetic acid using Method 7 followed by Method 5.
[M-H].sup.-=233.1 m/z. Activity: A
Example 71
##STR00410##
[0788] Oxadiazole 76 was prepared in 2 steps by first forming the
bis-oxadiazole from bromobenzene-2,4-dicarboxylic acid and butryic
hydrazide using Method 8 followed by Method 1. [M-H].sup.-=341.1
m/z. Activity: A
Example 72
##STR00411##
[0790] Oxadiazole 77 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
pivaloic hydrazide using Method 8 followed by Method 5.
[M-H].sup.-=245.1 m/z. Activity: A
Example 73
##STR00412##
[0792] Oxadiazole 78 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic hydrazide
and 5-hexenoic acid using Method 7 followed by Method 5.
[M-H].sup.-=257.1 m/z. Activity: A
Example 74
##STR00413##
[0794] Oxadiazole 79 was prepared in 2 steps by first forming the
oxadiazole from
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic
acid and benzoic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=283.1 m/z. Activity: B
Example 75
##STR00414##
[0796] Oxadiazole 80 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
furoic hydrazide using Method 8 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=255.0 m/z. Activity: A
Example 76
##STR00415##
[0798] In a microwave reactor tube,
4-chloro-2-(trifluoromethyl)benzoic acid (300 mg, 1.34 mmol) and
benzoic hydrazide (182 mg, 1.34 mmol) were dissolved in dry
acetonitrile (6 mL). Polystyrene-supported triphenylphosphine (3.0
equiv, 1.80 g, 2.23 mmol/g loading) and trichloroacetonitrile (270
uL, 2.68 mmol) were added, and the mixture was sealed and heated in
a microwave reactor at 130.degree. C. for 2 hours. The reaction was
then filtered and the resin was washed with excess tetrahydrofuran
and methylene chloride. The filtrate was concentrated onto silica
gel and purified by column chromatography using a gradient of
25-50% ethyl acetate/hexanes to provide the 300 mg of the desired
oxadiazole in 70% yield.
[0799]
2-(4-Chloro-2-(trifluoromethyl)phenyl)-5-phenyl-1,3,4-oxadiazole
(296 mg, 0.921 mmol) was dissolved in 6 mL anhydrous
tetrahydrofuran in a microwave reaction tube.
Bis(pinacolato)diboron (278 mg, 1.09 mmol) was added followed by
potassium acetate (206 mg, 2.10 mmol), palladium(II) acetate (12
mg, 0.055 mmol) and 1,3-bis(2,6-di-isopropylphenyl)imidazolium
chloride (46 mg, 0.11 mmol). The reaction was heated in a microwave
reactor was heated to 110.degree. C. for 20 min. A slurry of
palladium(II) acetate and the imidazolum catalyst in 1 mL
tetrahydrofuran was then added and the reaction was reheated under
the same conditions. This was repeated a third time after which
point the reaction was filtered through a plug of slica gel using
1:1 ethyl acetate/hexanes (v/v) as eluent. The filtrate was then
concentrated onto silica gel and purified by column chromatography
using a gradient of 25-50% ethyl acetate/hexanes to provide the 300
mg of the desired oxadiazole in 79% yield.
[0800] The resulting pinacol ester
(2-phenyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoro-
methyl)phenyl)-1,3,4-oxadiazole) was then converted to boronic acid
81 using Method 5 and was isolated after precipitation from the
reaction mixture. [M-H].sup.-=333.1 m/z. Activity: C
Example 77
##STR00416##
[0802]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide (300
mg, 1.15 mmol) and N-Boc-.beta.-alanine (227 mg, 1.20 mmol) were
dissolved in 10 mL anhydrous dichloromethane. HOBt (187 mg, 1.37
mmol) and EDC (263 mg, 1.37 mmol) were added followed by
triethylamine (480 uL, 3.43 mmol). The reaction was allowed to stir
for 12 h at room temperature after which point it was transferred
to a separatory funnel with excess dichloromethane and washed with
0.5 M citric acid (2.times.75 mL) and saturated NaHCO.sub.3
(2.times.75 mL). The organic layer was then dried over MgSO.sub.4,
filtered and concentrated to provide the desired diacyl hydrazone
as a while foamy solid in 93% yield (461 mg) which was used
directly to form the oxadiazole in the following step.
[0803] The diacyl hydrazone (461 mg, 1.06 mmol) was dissolved in
anhydrous tetrahydrofuran. Burgess' reagent (355 mg, 1.60 mmol) was
added and the reaction was heated to 60.degree. C. in a sealed tube
for 20 h. After this point, the reaction was allowed to cool and
transferred to a separatory funnel with excess saturated
NaHCO.sub.3 (50 mL) and ethyl acetate (50 mL). The organic layer is
washed with saturated NaCl (50 mL), dried over MgSO.sub.4, and
concentrated under vacuum to provide a crude oil that is purified
using silica gel chromatography with a gradient of 20-70%
ethyl/hexanes to provide the 187 mg of the desired oxadiazole in
43% yield.
[0804] The resulting pinacol ester (tert-butyl
2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-oxadia-
zol-2-yl)ethylcarbamate) was then converted to boronic acid 82
using Method 5 and was isolated after precipitation from the
reaction mixture. [M-H].sup.-=332.1 m/z. Activity: B
Example 78
##STR00417##
[0806] Carbamate 83 was prepared using the analogous procedure as
Example 77 except that N-Boc glycine was used in place of
N-Boc-.beta.-alanine. [M-H].sup.-=318.1 m/z. Activity: B
Example 79
##STR00418##
[0808] Carbamate 82 (20 mg, 0.060 mmol) was dissolved in 5 mL
methylene chloride. Excess trifluoroacetic acid (5 mL) was added
and the reaction was allowed to stir at room temperature for 10
min. The reaction was then diluted with toluene (40 mL) and
azeotroped under vacuum to remove the excess acid. This was
repeated 2 times and the resultant solid was dried under vacuum
overnight to provide the desired amine 84 in quantitative yield (14
mg). [M-H].sup.-=232.1 m/z. Activity: D
Example 80
##STR00419##
[0810] Amine 84 (17 mg, 0.050 mmol) was suspended in 5 mL methylene
chloride. Acetic anhydride (49 .mu.L, 0.49 mmol) was added followed
by NaHCO.sub.3 (29 mg, 0.25 mmol) and allowed to stir at room
temperature for 10 min. An additional 49 uL of acetic anhydride and
29 mg of NaHCO.sub.3 were then added and the reaction was allowed
to stir for an additional hour at which point the reaction was
determined to be complete by LC/MS. Methanol (1 mL) was added and
the mixture was allowed to stir at room temperature for 20 min. The
reaction mixture was then filtered and concentrated to provide 6 mg
of amide 85 in 45% yield. [M-H].sup.-=274.1 m/z. Activity: C
Example 81
##STR00420##
[0812] Tert-butyl
2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-oxadia-
zol-2-yl)ethylcarbamate (187 mg, 0.450 mmol) was dissolved in 10 mL
2N HCl in dioxane and allowed to stir at room temperature for 2 h.
After this point the solvent was removed under vacuum to provide
the desired free amine in quantitative yield as the HCl salt. A
portion of this free amine (63 mg, 0.18 mmol) was dissolved in 3 mL
anhydrous THF. Methyl chloroformate (18 .mu.L, 0.23 mmol) was added
followed by diisopropylethylamine (83 .mu.L, 0.47 mmol) and the
reaction was allowed to stir at room temperature for 2 h at which
point there is no more starting material visible by LC/MS. Water
(30 mL) was added and the mixture is acidified to pH <4 with 0.5
M citric acid. The solid that remains was collected via vacuum
filtration and washed with excess water to provide the desired
pinacol ester in 12% yield (8.0 mg).
[0813] The resulting pinacol ester (methyl
2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-oxadia-
zol-2-yl)ethylcarbamate) was then converted to amide 86 using
Method 5 and was isolated after precipitation from the reaction
mixture. [M-H].sup.-=290.1 m/z. Activity: B
Example 82
##STR00421##
[0815] Benzothiazole 87 was prepared in two steps from the
corresponding aryl bromide using Method 3 followed by Method 5 and
purified using flash silica gel chromatography. [M-H].sup.-=254.1
m/z. Activity: D
Example 83
##STR00422##
[0817] Benzothiazole 88 was prepared in two steps from the
corresponding aryl bromide using Method 3 followed by Method 5 and
purified using flash silica gel chromatography. [M-H].sup.-=192.0
m/z. Activity: C
Example 84
##STR00423##
[0819] Thiazole 89 was prepared in two steps from the corresponding
aryl bromide using Method 3 followed by Method 5 and purified using
flash silica gel chromatography. [M-H].sup.-=218.1 m/z. Activity
D
Example 85
##STR00424##
[0821] Oxazole 90 was prepared in two steps from the corresponding
aryl bromide using Method 3 followed by Method 5 and purified using
flash silica gel chromatography. [M-H].sup.-=188.1 m/z. Activity:
B
Example 86
##STR00425##
[0823] Pyrazole 92 was prepared in 5 steps from
3-(4-bromophenyl)-1-phenylpyrazole-4-propionic acid (1.00 g, 2.69
mmol) starting with the methylation of the free acid using
trimethylsilyl-diazomethane (4.0 equiv in hexanes) in 1:1
toluene/methanol (0.05 M) for 1 h after which point the reaction
was concentrated and dried under vacuum. The crude mixture was then
redissolved in THF (0.15 M) and cooled to 0.degree. C. in an ice
bath under N.sub.2. DIBAL (3.5 equiv, 1.0 M in toluene) was added
drop wise and the reaction was allowed to warm to room temperature
and allowed to stir for 2 h. The reaction was then quenched
methanol (20 mL) followed by the addition of a saturated solution
of Rochelle's salt (100 mL) After 1 h, the reaction was transferred
to a separatory funnel with excess ethyl acetate and water after
which the water layer was washed with ethyl acetate (2.times.75
mL). The organic layers were combined and washed with brine
(2.times.75 mL), dried over MgSO.sub.4, and concentrated to provide
the desired product as a crude oil in quantitative yield.
[0824] The crude alcohol (340 mg, 0.95 mmol) was then redissolved
in anhydrous N,N-dimethylforamide (0.20 M) and cooled to 0.degree.
C. in an ice bath. Sodium hydride (3.0 equiv) was added portion
wise and allowed to stir for 10 min after which point iodomethane
(2.0 equiv) was added and the reaction was allowed to stir for 2 h
at room temperature. The reaction was then quenched with saturated
NH.sub.4CL and was transferred to a separatory funnel with excess
ethyl acetate and water after which the water layer was washed with
ethyl acetate (2.times.75 mL). The organic layers were combined and
washed with brine (2.times.75 mL), dried over MgSO.sub.4, and
concentrated to provide the desired ether as a crude oil in
quantitative yield.
[0825] The resulting methyl ether was then converted to the desired
pyrazole 92 using Method 3 followed by Method 5 and purified using
flash silica gel chromatography. [M-H].sup.-=335.1 m/z. Activity:
D
Example 87
##STR00426##
[0826] Part A
##STR00427##
[0828] At 0.degree. C., aldehyde 93 (15) (1.8 mmol, 1.0 equiv) was
dissolved in 1:1 tetrahydrofuran/methanol (14 ml) and treated with
sodium borohydride (136 mg, 3.6 mmol, 2.0 equiv). After stirring
for 2 h, the mixture was diluted with water (100 ml) and extracted
with ethyl acetate (100 ml). The organic layer was washed with
brine, dried over sodium sulfate, and concentrated in vacuo. The
resulting oil was purified by flash silica gel chromatography
(5.fwdarw.30% ethyl acetate/hexanes) to give a colorless oil (500
mg).
Part B
##STR00428##
[0830] Benzylic alcohol 94 (185 mg, 0.6 mmol, 1.0 equiv) and
iodomethane (128 mg, 0.9 mmol, 1.5 equiv) were dissolved in
dimethylformamide (3 ml) and, at 0.degree. C., were treated with
sodium hydride (36 mg, 0.9 mmol, 1.5 equiv of a 60% dispersion in
mineral oil). The mixture was stirred for 2 h and then quenched by
addition of saturated aqueous ammonium chloride (1 ml). The mixture
was split between water (100 ml) and extracted with ethyl acetate
(100 ml). The organic layer was washed with brine, dried over
sodium sulfate, and concentrated in vacuo. Purification by flash
silica gel chromatography (1.fwdarw.5% ethyl acetate/hexanes) to
give a colorless oil (143 mg). The resulting aryl bromide was
converted to the boronic acid 95 by Method 1. [M-H].sup.-=285.1
m/z. Activity: B
Example 88
##STR00429##
[0832] Benzyl alcohol 96 was prepared by reduction of the
benzaldehyde-boronic acid as described for 94 and purified by flash
silica gel chromatography (1.fwdarw.5% methanol/dichloromethane).
[M-H].sup.-=257.1 m/z. Activity: D
Example 89
##STR00430##
[0834] The benzyl ether 97 was made according to the procedures
described for 95. [M-H].sup.-=361.2 m/z. Activity: D
Example 90
##STR00431##
[0836] The bromobenzaldehyde 93 (15) (500 mg, 1.6 mmol, 1.0 equiv)
and ethylene glycol (712 mg, 11.5 mmol, 7.0 equiv) with
toluenesulfonic acid (9 mg, 3 mol %) were dissolved in toluene (35
ml) and heated at reflux 24 h with azeotropic removal of water with
a Dean-Stark apparatus. After cooling, the mixture was split
between 5% aqueous sodium bicarbonate (100 ml), and the organic
layer was then washed with water (100 ml) and then brine (50 ml),
dried over sodium sulfate, and concentrated in vacuo. The resultant
clear oil was purified by flash silica gel chromatography
(1.fwdarw.5% ethyl acetate/hexanes) to give a colorless oil (534
mg).
[0837] This pure acetal was then converted to the boronic acid 98
by Method 1. It was important to stir the mixture after the quench
with 2N aqueous HCl for 1 h to ensure full hydrolysis of the
acetal. [M-H].sup.-=269.1 m/z. Activity: A
Example 91
##STR00432##
[0839] Benzaldehyde-boronic acid 98 (500 mg, 1.85 mmol, 1 equiv)
and pinacol (263 mg, 2.2 mmol, 1.2 equiv) were heated at reflux in
benzene (12 ml) for 5 h, with azeotropic removal of water using a
Dean-Stark apparatus. The solution was concentrated and
purification by flash silica gel chromatography (1.fwdarw.10% ethyl
acetate/hexanes) gave pinacol ester (436 mg).
[0840] The product ester and methyl
(triphenylphosphoranylidene)acetate (540 mg, 1.6 mmol, 1.3 equiv)
were heated at 90.degree. C. in dry toluene for 18 h. The mixture
was cooled and split split between water (150 ml) and ethyl acetate
(150 ml), and the organic layer was washed with brine and dried
over sodium sulfate. The oil from concentration in vacuo was
purified by flash silica gel chromatography (1.fwdarw.30% ethyl
acetate/hexanes) to give a clear oil (70% yield). The pinacol ester
was cleaved by Method 5 to produce boronic acid 100.
[M-H].sup.-=325.1 m/z. Activity: A
Example 92
##STR00433##
[0842] The thienyl-unsaturated ester boronic acid 101 was prepared
by condition similar to those for compound 100. [M-H].sup.-=211.0
m/z. Activity: C
Example 93
##STR00434##
[0844] Bromobenzaldehyde 93 (15) (420 mg, 1.4 mmol, 1.0 equiv) and
methyl (triphenylphos-phoranylidene)acetate (690 mg, 2.1 mmol, 1.5
equiv) were heated at 90.degree. C. in dry toluene for 18 h. The
mixture was cooled and split split between water (150 mil) and
ethyl acetate (150 ml), and the organic layer was washed with brine
and dried over sodium sulfate. The oil from concentration in vacuo
was purified by flash silica gel chromatography (1.fwdarw.10% ethyl
acetate/hexanes) to give a clear oil (55% yield).
[0845] The unsaturated ester (276 mg, 0.764, 1.0 equiv) in dry
methanol (10 ml) was stirred under nitrogen atmosphere with
magnesium turnings (279 mg, 11.5 mmol, 15 equiv) for 6 h at
23.degree. C. The mixture was filtered, diluted with ethyl acetate
(100 ml) and then washed with 1N aqueous HCl (100 ml) and brine
(100 ml). The residue from concentration in vacuo was purified by
flash silica gel chromatography (1.fwdarw.10% ethyl
acetate/hexanes) to give the saturated ester (70% yield). The
resulting aryl bromide was converted to the boronic acid pinacol
ester 102 by Method 3 and the resultant pinacol ester cleaved by
method 5. [M-H].sup.-=327.1 m/z. Activity: B
Example 94
##STR00435##
[0847] The pinacol ester of compound 100 (442 mg, 1.1 mmol, 1.0
equiv) was dissolved in 3:1 tetrahydrofuran/water (8 ml) and
stirred with lithium hydroxide (78 mg, 3.25 mmol, 3.0 equiv) at
50.degree. C. for 3 h. The mixture was diluted with ethyl acetate
(50 ml), washed with 1N aqueous HCl (50 ml) and then brine (25 ml)
and concentrated in vacuo. Purification by flash silica gel
chromatography (1.fwdarw.20% ethyl acetate/hexanes) gave product
(60% yield) which was used directly in the next step.
[0848] Carboxylic acid (133 mg, 0.34 mmol, 1.0 equiv) was dissolved
in dry dichloromethane (5 ml) and treated with EDC-HCl (78 mg, 0.41
mmol, 1.2 equiv), HOBt (55 mg, 0.41 mmol, 1.2 equiv), iPr.sub.2EtN
(130 mg, 1.02 mmol, 3.0 equiv), dimethylamine (0.4 ml of a 2 M
solution in tetrahydrofuran, 0.56 mmol, 2.2 equiv), and DMAP (2 mg,
0.02 mmol, 0.05 equiv). The mixture was stirred at 23.degree. C.
for 16 h and then split between 5% aqueous sodium bicarbonate and
ethyl acetate (100 ml each). The organic layer was washed with
brine (50 ml) and concentrated in vacuo. Purification by flash
silica gel chromatography (1.fwdarw.10% methanol/dichloromethane)
gave the desired amide (84% yield) which was cleaved by Method 5 to
produce the arylboronic acid 103. [M-H].sup.-=338.2 m/z. Activity:
B
Example 95
##STR00436##
[0850] Benzaldehydeboronic acid 98 (240 mg, 0.89 mmol, 1.0 equiv)
was suspended in water (10 ml) with hydroxylamine hydrochloride
(195 mg, 2.80 mmol, 3.0 equiv) and sodium acetate (230 mg, 2.80
mmol, 3.0 equiv). The mixture was heated at 60.degree. C. for 16 h
and then cooled to room temperature. Addition of 1N HCl to achieve
pH 1 produced (104) as a white precipitate that was collected and
washed with water (64% yield). [M-H].sup.-=266.1 m/z. Activity:
B
Example 96
##STR00437##
[0852] 4-(Benzyloxy)-2-formylphenylboronic acid (72 mg, 0.28 mmol)
was suspended in water (10 mL) followed by the addition of
hydroxylamine hydrochloride (62 mg, 0.89 mmol). The pH was adjusted
to 4 with 1N NaOH and the reaction was heated to 60.degree. C. for
16 h after which point LC/MS analysis showed only the desired
product. Additional water is added (50 mL) and the pH is adjusted
to <2 with 6N HCl. The resultant solid is isolated using vacuum
filtration, washed with excess water and dried under vacuum to
provide 55 mg of benzoazaborine 105 in 77% yield. [M-H].sup.-=252.1
m/z. Activity: B
Example 97
##STR00438##
[0854] 4-(Benzyloxy)-2-formylphenylboronic acid (100 mg, 0.391
mmol) was dissolved in 20 mL water/ethanol (1:1 v/v) followed by
the addition of N-benzylhydroxylamine hydrochloride (62 mg, 0.391
mmol). The reaction was basified to pH=7 with 1N NaOH and stirred
at room temperature for 6 h after which point there was no more
starting material remaining by LC/MS analysis. The ethanol was
removed under a stream of N.sub.2 and 100 mL 1N HCl was added. The
white solid that precipitated was collected using vacuum
filtration, washed with excess water and dried under vacuum to
provide 55 mg of nitrone 106 in 39% yield. [M-H].sup.-=360.2 m/z.
Activity: C
Example 98
##STR00439##
[0856] 2-Formyl-4-phenethoxyphenylboronic acid (111 mg, 0.411 mmol)
and 2-hydroxyethyl hydrazine (33 mL, 0.43 mmol) are dissolved in 10
mL ethanol and heated to 50.degree. C. for 12 h. The reaction is
allowed to cool and the solvent is removed under a stream of
N.sub.2 until there is only 2 mL of ethanol left. 1N HCl (50 mL) is
then added until a solid crashes out which is isolated using vacuum
filtration and washed with excess water. The resultant solid is
dried under vacuum overnight to provide 10 mg of benzodiazoborine
107 in 8% yield. [M-H].sup.-=309.1 m/z. Activity: D
Example 99
##STR00440##
[0858] Benzodiazoborine 108 was prepared using the analogous
procedure as example 98 except that N-methyhydrazine was used in
place of 2-hydroxyethyl hydrazine. [M-H].sup.-=279.1 m/z. Activity:
D
Example 100
##STR00441##
[0860] Benzodiazoborine 109 was prepared using the analogous
procedure as example 98 except that N-benzylhydrazine was used in
place of 2-hydroxyethyl hydrazine. [M-H].sup.-=341.2 m/z. Activity:
B
Example 101
##STR00442##
[0862] 4-(Benzyloxy)-2-formylphenylboronic acid (78 mg, 0.31 mmol)
is dissolved in 5 mL methylene chloride. N-Methyl-N-benzylamine (41
.mu.L, 0.32 mmol) is added and the mixture is allowed to stir at
room temperature for 20 min. Sodium triacetoxyborohydride (68 mg,
0.32 mmol) is then added and the reaction is allowed to stir at
room temperature for 30 min after which point there is no starting
material visible by LC/MS. The solvent is evaporated under a stream
of N.sub.2. The resultant solid is resuspended in a solution of 2%
acetic acid in water (50 mL). The solid that forms is isolated
using vacuum filtration, washed with excess water, and dried under
vacuum to provide 93 mg of amine 110 in 85% yield.
[M-H].sup.-=360.2 m/z. Activity: C
Example 102
##STR00443##
[0864] Amine 111 was prepared using the analogous procedure as
example 101 except that benzylamine was used in place of
N-methyl-N-benzylamine. [M-H].sup.-=364.2 m/z. Activity: C.
Example 103
##STR00444##
[0866]
(E)-3-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acryli-
c acid (80 mg, 0.29 mmol) was dissolved in 10 mL anhydrous
dichloromethane and benzylamine (33 .mu.L, 0.31 mmol) was added.
HOBt (47 mg, 0.35 mmol) and EDC (67 mg, 0.35 mmol) were then added
followed by triethylamine (59 uL, 58 mmol). The reaction was
allowed to stir for 12 h at room temperature after which point it
was transferred to a separatory funnel with excess dichloromethane
and washed with 0.5 M citric acid (2.times.75 mL) and saturated
NaHCO.sub.3 (2.times.75 mL). The organic layer was then dried over
MgSO.sub.4, filtered and concentrated to provide the desired
ketoamide as a white solid in 94% yield (100 mg) which was used
directly in the following step.
[0867] The resulting pinacol ester
((E)-N-benzyl-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ac-
rylamide) was then converted to amide 112 using Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=280.1 m/z. Activity: C
Example 104
##STR00445##
[0869] Amide 113 was prepared using the analogous procedure as
example 103 except that N-Boc-m-phenylenediamine was used in place
of benzylamine. [M-H].sup.-=381.2 m/z. Activity: D
Example 105
##STR00446##
[0871] Amide 114 was prepared using the analogous procedure as
example 103 except that N-methyl-N-benzylamine was used in place of
benzylamine. [M-H].sup.-=294.1 m/z. Activity: C
Example 106
##STR00447##
[0873] 4-(Benzyloxy)-2-formylphenylboronic acid (100 mg, 0.39 mmol)
and O-benzylhydroxylamine hydrochloride (62 mg, 0.39 mmol) were
dissolved in 5 mL ethanol. The reaction was allowed to stir at room
temperature for 14 h. The reaction was then added to 1N HCl (75 mL)
and a solid crashed out which was collected via vacuum filtration
and washed with excess water to provide 92 mg of the benzyloxyimine
115 after drying under vacuum overnight. [M-H].sup.-=360.1 m/z.
Activity: B
Example 107
##STR00448##
[0875] 2-Formylphenylboronic acid (150 mg, 1.0 mmol) and
3-phenylpropionic hydrazide (164 mg, 1.0 mmol) were dissolved in 5
mL ethanol. The reaction was heated to 50.degree. C. for 14 h after
which point there was more starting material by LC/MS analysis. The
reaction was allowed to cool after which point 100 mL 1N HCl was
added to the reaction and the solid which crashes out is collected
by vacuum filtration and washed with excess water. The solid is
dried under vacuum overnight to provide 200 mg of acyl hydrazone
116 as a white solid in 68% yield. [M-H].sup.-=295.1 m/z. Activity:
D
Example 108
##STR00449##
[0877] Acyl hydrazone 117 was prepared using the analogous
procedure as example 107 except that N-Boc glycine hydrazide was
used in place of 3-phenylpropionic hydrazide and
2-formyl-4-benzyloxyphenylboronic acid was used in place of
2-formylphenylboronic acid. [M-H].sup.-=426.1 m/z. Activity: B
Example 109
##STR00450##
[0879] Acyl hydrazone 117 (58 mg, 0.14 mmol) is suspended in 10 mL
ethyl acetate saturated with HCl. The reaction is allowed to stir
for 30 min. The solvent is then removed under a stream of N.sub.2
over the course of 1.5 h. The resulting oil is triturated with
tert-butyl methylether until a solid forms, which is filtered and
washed with excess tert-butyl methylether to provide 35 mg of acyl
hydrazone 118 as the hydrochloride salt in 70% yield.
[M-H].sup.-=326.1 m/z. Activity: D
Example 110
##STR00451##
[0881] Acyl hydrazone 119 was prepared using the analogous
procedure as example 107 except that 3-maleimidopropionic hydrazide
was used in place of 3-phenylpropionic hydrazide and
2-formyl-4-phenethoxyphenylboronic acid was used in place of
2-formylphenylboronic acid. [M-H].sup.-=434.1 m/z. Activity: A
Example 111
##STR00452##
[0883] Acyl hydrazone 120 was prepared using the analogous
procedure as example 107 except that acetic hydrazide was used in
place of 3-phenylpropionic hydrazide and
2-formyl-4-benzyloxyphenylboronic acid was used in place of
2-formylphenylboronic acid. [M-H].sup.-=325.1 m/z. Activity: A
Example 112
##STR00453##
[0885] Acyl hydrazone 121 was prepared using the analogous
procedure as example 107 except that pheylacetic hydrazide was used
in place of 3-phenylpropionic hydrazide. [M-H].sup.-=281.1 m/z.
Activity: D
Example 113
##STR00454##
[0887] Acyl hydrazone 122 was prepared using the analogous
procedure as example 107 except that indole-3-acetic acid hydrazide
was used in place of 3-phenylpropionic hydrazide. [M-H].sup.-=320.1
m/z. Activity: D
Example 114
##STR00455##
[0889] Acyl hydrazone 123 was prepared using the analogous
procedure as example 107 except that (2-methyl-thiazol-4-yl)acetic
acid hydrazide was used in place of 3-phenylpropionic hydrazide.
[M-H].sup.-=302.1 m/z. Activity: D
Example 115
##STR00456##
[0891] Acyl hydrazone 124 was prepared using the analogous
procedure as example 107 except that pheylacetic hydrazide was used
in place of 3-phenylpropionic hydrazide and
2-formyl-4-benzyloxyphenylboronic acid was used in place of
2-formylphenylboronic acid. [M-H].sup.-=387.2 m/z. Activity: B
Example 116
##STR00457##
[0893] Acyl hydrazone 125 was prepared using the analogous
procedure as example 107 except 2-picolinyl hydrazide was used in
place of 3-phenylpropionic hydrazide and
2-formyl-4-benzyloxyphenylboronic acid was used in place of
2-formylphenylboronic acid. [M-H].sup.-=374.1 m/z. Activity: B
Example 117
##STR00458##
[0895] A mixture of 4-ethynylbenzeneboronic acid (42 mg, 0.289
mmol, 1.0 equiv), benzyl azide (38.5 mg, 0.289 mmol, 1.0 equiv),
copper sulfate (0.5 mg, 0.003 mmol, 1 mol %), and sodium ascorbate
(5 mg, 0.03 mmol, 0.1 equiv) were stirred in 2:1 tert-butanol/water
(3 ml) for 14 h at 23.degree. C. The mixture was split between
ethyl acetate (25 ml) and water (25 ml), and the organic layer was
washed with brine (20 ml) and dried over sodium sulfate. The
residue upon concentration was purified by flash silica gel
chromatography (1.fwdarw.30% methanol/dichloromethane) to give a
white solid (70% yield). [2M-H.sub.20].sup.-=539.1 m/z. Activity:
A
Example 118
##STR00459##
[0897] Compound 127 was prepared by methods described for Example
117. [M-H].sup.-=346.1.1 m/z. Activity: C
Example 119
##STR00460##
[0899] Compound 128 was prepared by methods described for Example
117. [M-H].sup.-=308.1 m/z. Activity: B
Example 120
##STR00461##
[0901] Compound 129 was prepared by methods described for Example
117. [M-H].sup.-=292.1 m/z. Activity: A
Example 121
##STR00462##
[0903] A mixture of 4-ethynylbenzeneboronic acid (180 mg, 1.23
mmol, 1.45 equiv), phenyl azide (100 mg, 0.84 mmol, 1.0 equiv),
copper powder (0.5 mg, 0.003 mmol, 1 mol %), and sodium ascorbate
(16 mg, 0.08 mmol, 0.1 equiv) were stirred in 1:1
tert-butanol/water (6 ml) for 14 h at 23.degree. C. The mixture was
split between ethyl acetate (25 ml) and water (25 ml), and the
organic layer was washed with brine (20 ml) and dried over sodium
sulfate. The residue upon concentration was purified by flash
silica gel chromatography (1.fwdarw.10% methanol/dichloromethane)
to give 130 as a white solid (30% yield). [M-H].sup.-=264.1 m/z.
Activity: B
Example 122
##STR00463##
[0905] A 6 ml DMF solution of 4-bromomethylphenylboronic acid
pinacol ester (150 mg, 0.5 mmol, 1.0 equiv) was heated with sodium
azide (164 mg, 2.5 mmol, 5 equiv) at 60.degree. C. for 24 h. The
mixture was diluted with water (50 ml) and extracted with ethyl
acetate (50 ml). The organic layer was washed with water (50 ml),
then brine (30 ml) and then dried over sodium sulfate.
[0906] The clear oil produced upon concentration was then stirred
with phenylacetylene (62 mg, 0.6 mmol, 1.0 equiv), copper sulfate
(1 mg, 1 mol %), and sodium ascorbate (12 mg, 0.06 mmol, 0.1 equiv)
in 2:1 tert-butanol/water (6 ml) for 16 h at 23.degree. C. The
mixture was diluted with water (50 ml) and extracted with ethyl
acetate (50 ml). The organic layer was washed with water (50 ml),
then brine (30 ml) and then dried over sodium sulfate. The residue
from concentration in vacuo was purified by flash silica gel
chromatography (5460% ethyl acetate/hexanes) to give the pinacol
ester as a clear oil. This resultant pinacol ester was cleaved by
Method 5. [M-H].sup.-=278.1 m/z. Activity: B
Example 123
##STR00464##
[0907] Part A
##STR00465##
[0909] A flame-dried flask equipped with a rubber septum was
charged with 4-bromo-3-fluoroiodobenzene (1.0 g, 3.3 mmol, 1.0
equiv), copper(I) iodide (63 mg, 0.33 mmol. 0.1 equiv), and
bis(triphenylphosphine)palladium(II) dichloride (117 mg, 0.17 mmol,
0.05 equiv). Under argon atmosphere, the solids were suspended in
dry THF (8 ml), and triethylamine (1.15 ml, 8.3 mmol, 2.5 equiv)
and trimethylsilylacetylene (490 mg, 5 mmol, 1.5 equiv) were added.
The mixture was stirred at 23.degree. C. for 4 h, turning from
orange to black, and was then split between ethyl acetate (50 ml)
and water (50 ml). The organic layer was washed with brine (25 ml)
and dried over sodium sulfate. The residue from concentration in
vacuo was restored in methanol (15 ml) and stirred with potassium
carbonate (1.4 g, 10 mmol, 3.0 equiv) for 1 h. The mixture was
split between ethyl acetate (50 ml) and water (50 ml) and the
organic layer was washed with brine (25 ml) and then dried over
sodium sulfate and concentrated in vacuo. Purification by flash
silica gel chromatography (hexanes) gave acetylene 132 as a pale
yellow solid (60% yield).
Part B
##STR00466##
[0911] 4-Bromo-3-fluorophenylacetylene (132) (400 mg, 2.0 mmol, 1.0
equiv), copper powder (126 mg, 2.0 mmol, 1.0 equiv), copper sulfate
(6 mg, 0.1 mmol, 0.05 equiv), and sodium ascorbate (40 mg, 0.2
mmol, 0.1 equiv) in 2:1 tert-butanol/water (6 ml) were stirred for
16 h at 23.degree. C. The mixture was diluted with water (50 ml)
and extracted with ethyl acetate (50 ml). The organic layer was
washed with water (50 ml), then brine (30 ml) and then dried over
sodium sulfate. The residue from concentration in vacuo was
purified by flash silica gel chromatography (5.fwdarw.60% ethyl
acetate/hexanes) to give the triazole 133 as a white solid (35
mg).
Part C
##STR00467##
[0913] The aryl bromide 133 was converted to arylboronic acid 134
by Method 1. [M-H].sup.-=282.1 m/z. Activity: B
Example 124
##STR00468##
[0914] Part A
##STR00469##
[0916] 4-Bromo-3-fluorophenylacetylene (900 mg, 4.5 mmol, 1.0
equiv) and benzyl azide (600 mg, 4.5 mmol, 1.0 equiv) were
suspended in water (15 ml) and heated in a sealed tube at
120.degree. C. for 24 h. The mixture was cooled and extracted with
ethyl acetate (50 ml), and the organic layer was washed with brine
and dried over sodium sulfate. The 1,5-triazole 135 (10% yield) was
precipitated from 40% ethyl acetate/hexanes, and the 1,4-triazole
136 (25% yield) was isolated after purification of the mother
liquor by flash silica gel chromatography (5460% ethyl
acetate/hexanes).
Part B
[0917] The 1,4 isomer 136 was converted to boronic acid 137 by
Method 4 and Method 5. [M-H].sup.-=296.1 m/z. Activity: B
Example 125
##STR00470##
[0919] The 1,5-triazole-arylbromide 135 was converted to the
arylboronic acid 138 by Method 1. [M-H].sup.-=296.1 m/z. Activity:
C
Example 126
##STR00471##
[0920] Part A
##STR00472##
[0922] 4-Bromo-3-fluoroaniline (1.0 g, 5.26 mmol, 1.0 equiv) was
dissolved in 25 ml of CH3-CN and cooled to 0.degree. C. With
stirring, tert-BuONO (1.04 ml, 7.9 mmol, 1.5 equiv) was added
portionwise over 5 minutes, followed by dropwise addition of
trimethylsilylazide (0.67 g, 5.8 mmol, 1.2 equiv). The resulting
pale-yellow solution was stirred at 23.degree. C. for 1.5 h. The
mixture was then diluted with water (50 ml) and extracted with
ethyl acetate (50 ml). The organic layer was washed with water (50
ml), then brine (30 ml) and then dried over sodium sulfate.
Concentration in vacuo gave a yellow oil used without
purification.
[0923] Crude azide (490 mg, 2.25 mmol, 1.0 equiv) and
phenylacetylene (231 mg, 2.25 mmol, 1.0 equiv) were suspended in
water (15 ml) and heated in a sealed tube at 120.degree. C. for 24
h. The mixture was cooled and extracted with ethyl acetate (50 ml),
and the organic layer was washed with brine and dried over sodium
sulfate. The 1,5-triazole 140 (25% yield) was precipitated from 40%
ethyl acetate/hexanes, and the 1,4-triazole 139 (45% yield) was
isolated after purification of the mother liquor by flash silica
gel chromatography (5-60% ethyl acetate/hexanes).
Part B
[0924] The 1,4-regioisomer 141 was converted to the arylboronic
acid by Method 4. [M-H].sup.-=282.1 m/z. Activity: B
Example 127
##STR00473##
[0926] The 1,5-triazole-arylbromide 142 was converted to the
arylboronic acid by Method 1. [M-H].sup.-=282.1 m/z. Activity:
C
Example 128
##STR00474##
[0928] 1,4-Triazole 143 was prepared according to the procedure
described in example 126. [M-H].sup.-=264.1 m/z. Activity: A
Example 129
##STR00475##
[0930] 1,5-Triazole 144 was prepared according to the procedure
described in example 127. [M-H].sup.-=264.1 m/z. Activity: B
Example 130
##STR00476##
[0931] Part A
##STR00477##
[0933] A flask is charged with 4-bromo-3-fluorobenzylaldehyde (1.5
g, 7.5 mmol, 1.0 equiv) in MeOH-THF (3:1, 20 mL) was added an
aqueous solution of hydroxylamine (0.67 g, 1.3 equiv. in 2 mL
water) in one portion. The ph was adjusted to 9 with 6N KOH, and
stirred at rt for 2 h. After the disappearance of the aldehyde by
TLC analysis, sodium cyanoborohydride (0.93 g, 2 equiv.) was added
and the solution was acidified to pH 2-3 using concentrated HCl.
The solution was allowed to stir over night. The solution was
basified with 2N KOH to a pH of 11, extracted with DCM (3.times.50
mL), dried, concentrated in vacuo to afford a off white solid
hydroxylamine 145 (1.4 g).
Part B
##STR00478##
[0935] The mixture of 145 (500 mg, 1.0 equiv.), 146 (820 mg, 3
equiv.), 147 (400 mg, 1.5 equiv.) and 1 g of 4 A molecular sieves
in 5 mL of 1,2-dichloroethane was heated at reflux for 14 h. TLC
analysis showed no more starting material remaining. The mixture
was cooled to rt and filtered to remove sieves and wash solid with
ethyl acetate. The organic mixtures were washed with brine, dried
and concentrated. Purification on silica gel (0-30% ethyl acetate
in hexanes) gave isoxazolidine as a yellow oil (470 mg). Conversion
to the boronic acid 148 was achieved by Methods 3 and 5.
[M-H].sup.-=372.1 m/z. Activity: B
Example 131
##STR00479##
[0937] (8-Bromo-1-naphthyl)methanol 149 (210 mg, 1.0 equiv.),
phenol 150 (130 mg, 1.3 equiv.), triphenylphosphine (465 mg, 2.0
equiv.), triethylamine (0.25 mL, 2.0 equiv.) were dissolved in 2 mL
THF and cooled to 0.degree. C. under nitrogen. Diisopropyl
azodicarboxylate (0.34 mL, 2.0 equiv.) was added dropwise and the
mixture was warmed to rt and stirred overnight. The mixture was
concentrated and purified using flash silica gel chromatography (12
g, 0-10% EtOAc in hexanes) to provide coupled product 100 mg.
Conversion to boronic acid 151 was achieved by Method 1.
[M-H].sup.-=295.1 m/z. Activity: D
Example 132
##STR00480##
[0939] Compound 152 was synthesized via Method 12 from 152 and 153.
[M-H].sup.-=266.1 m/z. Activity: A
Example 133
##STR00481##
[0941] Compound 156 was synthesized via Method 12 from 152 and 155.
[M-H].sup.-=264.1 m/z. Activity: A
Example 134
##STR00482##
[0943] Compound 159 was synthesized via Method 12 from 157 and 158.
[M-H].sup.-=266.1 m/z. Activity: A
Example 135
##STR00483##
[0945] Compound 160 was synthesized via Method 12 from
phenylacetylene and 157. [M-H].sup.-=264.1 m/z. Activity: A
Example 136
##STR00484##
[0947] Compound 161 was synthesized via Method 12 from 1-heptene
and 157. [M-H].sup.-=260.2 m/z. Activity: A
Example 137
##STR00485##
[0949] Compound 162 was synthesized via Method 12 from
2-methyl-1-heptene and 157. [M-H].sup.-=274.2 m/z. Activity: A
Example 138
##STR00486##
[0951] Compound 163 was synthesized via Method 12 from
.beta.-propylstyrene and 157. [M-H].sup.-=308.2 m/z. Activity:
C
Example 139
##STR00487##
[0953] Compound 164 was synthesized via Method 12 from
2-pentyl-1-hexene and 157. [M-H].sup.-=330.2 m/z. Activity: C
Example 140
##STR00488##
[0955] Compound 165 was synthesized via Method 12 from
3-vinylpyridine and 157. [M-H].sup.-=267.1 m/z. Activity: B
Example 141
##STR00489##
[0957] Compound 166 was synthesized via Method 12 from
3-pyridylacetylene and 157. [M-H].sup.-=265.1 m/z. Activity: A
Example 142
##STR00490##
[0959] Compound 167 was synthesized via Method 12 from
2-bromobenzaldehdye and 1-pentene, followed by methods 5 and 3.
[M-H].sup.-=232.1 m/z. Activity: B
Example 143
##STR00491##
[0961] Compound 168 was synthesized via Method 12 from
2-bromobenzaldehdye and 1-pentyne, followed by methods 5 and 3.
[M-H].sup.-=230.1 m/z. Activity: D
Example 144
##STR00492##
[0963] A mixture of 1,3-dihydroxypropane 170 (340 mg, 2 mmol, 1.0
equiv.), 4-bromo-3-fluorobenzaldehyde 169 (450 mg, 2 mmol, 1.0
equiv.), and p-toluenesulfonic acid (0.1 g, 0.25 equiv.) in toluene
(30 mL) was refluxed for 24 h with a Dean-Stark trap attached for
removal of water. The mixture was diluted with EtOAc, washed with
sat. sodium bicarbonate and brine, dried and concentrated. The
crude mixture was purified on a silica gel column (5-20% EtOAc in
hexane) to give major isomer 171 (210 mg) and minor isomer 172 (70
mg). Compound 173 was synthesized from 171 according to Method 1.
[M-H].sup.-=301.1 m/z. Activity: A
Example 145
##STR00493##
[0965] Compound 174 was synthesized from 172 according to Method 1.
[M-H].sup.-=301.1 m/z. Activity: A
Example 146
##STR00494##
[0967] Compound 175 was synthesized from 4-bromobenzaldehyde by
methods described for example 145. [M-H].sup.-=283.1 m/z. Activity:
A
Example 147
##STR00495##
[0968] Step A
##STR00496##
[0970] To a mixture of diol 176 (540 mg, 3.9 mmol, 1.0 equiv.),
4-bromobenzaldehyde (795 mg, 4.3 mmol, 1.1 equiv.), and
p-toluenesulfonic acid (1 g, 5.3 mmol, 1.3 equiv) in toluene (6 mL)
was added crushed molecular sieves 1.2 g. The mixture was stirred
at rt for 3.5 h, then 10 ml of sat. NaHCO.sub.3 was added. The
mixture was filtered through celite, washed with EtOAc. The
combined organic layers were washed with water, brine, dried and
concentrated. The crude was purified on a silica gel column (hexane
to 5-20% EtOAc in hexane) to give trans product 177 590 mg and cis
product 178 540 mg.
Step B
[0971] Compound 179 was synthesized from 177 by Method 1.
[M-H].sup.-=269.1 m/z. Activity: A
Example 148
##STR00497##
[0973] Compound 180 was synthesized from 178 by Method 1.
[M-H].sup.-=269.1 m/z. Activity: A
Example 149
##STR00498##
[0975] Boronic acid 181 was prepared by methods described for
example 147. [M-H].sup.-=269.1 m/z. Activity: A
Example 150
##STR00499##
[0977] Boronic acid 182 was prepared by methods described for
example 148. [M-H].sup.-=269.1 m/z. Activity: A
Example 151
##STR00500##
[0979] To the suspension of propyltriphenylphosphonium bromide (140
mg, 1.1 equiv.) in 3 mL of THF is added drop wise 0.16 mL of a 2.5
M solution of BuLi in hexanes under nitrogen at 0 C. After 15 min,
the red solution is cooled at -78.degree. C. and treated with
benzaldehyde 93 (100 mg, 1 equiv.) in 1 mL THF. After an additional
15 min, the solution was slowly warmed to rt for 1 h, then water (2
ml) and brine (10 ml) are added followed by an extractive workup
using ethyl acetate (100 ml). The organic extract is dried
(MgSO.sub.4), filtered, concentrated, and purified to give desired
product olefin as 1:3 trans to cis mixture. The mixture was
dissolved in 2 ml toluene, AIBN (5 mg) and PhSH (5 .mu.l) were
added. The solution was heated to 80.degree. C. for 2 h, cooled to
rt and filtered through short silica gel column. Hexanes was used
to wash the product out and the combined solution was concentrated
to give the aryl bromide as a single trans isomer.
[0980] The aryl bromide was converted by Method 1 to boronic acid
183. [M-H].sup.-=295.1 m/z. Activity: B
Example 152
##STR00501##
[0982] Compound 184 was by methods described for example 151, using
3-phenylpropyl triphenylphosphonium bromide in place of
propyltriphenylphosphonium bromide. [M-H].sup.-=371.2 m/z.
Activity: C
Example 153
##STR00502##
[0984] 6-Bromo-2-naphthol (2.8 g, 12.5 mmol), 2-chloropyridine (1.7
g, 15 mmol, 1.2 eq.), and NaOH (750 mg, 19 mmol, 1.5 eq.) were
combined in NMP (15 mL) and heated in the microwave at 220.degree.
C. during 15 min. The reaction mixture was diluted with water and
extracted into MTBE; the organic phase was dried on
Na.sub.2SO.sub.4 and concentrated. Chromatography on silica
(1.fwdarw.10% EtOAc/hexanes) gave
6-bromonaphthalene-2-(2-pyridyl)ether as a white solid, 3.31 g.
This material was converted to the 6-pinacolboronate via Method 3
and the free boronate via Method 5, giving compound 185 as a white
solid (1.11 g, 38%). [M-H].sup.-=264.1 m/z. Activity: A
Example 154
##STR00503##
[0986] 6-Hydroxynaphthalene-2-boronic acid (1.5 g, 8 mmol) was
dissolved in MTBE (75 mL) and stirred with pinacol (943 mg, 8 mmol)
for 1 h, then dried on Na.sub.2SO.sub.4 and concentrated to crude
pinacol ester which was used without further purification.
[0987] This crude ester (220 mg, 0.81 mmol), NaOH (150 mg, 3.7
mmol, 4.5 eq.), and chloropyrazine (215 uL, 2.4 mmol, 3 eq.) were
dissolved in DMF (3 mL) and heated via microwave at 160.degree. C.
for 15 min. Dilution with water and extraction into EtOAc, followed
by purification via chromatography on silica gel (4-, 20%
EtOAc/hexanes) gave the pinacol ester as a yellow oil. This was
deprotected to the free boronic acid via Method 5 to give 186 as a
yellowish solid (172 mg, 79%), approx. 90% pure by rp-hplc.
[M-H].sup.-=265.1 m/z. Activity: A
Example 155
##STR00504##
[0989] 6-Bromo-2-chloroquinoline (2.5 g, 10.3 mmol) was converted,
via Methods 11, 3, and 5, to compound 187 (1.31 g, 47%) as a white
solid. [M-H].sup.-=264.1 m/z. Activity: A
Example 156
##STR00505##
[0991] 7-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) was converted,
via Methods 11, 3, and 5, to compound 188 (113 g, 41%) as a white
solid. [M-H].sup.-=264.1 m/z. Activity: A
Example 157
##STR00506##
[0993] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and
3-methoxyphenol (330 uL, 3. eq.) were converted, via Methods 11, 3,
and 5, to compound 189 (141 mg, 46%) as a white solid.
[M-H].sup.-=294.1 m/z. Activity: A
Example 158
##STR00507##
[0995] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and potassium
tert-butoxide (230 mg, 2.0 eq.) were dissolved in cyclopentanol (3
mL) and heated by microwave at 150.degree. C. for 30 min.
Extraction from water into MTBE and drying on Na.sub.2SO.sub.4 gave
the crude ether. This was converted, via Methods 3 and 5, to
compound 190 (66 mg, 25%) as a yellow waxy solid. [M-H].sup.-=256.1
m/z. Activity: A
Example 159
##STR00508##
[0997] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and potassium
tert-butoxide (230 mg, 2.0 eq.) were dissolved in n-butanol (3 mL)
and heated by microwave at 150.degree. C. for 30 min. Extraction
from water into MTBE and drying on Na.sub.2SO.sub.4 gave the crude
ether. This was converted, via Methods 3 and 5, to compound 191 (74
mg, 29%). [M-H].sup.-=244.1 m/z. Activity: A
Example 140
##STR00509##
[0999] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and potassium
tert-butoxide (230 mg, 2.0 eq.) were dissolved in cyclohexanol (3
mL) and heated at 120.degree. C. for 16 hours. Extraction from
water into MTBE and drying on Na.sub.2SO.sub.4 gave the crude
ether. This was converted, via Methods 3 and 5, to compound 192
(156 mg, 57%). [M-H].sup.-=270.1 m/z. Activity: B
Example 161
##STR00510##
[1001] 6-Bromo-2-chloroquinoline (200 mg, 0.8 mmol) and NaH (40 mg,
2.0 eq.) were dissolved in BnOH (2 mL) and heated at 120.degree. C.
for 16 hours. Extraction from water into MTBE and drying on
Na.sub.2SO.sub.4 gave the crude ether. This was converted, via
Methods 3 and 5, to compound 193 (40 mg, 18%). [M-H].sup.-=278.1
m/z. Activity: A
Example 162
##STR00511##
[1003] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and
3-(dimethylamino)phenol (3 mmol, 3.0 eq.) were converted, via
Methods 11, 3, and 5, to compound 194 (140 mg, 44%).
[M-H].sup.-=307.1 m/z. Activity: A
Example 163
##STR00512##
[1005] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and
3-nitrophenol (3 mmol, 3.0 eq.) were converted, via Methods 11, 3,
and 5, to compound 195 (83 mg, 26%). [M-H].sup.-=309.1 m/z.
Activity: A
Example 164
##STR00513##
[1007] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and
2-chlorophenol (3 mmol, 3.0 eq.) were converted, via Methods 11, 3,
and 5, to compound 196 (132 mg, 43%). [M-H].sup.-=298.1 m/z.
Activity: A
Example 165
##STR00514##
[1009] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and
3-chlorophenol (3 mmol, 3.0 eq.) were converted, via Methods 11, 3,
and 5, to compound 197 (93 mg, 30%). [M-H].sup.-=298.1 m/z.
Activity: A
Example 166
##STR00515##
[1011] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and
3-cyanophenol (3 mmol, 3.0 eq.) were converted, via Methods 11, 3,
and 5, to compound 198 (46 mg, 15%). [M-H].sup.-=289.1 m/z.
Activity: A
Example 167
##STR00516##
[1013] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and catechol (3
mmol, 3.0 eq.) were converted, via Methods 11, 3, and 5, to
compound 199 (78 mg, 28%). [M-H].sup.-=280.2 m/z. Activity: A
Example 168
##STR00517##
[1015] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and guaiacol (3
mmol, 3.0 eq.) were converted, via Methods 11, 3, and 5, to
compound 200 (159 mg, 61%). [M-H].sup.-=294.1 m/z. Activity: A
Example 169
##STR00518##
[1017] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and
4-chlorophenol (3 mmol, 3.0 eq.) were converted, via Methods 11, 3,
and 5, to compound 201 (63 mg, 21%). [M-H].sup.-=298.1 m/z.
Activity: A
Example 170
##STR00519##
[1019] 6-Bromo-2-chloroquinoline (200 mg, 0.8 mmol) and 25%
methanolic NaOMe (2 mL) were heated at 50.degree. C. for 16 hours.
Extraction from water into EtOAc and drying on Na.sub.2SO.sub.4
gave the crude ether. This was converted, via Methods 3 and 5, to
compound 202 (110 mg, 66%). [M-H].sup.-=202.1 m/z. Activity: B
Example 171
##STR00520##
[1021] Ethoxyquinoline 203 was prepared by methods used for example
170. (110 mg, 66%). [M-H].sup.-=215.1 m/z. Activity: B
Example 172
##STR00521##
[1023] 6-Bromo-2-chloroquinoline (200 mg, 0.8 mmol) and
N-methylbenzylamine (2 mL) were heated at 120.degree. C. for 16
hours. Extraction from 2M NaOH into DCM and drying on
Na.sub.2SO.sub.4 gave the crude 2-aminoquinoline. This was
converted, via Methods 3 and 5, to compound 204 (110 mg, 46%).
[M-H].sup.-=291.1 m/z. Activity: A
Example 173
##STR00522##
[1025] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and
N-methylaniline (2 mL) were heated at 120.degree. C. for 16 hours.
Extraction from 2M NaOH into DCM and drying on Na.sub.2SO.sub.4
gave the crude 2-aminoquinoline. This was converted, via Methods 3
and 5, to compound 205 (88 mg, 31%). [M-H].sup.-=277.0 m/z.
Activity: B
Example 174
##STR00523##
[1027] 6-Bromo-2-chloroquinoline (1 g, 4.1 mmol) and aniline (8 mL)
were heated at 100.degree. C. for 16 hours. Some dark color was
removed by pushing through a plug of silica gel with MTBE. The
eluent was taken up in hexanes, washed with water, and
concentrated; the residue was shaken with water (100 mL) and
hexanes (20 mL), giving a beige solid which was collected by
filtration and washed with water. This material was converted, via
Methods 3 and 5, to compound 206 (647 mg, 60%). [M-H].sup.-=263.1
m/z. Activity: A
Example 175
##STR00524##
[1029] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and
tetrahydroquinoline (2 mL) were heated at 120.degree. C. for 16
hours. The material was taken up in DCM (20 mL) and treated with
NEt.sub.3 (6 mL) and Ac.sub.2O (3 mL) for 2 h, then extracted from
0.1 M NaOH into DCM. Drying on Na.sub.2SO.sub.4 and concentration
gave a crude residue which was converted, via Methods 3 and 5, to
compound 207 (151 mg, 48%). [M-H].sup.-=303.1 m/z. Activity: B
Example 176
##STR00525##
[1031] 6-hydroxynaphthalene-2-boronic acid (1.5 g, 8 mmol) was
dissolved in MTBE (75 mL) and stirred with pinacol (943 mg, 8 mmol)
for 1 h, then dried on Na.sub.2SO.sub.4 and concentrated to crude
pinacol ester which was used without further purification.
[1032] This crude ester (220 mg, 0.81 mmol), NaOH (150 mg, 3.7
mmol, 4.5 eq.), and 2-bromo-pyrimidine (390 mg, 2.4 mmol, 3.0 eq.)
were dissolved in DMF (3 mL) and heated via microwave at
160.degree. C. for 15 min. Dilution with water and extraction into
EtOAc, followed by purification via chromatography on silica gel
(4.fwdarw.20% EtOAc/hexanes) gave the pinacol ester as a yellow
oil. This was deprotected to the free boronic acid via Method 5 to
give 208 (54 mg, 25%). [M-H].sup.-=265.1 m/z. Activity: A
Example 177
##STR00526##
[1034] 6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and
3-hydroxypyridine (3 mmol, 3. eq.) were converted, via Methods 11,
3, and 5, to compound 209 (69 mg, 26%). [M-H].sup.-=265.1 m/z.
Activity: A
Example 178
##STR00527##
[1036] A solution of 4-bromoaniline (9.0 g, 52.3 mmol) in PhMe (100
mL) and pyridine (8.5 mL, 110 mmol, 2.0 eq.) was cooled in an ice
bath and slowly treated with propionyl chloride (5.5 mL, 63 mmol,
1.2 eq.). After 2 h, the reaction mixture was added to 0.1 M HCl
and extracted into EtOAc. Concentration followed by
recrystallization of the residue from EtOH/water gave
N-propionyl-4-bromoaniline (10.64 g, 89%). [M-H].sup.-=278.1
m/z.
[1037] Phosphorous oxychloride (3 mL, excess) was treated with DMF
(650 uL, 8.7 mmol, 1.5 eq.) and the solution allowed to return to
ambient temperature. N-propionyl-4-bromoaniline (1.32 g, 5.8 mmol,
1 eq.) was added and the mixture heated at 85.degree. C. for 4 h.
The hot mixture was poured onto ice (100 g), stirred until melted,
and the solids were collected by filtration. Washing with water and
drying in vacuo gave clean 6-bromo-2-chloro-3-methylquinoline (914
mg, 61%). This intermediate (250 mg, 1.0 mmol) and phenol (3 mmol,
3. eq.) were converted, via Methods 11, 3, and 5, to compound 210
(118 mg, 42%). [M-H].sup.-=278.1 m/z. Activity: A
Example 179
##STR00528##
[1039] 2-Quinoxalinol (2.9 g, 20 mmol) and silver sulfate (3.1 g,
10 mmol, 0.5 eq.) in sulfuric acid (20 mL) were treated with
bromine (1.03 mL, 20 mmol, 1.0 eq.). After stirring at ambient
temperature for 18 h, the reaction mixture was diluted with carbon
tetrachloride (50 mL), heated to 50.degree. C., and filtered. The
filtrate was poured onto ice and the solids collected by filtration
and recrystallized from HOAc, giving 6-bromo-2-quinoxalinol (1.8 g,
40%).
[1040] 6-Bromo-2-quinoxalinol (631 mg) in POCl.sub.3 (6.3 mL) was
refluxed for 2 h, then poured onto ice. The solution was
neutralized to pH 7 by addition of NH.sub.4OH, and the resulting
solid collected by filtration. Washing with water and drying in
vacuo gave 6-bromo-2-chloroquinoxaline (627 mg, 92%).
[1041] This intermediate (250 mg, 1.0 mmol) and phenol (3 mmol, 3.0
eq.) were converted, via Methods 11, 3, and 5, to compound 211 (4.4
mg, 2%). [M-H].sup.-=265.1 m/z. Activity: B
Example 180
##STR00529##
[1043] 4-Bromo-2-methylaniline (1.8 g, 10 mmol) in PhMe (25 mL) was
treated with ethyl acetoacetate (1.3 mL, 11 mmol, 1.1 eq.) and
refluxed during 18 h. Upon cooling a precipitate of
N-acetoacetyl-4-bromo-2-methylaniline (1.59 g, 60%) formed, which
was collected by filtration and used without further
purification.
[1044] This acetoacetamide (1 g, 3.7 mmol) was dissolved in
sulfuric acid (5 mL) and heated at 120.degree. C. during 2 h. The
hot solution was poured onto ice (100 g), giving a white solid
which was collected by filtration, washed with water, and dried in
vacuo to give 6-bromo-4,8-dimethyl-2-quinolone (418 mg, 45%).
[1045] This quinolone (410 mg, 1.6 mmol) in POCl.sub.3 (5 mL) was
refluxed for 2 h, then poured onto ice. The solution was
neutralized to pH 7 by addition of NH.sub.4OH, and the resulting
solid collected by filtration. Washing with water and drying in
vacuo gave 6-bromo-2-chloro-4,8-dimethyl-quinoline (407 mg,
93%).
[1046] This intermediate (200 mg, 0.74 mmol) and phenol (3 mmol,
3.0 eq.) were converted, via Methods 11, 3, and 5, to compound 212
(141 mg, 65%). [M-H].sup.-=292.1 m/z. Activity: B
Example 181
##STR00530##
[1048] Compound 213 was produced in a manner analogous to compound
212, using 4-bromoaniline in place of 4-bromo-2-methylaniline.
Yield 131 mg. [M-H].sup.-=278.1 m/z. Activity: A
Example 182
##STR00531##
[1050] A solution of 6-bromobenzothiazolin-2-one (500 mg, 2.2 mmol)
in POCI.sub.3 (5 mL) was refluxed during 18 h, then poured onto
ice. The solution was neutralized to pH 9 by addition of
NH.sub.4OH, and the resulting solid collected by filtration.
Washing with water and drying in vacuo gave
6-bromo-2-chlorobenzothiazole (450 mg, 83%).
[1051] This intermediate (200 mg, 0.8 mmol) and phenol (3 mmol, 3.0
eq.) were converted, via Methods 11, 3, and 5, to compound 214 (25
mg, 12%). [M-H].sup.-=270.1 m/z. Activity: A
Example 183
##STR00532##
[1053] 6-Bromo-2-chloroquinoline (500 mg, 2.0 mmol) and
2-hydroxypyridine (3 mmol, 3.0 eq.) were converted, via Methods 11,
3, and 5, to compound 215 (35 mg, 7%). [M-H].sup.-=265.1 m/z.
Activity: A
Example 184
##STR00533##
[1055] 6-Hydroxynaphthalene-2-boronic acid (1.5 g, 8 mmol) was
dissolved in MTBE (75 mL) and stirred with pinacol (943 mg, 8 mmol)
for 1 h, then dried on Na.sub.2SO.sub.4 and concentrated to crude
pinacol ester which was used without further purification.
[1056] Phenylboronic acid (140 mg, 1.1 mmol, 2.0 eq.) was
coevaporated with PhMe twice to produce the anhydride. This was
treated with crude 6-hydroxynaphthalene-2-boronic acid pinacol
ester (150 mg, 0.56 mmol), DCM (5 mL), NEt.sub.3 (400 uL, 3 mmol, 5
eq.), and cupric acetate (100 mg, 0.53 mmol, 0.95 eq.) and stirred
at ambient temperature during 16 h. The mixture was extracted from
0.1M NaOH into DCM, dried on Na.sub.2SO.sub.4, concentrated, and
chromatographed on silica gel (0-2% EtOAc/hexanes) to give
6-phenoxynaphthalene-2-boronic acid pinacol ester, which was
deprotected via Method 5 to provide compound 216 (54 mg, 37%).
[M-H].sup.-=263.1 m/z. Activity: A
Example 185
##STR00534##
[1058] The corresponding pinacol ester (22 mg, 0.066 mmol) was
cleaved according to Method 5 to give compound 217 (17 mg, quant.).
[M-H].sup.-=251.1 m/z. Activity: A
Example 186
##STR00535##
[1060] The corresponding bromide (256 mg, 1.0 mmol) was reacted
according to Method 2 to give compound 218 (37 mg, 17%).
[M-H].sup.-=214.1 m/z. Activity: D
Example 187
##STR00536##
[1062] The corresponding bromide (336 mg, 1.1 mmol) was converted
via Methods 3 and 5 to compound 219 (77 mg, 26%). [M-H].sup.-=273.1
m/z. Activity: B
Example 188
##STR00537##
[1064] The corresponding pinacol ester (200 mg, 0.8 mmol) was
cleaved according to Method 5 to give compound 220 (89 mg, 66%).
[M-H].sup.-=181.1 m/z. Activity: C
Example 189
##STR00538##
[1066] 6-Bromoquinaldine (1 g, 4.5 mmol) in CCl.sub.4 (6 mL) was
treated with NBS (750 mg, 4.2 mmol, 0.95 eq.) and a few crystals of
benzoyl peroxide and refluxed during 2 h. The hot solution was
filtered, the filtrated cooled, and the resulting crystals
collected by filtration and used without further purification.
[1067] A solution of phenol (60 mg, 0.63 mmol, 2.0 eq.) in NMP was
treated with 60% NaH dispersion (25 mg, 0.63 mmol, 2.0 eq.) and the
dibromoquinaldine produced in the previous step (150 mg, 0.31
mmol). After stirring at ambient temperature for 18 h, the reaction
was extracted from 0.1M NaOH into MTBE, dried on Na.sub.2SO.sub.4,
concentrated, and chromatographed on silica gel (0.fwdarw.10%
EtOAc/hexanes) to give a-phenoxy-6-bromoquinaldine (93 mg,
94%).
[1068] This bromide was converted via Methods 3 and 5 to compound
221 (48 mg, 58%). [M-H].sup.-=278.1 m/z. Activity: B
Example 190
##STR00539##
[1070] 4-Bromoiodobenzene (460 mg, 1.6 mmol, 1.5 eq.),
1-isoamylpyrazole-4-boronic acid (200 mg, 1.1 mmol), potassium
acetate (100 mg, 1.0 eq.), Pd(dppf)Cl.sub.2 (100 mg, 0.1 eq.), and
Cs.sub.2CO.sub.3 (1 g, 3.0 eq.) in DMSO (5 mL) were heated under
argon at 80.degree. C. during 1 h. The reaction mixture was
extracted from water into ether, dried Na.sub.2SO.sub.4,
concentrated, and chromatographed on silica gel (0.fwdarw.10%
EtOAc/hexanes) to give 1-isoamyl-4-(4-bromophenyl)pyrazole (263 mg,
82%).
[1071] This bromide was converted via Methods 3 and 5 to compound
222 (147 mg, 64%). [M-H].sup.-=257.2 m/z. Activity: A
Example 191
##STR00540##
[1073] The corresponding iodide (125 mg, 0.4 mmol) was converted
via Methods 3 and 5 to compound 223 (9 mg, 10%). [M-H].sup.-=237.1
m/z. Activity: D
Example 192
##STR00541##
[1075] 2-(4-Iodophenyl)benzimidazole (200 mg, 0.6 mmol) was
methylated with iodomethane (180 mg, 1.2 mmol, 2.0 eq.) and NaH (45
mg, 1.8 mmol, 3 eq.) in DMF (3 mL) for 18 h. Dilution with diethyl
ether, washing with water, drying over Na.sub.2SO.sub.4, and
chromatography (10.fwdarw.25% EtOAc/hexanes) gave
1-methyl-2-(4-iodophenyl)benzimidazole (124 mg, 59%).
[1076] This iodide was converted via Method 2 to compound 224 (9
mg, 10%). Activity: D
Example 193
##STR00542##
[1078] 4-Bromo-3-fluoroiodobenzene (250 mg, 0.7 mmol, 1.2 eq.),
4-methyl-2-phenylthiazole-5-boronic acid pinacol ester (170 mg, 0.6
mmol), potassium acetate (70 mg, 1.0 eq.), Pd(dppf)Cl.sub.2 (70 mg,
0.1 eq.), and Cs.sub.2CO.sub.3 (700 mg, 3.0 eq.) in DMSO (5 mL)
were heated under argon at 80.degree. C. during 1 h. The reaction
mixture was extracted from water into diethyl ether, dried over
Na.sub.2SO.sub.4, concentrated, and chromatographed on silica gel
(5-+10% EtOAc/hexanes) to give the corresponding bromide to 225
(169 mg, 85%).
[1079] This bromide was converted via Methods 3 and 5 to compound
225 (15 mg, 10%). Activity: B
Example 194
##STR00543##
[1081] 4-Bromo-3-fluoroiodobenzene (250 mg, 0.8 mmol, 1.2 eq.),
1-benzylpyrazole-4-boronic acid pinacol ester (200 mg, 0.7 mmol),
potassium acetate (70 mg, 1 eq.), Pd(dppf)Cl.sub.2 (70 mg, 0.1
eq.), and Cs.sub.2CO.sub.3 (700 mg, 3.0 eq.) in DMSO (5 mL) were
heated under argon at 80.degree. C. during 1 h. The reaction
mixture was extracted from water into diethyl ether, dried over
Na.sub.2SO.sub.4, concentrated, and chromatographed on silica gel
(5.fwdarw.10% EtOAc/hexanes) to give the corresponding bromide to
226 (193 mg, 83%).
[1082] This bromide was converted via Methods 3 and 5 to compound
226 (13 mg, 8%). [M-H].sup.-=295.1 m/z. Activity: A
Example 195
##STR00544##
[1084] 4-Bromo-iodobenzene (240 mg, 0.8 mmol, 1.2 eq.),
1-benzylpyrazole-4-boronic acid pinacol ester (200 mg, 0.7 mmol),
potassium acetate (70 mg, 1 eq.), Pd(dppf)Cl.sub.2 (70 mg, 0.1
eq.), and Cs.sub.2CO.sub.3 (700 mg, 3.0 eq.) in DMSO (5 mL) were
heated under argon at 80.degree. C. during 1 h. The reaction
mixture was extracted from water into diethyl ether, dried over
Na.sub.2SO.sub.4, concentrated, and chromatographed on silica gel
(5-10% EtOAc/hexanes) to give 1-benzyl-4-(4-bromophenyl)pyrazole
(218 mg, 99%).
[1085] This bromide was converted via Methods 3 and 5 to compound
227 (142 mg, 73%). [M-H].sup.-=277.1 m/z. Activity: A
Example 196
##STR00545##
[1087] 4-Bromo-iodobenzene (250 mg, 0.9 mmol, 1.2 eq.),
2-methoxynaphthalene-6-boronic acid (150 mg, 0.7 mmol), potassium
acetate (70 mg, 1.0 eq.), Pd(dppf)Cl.sub.2 (70 mg, 0.1 eq.), and
Cs.sub.2CO.sub.3 (700 mg, 3.0 eq.) in DMSO (5 mL) were heated under
argon at 80.degree. C. during 1 h. The reaction mixture was
extracted from water into diethyl ether, dried over
Na.sub.2SO.sub.4, concentrated, and chromatographed on silica gel
(5.fwdarw.20% EtOAc/hexanes) to
2-methoxy-6-(4-bromophenyl)naphthalene (131 mg, 56%).
[1088] This bromide was converted via Methods 3 and 5 to compound
228 (47 mg, 41%). [M-H].sup.-=277.1 m/z. Activity: B
Example 197
##STR00546##
[1090] 4-Bromo-3-fluoroiodobenzene (250 mg, 0.8 mmol, 1.2 eq.),
quinoline-5-boronic acid (120 mg, 0.7 mmol), potassium acetate (70
mg, 1 eq.), Pd(dppf)Cl.sub.2 (70 mg, 0.1 eq.), and Cs.sub.2CO.sub.3
(700 mg, 3.0 eq.) in DMSO (5 mL) were heated under argon at
80.degree. C. during 1 h. The reaction mixture was extracted from
water into ether, dried over Na.sub.2SO.sub.4, concentrated, and
chromatographed on silica gel (5-20% EtOAc/hexanes) to give
5-(4-bromo-3-fluorophenyl)quinoline (220 mg, quant.).
[1091] This bromide was converted via Methods 3 and 5 to compound
229 (39 mg, 20%). [M-H].sup.-=266.1 m/z. Activity: B
Example 198
##STR00547##
[1093] 4-Bromo-3-fluoroiodobenzene (250 mg, 0.8 mmol, 1.2 eq.),
indole-4-boronic acid (110 mg, 0.7 mmol), potassium acetate (70 mg,
1 eq.), Pd(dppf)Cl.sub.2 (70 mg, 0.1 eq.), and Cs.sub.2CO.sub.3
(700 mg, 3 eq.) in DMSO (5 mL) were heated under argon at
80.degree. C. during 1 h. The reaction mixture was extracted from
water into ether, dried Na.sub.2SO.sub.4, concentrated, and
chromatographed on silica gel (5.fwdarw.15% EtOAc/hexanes) to give
4-(4-bromo-3-fluorophenyl)indole (164 mg, 83%).
[1094] This bromide was converted via Methods 3 and 5 to compound
230 (77 mg, 53%). [M-H].sup.-=254.1 m/z. Activity: B
Example 199
##STR00548##
[1096] 2-Phelylmalondialdehyde (200 mg, 1.4 mmol) in EtOH (10 mL)
was treated with 4-bromophenylhydrazine HCl (300 mg, 1.4 mmol) and
NEt.sub.3 (200 uL, 1.4 mmol) and refluxed for 1 h. The solution was
diluted slightly with water, chilled, and the resulting precipitate
of 1-(4-bromophenyl)-4-phenylpyrazole collected by filtration (179
mg, 44%).
[1097] This bromide was converted via Methods 3 and 5 to compound
231 (35 mg, 23%). [M-H].sup.-=263.1 m/z. Activity: A
Example 200
##STR00549##
[1099] 2-(4-Bromophenyl)malondialdehyde (250 mg, 1.1 mmol) in EtOH
(10 mL) was treated with phenylhydrazine (110 uL, 1.1 mmol) and
refluxed for 1 h. The solution was diluted slightly with water,
chilled, and the resulting precipitate of
4-(4-bromophenyl)-1-phenylpyrazole collected by filtration (270 mg,
82%).
[1100] This bromide was converted via Methods 3 and 5 to compound
232 (155 mg, 68%). [M-H].sup.-=263.0 m/z. Activity: A
Example 201
##STR00550##
[1102] 4-(4-Bromophenyl)piperidine HCl (1 g, 3.7 mmol) in DCM (6
mL) was treated with K.sub.2CO.sub.3 (1.3 g, 9 mmol, 2.5 eq.) and
Boc2O (1.35 g, 6 mmol, 1.6 eq). The mixture was diluted with water,
extracted with MTBE, washed with brine, dried on Na.sub.2SO.sub.4,
and concentrated. Chromatography on silica gel (2.fwdarw.8%
EtOAc/hexanes) gave 1-Boc-4-(4-bromophenyl)piperidine (944 mg,
76%)._This bromide was converted via Method 3 to
1-Boc-4-(4-boronophenyl)piperidine pinacol ester (1.16 g,
quant.).
[1103] A portion of this ester (270 mg) was deprotected via Method
5 to give compound 233 (144 mg, 68%). [M-H].sup.-=304.2 m/z.
Activity: A
Example 202
##STR00551##
[1105] 4-Bromophenethylamine (2 mL, 13 mmol) in DCM (12 mL) was
treated with K.sub.2CO.sub.3 (2.7 g, 20 mmol, 1.5 eq.) and Boc20
(3.1 g, 14 mmol, 1.1 eq.). The mixture was diluted with water,
extracted with MTBE, washed with brine, dried on Na.sub.2SO.sub.4,
and concentrated to give clean N-Boc-4-bromophenethylamine (4 g,
quant.).
[1106] This carbamate was dissolved in DMF (40 mL) and treated with
60% NaH dispersion (1.7 g, 42 mmol, 3.0 eq.) and MeI (1.7 mL, 28
mmol, 2.0 eq.). After stirring at ambient temperature 18 h, the
reaction mixture is extracted from 0.1M NaOH into MTBE, dried on
Na.sub.2SO.sub.4, and concentrated to clean
N-Boc-N-methyl-4-bromophenethylamine (4.67 g, quant.). 1 g of this
bromide (3.2 mmol) was converted via Method 3 to
N-Boc-N-methyl-4-boronophenethylamine pinacol ester (981 mg,
85%).
[1107] A portion of this ester (150 mg) was deprotected via Method
5 to give compound 234 (95 mg, 82%). [M-H].sup.-=278.1 m/z.
Activity: A
Example 203
##STR00552##
[1109] A solution of 4-bromodihydrocinnamic acid (1.5 g, 6.6 mmol)
in THF (10 mL) and DMF (10 mL) was treated with 2.0M methylamine in
THF (10 mL, 3.0 eq.) and HBTU (2.75 g, 7.2 mmol, 1.1 eq.) The
mixture was diluted with water, extracted with MTBE, washed with
brine, dried on Na.sub.2SO.sub.4, and pushed through a pad of
silica gel using 50% EtOAc/hexanes, giving
N-methyl-4-bromodihydrocinnamide.
[1110] This amide was dissolved in THF (20 mL) and treated with
borane-dimethylsulfide complex (1.25 mL, 13 mmol, 2.0 eq.) and
refluxed for 3 h. The reaction was quenched with MeOH, then treated
with 6M HCl to a pH of 1 and concentrated in vacuo. The residue was
extracted from IM NaOH into DCM, dried Na.sub.2SO.sub.4, and
concentrated to N-methyl-3-(4-bromophenyl)propylamine (562 mg, 38%)
which is used without further purification.
[1111] This amine in DCM (5 mL) was treated with K.sub.2CO.sub.3
(500 mg, 3.7 mmol, 1.5 eq.) and Boc2O (900 mg, 4 mmol, 1.6 eq.).
The mixture was diluted with water, extracted with MTBE, washed
with brine, dried on Na.sub.2SO.sub.4, concentrated, and
chromatographed to give clean
N-Boc-N-methyl-3-(4-bromophenyl)propylamine (546 mg, 68%). This
bromide was converted via Method 3 to
N-Boc-N-methyl-3-(4-boronophenyl)propylamine pinacol ester (594 mg,
95%).
[1112] A portion of this ester (100 mg) was deprotected via Method
5 to give compound 235 (59 mg, 76%). [M-H].sup.-=292.2 m/z.
Activity: A
Example 204
##STR00553##
[1114] 1-Boc-4-(4-boronophenyl)piperidine pinacol ester (887 mg,
2.3 mmol), prepared in the synthesis of compound 233, was dissolved
in TFA (10 mL), stirred for 1 h, and coevaporated with twice with
PhMe to give deprotected salt with pinacol ester intact (by NMR and
LC). 190 mg of this salt (0.47 mmol) in DCM (5 mL) was treated with
NEt.sub.3 (250 uL, 1.8 mmol, 3.8 eq.) and benzenesulfonyl chloride
(75 uL, 0.57 mmol, 1.2 eq.). After stirring at ambient temperature
16 h, the reaction mixture was diluted with DCM and concentrated
onto silica gel. Chromatography (3.fwdarw.15% EtOAc/hexanes) gave
1-benzenesulfonyl-4-(4-boronophenyl)piperidine pinacol ester.
Deprotection of this ester via Method 5 gave compound 236 (80 mg,
49%). [M-H].sup.-=344.1 m/z. Activity: B
##STR00554##
[1115] N-Boc-N-methyl-4-boronophenethylamine pinacol ester (430
mg), prepared in the synthesis of compound 234, was dissolved in
TFA (5 mL), stirred for 1 h, and coevaporated with twice with PhMe
to give deprotected salt with pinacol ester intact (by NMR and LC).
208 mg of this salt (0.55 mmol) in DCM (5 mL) was treated with
NEt.sub.3 (250 uL, 1.8 mmol, 3.3 eq.) and benzenesulfonyl chloride
(85 uL, 0.67 mmol, 1.2 eq.). After stirring at ambient temperature
16 h, the reaction mixture was diluted with DCM and concentrated
onto silica gel. Chromatography (2.fwdarw.15% EtOAc/hexanes) gave
N-benzenesulfonyl-N-methyl-4-boronophenethylamine pinacol ester.
Deprotection of this ester via Method 5 gave compound 237 (117 mg,
66%). [M-H].sup.-=318.1 m/z. Activity: A
Example 206
##STR00555##
[1117] N-Boc-N-methyl-3-(4-boronophenyl)propylamine pinacol ester
(494 mg), prepared in the synthesis of compound 235, was dissolved
in TFA (5 mL), stirred for 1 h, and coevaporated with twice with
PhMe to give deprotected salt with pinacol ester intact (by NMR and
LC). 256 mg of this salt (0.66 mmol) in DCM (5 mL) was treated with
NEt.sub.3 (300 uL, 2.2 mmol, 3.3 eq.) and benzenesulfonyl chloride
(100 uL, 0.79 mmol, 1.2 eq.). After stirring at ambient temperature
16 h, the reaction mixture was diluted with DCM and concentrated
onto silica gel. Chromatography (2.fwdarw.15% EtOAc/hexanes) gave
N-benzenesulfonyl-N-methyl-3-(4-boronophenyl)propylamine pinacol
ester. Deprotection of this ester via Method 5 gave compound 238
(135 mg, 62%). [M-H].sup.-=332.1 m/z. Activity: A
Example 207
##STR00556##
[1119] Oxadiazole 239 was prepared in 2 steps by first forming the
oxadiazole from
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
4-oxo-4-(1-piperidinyl)butanoic acid using Method 7 followed by
Method 5 and was isolated after precipitation from the reaction
mixture. [M-H].sup.-=328.1 m/z. Activity: B
Example 20
##STR00557##
[1121] Oxadiazole 60 was prepared in 2 steps by first forming the
oxadiazole from
5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)furan-3-carboxylic
acid and hexanoic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[2M-H.sub.2O].sup.-=481.0 m/z. Activity: B
Example 209
##STR00558##
[1123] Benzoxazole 241 was prepared in 3 steps by first forming the
benzoxazole from 2-amino-5-chlorophenol and phenyl acetic acid
using Method 13 followed by conversion to the boronate ester using
Method 15 followed by Method 5. [M-H].sup.-=252.0 m/z. Activity:
A
Example 210
##STR00559##
[1125] Benzoxazole 242 was prepared in 3 steps by first forming the
benzoxazole from 2-amino-4-bromophenol and 3-phenylpropionic acid
using Method 13 followed by conversion to the boronate ester using
Method 3 followed by Method 5. [M-H].sup.-=266.1 m/z. Activity:
A
Example 211
##STR00560##
[1127] Benzoxazole 243 was prepared in 3 steps by first forming the
benzoxazole from 2-amino-5-chlorophenol and 3-phenylpropionic acid
using Method 13 followed by conversion to the boronate ester using
Method 15 followed by Method 5. [M-H].sup.-=266.1 m/z. Activity:
A
Example 212
##STR00561##
[1129] Benzoxazole 244 was prepared in 3 steps by first forming the
benzoxazole from 2-amino-5-chlorophenol and butyric acid using
Method 13 followed by conversion to the boronate ester using Method
15 followed by Method 5. [M-H].sup.-=204.1 m/z. Activity: A
Example 213
##STR00562##
[1131] Benzoxazole 245 was prepared in 3 steps by first forming the
benzoxazole from 2-amino-5-chlorophenol and hexanoic acid using
Method 13 followed by conversion to the boronate ester using Method
15 followed by Method 5. [M-H].sup.-=233.9 m/z. Activity: A
Example 214
##STR00563##
[1133] Benzoxazole 246 was prepared in 3 steps by first forming the
benzoxazole from 2-amino-5-chlorophenol and
5,5,5-trifluoropentanoic acid using Method 13 followed by
conversion to the boronate ester using Method 15 followed by Method
5. [M-H].sup.-=272.1 m/z. Activity: A
Example 215
##STR00564##
[1135] Benzoxazole 247 was prepared in 3 steps by first forming the
benzoxazole from 2-amino-5-chlorophenol and
4-oxo-4-(1-piperidinyl)butanoic acid using Method 13 followed by
conversion to the boronate ester using Method 15 followed by Method
5. [M-H].sup.-=301.1 m/z. Activity: B
Example 216
##STR00565##
[1137] Benzoxazole 248 was prepared in 3 steps by first forming the
benzoxazole from 2-amino-5-chlorophenol and
5-oxo-1-phenyl-pyrrolidine-3-carboxylic acid using Method 13
followed by conversion to the boronate ester using Method 15
followed by Method 5. [M-H].sup.-=321.1 m/z. Activity: B
Example 217
##STR00566##
[1139] Benzoxazole 249 was prepared in 3 steps by first forming the
benzoxazole from 2-amino-5-chlorophenol and
5-oxo-1-phenyl-pyrrolidine-3-carboxylic acid using Method 13
followed by conversion to the boronate ester using Method 15
followed by Method 5. [M-H].sup.-=335.1 m/z. Activity: B
Example 21
##STR00567##
[1140] Part A
##STR00568##
[1142] 5-Fluoro-2(3H)-benzoxazolone 250 (0.50 g, 1.0 equiv) and
phosphorus pentachloride (1.36 g, 2.0 equiv) were placed in a
microwave reactor vial. The reaction was sealed and heated to
175.degree. C. in a microwave reactor for 45 min. The reaction was
then quenched with excess saturated sodium bicarbonate (100 mL)
which resulted in significant fuming. The reaction mixture was then
transferred to a separatory funnel with excess water and ethyl
acetate at which point the water layer was washed with ethyl
acetate (2.times.50 mL). The organic layers were combined, dried
over MgSO.sub.4 and concentrated under vacuum to provide 500 mg of
the desired product 251 that was taken on directly to the next
step.
[1143] Compound 251 (0.50 g, 1.0 equiv) was suspended in 10 mL of
water in a microwave reactor vial. Sodium hydroxide (1.60 g, 15.0
equiv) was added and the mixture was stirred at room temperature
until all the sodium hydroxide dissolved. The reaction was then
heated to 150.degree. C. in a microwave reactor for 20 min after
which 1N HCl was added until a solid crashes out (pH .about.7). The
solid is isolated via vacuum filtration, washed with excess water
and dried on the high vac to provide 300 mg of the desired
aminophenol 252 (70% yield).
Part B
##STR00569##
[1145] Benzoxazole 253 was prepared in 3 steps by first forming the
benzoxazole from 2-amino-5-chloro-4-fluorophenol 252 and
3-phenylpropionic acid using Method 13 followed by conversion to
the boronate ester using Method 15 followed by Method 5.
[M-H].sup.-=284.1 m/z. Activity: A
Example 219
##STR00570##
[1147] Benzodiazoborine 254 was prepared using the analogous
procedure as example 98 except that N-benzylhydrazine was used in
place of 2-hydroxyethyl hydrazine and
(2-formyl-4,5-methylenedioxy)phenylboronic acid was used in place
of benzene boronic acid 98. [M-H].sup.-=279.1 m/z. Activity: D
Example 220
##STR00571##
[1149] Benzodiazoborine 255 was prepared using the analogous
procedure as example 98 except that N-benzylhydrazine was used in
place of 2-hydroxyethyl hydrazine and
5-methoxy-2-formylphenylboronic acid was used in place of benzene
boronic acid 98. [M-H].sup.-=265.1 m/z. Activity: D
Example 221
##STR00572##
[1151] Benzodiazoborine 256 was prepared using the analogous
procedure as example 98 except that N-benzylhydrazine was used in
place of 2-hydroxyethyl hydrazine and 3-formylthiophene-2-boronic
acid was used in place of benzene boronic acid 98.
[M-H].sup.-=241.1 m/z. Activity: D
Example 222
##STR00573##
[1153] Benzodiazoborine 257 was prepared using the analogous
procedure as example 98 except that N-benzylhydrazine was used in
place of 2-hydroxyethyl hydrazine and 4-formylthiophene-3-boronic
acid was used in place of benzene boronic acid 98.
[M-H].sup.-=241.1 m/z. Activity: D
Example 223
##STR00574##
[1155] Benzodiazoborine 258 was prepared using the analogous
procedure as example 98 except that hydrazine was used in place of
2-hydroxyethyl hydrazine and 4-(benzyloxy)-2-formylphenylboronic
acid was used in place of benzene boronic acid 98.
[M-H].sup.-=251.1 m/z. Activity: D
Example 224
##STR00575##
[1157] Benzoxazole 259 was prepared in 2 steps by first forming the
benzoxazole from 2-amino-3-hydroxypyridine and 2-bromo benzoic acid
using Method 13 followed by conversion to the boronic acid using
Method 1. [M-H].sup.-=239.0 m/z. Activity: D
Example 225
##STR00576##
[1159] Oxadiazole 260 was prepared in 2 steps starting with
oxadiazole formation between 2-bromo-5-methoxybenzoic acid and
butyric hydrazide using Method 8 followed by lithiation using
Method 1. [M-H].sup.-=261.1 m/z. Activity: D
Example 226
##STR00577##
[1161] Oxadiazole 261 was prepared in 2 steps starting with
oxadiazole formation between 2-bromo-5-fluorobenzoic acid and
butyric hydrazide using Method 8 followed by lithiation using
Method 1. [M-H].sup.-=249.0 m/z. Activity: D
Example 227
##STR00578##
[1163] Oxadiazole 262 was prepared in 2 steps starting with
oxadiazole formation between 2-bromo-6-fluorobenzoic acid and
butyric hydrazide using Method 8 followed by lithiation using
Method 1. [M-H].sup.-=249.2 m/z. Activity: D
Example 228
##STR00579##
[1165] Oxadiazole 263 was prepared in 2 steps by first forming the
oxadiazole from
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide and
3-(2-oxo-pyrrolidin-1-yl)-propionic acid using Method 7 followed by
Method 5 and was isolated after precipitation from the reaction
mixture. [M-H].sup.-=300.1 m/z. Activity: D
Example 229
##STR00580##
[1167] Oxadiazole 264 was prepared in 2 steps by first forming the
oxadiazole from
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
furoic hydrazide using Method 8 followed by Method 5 and was
isolated after precipitation from the reaction mixture.
[M-H].sup.-=455.1 m/z. Activity: D.
Example 2
##STR00581##
[1169] Oxadiazole 265 was prepared in 2 steps by first forming the
oxadiazole from
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
3-phenylpropionic hydrazide using Method 8 followed by Method 5 and
was isolated after precipitation from the reaction mixture.
[M-H].sup.-=293.1 m/z. Activity: D
Example 231
##STR00582##
[1171] Thiadiazole 266 was prepared in 2 steps by first forming the
thiadiazole from 2-bromobenzoic acid and butyric hydrazide using
Method 9 followed by lithiation using Method 1. [M-H].sup.-=247.1
m/z. Activity: D.
Example 232
##STR00583##
[1173] Thiadiazole 267 was prepared in 2 steps starting with
thaidiazole formation between 2-bromo-5-phenethoxybenzoic acid 16
and propionic hydrazide using Method 9 followed by lithiation using
Method 1. [M-H].sup.-=267.1 m/z. Activity: A
Example 233
##STR00584##
[1175] Oxadiazole 268 was prepared in 2 steps starting with
oxadiazole formation between 2-bromo-5-phenethoxybenzoic acid 16
and 1-methyl-1H-imidazole-5-carbohydrazide using Method 7 followed
by lithiation using Method 1. [M-H].sup.-=389.0 m/z. Activity:
B.
Example 234
##STR00585##
[1177] Oxadiazole 269 was prepared in 2 steps starting with
oxadiazole formation between 2-bromo-5-phenethoxybenzoic acid 16
and 2-methyl-1,3-thiazole-4-carbohydrazide using Method 7 followed
by lithiation using Method 1. [M+H].sup.+=408.3 m/z. Activity:
C.
Example 235
##STR00586##
[1179] Oxadiazole 271 was prepared in analogous fashion to the
oxadiazole 17 in example 12 except that 1-bromobutane was used in
the place of phenethylbromide in part A to synthesize
2-bromo-5-butoxybenzaldehyde 270. Aldehyde 270 was then converted
to the desired oxadiazole using the oxidation, cyclization and
lithiation steps in part B. [M-H].sup.-=303.2 m/z. Activity: B
Example 236
##STR00587##
[1181] Oxadiazole 272 was prepared in analogous fashion to the
oxadiazole 17 in example 12 except that 1-bromobutane was used in
the place of phenethylbromide in part A to synthesize
2-bromo-5-butoxybenzaldehyde 270 and that acetic hydrazide was used
in place of butyric hydrazide during the cyclization step in part
B. [M-H].sup.-=275.1 m/z. Activity: B
Example 237
##STR00588##
[1183] In a microwave reactor tube,
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (300
mg, 1.0 equiv), polystyrene-supported triphenylphosphine (3.0
equiv) and trichloroacetonitrile (0.18 mL, 2.0 equiv) were added,
and the mixture was sealed and heated in a microwave reactor at
100.degree. C. for 30 min. N-Hydroxy-butyramidine (0.14 mL, 1.1
equiv) was then added followed by N,N-diisopropyl ethylamine (0.43
mL, 2.0 equiv) and the reaction was reaheated in a microwave
reactor to 150.degree. C. for 1 h. The concentrated reaction
mixture was purified by flash silica gel chromatography
(hexanes/ethyl acetate) to provide oxadiazole-aryl boronic acid
pinacol ester in 32% yield. The boronate was then converted the
boronic acid 272 using Method 5. [M-H].sup.-=231.1 m/z. Activity:
A.
Example 238
##STR00589##
[1185] Oxadiazole 273 was prepared in two steps first using the
analogous procedure as example 238 except that
2-bromo-5-phenethoxybenzoic acid 16 was used in place of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. The
resultant oxadiazole was then converted to the corresponding
boronic acid using the lithiation conditions in Method 1.
[M-H].sup.-=351.2 m/z. Activity: B
Example 239
##STR00590##
[1187] Thiazole 276 was prepared in 3 steps from
2-bromo-5-phenethoxybenzoic acid 16. Acid 16 (700 mg, 1.0 equiv)
and 1-aminopentan-2-one hydrochloride (390 mg, 1.3 equiv) were
dissolved in 20 mL anhydrous dichloromethane. HOBt (353 mg, 1.2
equiv) and EDC (501 mg, 1.2 equiv) were added followed by
triethylamine (940 uL, 3.0 equiv). The reaction was allowed to stir
for 12 h at room temperature after which point it was transferred
to a separatory funnel with excess dichloromethane and washed with
0.5 M citric acid (2.times.75 mL) and saturated NaHCO.sub.3
(2.times.75 mL). The organic layer was then dried over MgSO.sub.4,
filtered and concentrated to provide the desired ketoamide 274 as a
yellow solid in quantitative yield (880 mg) which was used directly
to form the thiazole the in the following step.
[1188] Ketoamide 274 (308 mg, 1.0 equiv) was added to a microwave
reactor vial and dissolved in 5 mL anhydrous tetrahydrofuran after
which Lawesson's reagent (462 mg, 1.5 equiv) was then added. The
reaction was heated to 115 OC for 90 min in a microwave reactor
after which point it was loaded directly onto silica gel and
purified using flash silica gel chromatography using a gradient of
20-70% ethyl acetate/hexanes to provide 230 mg of the desired
thiazole 275 in 50% yield.
[1189] The resultant thiazole 275 was then converted to the
corresponding boronic acid using the lithiation conditions in
Method 1. [M+H].sup.+=368.2 m/z. Activity: B
Example 240
##STR00591##
[1191] Benzodiazoborine 277 was prepared in 3 steps by first
preparing the corresponding boronic acid aldehyde in analogous
fashion to example 90 except that aldehyde 270 used in place of
aldehyde 93. Benzodiazoborine 277 was then prepared using the
analogous procedure as example 96 except that
4-butoxy-2-formylphenylboronic acid was used in the place of 98.
[M-H].sup.-=218.1 m/z. Activity: C.
Example 241
##STR00592##
[1193] Benzothiazole 278 was prepared in 3 steps by first forming
the benzothiazole from 2-amino-5-chlorothiophenol and
3-phenylpropionic acid using Method 13 followed by conversion to
the boronate ester using Method 15 followed by Method 5.
[M-H].sup.-=282.2 m/z. Activity: A.
Example 242
##STR00593##
[1195] Piperidine 279 was prepared in 3 steps starting from
1-Boc-4(4-boronophenyl)piperidine pinacol ester 233 which was first
deprotected as described in Example 204. This salt (150 mg, 0.374
mmol) was dissolved in tetrahydrofuran (5 mL) and treated with
triethylamine (41.6 mg, 0.411 mmol, 1.1 eq.) and benzaldehyde (43.6
mg, 0.411 mmol, 1.1 eq.) and stirred for 30 minutes while being
cooled in an ice bath. To this solution sodium
triacetoxyborohydride (87 mg, 0.411 mmol, 1.1 eq.) was added in
portions and the reaction was allowed to warm to ambient
temperature and stir for 16 h. The reaction was diluted with ethyl
acetate (50 mL) and washed with water (2.times.15 mL). The organic
layer was dried over magnesium sulfate, filtered and evaporated
onto silica gel. Purification using silica gel chromatography
(gradient of 0 to 20% ethyl acetate/hexanes) gave
1-benzyl-4-(4-boronophenyl)piperidine pinacol ester. Deprotection
of this ester via Method 5 gave compound 279 (30 mg, 30%).
[M-H].sup.-=294.2 m/z. Activity: C.
Example 243
##STR00594##
[1197] Piperidine 280 was prepared using the analogous procedure as
example 242 except that 4-isopropylbenzaldehyde was used in place
of benzaldehyde. [M-H].sup.-=336.3 m/z. Activity: B.
Example 244
##STR00595##
[1199] Oxadiazole 281 was prepared in 2 steps by first forming the
oxadiazole from
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and
hexanoic hydrazide using Method 8 followed by Method 5 and was
isolated and purified by using flash silica gel chromatography.
[M-H].sup.-=259.1 m/z. Activity: D
Example 245
##STR00596##
[1201] 2-Bromobenzhydrazide (1.03 g, 4.8 mmol, 1.0 equiv) and
1,1'-carbonyldiimidazole (1.01 g, 6.23 mmol, 1.3 equiv) were heated
in 1,4-dioxane (20 mL) for 4 h at 80.degree. C. The mixture was
concentrated in vacuo, and the resulting residue split between
ethyl acetate and water (100 mL each). The organic layer was washed
with brine, dried over sodium sulfate, and concentrated in vacuo to
afford a white solid (1.1 g, 95% yield). A portion of this
intermediate oxadiazolidinone (820 mg, 3.4 mmol, 1.0 equiv) was
suspended in a solution of dimethylamine (2.0 M in THF, 20 mL) and
stirred at 23.degree. C. overnight. The resulting solution was
concentrated in vacuo; the residue was re-suspended in dry
dichloromethane (30 mL) and concentrated in vacuo. This residue was
again re-suspended in dry dichloromethane (5 mL) and treated with
p-toluenesulfonyl chloride (681 mg, 3.57 mmol, 1.05 equiv) and
triethylamine (1.2 ml, 8.5 mmol, 2.5 equiv). After stirring at
23.degree. C. for 16 h, the mixture was split between ethyl acetate
and water (50 mL each), and the organic layer was washed with
brined and dried over sodium sulfate. Concentration in vacuo gave a
residue which, upon purification by silica gel chromatography
(30.fwdarw.100% ethyl acetate/hexanes) gave
dimethylamino-oxadiazole as a white solid. This bromide was
converted to the boronic acid by Method 1, and was isolated and
purified by using flash silica gel chromatography to provide 282 as
a white solid. [2M-H.sub.2O].sup.-=447.1 m/z. Activity: D
Example 246
##STR00597##
[1203] 2-Bromobenzhydrazide (500 mg, 2.32 mmol, 1.0 equiv) and
isobutyryl chloride (372 mg, 3.49 mmol, 1.5 equiv) were stirred
with sodium bicarbonate (590 mg, 7.0 mmol, 3.0 equiv) in water and
1,4-dioxane (10 mL each), at 0.degree. C. for 1 h. The mixture was
split between ethyl acetate and water (50 mL each), and the organic
layer was washed with brine, dried over sodium sulfate, and
concentrated in vacuo to a white solid. This solid was dissolved in
dry dichloromethane (5 mL), and the solution was concentrated to
2.5 mL in vacuo. This solution was treated with p-toluenesulfonyl
chloride (465 mg, 2.44 mmol, 1.05 equiv) and triethylamine (0.8 ml,
5.8 mmol, 2.5 equiv) and stirred at 23.degree. C. for 16 h. The
mixture was split between ethyl acetate and water (50 mL each), and
the organic layer was washed with brine, dried over sodium sulfate,
and concentrated in vacuo to give oxadiazole as a clear oil. This
bromide was converted to the boronic acid by Method 1, and was
isolated and purified by using flash silica gel chromatography to
provide 283 as a white solid. [M-H].sup.-=231.1 m/z. Activity:
D
Example 247
##STR00598##
[1205] Oxadiazole 284 was prepared using the analogous procedure as
example 246 except that isovaleryl chloride was used in place of
isobutyryl chloride. [M-H].sup.-=245.1 m/z. Activity: D.
Example 248
##STR00599##
[1207] Oxadiazole 285 was prepared in 2 steps by first forming the
oxadiazole from
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzhydrazide and
3,3,3-trifluorobutanoic acid using Method 7 followed by Method 5
and was isolated and purified by using flash silica gel
chromatography. [M-H].sup.-=285.0 m/z. Activity: D
Example 249
##STR00600##
[1209] 2-Bromobenzhydrazide (500 mg, 2.32 mmol, 1.0 equiv) and
ethyl chloroformate (359 mg, 2.88 mmol, 1.2 equiv) were stirred
with sodium bicarbonate (605 mg, 7.2 mmol, 3.0 equiv) in water and
1,4-dioxane (10 mL each), at 0.degree. C. for 1 h. The mixture was
split between ethyl acetate and water (50 mL each), and the organic
layer was washed with brine, dried over sodium sulfate, and
concentrated in vacuo to a white solid. This solid was dissolved in
dry dichloromethane (5 mL), and the solution was concentrated to
2.5 mL in vacuo. This solution was treated with p-toluenesulfonyl
chloride (480 mg, 2.52 mmol, 1.05 equiv) and triethylamine (0.84
ml, 6.0 mmol, 2.5 equiv) and stirred at 23.degree. C. for 16 h. The
mixture was split between ethyl acetate and water (50 mL each), and
the organic layer was washed with brine, dried over sodium sulfate,
and concentrated in vacuo to give oxadiazole as a clear oil. This
bromide was converted to the boronic acid by Method 3 followed by
method 5, and purification using silica gel chromatography gave the
286 as a white solid. [2M-H.sub.2O].sup.-=488.8 m/z. Activity:
D
Example 250
##STR00601##
[1211] The pinacol ester of compound 100 (18 mg, 0.04 mmol, 1.0
equiv) was dissolved in 3:1 tetrahydrofuran/water (1.2 mL) and
stirred with lithium hydroxide (6 mg, 0.26 mmol, 6.0 equiv) at
50.degree. C. for 2 h. The mixture was diluted with ethyl acetate
(50 mL), washed with 1N aqueous HCl (100 mL) and then brine (15 mL)
and concentrated in vacuo to yield 17 mg of crude carboxylic acid,
which was used in the next step without purification.
[1212] Carboxylic acid (8 mg, 0.02 mmol, 1.0 equiv) was dissolved
in dry dichloromethane (1 mL) and treated with 3-aminomethyl
pyridine (4 mg, 0.04 mmol, 2.0 equiv), HBTU (8 mg, 0.03 mmol, 1.5
equiv) and iPr.sub.2EtN (8 mg, 0.06 mmol, 3.0 equiv). The mixture
was stirred at 23.degree. C. for 16 h and then split between 5%
aqueous sodium bicarbonate and ethyl acetate (20 mL each). The
organic layer was concentrated in vacuo to yield 10 mg crude
product. The crude product was cleaved by Method 5 to produce the
arylboronic acid 287 after HPLC purification. [M-H].sup.-=401.2
m/z. Activity: D
Example 251
##STR00602##
[1214] Boronic acid 288 was prepared using the analogous procedure
as example 250 except 2-furylmethylamine was used in place of
isobutyryl chloride. [M-H].sup.-=390.2 m/z. Activity: D.
Example 252
##STR00603##
[1216] A mixture of 1-bromo-2-fluoro-4-iodobenzene (460 mg, 1.5
mmol, 1.0 equiv), 3-isopropylphenyl-boronic acid (250 mg, 1.5 mmol,
1.0 equiv), Pd(PPh.sub.3).sub.2Cl.sub.2 (35 mg, 0.05 mmol, 0.03
equiv) and NaHCO.sub.3 (640 mg, in 4 mL water) were added to a
flask and dioxane (4 mL) was added. The mixture was purged with
argon for 5 min, and then stirred at 80.degree. C. under an argon
atmosphere for 6 h. The reaction was diluted with ethyl acetate
(200 mL), washed with 60 mL water, then 40 mL brine, dried and
concentrated. Purification via silica gel column chromatography
with (gradient of 0-2.5% ethyl acetate/hexanes) gave desired the
biphenyl bromide as yellow oil 340 mg. The biphenyl bromide was
converted to 289 by Method 1. [M-H].sup.-=357.1 m/z. Activity:
A
Example 253
##STR00604##
[1217] Part A
[1218] To a solution of 2-amino-4-bromophenol (2 g, 8.9 mmol, 1.0
equiv) in HCl (5 M, 12.5 mL, 7.0 equiv) was added drop-wise a
solution of sodium nitrite (0.62 g, 8.9 mmol, 1.0 equiv) in water
(5 mL) at 0.degree. C. The mixture was stirred at this temperature
for 30 min after which a cooled solution of KI (1.5 g, 8.9 mmol,
1.0 equiv) in H.sub.2O (14 mL) was slowly added at 0.degree. C. The
mixture was then allowed to warm to room temperature and stirred
overnight. The reaction mixture was diluted with ethyl acetate (200
mL) and the separated aqueous phase was extracted with ethyl
acetate (100 mL.times.3). The combined organic fraction was washed
with Na.sub.2S.sub.2O.sub.3 (10%, 40 mL), water (100 mL.times.2)
and brine (40 mL), dried over Na.sub.2SO.sub.4 and concentrated to
dryness.
[1219] The residue was purified by flash silica gel chromatography
(ethyl acetate/hexanes) to afford 1.1 g 4-bromo-2-iodo-pheno as a
yellow solid.
Part B
##STR00605##
[1221] 4-Phenyl-1-pentyne (131 mg, 1.0 mmol, 1.0 equiv) was added
to a suspension of 4-bromo-2-iodophenol (300 mg, 1.0 mmol, 1.0
equiv) and Cu.sub.2O (85 mg, 0.6 mmol) in dry pyridine (4 mL). The
mixture was refluxed under nitrogen for 4 h. The mixture was
filtered through celite and washed with ethyl acetate. The pyridine
was evaporated under reduced pressure, and the residue was purified
by chromatography (combiflash, hexane) gave partially pure desired
product 290 (276 mg). The benzofuran bromide 290 was converted to
desired boronic acid 291 by Method 3 followed by Method 5.
[M-H].sup.-=265.0 m/z. Activity: A.
Example 254
##STR00606##
[1223] Part A
[1224] 6-Chloro-2-phenethylbenzofuran 292 was prepared using the
analogous procedure as example 253 except 2-amino-5-chlorophenol
hydrochloride was used in place of 2-amino-4-bromophenol.
##STR00607##
Part B
[1225] Benzofuran 293 was synthesized from 292 according to the
following procedure: 292 (160 mg, 0.6 mmol, 1.0 equiv), tetramethyl
dioxaborolane (160 mg, 1.2 mmol, 2.0 equiv), phospine ligand and
palladium diacetate were added together in to 8 mL toluene. The
mixture was purged with Ar for 5 min, and then was heated to
80.degree. C. for 5 h. The reaction was cooled to room temperature
and water (20 mL) was added after which diethyl ether (3.times.50
mL) was used to extract the product. The organic layer was washed
with brine, dried (Na.sub.2SO.sub.4), and concentrated.
Purification on combiflash (10-15-20% ethyl acetate in hexanes)
gave 50 mg of the desired pinacol ester. This was converted to
compound 293 by Method 5. [M-H].sup.-=265.2 m/z. Activity: A.
Example 255
##STR00608##
[1226] Part A
##STR00609##
[1228] A mixture of 3-iodopyridine (980 mg, 4.8 mmol, 1.0 equiv),
2-bromo-5-hydroxybenzaldehyde (960 mg, 4.8 mmol, 1.0 equiv), cesium
carbonate (3.11 g, 9.6 mmol, 2.0 equiv), copper iodide (182 mg,
0.96 mmol, 0.2 equiv), and N,N-dimethylglycine HCl salt (533 mg,
3.8 mmol, 0.8 equiv) are suspended in 10 mL of dioxane in a sealed
tube and heated to 90.degree. C. under a nitrogen atmosphere. After
16 h, the cooled mixture was filtered through a bed of celite with
small amount of silica gel on top of it. Ethyl acetate (3.times.20
mL) was used to wash the celite. The filtrate was concentrated in
vacuo. The residual oil was loaded on a silica gel column and
eluted with ethyl acetate/hexanes (15-20%) to afford 0.4 g of the
corresponding aldehyde.
[1229] A solution of the aldehyde (160 mg, 0.58 mmol, 1.0 equiv) in
tetrahydrofuran (10 mL) is placed in a flask with stir bar and
isoprene (404 mg, 5.8 mmol, 10 equiv), 2.7M phosphate buffer (1.7
mL, 4.6 mmol, 8.0 equiv), and NaClO.sub.2 (208 mg, 2.3 mmol, 4.0
equiv) are added. The reaction is stirred at room temperature for 2
h and stopped by the addition of water (30 mL), acidificaiton to pH
1 with 6M HCl, and extraction (3.times.50 mL methylene chloride).
The organic layers are dried on Na.sub.2SO.sub.4 and concentrated
to give 294 as a white foam (182 mg), which is used without further
purification.
Part B
##STR00610##
[1231] A solution of the acid 294 (140 mg, 0.48 mmol, 1.0 equiv) in
methylene chloride (5 mL) is treated with oxalyl chloride (91 mg,
0.71 mmol, 1.5 equiv) followed by a drop of N,N-dimethylforamide
and stirred 23.degree. C. for 3 h. The mixture was concentrated in
vacuo and resuspended in methylene chloride (6 mL). To this mixture
were treated with triethylamine (96 mg, 0.96 mmol, 2.0 equiv)
followed by butyric hydrazide (73 mg, 0.71 mmol, 1.5 equiv) and
catalytic DMAP. After 20 min at 23.degree. C., the reaction mixture
was split between water and methylene chloride. The aqueous layer
was back extracted again with methylene chloride. The combined
organics were washed with 5% NaHCO.sub.3 and then brine, dried over
sodium sulfate and concentrated in vacuo to yield 150 mg crude
material. The crude material was suspended in POCl.sub.3 (6 mL) and
heated at 90.degree. C. for 2 h after which point the mixture was
poured into ice water. Methylene chloride was used to extract the
aqueous layer and the organic layer was washed with brine, dried
over sodium sulfate, and concentrated in vacuo. HPLC purification
(FA 10-80) gave oxadiazole 295 (8 mg), which was converted to
compound 296 by Method 1. [M+H].sup.+=326.0 m/z. Activity: B.
Example 256
##STR00611##
[1233] 4-Bromo-3-fluorophenol (200 mg, 1.0 mmol, 1.0 equiv),
5-fluoropyridin-3-ylboronic acid (221 mg, 1.5 mmol, 1.5 equiv),
copper (II) acetate (190 mg, 0.481 mmol, 1.0 equiv) and 4 A MS were
suspended in 10 mL methylene chloride. Triethylamine (530 mg, 5.0
mmol, 5.0 equiv) was then added after which point the reaction
turned from blue to brown and was stirred at room temperature for
16 h under ambient atmosphere after which point the reaction turned
back blue. The slurry was filtered through a small pad of celite
and washed with 30% ethyl acetate in hexanes. The combined filtrate
was concentrated in vacuo. Purification using flash silica gel
chromatography gave the desired biaryl bromide (45 mg) which was
converted to boronic acid 297 by Method 1. [M-H].sup.-=250.1 m/z.
Activity: A.
Example 257
##STR00612##
[1235] Biaryl boronic acid 298 was prepared using the analogous
procedure as example 256 except that 4-fluoropyridin-3-ylboronic
acid was used in place of 5-fluoropyridin-3-ylboronic acid.
[M-H].sup.-=250.1 m/z. Activity: A.
Example 258
##STR00613##
[1237] 1-Boc-piperidin-4-ylacetic acid (1.7 g, 7.0 mmol, 1.0 equiv)
and 4-chloro aminophenol (1.0 g, 7.0 mmol, 1.0 equiv) were added to
a sealed flask. Acetonitrile (20 mL) was added followed by
triphenylphosphine resin (11.1 g, 1.88 mmol/g, 4.0 equiv) and
trichloroacetonitrile (2.0 g, 14 mmol, 2.0 equiv). The flask was
sealed and heated at 100.degree. C. for 20 h and cooled to room
temperature. The resin was rinsed with excess
tetrahydrofuran/methylene chloride (1:1). The resulting filtrate
was then concentrated to yield the corresponding Boc-deprotected
benzoxazole chloride. The solid was washed with 30% ethyl acetate
in hexanes to get rid of the non polar impurities and used directly
in next step.
[1238] To a solution of the amine (1.2 g, 4.8 mmol, 1.0 equiv) and
triethylamine (1.5 g, 14.4 mmol, 4.0 equiv) in 70 mL of methanol
was added di-tert-butyl dicarbonate (1.3 g, 5.7 mmol, 1.2 equiv)
and the mixture stirred at room temperature for 24 h. The solvent
was evaporated and the residue was suspended in 100 mL of ethyl
acetate. The mixture was washed with a saturated sodium bicarbonate
solution (50 mL) and subsequently with water (2.times.100 mL). The
organic layer was dried with anhydrous sodium sulfate and
concentrated. The Boc-protected benzoxazole chloride 1.2 g was
obtained as yellow oil and was used directly in the conversion to
the boronate ester using Method 15 to provide pinacol ester 300
followed by Method 5 to provide 299. [M-H].sup.-=359.1 m/z.
Activity: A.
Example 259
##STR00614##
##STR00615##
[1240] Boc protected benzoxazole pinacol ester 300 (600 mg, 1.4
mmol, 1.0 equiv) is stirred in trifluoroacetic acid (6 mL) for 1 h,
after which point the solution was evaporated under reduced
pressure. The crude material was azeotroped twice with toluene (75
mL) after which point the piperidine salt was used directly in the
next step.
[1241] The crude amine TFA salt (200 mg, 0.45 mmol, 1.0 equiv) is
dissolved in 4 mL dry methylene chloride. Triethylamine (181 mg,
1.82 mmol, 4.0 equiv) and 4-isopropylbenzaldehyde (135 mg, 0.9
mmol, 2.0 equiv) were added followed by the addition of sodium
triacetoxyborohydride (386 mg, 1.82 mmol, 4.0 equiv). The reaction
was stirred at room temperature for 20 h then concentrated.
Methanol was added to the residue to quench the unreacted
borohydride after which point the crude material was directly
purified with HPLC (FA 10-80) to give 50 mg of pure pinacol ester,
which was converted to compound 301 by Method 5. [M-H].sup.-=391.2
m/z. Activity: B
Example 260
##STR00616##
[1243] Benzoxazole 302 was prepared using the analogous procedure
as example 259 except that benzaldehyde was used in place of
4-isopropylbenzaldehyde. [M-H].sup.-=349.2 m/z. Activity: B.
Example 261
##STR00617##
[1245] Benzoxazole 303 was prepared using the analogous procedure
as example 259 except that propionaldehyde was used in place of
4-isopropylbenzaldehyde. [M-H].sup.-=301.2 m/z. Activity: C.
Example 262
##STR00618##
[1247] Benzoxazole 304 was prepared using the analogous procedure
as example 259 except that isobutyraldehyde was used in place of
4-isopropylbenzaldehyde. [M-H].sup.-=315.2 m/z. Activity: D.
Example 263
##STR00619##
[1249] Boc-protected benzoxazole pinacol ester 300 is deprotected
as in example 259 and the crude amine TFA salt (190 mg, 0.43 mmol,
1.0 equiv) is dissolved in 5 mL dry methylene chloride.
Triethylamine (175 mg, 1.73 mmol, 4.0 equiv) followed by
benzenesulfonyl chloride (153 mg, 0.86 mmol, 2.0 equiv) were added.
The reaction was stirred at room temperature for 20 h and then
concentrated under reduced pressure. Methanol was added to the
residue and the crude material was directly purified with HPLC (FA
10-80) to give 70 mg pure sulfonamide pinacol ester product, which
was converted to compound 305 by Method 5. [M-H].sup.-=399.0 m/z.
Activity: B.
Example 264
##STR00620##
[1251] Boc-protected benzoxazole pinacol ester 300 is deprotected
as in example 259 and the crude amine TFA salt (200 mg, 0.45 mmol,
1.0 equiv) is dissolved in 5 mL dry methylene chloride.
Triethylamine (181 mg, 1.8 mmol, 4.0 equiv) and hydrocinnamoyl
chloride (154 mg, 0.9 mmol, 2.0 equiv) were added. The reaction was
stirred at room temperature for 20 h and then concentrated.
Methanol was added to the residue and the crude material was
directly purified with HPLC (FA 10-80) to give 60 mg pure amide
pinacol ester product, which was converted to compound 306 by
Method 5. [M-H].sup.-=391.1 m/z. Activity: A.
Example 265
##STR00621##
[1253] 5-Bromophthalic anhydride (1.0 g, 4.4 mmol) in ethanol (10
mL) was treated with n-amylamine (562 uL, 4.9 mmol, 1.1 eq.) and
heated at reflux overnight. The mixture was diluted into 0.1M HCl
(100 mL) and the resulting white solid collected by filtration,
washed with water, and dried in vacuo to give 136 mg of the
corresponding phthalimide as a white solid. The filtrate was
diluted with brine and chilled at -20.degree. C. for 2 d. A second
crop of precipitate was collected, washed with water, and dried in
vacuo to give another 116 mg phthalimide as a white solid. The
crops are identical by NMR and combined to give a total yield of
252 mg (0.85 mmol, 19%). This material was used without further
purification.
[1254] This precipitated phthalimide (250 mg, 0.84 mmol) was
converted using methods 3 followed by method 5, to form boronic
acid 307 (22 mg, 10%) as a white solid. [M-H].sup.-=260.1 m/z.
Activity: A.
Example 266
##STR00622##
[1256] 5-Bromo-2-benzylphthalimide was produced from
5-bromophthalic anhydride (1.0 g, 4.4 mmol) using the analogous
procedure as example 265 except that benzylamine was used in the
place of n-amylamine, to provide 421 mg (30%) of product as a white
crystals.
[1257] This precipitated phthalimide (200 mg, 0.63 mmol) was
converted using methods 3 followed by method 5, to form boronic
acid 308 (67 mg, 38%) as an off-white solid. Activity: A.
Example 267
##STR00623##
[1259] 5-Bromo-2-phenethylphthalimide was produced from
5-bromophthalic anhydride (1.0 g, 4.4 mmol) using the analogous
procedure as example 265 except that phenethylamine was used in the
place of n-amylamine, to provide 521 mg (36%) of product as a white
crystals.
[1260] This precipitated phthalimide (270 mg, 0.82 mmol) was
converted using methods 3 followed by method 5, to form boronic
acid 309 (106 mg, 44%) as a brownish powder. [M-H].sup.-=294.0 m/z.
Activity: A.
Example 269
##STR00624##
[1262] 3-Fluoro-4-bromotoluene (5.0 g, 27 mmol) in carbon
tetrachloride (50 mL) was treated with N-bromosuccinimide (7.0 g,
40 mmol, 1.5 eq) and heated to 80.degree. C. Benzoyl peroxide (65
mg, 0.27 mmol, 0.01 eq.) was added and heating was continued for 1
h. The reaction was then cooled to ambient temperature and
filtered, and the filtercake was washed sparingly with chloroform.
The filtrate was washed with water and brine, dried over
Na.sub.2SO.sub.4, and concentrated to give crude
3-fluoro-4-bromobenzyl bromide as a clear oil which was used
without further purification.
[1263] This crude benzyl bromide (27 mmol) and sodium cyanide (2.38
g, 54 mmol, 2.0 eq.) were combined in ethanol (100 mL) and heated
at 80.degree. C. for 2 h. The reaction mixture was concentrated to
dryness in vacuo, suspended in water, and extracted with ethyl
acetate. Washing with brine and drying over Na.sub.2SO.sub.4 gave,
after removal of the solvent, a red oil which was purified using
silica gel chromatography (gradient of 2->12% ethyl
acetate/hexanes) to provide 3-fluoro-4-bromophenylacetonitrile as
white needles (1.96 g, 35% over 2 steps).
[1264] A solution of lithium aluminum hydride (IM in THF, 14 mL, 14
mmol, 3.0 eq.) was chilled in an ice bath and slowly treated with
sulfuric acid (390 uL, 7.0 mmol, 1.5 eq.). After the visible
reaction was complete, a solution of the nitrile produced above
(1.0 g, 4.7 mmol) in tetrahydrofuran (10 mL) was dripped in to the
mixture slowly. The mixture was stirred at 0.degree. C. for 20 min,
then refluxed for 30 min. After cooling to room temperature, the
excess reagents were quenched with 2-propanol, followed by 4M NaOH.
After stirring to assure complete reaction, the resulting
suspension was filtered through celite and the filtercake was
washed well with 2-propanol. The filtrate was concentrated to give
crude 3-fluoro-4-bromophenethylamine as a clear oil which was used
without further purification.
[1265] This crude material (4.7 mmol) was dissolved in methylene
chloride (10 mL) and treated with potassium carbonate (1.0 g, 7.0
mmol, 1.5 eq.) and di-tert-butyldicarbonate (1.15 g, 5.2 mmol, 1.1
eq). The mixture was stirred at ambient temperature for 2 days,
then diluted with water, extracted into MTBE, washed with brine,
dried over Na.sub.2SO.sub.4, and concentrated to a white solid
which contains excess dicarbonate reagent. The material was taken
up in ethanol (20 mL) and treated with imidazole (200 mg). After
stirring for a few minutes, the solvent was removed under vacuum
and the residue dissolved in methylene chloride, washed several
times with 1% HCl, and concentrated to give crude
N-Boc-3-fluoro-4-bromophenethylamine as a yellow solid which was
used without further purification.
[1266] This crude material (4.7 mmol) was dissolved in
N,N-dimethylforamide (10 mL) and chilled in an ice bath. Sodium
hydride dispersion (60% in mineral oil, 560 mg, 14 mmol, 3.0 eq.)
was added and stirring continued until gas evolution ceased, then
iodomethane (580 uL, 9.4 mmol, 2.0 eq,) was added and the mixture
allowed to warm to room temperature. After stirring overnight, the
mixture is diluted with MTBE, washed with water and brine, dried
over Na.sub.2SO.sub.4, and concentrated to give crude
N-methyl-N-Boc-3-fluoro-4-bromophenethylamine (916 mg, 59% over 3
steps).
[1267] This material (916 mg, 2.76 mmol) was converted to the
pinacolatoboronate (351 mg, 34%) using Method 3. This boronate
ester (70 mg) was converted, via Method 5, to provide boronic acid
311 (52 mg) as a colorless oil. [M-H].sup.-=296.2 m/z. Activity:
A.
Example 270
##STR00625##
[1269] N-Methyl-N-Boc-3-fluoro-4-bromophenethylamine from Example
269 was converted to the corresponding boronate ester using method
3. This compound (280 mg, 0.74 mmol) was dissolved in
trifluoroacetic acid (4 mL) and stirred for 1 h. The acid was
removed under vacuum, and was then azeotroped twice with toluene,
to give the crude trifluoroacetate salt of
N-methyl-3-fluoro-4-pinacolboronato-phenethylamine as a clear
viscous oil.
[1270] This crude salt (100 mg, 0.25 mmol) was taken up in
methylene chloride (5 mL) and treated with triethylamine (150 uL,
1.0 mmol, 4.0 eq.). Benzenesulfonyl chloride (40 uL, 0.31 mmol, 1.2
eq.) was added and the solution stirred at ambient temperature
overnight. The mixture was diluted with methylene chloride and
treated with silica gel. Concentration and purification using
silica gel chromatography (gradient of 2->18% ethyl
acetate/hexanes) provided the benzenesulfonamide derivative as a
clear oil.
[1271] This material was converted, via Method 5, to provide
boronic acid 312 (29 mg, 34%) as a white solid. [M-H].sup.-=336.3
m/z. Activity: A.
Example 271
##STR00626##
[1273] A solution of 2-fluoro-4-bromobenzaldehyde (5.09 g, 25 mmol)
was dissolved in glyme (25 mL) and slowly treated over 10 minutes
with anhydrous hydrazine (25 mL, 0.8 mol, 32 eq.).
[1274] The resulting biphasic mixture was then held at reflux
overnight. The reflux condenser was replaced with a short-path
distillation head and about half the solvent distilled, at which
time the reaction flask showed one phase and two phases were
evident in the distillate. The undistilled residue was cooled and
treated with water (25 mL), forming a white precipitate. This solid
was collected by filtration, washed thoroughly with water, and
dried in vacuo to give 6-bromoindazole (4.21 g, 85%) as white
crystals.
[1275] 6-Bromoindazole (3.63 g, 18 mmol) was suspended in dioxane
(15 mL) and benzyl bromide (2.65 mL, 22 mmol, 1.2 eq.) was added.
The reaction was heated to reflux overnight, then allowed to cool
to 80.degree. C. after which point ethyl acetate (50 mL) added. The
cake was broken up with a spatula and after stirring for 20 min,
the solids were filtered off and washed with ethyl acetate, giving
glossy white crystals of the hydrobromide salt of
2-benzyl-6-bromoindazole. These were suspended in ethyl acetate
(100 mL) and shaken with saturated NaHCO.sub.3 (150 mL) until
dissolution. The layers were separated and the aqueous layer was
extracted with ethyl acetate (50 mL). The combined organic layers
were concentrated to an off-white powder which was recrystallized
from 66% ethanol (40 mL). Washing with water and drying in vacuo
gave 2-benzyl-6-bromoindazole (3.30 g, 62%) as shiny white
plates.
[1276] This material (3.0 g, 10.3 mmol) was converted to boronic
acid 313 (1.8 g, 69%) as a white powder using method 3 followed by
method 5. [M-H].sup.-=251.1 m/z. Activity: A.
Example 272
##STR00627##
[1278] 6-Bromoindazole, produced in example 271 (300 mg, 1.5 mmol)
and sodium hydroxide (90 mg, 2.3 mmol, 1.5 eq.) were suspended in
dioxane (3 mL) and phenethyl bromide (500 uL, 3.6 mmol, 2.4 eq).
was added. The reaction was heated to 80.degree. C. for 4 h. The
product was extracted from water into MTBE, washed with brine, and
dried with Na.sub.2SO.sub.4. Silica gel was added and the solvent
removed after which purification using silica gel chromatography
(gradient of 0->12% ethyl acetate/hexanes) separated two
products, 1-phenethyl-6-bromoindazole (122 mg) and
2-phenethyl-6-bromoindazole (273 mg, 60%).
[1279] 2-Phenethyl-6-bromoindazole (273 mg, 0.9 mmol) was converted
to boronic acid 314 (152 mg, 63%) as an off-white foam using method
3 followed by method 5. [2M-H.sub.2O].sup.-=513.0 m/z. Activity:
A.
Example 273
##STR00628##
[1281] 5-Bromoindazole, (300 mg, 1.5 mmol) and sodium hydroxide (90
mg, 2.3 mmol, 1.5 eq.) were suspended in dioxane (2 mL) and
phenethyl bromide (500 uL, 3.6 mmol, 2.4 eq). was added. The
reaction was heated to 80.degree. C. for 4 h. The product was
extracted from water into MTBE, washed with brine, and dried with
Na.sub.2SO.sub.4. Silica gel was added and the solvent removed
after which purification using silica gel chromatography (gradient
of 0->15% ethyl acetate/hexanes) separated two products,
1-phenethyl-5-bromoindazole (134 mg) and
2-phenethyl-5-bromoindazole (228 mg, 50%).
[1282] 2-Phenethyl-5-bromoindazole (228 mg, 0.76 mmol) was
converted to boronic acid 315 (131 mg, 65%) as a tan foam using
method 3 followed by method 5. [2M-H.sub.2O].sup.-=513.1 m/z.
Activity: A.
Example 274
##STR00629##
[1284] 5-Bromoindazole, (500 mg, 2.5 mmol), tetrabutylammonium
iodide (100 mg, 0.25 mmol, 0.1 eq.) and sodium hydroxide (150 mg,
3.8 mmol, 1.5 eq.) were suspended in para-xylene (10 mL) and benzyl
bromide (360 uL, 3 mmol, 1.2 eq) was added. The reaction was heated
to 130.degree. C. overnight. The mixture was diluted with MTBE,
washed with water and brine, and dried with Na.sub.2SO.sub.4. After
partial concentration in vacuo to a xylene solution purification
using silica gel chromatography (gradient of 0->10% ethyl
acetate/hexanes) separated two products, 1-benzyl-5-bromoindazole
(364 mg) and 2-benzyl-5-bromoindazole (302 mg).
[1285] 1-Benzyl-5-bromoindazole (364 mg, 1.3 mmol) was converted to
boronic acid 316 (126 mg, 40%) as a white solid using method 3
followed by method 5. [M-H].sup.-=251.1 m/z. Activity: A.
Example 275
##STR00630##
[1287] 5-Borono-2-aminopyridine pinacol ester (250 mg, 1.1 mmol)
and 94%-pure 2-bromoacetophenone containing
2,2,-dibromoacetophenone (250 mg, 1.25 mmol, 1.1 eq.) were combined
in ethanol (2.5 mL) and subjected to microwave heating at a
temperature of 130.degree. C. for 30 min. The solvent was removed
in vacuo and the pinacol ester cleaved using method 5. Purification
using silica gel chromatography of the product (gradient of
0->30% methanol/methylene chloride) afforded only one compound,
brominated imidazopyridine boronic acid 317 (84 mg) as a yellow
crystalline solid. [M-H].sup.-=317.0 m/z. Activity: A.
Example 276
##STR00631##
[1289] 1-Boc-4-(4-boronophenyl)piperazine pinacol ester (200 mg,
0.52 mmol) was converted, via method 5, to boronic acid 318 (121
mg, 77%) as a white solid. [M-H].sup.-=305.1 m/z. Activity: B.
Example 277
##STR00632##
[1291] A solution of 2-chloro-6-bromoquinoline (250 mg, 1.0 mmol)
and benzylnitrile (148 mg, 1.2 mmol, 1.2 eq.) in tetrahydrofuran
(20 mL) was treated with 1.0M NaHMDS in THF (2.6 mL, 2.6 mmol, 2.5
eq.) and stirred at ambient temperature overnight. LC/MS showed
complete conversion to the diarylacetonitrile intermediate.
Saturated aqueous ammonium acetate (5 mL) and sodium peroxide (320
mg, 4.1 mmol, 4.0 eq.) were added and the solution stirred at room
temperature for 24 h. LC/MS indicated incomplete conversion, about
40%. The reaction mixture was diluted with MTBE, washed with water
and brine, dried over Na.sub.2SO.sub.4, treated with silica gel,
concentrated, and purified using silica gel chromatography
(gradient of 0->8% ethyl acetate/hexanes), giving two products,
2-(6-bromoquinoline-2-yl)-2-phenylacetonitrile (185 mg) and
2-benzoyl-6-bromoquinoline (97 mg, 30%).
[1292] 2-Benzoyl-6-bromoquinoline (97 mg, 0.31 mmol) was converted
to boronic acid 319 (42 mg, 50%) as a brownish solid using method 3
followed by method 5. [M-H].sup.-=276.1 m/z. Activity: A.
Example 278
##STR00633##
[1294] Tert-butyl 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)
propionate (0.313 g) was dissolved in 5 mL of methylene chloride.
Trifluoroacetic acid was added (0.5 mL) and the reaction was
allowed to stir overnight at room temperature. The solvent and acid
were then removed under vacuum and the crude mixture was azeotroped
using toluene (2.times.50 mL) to provide crude deprotected acid 320
which was used directly.
[1295] A portion of acid 320 (72 mg, 1.0 equiv) was dissolved in 1
mL N,N-dimethyl foramide, followed by the addition of PyBOP (190
mg, 1.0 equiv) and phenethylamine (50 .mu.L, 1.11 equiv).
Triethylamine (150 .mu.L, 3.0 equiv) was then slowly added and the
reaction was allowed to stir at room temperature for 30 min. After
this point the reaction was transferred to a separatory funnel with
excess water and ethyl acetate. The water layer was extracted with
ethyl acetate (3.times.50 mL) and dried over Na.sub.2SO.sub.4 and
concentrated. This residue was used directly to form the desired
boronic acid 321 using method 5 and was purified using
semi-preparatory reverse phase liquid chromatography.
[M-H].sup.-=220.1 m/z. Activity: C.
Example 279
##STR00634##
[1297] Boronic acid 322 was prepared using the analogous procedure
as example 278 except that 1-(benzyloxycarbonyl)piperazine was used
in place of phenethylamine. [M-H].sup.-=319.2 m/z. Activity: B.
Example 280
##STR00635##
[1299] Boronic acid 323 was prepared using the analogous procedure
as example 278 except that 1-Boc-piperazine was used in place of
phenethylamine. [M-H].sup.-=285.2 m/z. Activity: C.
Example 281
##STR00636##
[1301] 3-(4-Boronophenyl)propanoic acid (102 mg, 1.0 equiv) was
dissolved in 2 mL N,N-dimethylforamide after which BOP (293 mg, 1.0
equiv), DIPEA (300 .mu.L, 3.2 equiv) and benzylamine (100 uL, 1.78
equiv) were added and the reaction was allowed to stir for 16 h at
room temperature. After this point, 25 mL of water was added and
the mixture was transferred to a separatory funnel. The water layer
was extracted with ethyl acetate (2.times.50 mL). The organics were
combined, dried over MgSO.sub.4, and concentrated to provide crude
material that was purified by silica gel chromatography (gradient
50% ethyl acetate/hexanes to 1% methanol/ethyl acetate to provide
88 mg of boronic acid 324. [M-H].sup.-=282.2 m/z. Activity: C
Example 282
##STR00637##
[1303] 4-Hydroxyphenylboronic acid (63 mg, 1.0 equiv) was suspended
in 2 mL 5% sodium bicarbonate solution and a 12 mL of
tetrahydrofuran/water solution is added (1:1 v/v).
4-(Bromomethyl)phenylboronic acid (116 mg, 1.2 equiv) was then
added and the reaction was allowed to stir for 16 h at room
temperature. After this point, the tetrahydrofuran was removed
under vacuum and the reaction was acidified to pH <2 with 1N
HCl. The mixture was transferred to a separatory funnel and the
water layer was extracted with methylene chloride (2.times.75 mL).
The organics were combined, dried over MgSO.sub.4 and concentrated
to provide crude material that was purified by silica gel
chromatography (gradient 50% ethyl acetate/hexanes to 5%
methanol/ethyl acetate to provide boronic acid 325.
[M-H].sup.-=271.1 m/z. Activity: C
Example 283
##STR00638##
[1305] 3-Hydroxyphenylboronic acid (40 mg, 1.05 equiv) and
4-(bromomethyl)phenylboronic acid (65 mg, 1.0 equiv) were dissolved
in 6 mL solution of tetrahydrofuran/N,N-dimethylforamide (1:1 v/v).
Sodium hydride (36 mg, 5.0 equiv) is added and the reaction is
allowed to stir at room temperature overnight. Water (25 mL) is
then added and the reaction is acidified to pH<2 with 1N HCl and
transferred to a separatory funnel. The water layer is washed with
ethyl acetate (1.times.75 mL) and diethyl ether (1.times.75 mL).
The water layer is then concentrated under vacuum to provide crude
oil which is triturated with tetrahydrofuran and methanol to
provide the desired boronic acid 326. [2M-3H.sub.2O].sup.-=488.0
m/z. Activity: A
Example 284
##STR00639##
[1306] Part A
##STR00640##
[1308] 4-(1-Boc-piperidin-4-yl)-butanoic acid (6.45 g, 1.0 equiv)
was dissolved in 40 mL methylene chloride and cooled to 0.degree.
C. in an ice bath. Ethyl chloroformate (2.9 mL, 1.28 equiv) was
added followed, by N,N'-dimethylhydroxylamine hydrochloride (2.6 g,
1.1 equiv) and triethylamine (10 mL, 3.0 equiv). The reaction was
allowed to warm to room temperature overnight during which time the
was the formation of significant amounts of white precipitate. The
reaction was then diluted with water (50 mL) and extracted with
methylene chloride (2.times.75 mL). The combined organics were
combined, dried over MgSO.sub.4, and concentrated to provide crude
327 which was used directly in the next step.
[1309] Oxazole (710 mg, 1.3 equiv) was dissolved in 5 mL of tetra
hydrofuran and cooled to -78.degree. C. in a dry ice/acetone bath.
Isopropyl magnesium chloride (5.0 mL, 2.0 M in diethyl ether, 1.23
equiv) was added over 5 minutes and the reaction was allowed to
stir for 20 min at -20.degree. C. during which time the solution
turned orange. Weinreb amide 327 (2.56 g, 1.0 equiv) dissolved in 5
mL tetrahydrofuran was then added and the reaction was allowed to
warm to room temp overnight. After this point, 40 mL of saturated
ammonium chloride was added after which the reaction was
transferred to a separatory funnel. The water layer was washed with
diethyl ether (2.times.100 mL). The organic layers were dried over
MgSO.sub.4, filtered and concentrated to provide crude material
which was purified using silica gel chromatography (gradient of
20-70% ethyl acetate/hexanes) to provide 500 mg of ketooxazole
328.
Part B
##STR00641##
[1311] Ketooxazole 328 was dissolved in 15 mL diethyl ether.
Anhydrous HCl was bubbled through the solution for a few seconds
and allowed to stir for 20 min after which point TLC analysis
indicated that there was no more starting material. The rxn was
then concentrated and used directly.
[1312] 4-(Bromomethyl)phenylboronic acid (125 mg, 1.03 equiv) and
the HCl salt of 328 (146 mg, 1.0 equiv) were dissolved in 4 mL of
methylene chloride. Hunig's base (300 .mu.L) was added and the
reaction was allowed to stir overnight with the formation of a
significant amount of solid in the flask. The reaction is quenched
with water and acidified to pH<2 with 1N HCl. However in this
case the product stayed in the water layer. The organic layer was
removed and a 5% solution of sodium carbonate was added which
caused the desired product to crash out the water layer to provide
boronic acid 329. [M-H].sup.-=355.1 m/z. Activity: C.
Example 285
TABLE-US-00023 [1313] TABLE A Other boronic acids tested
##STR00642## C ##STR00643## C ##STR00644## D ##STR00645## D
##STR00646## C ##STR00647## A ##STR00648## D ##STR00649## C
##STR00650## D ##STR00651## D ##STR00652## B ##STR00653## D
##STR00654## B ##STR00655## B ##STR00656## B ##STR00657## C
##STR00658## C ##STR00659## C
Biological Protocols
Example 286
Inhibition of Rat and Human FAAH
[1314] The following assays may be used to determine the inhibition
of FAAH by the compounds of the present invention: (1) a
fluorescence-based assay for fatty acid amide hydrolase compatible
with high-throughput screening as described in Manjunath et al.,
Analytical Biochemistry (2005) 343:143-151; and (2) a
high-throughput screening for the discovery of inhibitors of fatty
acid amide hydrolase using a microsome-based fluorescent assay.
Wang et al., Biomolecular Screening (2006) 1-9.
[1315] Rat FAAH Preparation:
[1316] Five rat livers were homogenized in five fold volume with
ice cold Tris (20 mM pH 8.0) and 0.32 M Sucrose solution via an
Ultra Turrax T25 homogenizer. All subsequent preparation steps were
carried out at 4.degree. C. The homogenate was centrifuged at 6000
g, for 20 minutes and the pellet, containing nuclear debris and
mitochondria was discarded. The supernatant was centrifuged at
40,000 g for 30 minutes. The supernatant was discarded and the
pellet solubilized via a dounce homogenizer in resuspension buffer
(20 mM Hepes pH 7.8, 10% v/v glycerol, 1 mM EDTA, 1% triton X-100)
overnight at 4.degree. C. to resolubilize membrane bound FAAH. The
solution was centrifuged at 40,000 g for 30 minutes and the pellet
discarded. The supematant containing rat FAAH was aliquoted and
flash frozen with liquid nitrogen and stored for long term usage at
-80.degree. C.
[1317] Human FAAH Preparation:
[1318] COS-7 cells were split the day before, 1:5 into 150
mm.times.25 mm cell culture dishes (Corning Inc., Cat. No. 430599).
Transient transfection took place at 30-40% confluency according to
FuGENE 6 Transfection Reagent (Roche, Cat. No. 11814 443 001).
[1319] Transfection Procedure:
[1320] The FuGENE transfection 6 reagent (45 uL) was added to 1410
.mu.L of media (DMEM, serum free without pen/strep) in a 15 mL
conical tube and incubated at room temp for 5 minutes, followed by
the addition of FAAH plasmid DNA (15 .mu.g) (OriGene Cat. No.
TC119221, Genbank Accession No. NM.sub.--001441.1, 0.67 ug/uL) and
a further incubation of 15 minutes at room temperature. The
resulting solution was added into one dish of 30-40% confluent
COS-7 cells in a drop-wise manner. The COS-7 cell dish was
subsequently incubated for 48 hours. The cells are then
harvested.
[1321] Harvest Procedure:
[1322] Media was aspirated from the dishes and the cells rinsed
with 10 mL PBS. The PBS was removed and 3 mL of PBS added to the
dish. The dish was scraped to resuspend the cells, and the
subsequent cell suspension collected into a 15 mL conical tube. The
cells were pelleted by centrifugation at 1200 rpm for 5 minutes in
a bench top centrifuge. PBS was removed and the cell pellet snap
frozen in liquid nitrogen and stored at -80.degree. C.
[1323] COS-7 Cells--FAAH Purification: [1324] (1) Fractionation:
Frozen cell pellets from transient transfections were thawed on ice
and resuspended in 12.5 mM Hepes pH 8.0, 100 mM NaCl, 1 mM EDTA (10
mL/0.2 g cell pellet). The pellets were dounce homogenized and then
sonicated to produce cell extract.
[1325] The cell extract was subsequently centrifuged at 1000 g to
remove cellular debris. The pellet was discarded and the
supernatant centrifuged at 13,000 g for 20 minutes. The pellet
contained membrane bound FAAH. The supernatant was discarded and
the pellet resolubilized. [1326] (2) Re-solubilization: The
fraction of interest, (13,000 g, membrane fraction) was
re-suspended in 2.3 mL re-suspension buffer (20 mM Hepes pH 7.8,
10% v/v Glycerol, 1 mM EDTA, 1% Triton X-100) and the sample
incubated on ice for 1 hour and then centrifuged to remove any
particulate matter. The supernatant containing solubilized human
FAAH was aliquoted and snap frozen in liquid nitrogen and stored at
-80.degree. C. until use. [1327] (3) Characterization: Protein
Concentration determined by Bradford assay. [1328] SDS gel and
Western blot to confirm presence of FAAH [1329] FAAH activity assay
[1330] Km determination--96-well assay [1331] Linear
dependence--96-well assay [1332] Standard compound Ki
determination--384-well assay
[1333] Rat FAAH Biochemical Inhibition Assay; Materials and
Methods:
[1334] Rat FAAH biochemical assays were carried out in a 96 well
flat bottom black non-treated polystyrene plates (Corning Costar
Catalogue #3915). FAAH reaction buffer: 50 mM Hepes (pH 7.5), 1 mM
EDTA, 0.2% Triton X-100. FAAH substrate--AMC Arachidonoyl Amide
(Cayman Chemicals Company, Catalog #10005098). The reaction was
read in an Envision microtiter plate reader [Excitation filter 355
nm (40 nm bandpass); Emmision filter 460 nm (25 nm bandpass)]. The
raw fluorescence was plotted on the y axis and the inhibitor
concentration on the x axis to give a dose response inhibition
curve. The data was fitted to a single site competitive inhibition
equation, fixing the Km for the rat and human enzyme to 12 .mu.M
and 9 .mu.M respectively.
[1335] Rat FAAH Biochemical Inhibition Assay; Experimental
Protocol:
[1336] The principle of this assay was the hydrolysis of
AMC-Arichodonoyl, a fluorescent analogue of Anandamide, which
results in the formation of Arachidonic acid and AMC. The formation
of AMC results in an increase in fluorescence (see, for example,
Manjunath et al., Analytical Biochemistry (2005) 343:143-151; and
Wang et al., Biomolecular Screening (2006) 1-9). The inhibition of
product formation and hence fluorescence as a function of inhibitor
concentration enables the determination of Ki for the
compounds.
[1337] A 0.49 mg/ml Rat liver FAAH solution was made up in FAAH
reaction buffer, and 78 ul pipetted into a 96 well plate. To this
was added 2 uL of a 3 fold serially diluted inhibitor from a DMSO
stock solution. The FAAH solution and inhibitor were incubated for
30 minutes at room temperature. The FAAH reaction was initiated by
the addition of 80 .mu.L of 40 .mu.M AMC Arachidonoyl Amide in FAAH
reaction buffer, yielding a final reaction FAAH rat liver
preparation concentration of 0.25 mg/mL and AMC-Arachidonoyl
substrate concentration of 20 .mu.M, reaction volume 160 .mu.L. The
reaction was allowed to proceed for 4 hours at room temperature.
The reaction was stopped by the addition of 80 .mu.L 12 uM
a-ketoheterocycle (Cayman Chemicals, catalogue #10435). The
microtiter plate was read in the envision plate reader.
[1338] Human FAAH assay; Experimental Protocol: A 0.1 mg/mL Human
FAAH solution was made up in FAAH reaction buffer, and 24 ul
pipeted into a 384 well plate. To this was added 1 .mu.L of a 3
fold serially diluted inhibitor from a DMSO stock solution. The
FAAH solution and inhibitor were incubated for 30 minutes at room
temperature. The FAAH reaction was initiated by the addition of 25
.mu.L of 40 .mu.M AMC Arachidonoyl Amide in FAAH reaction buffer,
yielding a final reaction human FAAH preparation concentration of
0.05 mg/ml and AMC-Arachidonoyl substrate concentration of 20
.mu.M, reaction volume 50 .mu.L. The reaction was allowed to
proceed for 4 hours at room temperature. The reaction was stopped
by the addition of 25 .mu.L 12 .mu.M a-ketoheterocycle (Cayman
Chemicals, catalogue #10435). The microtiter plate was read in the
envision plate reader.
[1339] The raw fluorescence was plotted on the y axis and the
inhibitor concentration on the x axis to give a dose response
inhibition curve. The data was fitted to a single site competitive
inhibition equation, fixing the Km for the rat and human enzyme to
12 .mu.M and 9 .mu.M respectively.
Example 287
Inhibition of FAAH in its Native Cellular Environment
[1340] Cellular FAAH Inhibition Assay:
[1341] This assay measures the activity of FAAH in its native
cellular environment. Radiolabelled anandamide, tritiated on its
ethanolamine component was added to a cell suspension. Anadamide
diffuses into the cell, whereby the native cellular FAAH hydrolyses
anandamide into arachdonic acid and ethanolamine. The cellular
reaction was quenched in a methanol/chloroform mixture.
Ethanolamine partitions into the aqueous phase and was counted via
a scintillation counter giving a measure of cellular FAAH activity.
Inhibition studies were performed by pre-incubating the cells with
serially diluted inhibitor, followed by the addition of
radiolabeled anandamide.
[1342] Cell Preparation:
[1343] RBL-2H3 and T-47D adherent cells were cultured via the
standard protocols. Cells were trypsinized and washed 3 times in
RPMI buffer plus 0.1% BSA. The cells were resuspended, counted and
diluted to a final cell density of 1.times.10.sup.6 cells/mL. Human
PBMC were isolated from whole blood and used at a final cell
density of 4.5.times.10.sup.6 cells/mL in RPMI plus 0.1% BSA
buffer.
[1344] Anandamide Substrate Solution:
[1345] A 10 nM .sup.3H anandamide substrate solution was prepared
by diluting from a 16.7 .mu.M (1 .mu.Ci/.mu.L) stock in RPMI buffer
plus 0.1% BSA, and incubated at room temperature for 90 minutes. A
substrate-inhibitor solution was made by adding serially diluted
inhibitor from a DMSO stock solution to the desired concentration
into the substrate solution.
[1346] Assay:
[1347] A 350 .mu.L cell suspensions was incubated with serially
diluted inhibitor added from a DMSO stock and incubated for 30
minutes with constant agitation. Cells were pelleted and the
supernatant removed. The cells were resuspended in 300 .mu.L of 10
nM substrate+serially diluted inhibitor, to maintain a constant
free inhibitor concentration during the time-course of the
reaction. The RBL-2H3 and T-47D cells were incubated with the
substrate - inhibitor for 5 minutes and PBMC for 15 minutes. The
reaction was quenched by the addition of 700 .mu.L of
methanol:chloroform (1:1 v/v), which lyses the cells and
inactivates FAAH. Sampled were vortexed and centrifuged to separate
the aqueous and organic solutions. .sup.3H ethanolamine, the polar
product of anandamide hydrolysis partitions into the aqueous phase
and was counted via a scintillation counter.
[1348] Data Analysis:
[1349] The radioactivity in the aqueous phase was plotted with
respect to inhibitor concentration to generate dose response
inhibition curves, and the data fitted to determine the
IC.sub.50.
Example 288
FAAH Cell-Based Assay Protocol for Human and Rat Whole Blood
[1350] This assay measures the cellular activity of FAAH in whole
blood via the hydrolysis of radiolabeled anandamide by the same
methodology and principle used in the cell based assay described in
Example 172. FAAH is found to be expressed in the cells of the
immune system.
[1351] Substrate Solution:
[1352] .sup.3H Anandamide (1 .mu.C/.mu.L, 16.7 .mu.M stock) was
added to a final concentration of 40 nM (4.times.) for the human
whole blood assays and 20 nM (2.times.) for rat whole blood assays
to the RMPI buffer plus 0.1% BSA. The .sup.3H anandamide stock
solutions were incubated for 90 minutes at room temperature prior
to use in the whole blood assay.
[1353] Human Whole Blood Cellular FAAH Assay:
[1354] Human blood (262.5 L) was pre-incubated with serially
diluted inhibitor added from DMSO stock solution for 30 minutes.
The assay was initiated by the addition of 40 nM .sup.3H anandamide
(87.5 .mu.L) yielding a final assay volume of 350 .mu.L and .sup.3H
anandamide substrate concentration of 10 nM. The reaction mixture
was incubated for 30 minutes at room temperature, and the reaction
stopped by the addition of 700 .mu.L of methanol: chloroform (1:1
v/v). This lyses the cells and inactivates the FAAH. The solution
was vortexed and .sup.3H ethanolamine, the radiolabeled product of
.sup.3H anandamide hydrolysis partitioning into the aqueous phase,
and was counted via a scintillation counter.
[1355] Rat Whole Blood Cellular FAAH Assay:
[1356] Rat blood (175 .mu.L) was pre-incubated with serially
diluted inhibitor added from DMSO stock solution for 30 minutes.
The assay was initiated by the addition of 20 nM .sup.3H anandamide
(175 .mu.L) yielding a final assay volume of 350 ul and .sup.3H
anandamide substrate concentration of 10 nM. The reaction mixture
was incubated for 30 minutes at room temperature, and the reaction
stopped by the addition of 700 .mu.L of methanol: chloroform (1:1
v/v). This lyses the cells and inactivates the FAAH. The solution
was vortexed and .sup.3H ethanolamine, the radiolabeled product of
.sup.3H anandamide hydrolysis partitioning into the aqueous phase,
and was counted via a scintillation counter.
[1357] Data Analysis:
[1358] The radioactivity in the aqueous phase was plotted with
respect to inhibitor concentration to generate dose response
inhibition curves, and the data fitted to determine the
IC.sub.50.
Example 289
In Vivo Analysis of Boronic Acid and Boronic Ester Derivatives in a
Pain Model
[1359] This assay may be used to evaluate the effect of the
compounds of the present invention on the reflexive withdrawal of
the rat from an acute noxious stimulus (hot surface).
[1360] (1) Heat plate to testing temperature (Hot plate analgesia
meter; Harvard Apparatus)--takes about 10-15 min (the actual
surface temperature is not reflected in the LED read out. The
actual surface temperature is 10.degree. C. less than the read out
indicates).
TABLE-US-00024 Read-out Surface temp 57.degree. C. 47.degree. C.
62.degree. C. 52.degree. C. 65.degree. C. 55.degree. C.
[1361] (2) Place plexi-glass cylinder on hot plate. Place rat
within cylinder and start timer. When the rat either licks its hind
paw or jumps, stop the timer and remove from hot plate. Record the
response latency (in sec), usually 6-7 sec at 52.degree. C. Measure
baseline latencies for all rats.
[1362] (3) Inject drug or vehicle.
[1363] (4) Measure response 5, 15, 30, 60, 90, 120 min, etc. after
drug injection. Cut-off time for 52.degree. C. is 30 sec. A rat
that does not respond by 30 sec. is assigned a latency of 30
sec.
[1364] (5) Clean hot plate surface in between time points with
water, dry with kimwipe and wait until temperature read out has
returned to 57.degree. C.
[1365] Data may be expressed as either latency or percent maximum
possible effect [% MPE=(drug latency-baseline
latency)/(cut-off-baseline latency).times.100].
[1366] Other temperatures may be used (e.g., 47.degree. C.,
55.degree. C.). Cut-off time should be adjusted accordingly (e.g.,
40 sec at 47.degree. C.; 20 sec at 55.degree. C.). Increased
temperatures recruit myelinated afferents (A.delta.-fibers) whereas
lower temperatures involve unmyelinated afferents (c-fibers).
Sensitivity to drug effects may be altered with different plate
temperatures.
Example 290
Evidence for Covalent Complex Formation between Serine-241 of FAAH
and Boronic Acid Inhibitors
[1367] Treatment of rat FAAH protein with the active site-directed
irreversible inhibitor methoxy arachidonyl fluorophosphonate
results in a crystal structure wherein methoxy arachidonyl
phosphonate is covalently bound to the side chain of Ser-241
(Bracey et al., Science (2002) 298:1793-1796).
[1368] Based on this data, it is hypothesized that the boronic acid
compounds provided by the present invention form reversible
covalent complexes with the nucleophilic side chain of Ser-241.
This hypothesis is consistent with the kinetic data. Molecular
modeling studies of aryl boronic acid compounds provided herein
indicates that the aryl ring can be directed to bind either in the
narrow hydrophobic channel of the enzyme near Ser241, which is
confluent with the membrane portion and the acyl chain binding
pocket, or alternatively bind toward the cytosolic portion.
[1369] To distinguish between these two binding modes, a mutant
protein was cloned and expressed which was identical to the rat
FAAH protein sequence, except at four positions in the sequence:
I491V, V495M, L192F, and F194Y. These four residues line the narrow
hydrophobic channel near Ser-241 in the rat x-ray structure.
Starting from the published X-ray crystal structure of rat FAAH, a
3-D homology model was built of human FAAH using the program
DeepView (Nicolas Guex, Manuel Peitsch, Torsten Schwede Alexandre
Diemand "DeepView/Swiss-Pdbviewer" (1995-2001)). Based on this 3-D
homology model of the human protein, mutation of these four
residues to the corresponding amino acids in the human sequence was
predicted to significantly influence the binding of the aryl
boronic acid compounds if the aryl ring is in close proximity to
these residues.
[1370] The inhibition constant (K.sub.i) was measured for a panel
of eleven boronic acid-containing compounds differing in their
ability to inhibit rat and human FAAH. Table B below summarizes the
statistical analysis for the panel of eleven compounds, comparing
the ratio of inhibition constants for the wild-type rat and human
enzymes (R/H) to ratio of inhibition constants for the mutant rat
and human enzymes (M/H). The data indicates that the compounds bind
at Serine-241 with the aryl ring directed toward the narrow
hydrophobic channel.
TABLE-US-00025 TABLE B R/H M/H 11 11 nObs 2.99 1.08 Mean 3.45 0.48
StDev 0.02 0.49 Min 11.86 1.8 Max
EQUIVALENTS
[1371] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
Sequence CWU 1
1
11579PRTHomo sapiens 1Met Val Gln Tyr Glu Leu Trp Ala Ala Leu Pro
Gly Ala Ser Gly Val1 5 10 15 Ala Leu Ala Cys Cys Phe Val Ala Ala
Ala Val Ala Leu Arg Trp Ser 20 25 30 Gly Arg Arg Thr Ala Arg Gly
Ala Val Val Arg Ala Arg Gln Arg Gln 35 40 45 Arg Ala Gly Leu Glu
Asn Met Asp Arg Ala Ala Gln Arg Phe Arg Leu 50 55 60 Gln Asn Pro
Asp Leu Asp Ser Glu Ala Leu Leu Ala Leu Pro Leu Pro65 70 75 80 Gln
Leu Val Gln Lys Leu His Ser Arg Glu Leu Ala Pro Glu Ala Val 85 90
95 Leu Phe Thr Tyr Val Gly Lys Ala Trp Glu Val Asn Lys Gly Thr Asn
100 105 110 Cys Val Thr Ser Tyr Leu Ala Asp Cys Glu Thr Gln Leu Ser
Gln Ala 115 120 125 Pro Arg Gln Gly Leu Leu Tyr Gly Val Pro Val Ser
Leu Lys Glu Cys 130 135 140 Phe Thr Tyr Lys Gly Gln Asp Ser Thr Leu
Gly Leu Ser Leu Asn Glu 145 150 155 160 Gly Val Pro Ala Glu Cys Asp
Ser Val Val Val His Val Leu Lys Leu 165 170 175 Gln Gly Ala Val Pro
Phe Val His Thr Asn Val Pro Gln Ser Met Phe 180 185 190 Ser Tyr Asp
Cys Ser Asn Pro Leu Phe Gly Gln Thr Val Asn Pro Trp 195 200 205 Lys
Ser Ser Lys Ser Pro Gly Gly Ser Ser Gly Gly Glu Gly Ala Leu 210 215
220 Ile Gly Ser Gly Gly Ser Pro Leu Gly Leu Gly Thr Asp Ile Gly
Gly225 230 235 240 Ser Ile Arg Phe Pro Ser Ser Phe Cys Gly Ile Cys
Gly Leu Lys Pro 245 250 255 Thr Gly Asn Arg Leu Ser Lys Ser Gly Leu
Lys Gly Cys Val Tyr Gly 260 265 270 Gln Glu Ala Val Arg Leu Ser Val
Gly Pro Met Ala Arg Asp Val Glu 275 280 285 Ser Leu Ala Leu Cys Leu
Arg Ala Leu Leu Cys Glu Asp Met Phe Arg 290 295 300 Leu Asp Pro Thr
Val Pro Pro Leu Pro Phe Arg Glu Glu Val Tyr Thr305 310 315 320 Ser
Ser Gln Pro Leu Arg Val Gly Tyr Tyr Glu Thr Asp Asn Tyr Thr 325 330
335 Met Pro Ser Pro Ala Met Arg Arg Ala Val Leu Glu Thr Lys Gln Ser
340 345 350 Leu Glu Ala Ala Gly His Thr Leu Val Pro Phe Leu Pro Ser
Asn Ile 355 360 365 Pro His Ala Leu Glu Thr Leu Ser Thr Gly Gly Leu
Phe Ser Asp Gly 370 375 380 Gly His Thr Phe Leu Gln Asn Phe Lys Gly
Asp Phe Val Asp Pro Cys385 390 395 400 Leu Gly Asp Leu Val Ser Ile
Leu Lys Leu Pro Gln Trp Leu Lys Gly 405 410 415 Leu Leu Ala Phe Leu
Val Lys Pro Leu Leu Pro Arg Leu Ser Ala Phe 420 425 430 Leu Ser Asn
Met Lys Ser Arg Ser Ala Gly Lys Leu Trp Glu Leu Gln 435 440 445 His
Glu Ile Glu Val Tyr Arg Lys Thr Val Ile Ala Gln Trp Arg Ala 450 455
460 Leu Asp Leu Asp Val Val Leu Thr Pro Met Leu Ala Pro Ala Leu
Asp465 470 475 480 Leu Asn Ala Pro Gly Arg Ala Thr Gly Ala Val Ser
Tyr Thr Met Leu 485 490 495 Tyr Asn Cys Leu Asp Phe Pro Ala Gly Val
Val Pro Val Thr Thr Val 500 505 510 Thr Ala Glu Asp Glu Ala Gln Met
Glu His Tyr Arg Gly Tyr Phe Gly 515 520 525 Asp Ile Trp Asp Lys Met
Leu Gln Lys Gly Met Lys Lys Ser Val Gly 530 535 540 Leu Pro Val Ala
Val Gln Cys Val Ala Leu Pro Trp Gln Glu Glu Leu545 550 555 560 Cys
Leu Arg Phe Met Arg Glu Val Glu Arg Leu Met Thr Pro Glu Lys 565 570
575 Gln Ser Ser
* * * * *