U.S. patent application number 16/316851 was filed with the patent office on 2019-08-01 for c7, c12, and c16 substituted neuroactive steroids and their methods of use.
This patent application is currently assigned to Sage Therapeutics, Inc.. The applicant listed for this patent is Sage Therapeutics, Inc.. Invention is credited to Maria Jesus Blanco-Pillado, Andrew Griffin, Boyd L. Harrison, Gabriel Martinez Botella, Albert Jean Robichaud, Francesco G. Salituro.
Application Number | 20190233465 16/316851 |
Document ID | / |
Family ID | 59388162 |
Filed Date | 2019-08-01 |
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United States Patent
Application |
20190233465 |
Kind Code |
A1 |
Robichaud; Albert Jean ; et
al. |
August 1, 2019 |
C7, C12, AND C16 SUBSTITUTED NEUROACTIVE STEROIDS AND THEIR METHODS
OF USE
Abstract
Described herein are neuroactive steroids of Formula (I),
Formula (V), or Formula (IX) or a pharmaceutically acceptable salt
thereof; wherein each instance of R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.11a, R.sup.11b, R.sup.12,
R.sup.16, R.sup.17, R.sup.19, and are as herein. Such compounds are
envisioned, in certain embodiments, to behave as GABA modulators.
Also provided are pharmaceutical compositions comprising a compound
described herein and methods of use and treatment, e.g., such as
for inducing sedation and/or anesthesia. ##STR00001##
Inventors: |
Robichaud; Albert Jean;
(Boston, MA) ; Martinez Botella; Gabriel;
(Wayland, MA) ; Harrison; Boyd L.; (Princeton
Junction, NJ) ; Salituro; Francesco G.; (Marlborough,
MA) ; Griffin; Andrew; (L'lle Bizard, CA) ;
Blanco-Pillado; Maria Jesus; (Arlington, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sage Therapeutics, Inc. |
Cambridge |
MA |
US |
|
|
Assignee: |
Sage Therapeutics, Inc.
Cambridge
MA
|
Family ID: |
59388162 |
Appl. No.: |
16/316851 |
Filed: |
July 11, 2017 |
PCT Filed: |
July 11, 2017 |
PCT NO: |
PCT/US2017/041605 |
371 Date: |
January 10, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62360887 |
Jul 11, 2016 |
|
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|
62360876 |
Jul 11, 2016 |
|
|
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62360884 |
Jul 11, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07J 1/0029 20130101;
C07J 43/003 20130101; C07J 7/006 20130101; C07J 41/005 20130101;
C07J 7/003 20130101; C07J 41/0094 20130101; C07J 7/002 20130101;
A61P 25/00 20180101 |
International
Class: |
C07J 43/00 20060101
C07J043/00; C07J 41/00 20060101 C07J041/00; C07J 7/00 20060101
C07J007/00; C07J 1/00 20060101 C07J001/00; A61P 25/00 20060101
A61P025/00 |
Claims
1. A compound of Formula (I): ##STR00295## or a pharmaceutically
acceptable salt thereof, wherein represents a single or double bond
as valency permits; each of R.sup.2, R.sup.4, R.sup.6, R.sup.11a,
and R.sup.11b is independently hydrogen, halogen, cyano, nitro,
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
heteroaryl, --OR.sup.A1, --SR.sup.A1, --N(R.sup.A1).sub.2,
--NHC(.dbd.O)R.sup.A1, --NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1, wherein each
instance of R.sup.A1 is independently hydrogen, alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen
protecting group when attached to an oxygen atom, a sulfur
protecting group when attached to a sulfur atom, a nitrogen
protecting group when attached to a nitrogen atom, or two R.sup.A1
groups are joined to form an heterocyclic or heteroaryl ring; and
R.sup.A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, or heteroaryl; or R.sup.11a and R.sup.11b together form oxo;
R.sup.3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, or heteroaryl; R.sup.5 is absent or hydrogen;
and represents a single or double bond, wherein when one of at site
is a double bond, the other is a single bond; when both of are
single bonds, then R.sup.5 is hydrogen; and when one of the is a
double bond, R.sup.5 is absent; R.sup.17 is alkoxy, cyano, nitro,
aryl, heteroaryl, or --C(O)R.sup.B1, --C(O)CH.sub.2R.sup.B1, or
--C(O)CH.sub.2CH.sub.2R.sup.B1, wherein R.sup.B1 is hydrogen, --OH,
alkoxy, aryl, or heteroaryl; R.sup.19 is hydrogen or alkyl; and
R.sup.7 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, heteroaryl, --OR.sup.A1,
--SR.sup.A1, --N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(.dbd.O).sub.2OR.sup.A1.
2-5. (canceled)
6. The compound of claim 2, wherein R.sup.3 is C.sub.1-C.sub.6
alkyl.
7. (canceled)
8. The compound of claim 2, wherein the compound of Formula (I) is
a compound of Formula (II-c) or (II-d): ##STR00296##
9. (canceled)
10. The compound of claim 8, wherein R.sup.7 is --CH.sub.3,
--CH.sub.2CH.sub.3, --OH, --OCH.sub.3, or --CH.sub.2OCH.sub.3.
11. The compound of claim 8, wherein R.sup.17 is --OCH.sub.3, --CN,
or --C(O)CH.sub.3.
12. (canceled)
13. The compound of claim 8, wherein R.sup.17 is
--C(O)CH.sub.2R.sup.B1.
14-17. (canceled)
18. The compound of claim 13, wherein R.sup.B1 is ##STR00297##
19-31. (canceled)
32. A compound of Formula (V): ##STR00298## or a pharmaceutically
acceptable salt thereof, wherein represents a single or double bond
as valency permits; each of R.sup.2, R.sup.4, R.sup.6, R.sup.11a,
and R.sup.11b is independently hydrogen, halogen, cyano, nitro,
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
heteroaryl, --OR.sup.A1, --SR.sup.A1, --N(R.sup.A1).sub.2,
--NHC(.dbd.O)R.sup.A1, --NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1, wherein each
instance of R.sup.A1 is independently hydrogen, alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen
protecting group when attached to an oxygen atom, a sulfur
protecting group when attached to a sulfur atom, a nitrogen
protecting group when attached to a nitrogen atom, or two R.sup.A1
groups are joined to form an heterocyclic or heteroaryl ring; and
R.sup.A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, or heteroaryl; or R.sup.11a and R.sup.11b together form oxo;
R.sup.3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, or heteroaryl; R.sup.5 is absent or hydrogen;
and represents a single or double bond, wherein when one of at site
is a double bond, the other is a single bond; when both of are
single bonds, then R.sup.5 is hydrogen; and when one of the is a
double bond, R.sup.5 is absent; R.sup.17 is alkoxy, cyano, nitro,
aryl, heteroaryl, --C(O)R.sup.B1, --C(O)CH.sub.2R.sup.B1, or
--C(O)CH.sub.2CH.sub.2R.sup.B1, wherein R.sup.B1 is hydrogen, --OH,
alkoxy, aryl, or heteroaryl; R.sup.19 is hydrogen or alkyl; and
R.sup.12 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, heteroaryl, --OR.sup.A1,
--SR.sup.A1, --N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(.dbd.O).sub.2OR.sup.A1.
33-35. (canceled)
36. The compound of claim 32 wherein R.sup.3 is C.sub.1-C.sub.6
alkyl.
37. (canceled)
38. The compound of claim 32, wherein the compound of Formula (V)
is a compound of Formula (VI-c) or (VI-d): ##STR00299##
39. (canceled)
40. The compound of claim 38, wherein R.sup.12 is --CH.sub.3,
--CH.sub.2CH.sub.3, --OH, --OCH.sub.3, or --CH.sub.2OCH.sub.3.
41. The compound of claim 38, wherein R.sup.17 is --OCH.sub.3,
--CN, or --C(O)CH.sub.3.
42. (canceled)
43. The compound of claim 38, wherein R.sup.17 is
--C(O)CH.sub.2R.sup.B1.
44-47. (canceled)
48. The compound of claim 43, wherein R.sup.B1 is ##STR00300##
49-57. (canceled)
58. A compound of Formula (IX): ##STR00301## or a pharmaceutically
acceptable salt thereof, wherein represents a single or double bond
as valency permits; each of R.sup.2, R.sup.4, R.sup.6, R.sup.11a,
and R.sup.11b is independently hydrogen, halogen, cyano, nitro,
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
heteroaryl, --OR.sup.A1, --SR.sup.A1, --N(R.sup.A1).sub.2,
--NHC(.dbd.O)R.sup.A1, --NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1, wherein each
instance of R.sup.A1 is independently hydrogen, alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen
protecting group when attached to an oxygen atom, a sulfur
protecting group when attached to a sulfur atom, a nitrogen
protecting group when attached to a nitrogen atom, or two R.sup.A1
groups are joined to form an heterocyclic or heteroaryl ring; and
R.sup.A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, or heteroaryl; or R.sup.11a and R.sup.11b together form oxo;
R.sup.3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, or heteroaryl; R.sup.5 is absent or hydrogen;
and represents a single or double bond, wherein when one of at site
is a double bond, the other is a single bond; when both of are
single bonds, then R.sup.5 is hydrogen; and when one of the is a
double bond, R.sup.5 is absent; R.sup.17 is alkoxy, cyano, nitro,
aryl, heteroaryl, --C(O)R.sup.B1, --C(O)CH.sub.2R.sup.B1, or
--C(O)CH.sub.2CH.sub.2R.sup.B1, wherein R.sup.B1 is hydrogen, --OH,
--N(R.sup.A1).sub.2, alkoxy, aryl, or heteroaryl; R.sup.19 is
hydrogen or alkyl; and R.sup.16 is halogen, cyano, nitro, alkyl,
alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,
--OR.sup.A1, --SR.sup.A1, --N(R.sup.A1).sub.2,
--NHC(.dbd.O)R.sup.A1, --NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1.
59. (canceled)
60. (canceled)
61. The compound of claim 58, wherein R.sup.3 is C.sub.1-C.sub.6
alkyl.
62. (canceled)
63. The compound of claim 58, wherein the compound of Formula (IX)
is a compound of Formula (X-c) or (X-d): ##STR00302##
64. (canceled)
65. The compound of claim 63, wherein R.sup.16 is --CH.sub.3,
--CH.sub.2CH.sub.3, --OH, --OCH.sub.3, or --CH.sub.2OCH.sub.3.
66. The compound of claim 63, wherein R.sup.17 is --OCH.sub.3,
--CN, or --C(O)CH.sub.3.
67. (canceled)
68. The compound of claim 63, wherein R.sup.17 is
--C(O)CH.sub.2R.sup.B1.
69-72. (canceled)
73. The compound of claim 68, wherein R.sup.B1 is ##STR00303##
74-81. (canceled)
82. A compound of claim 1, selected from the group consisting of:
##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308##
##STR00309## ##STR00310##
83. A pharmaceutically acceptable salt of a compound of claim 1
selected from the group consisting of: ##STR00311## ##STR00312##
##STR00313## ##STR00314## ##STR00315## ##STR00316##
##STR00317##
84. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable excipient.
85-99. (canceled)
100. A composition for use in treating disorders related to GABA
function in a subject in need thereof, comprising a therapeutically
effective amount of a compound of claim 1.
101. A method of treating a CNS-related disorder in a subject in
need thereof, comprising an effective amount of a compound of claim
1.
102. The method of claim 101, wherein the CNS-related disorder is a
sleep disorder, a mood disorder, a schizophrenia spectrum disorder,
a convulsive disorder, a disorder of memory and/or cognition, a
movement disorder, a personality disorder, autism spectrum
disorder, pain, traumatic brain injury, a vascular disease, a
substance abuse disorder and/or withdrawal syndrome, or
tinnitus.
103-104. (canceled)
105. A compound of claim 32, selected from the group consisting of:
##STR00318## ##STR00319## ##STR00320## ##STR00321##
106. A compound of claim 58, selected from the group consisting of:
##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326##
##STR00327##
107. A pharmaceutically acceptable salt of a compound of claim 32,
selected from the group consisting of: ##STR00328## ##STR00329##
##STR00330## ##STR00331##
108. A pharmaceutically acceptable salt of a compound of claim 58,
selected from the group consisting of: ##STR00332## ##STR00333##
##STR00334## ##STR00335## ##STR00336## ##STR00337##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Ser. No. 62/360,887
filed Jul. 11, 2016, U.S. Ser. No. 62/360,884 filed Jul. 11, 2016,
and U.S. Ser. No. 62/360,876 filed Jul. 11, 2016, which are
incorporated herein by reference.
BACKGROUND
[0002] Brain excitability is defined as the level of arousal of an
animal, a continuum that ranges from coma to convulsions, and is
regulated by various neurotransmitters. In general,
neurotransmitters are responsible for regulating the conductance of
ions across neuronal membranes. At rest, the neuronal membrane
possesses a potential (or membrane voltage) of approximately -70
mV, the cell interior being negative with respect to the cell
exterior. The potential (voltage) is the result of ion (K.sup.+,
Na.sup.+, Cl.sup.-, organic anions) balance across the neuronal
semipermeable membrane. Neurotransmitters are stored in presynaptic
vesicles and are released under the influence of neuronal action
potentials. When released into the synaptic cleft, an excitatory
chemical transmitter such as acetylcholine will cause membrane
depolarization, e.g., a change of potential from -70 mV to -50 mV.
This effect is mediated by postsynaptic nicotinic receptors which
are stimulated by acetylcholine to increase membrane permeability
to Na.sup.+ ions. The reduced membrane potential stimulates
neuronal excitability in the form of a postsynaptic action
potential.
[0003] In the case of the GABA receptor complex (GRC), the effect
on brain excitability is mediated by GABA, a neurotransmitter. GABA
has a profound influence on overall brain excitability because up
to 40% of the neurons in the brain utilize GABA as a
neurotransmitter. GABA regulates the excitability of individual
neurons by regulating the conductance of chloride ions across the
neuronal membrane. GABA interacts with its recognition site on the
GRC to facilitate the flow of chloride ions down an electrochemical
gradient of the GRC into the cell. An intracellular increase in the
levels of this anion causes hyperpolarization of the transmembrane
potential, rendering the neuron less susceptible to excitatory
inputs, i.e., reduced neuron excitability. In other words, the
higher the chloride ion concentration in the neuron, the lower the
brain excitability and level of arousal.
[0004] It is well-documented that the GRC is responsible for the
mediation of anxiety, seizure activity, and sedation. Thus, GABA
and drugs that act like GABA or facilitate the effects of GABA
(e.g., the therapeutically useful barbiturates and benzodiazepines
(BZs), such as Valium.RTM.) produce their therapeutically useful
effects by interacting with specific regulatory sites on the GRC.
Accumulated evidence has now indicated that in addition to the
benzodiazepine and barbiturate binding site, the GRC contains at
least one distinct site for interaction with neuroactive steroids.
See, e.g., Lan, N. C. et al., Neurochem. Res. (1991)
16:347-356.
[0005] Neuroactive steroids can occur endogenously. The most potent
endogenous neuroactive steroids are 3.alpha.-hydroxy-5-reduced
pregnan-20-one and 3.quadrature..quadrature.21-dihydroxy-5-reduced
pregnan-20-one, metabolites of hormonal steroids progesterone and
deoxycorticosterone, respectively. The ability of these steroid
metabolites to alter brain excitability was recognized in 1986
(Majewska, M. D. et al., Science 232:1004-1007 (1986); Harrison, N.
L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).
[0006] New and improved neuroactive steroids are needed that act as
modulating agents for brain excitability, as well as agents for the
prevention and treatment of CNS-related diseases. The compounds,
compositions, and methods described herein are directed toward this
end.
SUMMARY OF THE INVENTION
[0007] Compounds as described herein, act, in certain embodiments,
as GABA modulators, e.g., effecting the GABA.sub.A receptor in
either a positive or negative manner. As modulators of the
excitability of the central nervous system (CNS), as mediated by
their ability to modulate GABA.sub.A receptor, such compounds are
expected to have CNS-activity.
[0008] Thus, in another aspect, provided are methods of treating a
CNS-related disorder in a subject in need thereof, comprising
administering to the subject an effective amount of a compound as
described herein, e.g., a compound of Formula (I), a compound of
Formula (V), or a compound of Formula (IX). In certain embodiments,
the CNS-related disorder is selected from the group consisting of a
sleep disorder, a mood disorder, a schizophrenia spectrum disorder,
a convulsive disorder, a disorder of memory and/or cognition, a
movement disorder, a personality disorder, autism spectrum
disorder, pain, traumatic brain injury, a vascular disease, a
substance abuse disorder and/or withdrawal syndrome, and tinnitus.
In certain embodiments, the compound is administered orally,
subcutaneously, intravenously, or intramuscularly. In certain
embodiments, the compound is administered chronically. In certain
embodiments, the compound is administered continuously, e.g., by
continuous intravenous infusion.
[0009] In an aspect, provided herein is a compound of Formula
(I):
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein represents a
single or double bond as valency permits; each of R.sup.2, R.sup.4,
R.sup.6, R.sup.11a, and R.sup.11b is independently hydrogen,
halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, --OR.sup.A1, --SR.sup.A1,
--N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1, --NHC(.dbd.O)OR.sup.A1,
--S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(.dbd.O).sub.2OR.sup.A1, wherein each instance of R.sup.A1 is
independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, a nitrogen protecting group when attached to a
nitrogen atom, or two R.sup.A1 groups are joined to form an
heterocyclic or heteroaryl ring; and R.sup.A2 is alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or
R.sup.11a and R.sup.11b together form oxo; R.sup.3 is hydrogen,
alkyl, alkenyl, alkynyl carbocyclyl, heterocyclyl, aryl, or
heteroaryl; R.sup.5 is absent or hydrogen; and represents a single
or double bond, wherein when one of at site is a double bond, the
other is a single bond; when both of are single bonds, then R.sup.5
is hydrogen; and when one of the is a double bond, R.sup.5 is
absent; R.sup.17 is alkoxy, cyano, nitro, aryl, heteroaryl, or
--C(O)R.sup.B1, --C(O)CH.sub.2R.sup.B1, or
--C(O)CH.sub.2CH.sub.2R.sup.B1, wherein R.sup.B1 is hydrogen, --OH,
alkoxy, aryl, or heteroaryl; R.sup.19 is hydrogen or alkyl; and
R.sup.7 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, heteroaryl, --OR.sup.A1,
--SR.sup.A1, --N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(.dbd.O).sub.2OR.sup.A1.
[0010] In some embodiments, R.sup.3 is alkyl.
[0011] In some embodiments, the compound of Formula (I) is a
compound of Formula (I-a) or (I-b):
##STR00003##
[0012] In some embodiments, each of R.sup.2, R.sup.4, and R.sup.6,
R.sup.11a, and R.sup.11b is independently hydrogen; In some
embodiments, R.sup.2, R.sup.4, R.sup.6, R.sup.11a, and R.sup.11b
are all hydrogen. In some embodiments, each of R.sup.2, R.sup.4,
and R.sup.6 is independently halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, or --OH; In some embodiments, R.sup.3 is
C.sub.1-C.sub.6 alkyl (e.g. C.sub.1-C.sub.6 haloalkyl or
--CH.sub.3).
[0013] In some embodiments, the compound of Formula (I) is a
compound of Formula (II-a) or (II-b):
##STR00004##
[0014] In some embodiments, the compound of Formula (I) is a
compound of Formula (II-c) or (II-d):
##STR00005##
[0015] In some embodiments, R.sup.19 is --CH.sub.3. In some
embodiments, R.sup.7 is alkyl (e.g., unsubstituted alkyl or
--CH.sub.2OR.sup.A1) or --OR.sup.A1. In some embodiments, R.sup.7
is --CH.sub.3, --CH.sub.2CH.sub.3, --OH, --OCH.sub.3, or
--CH.sub.2OCH.sub.3. In some embodiments, R.sup.17 is --OCH.sub.3,
--CN, or --C(O)CH.sub.3. In some embodiments, R.sup.7 is
--C(O)CH.sub.2R.sup.C1. In some embodiments, R.sup.17 is
--C(O)CH.sub.2R.sup.B1. In some embodiments, R.sup.17 is alkoxy,
cyano, or --C(O)R.sup.B1. In some embodiments, R.sup.B1 is
pyrazolyl (e.g., a cyano-substituted pyrazolyl). In some
embodiments, R.sup.B1 is tetrazolyl (e.g., a methyl-substituted
tetrazolyl). In some embodiments, R.sup.B1 is a bicyclic heteroaryl
(e.g., a methoxy-substituted bicyclic heteroaryl.
In some embodiments, R.sup.B1 is
##STR00006##
In some embodiments, R.sup.B1 is
##STR00007##
[0016] In some embodiments, R.sup.6 is halogen. In some
embodiments, R is fluorine.
[0017] In some embodiments, each of R.sup.11a and R.sup.11b is
independently hydrogen, C.sub.1-C.sub.6 alkyl (e.g. C.sub.1-C.sub.6
haloalkyl), C.sub.1-C.sub.6 alkoxy (e.g. C.sub.1-C.sub.6
alkoxyhalo), or --OH. In some embodiments, R.sup.11a and R.sup.11b
together form oxo. In some embodiments, R.sup.17 is C.sub.1-C.sub.6
alkoxy (e.g. --OCH.sub.3), cyano, or nitro. In some embodiments,
R.sup.19 is hydrogen or substituted or unsubstituted
C.sub.1-C.sub.6 alkyl (e.g. --CH.sub.2OR.sup.X, wherein R.sup.X is
hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy).
[0018] In some embodiments, the compound of Formula (I) is a
compound of Formula (III-a) or (III-b):
##STR00008##
wherein R.sup.a is hydrogen, halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3), or --OH. In some embodiments, the compound of Formula
(I) is a compound of Formula (IV-a) or (IV-b):
##STR00009##
wherein: m is 0, 1, or 2; n is 0, 1, or 2; each R.sup.b is
independently hydrogen, halogen, or C.sub.1-C.sub.6 alkyl; and each
R is independently halogen, C.sub.1-C.sub.6 alkyl (e.g. --CH.sub.3
or C.sub.1-C.sub.6 haloalkyl), C.sub.1-C.sub.6 alkoxy, cyano, or
--OH. In some embodiments, A is a 5-10-membered ring. In some
embodiments, A is a fused bicyclic ring. In some embodiments, A is
monocyclic heteroaryl or bicyclic heteroaryl. In an aspect,
provided is a compound of Formula (V):
##STR00010##
or a pharmaceutically acceptable salt thereof, wherein represents a
single or double bond as valency permits; each of R.sup.2, R.sup.4,
R.sup.6, R.sup.11a, and R.sup.11b is independently hydrogen,
halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, --OR.sup.A1, --SR.sup.A1,
--N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1, --NHC(.dbd.O)OR.sup.A1,
--S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(.dbd.O).sub.2OR.sup.A1, wherein each instance of R.sup.A1 is
independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, a nitrogen protecting group when attached to a
nitrogen atom, or two R.sup.A1 groups are joined to form an
heterocyclic or heteroaryl ring; and R.sup.A2 is alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or
R.sup.11a and R.sup.11b together form oxo; R.sup.3 is hydrogen,
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or
heteroaryl; R.sup.5 is absent or hydrogen; and represents a single
or double bond, wherein when one of at site is a double bond, the
other is a single bond; when both of are single bonds, then R.sup.5
is hydrogen; and when one of the is a double bond, R.sup.5 is
absent; R.sup.17 is alkoxy, cyano, nitro, aryl, heteroaryl,
--C(O)R.sup.B1, --C(O)CH.sub.2R.sup.B1, or
--C(O)CH.sub.2CH.sub.2R.sup.B1, wherein R.sup.B1 is hydrogen, --OH,
alkoxy, aryl, or heteroaryl; R.sup.19 is hydrogen or alkyl; and
R.sup.12 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, heteroaryl, --OR.sup.A1,
--SR.sup.A1, --N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(.dbd.O).sub.2OR.sup.A1.
[0019] In some embodiments, R.sup.3 is alkyl.
[0020] In some embodiments, the compound of Formula (V) is a
compound of Formula (V-a) or (V-b):
##STR00011##
[0021] In some embodiments, each of R.sup.2, R.sup.4, R.sup.6,
R.sup.11a, and R.sup.11b is independently hydrogen. In some
embodiments, R.sup.2, R.sup.4, R.sup.6, R.sup.11a, and R.sup.11b
are all hydrogen.
[0022] In some embodiments, each of R.sup.2, R.sup.4, and R.sup.6
is independently halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, or --OH.
[0023] In some embodiments, R.sup.3 is C.sub.1-C.sub.6 alkyl (e.g.
C.sub.1-C.sub.6 haloalkyl or --CH.sub.3).
[0024] In some embodiments, the compound of Formula (V) is a
compound of Formula (VI-a) or (VI-b):
##STR00012##
[0025] In some embodiments, the compound of Formula (V) is a
compound of Formula (VI-c) or (VI-d):
##STR00013##
[0026] In some embodiments, R.sup.19 is --CH.sub.3. In some
embodiments, R.sup.12 is --OR.sup.A1. In some embodiments, R.sup.12
is --CH.sub.3, --CH.sub.2CH.sub.3, --OH, --OCH.sub.3, or
--CH.sub.2OCH.sub.3. In some embodiments, R.sup.17 is --OCH.sub.3,
--CN, or --C(O)CH.sub.3. In some embodiments, R.sup.17 is
--C(O)CH.sub.2R.sup.C1. In some embodiments, R.sup.17 is
--C(O)CH.sub.2R.sup.B1. In some embodiments, R.sup.17 is alkoxy,
cyano, or --C(O)R.sup.B1.
[0027] In some embodiments, R.sup.B1 is pyrazolyl (e.g., a
cyano-substituted pyrazolyl). In some embodiments, R.sup.B1 is
tetrazolyl (e.g., a methyl-substituted tetrazolyl). In some
embodiments, R.sup.B1 is a bicyclic heteroaryl (e.g., a
methoxy-substituted bicyclic heteroaryl. In some embodiments,
R.sup.B1 is
##STR00014##
In some embodiments, R.sup.B1 is
##STR00015##
[0028] In some embodiments, R.sup.6 is halogen. In some
embodiments, R.sup.6 is fluorine.
[0029] In some embodiments, each of R.sup.11a and R.sup.11b is
independently hydrogen, C.sub.1-C.sub.6 alkyl (e.g. C.sub.1-C.sub.6
haloalkyl), C.sub.1-C.sub.6 alkoxy (e.g. C.sub.1-C.sub.6
haloalkoxy), or --OH. In some embodiments, R.sup.11a and R.sup.11b
together form oxo. In some embodiments, R.sup.17 is C.sub.1-C.sub.6
alkoxy (e.g. --OCH.sub.3) or cyano. In some embodiments, R.sup.19
is hydrogen or substituted or unsubstituted C.sub.1-C.sub.6 alkyl
(e.g. --CH.sub.2OR.sup.X, wherein R.sup.X is hydrogen,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy). In some
embodiments, the compound of Formula (V) is a compound of Formula
(VII-a) or (VII-b):
##STR00016##
wherein R.sup.a is hydrogen, halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3), or --OH. In some embodiments, the compound of Formula
(V) is a compound of Formula (VIII-a) or (VIII-b):
##STR00017##
wherein m is 0, 1, or 2, n is 0, 1, or 2, and each R.sup.b is
independently hydrogen, halogen, or C.sub.1-C.sub.6 alkyl; and each
R.sup.c is independently halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3 or C.sub.1-C.sub.6 haloalkyl), C.sub.1-C.sub.6 alkoxy,
cyano, or --OH.
[0030] In some embodiments, A is a 5-10-membered ring. In some
embodiments, A is a fused bicyclic ring. In some embodiments, A is
monocyclic heteroaryl or bicyclic heteroaryl.
In an aspect, provided herein is a compound of Formula (IX):
##STR00018##
[0031] or a pharmaceutically acceptable salt thereof, wherein
represents a single or double bond as valency permits; each of
R.sup.2, R.sup.4, R.sup.6, R.sup.11a, and R.sup.11b is
independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, --OR.sup.A1,
--SR.sup.A1, --N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(.dbd.O).sub.2OR.sup.A1, wherein each instance of R.sup.A1 is
independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, a nitrogen protecting group when attached to a
nitrogen atom, or two R.sup.A1 groups are joined to form an
heterocyclic or heteroaryl ring; and R.sup.A2 is alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or
R.sup.11a and R.sup.11b together form oxo; R.sup.3 is hydrogen,
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or
heteroaryl; R.sup.5 is absent or hydrogen; and represents a single
or double bond, wherein when one of at site is a double bond, the
other is a single bond; when both of are single bonds, then R.sup.5
is hydrogen; and when one of the is a double bond, R.sup.5 is
absent; R.sup.17 is alkoxy, cyano, nitro, aryl, heteroaryl,
--C(O)R.sup.B1, --C(O)CH.sub.2R.sup.B1, or
--C(O)CH.sub.2CH.sub.2R.sup.B1, wherein R.sup.B1 is hydrogen, --OH,
--N(R.sup.A1).sub.2, alkoxy, aryl, or heteroaryl; R.sup.19 is
hydrogen or alkyl; and R.sup.16 is halogen, cyano, nitro, alkyl,
alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,
--OR.sup.A1, --SR.sup.A1, --N(R.sup.A1).sub.2,
--NHC(.dbd.O)R.sup.A1, --NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1.
[0032] In some embodiments, R.sup.3 is alkyl.
[0033] In some embodiments, the compound of Formula (IX) is a
compound of Formula (IX-a) or (IX-b):
##STR00019##
[0034] In some embodiments, each of R.sup.2, R.sup.4, and R.sup.6,
R.sup.11a, and R.sup.11b is independently hydrogen.
[0035] In some embodiments, R.sup.2, R.sup.4, and R.sup.6,
R.sup.11a, and R.sup.11b are all hydrogen. In some embodiments,
each of R.sup.2, R.sup.4, and R.sup.6 is independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, or --OH.
[0036] In some embodiments, R.sup.3 is C.sub.1-C.sub.6 alkyl (e.g.
C.sub.1-C.sub.6 haloalkyl or --CH.sub.3).
[0037] In some embodiments, the compound of Formula (IX) is a
compound of Formula (X-a) or (X-b):
##STR00020##
[0038] In some embodiments, the compound of Formula (IX) is a
compound of Formula (X-c) or (X-d):
##STR00021##
[0039] In some embodiments, R.sup.19 is --CH.sub.3. In some
embodiments, R.sup.16 is alkyl or --OR.sup.A1. In some embodiments,
R.sup.16 is --CH.sub.3, --CH.sub.2CH.sub.3, --OH, --OCH.sub.3, or
--CH(CH.sub.3).sub.2. In some embodiments, R.sup.17 is --OCH.sub.3,
--CN, or --C(O)CH.sub.3. In some embodiments, R.sup.17 is
--C(O)CH.sub.2R.sup.C1. In some embodiments, R.sup.17 is
--C(O)CH.sub.2R.sup.B1. In some embodiments, R.sup.17 is alkoxy,
cyano, or --C(O)R.sup.B1. In some embodiments, R.sup.B1 is
pyrazolyl (e.g., a cyano-substituted pyrazolyl). In some
embodiments, R.sup.B1 is tetrazolyl (e.g., a methyl-substituted
tetrazolyl). In some embodiments, R.sup.B1 is a bicyclic heteroaryl
(e.g., a methoxy-substituted bicyclic heteroaryl. In some
embodiments, R.sup.B1 is
##STR00022##
In some embodiments, R.sup.B1 is
##STR00023##
[0040] In some embodiments, R.sup.6 is halogen. In some
embodiments, R.sup.6 is fluorine.
[0041] In some embodiments, each of R.sup.11a and R.sup.11b is
independently hydrogen, C.sub.1-C.sub.6 alkyl (e.g. C.sub.1-C.sub.6
haloalkyl), C.sub.1-C.sub.6 alkoxy (e.g. C.sub.1-C.sub.6
haloalkoxy), or --OH. In some embodiments, R.sup.11a and R.sup.11b
together form oxo.
[0042] In some embodiments, R.sup.17 is C.sub.1-C.sub.6 alkoxy
(e.g. --OCH.sub.3), cyano, or nitro.
[0043] In some embodiments, R.sup.19 is hydrogen or substituted or
unsubstituted C.sub.1-C.sub.6 alkyl (e.g. --CH.sub.2OR.sup.X,
wherein R.sup.X is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy).
[0044] In some embodiments, the compound of Formula (IX) is a
compound of Formula (X-a) or (X-b):
##STR00024##
wherein R.sup.a is hydrogen, halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3), or --OH.
[0045] In some embodiments, the compound of Formula (IX) is a
compound of Formula (XI-a) or (XI-b):
##STR00025##
wherein m is 0, 1, or 2, n is 0, 1, or 2, each R.sup.b is
independently hydrogen, halogen, or C.sub.1-C.sub.6 alkyl, and each
R.sup.c is independently halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3 or C.sub.1-C.sub.6 haloalkyl), C.sub.1-C.sub.6 alkoxy,
cyano, or --OH.
[0046] In some embodiments, A is a 5-10-membered ring. In some
embodiments, A is a fused bicyclic ring. In some embodiments, A is
monocyclic heteroaryl or bicyclic heteroaryl.
[0047] In an aspect, also provided herein are compounds described
in Table 1 or pharmaceutically acceptable salts thereof.
[0048] In an aspect, provided herein is a pharmaceutical
composition comprising a compound described herein (e.g., a
compound of the Formula (I), Formula (V), or Formula (IX)) and a
pharmaceutically acceptable excipient.
[0049] In an aspect, provided herein is a method of inducing
sedation and/or anesthesia in a subject, comprising administering
to the subject an effective amount of a compound described herein
(e.g., a compound of the Formula (I), Formula (V), or Formula
(IX)), or a pharmaceutically acceptable salt thereof.
[0050] In an aspect, provided herein is a method of administering
an effective amount of a compound, a pharmaceutically acceptable
salt thereof, or pharmaceutical composition of a compound described
herein (e.g., a compound of the Formula (I), Formula (V), or
Formula (IX)), to a subject in need thereof, wherein the subject
experiences sedation and/or anesthesia within two hours of
administration. In some embodiments, the subject experiences
sedation and/or anesthesia within one hour of administration. In
some embodiments, the subject experiences sedation and/or
anesthesia instantaneously. In some embodiments, the compound is
administered by intravenous administration. In some embodiments,
the compound is administered chronically.
[0051] In some embodiments, the subject is a mammal. In some
embodiments, the subject is a human.
[0052] In some embodiments, the compound is administered in
combination with another therapeutic agent.
[0053] In an aspect, provided herein is a method for treating
seizure in a subject, comprising administering to the subject an
effective amount of a compound described herein (e.g., a compound
of the Formula (I), Formula (V), or Formula (IX).
[0054] In an aspect, provided herein is a method for treating
epilepsy or status epilepticus in a subject, the method comprising
administering to the subject an effective amount of a compound
described herein (e.g., a compound of the Formula (I), Formula (V),
or Formula (IX)).
[0055] In an aspect, provided herein is a method for treating a
neuroendocrine disorder or dysfunction in a subject, comprising
administering to the subject an effective amount of a compound
described herein (e.g., a compound of the Formula (I), Formula (V),
or Formula (IX)).
[0056] In an aspect, provided herein is a method for treating a
neurodegenerative disease or disorder in a subject, comprising
administering to the subject an effective amount of a compound
described herein (e.g., a compound of the Formula (I), Formula (V),
or Formula (IX)).
[0057] In an aspect, provided herein is a method for treating a
movement disorder or tremor in a subject, comprising administering
to the subject an effective amount of a compound described herein
(e.g., a compound of the Formula (I), Formula (V), or Formula
(IX)).
[0058] In an aspect, provided herein is a method for treating a
mood disorder or anxiety disorder in a subject, comprising
administering to the subject an effective amount of a compound
described herein (e.g., a compound of the Formula (I), Formula (V),
or Formula (IX)).
[0059] In an aspect, provided herein is a method for treating
disorders related to GABA function in a subject in need thereof,
the method comprising administering to the subject a
therapeutically effective amount of a compound, a pharmaceutically
acceptable salt thereof, or pharmaceutical composition of a
compound described herein (e.g., a compound of the Formula (I),
Formula (V), or Formula (IX)).
[0060] In an aspect, provided herein is a kit comprising a solid
composition comprising a compound described herein (e.g., a
compound of the Formula (I), Formula (V), or Formula (IX)) and a
sterile diluent.
[0061] Thus, in another aspect, provided are methods of treating a
CNS-related disorder in a subject in need thereof, comprising
administering to the subject an effective amount of a compound as
described herein (e.g., a compound of the Formula (I), Formula (V),
or Formula (IX)). In certain embodiments, the CNS-related disorder
is selected from the group consisting of a sleep disorder, a mood
disorder, a schizophrenia spectrum disorder, a convulsive disorder,
a disorder of memory and/or cognition, a movement disorder, a
personality disorder, autism spectrum disorder, pain, traumatic
brain injury, a vascular disease, a substance abuse disorder and/or
withdrawal syndrome, and tinnitus. In certain embodiments, the
compound is administered orally, subcutaneously, intravenously, or
intramuscularly. In certain embodiments, the compound is
administered chronically. In certain embodiments, the compound is
administered continuously, e.g., by continuous intravenous
infusion.
[0062] In some embodiments, the subject is a subject with Rett
syndrome, Fragile X syndrome, or Angelman syndrome.
Definitions
Chemical Definitions
[0063] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3.sup.rd Edition, Cambridge
University Press, Cambridge, 1987.
[0064] Isomers, e.g., stereoisomers, can be isolated from mixtures
by methods known to those skilled in the art, including chiral high
pressure liquid chromatography (HPLC), supercritical fluid
chromatography (SFC), and the formation and crystallization of
chiral salts; or preferred isomers can be prepared by asymmetric
syntheses. See, for example, Jacques et al., Enantiomers, Racemates
and Resolutions (Wiley Interscience, New York, 1981); Wilen et al.,
Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon
Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables of Resolving
Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of
Notre Dame Press, Notre Dame, Ind. 1972). The invention
additionally encompasses compounds described herein as individual
isomers substantially free of other isomers, and alternatively, as
mixtures of various isomers.
[0065] The absolute configuration of an asymmetric center can be
determined using methods known to one skilled in the art. In some
embodiments, the absolute configuration of an asymmetric center in
a compound can be elucidated from the X-ray single-crystal
structure of the compound. In some embodiments, the absolute
configuration of an asymmetric center elucidated by the X-ray
crystal structure of a compound can be used to infer the absolute
configuration of a corresponding asymmetric center in another
compound obtained from the same or similar synthetic methodologies.
In some embodiments, absolute configuration of an asymmetric center
can be determined using nuclear magnetic resonance (NMR)
spectroscopy, e.g., through nuclear Overhauser effect (NOE)
experiments.
[0066] As used herein a pure enantiomeric compound is substantially
free from other enantiomers or stereoisomers of the compound (i.e.,
in enantiomeric excess). In other words, an "S" form of the
compound is substantially free from the "R" form of the compound
and is, thus, in enantiomeric excess of the "R" form. The term
"enantiomerically pure" or "pure enantiomer" denotes that the
compound comprises more than 75% by weight, more than 80% by
weight, more than 85% by weight, more than 90% by weight, more than
91% by weight, more than 92% by weight, more than 93% by weight,
more than 94% by weight, more than 95% by weight, more than 96% by
weight, more than 97% by weight, more than 98% by weight, more than
98.5% by weight, more than 99% by weight, more than 99.2% by
weight, more than 99.5% by weight, more than 99.6% by weight, more
than 99.7% by weight, more than 99.8% by weight or more than 99.9%
by weight, of the enantiomer. In certain embodiments, the weights
are based upon total weight of all enantiomers or stereoisomers of
the compound.
[0067] In the compositions provided herein, an enantiomerically
pure compound can be present with other active or inactive
ingredients. For example, a pharmaceutical composition comprising
enantiomerically pure R-compound can comprise, for example, about
90% excipient and about 10% enantiomerically pure R-compound. In
certain embodiments, the enantiomerically pure R-compound in such
compositions can, for example, comprise, at least about 95% by
weight R-compound and at most about 5% by weight S-compound, by
total weight of the compound. For example, a pharmaceutical
composition comprising enantiomerically pure S-compound can
comprise, for example, about 90% excipient and about 10%
enantiomerically pure S-compound. In certain embodiments, the
enantiomerically pure S-compound in such compositions can, for
example, comprise, at least about 95% by weight S-compound and at
most about 5% by weight R-compound, by total weight of the
compound. In certain embodiments, the active ingredient can be
formulated with little or no excipient or carrier.
[0068] The articles "a" and "an" may be used herein to refer to one
or to more than one (i.e. at least one) of the grammatical objects
of the article. By way of example "an analogue" means one analogue
or more than one analogue.
[0069] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-5, C.sub.4-5,
and C.sub.5-6 alkyl.
[0070] The following terms are intended to have the meanings
presented therewith below and are useful in understanding the
description and intended scope of the present invention.
[0071] "Alkyl" refers to a radical of a straight-chain or branched
saturated hydrocarbon group having from 1 to 20 carbon atoms
("C.sub.1-20 alkyl"). In some embodiments, an alkyl group has 1 to
12 carbon atoms ("C.sub.1-12 alkyl"). In some embodiments, an alkyl
group has 1 to 8 carbon atoms ("C.sub.1-8 alkyl"). In some
embodiments, an alkyl group has 1 to 6 carbon atoms ("C.sub.1-6
alkyl", also referred to herein as "lower alkyl"). In some
embodiments, an alkyl group has 1 to 5 carbon atoms ("C.sub.1-5
alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon
atoms ("C.sub.1-4 alkyl"). In some embodiments, an alkyl group has
1 to 3 carbon atoms ("C.sub.1-3 alkyl"). In some embodiments, an
alkyl group has 1 to 2 carbon atoms ("C.sub.1-2 alkyl"). In some
embodiments, an alkyl group has 1 carbon atom ("C.sub.1 alkyl"). In
some embodiments, an alkyl group has 2 to 6 carbon atoms
("C.sub.2-6 alkyl"). Examples of C.sub.1-6 alkyl groups include
methyl (C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), and n-hexyl (C.sub.6).
Additional examples of alkyl groups include n-heptyl (C.sub.7),
n-octyl (C.sub.8) and the like. Unless otherwise specified, each
instance of an alkyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a
"substituted alkyl") with one or more substituents; e.g., for
instance from 1 to 5 substituents, 1 to 3 substituents, or 1
substituent. In certain embodiments, the alkyl group is
unsubstituted C.sub.1-10 alkyl (e.g., --CH.sub.3). In certain
embodiments, the alkyl group is substituted C.sub.1-10 alkyl.
Common alkyl abbreviations include Me (--CH.sub.3), Et
(--CH.sub.2CH.sub.3), iPr (--CH(CH.sub.3).sub.2), nPr
(--CH.sub.2CH.sub.2CH.sub.3), n-Bu
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), or i-Bu
(--CH.sub.2CH(CH.sub.3).sub.2).
[0072] "Alkenyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon double bonds, and no triple bonds ("C.sub.2
2.sub.0 alkenyl"). In some embodiments, an alkenyl group has 2 to
10 carbon atoms ("C.sub.2-10 alkenyl"). In some embodiments, an
alkenyl group has 2 to 8 carbon atoms ("C.sub.2-8 alkenyl"). In
some embodiments, an alkenyl group has 2 to 6 carbon atoms
("C.sub.2-6 alkenyl"). In some embodiments, an alkenyl group has 2
to 5 carbon atoms ("C.sub.2-5 alkenyl"). In some embodiments, an
alkenyl group has 2 to 4 carbon atoms ("C.sub.2-4 alkenyl"). In
some embodiments, an alkenyl group has 2 to 3 carbon atoms
("C.sub.2-3 alkenyl"). In some embodiments, an alkenyl group has 2
carbon atoms ("C.sub.2 alkenyl"). The one or more carbon carbon
double bonds can be internal (such as in 2-butenyl) or terminal
(such as in 1-butenyl). Examples of C.sub.2-4 alkenyl groups
include ethenyl (C.sub.2), 1-propenyl (C.sub.3), 2-propenyl
(C.sub.3), 1-butenyl (C.sub.4), 2-butenyl (C.sub.4), butadienyl
(C.sub.4), and the like. Examples of C.sub.2-6 alkenyl groups
include the aforementioned C.sub.2-4 alkenyl groups as well as
pentenyl (C.sub.5), pentadienyl (C.sub.5), hexenyl (C.sub.6), and
the like. Additional examples of alkenyl include heptenyl
(C.sub.7), octenyl (C.sub.8), octatrienyl (C.sub.8), and the like.
Unless otherwise specified, each instance of an alkenyl group is
independently optionally substituted, i.e., unsubstituted (an
"unsubstituted alkenyl") or substituted (a "substituted alkenyl")
with one or more substituents e.g., for instance from 1 to 5
substituents, 1 to 3 substituents, or 1 substituent. In certain
embodiments, the alkenyl group is unsubstituted C.sub.2-10 alkenyl.
In certain embodiments, the alkenyl group is substituted C.sub.2-10
alkenyl.
[0073] "Alkynyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon triple bonds, and optionally one or more double
bonds ("C.sub.2-20 alkynyl"). In some embodiments, an alkynyl group
has 2 to 10 carbon atoms ("C.sub.2-10 alkynyl"). In some
embodiments, an alkynyl group has 2 to 8 carbon atoms ("C.sub.2-8
alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon
atoms ("C.sub.2-6 alkynyl"). In some embodiments, an alkynyl group
has 2 to 5 carbon atoms ("C.sub.2-5 alkynyl"). In some embodiments,
an alkynyl group has 2 to 4 carbon atoms ("C.sub.2-4 alkynyl").
[0074] In some embodiments, an alkynyl group has 2 to 3 carbon
atoms ("C.sub.2-3 alkynyl"). In some embodiments, an alkynyl group
has 2 carbon atoms ("C.sub.2 alkynyl"). The one or more carbon
carbon triple bonds can be internal (such as in 2-butynyl) or
terminal (such as in 1-butynyl). Examples of C.sub.2-4 alkynyl
groups include, without limitation, ethynyl (C.sub.2), 1-propynyl
(C.sub.3), 2-propynyl (C.sub.3), 1-butynyl (C.sub.4), 2-butynyl
(C.sub.4), and the like. Examples of C.sub.2-6 alkenyl groups
include the aforementioned C.sub.2-4 alkynyl groups as well as
pentynyl (C.sub.5), hexynyl (C.sub.6), and the like. Additional
examples of alkynyl include heptynyl (C.sub.7), octynyl (C.sub.8),
and the like. Unless otherwise specified, each instance of an
alkynyl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted alkynyl") or substituted (a
"substituted alkynyl") with one or more substituents; e.g., for
instance from 1 to 5 substituents, 1 to 3 substituents, or 1
substituent. In certain embodiments, the alkynyl group is
unsubstituted C.sub.2-10 alkynyl. In certain embodiments, the
alkynyl group is substituted C.sub.2-10 alkynyl.
[0075] "Aryl" refers to a radical of a monocyclic or polycyclic
(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g.,
having 6, 10, or 14 .pi. electrons shared in a cyclic array) having
6-14 ring carbon atoms and zero heteroatoms provided in the
aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an
aryl group has six ring carbon atoms ("C.sub.6 aryl"; e.g.,
phenyl). In some embodiments, an aryl group has ten ring carbon
atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and
2-naphthyl). In some embodiments, an aryl group has fourteen ring
carbon atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is
fused with one or more carbocyclyl or heterocyclyl groups wherein
the radical or point of attachment is on the aryl ring, and in such
instances, the number of carbon atoms continue to designate the
number of carbon atoms in the aryl ring system. Aryl groups
include, but are not limited to, phenyl, naphthyl, indenyl, and
tetrahydronaphthyl. Unless otherwise specified, each instance of an
aryl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted aryl") or substituted (a
"substituted aryl") with one or more substituents. In certain
embodiments, the aryl group is unsubstituted C.sub.6-14 aryl. In
certain embodiments, the aryl group is substituted C.sub.6-14
aryl.
[0076] In certain embodiments, an aryl group substituted with one
or more of groups selected from halo, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 haloalkyl, cyano, hydroxy, C.sub.1-C.sub.8 alkoxy,
and amino.
[0077] Examples of representative substituted aryls include the
following
##STR00026##
wherein one of R.sup.56 and R.sup.57 may be hydrogen and at least
one of R.sup.56 and R.sup.57 is each independently selected from
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 haloalkyl, 4-10 membered
heterocyclyl, alkanoyl, C.sub.1-C.sub.8 alkoxy, heteroaryloxy,
alkylamino, acylamino, heteroarylamino, NR.sup.58COR.sup.59,
NR.sup.58SOR.sup.59NR.sup.58SO.sub.2R.sup.59, COOalkyl, COOaryl,
CONR.sup.58R.sup.59, CONR.sup.58OR.sup.59, NR.sup.58R.sup.59,
SO.sub.2NR.sup.58R.sup.59, S-alkyl, SOalkyl, SO.sub.2 alkyl, Saryl,
SOaryl, SO.sub.2 aryl; or R.sup.56 and R.sup.57 may be joined to
form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,
optionally containing one or more heteroatoms selected from the
group N, O, or S. R.sup.60 and R.sup.61 are independently hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.10
cycloalkyl, 4-10 membered heterocyclyl, C.sub.6-C.sub.10 aryl,
substituted C.sub.6-C.sub.10 aryl, 5-10 membered heteroaryl, or
substituted 5-10 membered heteroaryl.
[0078] Other representative aryl groups having a fused heterocyclyl
group include the following:
##STR00027##
wherein each W is selected from C(R.sup.66).sub.2, NR.sup.66, O,
and S; and each Y is selected from carbonyl, NR.sup.66, O and S;
and R.sup.66 is independently hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, and 5-10 membered heteroaryl.
[0079] "Halo" or "halogen," independently or as part of another
substituent, mean, unless otherwise stated, a fluorine (F),
chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide"
by itself or as part of another substituent, refers to a fluoride,
chloride, bromide, or iodide atom. In certain embodiments, the halo
group is either fluorine or chlorine.
[0080] "Haloalkyl" and "haloalkoxy" can include alkyl and alkoxy
structures that are substituted with one or more halo groups or
with combinations thereof. For example, the terms "fluoroalkyl" and
"fluoroalkoxy" include haloalkyl and haloalkoxy groups,
respectively, in which the halo is fluorine.
[0081] "Hydroxy" or "hydroxyl," independently or as part of another
substituent, mean, unless otherwise stated, a --OH group.
[0082] Hydroxyalkyl" or "hydroxylalkyl" can include alkyl
structures that are substituted with one or more hydroxyl
groups.
[0083] "Heteroaryl" refers to a radical of a 5-10 membered
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10 .pi. electrons shared in a cyclic array) having ring carbon
atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In
heteroaryl groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. Heteroaryl bicyclic ring systems can include one or more
heteroatoms in one or both rings. "Heteroaryl" includes ring
systems wherein the heteroaryl ring, as defined above, is fused
with one or more carbocyclyl or heterocyclyl groups wherein the
point of attachment is on the heteroaryl ring, and in such
instances, the number of ring members continue to designate the
number of ring members in the heteroaryl ring system. "Heteroaryl"
also includes ring systems wherein the heteroaryl ring, as defined
above, is fused with one or more aryl groups wherein the point of
attachment is either on the aryl or heteroaryl ring, and in such
instances, the number of ring members designates the number of ring
members in the fused (aryl/heteroaryl) ring system. Bicyclic
heteroaryl groups wherein one ring does not contain a heteroatom
(e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of
attachment can be on either ring, i.e., either the ring bearing a
heteroatom (e.g., 2-indolyl) or the ring that does not contain a
heteroatom (e.g., 5-indolyl).
[0084] In some embodiments, a heteroaryl group is a 5-10 membered
aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from nitrogen, oxygen, and
sulfur ("5-10 membered heteroaryl"). In some embodiments, a
heteroaryl group is a 5-8 membered aromatic ring system having ring
carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur ("5-6
membered heteroaryl"). In some embodiments, the 5-6 membered
heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen,
and sulfur. In some embodiments, the 5-6 membered heteroaryl has
1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In
some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom
selected from nitrogen, oxygen, and sulfur. Unless otherwise
specified, each instance of a heteroaryl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
heteroaryl") or substituted (a "substituted heteroaryl") with one
or more substituents. In certain embodiments, the heteroaryl group
is unsubstituted 5-14 membered heteroaryl. In certain embodiments,
the heteroaryl group is substituted 5-14 membered heteroaryl.
[0085] Exemplary 5-membered heteroaryl groups containing one
heteroatom include, without limitation, pyrrolyl, furanyl and
thiophenyl. Exemplary 5-membered heteroaryl groups containing two
heteroatoms include, without limitation, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary
5-membered heteroaryl groups containing three heteroatoms include,
without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
Exemplary 5-membered heteroaryl groups containing four heteroatoms
include, without limitation, tetrazolyl. Exemplary 6-membered
heteroaryl groups containing one heteroatom include, without
limitation, pyridinyl. Exemplary 6-membered heteroaryl groups
containing two heteroatoms include, without limitation,
pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered
heteroaryl groups containing three or four heteroatoms include,
without limitation, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom
include, without limitation, azepinyl, oxepinyl, and thiepinyl.
Exemplary 5,6-bicyclic heteroaryl groups include, without
limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and
purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without
limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[0086] Examples of representative heteroaryls include the following
formulae:
##STR00028##
wherein each Y is selected from carbonyl, N, NR.sup.65, O, and S;
and R.sup.65 is independently hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, and 5-10 membered heteroaryl.
[0087] "Carbocyclyl" or "carbocyclic" refers to a radical of a
nonaromatic cyclic hydrocarbon group having from 3 to 10 ring
carbon atoms ("C.sub.3-10 carbocyclyl") and zero heteroatoms in the
nonaromatic ring system. In some embodiments, a carbocyclyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 carbocyclyl"). Exemplary C.sub.3-6 carbocyclyl groups
include, without limitation, cyclopropyl (C.sub.3), cyclopropenyl
(C.sub.3), cyclobutyl (C.sub.4), cyclobutenyl (C.sub.4),
cyclopentyl (C.sub.5), cyclopentenyl (C.sub.5), cyclohexyl
(C.sub.6), cyclohexenyl (C.sub.6), cyclohexadienyl (C.sub.6), and
the like. Exemplary C.sub.3-8 carbocyclyl groups include, without
limitation, the aforementioned C.sub.3-6 carbocyclyl groups as well
as cycloheptyl (C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl
(C.sub.7), cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8),
cyclooctenyl (C.sub.8), bicyclo[2.2.1]heptanyl (C.sub.7),
bicyclo[2.2.2]octanyl (C.sub.8), and the like. Exemplary C.sub.3-10
carbocyclyl groups include, without limitation, the aforementioned
C.sub.3-8 carbocyclyl groups as well as cyclononyl (C.sub.9),
cyclononenyl (C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl
(C.sub.10), octahydro-1H-indenyl (C.sub.9), decahydronaphthalenyl
(C.sub.10), spiro[4.5]decanyl (C.sub.10), and the like. As the
foregoing examples illustrate, in certain embodiments, the
carbocyclyl group is either monocyclic ("monocyclic carbocyclyl")
or contain a fused, bridged or spiro ring system such as a bicyclic
system ("bicyclic carbocyclyl") and can be saturated or can be
partially unsaturated. "Carbocyclyl" also includes ring systems
wherein the carbocyclyl ring, as defined above, is fused with one
or more aryl or heteroaryl groups wherein the point of attachment
is on the carbocyclyl ring, and in such instances, the number of
carbons continue to designate the number of carbons in the
carbocyclic ring system. Unless otherwise specified, each instance
of a carbocyclyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted
(a "substituted carbocyclyl") with one or more substituents. In
certain embodiments, the carbocyclyl group is unsubstituted
C.sub.3-10 carbocyclyl. In certain embodiments, the carbocyclyl
group is a substituted C.sub.3-10 carbocyclyl.
[0088] In some embodiments, "carbocyclyl" is a monocyclic,
saturated carbocyclyl group having from 3 to 10 ring carbon atoms
("C.sub.3-10 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 cycloalkyl"). In some
embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 cycloalkyl"). In some embodiments, a cycloalkyl group
has 5 to 6 ring carbon atoms ("C.sub.5-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 cycloalkyl"). Examples of C.sub.5-6 cycloalkyl groups
include cyclopentyl (C.sub.5) and cyclohexyl (C.sub.5). Examples of
C.sub.3-6 cycloalkyl groups include the aforementioned C.sub.5-6
cycloalkyl groups as well as cyclopropyl (C.sub.3) and cyclobutyl
(C.sub.4). Examples of C.sub.3-8 cycloalkyl groups include the
aforementioned C.sub.3-6 cycloalkyl groups as well as cycloheptyl
(C.sub.7) and cyclooctyl (C.sub.8). Unless otherwise specified,
each instance of a cycloalkyl group is independently unsubstituted
(an "unsubstituted cycloalkyl") or substituted (a "substituted
cycloalkyl") with one or more substituents. In certain embodiments,
the cycloalkyl group is unsubstituted C.sub.3-10 cycloalkyl. In
certain embodiments, the cycloalkyl group is substituted C.sub.3-10
cycloalkyl.
[0089] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3-
to 10-membered nonaromatic ring system having ring carbon atoms and
1 to 4 ring heteroatoms, wherein each heteroatom is independently
selected from nitrogen, oxygen, sulfur, boron, phosphorus, and
silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups that
contain one or more nitrogen atoms, the point of attachment can be
a carbon or nitrogen atom, as valency permits. A heterocyclyl group
can either be monocyclic ("monocyclic heterocyclyl") or a fused,
bridged or spiro ring system such as a bicyclic system ("bicyclic
heterocyclyl"), and can be saturated or can be partially
unsaturated. Heterocyclyl bicyclic ring systems can include one or
more heteroatoms in one or both rings. "Heterocyclyl" also includes
ring systems wherein the heterocyclyl ring, as defined above, is
fused with one or more carbocyclyl groups wherein the point of
attachment is either on the carbocyclyl or heterocyclyl ring, or
ring systems wherein the heterocyclyl ring, as defined above, is
fused with one or more aryl or heteroaryl groups, wherein the point
of attachment is on the heterocyclyl ring, and in such instances,
the number of ring members continue to designate the number of ring
members in the heterocyclyl ring system. Unless otherwise
specified, each instance of heterocyclyl is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
heterocyclyl") or substituted (a "substituted heterocyclyl") with
one or more substituents. In certain embodiments, the heterocyclyl
group is unsubstituted 3-10 membered heterocyclyl. In certain
embodiments, the heterocyclyl group is substituted 3-10 membered
heterocyclyl.
[0090] In some embodiments, a heterocyclyl group is a 5-10 membered
nonaromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10
membered heterocyclyl"). In some embodiments, a heterocyclyl group
is a 5-8 membered nonaromatic ring system having ring carbon atoms
and 1-4 ring heteroatoms, wherein each heteroatom is independently
selected from nitrogen, oxygen, and sulfur ("5-8 membered
heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6
membered nonaromatic ring system having ring carbon atoms and 1-4
ring heteroatoms, wherein each heteroatom is independently selected
from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In
some embodiments, the 5-6 membered heterocyclyl has 1-3 ring
heteroatoms selected from nitrogen, oxygen, and sulfur. In some
embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms
selected from nitrogen, oxygen, and sulfur. In some embodiments,
the 5-6 membered heterocyclyl has one ring heteroatom selected from
nitrogen, oxygen, and sulfur.
[0091] Exemplary 3-membered heterocyclyl groups containing one
heteroatom include, without limitation, azirdinyl, oxiranyl,
thiorenyl. Exemplary 4-membered heterocyclyl groups containing one
heteroatom include, without limitation, azetidinyl, oxetanyl and
thietanyl. Exemplary 5-membered heterocyclyl groups containing one
heteroatom include, without limitation, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary
5-membered heterocyclyl groups containing two heteroatoms include,
without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and
oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups
containing three heteroatoms include, without limitation,
triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary
6-membered heterocyclyl groups containing one heteroatom include,
without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl
groups containing two heteroatoms include, without limitation,
piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered
heterocyclyl groups containing two heteroatoms include, without
limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups
containing one heteroatom include, without limitation, azepanyl,
oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups
containing one heteroatom include, without limitation, azocanyl,
oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups
fused to a C.sub.6 aryl ring (also referred to herein as a
5,6-bicyclic heterocyclic ring) include, without limitation,
indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl
groups fused to an aryl ring (also referred to herein as a
6,6-bicyclic heterocyclic ring) include, without limitation,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
[0092] Particular examples of heterocyclyl groups are shown in the
following illustrative examples:
##STR00029##
wherein each W is selected from CR.sup.67, C(R.sup.67).sub.2,
NR.sup.67, O, and S; and each Y is selected from NR.sup.67, O, and
S; and R.sup.67 is independently hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, and 5-10-membered heteroaryl. These
heterocyclyl rings may be optionally substituted with one or more
groups selected from the group consisting of acyl, acylamino,
acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl (e.g., amido), aminocarbonylamino,
aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl,
cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, --S-alkyl,
--S-aryl, --S(O)-alkyl, --S(O)-aryl, --S(O).sub.2-alkyl, and
--S(O).sub.2-aryl. Substituting groups include carbonyl or
thiocarbonyl which provide, for example, lactam and urea
derivatives.
[0093] "Acyl" refers to a radical --C(O)R.sup.20, where R.sup.20 is
hydrogen, substituted or unsubstitued alkyl, substituted or
unsubstitued alkenyl, substituted or unsubstitued alkynyl,
substituted or unsubstitued carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstitued heteroaryl, as defined herein.
"Alkanoyl" is an acyl group wherein R.sup.20 is a group other than
hydrogen. Representative acyl groups include, but are not limited
to, formyl (--CHO), acetyl (--C(.dbd.O)CH.sub.3),
cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl
(--C(.dbd.O)Ph), benzylcarbonyl (--C(.dbd.O)CH.sub.2Ph),
--C(O)--C.sub.1-C.sub.8 alkyl,
--C(O)--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--C(O)--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--C(O)--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--C(O)--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein t is
an integer from 0 to 4. In certain embodiments, R.sup.21 is
C.sub.1-C.sub.8 alkyl, substituted with halo or hydroxy; or
C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, arylalkyl, 5-10 membered heteroaryl or
heteroarylalkyl, each of which is substituted with unsubstituted
C.sub.1-C.sub.4 alkyl, halo, unsubstituted C.sub.1-C.sub.4 alkoxy,
unsubstituted C.sub.1-C.sub.4 haloalkyl, unsubstituted
C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted C.sub.1-C.sub.4
haloalkoxy or hydroxy.
[0094] "Acylamino" refers to a radical --NR.sup.22C(O)R.sup.23,
where each instance of R.sup.22 and R.sup.23 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, as defined herein, or
R.sup.22 is an amino protecting group. Exemplary "acylamino" groups
include, but are not limited to, formylamino, acetylamino,
cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino,
benzoylamino and benzylcarbonylamino. Particular exemplary
"acylamino" groups are --NR.sup.24C(O)--C.sub.1-C.sub.8 alkyl,
--NR.sup.24C(O)--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--NR.sup.24C(O)--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--NR.sup.24C(O)--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--NR.sup.24C(O)--(CH.sub.2).sub.t(4-10 membered heterocyclyl),
wherein t is an integer from 0 to 4, and each R.sup.24
independently represents hydrogen or C.sub.1-C.sub.8 alkyl. In
certain embodiments, R.sup.25 is H, C.sub.1-C.sub.8 alkyl,
substituted with halo or hydroxy; C.sub.3-C.sub.10 cycloalkyl, 4-10
membered heterocyclyl, C.sub.6-C.sub.10 aryl, arylalkyl, 5-10
membered heteroaryl or heteroarylalkyl, each of which is
substituted with unsubstituted C.sub.1-C.sub.4 alkyl, halo,
unsubstituted C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4
haloalkyl, unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or
unsubstituted C.sub.1-C.sub.4 haloalkoxy or hydroxy; and R.sup.26
is H, C.sub.1-C.sub.8 alkyl, substituted with halo or hydroxy;
C.sub.3-C.sub.10 cycloalkyl, 4-10-membered heterocyclyl,
C.sub.6-C.sub.10 aryl, arylalkyl, 5-10-membered heteroaryl or
heteroarylalkyl, each of which is substituted with unsubstituted
C.sub.1-C.sub.4 alkyl, halo, unsubstituted C.sub.1-C.sub.4 alkoxy,
unsubstituted C.sub.1-C.sub.4 haloalkyl, unsubstituted
C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted C.sub.1-C.sub.4
haloalkoxy or hydroxy; provided at least one of R.sup.25 and
R.sup.26 is other than H.
[0095] "Acyloxy" refers to a radical --OC(O)R.sup.27, where
R.sup.27 is hydrogen, substituted or unsubstitued alkyl,
substituted or unsubstitued alkenyl, substituted or unsubstitued
alkynyl, substituted or unsubstitued carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstitued heteroaryl, as defined herein.
Representative examples include, but are not limited to, formyl,
acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and
benzylcarbonyl. In certain embodiments, R.sup.28 is C.sub.1-C.sub.8
alkyl, substituted with halo or hydroxy; C.sub.3-C.sub.10
cycloalkyl, 4-10-membered heterocyclyl, C.sub.6-C.sub.10 aryl,
arylalkyl, 5-10-membered heteroaryl or heteroarylalkyl, each of
which is substituted with unsubstituted C.sub.1-C.sub.4 alkyl,
halo, unsubstituted C.sub.1-C.sub.4 alkoxy, unsubstituted
C.sub.1-C.sub.4 haloalkyl, unsubstituted C.sub.1-C.sub.4
hydroxyalkyl, or unsubstituted C.sub.1-C.sub.4 haloalkoxy or
hydroxy.
[0096] "Alkoxy" refers to the group --OR.sup.29 where R.sup.29 is
substituted or unsubstituted alkyl, substituted or unsubstitued
alkenyl, substituted or unsubstitued alkynyl, substituted or
unsubstitued carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstitued heteroaryl. Particular alkoxy groups are methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy
groups are lower alkoxy, i.e., with between 1 and 6 carbon atoms.
Further particular alkoxy groups have between 1 and 4 carbon
atoms.
[0097] In certain embodiments, R.sup.29 is a group that has 1 or
more substituents, for instance from 1 to 5 substituents, and
particularly from 1 to 3 substituents, in particular 1 substituent,
selected from the group consisting of amino, substituted amino,
C.sub.6-C.sub.10 aryl, aryloxy, carboxyl, cyano, C.sub.3-C.sub.10
cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered
heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--. Exemplary "substituted alkoxy" groups include,
but are not limited to, --O--(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), --O--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--O--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--O--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein t is an
integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or
heterocyclyl groups present, may themselves be substituted by
unsubstituted C.sub.1-C.sub.4 alkyl, halo, unsubstituted
C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4 haloalkyl,
unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted
C.sub.1-C.sub.4 haloalkoxy or hydroxy. Particular exemplary
`substituted alkoxy` groups are --OCF.sub.3, --OCH.sub.2CF.sub.3,
--OCH.sub.2Ph, --OCH.sub.2-cyclopropyl, --OCH.sub.2CH.sub.2OH, and
--OCH.sub.2CH.sub.2NMe.sub.2.
[0098] "Amino" refers to the radical --NH.sub.2.
[0099] "Substituted amino" refers to an amino group of the formula
--N(R.sup.38).sub.2 wherein R.sup.38 is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, or
an amino protecting group, wherein at least one of R.sup.38 is not
a hydrogen. In certain embodiments,
each R.sup.38 is independently selected from hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 alkenyl, C.sub.3-C.sub.8
alkynyl, C.sub.6-C.sub.10 aryl, 5-10 membered heteroaryl, 4-10
membered heterocyclyl, or C.sub.3-C.sub.10 cycloalkyl; or
C.sub.1-C.sub.8 alkyl, substituted with halo or hydroxy;
C.sub.3-C.sub.8 alkenyl, substituted with halo or hydroxy;
C.sub.3-C.sub.8 alkynyl, substituted with halo or hydroxy, or
--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl), --(CH.sub.2).sub.t(5-10
membered heteroaryl), --(CH.sub.2).sub.t(C.sub.3-C.sub.10
cycloalkyl), or --(CH.sub.2).sub.t(4-10 membered heterocyclyl),
wherein t is an integer between 0 and 8, each of which is
substituted by unsubstituted C.sub.1-C.sub.4 alkyl, halo,
unsubstituted C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4
haloalkyl, unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or
unsubstituted C.sub.1-C.sub.4 haloalkoxy or hydroxy; or both
R.sup.38 groups are joined to form an alkylene group.
[0100] Exemplary "substituted amino" groups include, but are not
limited to, --NR.sup.39--C.sub.1-C.sub.8 alkyl,
--NR.sup.39--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--NR.sup.39--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--NR.sup.39--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--NR.sup.39--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein
t is an integer from 0 to 4, for instance 1 or 2, each R.sup.39
independently represents hydrogen or C.sub.1-C.sub.8 alkyl; and any
alkyl groups present, may themselves be substituted by halo,
substituted or unsubstituted amino, or hydroxy; and any aryl,
heteroaryl, cycloalkyl, or heterocyclyl groups present, may
themselves be substituted by unsubstituted C.sub.1-C.sub.4 alkyl,
halo, unsubstituted C.sub.1-C.sub.4 alkoxy, unsubstituted
C.sub.1-C.sub.4 haloalkyl, unsubstituted C.sub.1-C.sub.4
hydroxyalkyl, or unsubstituted C.sub.1-C.sub.4 haloalkoxy or
hydroxy. For the avoidance of doubt the term `substituted amino`
includes the groups alkylamino, substituted alkylamino,
alkylarylamino, substituted alkylarylamino, arylamino, substituted
arylamino, dialkylamino, and substituted dialkylamino as defined
below. Substituted amino encompasses both monosubstituted amino and
disubstituted amino groups.
[0101] "Azido" refers to the radical --N.sub.3.
[0102] "Carbamoyl" or "amido" refers to the radical
--C(O)NH.sub.2.
[0103] "Substituted carbamoyl" or "substituted amido" refers to the
radical --C(O)N(R.sup.62).sub.2 wherein each R.sup.62 is
independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstitued alkenyl, substituted or unsubstitued
alkynyl, substituted or unsubstitued carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstitued heteroaryl, or an amino protecting
group, wherein at least one of R.sup.62 is not a hydrogen. In
certain embodiments, R.sup.62 is selected from H, C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, and 5-10 membered heteroaryl; or
C.sub.1-C.sub.8 alkyl substituted with halo or hydroxy; or
C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, or 5-10 membered heteroaryl, each of which
is substituted by unsubstituted C.sub.1-C.sub.4 alkyl, halo,
unsubstituted C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4
haloalkyl, unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or
unsubstituted C.sub.1-C.sub.4 haloalkoxy or hydroxy; provided that
at least one R.sup.62 is other than H.
[0104] "Carboxy" refers to the radical --C(O)OH.
[0105] "Cyano" refers to the radical --CN.
[0106] "Oxo" refers to .dbd.O.
[0107] "Nitro" refers to the radical --NO.sub.2.
[0108] "Ethenyl" refers to substituted or unsubstituted
--(C.dbd.C)--. "Ethylene" refers to substituted or unsubstituted
--(C--C)--. "Ethynyl" refers to --(C.ident.C)--.
[0109] "Nitrogen-containing heterocyclyl" group means a 4- to
7-membered nonaromatic cyclic group containing at least one
nitrogen atom, for example, but without limitation, morpholine,
piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl),
pyrrolidine (e.g. 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine,
pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline,
pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl
piperazine. Particular examples include azetidine, piperidone and
piperazone.
[0110] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups, as defined herein, are optionally
substituted (e.g., "substituted" or "unsubstituted" alkyl,
"substituted" or "unsubstituted" alkenyl, "substituted" or
"unsubstituted" alkynyl, "substituted" or "unsubstituted"
carbocyclyl, "substituted" or "unsubstituted" heterocyclyl,
"substituted" or "unsubstituted" aryl or "substituted" or
"unsubstituted" heteroaryl group). In general, the term
"substituted", whether preceded by the term "optionally" or not,
means that at least one hydrogen present on a group (e.g., a carbon
or nitrogen atom) is replaced with a permissible substituent, e.g.,
a substituent which upon substitution results in a stable compound,
e.g., a compound which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
or other reaction. Unless otherwise indicated, a "substituted"
group has a substituent at one or more substitutable positions of
the group, and when more than one position in any given structure
is substituted, the substituent is either the same or different at
each position. The term "substituted" is contemplated to include
substitution with all permissible substituents of organic
compounds, any of the substituents described herein that results in
the formation of a stable compound. The present invention
contemplates any and all such combinations in order to arrive at a
stable compound. For purposes of this invention, heteroatoms such
as nitrogen may have hydrogen substituents and/or any suitable
substituent as described herein which satisfy the valencies of the
heteroatoms and results in the formation of a stable moiety.
[0111] Exemplary carbon atom substituents include, but are not
limited to, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H,
--SO.sub.3H, --OH, --OR.sup.aa, --ON(R.sup.bb).sub.2,
--N(R.sup.bb).sub.2, --N(R.sup.bb).sub.3.sup.+X.sup.-,
--N(OR.sup.cc)R.sup.bb--SH, --SR.sup.aa, --SSR.sup.cc,
--C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO, --C(OR.sub.cc).sub.2,
--CO.sub.2R.sup.aa, --OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.O)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.O)R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bb)OR.sup.aa,
--C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa,
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa,
--SO.sub.2OR.sup.aa, --OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa,
--OS(.dbd.O)R.sup.aa, --Si(R.sup.aa).sub.3,
--OSi(R.sup.aa).sub.3--C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa,
--SC(.dbd.O)SR.sup.aa, --OC(.dbd.O)SR.sup.aa,
--SC(.dbd.O)OR.sup.aa, --SC(.dbd.O)R.sup.aa,
--P(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
--OP(.dbd.O).sub.2N(R.sup.bb).sub.2, --P(.dbd.O)(NR.sup.bb).sub.2,
--OP(.dbd.O)(NR.sup.bb).sub.2,
--NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
--NR.sup.bbP(.dbd.O)(NR.sup.bb).sub.2, --P(R.sup.cc).sub.2,
--P(R.sup.cc).sub.3, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--B(R.sup.aa).sub.2, --B(OR.sup.cc).sub.2, --BR.sup.aa(OR.sup.cc),
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.310 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups;
[0112] each instance of R.sup.aa is, independently, selected from
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.aa groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0113] each instance of R.sup.bb is, independently, selected from
hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.bb groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0114] each instance of R.sup.cc is, independently, selected from
hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.C groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0115] each instance of R.sup.dd is, independently, selected from
halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H,
--OH, --OR.sup.ee, --ON(R).sub.2, --N(R).sub.2,
--N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff, --SH,
--SR.sup.ee, --SSR.sup.ee, --C(.dbd.O)R.sup.ee, --CO.sub.2H,
--CO.sub.2R.sup.ee, --OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee,
--C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee,
--NR.sup.ffC(.dbd.O)N(R).sub.2, --C(.dbd.NR.sup.ff)OR.sup.ee,
--OC(.dbd.NR.sup.ff)R.sup.ee--OC(.dbd.NR.sup.ff)OR.sup.ee,
--C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffSO.sub.2R.sup.ee--SO.sub.2N(R.sup.ff).sub.2,
--SO.sub.2R.sup.ee, --SO.sub.2OR.sup.ee, --OSO.sub.2R.sup.ee,
--S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi(R.sup.ee).sub.3,
--C(.dbd.S)N(R).sub.2, --C(.dbd.O)SR.sup.ee, --C(.dbd.S)SR.sup.ee,
--SC(.dbd.S)SR.sup.ee, --P(.dbd.O).sub.2R.sup.ee,
--P(.dbd.O)(R.sup.ee).sub.2, --OP(.dbd.O)(R.sup.ee).sub.2,
--OP(.dbd.O)(OR.sup.ee).sub.2, C.sub.1-6 alkyl, C.sub.1-6
perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
carbocyclyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
[0116] each instance of R.sup.ee is, independently, selected from
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10
membered heterocyclyl, and 3-10 membered heteroaryl, wherein each
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups;
[0117] each instance of R.sup.ff is, independently, selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl and 5-10 membered heteroaryl, or two
R.sup.ff groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0118] each instance of R.sup.gg is, independently, halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1-6
alkyl, --ON(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl).sub.2,
--N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, --NH(C.sub.1-6
alkyl).sub.2.sup.+X.sup.-, --NH.sub.2(C.sub.1-6
alkyl).sub.3.sup.+X.sup.-, --NH.sub.3.sup.+X.sup.-, --N(OC.sub.1-6
alkyl)(C.sub.1-6 alkyl), --N(OH)(C.sub.1-6 alkyl), --NH(OH), --SH,
--SC.sub.1-6 alkyl, --SS(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-6
alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6 alkyl),
--OC(.dbd.O)(C.sub.1-6 alkyl), --OCO.sub.2(C.sub.1-6 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)N(C.sub.1-6 alkyl).sub.2,
--OC(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl)C(.dbd.O)(C.sub.1-6 alkyl),
--NHCO.sub.2(C.sub.1-6 alkyl), --NHC(.dbd.O)N(C.sub.1-6
alkyl).sub.2, --NHC(.dbd.O)NH(C.sub.1-6 alkyl),
--NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl),
--OC(.dbd.NH)(C.sub.1-6 alkyl), --OC(.dbd.NH)OC.sub.1-6 alkyl,
--C(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6
alkyl), --C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6
alkyl).sub.2, --OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2,
--NHC(NH)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2,
--NHSO.sub.2(C.sub.1-6 alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2,
--SO.sub.2NH(C.sub.1-6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2C.sub.1-6 alkyl, --SO.sub.2OC.sub.1-6 alkyl,
--OSO.sub.2C.sub.1-6 alkyl, --SOC.sub.1-6 alkyl, --Si(C.sub.1-6
alkyl).sub.3, --OSi(C.sub.1-6 alkyl).sub.3--C(.dbd.S)N(C.sub.1-6
alkyl).sub.2, C(.dbd.S)NH(C.sub.1-6 alkyl), C(.dbd.S)NH.sub.2,
--C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl,
--SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O).sub.2(C.sub.1-6 alkyl),
--P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6
alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered
heterocyclyl, 5-10 membered heteroaryl; wherein X.sup.- is a
counterion.
[0119] A "counterion" or "anionic counterion" is a negatively
charged group associated with a cationic quaternary amino group in
order to maintain electronic neutrality. Exemplary counterions
include halide ions (e.g., F.sup.-, Cl.sup.-, Br.sup.-, I.sup.-),
NO.sub.3.sup.-, ClO.sub.4.sup.-, OH.sup.-, H.sub.2PO.sub.4.sup.-,
HSO.sub.4.sup.-, sulfonate ions (e.g., methansulfonate,
trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate,
10-camphor sulfonate, naphthalene-2-sulfonate,
naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic
acid-2-sulfonate, and the like), and carboxylate ions (e.g.,
acetate, ethanoate, propanoate, benzoate, glycerate, lactate,
tartrate, glycolate, and the like).
[0120] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quarternary nitrogen atoms. Exemplary nitrogen atom substitutents
include, but are not limited to, hydrogen, --OH, --OR.sup.aa,
--N(R.sup.cc).sub.2, --CN, --C(.dbd.O)R.sup.aa,
--C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa,
--SO.sub.2R.sup.aa, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14-membered heteroaryl, or two
R.sup.cc groups attached to a nitrogen atom are joined to form a
3-14-membered heterocyclyl or 5-14-membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups, and wherein R.sup.aa, R.sup.bb, R.sup.cc
and R.sup.dd are as defined above.
[0121] In certain embodiments, the substituent present on a
nitrogen atom is an amino protecting group (also referred to herein
as a nitrogen protecting group). Amino protecting groups include,
but are not limited to, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)OR.sup.aa,
--C(.dbd.O)N(R.sup.cc).sub.2, --S(.dbd.O).sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)R.sup.aa, --C(.dbd.NR.sup.cc)OR.sup.aa,
--C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2, --SO.sub.2N(R.sup.cc).sub.2,
--SO.sub.2R.sup.cc, --SO.sub.2OR.sup.cc, --SOR.sup.aa,
--C(.dbd.S)N(R.sup.cc).sub.2, --C(.dbd.O)SR.sup.cc,
--C(.dbd.S)SR.sup.cc, C.sub.1-10 alkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14-membered
heterocyclyl, C.sub.6-14 aryl, and 5-14-membered heteroaryl groups,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups, and wherein R.sup.aa, R.sup.bb, R.sup.cc
and R.sup.dd are as defined herein. Amino protecting groups are
well known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0122] Exemplary amino protecting groups include, but are not
limited to amide groups (e.g., --C(.dbd.O)R.sup.aa), which include,
but are not limited to, formamide and acetamide; carbamate groups
(e.g., --C(.dbd.O)OR.sup.aa), which include, but are not limited
to, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC),
and benzyl carbamate (Cbz); sulfonamide groups (e.g.,
--S(.dbd.O).sub.2R.sup.aa), which include, but are not limited to,
p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and
N-[2-(trimethylsilyl)ethoxy]methylamine (SEM).
[0123] In certain embodiments, the substituent present on an oxygen
atom is an oxygen protecting group (also referred to as a hydroxyl
protecting group). Oxygen protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein. Oxygen protecting groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0124] Exemplary oxygen protecting groups include, but are not
limited to, methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl
(MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl
(TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate
(mesylate), and tosylate (Ts).
[0125] In certain embodiments, the substituent present on an sulfur
atom is an sulfur protecting group (also referred to as a thiol
protecting group). Sulfur protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein. Sulfur protecting groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0126] These and other exemplary substituents are described in more
detail in the Detailed Description, Examples, and Claims. The
invention is not intended to be limited in any manner by the above
exemplary listing of substituents.
Other Definitions
[0127] As used herein, the term "modulation" refers to the
inhibition or potentiation of GABA receptor function. A "modulator"
(e.g., a modulator compound) may be, for example, an agonist,
partial agonist, antagonist, or partial antagonist of the GABA
receptor.
[0128] "Pharmaceutically acceptable" means approved or approvable
by a regulatory agency of the Federal or a state government or the
corresponding agency in countries other than the United States, or
that is listed in the U.S. Pharmacopoeia or other generally
recognized pharmacopoeia for use in animals, and more particularly,
in humans.
[0129] "Pharmaceutically acceptable salt" refers to a salt of a
compound of the invention that is pharmaceutically acceptable and
that possesses the desired pharmacological activity of the parent
compound. In particular, such salts are non-toxic may be inorganic
or organic acid addition salts and base addition salts.
Specifically, such salts include: (1) acid addition salts, formed
with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the like.
Salts further include, by way of example only, sodium, potassium,
calcium, magnesium, ammonium, tetraalkylammonium, and the like; and
when the compound contains a basic functionality, salts of
non-toxic organic or inorganic acids, such as hydrochloride,
hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the
like. The term "pharmaceutically acceptable cation" refers to an
acceptable cationic counter-ion of an acidic functional group. Such
cations are exemplified by sodium, potassium, calcium, magnesium,
ammonium, tetraalkylammonium cations, and the like. See, e.g.,
Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.
[0130] "Solvate" refers to forms of the compound that are
associated with a solvent or water (also referred to as "hydrate"),
usually by a solvolysis reaction. This physical association
includes hydrogen bonding. Conventional solvents include water,
ethanol, acetic acid, and the like. The compounds of the invention
may be prepared e.g. in crystalline form and may be solvated or
hydrated. Suitable solvates include pharmaceutically acceptable
solvates, such as hydrates, and further include both stoichiometric
solvates and non-stoichiometric solvates. In certain instances the
solvate will be capable of isolation, for example when one or more
solvent molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolable solvates. Representative solvates include hydrates,
ethanolates and methanolates.
[0131] "Stereoisomers": It is also to be understood that compounds
that have the same molecular formula but differ in the nature or
sequence of bonding of their atoms or the arrangement of their
atoms in space are termed "isomers." Isomers that differ in the
arrangement of their atoms in space are termed "stereoisomers."
Stereoisomers that are not mirror images of one another are termed
"diastereomers" and those that are non-superimposable mirror images
of each other are termed "enantiomers." When a compound has an
asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0132] "Tautomers" refer to compounds that are interchangeable
forms of a particular compound structure, and that vary in the
displacement of hydrogen atoms and electrons. Thus, two structures
may be in equilibrium through the movement of it electrons and an
atom (usually H). For example, enols and ketones are tautomers
because they are rapidly interconverted by treatment with either
acid or base. Another example of tautomerism is the aci- and
nitro-forms of phenylnitromethane, that are likewise formed by
treatment with acid or base. Tautomeric forms may be relevant to
the attainment of the optimal chemical reactivity and biological
activity of a compound of interest.
[0133] A "subject" to which administration is contemplated
includes, but is not limited to, humans (i.e., a male or female of
any age group, e.g., a pediatric subject (e.g, infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult
or senior adult)) and/or a non-human animal, e.g., a mammal such as
primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs,
horses, sheep, goats, rodents, cats, and/or dogs. In certain
embodiments, the subject is a human. In certain embodiments, the
subject is a non-human animal. The terms "human," "patient," and
"subject" are used interchangeably herein.
[0134] Disease, disorder, and condition are used interchangeably
herein.
[0135] As used herein, and unless otherwise specified, the terms
"treat," "treating" and "treatment" contemplate an action that
occurs while a subject is suffering from the specified disease,
disorder or condition, which reduces the severity of the disease,
disorder or condition, or retards or slows the progression of the
disease, disorder or condition ("therapeutic treatment"), and also
contemplates an action that occurs before a subject begins to
suffer from the specified disease, disorder or condition
("prophylactic treatment").
[0136] In general, the "effective amount" of a compound refers to
an amount sufficient to elicit the desired biological response,
e.g., to treat a CNS-related disorder, is sufficient to induce
anesthesia or sedation. As will be appreciated by those of ordinary
skill in this art, the effective amount of a compound of the
invention may vary depending on such factors as the desired
biological endpoint, the pharmacokinetics of the compound, the
disease being treated, the mode of administration, and the age,
weight, health, and condition of the subject. An effective amount
encompasses therapeutic and prophylactic treatment.
[0137] As used herein, and unless otherwise specified, a
"therapeutically effective amount" of a compound is an amount
sufficient to provide a therapeutic benefit in the treatment of a
disease, disorder or condition, or to delay or minimize one or more
symptoms associated with the disease, disorder or condition. A
therapeutically effective amount of a compound means an amount of
therapeutic agent, alone or in combination with other therapies,
which provides a therapeutic benefit in the treatment of the
disease, disorder or condition. The term "therapeutically effective
amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease or condition, or
enhances the therapeutic efficacy of another therapeutic agent.
[0138] As used herein, and unless otherwise specified, a
"prophylactically effective amount" of a compound is an amount
sufficient to prevent a disease, disorder or condition, or one or
more symptoms associated with the disease, disorder or condition,
or prevent its recurrence. A prophylactically effective amount of a
compound means an amount of a therapeutic agent, alone or in
combination with other agents, which provides a prophylactic
benefit in the prevention of the disease, disorder or condition.
The term "prophylactically effective amount" can encompass an
amount that improves overall prophylaxis or enhances the
prophylactic efficacy of another prophylactic agent.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0139] Provided herein are compounds (e.g., a compound of Formula
(I), a compound of Formula (V), or a compound of Formula (IX)),
pharmaceutical compositions, and their methods of use to treat a
disease or disorder as described herein.
Compounds
[0140] Compounds described herein are generally designed to
modulate GABA function, and therefore to act as neuroactive
steroids for the treatment and prevention of CNS-related conditions
in a subject. Modulation, as used herein, refers to the inhibition
or potentiation of GABA receptor function. Accordingly, the
compounds and pharmaceutical compositions provided herein find use
as therapeutics for preventing and/or treating CNS conditions in
mammals including humans and non-human mammals. Thus, and as stated
earlier, the present invention includes within its scope, and
extends to, the recited methods of treatment, as well as to the
compounds for such methods, and to the use of such compounds for
the preparation of medicaments useful for such methods.
[0141] In an aspect, provided herein is a compound of Formula
(I):
##STR00030##
[0142] or a pharmaceutically acceptable salt thereof, wherein
represents a single or double bond as valency permits; each of
R.sup.2, R.sup.4, R.sup.6, R.sup.11a, and R.sup.11b is
independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, --OR.sup.A1,
--SR.sup.A1, --N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(.dbd.O).sub.2OR.sup.A1, wherein each instance of R.sup.A1 is
independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, a nitrogen protecting group when attached to a
nitrogen atom, or two R.sup.A1 groups are joined to form an
heterocyclic or heteroaryl ring; and R.sup.A2 is alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or
R.sup.11a and R.sup.11b together form oxo; R.sup.3 is hydrogen,
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or
heteroaryl; R.sup.5 is absent or hydrogen; and represents a single
or double bond, wherein when one of at site is a double bond, the
other is a single bond; when both of are single bonds, then R.sup.5
is hydrogen; and when one of the is a double bond, R.sup.5 is
absent; R.sup.17 is alkoxy, cyano, nitro, aryl, heteroaryl, or
--C(O)R.sup.B1, --C(O)CH.sub.2R.sup.B1, or
--C(O)CH.sub.2CH.sub.2R.sup.B1, wherein R.sup.B1 is hydrogen, --OH,
alkoxy, aryl, or heteroaryl; R.sup.19 is hydrogen or alkyl; and
R.sup.7 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, heteroaryl, --OR.sup.A1,
--SR.sup.A1, --N(R.sup.A1).sub.2,
--NHC(.dbd.O)R.sup.A1--NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1.
[0143] In some embodiments, R.sup.3 is alkyl.
[0144] In some embodiments, the compound of Formula (I) is a
compound of Formula (I-a) or (I-b):
##STR00031##
[0145] In some embodiments, each of R.sup.2, R.sup.4, and R.sup.6,
R.sup.11a, and R.sup.11b is independently hydrogen;
[0146] In some embodiments, R.sup.2, R.sup.4, R.sup.6, R.sup.11a,
and R.sup.11b are all hydrogen. In some embodiments, each of
R.sup.2, R.sup.4, and R.sup.6 is independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, or --OH; In some
embodiments, R.sup.3 is C.sub.1-C.sub.6 alkyl (e.g. C.sub.1-C.sub.6
haloalkyl or --CH.sub.3).
[0147] In some embodiments, the compound of Formula (I) is a
compound of Formula (II-a) or (II-b):
##STR00032##
[0148] In some embodiments, the compound of Formula (I) is a
compound of Formula (II-c) or (II-d):
##STR00033##
In some embodiments, R.sup.19 is --CH.sub.3. In some embodiments,
R.sup.7 is alkyl (e.g., unsubstituted alkyl or --CH.sub.2OR.sup.A1)
or --OR.sup.A1. In some embodiments, R.sup.7 is --CH.sub.3,
--CH.sub.2CH.sub.3, --OH, --OCH.sub.3, or --CH.sub.2OCH.sub.3. In
some embodiments, R.sup.17 is --OCH.sub.3, --CN, or --C(O)CH.sub.3.
In some embodiments, R.sup.17 is --C(O)CH.sub.2R.sup.C1. In some
embodiments, R.sup.17 is --C(O)CH.sub.2R.sup.B1. In some
embodiments, R.sup.17 is alkoxy, cyano, or --C(O)R.sup.B1. In some
embodiments, R.sup.B1 is pyrazolyl (e.g., a cyano-substituted
pyrazolyl). In some embodiments, R.sup.B1 is tetrazolyl (e.g., a
methyl-substituted tetrazolyl). In some embodiments, R.sup.B1 is a
bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic
heteroaryl. In some embodiments, R.sup.B1 is
##STR00034##
In some embodiments, R.sup.B1 is
##STR00035##
[0149] In some embodiments, R.sup.6 is halogen. In some
embodiments, R.sup.6 is fluorine.
[0150] In some embodiments, each of R.sup.11a and R.sup.11b is
independently hydrogen, C.sub.1-C.sub.6 alkyl (e.g. C.sub.1-C.sub.6
haloalkyl), C.sub.1-C.sub.6 alkoxy (e.g. C.sub.1-C.sub.6
alkoxyhalo), or --OH. In some embodiments, R.sup.11a and R.sup.11b
together form oxo. In some embodiments, R.sup.17 is C.sub.1-C.sub.6
alkoxy (e.g. --OCH.sub.3), cyano, or nitro. In some embodiments,
R.sup.19 is hydrogen or substituted or unsubstituted
C.sub.1-C.sub.6 alkyl (e.g. --CH.sub.2OR.sup.X, wherein R.sup.X is
hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy).
[0151] In some embodiments, the compound of Formula (I) is a
compound of Formula (III-a) or (III-b):
##STR00036##
wherein R.sup.a is hydrogen, halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3), or --OH. In some embodiments, the compound of Formula
(I) is a compound of Formula (IV-a) or (IV-b):
##STR00037##
wherein: m is 0, 1, or 2; n is 0, 1, or 2; each R.sup.b is
independently hydrogen, halogen, or C.sub.1-C.sub.6 alkyl; and each
R.sup.c is independently halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3 or C.sub.1-C.sub.6 haloalkyl), C.sub.1-C.sub.6 alkoxy,
cyano, or --OH. In some embodiments, A is a 5-10-membered ring. In
some embodiments, A is a fused bicyclic ring. In some embodiments,
A is monocyclic heteroaryl or bicyclic heteroaryl.
[0152] In an aspect, provided is a compound of Formula (V):
##STR00038##
or a pharmaceutically acceptable salt thereof, wherein, represents
a single or double bond as valency permits; each of R.sup.2,
R.sup.4, R.sup.6, R.sup.11a, and R.sup.11b is independently
hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, heteroaryl, --OR.sup.A1,
--SR.sup.A1, --N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(O).sub.2OR.sup.A1, wherein each instance of R.sup.A1 is
independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, a nitrogen protecting group when attached to a
nitrogen atom, or two R.sup.A1 groups are joined to form an
heterocyclic or heteroaryl ring; and R.sup.A2 is alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or
R.sup.11a and R.sup.11b together form oxo; R.sup.3 is hydrogen,
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or
heteroaryl; R.sup.5 is absent or hydrogen; and represents a single
or double bond, wherein when one of at site is a double bond, the
other is a single bond; when both of are single bonds, then R.sup.5
is hydrogen; and when one of the is a double bond, R.sup.5 is
absent; R.sup.17 is alkoxy, cyano, nitro, aryl, heteroaryl,
--C(O)R.sup.B1, --C(O)CH.sub.2R.sup.B1, or
--C(O)CH.sub.2CH.sub.2R.sup.B1, wherein R.sup.B1 is hydrogen, --OH,
alkoxy, aryl, or heteroaryl; R.sup.19 is hydrogen or alkyl; and
R.sup.12 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, heteroaryl, --OR, --SR.sup.A1,
--N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1, --NHC(.dbd.O)OR.sup.A1,
--S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(.dbd.O).sub.2OR.sup.A1.
[0153] In some embodiments, R.sup.3 is alkyl.
[0154] In some embodiments, the compound of Formula (V) is a
compound of Formula (V-a) or (V-b):
##STR00039##
In some embodiments, each of R.sup.2, R.sup.4, R.sup.6, R.sup.11a,
and R.sup.11b is independently hydrogen. In some embodiments,
R.sup.2, R.sup.4, R.sup.6, R.sup.11a, and R.sup.11b are all
hydrogen. In some embodiments, each of R.sup.2, R.sup.4, and
R.sup.6 is independently halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, or --OH. In some embodiments, R.sup.3 is
C.sub.1-C.sub.6 alkyl (e.g. C.sub.1-C.sub.6 haloalkyl or
--CH.sub.3). In some embodiments, the compound of Formula (V) is a
compound of Formula (VI-a) or (VI-b):
##STR00040##
In some embodiments, the compound of Formula (V) is a compound of
Formula (VI-c) or (VI-d):
##STR00041##
In some embodiments, R.sup.19 is --CH.sub.3. In some embodiments,
R.sup.12 is --OR.sup.A1. In some embodiments, R.sup.12 is
--CH.sub.3, --CH.sub.2CH.sub.3, --OH, --OCH.sub.3, or
--CH.sub.2OCH.sub.3. In some embodiments, R.sup.17 is --OCH.sub.3,
--CN, or --C(O)CH.sub.3. In some embodiments, R.sup.17 is
--C(O)CH.sub.2R.sup.C1. In some embodiments, R.sup.17 is
--C(O)CH.sub.2R.sup.B1. In some embodiments, R.sup.17 is alkoxy,
cyano, or --C(O)R.sup.B1.
[0155] In some embodiments, R.sup.B1 is pyrazolyl (e.g., a
cyano-substituted pyrazolyl). In some embodiments, R.sup.B1 is
tetrazolyl (e.g., a methyl-substituted tetrazolyl). In some
embodiments, R.sup.B1 is a bicyclic heteroaryl (e.g., a
methoxy-substituted bicyclic heteroaryl. In some embodiments,
R.sup.B1 is
##STR00042##
In some embodiments, R.sup.B1 is
##STR00043##
[0156] In some embodiments, R.sup.6 is halogen. In some
embodiments, R.sup.6 is fluorine.
[0157] In some embodiments, each of R.sup.11a and R.sup.11b is
independently hydrogen, C.sub.1-C.sub.6 alkyl (e.g. C.sub.1-C.sub.6
haloalkyl), C.sub.1-C.sub.6 alkoxy (e.g. C.sub.1-C.sub.6
haloalkoxy), or --OH. In some embodiments, R.sup.11a and R.sup.11b
together form oxo. In some embodiments, R.sup.17 is C.sub.1-C.sub.6
alkoxy (e.g. --OCH.sub.3) or cyano. In some embodiments, R.sup.19
is hydrogen or substituted or unsubstituted C.sub.1-C.sub.6 alkyl
(e.g. --CH.sub.2OR.sup.X, wherein R.sup.X is hydrogen,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy). In some
embodiments, the compound of Formula (V) is a compound of Formula
(VII-a) or (VII-b):
##STR00044##
wherein R.sup.a is hydrogen, halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3), or --OH. In some embodiments, the compound of Formula
(V) is a compound of Formula (VIII-a) or (VIII-b):
##STR00045##
wherein m is 0, 1, or 2, n is 0, 1, or 2, and each R.sup.b is
independently hydrogen, halogen, or C.sub.1-C.sub.6 alkyl; and each
R.sup.c is independently halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3 or C.sub.1-C.sub.6 haloalkyl), C.sub.1-C.sub.6 alkoxy,
cyano, or --OH.
[0158] In some embodiments, A is a 5-10-membered ring. In some
embodiments, A is a fused bicyclic ring. In some embodiments, A is
monocyclic heteroaryl or bicyclic heteroaryl.
[0159] In an aspect, provided herein is a compound of Formula
(IX):
##STR00046##
[0160] or a pharmaceutically acceptable salt thereof, wherein
represents a single or double bond as valency permits; each of
R.sup.2, R.sup.4, R.sup.6, R.sup.11a, and R.sup.11b is
independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, --OR.sup.A1,
--SR.sup.A1, --N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2, --SO.sub.2R.sup.A2, or
--S(.dbd.O).sub.2OR.sup.A1, wherein each instance of R.sup.A1 is
independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, a nitrogen protecting group when attached to a
nitrogen atom, or two R.sup.A1 groups are joined to form an
heterocyclic or heteroaryl ring; and R.sup.A2 is alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or
R.sup.11a and R.sup.11b together form oxo; R.sup.3 is hydrogen,
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or
heteroaryl; R.sup.5 is absent or hydrogen; and represents a single
or double bond, wherein when one of at site is a double bond, the
other is a single bond; when both of are single bonds, then R.sup.5
is hydrogen; and when one of the is a double bond, R.sup.5 is
absent; R.sup.17 is alkoxy, cyano, nitro, aryl, heteroaryl,
--C(O)R.sup.B1, --C(O)CH.sub.2R.sup.B1, or
--C(O)CH.sub.2CH.sub.2R.sup.B1, wherein R.sup.B1 is hydrogen, --OH,
--N(R.sup.A1).sub.2, alkoxy, aryl, or heteroaryl; R.sup.19 is
hydrogen or alkyl; and R.sup.16 is halogen, cyano, nitro, alkyl,
alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,
--OR.sup.A1, --SR.sup.A1, --N(R.sup.A1).sub.2,
--NHC(.dbd.O)R.sup.A1, --NHC(.dbd.O)OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1.
[0161] In some embodiments, R.sup.3 is alkyl.
[0162] In some embodiments, the compound of Formula (IX) is a
compound of Formula (IX-a) or (IX-b):
##STR00047##
[0163] In some embodiments, each of R.sup.2, R.sup.4, and R.sup.6,
R.sup.11a, and R.sup.11b is independently hydrogen. In some
embodiments, R.sup.2, R.sup.4, and R.sup.6, R.sup.11a, and
R.sup.11b are all hydrogen. In some embodiments, each of R.sup.2,
R.sup.4, and R.sup.6 is independently halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, or --OH.
[0164] In some embodiments, R.sup.3 is C.sub.1-C.sub.6 alkyl (e.g.
C.sub.1-C.sub.6 haloalkyl or --CH.sub.3).
[0165] In some embodiments, the compound of Formula (IX) is a
compound of Formula (X-a) or (X-b):
##STR00048##
[0166] In some embodiments, the compound of Formula (IX) is a
compound of Formula (X-c) or (X-d):
##STR00049##
[0167] In some embodiments, R.sup.19 is --CH.sub.3. In some
embodiments, R.sup.16 is alkyl. In some embodiments, R.sup.16 is
--CH.sub.3, --CH.sub.2CH.sub.3, --OH, --OCH.sub.3, or
--CH(CH.sub.3).sub.2. In some embodiments, R.sup.17 is --OCH.sub.3,
--CN, or --C(O)CH.sub.3. In some embodiments, R.sup.17 is
--C(O)CH.sub.2R.sup.C1. In some embodiments, R.sup.17 is
--C(O)CH.sub.2R.sup.B1. In some embodiments, R.sup.17 is alkoxy,
cyano, or --C(O)R.sup.B1 In some embodiments, R.sup.B1 is pyrazolyl
(e.g., a cyano-substituted pyrazolyl). In some embodiments,
R.sup.B1 is tetrazolyl (e.g., a methyl-substituted tetrazolyl). In
some embodiments, R.sup.B1 is a bicyclic heteroaryl (e.g., a
methoxy-substituted bicyclic heteroaryl. In some embodiments,
R.sup.B1 is
##STR00050##
In some embodiments, R.sup.B1 is
##STR00051##
[0168] In some embodiments, R.sup.6 is halogen. In some
embodiments, R.sup.6 is fluorine.
[0169] In some embodiments, each of R.sup.11a and R.sup.11b is
independently hydrogen, C.sub.1-C.sub.6 alkyl (e.g. C.sub.1-C.sub.6
haloalkyl), C.sub.1-C.sub.6 alkoxy (e.g. C.sub.1-C.sub.6
haloalkoxy), or --OH. In some embodiments, R.sup.11a and R.sup.11b
together form oxo.
[0170] In some embodiments, R.sup.17 is C.sub.1-C.sub.6 alkoxy
(e.g. --OCH.sub.3), cyano, or nitro.
[0171] In some embodiments, R.sup.19 is hydrogen or substituted or
unsubstituted C.sub.1-C.sub.6 alkyl (e.g. --CH.sub.2OR.sup.X,
wherein R.sup.X is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy).
[0172] In some embodiments, the compound of Formula (IX) is a
compound of Formula (X-a) or (X-b):
##STR00052##
wherein R.sup.a is hydrogen, halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3), or --OH.
[0173] In some embodiments, the compound of Formula (IX) is a
compound of Formula (XI-a) or (XI-b):
##STR00053##
wherein m is 0, 1, or 2, n is 0, 1, or 2, each R.sup.b is
independently hydrogen, halogen, or C.sub.1-C.sub.6 alkyl, and each
R.sup.c is independently halogen, C.sub.1-C.sub.6 alkyl (e.g.
--CH.sub.3 or C.sub.1-C.sub.6 haloalkyl), C.sub.1-C.sub.6 alkoxy,
cyano, or --OH.
[0174] In some embodiments, A is a 5-10-membered ring. In some
embodiments, A is a fused bicyclic ring. In some embodiments, A is
monocyclic heteroaryl or bicyclic heteroaryl.
[0175] Also provided herein are compounds described in Table 1
below or pharmaceutically acceptable salts thereof.
TABLE-US-00001 TABLE 1 Exemplary Compounds of the Invention Com-
pound num- Compound structure ber ##STR00054## 1 ##STR00055## 2
##STR00056## 3 ##STR00057## 4 ##STR00058## 5 ##STR00059## 6
##STR00060## 7 ##STR00061## 8 ##STR00062## 9 ##STR00063## 10
##STR00064## 11 ##STR00065## 12 ##STR00066## 13 ##STR00067## 14
##STR00068## 15 ##STR00069## 16 ##STR00070## 17 ##STR00071## 18
##STR00072## 19 ##STR00073## 20 ##STR00074## 21 ##STR00075## 23
##STR00076## 24 ##STR00077## 25 ##STR00078## 26 ##STR00079## 27
##STR00080## 28 ##STR00081## 29 ##STR00082## 30 ##STR00083## 31
##STR00084## 34 ##STR00085## 35 ##STR00086## 36 ##STR00087## 37
##STR00088## 38 ##STR00089## 39 ##STR00090## 40 ##STR00091## 41
##STR00092## 42 ##STR00093## 43 ##STR00094## 44 ##STR00095## 45
##STR00096## 46 ##STR00097## 47 ##STR00098## 48 ##STR00099## 49
##STR00100## 50 ##STR00101## 51 ##STR00102## 52 ##STR00103## 53
##STR00104## 54 ##STR00105## 55 ##STR00106## 56 ##STR00107## 58
##STR00108## 59 ##STR00109## 60 ##STR00110## 61 ##STR00111## 62
##STR00112## 63 ##STR00113## 64 ##STR00114## 65 ##STR00115## 66
##STR00116## 67 ##STR00117## 68 ##STR00118## 69 ##STR00119## 70
##STR00120## 71 ##STR00121## 72 ##STR00122## 73 ##STR00123## 74
##STR00124## 75 ##STR00125## 76 ##STR00126## 77 ##STR00127## 78
##STR00128## 79 ##STR00129## 80 ##STR00130## 81 ##STR00131## 82
##STR00132## 83 ##STR00133## 84 ##STR00134## 85 ##STR00135## 86
##STR00136## 87 ##STR00137## 88 ##STR00138## 89 ##STR00139## 90
##STR00140## 91 ##STR00141## 92
ALTERNATIVE EMBODIMENTS
[0176] In an alternative embodiment, compounds described herein may
also comprise one or more isotopic substitutions. For example,
hydrogen may be .sup.2H (D or deuterium) or .sup.3H (T or tritium);
carbon may be, for example, .sup.13C or .sup.14C; oxygen may be,
for example, .sup.18O; nitrogen may be, for example, .sup.15N, and
the like. In other embodiments, a particular isoptope (e.g.,
.sup.3H, .sup.13C, .sup.14C, .sup.18O, or .sup.15N) can represent
at least 1%, at least 5%, at least 10%, at least 15%, at least 20%,
at least 25%, at least 30%, at least 35%, at least 40%, at least
45%, at least 50%, at least at least 60%, at least 65%, at least
70%, at least 75%, at least 80%, at least 85%, at least 90%, at
least 95%, at least 99%, or at least 99.9% of the total isotopic
abundance of an element that occupies a specific site of the
compound.
Pharmaceutical Compositions
[0177] In one aspect, the invention provides a pharmaceutical
composition comprising a compound of the present invention (also
referred to as the "active ingredient") and a pharmaceutically
acceptable excipient. In certain embodiments, the pharmaceutical
composition comprises an effective amount of the active ingredient.
In certain embodiments, the pharmaceutical composition comprises a
therapeutically effective amount of the active ingredient. In
certain embodiments, the pharmaceutical composition comprises a
prophylactically effective amount of the active ingredient.
[0178] The pharmaceutical compositions provided herein can be
administered by a variety of routes including, but not limited to,
oral (enteral) administration, parenteral (by injection)
administration, rectal administration, transdermal administration,
intradermal administration, intrathecal administration,
subcutaneous (SC) administration, intravenous (IV) administration,
intramuscular (IM) administration, and intranasal
administration.
[0179] Generally, the compounds provided herein are administered in
an effective amount. The amount of the compound actually
administered will typically be determined by a physician, in the
light of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual compound
administered, the age, weight, and response of the individual
patient, the severity of the patient's symptoms, and the like.
[0180] When used to prevent the onset of a CNS-disorder, the
compounds provided herein will be administered to a subject at risk
for developing the condition, typically on the advice and under the
supervision of a physician, at the dosage levels described above.
Subjects at risk for developing a particular condition generally
include those that have a family history of the condition, or those
who have been identified by genetic testing or screening to be
particularly susceptible to developing the condition.
[0181] The pharmaceutical compositions provided herein can also be
administered chronically ("chronic administration"). Chronic
administration refers to administration of a compound or
pharmaceutical composition thereof over an extended period of time,
e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3
years, 5 years, etc, or may be continued indefinitely, for example,
for the rest of the subject's life. In certain embodiments, the
chronic administration is intended to provide a constant level of
the compound in the blood, e.g., within the therapeutic window over
the extended period of time.
[0182] The pharmaceutical compositions of the present invention may
be further delivered using a variety of dosing methods. For
example, in certain embodiments, the pharmaceutical composition may
be given as a bolus, e.g., in order to raise the concentration of
the compound in the blood to an effective level. The placement of
the bolus dose depends on the systemic levels of the active
ingredient desired throughout the body, e.g., an intramuscular or
subcutaneous bolus dose allows a slow release of the active
ingredient, while a bolus delivered directly to the veins (e.g.,
through an IV drip) allows a much faster delivery which quickly
raises the concentration of the active ingredient in the blood to
an effective level. In other embodiments, the pharmaceutical
composition may be administered as a continuous infusion, e.g., by
IV drip, to provide maintenance of a steady-state concentration of
the active ingredient in the subject's body. Furthermore, in still
yet other embodiments, the pharmaceutical composition may be
administered as first as a bolus dose, followed by continuous
infusion.
[0183] The compositions for oral administration can take the form
of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Typical unit dosage forms include
prefilled, premeasured ampules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of
solid compositions. In such compositions, the compound is usually a
minor component (from about 0.1 to about 50% by weight or
preferably from about 1 to about 40% by weight) with the remainder
being various vehicles or excipients and processing aids helpful
for forming the desired dosing form.
[0184] With oral dosing, one to five and especially two to four and
typically three oral doses per day are representative regimens.
Using these dosing patterns, each dose provides from about 0.01 to
about 20 mg/kg of the compound provided herein, with preferred
doses each providing from about 0.1 to about 10 mg/kg, and
especially about 1 to about 5 mg/kg.
[0185] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses,
generally in an amount ranging from about 0.01 to about 20% by
weight, preferably from about 0.1 to about 20% by weight,
preferably from about 0.1 to about 10% by weight, and more
preferably from about 0.5 to about 15% by weight.
[0186] Injection dose levels range from about 0.1 mg/kg/hour to at
least 20 mg/kg/hour, all for from about 1 to about 120 hours and
especially 24 to 96 hours. A preloading bolus of from about 0.1
mg/kg to about 10 mg/kg or more may also be administered to achieve
adequate steady state levels. The maximum total dose is not
expected to exceed about 5 g/day for a 40 to 80 kg human
patient.
[0187] Liquid forms suitable for oral administration may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, colorants, flavors and the like. Solid forms may
include, for example, any of the following ingredients, or
compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatin; an excipient such as starch
or lactose, a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate; a glidant
such as colloidal silicon dioxide; a sweetening agent such as
sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate, or orange flavoring.
[0188] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
excipients known in the art. As before, the active compound in such
compositions is typically a minor component, often being from about
0.05 to 10% by weight with the remainder being the injectable
excipient and the like.
[0189] Transdermal compositions are typically formulated as a
topical ointment or cream containing the active ingredient(s). When
formulated as a ointment, the active ingredients will typically be
combined with either a paraffinic or a water-miscible ointment
base. Alternatively, the active ingredients may be formulated in a
cream with, for example an oil-in-water cream base. Such
transdermal formulations are well-known in the art and generally
include additional ingredients to enhance the dermal penetration of
stability of the active ingredients or Formulation. All such known
transdermal formulations and ingredients are included within the
scope provided herein.
[0190] The compounds provided herein can also be administered by a
transdermal device. Accordingly, transdermal administration can be
accomplished using a patch either of the reservoir or porous
membrane type, or of a solid matrix variety.
[0191] The above-described components for orally administrable,
injectable or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's Pharmaceutical
Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa.,
which is incorporated herein by reference.
[0192] The compounds of the present invention can also be
administered in sustained release forms or from sustained release
drug delivery systems. A description of representative sustained
release materials can be found in Remington's Pharmaceutical
Sciences.
[0193] The present invention also relates to the pharmaceutically
acceptable acid addition salt of a compound of the present
invention. The acid which may be used to prepare the
pharmaceutically acceptable salt is that which forms a non-toxic
acid addition salt, i.e., a salt containing pharmacologically
acceptable anions such as the hydrochloride, hydroiodide,
hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate,
lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate,
para-toluenesulfonate, and the like.
[0194] In another aspect, the invention provides a pharmaceutical
composition comprising a compound of the present invention and a
pharmaceutically acceptable excipient, e.g., a composition suitable
for injection, such as for intravenous (IV) administration.
[0195] Pharmaceutically acceptable excipients include any and all
diluents or other liquid vehicles, dispersion or suspension aids,
surface active agents, isotonic agents, preservatives, lubricants
and the like, as suited to the particular dosage form desired,
e.g., injection. General considerations in the formulation and/or
manufacture of pharmaceutical compositions agents can be found, for
example, in Remington's Pharmaceutical Sciences, Sixteenth Edition,
E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and
Remington: The Science and Practice of Pharmacy, 21.sup.st Edition
(Lippincott Williams & Wilkins, 2005).
[0196] For example, injectable preparations, such as sterile
injectable aqueous suspensions, can be formulated according to the
known art using suitable dispersing or wetting agents and
suspending agents. Exemplary excipients that can be employed
include, but are not limited to, water, sterile saline or
phosphate-buffered saline, or Ringer's solution.
[0197] In certain embodiments, the pharmaceutical composition
further comprises a cyclodextrin derivative. The most common
cyclodextrins are .alpha.-, .beta.- and .gamma.-cyclodextrins
consisting of 6, 7 and 8 .quadrature..quadrature.1,4-linked glucose
units, respectively, optionally comprising one or more substituents
on the linked sugar moieties, which include, but are not limited
to, substituted or unsubstituted methylated, hydroxyalkylated,
acylated, and sulfoalkylether substitution. In certain embodiments,
the cyclodextrin is a sulfoalkyl ether .beta.-cyclodextrin, e.g.,
for example, sulfobutyl ether .beta.-cyclodextrin, also known as
Captisol.RTM.. See, e.g., U.S. Pat. No. 5,376,645. In certain
embodiments, the composition comprises
hexapropyl-.quadrature.-cyclodextrin. In a more particular
embodiment, the composition comprises
hexapropyl-.quadrature.-cyclodextrin (10-50% in water).
[0198] The injectable composition 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.
[0199] Generally, the compounds provided herein are administered in
an effective amount. The amount of the compound actually
administered will typically be determined by a physician, in the
light of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual compound
administered, the age, weight, response of the individual patient,
the severity of the patient's symptoms, and the like.
[0200] The compositions are presented in unit dosage forms to
facilitate accurate dosing. The term "unit dosage forms" refers to
physically discrete units suitable as unitary dosages for human
subjects and other mammals, each unit containing a predetermined
quantity of active material calculated to produce the desired
therapeutic effect, in association with a suitable pharmaceutical
excipient. Typical unit dosage forms include pre-filled,
pre-measured ampules or syringes of the liquid compositions. In
such compositions, the compound is usually a minor component (from
about 0.1% to about 50% by weight or preferably from about 1% to
about 40% by weight) with the remainder being various vehicles or
carriers and processing aids helpful for forming the desired dosing
form.
[0201] The compounds provided herein can be administered as the
sole active agent, or they can be administered in combination with
other active agents. In one aspect, the present invention provides
a combination of a compound of the present invention and another
pharmacologically active agent. Administration in combination can
proceed by any technique apparent to those of skill in the art
including, for example, separate, sequential, concurrent, and
alternating administration.
[0202] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for administration to humans, it
will be understood by the skilled artisan that such compositions
are generally suitable for administration to animals of all sorts.
Modification of pharmaceutical compositions suitable for
administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design
and/or perform such modification with ordinary experimentation.
General considerations in the formulation and/or manufacture of
pharmaceutical compositions can be found, for example, in
Remington: The Science and Practice of Pharmacy 21.sup.st ed.,
Lippincott Williams & Wilkins, 2005.
Methods of Use and Treatment
[0203] In an aspect, provided is a method of alleviating or
preventing seizure activity in a subject, comprising administering
to the subject in need of such treatment an effective amount of a
compound of the present invention. In some embodiments, the method
alleviates or prevents epileptogenesis.
[0204] In some embodiments, such compounds are envisioned to be
useful as therapeutic agents for treating a CNS-related disorder
(e.g., sleep disorder, a mood disorder such as depression, a
schizophrenia spectrum disorder, a convulsive disorder,
epileptogenesis, a disorder of memory and/or cognition, a movement
disorder, a personality disorder, autism spectrum disorder, pain,
traumatic brain injury, a vascular disease, a substance abuse
disorder and/or withdrawal syndrome, or tinnitus) in a subject in
need (e.g., a subject with Rett syndrome, Fragile X syndrome, or
Angelman syndrome). Exemplary CNS conditions related to
GABA-modulation include, but are not limited to, sleep disorders
[e.g., insomnia], mood disorders [e.g., depression, dysthymic
disorder (e.g., mild depression), bipolar disorder (e.g., I and/or
II), anxiety disorders (e.g., generalized anxiety disorder (GAD),
social anxiety disorder), stress, post-traumatic stress disorder
(PTSD), compulsive disorders (e.g., obsessive compulsive disorder
(OCD))], schizophrenia spectrum disorders [e.g., schizophrenia,
schizoaffective disorder], convulsive disorders [e.g., epilepsy
(e.g., status epilepticus (SE)), seizures], disorders of memory
and/or cognition [e.g., attention disorders (e.g., attention
deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's
type dementia, Lewis body type dementia, vascular type dementia],
movement disorders [e.g., Huntington's disease, Parkinson's
disease], personality disorders [e.g., anti-social personality
disorder, obsessive compulsive personality disorder], autism
spectrum disorders (ASD) [e.g., autism, monogenetic causes of
autism such as synaptophathy's, e.g., Rett syndrome, Fragile X
syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury
related pain syndromes, acute pain, chronic pain], traumatic brain
injury (TBI), vascular diseases [e.g., stroke, ischemia, vascular
malformations], substance abuse disorders and/or withdrawal
syndromes [e.g., addition to opiates, cocaine, and/or alcohol], and
tinnitus.
[0205] In yet another aspect, provided is a combination of a
compound of the present invention and another pharmacologically
active agent. The compounds provided herein can be administered as
the sole active agent or they can be administered in combination
with other agents. Administration in combination can proceed by any
technique apparent to those of skill in the art including, for
example, separate, sequential, concurrent and alternating
administration.
[0206] In another aspect, provided is a method of treating or
preventing brain excitability in a subject susceptible to or
afflicted with a condition associated with brain excitability,
comprising administering to the subject an effective amount of a
compound of the present invention to the subject.
[0207] In yet another aspect, provided is a method of treating or
preventing stress or anxiety in a subject, comprising administering
to the subject in need of such treatment an effective amount of a
compound of the present invention, or a composition thereof.
[0208] In yet another aspect, provided is a method of alleviating
or preventing insomnia in a subject, comprising administering to
the subject in need of such treatment an effective amount of a
compound of the present invention, or a composition thereof.
[0209] In yet another aspect, provided is a method of inducing
sleep and maintaining substantially the level of REM sleep that is
found in normal sleep, wherein substantial rebound insomnia is not
induced, comprising administering an effective amount of a compound
of the present invention.
[0210] In yet another aspect, provided is a method of alleviating
or preventing PMS or PND in a subject, comprising administering to
the subject in need of such treatment an effective amount of a
compound of the present invention.
[0211] In yet another aspect, provided is a method of treating or
preventing mood disorders in a subject, comprising administering to
the subject in need of such treatment an effective amount of a
compound of the present invention. In certain embodiments the mood
disorder is depression.
[0212] In yet another aspect, provided is a method of cognition
enhancement or treating memory disorder by administering to the
subject a therapeutically effective amount of a compound of the
present invention. In certain embodiments, the disorder is
Alzheimer's disease. In certain embodiments, the disorder is Rett
syndrome.
[0213] In yet another aspect, provided is a method of treating
attention disorders by administering to the subject a
therapeutically effective amount of a compound of the present
invention. In certain embodiments, the attention disorder is
ADHD.
[0214] In certain embodiments, the compound is administered to the
subject chronically. In certain embodiments, the compound is
administered to the subject orally, subcutaneously,
intramuscularly, or intravenously.
Neuroendocrine Disorders and Dysfunction
[0215] Provided herein are methods that can be used for treating
neuroendocrine disorders and dysfunction. As used herein,
"neuroendocrine disorder" or "neuroendocrine dysfunction" refers to
a variety of conditions caused by imbalances in the body's hormone
production directly related to the brain. Neuroendocrine disorders
involve interactions between the nervous system and the endocrine
system. Because the hypothalamus and the pituitary gland are two
areas of the brain that regulate the production of hormones, damage
to the hypothalamus or pituitary gland, e.g., by traumatic brain
injury, may impact the production of hormones and other
neuroendocrine functions of the brain. In some embodiments, the
neuroendocrine disorder or dysfunction is associated with a women's
health disorder or condition (e.g., a women's health disorder or
condition described herein). In some embodiments, the
neuroendocrine disorder or dysfunction is associated with a women's
health disorder or condition is polycystic ovary syndrome.
[0216] Symptoms of neuroendocrine disorder include, but are not
limited to, behavioral, emotional, and sleep-related symptoms,
symptoms related to reproductive function, and somatic symptoms;
including but not limited to fatigue, poor memory, anxiety,
depression, weight gain or loss, emotional lability, lack of
concentration, attention difficulties, loss of lipido, infertility,
amenorrhea, loss of muscle mass, increased belly body fat, low
blood pressure, reduced heart rate, hair loss, anemia,
constipation, cold intolerance, and dry skin.
Neurodegenerative Diseases and Disorders
[0217] The methods described herein can be used for treating
neurodegenerative diseases and disorders. The term
"neurodegenerative disease" includes diseases and disorders that
are associated with the progressive loss of structure or function
of neurons, or death of neurons. Neurodegenerative diseases and
disorders include, but are not limited to, Alzheimer's disease
(including the associated symptoms of mild, moderate, or severe
cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic
and ischemic injuries; ataxia and convulsion (including for the
treatment and prevention and prevention of seizures that are caused
by schizoaffective disorder or by drugs used to treat
schizophrenia); benign forgetfulness; brain edema; cerebellar
ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed
head injury; coma; contusive injuries (e.g., spinal cord injury and
head injury); dementias including multi-infarct dementia and senile
dementia; disturbances of consciousness; Down syndrome;
drug-induced or medication-induced Parkinsonism (such as
neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism,
or tardive dyskinesia, neuroleptic malignant syndrome, or
medication-induced postural tremor); epilepsy; fragile X syndrome;
Gilles de la Tourette's syndrome; head trauma; hearing impairment
and loss; Huntington's disease; Lennox syndrome; levodopa-induced
dyskinesia; mental retardation; movement disorders including
akinesias and akinetic (rigid) syndromes (including basal ganglia
calcification, corticobasal degeneration, multiple system atrophy,
Parkinsonism-ALS dementia complex, Parkinson's disease,
postencephalitic parkinsonism, and progressively supranuclear
palsy); muscular spasms and disorders associated with muscular
spasticity or weakness including chorea (such as benign hereditary
chorea, drug-induced chorea, hemiballism, Huntington's disease,
neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea),
dyskinesia (including tics such as complex tics, simple tics, and
symptomatic tics), myoclonus (including generalized myoclonus and
focal cyloclonus), tremor (such as rest tremor, postural tremor,
and intention tremor) and dystonia (including axial dystonia,
dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia,
and focal dystonia such as blepharospasm, oromandibular dystonia,
and spasmodic dysphonia and torticollis); neuronal damage including
ocular damage, retinopathy or macular degeneration of the eye;
neurotoxic injury which follows cerebral stroke, thromboembolic
stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm,
hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and
cardiac arrest; Parkinson's disease; seizure; status epilecticus;
stroke; tinnitus; tubular sclerosis, and viral infection induced
neurodegeneration (e.g., caused by acquired immunodeficiency
syndrome (AIDS) and encephalopathies). Neurodegenerative diseases
also include, but are not limited to, neurotoxic injury which
follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke,
cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia,
hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods of
treating or preventing a neurodegenerative disease also include
treating or preventing loss of neuronal function characteristic of
neurodegenerative disorder.
Mood Disorders
[0218] Also provided herein are methods for treating a mood
disorder, for example clinical depression, postnatal depression or
postpartum depression, perinatal depression, atypical depression,
melancholic depression, psychotic major depression, cataonic
depression, seasonal affective disorder, dysthymia, double
depression, depressive personality disorder, recurrent brief
depression, minor depressive disorder, bipolar disorder or manic
depressive disorder, depression caused by chronic medical
conditions, treatment-resistant depression, refractory depression,
suicidality, suicidal ideation, or suicidal behavior. In some
embodiments, the method described herein provides therapeutic
effect to a subject suffering from depression (e.g., moderate or
severe depression). In some embodiments, the mood disorder is
associated with a disease or disorder described herein (e.g.,
neuroendocrine diseases and disorders, neurodegenerative diseases
and disorders (e.g., epilepsy), movement disorders, tremor (e.g.,
Parkinson's Disease), women's health disorders or conditions).
[0219] Clinical depression is also known as major depression, major
depressive disorder (MDD), severe depression, unipolar depression,
unipolar disorder, and recurrent depression, and refers to a mental
disorder characterized by pervasive and persistent low mood that is
accompanied by low self-esteem and loss of interest or pleasure in
normally enjoyable activities. Some people with clinical depression
have trouble sleeping, lose weight, and generally feel agitated and
irritable. Clinical depression affects how an individual feels,
thinks, and behaves and may lead to a variety of emotional and
physical problems. Individuals with clinical depression may have
trouble doing day-to-day activities and make an individual feel as
if life is not worth living.
[0220] Peripartum depression refers to depression in pregnancy.
Symptoms include irritability, crying, feeling restless, trouble
sleeping, extreme exhaustion (emotional and/or physical), changes
in appetite, difficulty focusing, increased anxiety and/or worry,
disconnected feeling from baby and/or fetus, and losing interest in
formerly pleasurable activities.
[0221] Postnatal depression (PND) is also referred to as postpartum
depression (PPD), and refers to a type of clinical depression that
affects women after childbirth. Symptoms can include sadness,
fatigue, changes in sleeping and eating habits, reduced sexual
desire, crying episodes, anxiety, and irritability. In some
embodiments, the PND is a treatment-resistant depression (e.g., a
treatment-resistant depression as described herein). In some
embodiments, the PND is refractory depression (e.g., a refractory
depression as described herein).
[0222] In some embodiments, a subject having PND also experienced
depression, or a symptom of depression during preganancy. This
depression is referred to herein as) perinatal depression. In an
embodiment, a subject experiencing perinatal depression is at
increased risk of experiencing PND.
[0223] Atypical depression (AD) is characterized by mood reactivity
(e.g., paradoxical anhedonia) and positivity, significant weight
gain or increased appetite. Patients suffering from AD also may
have excessive sleep or somnolence (hypersomnia), a sensation of
limb heaviness, and significant social impairment as a consequence
of hypersensitivity to perceived interpersonal rejection.
[0224] Melancholic depression is characterized by loss of pleasure
(anhedonia) in most or all activities, failures to react to
pleasurable stimuli, depressed mood more pronounced than that of
grief or loss, excessive weight loss, or excessive guilt.
[0225] Psychotic major depression (PMD) or psychotic depression
refers to a major depressive episode, in particular of melancholic
nature, where the individual experiences psychotic symptoms such as
delusions and hallucinations.
[0226] Catatonic depression refers to major depression involving
disturbances of motor behavior and other symptoms. An individual
may become mute and stuporose, and either is immobile or exhibits
purposeless or bizarre movements.
[0227] Seasonal affective disorder (SAD) refers to a type of
seasonal depression wherein an individual has seasonal patterns of
depressive episodes coming on in the fall or winter.
[0228] Dysthymia refers to a condition related to unipolar
depression, where the same physical and cognitive problems are
evident. They are not as severe and tend to last longer (e.g., at
least 2 years).
[0229] Double depression refers to fairly depressed mood
(dysthymia) that lasts for at least 2 years and is punctuated by
periods of major depression.
[0230] Depressive Personality Disorder (DPD) refers to a
personality disorder with depressive features.
[0231] Recurrent Brief Depression (RBD) refers to a condition in
which individuals have depressive episodes about once per month,
each episode lasting 2 weeks or less and typically less than 2-3
days.
[0232] Minor depressive disorder or minor depression refers to a
depression in which at least 2 symptoms are present for 2
weeks.
[0233] Bipolar disorder or manic depressive disorder causes extreme
mood swings that include emotional highs (mania or hypomania) and
lows (depression). During periods of mania the individual may feel
or act abnormally happy, energetic, or irritable. They often make
poorly thought out decisions with little regard to the
consequences. The need for sleep is usually reduced. During periods
of depression there may be crying, poor eye contact with others,
and a negative outlook on life. The risk of suicide among those
with the disorder is high at greater than 6% over 20 years, while
self harm occurs in 30-40%. Other mental health issues such as
anxiety disorder and substance use disorder are commonly associated
with bipolar disorder.
[0234] Depression caused by chronic medical conditions refers to
depression caused by chronic medical conditions such as cancer or
chronic pain, chemotherapy, chronic stress.
[0235] Treatment-resistant depression refers to a condition where
the individuals have been treated for depression, but the symptoms
do not improve. For example, antidepressants or physchological
counseling (psychotherapy) do not ease depression symptoms for
individuals with treatment-resistant depression. In some cases,
individuals with treatment-resistant depression improve symptoms,
but come back. Refractory depression occurs in patients suffering
from depression who are resistant to standard pharmacological
treatments, including tricyclic antidepressants, MAOIs, SSRIs, and
double and triple uptake inhibitors and/or anxiolytic drugs, as
well as non-pharmacological treatments (e.g., psychotherapy,
electroconvulsive therapy, vagus nerve stimulation and/or
transcranial magnetic stimulation).
[0236] Post-surgical depression refers to feelings of depression
that follow a surgical procedure (e.g., as a result of having to
confront one's mortality). For example, individuals may feel
sadness or empty mood persistently, a loss of pleasure or interest
in hobbies and activities normally enjoyed, or a persistent felling
of worthlessness or hopelessness.
[0237] Mood disorder associated with conditions or disorders of
women's health refers to mood disorders (e.g., depression)
associated with (e.g., resulting from) a condition or disorder of
women's health (e.g., as described herein).
[0238] Suicidality, suicidal ideation, suicidal behavior refers to
the tendency of an individual to commit suicide. Suicidal ideation
concerns thoughts about or an unusual preoccupation with suicide.
The range of suicidal ideation varies greatly, from e.g., fleeting
thoughts to extensive thoughts, detailed planning, role playing,
incomplete attempts. Symptoms include talking about suicide,
getting the means to commit suicide, withdrawing from social
contact, being preoccupied with death, feeling trapped or hopeless
about a situation, increasing use of alcohol or drugs, doing risky
or self-destructive things, saying goodbye to people as if they
won't be seen again.
[0239] Symptoms of depression include persistent anxious or sad
feelings, feelings of helplessness, hopelessness, pessimism,
worthlessness, low energy, restlessness, difficulty sleeping,
sleeplessness, irritability, fatigue, motor challenges, loss of
interest in pleasurable activities or hobbies, loss of
concentration, loss of energy, poor self-esteem, absence of
positive thoughts or plans, excessive sleeping, overeating,
appetite loss, insomnia, self-harm, thoughts of suicide, and
suicide attempts. The presence, severity, frequency, and duration
of symptoms may vary on a case to case basis. Symptoms of
depression, and relief of the same, may be ascertained by a
physician or psychologist (e.g., by a mental state
examination).
[0240] In some embodiments, the method provides therapeutic effect
(e.g., as measured by reduction in Hamilton Depression Score
(HAM-D)) within 4, 3, 2, 1 days; 96, 84, 72, 60, 48, 24, 20, 16,
12, 10, 8 hours or less. In some embodiments, the therapeutic
effect is a decrease from baseline in HAM-D score at the end of a
treatment period (e.g., 12, 24, 48 hours after administration; 24,
48, 72, 96 hours or more). In some embodiments, the decrease from
baseline in HAM-D score is from severe (e.g., HAM-D score of 24 or
greater) to symptom-free (e.g., HAM-D score of 7 or lower). In some
embodiments, the baseline score is about 10 to 52 (e.g., more than
10, 15, or 20; 10 to 52, 12 to 52, 15 to 52, 17 to 52, 20 to 52, 22
to 52). In some embodiments, the baseline score is at least 10, 15,
or 20. In some embodiments, the HAM-D score at the end of the
treatment period is about 0 to 10 (e.g., less than 10; 0 to 10, 0
to 6, 0 to 4, 0 to 3, 0 to 2, 1.8). In some embodiments, the HAM-D
score at the end of the treatment period is less than 10, 7, 5, or
3. In some embodiments, the decrease in HAM-D score is from a
baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to
27, 25 to 27, 26 to 27) to a HAM-D score at the end of the
treatment period is about 0 to 10 (e.g., less than 10; 0 to 10, 0
to 6, 0 to 4, 0 to 3, 0 to 2, 1.8). In some embodiments, the
decrease in the baseline HAM-D score to HAM-D score at the end of
the treatment period is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50,
or 100 fold). In some embodiments, the percentage decrease in the
baseline HAM-D score to HAM-D score at the end of the treatment
period is at least 50% (e.g., 60%, 70%, 80%, 90%). In some
embodiments, the therapeutic effect is a decrease from baseline in
HAM-D score at the end of a treatment period (e.g., 12, 24, 48
hours after administration; 24, 48, 72, 96 hours or more) at least
10, 15, or 20 points. In some embodiments, the therapeutic effect
is a decrease from baseline in HAM-D score at the end of a
treatment period (e.g., 12, 24, 48 hours after administration; 24,
48, 72, 96 hours or more) at least 5, 7, or 10 points more relative
to the therapeutic effect provided by a placebo treatment.
[0241] In some embodiments, the method provides therapeutic effect
(e.g., as measured by reduction in Montgomery-Asberg Depression
Rating Scale (MADRS)) within 4, 3, 2, 1 days; 96, 84, 72, 60, 48,
24, 20, 16, 12, 10, 8 hours or less. The Montgomery-Asberg
Depression Rating Scale (MADRS) is a ten-item diagnostic
questionnaire (regarding apparent sadness, reported sadness, inner
tension, reduced sleep, reduced appetite, concentration
difficulties, lassitude, inability to feel, pessimistic thoughts,
and suicidal thoughts) which psychiatrists use to measure the
severity of depressive episodes in patients with mood disorders.
0-6 indicates normal/symptom absent; 7-19 indicates mild
depression; 20-34 indicates moderate depression; and >34
indicates severe depression. In some embodiments, the therapeutic
effect is a decrease from baseline in MADRS score at the end of a
treatment period (e.g., 12, 24, 48 hours after administration; 24,
48, 60, 72, 96 hours or more). In some embodiments, the decrease
from baseline in MADRS score is from severe (e.g., MADRS score of
30 or greater) to symptom-free (e.g., MADRS score of 20 or lower).
For example, the mean change from baseline in MADRS total score
from treatment with a compound described herein is about -15, -20,
-25, -30, while the mean change from baseline in MADRS total score
from treatment with placebo is about -15, -10, -5.
[0242] In some embodiments, the method provides therapeutic effect
(e.g., as measured by reduction in Edinburgh Postnatal Depression
Scale (EPDS)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours
or less. In some embodiments, the therapeutic effect is a
improvement measured by the EPDS.
[0243] In some embodiments, the method provides therapeutic effect
(e.g., as measured by reduction in Clinical Global
Impression-Improvement Scale (CGI)) within 4, 3, 2, 1 days; 24, 20,
16, 12, 10, 8 hours or less. In some embodiments, the therapeutic
effect is a CGI score of 2 or less.
[0244] In some embodiments, the method provides therapeutic effect
(e.g., as measured by reduction in Generalized Anxiety Disorder
7-Item Scale (GAD-7)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8
hours or less.
Anxiety Disorders
[0245] Provided herein are methods for treating anxiety disorders
(e.g., generalized anxiety disorder, panic disorder, obsessive
compulsive disorder, phobia, post-traumatic stress disorder).
Anxiety disorder is a blanket term covering several different forms
of abnormal and pathological fear and anxiety. Current psychiatric
diagnostic criteria recognize a wide variety of anxiety
disorders.
[0246] Generalized anxiety disorder is a common chronic disorder
characterized by long-lasting anxiety that is not focused on any
one object or situation. Those suffering from generalized anxiety
experience non-specific persistent fear and worry and become overly
concerned with everyday matters. Generalized anxiety disorder is
the most common anxiety disorder to affect older adults.
[0247] In panic disorder, a person suffers from brief attacks of
intense terror and apprehension, often marked by trembling,
shaking, confusion, dizziness, nausea, difficulty breathing. These
panic attacks, defined by the APA as fear or discomfort that
abruptly arises and peaks in less than ten minutes, can last for
several hours and can be triggered by stress, fear, or even
exercise; although the specific cause is not always apparent. In
addition to recurrent unexpected panic attacks, a diagnosis of
panic disorder also requires that said attacks have chronic
consequences: either worry over the attacks' potential
implications, persistent fear of future attacks, or significant
changes in behavior related to the attacks. Accordingly, those
suffering from panic disorder experience symptoms even outside of
specific panic episodes. Often, normal changes in heartbeat are
noticed by a panic sufferer, leading them to think something is
wrong with their heart or they are about to have another panic
attack. In some cases, a heightened awareness (hypervigilance) of
body functioning occurs during panic attacks, wherein any perceived
physiological change is interpreted as a possible life threatening
illness (i.e. extreme hypochondriasis).
[0248] Obsessive compulsive disorder is a type of anxiety disorder
primarily characterized by repetitive obsessions (distressing,
persistent, and intrusive thoughts or images) and compulsions
(urges to perform specific acts or rituals). The OCD thought
pattern may be likened to superstitions insofar as it involves a
belief in a causative relationship where, in reality, one does not
exist. Often the process is entirely illogical; for example, the
compulsion of walking in a certain pattern may be employed to
alleviate the obsession of impending harm.
[0249] And in many cases, the compulsion is entirely inexplicable,
simply an urge to complete a ritual triggered by nervousness. In a
minority of cases, sufferers of OCD may only experience obsessions,
with no overt compulsions; a much smaller number of sufferers
experience only compulsions.
[0250] The single largest category of anxiety disorders is that of
phobia, which includes all cases in which fear and anxiety is
triggered by a specific stimulus or situation. Sufferers typically
anticipate terrifying consequences from encountering the object of
their fear, which can be anything from an animal to a location to a
bodily fluid.
[0251] Post-traumatic stress disorder or PTSD is an anxiety
disorder which results from a traumatic experience. Post-traumatic
stress can result from an extreme situation, such as combat, rape,
hostage situations, or even serious accident. It can also result
from long term (chronic) exposure to a severe stressor, for example
soldiers who endure individual battles but cannot cope with
continuous combat. Common symptoms include flashbacks, avoidant
behaviors, and depression.
Women's Health Disorders
[0252] Provided herein are methods for treating conditions or
disorders related to women's health. Conditions or disorders
related to women's health include, but are not limited to,
Gynecological health and disorders (e.g., premenstrual syndrome
(PMS), premenstrual dysphoric disorder (PMDD)), pregnancy issues
(e.g., miscarriage, abortion), infertility and related disorders
(e.g., polycystic ovary syndrome (PCOS)), other disorders and
conditions, and issues related to women's overall health and
wellness (e.g., menopause).
[0253] Gynecological health and disorders affecting women include
menstruation and menstrual irregularities; urinary tract health,
including urinary incontinence and pelvic floor disorders; and such
disorders as bacterial vaginosis, vaginitis, uterine fibroids, and
vulvodynia.
[0254] Premenstrual syndrome (PMS) refers to physical and emotional
symptoms that occur in the one to two weeks before a women's
period. Symptoms vary but can include bleeding, mood swings, tender
breasts, food cravings, fatigue, irritability, acne, and
depression.
[0255] Premenstrual dysphoric disorder (PMDD) is a severe form of
PMS. The symptoms of PMDD are similar to PMS but more severe and
may interfere with work, social activity, and relationships. PMDD
symptoms include mood swings, depressed mood or feelings of
hopelessness, marked anger, increased interpersonal conflicts,
tension and anxiety, irritability, decreased interest in usual
activities, difficulty concentrating, fatigue, change in appetite,
feeling out of control or overwhelmed, sleep problems, physical
problems (e.g., bloating, breast tenderness, swelling, headaches,
joint or muscle pain).
[0256] Pregnancy issues include preconception care and prenatal
care, pregnancy loss (miscarriage and stillbirth), preterm labor
and premature birth, sudden infant death syndrome (SIDS),
breastfeeding, and birth defects.
[0257] Miscarriage refers to a pregnancy that ends on its own,
within the first 20 weeks of gestation.
[0258] Abortion refers to the deliberate termination of a
pregnancy, which can be performed during the first 28 weeks of
pregnancy.
[0259] Infertility and related disorders include uterine fibroids,
polycystic ovary syndrome, endometriosis, and primary ovarian
insufficiency.
[0260] Polycystic ovary syndrome (PCOS) refers to an endocrine
system disorder among women of reproductive age. PCOS is a set of
symptoms resulting from an elevated male hormone in women. Most
women with PCOS grow many small cysts on their ovaries.
[0261] Symptoms of PCOS include irregular or no menstrual periods,
heavy periods, excess body and facial hair, acne, pelvic pain,
difficulty getting pregnant, and patches of thick, darker, velvety
skin. PCOS may be associated with conditions including type 2
diabetes, obesity, obstructive sleep apnea, heart disease, mood
disorders, and endometrial cancer.
[0262] Other disorders and conditions that affect only women
include Turner syndrome, Rett syndrome, and ovarian and cervical
cancers.
[0263] Issues related to women's overall health and wellness
include violence against women, women with disabilities and their
unique challenges, osteoporosis and bone health, and menopause.
[0264] Menopause refers to the 12 months after a woman's last
menstrual period and marks the end of menstrual cycles. Menopause
typically occurs in a woman's 40s or 50s. Physical symptoms such as
hot flashes and emotional symptoms of menopause may disrupt sleep,
lower energy, or trigger anxiety or feelings of sadness or loss.
Menopause includes natural menopause and surgical menopause, which
is a type of induced menopause due to an event such as surgery
(e.g., hysterectomy, oophorectomy; cancer). It is induced when the
ovaries are gravely damaged by, e.g., radiation, chemotherapy, or
other medications.
Epilepsy
[0265] The compound of Formula (I), the compound of Formula (V), or
the compound of Formula (IX), or pharmaceutically acceptable salt,
or a pharmaceutically acceptable composition thereof, can be used
in a method described herein, for example in the treatment of a
disorder described herein such as epilepsy, status epilepticus, or
seizure, for example as described in WO2013/112605 and
WO/2014/031792, the contents of which are incorporated herein in
their entirety.
[0266] Epilepsy is a brain disorder characterized by repeated
seizures over time. Types of epilepsy can include, but are not
limited to generalized epilepsy, e.g., childhood absence epilepsy,
juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on
awakening, West syndrome, Lennox-Gastaut syndrome, partial
epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy,
benign focal epilepsy of childhood.
Epileptogenesis
[0267] The compounds and methods described herein can be used to
treat or prevent epileptogenesis. Epileptogenesis is a gradual
process by which a normal brain develops epilepsy (a chronic
condition in which seizures occur). Epileptogenesis results from
neuronal damage precipitated by the initial insult (e.g., status
epilepticus).
Status Epilepticus (SE)
[0268] Status epilepticus (SE) can include, e.g., convulsive status
epilepticus, e.g., early status epilepticus, established status
epilepticus, refractory status epilepticus, super-refractory status
epilepticus; non-convulsive status epilepticus, e.g., generalized
status epilepticus, complex partial status epilepticus; generalized
periodic epileptiform discharges; and periodic lateralized
epileptiform discharges. Convulsive status epilepticus is
characterized by the presence of convulsive status epileptic
seizures, and can include early status epilepticus, established
status epilepticus, refractory status epilepticus, super-refractory
status epilepticus. Early status epilepticus is treated with a
first line therapy. Established status epilepticus is characterized
by status epileptic seizures which persist despite treatment with a
first line therapy, and a second line therapy is administered.
Refractory status epilepticus is characterized by status epileptic
seizures which persist despite treatment with a first line and a
second line therapy, and a general anesthetic is generally
administered. Super refractory status epilepticus is characterized
by status epileptic seizures which persist despite treatment with a
first line therapy, a second line therapy, and a general anesthetic
for 24 hours or more.
[0269] Non-convulsive status epilepticus can include, e.g., focal
non-convulsive status epilepticus, e.g., complex partial
non-convulsive status epilepticus, simple partial non-convulsive
status epilepticus, subtle non-convulsive status epilepticus;
generalized non-convulsive status epilepticus, e.g., late onset
absence non-convulsive status epilepticus, atypical absence
non-convulsive status epilepticus, or typical absence
non-convulsive status epilepticus.
[0270] The compound of Formula (I), a compound of Formula (V), or a
compound of Formula (IX) or pharmaceutically acceptable salt, or a
pharmaceutically acceptable composition thereof, can also be
administered as a prophylactic to a subject having a CNS disorder
e.g., a traumatic brain injury, status epilepticus, e.g.,
convulsive status epilepticus, e.g., early status epilepticus,
established status epilepticus, refractory status epilepticus,
super-refractory status epilepticus; non-convulsive status
epilepticus, e.g., generalized status epilepticus, complex partial
status epilepticus; generalized periodic epileptiform discharges;
and periodic lateralized epileptiform discharges; prior to the
onset of a seizure.
Seizure
[0271] A seizure is the physical findings or changes in behavior
that occur after an episode of abnormal electrical activity in the
brain. The term "seizure" is often used interchangeably with
"convulsion." Convulsions are when a person's body shakes rapidly
and uncontrollably. During convulsions, the person's muscles
contract and relax repeatedly.
[0272] Based on the type of behavior and brain activity, seizures
are divided into two broad categories: generalized and partial
(also called local or focal). Classifying the type of seizure helps
doctors diagnose whether or not a patient has epilepsy.
[0273] Generalized seizures are produced by electrical impulses
from throughout the entire brain, whereas partial seizures are
produced (at least initially) by electrical impulses in a
relatively small part of the brain. The part of the brain
generating the seizures is sometimes called the focus.
[0274] There are six types of generalized seizures. The most common
and dramatic, and therefore the most well known, is the generalized
convulsion, also called the grand-mal seizure. In this type of
seizure, the patient loses consciousness and usually collapses. The
loss of consciousness is followed by generalized body stiffening
(called the "tonic" phase of the seizure) for 30 to 60 seconds,
then by violent jerking (the "clonic" phase) for 30 to 60 seconds,
after which the patient goes into a deep sleep (the "postictal" or
after-seizure phase). During grand-mal seizures, injuries and
accidents may occur, such as tongue biting and urinary
incontinence.
[0275] Absence seizures cause a short loss of consciousness (just a
few seconds) with few or no symptoms. The patient, most often a
child, typically interrupts an activity and stares blankly. These
seizures begin and end abruptly and may occur several times a day.
Patients are usually not aware that they are having a seizure,
except that they may be aware of "losing time."
[0276] Myoclonic seizures consist of sporadic jerks, usually on
both sides of the body. Patients sometimes describe the jerks as
brief electrical shocks. When violent, these seizures may result in
dropping or involuntarily throwing objects.
[0277] Clonic seizures are repetitive, rhythmic jerks that involve
both sides of the body at the same time.
[0278] Tonic seizures are characterized by stiffening of the
muscles.
[0279] Atonic seizures consist of a sudden and general loss of
muscle tone, particularly in the arms and legs, which often results
in a fall.
[0280] Seizures described herein can include epileptic seizures;
acute repetitive seizures; cluster seizures; continuous seizures;
unremitting seizures; prolonged seizures; recurrent seizures;
status epilepticus seizures, e.g., refractory convulsive status
epilepticus, non-convulsive status epilepticus seizures; refractory
seizures; myoclonic seizures; tonic seizures; tonic-clonic
seizures; simple partial seizures; complex partial seizures;
secondarily generalized seizures; atypical absence seizures;
absence seizures; atonic seizures; benign Rolandic seizures;
febrile seizures; emotional seizures; focal seizures; gelastic
seizures; generalized onset seizures; infantile spasms; Jacksonian
seizures; massive bilateral myoclonus seizures; multifocal
seizures; neonatal onset seizures; nocturnal seizures; occipital
lobe seizures; post traumatic seizures; subtle seizures; Sylvan
seizures; visual reflex seizures; or withdrawal seizures. In some
embodiments, the seizure is a generalized seizure associated with
Dravet Syndrome, Lennox-Gastaut Syndrome, Tuberous Sclerosis
Complex, Rett Syndrome or PCDH19 Female Pediatric Epilepsy.
Movement Disorders
[0281] Also described herein are methods for treating a movement
disorder. As used herein, "movement disorders" refers to a variety
of diseases and disorders that are associated with hyperkinetic
movement disorders and related abnormalities in muscle control.
Exemplary movement disorders include, but are not limited to,
Parkinson's disease and parkinsonism (defined particularly by
bradykinesia), dystonia, chorea and Huntington's disease, ataxia,
tremor (e.g., essential tremor), myoclonus and startle, tics and
Tourette syndrome, Restless legs syndrome, stiff person syndrome,
and gait disorders.
Tremor
[0282] The methods described herein can be used to treat tremor,
for example the compound of Forumula (I) can be used to treat
cerebellar tremor or intention tremor, dystonic tremor, essential
tremor, orthostatic tremor, parkinsonian tremor, physiological
tremor, psychogenic tremor, or rubral tremor. Tremor includes
hereditary, degenerative, and idiopathic disorders such as Wilson's
disease, Parkinson's disease, and essential tremor, respectively;
metabolic diseases (e.g., thyoid-parathyroid-, liver disease and
hypoglycemia); peripheral neuropathies (associated with
Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex
regional pain syndrome); toxins (nicotine, mercury, lead, CO,
Manganese, arsenic, toluene); drug-induced (narcoleptics,
tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators,
theophylline, caffeine, steroids, valproate, amiodarone, thyroid
hormones, vincristine); and psychogenic disorders. Clinical tremor
can be classified into physiologic tremor, enhanced physiologic
tremor, essential tremor syndromes (including classical essential
tremor, primary orthostatic tremor, and task- and position-specific
tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor,
Holmes' tremor (i.e., rubral tremor), palatal tremor, neuropathic
tremor, toxic or drug-induced tremor, and psychogenic tremor.
[0283] Tremor is an involuntary, at times rhythmic, muscle
contraction and relaxation that can involve oscillations or
twitching of one or more body parts (e.g., hands, arms, eyes, face,
head, vocal folds, trunk, legs).
[0284] Cerebellar tremor or intention tremor is a slow, broad
tremor of the extremities that occurs after a purposeful movement.
Cerebellar tremor is caused by lesions in or damage to the
cerebellum resulting from, e.g., tumor, stroke, disease (e.g.,
multiple sclerosis, an inherited degenerative disorder).
[0285] Dystonic tremor occurs in individuals affected by dystonia,
a movement disorder in which sustained involuntary muscle
contractions cause twisting and repetitive motions and/or painful
and abnormal postures or positions. Dystonic tremor may affect any
muscle in the body. Dystonic tremors occurs irregularly and often
can be relieved by complete rest.
[0286] Essential tremor or benign essential tremor is the most
common type of tremor. Essential tremor may be mild and
nonprogressive in some, and may be slowly progressive, starting on
one side of the body but affect both sides within 3 years. The
hands are most often affected, but the head, voice, tongue, legs,
and trunk may also be involved. Tremor frequency may decrease as
the person ages, but severity may increase. Heightened emotion,
stress, fever, physical exhaustion, or low blood sugar may trigger
tremors and/or increase their severity. Symptoms generally evolve
over time and can be both visible and persistent following
onset.
[0287] Orthostatic tremor is characterized by fast (e.g., greater
than 12 Hz) rhythmic muscle contractions that occurs in the legs
and trunk immediately after standing. Cramps are felt in the thighs
and legs and the patient may shake uncontrollably when asked to
stand in one spot. Orthostatic tremor may occurs in patients with
essential tremor.
[0288] Parkinsonian tremor is caused by damage to structures within
the brain that control movement. Parkinsonian tremor is often a
precursor to Parkinson's disease and is typically seen as a
"pill-rolling" action of the hands that may also affect the chin,
lips, legs, and trunk. Onset of parkinsonian tremor typically
begins after age 60. Movement starts in one limb or on one side of
the body and can progress to include the other side.
[0289] Physiological tremor can occur in normal individuals and
have no clinical significance. It can be seen in all voluntary
muscle groups. Physiological tremor can be caused by certain drugs,
alcohol withdrawl, or medical conditions including an overactive
thyroid and hypoglycemia. The tremor classically has a frequency of
about 10 Hz.
[0290] Psychogenic tremor or hysterical tremor can occur at rest or
during postural or kinetic movement. Patient with psychogenic
tremor may have a conversion disorder or another psychiatric
disease.
[0291] Rubral tremor is characterized by coarse slow tremor which
can be present at rest, at posture, and with intention. The tremor
is associated with conditions that affect the red nucleus in the
midbrain, classical unusual strokes.
[0292] Parkinson's Disease affects nerve cells in the brain that
produce dopamine. Symptoms include muscle rigidity, tremors, and
changes in speech and gait. Parkinsonism is characterized by
tremor, bradykinesia, rigidity, and postural instability.
Parkinsonism shares symptons found in Parkinson's Disease, but is a
symptom complex rather than a progressive neurodegenerative
disease.
[0293] Dystonia is a movement disorder characterized by sustained
or intermittent muscle contractions causing abnormal, often
repetitive movements or postures. Dystonic movements can be
patterned, twisting, and may be tremulous. Dystonia is often
initiated or worsened by voluntary action and associated with
overflow muscle activation.
[0294] Chorea is a neurological disorder characterized by jerky
involuntary movements typically affecting the shoulders, hips, and
face. Huntington's Disease is an inherited disease that causes
nerve cells in the brain to waste away. Symptoms include
uncontrolled movements, clumsiness, and balance problems.
Huntington's disease can hinder walk, talk, and swallowing.
[0295] Ataxia refers to the loss of full control of bodily
movements, and may affect the fingers, hands, arms, legs, body,
speech, and eye movements.
[0296] Myloclonus and Startle is a response to a sudden and
unexpected stimulus, which can be acoustic, tactile, visual, or
vestibular.
[0297] Tics are an involuntary movement usually onset suddenly,
brief, repetitive, but non-rhythmical, typically imitating normal
behavior and often occurring out of a background of normal
activity. Tics can be classified as motor or vocal, motor tics
associated with movements while vocal tics associated with sound.
Tics can be characterized as simple or complex. For example simple
motor tics involve only a few muscles restricted to a specific body
part. Tourette Syndrome is an inherited neuropsychiatric disorder
with onset in childhood, characterized by multiple motor tics and
at least one vocal tic.
[0298] Restless Legs Syndrome is a neurologic sensorimotor disorder
characterized by an overwhelming urge to move the legs when at
rest.
[0299] Stiff Person Syndrome is a progressive movement disorder
characterized by involuntary painful spasms and rigidity of
muscles, usually involving the lower back and legs.
[0300] Stiff-legged gait with exaggerated lumbar hyperlordosis
typically results. Characteristic abnormality on EMG recordings
with continuous motor unit activity of the paraspinal axial muscles
is typically observed. Variants include "stiff-limb syndrome"
producing focal stiffness typically affecting distal legs and
feet.
[0301] Gait disorders refer to an abnormalitiy in the manner or
style of walking, which results from neuromuscular, arthritic, or
other body changes. Gait is classified according to the system
responsible for abnormal locomotion, and include hemiplegic gait,
diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait,
choreiform gait, ataxic gait, and sensory gait.
Anesthesia/Sedation
[0302] Anesthesia is a pharmacologically induced and reversible
state of amnesia, analgesia, loss of responsiveness, loss of
skeletal muscle reflexes, decreased stress response, or all of
these simultaneously. These effects can be obtained from a single
drug which alone provides the correct combination of effects, or
occasionally with a combination of drugs (e.g., hypnotics,
sedatives, paralytics, analgesics) to achieve very specific
combinations of results. Anesthesia allows patients to undergo
surgery and other procedures without the distress and pain they
would otherwise experience.
[0303] Sedation is the reduction of irritability or agitation by
administration of a pharmacological agent, generally to facilitate
a medical procedure or diagnostic procedure.
[0304] Sedation and analgesia include a continuum of states of
consciousness ranging from minimal sedation (anxiolysis) to general
anesthesia.
[0305] Minimal sedation is also known as anxiolysis. Minimal
sedation is a drug-induced state during which the patient responds
normally to verbal commands. Cognitive function and coordination
may be impaired. Ventilatory and cardiovascular functions are
typically unaffected.
[0306] Moderate sedation/analgesia (conscious sedation) is a
drug-induced depression of consciousness during which the patient
responds purposefully to verbal command, either alone or
accompanied by light tactile stimulation. No interventions are
usually necessary to maintain a patent airway. Spontaneous
ventilation is typically adequate. Cardiovascular function is
usually maintained.
[0307] Deep sedation/analgesia is a drug-induced depression of
consciousness during which the patient cannot be easily aroused,
but responds purposefully (not a reflex withdrawal from a painful
stimulus) following repeated or painful stimulation. Independent
ventilatory function may be impaired and the patient may require
assistance to maintain a patent airway. Spontaneous ventilation may
be inadequate. Cardiovascular function is usually maintained.
[0308] General anesthesia is a drug-induced loss of consciousness
during which the patient is not arousable, even to painful stimuli.
The ability to maintain independent ventilatory function is often
impaired and assistance is often required to maintain a patent
airway. Positive pressure ventilation may be required due to
depressed spontaneous ventilation or drug-induced depression of
neuromuscular function. Cardiovascular function may be
impaired.
[0309] Sedation in the intensive care unit (ICU) allows the
depression of patients' awareness of the environment and reduction
of their response to external stimulation. It can play a role in
the care of the critically ill patient, and encompasses a wide
spectrum of symptom control that will vary between patients, and
among individuals throughout the course of their illnesses. Heavy
sedation in critical care has been used to facilitate endotracheal
tube tolerance and ventilator synchronization, often with
neuromuscular blocking agents.
[0310] In some embodiments, sedation (e.g., long-term sedation,
continuous sedation) is induced and maintained in the ICU for a
prolonged period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1
week, 2 week, 3 weeks, 1 month, 2 months). Long-term sedation
agents may have long duration of action. Sedation agents in the ICU
may have short elimination half-life.
[0311] Procedural sedation and analgesia, also referred to as
conscious sedation, is a technique of administering sedatives or
dissociative agents with or without analgesics to induce a state
that allows a subject to tolerate unpleasant procedures while
maintaining cardiorespiratory function.
EXAMPLES
[0312] In order that the invention described herein may be more
fully understood, the following examples are set forth. The
synthetic examples described in this application are offered to
illustrate the invention provided herein and are not to be
construed in any way as limiting its scope.
Materials and Methods
[0313] The compounds provided herein can be prepared from readily
available starting materials using the following general methods
and procedures. It will be appreciated that where typical or
preferred process conditions (i.e., reaction temperatures, times,
mole ratios of reactants, solvents, pressures, etc.) are given,
other process conditions can also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular reactants
or solvent used, but such conditions can be determined by one
skilled in the art by routine optimization.
[0314] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in T. W. Greene and P. G. M. Wuts, Protecting Groups in
Organic Synthesis, Second Edition, Wiley, New York, 1991, and
references cited therein.
[0315] The compounds provided herein may be isolated and purified
by known standard procedures. Such procedures include (but are not
limited to) recrystallization, column chromatography, HPLC, or
supercritical fluid chromatography (SFC). The following schemes are
presented with details as to the preparation of representative
oxysterols that have been listed herein. The compounds provided
herein may be prepared from known or commercially available
starting materials and reagents by one skilled in the art of
organic synthesis.
[0316] Exemplary chiral columns available for use in the
separation/purification of the enantiomers/diastereomers provided
herein include, but are not limited to, CHIRALPAK.RTM. AD-10,
CHIRALCEL.RTM. OB, CHIRALCEL.RTM. OB--H, CHIRALCEL.RTM. OD,
CHIRALCEL.RTM. OD-H, CHIRALCEL.RTM. OF, CHIRALCEL.RTM. OG,
CHIRALCEL.RTM. OJ and CHIRALCEL.RTM. OK.
[0317] Exemplary general method for preparative HPLC: Column:
Durashell. Mobile phase: A: water, B: acetonitrile. % B at 0 min:
41%, % B at 8 min: 71%, flow rate: 35 mL/min, detection wavelength:
220 nm.
[0318] Exemplary general method for analytical HPLC: Mobile phase:
A: water (10 mM NH.sub.4HCO.sub.3), B: acetonitrile Gradient:
5%-95% B in 1.6 or 2 min, flow rate: 1.8 or 2 mL/min; Column:
XBridge C18, 4.6*50 mm, 3.5 .quadrature.m at 45 C.
[0319] Exemplary general method for SFC: Column: CHIRALPAK.RTM. AD
(250 mm*30 mm, 5 inm), A=supercritical CO.sub.2, B=MeOH (0.1%
NH.sub.3--H.sub.2O), A:B=70:30, flow rate: 60 mL/min, column
temperature: 38.degree. C., nozzle pressure: 100 bar, detection
wavelength=220 nm.
[0320] Exemplary LCMS conditions include:
TABLE-US-00002 30-90AB_2MIN_E Column Xtimate C18 2.1 * 30 mm, 3 um
Mobile Phase A: water (4 L) + TFA (1.5 mL) B: acetonitrile (4 L) +
TFA (0.75 mL) TIME (min) B % 0 30 0.9 90 1.5 90 1.51 30 2 30 Flow
Rate 1.2 mL/min wavelength UV 220 nm Oven Temp 50.degree. C. MS
ionization ESI Detector PDA, ELSD 10-80AB_2MIN_E Column Xtimate C18
2.1 * 30 mm, 3 um Mobile Phase A: water (4 L) + TFA (1.5 mL) B:
acetonitrile (4 L) + TFA (0.75 mL) TIME (min) B % 0 10 0.9 80 1.5
80 1.51 10 2 10 Flow Rate 1.2 mL/min wavelength UV 220 nm Oven Temp
50.degree. C. MS ionization ESI Detector PDA, ELSD 30-90CD_3MIN_E
Column Xbrige Shield RP-18.5um, 2.1 * 50 mm Mobile Phase A: water
(1 L) + NH3H2O (0.5 mL) B: acetonitrile TIME (min) B % 0 30 2 90
2.48 90 2.49 30 3 30 Flow Rate 1.0 mL/min wavelength UV 220 nm Oven
Temp 30.degree. C. MS ionization ESI Detector PDA, ELSD
Steroid Inhibition of TBPS Binding
[0321] [.sup.35S]-t-Butylbicyclophosphorothionate (TBPS) binding
assays using rat brain cortical membranes in the presence of 5 mM
GABA has been described (Gee et al, J. Pharmacol. Exp. Ther. 1987,
241, 346-353; Hawkinson et al, Mol. Pharmacol. 1994, 46, 977-985;
Lewin, A. H et al., Mol. Pharmacol. 1989, 35, 189-194).
[0322] Briefly, cortices are rapidly removed following decapitation
of carbon dioxide-anesthetized Sprague-Dawley rats (200-250 g). The
cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose
using a glass/teflon homogenizer and centrifuged at 1500.times.g
for 10 min at 4.degree. C. The resultant supernatants are
centrifuged at 10,000.times.g for 20 min at 4.degree. C. to obtain
the P2 pellets. The P2 pellets are resuspended in 200 mM NaCl/50 mM
Na--K phosphate pH 7.4 buffer and centrifuged at 10,000.times.g for
10 min at 4.degree. C. This washing procedure is repeated twice and
the pellets are resuspended in 10 volumes of buffer. Aliquots (100
mL) of the membrane suspensions are incubated with 3 nM
[.sup.35S]-TBPS and 5 mL aliquots of test drug dissolved in
dimethyl sulfoxide (DMSO) (final 0.5%) in the presence of 5 mM
GABA. The incubation is brought to a final volume of 1.0 mL with
buffer. Nonspecific binding is determined in the presence of 2 mM
unlabeled TBPS and ranged from 15 to 25%. Following a 90 min
incubation at room temp, the assays are terminated by filtration
through glass fiber filters (Schleicher and Schuell No. 32) using a
cell harvester (Brandel) and rinsed three times with ice-cold
buffer. Filter bound radioactivity is measured by liquid
scintillation spectrometry. Non-linear curve fitting of the overall
data for each drug averaged for each concentration is done using
Prism (GraphPad). The data are fit to a partial instead of a full
inhibition model if the sum of squares is significantly lower by
F-test. Similarly, the data are fit to a two component instead of a
one component inhibition model if the sum of squares is
significantly lower by F-test. The concentration of test compound
producing 50% inhibition (IC.sub.50) of specific binding and the
maximal extent of inhibition (Imax) are determined for the
individual experiments with the same model used for the overall
data and then the means.+-.SEM.s of the individual experiments are
calculated. Picrotoxin serves as the positive control for these
studies as it has been demonstrated to robustly inhibit TBPS
binding.
[0323] Various compounds are or can be screened to determine their
potential as modulators of [.sup.35S]-TBPS binding in vitro. These
assays are or can be performed in accordance with the above
discussed procedures. The results of the TBPS binding assays are
shown in Table 2.
Abbreviations
[0324] PCC: pyridinium chlorochromate; t-BuOK: potassium
tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane;
Pd(t-Bu.sub.3P).sub.2: bis(tri-tert-butylphosphine)palladium(0);
AcCl: acetyl chloride; i-PrMgCl: Isopropylmagnesium chloride;
TBSCl: tert-Butyl(chloro)dimethylsilane; (i-PrO).sub.4Ti: titanium
tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me:
methyl; i-Pr: iso-propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl;
Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC:
dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP:
4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr:
ethylmagnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine;
AlaOH: alanine; Boc: t-butoxycarbonyl. Py: pyridine; TBAF:
tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS:
t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF.sub.3:
(Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl;
Ti(OiPr).sub.4: tetraisopropoxytitanium; LAH: Lithium Aluminium
Hydride; LDA: lithium diisopropylamide; LiOH.H.sub.2O: lithium
hydroxide hydrates; MAD: methyl aluminum
bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: acetonitrile; NBS:
N-bromosuccinimide; Na.sub.2SO.sub.4: sodium sulfate;
Na.sub.2S.sub.2O.sub.3: sodium thiosulfate; PE: petroleum ether;
MeCN: acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE:
methyl tert-butyl ether; EDCI:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; HATU:
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxide hexafluorophosphate.
Abbreviations
[0325] PCC: pyridinium chlorochromate; t-BuOK: potassium
tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane;
Pd(t-Bu.sub.3P).sub.2: bis(tri-tert-butylphosphine)palladium(0);
AcCi: acetyl chloride; i-PrMgCl: Isopropylmagnesium chloride;
TBSCi: tert-Butyl(chloro)dimethylsilane; (i-PrO).sub.4Ti: titanium
tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me:
methyl; i-Pr: iso-propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl;
Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC:
dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP:
4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr:
ethylmagnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine;
AlaOH: alanine; Boc: t-butoxycarbonyl. Py: pyridine; TBAF:
tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS:
t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF.sub.3:
(Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl;
Ti(OiPr).sub.4: tetraisopropoxytitanium; LAH: Lithium Aluminium
Hydride; LDA: lithium diisopropylamide; LiOH.H.sub.2O: lithium
hydroxide hydrates; MAD: methyl aluminum
bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: acetonitrile; NBS:
N-bromosuccinimide; Na.sub.2SO.sub.4: sodium sulfate;
Na.sub.2S.sub.2O.sub.3: sodium thiosulfate; PE: petroleum ether;
MeCN: acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE:
methyl tert-butyl ether; EDCI:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; HATU:
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxide hexafluorophosphate.
Example 1. Syntheses of Compounds 1 and 2
##STR00142## ##STR00143##
[0327] Step 1. To a solution of A1 (100 g, 290 mmol) in THF (500
mL) was added Pd--C(wet, 10%, 10 g) under N.sub.2. The suspension
was degassed under vacuum and purged with H.sub.2 for three times.
The mixture was stirred under H.sub.2 (15 psi) at 25 C for 48 hours
to give a black suspension. The reaction mixture was filtered
through a pad of Celite and washed with THF (500 mL). The filtrate
was concentrated and to give A2 (98 g, 97%) as a solid.
[0328] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.73-4.62 (m, 1H),
2.65-2.54 (m, 1H), 2.51-2.32 (m, 3H), 2.20-2.06 (m, 2H), 2.04 (s,
3H), 1.95-1.86 (m, 1H), 1.84-1.67 (m, 5H), 1.67-1.42 (m, 5H),
1.25-1.02 (m, 6H), 0.91-0.81 (m, 3H).
[0329] Step 2. To a solution of MePPh.sub.3Br (20.6 g, 57.7 mmol,
1.0 eq) in THF (200 mL) was added t-BuOK (6.47 g, 57.7 mmol, 1.0
eq) at 0.degree. C. After addition, the reaction mixture was heated
to 20.degree. C. and stirred for 1 hour. Then the mixture was added
to a solution A2 (20 g, 57.7 mmol, 1.0 eq) in THF (200 mL) and the
reaction mixture was stirred at 20.degree. C. for 2 h. The mixture
was treated with NH.sub.4Cl (100 mL, 10%) and extracted with EtOAc
(2.times.100 mL). The organic phase was separated and concentrated
in vacuum to afford product a crude residue. The residue was
triturated from MeOH/H.sub.2O (400 ml, 1/1) at 20.degree. C. to
give a crude residue. The crude residue was dissolved in DCM (200
mL), washed with saturated brine (2.times.50 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give A3
(19 g, 96%) as a solid.
[0330] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.75 (s, 1H), 4.64
(s, 1H), 2.51-2.44 (m, 1H), 2.35-2.32 (m, 1H), 2.23-2.11 (m, 2H),
2.04 (s, 3H), 1.99-1.93 (m, 1H), 1.86-1.63 (m, 7H), 1.54-1.19 (m,
7H), 1.08-1.01 (m, 1H), 0.99 (s, 3H), 0.90 (s, 3H), 0.89-0.81 (m,
1H).
[0331] Step 3. To a solution of A3 (19 g, 55.1 mmol) in ethanol
(100 mL) was added Pd--C(dry, 10%, 2 g) under N.sub.2. The
suspension was degassed under vacuum and purged with H.sub.2 for
three times. The mixture was stirred for 20 hrs at 15.degree. C.
under H.sub.2. The reaction mixture was filtered and the filtrate
was concentrated in vacuum to give A4 (18 g, 95%) as a solid.
[0332] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.72-4.67 (m, 1H),
2.46-2.40 (m, 1H), 2.13-2.03 (m, 4H), 1.94-1.91 (m, 1H), 1.80-1.22
(m, 15H), 1.15-1.01 (m, 4H), 0.94-0.75 (m, 8H).
[0333] Step 4. To a solution of A4 (18 g, 51.9 mmol) in MeOH (200
mL) was added K.sub.2CO.sub.3 (28.6 g, 207 mmol) in one portion at
15.degree. C. under N.sub.2. The mixture was stirred at 15.degree.
C. for 2 h and quenched with water (100 mL). The aqueous phase was
extracted with DCM (3.times.100 mL). The combined organic phase was
washed with saturated brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to afford A5 (15.2 g,
96%) as colourless oil.
[0334] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.62-3.60 (m, 1H),
2.62-2.40 (m, 1H), 2.11-2.04 (m, 2H), 1.96-1.90 (m, 1H), 1.80-1.02
(m, 20H), 0.90-0.80 (m, 6H), 0.76-0.70 (m, 1H).
[0335] Step 5. To a solution of A5 (8 g, 26.2 mmol) in DCM (100 mL)
was added silica gel (11.2 g) and PCC (11.2 g, 52.6 mmol) at
25.degree. C. The reaction mixture was stirred at 25.degree. C. for
1 h. The resulting mixture was filtered and the filtrate was
concentrated in vacuum. To a solution of the crude product in DCM
(20 mL) was added silica gel (20 g) and PE (100 mL). After stirring
at 25.degree. C. for 30 mins, the mixture was and filtered and the
filtrate was concentrated in vacuum to give A6 (7 g) as a
solid.
[0336] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.42-2.06 (m, 8H),
1.80-1.77 (m, 4H), 1.45-1.22 (m, 8H), 1.05-0.84 (m, 10H).
[0337] Step 6. A suspension of LiCl (2.05 g, 48.5 mmol, anhydrous)
in THF (200 mL, anhydrous) was stirred at 10.degree. C. for 30 mins
under N.sub.2. FeCl.sub.3 (4.11 g, 25.4 mmol, anhydrous) was added
at 10.degree. C. After cooling to -30.degree. C., MeMgBr (30.8 mL,
3M in diethyl ether) was added drop-wise at -30.degree. C. After
stirring at -30.degree. C. for 10 mins, A6 (7 g, 23.1 mmol) was
added at -30.degree. C. The mixture was stirred at -15.degree. C.
for 2 hours and quenched with citric acid (200 mL, 10% aq.). The
mixture was extracted with EtOAc (2.times.100 mL). The combined
organic phase was washed with saturated brine (300 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to
give a crude product, which was purified by a silica gel column
(PE/EtOAc=0.about.10/1) to give A7 (1 g, 14%, Rf=0.45 in PE/EtOAc)
and A8 (0.8 g, 11%, Rf=0.40 in PE/EtOAc) and a mixture (4 g) as
solid.
[0338] A7:
[0339] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.48-2.41 (m, 1H),
2.13-2.08 (m, 1H), 1.97-1.90 (m, 1H), 1.84-1.67 (m, 4H), 1.55-1.47
(m, 5H), 1.41-1.25 (m, 5H), 1.23-1.01 (m, 8H), 0.97-0.94 (m, 3H),
0.86 (s, 3H), 0.79 (s, 3H).
[0340] The stereochemistry at C7 of A7 was confirmed by NOE.
[0341] A8:
[0342] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.48-2.38 (m, 1H),
2.12-2.07 (m, 1H), 1.79-1.73 (m, 2H), 1.56-1.49 (m, 4H), 1.46-1.38
(m, 2H), 1.32-1.19 (m, 12H), 1.03-0.97 (m, 4H), 0.87 (s, 3H),
0.86-0.76 (m, 2H), 0.73 (s, 3H).
[0343] The stereochemistry at C7 of A8 was confirmed by NOE.
[0344] Step 7a (Compound 1). Into a over-dried bottom was added
t-BuOH (2 mL) and t-BuOK (703 mg, 6.27 mmol). After evaporating and
filling with N.sub.2, a solution of A7 (200 mg, 0.627 mmol) in DME
(1 mL) was added. After 30 min, a solution of TosMic (243 mg, 1.25
mmol) in DME (1 mL) was added. The mixture became yellow. The
resulting mixture was stirred at 25.degree. C. for 16 h and
quenched with water. The mixture was extracted with ethyl acetate
(3.times.30 mL). The combined organic layer was washed with brine.
The combined organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
flash chromatography eluting with (petroleum ether/ethyl
acetate=10/1) to give Compound 1 (50 mg, 24%) as a solid.
[0345] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.2.30-2.24 (m, 1H),
2.16-2.06 (m, 1H), 1.97-1.87 (m, 2H), 1.83-1.71 (m, 3H), 1.67-1.58
(m, 1H), 1.54-1.42 (m, 5H), 1.39-1.24 (m, 4H), 1.20-1.01 (m, 9H),
0.93-0.88 (m, 6H), 0.77 (s, 3H).
[0346] LCMS Rt=1.918 min in 3.0 min chromatography, 10-80 AB_3
MIN_E.M, purity 100%, MS ESI calcd. for C.sub.22H.sub.34N
[M+H--H.sub.2O].sup.+ 312, found 312.
[0347] Step 7b (Compound 2). In an oven-dried round bottom flask
was added t-BuOH (2 mL) and t-BuOK (703 mg, 6.27 mmol). The
reaction vessel was evaporated and filled with N.sub.2. A8 (200 mg,
0.627 mmol) in DME (1 mL) was added into the suspension. After 30
min, TosMIC (243 mg, 1.25 mmol) in DME (1 mL) was added. The
mixture became yellow. The resulting mixture was stirred at
25.degree. C. for 16 h. Water was added and the mixture was
stirred. Then it was extracted with ethyl acetate (3.times.30 mL).
The combined organic layer was washed with brine. The combined
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by flash chromatography
eluting with (petroleum ether:ethyl acetate=4:1) to give Compound 2
(13 mg, 6%) as a solid.
[0348] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.26-2.17 (m, 1H),
2.14-2.00 (m, 1H), 1.99-1.85 (m, 3H), 1.73-1.67 (m, 1H), 1.56-1.44
(m, 5H), 1.30-1.24 (m, 4H), 1.20 (s, 3H), 1.17-1.09 (m, 4H),
1.04-0.88 (m, 8H), 0.85-0.76 (m, 2H), 0.72 (s, 3H).
[0349] LCMS Rt=1.939 min in 3.0 min chromatography, 10-80 AB_3
MIN_E.M, purity 100%, MS ESI calcd. for C.sub.22H.sub.34NO
[M+H--H.sub.2O].sup.+312, found 312.
Example 2. Syntheses of Compounds 3 and 4
##STR00144##
[0351] Step 1a (B1). To a solution of A7 (200 mg, 0.627 mmol) in
MeOH (5 mL) was added NaBH.sub.4 (47.2 mg, 1.25 mmol) at 25.degree.
C. After stirring at 25.degree. C. for 30 mins, the reaction was
quenched by adding water (10 mL) and extracted with DCM (2.times.20
mL). The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to give B1 (180 mg, crude) as a
solid, which was directly used for next step without further
purification.
[0352] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.67-3.62 (m, 1H),
2.11-2.02 (m, 1H), 1.82-1.75 (m, 3H), 1.63-1.37 (m, 11H), 1.34-1.20
(m, 8H), 1.14-1.01 (m, 4H), 0.90 (d, J=4.0 Hz, 2H), 0.78 (s, 3H),
0.74 (s, 3H).
[0353] Step 2a (Compound 3). To a solution of B1 (180 mg, 0.561
mmol) in THF (5 mL) was added KOH (94.2 mg, 1.68 mmol) and
Me.sub.2SO.sub.4 (0.282 mg, 0.211 mL, 2.24 mmol) at 0.degree. C.
Then the mixture was warmed to 25.degree. C. and stirred at the
same temperature for 16 h. The mixture was quenched with 50 mL of
water and extracted with EtOAc (2.times.30 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuum to give crude product which was purified by
a silica gel column (PE/EtOAc=0-10/1) to give Compound 3 (21 mg,
11%) as a solid.
[0354] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.34 (s, 3H), 3.22
(t, J=8.0 Hz, 1H), 2.04-1.96 (m, 1H), 1.88-1.71 (m, 3H), 1.63-1.56
(m, 2H), 1.54-1.34 (m, 7H), 1.32-1.17 (m, 8H), 1.16-0.97 (m, 5H),
0.90 (d, J=4.0 Hz, 2H), 0.76 (s, 3H), 0.74 (s, 3H).
[0355] LCMS Rt=2.050 min in 3.0 min chromatography, 10-80 AB_3
MIN_E.M, purity 100%, MS ESI calcd. for C.sub.22H.sub.37O
[M+H--H.sub.2O].sup.+317, found 317.
[0356] Step 1b (B2). To a solution of A8 (200 mg, 0.627 mmol) in
MeOH (5 mL) was added NaBH.sub.4 (47.2 mg, 1.25 mmol) at 25.degree.
C. After stirring at 25.degree. C. for 30 mins, the reaction was
quenched by adding water (10 mL) and extracted with DCM (2.times.20
mL). The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to give B2 (170 mg, crude) as a
solid, which was directly used for next step without further
purification.
[0357] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.62-3.56 (m, 1H),
2.08-1.99 (m, 1H), 1.81-1.76 (m, 2H), 1.68-1.62 (m, 1H), 1.58-1.38
(m, 7H), 1.33-0.99 (m, 15H), 0.94 (d, J=8.0 Hz, 2H), 0.84-0.77 (m,
1H), 0.75 (s, 3H), 0.73 (s, 3H).
[0358] Step 2b (Compound 4). To a solution of B2 (170 mg, 0.530
mmol) in THF (5 mL) was added KOH (88.6 mg, 1.58 mmol) and
Me.sub.2SO.sub.4 (0.266 mg, 0.2 mL, 2.11 mmol) at 0.degree. C. Then
the mixture was warmed to 25.degree. C. and stirred at the same
temperature for 16 h. The mixture was quenched with the addition of
50 mL of water and extracted with EtOAc (2.times.30 mL). The
combined organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuum to give a crude product, which was
purified by a silica gel column (PE/EtOAc=0-10/1) to give Compound
4 (21 mg, 11%) as a solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 3.34 (s, 3H), 3.16 (t, J=8.0 Hz, 1H), 2.02-1.93 (m, 1H),
1.88 (dt, J=4.0, 12.0 Hz, 1H), 1.77-1.74 (m, 1H), 1.64-1.39 (m,
9H), 1.33-1.08 (m, 12H), 1.03-0.96 (m, 1H), 0.93 (d, J=8.0 Hz, 2H),
0.80-0.74 (m, 1H), 0.75 (s, 3H), 0.71 (s, 3H).
[0359] LCMS Rt=2.079 min in 3.0 min chromatography, 10-80 AB_3
MIN_E.M, purity 100%, MS ESI calcd. for C.sub.22H.sub.37O
[M+H--H.sub.2O].sup.+317, found 317.
Example 3. Syntheses of Compounds 5 and 6
##STR00145## ##STR00146##
[0361] Step 1. To a suspension of PPh.sub.3EtBr (1.91 g, 5.15 mmol)
in THF (10 mL) was added t-BuOK (0.577 g, 5.15 mmol) at 10.degree.
C. The color of the suspension turned dark red. After stirring at
40.degree. C. for 30 min, a solution of A7 (0.55 g, 1.72 mmol) in
THF (2 mL) was added at 40.degree. C. After stirring at 40.degree.
C. for 1 h, the reaction mixture was poured into 20 g of crushed
ice and stirred for 15 minutes. The organic layer was separated and
the water phase was extracted with EtOAc (2.times.20 mL). The
combined organic phase was washed with saturated brine (2.times.20
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered concentrated
and purified by flash column (0.about.10% of EtOAc in PE) to give
C1 (350 mg, 62%) as a solid.
[0362] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.14-5.08 (m, 1H),
2.41-2.32 (m, 1H), 2.26-2.12 (m, 2H), 1.87-1.70 (m, 2H), 1.67-1.44
(m, 10H), 1.40-1.08 (m, 11H), 1.07-1.03 (m, 1H), 1.05-0.99 (m, 1H),
0.91 (d, J.sup.=6.8 Hz, 3H), 0.86 (s, 3H), 0.77 (s, 3H).
[0363] Step 2. To a solution of C1 (200 mg, 0.605 mmol) in THF (3
mL) was added drop-wise a solution of BH.sub.3-Me.sub.2S (0.605 mL,
6.05 mmol) at 0.degree. C. The solution was stirred at 15.degree.
C. for 3 h. After cooling to 0.degree. C., a solution of NaOH
solution (3.62 mL, 2 M) was added very slowly. After addition,
H.sub.2O.sub.2 (683 mg, 6.05 mmol, 30% in water) was added slowly
and the inner temperature was maintained below 10.degree. C. After
stirring at 15.degree. C. for 2 h, the saturated aqueous
Na.sub.2S.sub.2O.sub.3 (50 mL) was added until the reaction
solution became clear. The mixture was extracted with EtOAc
(3.times.50 mL). The combined organic solution was washed with
saturated aqueous Na.sub.2S.sub.2O.sub.3 (2.times.20 mL), brine (20
mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give
the crude product (180 mg) as a solid, which was used in next step
without further purification.
[0364] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.77-3.66 (m, 1H),
1.82-1.71 (m, 3H), 1.54-1.42 (m, 8H), 1.32-1.06 (m, 19H), 0.91 (d,
J=8.0 Hz, 3H), 0.75 (s, 3H), 0.65 (s, 3H).
[0365] Step 3. To a solution of C3 (180 mg, 0.516 mmol) in DCM (5
mL) was added silica gel (222 mg) and PCC (222 mg, 1.03 mmol) at
25.degree. C. The reaction mixture was stirred at 25.degree. C. for
1 h. The resulting mixture was filtered and the filtrate
concentrated in vacuum. To a solution of the crude product in DCM
(20 mL) was added silica gel (20 g) and PE (100 mL). The mixture
was stirred at 25.degree. C. for 30 mins and filtered and the
filtrate was concentrated in vacuum to give crude product, which
was purified by flash column (0-10% of EtOAc in PE) to give
Compound 5 (29 mg, 16%) as a solid.
[0366] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.53 (t, J=8.0 Hz,
1H), 2.20-2.14 (m, 1H), 2.11 (s, 3H), 2.01-1.94 (m, 1H), 1.83-1.73
(m, 2H), 1.70-1.59 (m, 3H), 1.55-1.43 (m, 5H), 1.39-1.12 (m, 12H),
1.04-1.01 (m, 1H), 0.92 (d, J=8.0 Hz, 3H), 0.76 (s, 3H), 0.60 (s,
3H).
[0367] LCMS Rt=2.150 min in 3.0 min chromatography, 10-80 AB_3
MIN_E.M, purity 100%, MS ESI calcd. for C.sub.23H.sub.37O
[M+H--H.sub.2O].sup.+329, found 329.
[0368] Step 4. To a suspension of PPh.sub.3EtBr (1.21 g, 3.27 mmol)
in THF (10 mL) was added t-BuOK (0.366 g, 3.27 mmol) at 10.degree.
C. The color of the suspension turned dark red. After stirring at
40.degree. C. for 30 min, a solution of A8 (0.35 g, 1.09 mmol) in
THF (2 mL) was added at 40.degree. C. and the reaction mixture was
stirred at 40.degree. C. for 1 h. The reaction mixture was poured
into 20 g of crushed ice and stirred for 15 minutes. The organic
layer was separated and the water phase was extracted with EtOAc
(2.times.20 mL). The combined organic phase was washed with
saturated brine (2.times.20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered concentrated and purified by flash
column (0.about.10% of EtOAc in PE) to give C3 (140 mg, 39%) as a
solid.
[0369] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.15-5.12 (m, 1H),
2.31-2.22 (m, 3H), 1.81-1.73 (m, 1H), 1.70-1.61 (m, 4H), 1.56-1.40
(m, 7H), 1.34-1.18 (m, 12H), 0.95 (d, J=4.0 Hz, 3H), 0.89 (s, 3H),
0.87-0.79 (m, 1H), 0.72 (s, 3H).
[0370] Step 5. To a solution of C3 (120 mg, 0.363 mmol) in THF (3
mL) was added drop-wise a solution of BH.sub.3-Me.sub.2S (0.363 mL,
3.63 mmol) at 0.degree. C. The solution was stirred at 15.degree.
C. for 3 h. After cooling to 0.degree. C., a solution of NaOH
solution (2.17 mL, 2M) was added very slowly. After addition,
H.sub.2O.sub.2 (410 mg, 3.63 mmol, 30% in water) was added slowly
and the inner temperature was maintained below 10.degree. C. The
resulting solution was stirred at 15.degree. C. for 2 h. Then
saturated aqueous Na.sub.2S.sub.2O.sub.3 (50 mL) was added until
the reaction solution became clear. The mixture was extracted with
EtOAc (3.times.50 mL). The combined organic solution was washed
with saturated aqueous Na.sub.2S.sub.2O.sub.3 (2.times.20 mL),
brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated in
vacuum to give the crude product (100 mg) as a solid, which was
used in next step without further purification.
[0371] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.76-3.64 (m, 1H),
1.86-1.79 (m, 3H), 1.54-1.39 (m, 8H), 1.28-1.17 (m, 17H), 0.95 (d,
J=6.0 Hz, 3H), 0.82-0.74 (m, 2H), 0.71 (s, 3H), 0.67 (s, 3H).
[0372] Step 6. To a solution of C4 (100 mg, 0.286 mmol) in DCM (5
mL) was added silica gel (123 mg) and PCC (123 mg, 0.572 mmol) at
25.degree. C. The reaction mixture was stirred at 25.degree. C. for
1 h. The resulting mixture was filtered and the filtrate
concentrated by vacuum. To a solution of the crude product in DCM
(20 mL) was added silica gel (20 g) and PE (100 mL). The mixture
was stirred at 25.degree. C. for 30 mins and filtered and the
filtrate was concentrated in vacuum to give crude product. The
crude product was purified by flash column (0-10% of EtOAc in PE)
to give Compound 6 (13 mg, 13%) as a solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 2.48 (t, J=9.2 Hz, 1H), 2.16-2.09 (m, 4H),
2.01-1.95 (m, 1H), 1.86-1.82 (m, 1H), 1.73-1.59 (m, 2H), 1.54-1.42
(m, 5H), 1.40-1.14 (m, 13H), 1.05-0.96 (m, 1H), 0.95 (d, J=6.0 Hz,
3H), 0.88-0.80 (m, 1H), 0.71 (s, 3H), 0.62 (s, 3H)
[0373] LCMS Rt=2.184 min in 3.0 min chromatography, 10-80 AB_3
MIN_E.M, purity 100%, MS ESI calcd. for C.sub.23H.sub.37O
[M+H--H.sub.2O].sup.+329, found 329.
Example 4. Syntheses of Compounds 7, 8, 9, and 10
##STR00147## ##STR00148## ##STR00149##
[0374] Example 13. Syntheses of Compounds 7 and 8
[0375] Part I
[0376] Step 1. To a suspension of PPh.sub.3EtBr (72.7 g, 196 mmol)
in THF (200 mL) was added t-BuOK (21.9 g, 196 mmol) at 10.degree.
C. The color of the suspension was turned to dark red. After
stirring at 40.degree. C. for 30 min, a solution of A5 (20 g, 65.6
mmol) in THF (20 mL) was added at 40.degree. C. and the reaction
mixture was stirred at 40.degree. C. for 1 h. The reaction mixture
was poured into 200 g of crashed ice and stirred for 15 minutes.
The organic layer was separated and the water phase was extracted
with EtOAc (2.times.200 mL). The combined organic phase was washed
with saturated brine (2.times.200 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered concentrated and purified by flash
column (0.about.30% of EtOAc in PE) to give D1 (19.5 g, 94%) as a
solid.
[0377] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.20-5.01 (m, 1H),
3.70-3.50 (m, 1H), 2.48-2.15 (m, 3H), 1.89-1.52 (m, 8H), 1.52-1.09
(m, 7H), 1.09-0.93 (m, 5H), 0.93-0.70 (m, 11H).
[0378] Step 2. To a solution of D1 (10 g, 31.5 mmol) in anhydrous
DCM (100 mL) was added silica gel (10 g) and PCC (13.5 g, 63.0
mmol). The mixture was stirred at 15.degree. C. for 2 hours. The
reaction mixture was filtered, and the filtrate was concentrated.
The residue was purified by flash column (0.about.30% of EtOAc in
PE) to give D2 (6.6 g, 67%) as a solid.
[0379] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.20-50.8 (m, 1H),
2.49-2.15 (m, 6H), 2.15-1.95 (m, 2H), 1.95-1.72 (m, 2H), 1.72-1.19
(m, 10H), 1.19-0.95 (m, 7H), 0.95-0.75 (m, 6H).
[0380] Step 3. Under nitrogen atmosphere, anhydrous THF (100 mL)
was cooled to 10.degree. C. and anhydrous LiCl (3.54 g, 83.6 mmol)
was added in one portion. The mixture was stirred for 30 min to
obtain a clear solution. To this solution was added anhydrous
FeCl.sub.3 (7.44 g, 45.9 mmol) in one portion. The resulting
mixture was stirred for additional 30 mins. The reaction mixture
was cooled to -35.degree. C. and methyl magnesium bromide (3 M in
diethyl ether, 55.6 mL, 167 mmol) was added dropwise maintaining
the internal temperature between -35.degree. C. and -30.degree. C.
The above mixture was stirred for 30 min at -30.degree. C. A
solution of D2 (6.6 g, 20.9 mmol) in THF (20 mL) was added in one
portion. The internal temperature was allowed to -20.degree. C. and
held between -15.degree. C. and -20.degree. C. for 2 hrs. The
reaction mixture was poured into ice-cooled aqueous HCl (1 M, 200
mL), extracted with EtOAc (2.times.200 mL). The combined organic
layer was washed with water (200 mL), aqueous NaOH (10%,
2.times.200 mL) and brine (200 mL), dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by
column chromatography on silica gel (PE/EtOAc=20/1 to 20/1) to give
D3 (6.5 g, 94%) as a colorless oil.
[0381] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.15-5.05 (m, 1H),
2.42-2.11 (m, 3H), 1.90-1.40 (m, 16H), 1.40-1.10 (m, 5H), 1.10-0.81
(m, 10H), 0.81-0.69 (m, 3H).
[0382] Step 4. To a solution of D3 (6 g, 18.1 mmol) in THF (85 mL)
was added 9-BBN dimer (13.2 g, 54.3 mmol). The mixture was stirred
at 50.degree. C. for 2 hrs. After cooling to 0.degree. C., to the
reaction mixture was added ethanol (10.3 mL, 181 mmol) and NaOH
(36.1 mL, 5 M, 181 mmol) very slowly. After addition,
H.sub.2O.sub.2 (18.1 mL, 181 mmol, 30%) was added slowly and the
inner temperature was maintained below 15.degree. C. The resulting
solution was stirred at 75.degree. C. for 1 hrs. The mixture was
cooled and added to water (100 mL). The aqueous phase was extracted
with EtOAc (3.times.100 mL). The combined organic phase was washed
with saturated brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to give D4 (5.9 g,
crude) as colourless oil which was used directly for the next step
without purification.
[0383] Step 5. To a suspension of D4 (5.9 g, 16.9 mmol) in DCM (100
mL) was added silica gel (3 g) and PCC (5.45 g, 25.3 mmol) at
15.degree. C. The mixture was stirred at 15.degree. C. for 2 hrs.
The mixture was filtered and the filtrated cake was washed with DCM
(50 mL). The combined filtrate was concentrated in vacuum and
purified by flash column (0.about.30% of EtOAc in PE) to afford D5
(4.3 g, impure) as a solid.
[0384] Step 6. To a solution of D5 (500 mg, 1.44 mmol) in MeOH (10
ml) was added HBr (57.4 mg, 0.29 mmol, 40% in water) and Br.sub.2
(337 mg, 2.15 mmol) at 25.degree. C. The mixture was stirred at
25.degree. C. for 2 hrs. The mixture was quenched by sat.aq
NaHCO.sub.3 (10 mL), treated with water (20 mL), extracted with
EtOAc (2.times.20 mL). The combined organic phase was washed with
brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered,
concentrated in vacuum to afford D6 (480 mg, crude) as light yellow
oil, which was used directly for the next step.
[0385] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.97-3.86 (m, 2H),
2.86-2.71 (m, 1H), 2.24-1.96 (m, 2H), 1.93-1.68 (m, 6H), 1.54-1.43
(m, 5H), 1.35-1.23 (m, 5H), 1.21-1.15 (m, 5H), 0.96-0.79 (m, 4H),
0.77-0.58 (m, 7H).
[0386] Step 7. To a solution of 1H-pyrazolo[3,4-c]pyridine (139 mg,
1.17 mmol) in THF (10 mL) was added NaH (89.5 g, 2.24 mmol, 60%) in
portions at 25.degree. C. The mixture was stirred at 60.degree. C.
for 10 min. Then D6 (480 mg, 1.12 mmol) in THF (10 mL) was added
drop-wise to the solution. The mixture was stirred at 60.degree. C.
for 1 h. The mixture was poured into water (50 mL) and extrated
with EtOAc (3.times.20 mL). The combined organe layer was washed
with brine (50 mL), dried over with Na.sub.2SO.sub.4 and
concentrated to afford crude product. The residue was purified by
silica gel chromatography (100-200 mesh silica gel, Petroleum
ether/Ethyl acetate=0/1) to afford the mixture of D7 and D8 (290
mg, crude) as a solid.
[0387] Step 8 (Compounds 9 and 10). D8 (290 mg, 0.62 mmol) was
purified by SFC (column: OD (250 mm*30 mm, 10 um)), gradient:
40-40% B (A=0.1% NH.sub.3/H.sub.2O, B=EtOH), flow rate: 80 mL/min)
to give pure Compound 9 (48 mg, 16%) and pure Compound 10 (18 mg,
6%) as a solid.
[0388] Compound 9:
[0389] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.8 (s, 1H),
8.39-8.29 (m, 1H), 8.1 (s, 1H), 7.68-7.61 (d, J=4.8 Hz, 1H),
5.32-5.19 (m, 2H), 2.76-2.62 (m, 1H), 2.27-2.06 (m, 2H), 1.84-1.67
(m, 4H), 1.53-1.26 (m, 11H), 1.23-1.09 (m, 7H), 1.08-1.01 (m, 1H),
0.96-0.89 (d, J=7.2 Hz, 3H), 0.77 (s, 3H), 0.71 (s, 3H).
[0390] LCMS Rt=0.885 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.29H.sub.42N.sub.3O.sub.2
[M+H].sup.+ 464, found 464.
[0391] SFC Rt=1.785 min in 3 min chromatography, OD-H_3 UM 3_5_40_4
ML_3 MIN, purity: 100%.
[0392] Compound 10:
[0393] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.80 (s, 1H),
8.39-8.28 (m, 1H), 8.09 (s, 1H), 7.69-7.61 (d, J=4.8 Hz, 1H),
5.34-5.17 (m, 2H), 2.68-2.57 (m, 1H), 2.24-2.09 (m, 2H), 1.96-1.71
(m, 4H), 1.47-1.13 (m, 15H), 1.07-0.81 (m, 7H), 0.73 (s, 6H).
[0394] LCMS Rt=0.908 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 98%, MS ESI calcd. for C.sub.29H.sub.42N.sub.3O.sub.2
[M+H].sup.+ 464, found 464.
[0395] SFC Rt=2.132 min in 3 min chromatography, OD-H_3 UM 3_5_40_4
ML_3 MIN, purity: 99%.
[0396] Part II
[0397] Step 1. To a solution of D5 (500 mg, 1.44 mmol) in MeOH (10
ml) was added HBr (57.4 mg, 0.288 mmol, 40% in water) and Br.sub.2
(229 mg, 1.46 mmol) at 25.degree. C. The mixture was stirred at
25.degree. C. for 16 hrs. The mixture was quenched by sat.aq
NaHCO.sub.3 (10 mL), treated with water (20 mL), extracted with
EtOAc (2.times.20 mL). The combined organic phase was washed with
brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered,
concentrated in vacuum to afford D6 (500 mg, crude) as a solid used
directly for the next step.
[0398] Step 2 (Compounds 7 and 8). To a mixture of D6 (500 mg, 1.17
mmol) and K.sub.2CO.sub.3 (323 mg, 2.34 mmol) in acetone (3 mL) was
added 1H-pyrazolo[3,4-c]pyridine (1.45 mg, 1.22 mmol) at 25.degree.
C. The mixture was stirred at 25.degree. C. for 12 h. The mixture
was poured into water (50 mL) and extracted with EtOAc (3.times.20
mL). The combined organic layer was washed with brine (50 mL),
dried over with Na.sub.2SO.sub.4, filtered and concentrated to
afford crude product, which was purified by prep-HPLC separation
(column: Phenomenex Synergi C18 150*30 mm*4 um)), gradient: 28-58%
B (A=0.1% HCl, B=ACN), flow rate: 30 mL/min) and then SFC (column:
OJ (250 mm*30 mm, 10 um)), gradient: 35-35% B (A=0.1%
NH.sub.3H.sub.2O, B=ETOH), flow rate: 80 mL/min) to afford Compound
8 (15 mg, yield 75%) as a solid and Compound 7 (5 mg, yield 25%) as
a solid.
[0399] Compound 7:
[0400] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.26 (s, 1H),
8.27-8.17 (m, 1H), 7.98 (s, 1H), 7.58-7.49 (m, 1H), 5.32 (d, J=16.0
Hz, 1H), 5.22 (d, J=16.0 Hz, 1H), 2.62 (t, J=8.0 Hz, 1H), 2.24-2.09
(m, 2H), 1.97-1.89 (m, 1H), 1.81-1.72 (m, 2H), 1.52-1.42 (m, 4H),
1.37-1.13 (m, 14H), 1.05-0.98 (m, 1H), 0.96 (d, J=8.0 Hz, 3H),
0.90-0.82 (m, 1H), 0.74-0.71 (m, 6H).
[0401] LCMS Rt=2.406 in in 4.0 min chromatography, 10-80AB.lcm,
purity 99.3%, MS ESI calcd. for C.sub.29H.sub.42N.sub.3O.sub.2
[M+H].sup.+ 464, found 464.
[0402] Compound 8:
[0403] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.26 (s, 1H), 8.17
(d, J=8.0 Hz, 1H), 7.98 (s, 1H), 7.52 (dd, J=1.0, 8.0 Hz, 1H), 5.32
(d, J=16.0 Hz, 1H), 5.22 (d, J=16.0 Hz, 1H), 2.67 (t, J=8.0 Hz,
1H), 2.28-2.18 (m, 1H), 2.11-2.08 (m, 1H), 1.85-1.67 (m, 5H),
1.65-1.36 (m, 10H), 1.27-1.12 (m, 7H), 1.04 (br d, J=13.3 Hz, 1H),
0.93 (d, J=8.0 Hz, 3H), 0.77 (s, 3H), 0.71 (s, 3H).
[0404] LCMS Rt=2.358 in in 4.0 min chromatography, 10-80AB.lcm,
purity 99.7%, MS ESI calcd. for C.sub.29H.sub.42N.sub.3O.sub.2
[M+H].sup.+ 464, found 464.
Example 5. Synthesis of Compound 11
##STR00150## ##STR00151##
[0406] Step 1. To a solution of
chloro(methoxymethyl)triphenylphosphorane (19.7 g, 57.7 mmol) in
THF (200 mL) was added t-BuLi (44.3 mL, 57.7 mmol, 1.3 M in
n-hexane) at -10.degree. C., after addition, the reaction mixture
was stirred for 1 hour. Then the mixture was added to A2 (20 g,
57.7 mmol) in THF (200 mL) at 0.degree. C. and the reaction mixture
was stirred at 15.degree. C. for 2 h. The mixture was treated with
NH.sub.4Cl (100 mL, 10%), EtOAc (2.times.200 mL) was added. The
organic phase was separated, concentrated in vacuum to afford crude
product. The residue was purified by flash column (0.about.30% of
EtOAc in PE) to give E1 (5 g, 23%) as a solid.
[0407] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.77 (s, 1H),
4.75-4.60 (m, 1H), 3.56 (s, 3H), 2.60-2.42 (m, 2H), 2.31-1.98 (m,
8H), 1.80-1.38 (m, 6H), 1.38-1.19 (m, 4H), 1.19-0.80 (m, 9H).
[0408] Step 2. To a solution of E1 (5 g, 13.3 mmol) in MeOH (50 mL)
was added Pd--C(dry, 10%, 1 g) under N.sub.2. The suspension was
degassed under vacuum and purged with H.sub.2 for three times. The
mixture was stirred under H.sub.2 (15 psi) at 15.degree. C. for 16
hours to give a black suspension. The reaction mixture was filtered
through a pad of Celite and washed with EtOH (3.times.20 mL). The
filtrate was concentrated to E2 (3.8 g, 76%) as a solid.
[0409] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.78-4.60 (m, 1H),
3.42-3.35 (m, 1H), 3.35-3.28 (m, 4H), 2.50-2.38 (m, 1H), 2.20-1.95
(m, 5H), 1.85-1.60 (m, 7H), 1.60-1.18 (m, 8H), 1.18-0.91 (m, 2H),
0.91-0.76 (m, 7H).
[0410] Step 3. To a solution of E2 (3.8 g, 10.0 mmol) in MeOH (50
mL) was added K.sub.2CO.sub.3 (5.52 g, 40.0 mmol) in one portion at
15.degree. C. under N.sub.2. The mixture was stirred at 15.degree.
C. for 2 h. Water (20 mL) was added. The aqueous phase was
extracted with DCM (3.times.20 mL). The combined organic phase was
washed with saturated brine (2.times.20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to afford E3 (3 g, 90%)
as a solid.
[0411] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.68-3.51 (m, 1H),
3.51-3.39 (m, 1H), 3.35-3.28 (m, 4H), 2.50-2.38 (m, 1H), 2.20-2.01
(m, 2H), 1.85-1.70 (m, 5H), 1.70-1.46 (m, 5H), 1.46-1.12 (m, 7H),
1.12-0.91 (m, 1H), 0.91-0.70 (m, 7H).
[0412] Step 4. To a suspension of PPh.sub.3EtBr (11.5 g, 31.2 mmol)
in THF (50 mL) was added t-BuOK (3.5 g, 31.2 mmol) at 10.degree. C.
The color of the suspension turned dark red. After stirring at
40.degree. C. for 1 hour, a solution of E3 (3.5 g, 10.4 mmol) in
THF (20 mL) was added at 40.degree. C. and the reaction mixture was
stirred at 40.degree. C. for 16 h. The mixture was added saturated
NH.sub.4Cl solution (20 mL) and extracted with EtOAc (2.times.20
mL). The organic layer was separated and the water phase was
extracted with EtOAc (2.times.10 mL). The combined organic phase
was washed with saturated brine (2.times.20 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered concentrated and purified by
flash column (0.about.30% of EtOAc in PE) to give E4 (1.5 g, 42%)
as a solid.
[0413] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.15-5.05 (m, 1H),
3.68-3.55 (m, 1H), 3.51-3.39 (m, 1H), 3.35-3.28 (m, 4H), 2.40-2.31
(m, 1H), 2.22-2.10 (m, 2H), 2.01-1.49 (m, 8H), 1.49-1.11 (m, 6H),
1.11-0.75 (m, 14H).
[0414] The stereochemistry at C7 of E4 was confirmed by NOE.
[0415] Step 5. To a suspension of E4 (1.5 g, 4.32 mmol) in DCM (30
mL) was added silica gel (2 g) and PCC (1.86 g, 8.64 mmol) at
15.degree. C. The mixture was stirred at 15.degree. C. for 2 hrs.
The mixture was filtered and the filtrated cake was washed with DCM
(2.times.20 mL). The combined filtrate was concentrated in vacuum
and purified by flash column (0-30% of EtOAc in PE) to give crude
product E5 (1.3 g, 87%) as a solid.
[0416] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.19-5.10 (m, 1H),
3.52-3.45 (m, 1H), 3.31-3.28 (m, 3H), 3.28-3.19 (m, 1H), 2.45-2.15
(m, 7H), 2.15-2.02 (m, 3H), 1.85-1.75 (m, 1H), 1.75-1.62 (m, 4H),
1.62-1.25 (m, 7H), 0.99 (s, 3H), 0.98-0.80 (m, 5H).
[0417] Step 6. Under nitrogen atmosphere, anhydrous THF (20 mL) was
cooled to 10.degree. C. and anhydrous LiCl (589 mg, 13.9 mmol) was
added in one portion. The mixture was stirred for 30 min to obtain
a clear solution. To this solution was added anhydrous FeCl.sub.3
(1.24 g, 7.65 mmol) in one portion. The resulting mixture was
stirred for additional 30 mins. The reaction mixture was cooled to
-35.degree. C. and methyl magnesium bromide (9.26 mL, 27.8 mmol, 3
M in diethyl ether) was added dropwise maintaining the internal
temperature between -35.degree. C. and -30.degree. C. The above
mixture was stirred for 30 min at -30.degree. C. E5 (1.2 g, 3.48
mmol) in THF (20 mL) was added in one portion. The internal
temperature was allowed to -20.degree. C. and held between
-15.degree. C. and -20.degree. C. for 2 hrs. The reaction mixture
was poured to ice-cooled aqueous HCl (1 M, 20 mL), extracted with
EtOAc (2.times.20 mL). The combined organic layer was washed with
water (20 mL), aqueous NaOH (10%, 2.times.20 mL) and brine (20 mL),
dried over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by column chromatography on silica gel
(PE/EtOAc=20/1 to 5/1) to give E6 (1 g, 80%) as a solid.
[0418] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.19-5.10 (m, 1H),
3.52-3.45 (m, 1H), 3.29 (s, 3H), 3.20-3.19 (m, 1H), 2.42-2.10 (m,
3H), 1.85-1.76 (m, 1H), 1.76-1.62 (m, 5H), 1.62-1.40 (m, 3H),
1.40-1.11 (m, 13H), 1.01-0.82 (m, 6H), 0.72 (s, 3H).
[0419] Step 7. To a solution of E6 (1 g, 2.77 mmol) in THF (15 mL)
was added dropwise a solution of BH.sub.3-Me.sub.2S (2.77 mL, 27.7
mmol, 10M in THF) at 0.degree. C. The solution was stirred at
15.degree. C. for 3 h. After cooling to 0.degree. C., a solution of
NaOH solution (16.6 mL, 2M) was added very slowly. After addition,
H.sub.2O.sub.2 (2.76 mL, 27.7 mmol, 30% in water) was added slowly
and the inner temperature was maintained below 10.degree. C. The
resulting solution was stirred at 15.degree. C. for 2 h. Then
saturated aqueous Na.sub.2S.sub.2O.sub.3 (20 mL) was added until
the reaction solution became clear. The mixture was extracted with
EtOAc (3.times.20 mL). The combined organic solution was washed
with saturated aqueous Na.sub.2S.sub.2O.sub.3 (2.times.10 mL),
brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated in
vacuum to give E7 (0.9 g, crude) as a solid, which was used in next
step without further purification.
[0420] Step 8. To a suspension of E7 (0.9 g, 1.37 mmol) in DCM (20
mL) was added silica gel (1 g) and PCC (1.02 g, 4.74 mmol) at
15.degree. C. The mixture was stirred at 15.degree. C. for 2 hrs.
The mixture was filtered and the filtrated cake was washed with DCM
(2.times.20 mL). The combined filtrate was concentrated in vacuum,
purified by flash column (0.about.20% of EtOAc in PE) and
re-crystallized from DCM/n-hexane (2 mL/20 mL) at 15.degree. C. to
give Compound 11 (130 mg, 14%) as solid.
[0421] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.45-3.38 (m, 1H),
3.29-3.20 (m, 4H), 2.55-2.45 (m, 1H), 2.19-2.09 (m, 4H), 2.05-1.85
(m, 2H), 1.75-1.55 (m, 2H), 1.55-1.35 (m, 9H), 1.35-1.15 (m, 10H),
0.94-0.82 (m, 1H), 0.72 (s, 3H), 0.63 (s, 3H).
[0422] LCMS Rt=1.134 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 87%, MS ESI calcd. for
C.sub.24H.sub.39O.sub.2[M+H--H.sub.2O].sup.+359, found 359.
[0423] HPLC Rt=4.54 min in 8 min chromatography, 30-90_AB_1.2
ml_E.met, purity: 100%.
Example 6. Synthesis of Compound 12
##STR00152## ##STR00153##
[0425] Step 1. To a suspension of PPh.sub.3EtBr (26.5 g, 71.6 mmol)
in THF (100 mL) was added t-BuOK (8.03 g, 71.6 mmol) at 10.degree.
C. The color of the suspension turned dark red. After stirring at
40.degree. C. for 1 hour, a solution of E3 (8 g, 23.9 mmol) in THF
(20 mL) was added at 40.degree. C. and the reaction mixture was
stirred at 40.degree. C. for 16 h. The mixture was added saturated
NH.sub.4Cl solution (20 mL) and EtOAc (2.times.30 mL). The organic
layer was separated and the water phase was extracted with EtOAc
(2.times.30 mL). The combined organic phase was washed with
saturated brine (2.times.20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered concentrated and purified by flash
column (0.about.20% of EtOAc in PE) to give F1 (2.1 g, 25%) as
colorless oil.
[0426] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.15-5.05 (m, 1H),
3.68-3.55 (m, 1H), 3.40-3.35 (m, 1H), 3.31 (s, 3H), 2.43-2.32 (m,
1H), 2.22-2.10 (m, 2H), 2.01-1.89 (m, 1H), 1.89-1.50 (m, 8H),
1.50-1.22 (m, 9H), 1.10-0.82 (m, 11H).
[0427] The stereochemistry at C7 of F1 was confirmed by NOE.
[0428] Step 2. To a solution of F1 (2 g, 5.77 mmol) in DCM (50 mL)
was added DMP (4.87 g, 11.5 mmol). After that, the reaction was
stirred at 15.degree. C. for 30 min. The reaction mixture was added
aqueous saturated NaHCO.sub.3 (50 mL) solution, aqueous saturated
Na.sub.2S.sub.2O.sub.3 (50 mL) solution, extracted with DCM
(2.times.50 mL). The combined organic layer was washed with aqueous
saturated NaHCO.sub.3 (2.times.20 mL) solution and brine (20 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to
give F2 (1.95 g, 98%) as a solid.
[0429] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.19-5.10 (m, 1H),
3.50-3.35 (m, 2H), 3.30 (s, 3H), 2.46-2.15 (m, 7H), 2.15-1.98 (m,
3H), 1.78-1.50 (m, 9H), 1.50-1.21 (m, 4H), 1.05-1.12 (m, 4H), 0.89
(s, 3H).
[0430] Step 3. Under a nitrogen atmosphere, anhydrous THF (10 mL)
was cooled to 10.degree. C. and anhydrous LiCl (958 mg, 22.6 mmol)
was added in one portion. The mixture was stirred for 30 min to
obtain a clear solution. To this solution was added anhydrous
FeCl.sub.3 (2.01 mg, 12.4 mmol) in one portion. The resulting
mixture was stirred for additional 30 mins. The reaction mixture
was cooled to -35.degree. C. and methyl magnesium bromide (15.0 mL,
45.2 mmol, 3 M in diethyl ether) was added dropwise maintaining the
internal temperature between -35.degree. C. and -30.degree. C. The
above mixture was stirred for 30 min at -30.degree. C. A solution
of F2 (1.95 g, 5.65 mmol) in THF (10 mL) was added in one portion.
The internal temperature was allowed to -20.degree. C. and held
between -15.degree. C. and -20.degree. C. for 2 hrs. The reaction
mixture was poured into ice-cooled aqueous HCl (1 M, 20 mL),
extracted with EtOAc (2.times.20 mL). The combined organic layer
was washed with water (20 mL), aqueous NaOH (10%, 2.times.20 mL)
and brine (20 mL), dried over anhydrous sodium sulfate, filtered
and concentrated. The residue was purified by flash column
(0.about.30% of EtOAc in PE) to give F3 (1.6 g, 79%) as a
solid.
[0431] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.19-5.10 (m, 1H),
3.55-3.49 (m, 1H), 3.40-3.35 (m, 1H), 3.31 (s, 3H), 2.42-2.30 (m,
1H), 2.30-2.15 (m, 2H), 1.99-1.90 (m, 1H), 1.80-1.55 (m, 8H),
1.55-1.40 (m, 4H), 1.40-1.20 (m, 9H), 1.20-0.95 (m, 2H), 0.95-0.82
(m, 4H), 0.79 (s, 3H).
[0432] Step 3. To a solution of F3 (1.6 g, 4.43 mmol) in THF (25
mL) was added dropwise a solution of BH.sub.3-Me.sub.2S (4.43 mL,
44.3 mmol, 10M in THF) at 0.degree. C. The solution was stirred at
15.degree. C. for 3 h. After cooling to 0.degree. C., a solution of
NaOH solution (26.5 mL, 53.1 mmol, 2M) was added very slowly. After
addition, H.sub.2O.sub.2 (4.42 mL, 44.3 mmol, 30% in water) was
added slowly and the inner temperature was maintained below
10.degree. C. The resulting solution was stirred at 15.degree. C.
for 2 h. Then saturated aqueous Na.sub.2S.sub.2O.sub.3 (20 mL) was
added until the reaction solution became clear. The mixture was
extracted with EtOAc (3.times.20 mL). The combined organic solution
was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3
(2.times.10 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and
concentrated in vacuum to give F4 (1.66 g, crude) as a solid, which
was used in next step without further purification.
[0433] Step 4. To a solution of F4 (1.66 g, 4.4 mmol) in DCM (50
mL) was added DMP (3.73 g, 8.80 mmol) at 15.degree. C. The reaction
was stirred at 15.degree. C. for 10 min. To the reaction mixture
was added aqueous saturated NaHCO.sub.3 (50 mL) solution, aqueous
saturated Na.sub.2S.sub.2O.sub.3 (50 mL) solution and extracted
with DCM (2.times.20 mL). The combined organic layer was washed
with aqueous saturated NaHCO.sub.3 (3.times.20 mL) solution and
brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuum and purified by silica gel chromatography
(PE/EtOAc=15/1 to 10/1) to give Compound 12 (0.85 g, impure) as a
solid. Compound 12 (0.2 g, impure) was re-crystallized from MeCN
(15 mL) at 15.degree. C. to give Compound 12 (150 mg, 48%) as a
solid.
[0434] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.58-3.50 (m, 1H),
3.45-3.35 (m, 1H), 3.32 (s, 3H), 2.55-2.48 (m, 1H), 2.21-2.05 (m,
4H), 2.01-1.85 (m, 2H), 1.85-1.60 (m, 5H), 1.60-1.45 (m, 4H),
1.45-1.20 (m, 12H), 1.10-1.01 (m, 1H), 0.77 (s, 3H), 0.60 (s,
3H).
[0435] LCMS Rt=1.126 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for
C.sub.24H.sub.39O.sub.2[M+H--H.sub.2O].sup.+359, found 359.
Example 7. Synthesis of Compound 13
##STR00154##
[0437] Step 1. To a solution of Compound 11 (300 mg, 0.796 mmol) in
MeOH (10 ml) was added HBr (31.7 mg, 0.159 mmol, 40% in water) and
Br.sub.2 (131 mg, 0.835 mmol) at 25.degree. C. The mixture was
stirred at 25.degree. C. for 16 hrs and quenched by adding sat.aq
NaHCO.sub.3 (10 mL) and water (20 mL). The mixture was extracted
with EtOAc (2.times.20 mL). The combined organic phase was washed
with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated in vacuum to afford G1 (400 mg) as a solid, which
used directly for the next step.
[0438] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.96-3.87 (m, 2H),
3.46-3.34 (m, 1H), 3.34-3.20 (m, 5H), 2.77 (t, J=8 Hz, 1H),
2.23-2.06 (m, 1H), 1.98-1.83 (m, 2H), 1.80-1.61 (m, 3H), 1.49-1.40
(m, 5H), 1.38-1.19 (m, 12H), 0.91-0.82 (m, 1H), 0.74-0.64 (m,
6H).
[0439] Step 2. To a mixture of G1 (60 mg, 0.131 mmol) and
K.sub.2CO.sub.3 (36.2 mg, 0.2.62 mmol) in acetone (5 mL) was added
1H-pyrazole-4-carbonitrile (18.2 mg, 0.196 mmol) at 25.degree. C.
The reaction mixture was stirred at 25.degree. C. for 16 h and
treated with H.sub.2O (50 mL). The mixture was extracted with EtOAc
(3.times.50 mL). The combined organic solution was washed with
brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuum to give the crude product, which was
purified by flash column (0.about.30% of EtOAc in PE) twice to give
Compound 13 (15 mg, 25%) as a solid.
[0440] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (s, 1H), 7.81
(s, 1H), 5.05-4.87 (m, 2H), 2.54 (m, 1H), 3.40-3.38 (m, 1H),
3.37-3.27 (m, 4H), 2.55 (d, J=8 Hz, 1H), 2.23-2.15 (m, 1H),
2.041.96 (m, 1H), 1.76-1.72 (m, 2H), 1.52-1.49 (m, 8H), 1.32-1.21
(m, 10H), 1.11 (s, 1H), 0.88-0.85 (m, 1H), 0.73 (s, 3H), 0.69 (s,
3H).
[0441] LCMS Rt=1.054 in in 2.0 min chromatography, 30-90AB_2
MIN_E.M.lcm, purity 100%, MS ESI calcd. for
C.sub.28H.sub.42N.sub.3O.sub.3 [M+H].sup.+ 468, found 468.
Example 8. Syntheses of Compound 14
##STR00155##
[0443] Step 1. To a solution of Compound 12 (700 mg, 1.85 mmol) in
MeOH (10 ml) was added HBr (74 mg, 0.370 mmol, 40% in water) and
Br.sub.2 (304 mg, 1.94 mmol) at 25.degree. C. After stirring at
25.degree. C. for 16 hrs, the mixture was quenched with sat.aq
NaHCO.sub.3 (10 mL) and water (20 mL), extracted with EtOAc
(2.times.20 mL). The combined organic phase was washed with brine
(20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered,
concentrated in vacuum to afford H1 (900 mg) as a solid, which was
used directly for the next step.
[0444] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.92-3.88 (m, 2H),
3.58-3.46 (m, 1H), 3.41 (s, 3H), 3.37-3.27 (m, 3H), 2.84-2.80 (m,
1H), 1.91-1.89 (m, 2H), 1.78-1.65 (m, 3H), 1.54-1.40 (m, 5H),
1.40-1.17 (m, 12H), 0.91 (s, 1H), 0.79-0.75 (m, 3H), 0.62 (s,
3H).
[0445] Step 2. To a mixture of H1 (80 mg, 0.175 mmol) and
K.sub.2CO.sub.3 (48.3 mg, 0.350 mmol) in acetone (5 mL) was added
1H-pyrazole-4-carbonitrile (24.3 mg, 0.262 mmol) at 25.degree. C.
The reaction mixture was stirred at the 25.degree. C. for 16 h and
treated with H.sub.2O (50 mL), extracted with EtOAc (3.times.50
mL). The combined organic solution was washed with brine (20 mL),
dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give the
crude product, which was purified by flash column (0.about.30% of
EtOAc in PE) to give Compound 14 (23 mg, 28%) as a solid.
[0446] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.83 (d, J=18.8
Hz, 2H), 5.04-4.86 (m, 2H), 3.55-3.50 (m, 1H), 3.42-3.41 (m, 1H),
3.32 (s, 3H), 2.59 (t, J=9.2 Hz, 1H), 2.27-2.14 (m, 1H), 2.03-1.98
(m, 1H), 1.95-1.83 (m, 2H), 1.80-1.64 (m, 4H), 1.53-1.47 (m, 3H),
1.45-1.23 (m, 9H), 1.20 (s, 3H), 1.14-1.00 (m, 2H), 0.78 (s, 3H),
0.65 (s, 3H).
[0447] LCMS Rt=2.901 in in 4.0 min chromatography, 10-80AB.lcm,
purity 100%, MS ESI calcd. for C.sub.28H.sub.40N.sub.3O.sub.2
[M-H.sub.2O+H].sup.+450, found 450.
Example 9. Syntheses of Compounds 15, 16, and 17
##STR00156##
[0449] To a solution of G1 (200 mg, 0.439 mmol) in acetone (5 mL)
was added 5-methoxy-2H-benzo[d][1,2,3]triazole (98.1 mg, 0.658
mmol), followed by adding K.sub.2CO.sub.3 (121 mg, 0.878 mmol) at
25.degree. C. The resulting reaction mixture was stirred at
25.degree. C. for 16 hrs, treated with water (20 mL) and extracted
with EtOAc (3.times.20 mL). The combined organic solution was
washed with brine (20 mL), dried over Na.sub.2SO.sub.4 and
concentrated in vacuum to give the crude product, which was
purified by flash column (0.about.30% of EtOAc in PE) to give
impure Compound 15 (50 mg). The impure Compound 15 was purified by
prep. HPLC separation (column: YMC-Actus Triart C18 150*30 mm*5
um), gradient: 65-95% B (A=water(0.05% HCl)-ACN, B=ACN), flow rate:
25 mL/min) to give Compound 15 (18 mg, 8%) as a solid; and a
mixture of Compound 16 and Compound 17 (100 mg, crude). The mixture
of Compound 16 and Compound 17 (100 mg, crude) was purified by SFC
separation (column: OJ (250 mm*30 mm, 5 um)), gradient: 40-40% B
(A=0.1% NH.sub.3H.sub.2O, B=ETOH), flow rate: 60 mL/min) to give
Compound 16 (33 mg, 14%) as solid and Compound 17 (16 mg, 7%) as
solid.
[0450] Compound 15:
[0451] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.73 (d, J=8.0 Hz,
1H), 7.08-7.06 (m, 2H), 5.50-5.39 (m, 2H), 3.88 (s, 3H), 3.41-3.35
(m, 1H), 3.27 (s, 4H), 2.58 (t, J=8.0 Hz, 1H), 2.27-2.07 (m, 2H),
2.01-1.88 (m, 1H), 1.81-1.69 (m, 2H), 1.53-1.47 (m, 5H), 1.46-1.12
(m, 14H), 0.94-0.82 (m, 1H), 0.76 (s, 3H), 0.74 (s, 3H).
[0452] LCMS Rt=3.240 min in 4.0 min chromatography, 10-80AB.lcm,
purity 100%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.4
[M+H].sup.+ 524, found 524.
[0453] Compound 16:
[0454] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92 (d, J=8.0 Hz,
1H), 7.01 (dd, J=4.0, 8.0 Hz, 1H), 6.60 (d, J=4.0 Hz, 1H),
5.40-5.29 (m, 2H), 3.86 (s, 3H), 3.41-3.35 (m, 1H), 3.30-3.25 (m,
4H), 2.64 (t, J=8.0 Hz, 1H), 2.28-2.09 (m, 2H), 2.00-1.90 (m, 1H),
1.76-1.75 (m, 2H), 1.54-1.43 (m, 7H), 1.42-1.20 (m, 11H), 1.13 (s,
1H), 0.92-0.87 (m, 1H), 0.75 (s, 3H), 0.74 (s, 3H).
[0455] LCMS Rt=3.025 min in 4.0 min chromatography, 10-80AB.lcm,
purity 100%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.4
[M+H].sup.+ 524, found 524.
[0456] Compound 17:
[0457] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (d, J=4.0 Hz,
1H), 7.24-7.13 (m, 2H), 5.43-5.32 (m, 2H), 3.89 (s, 3H), 3.39-3.37
(m, 1H), 3.27 (s, 4H), 2.63 (t, J=12.0 Hz, 1H), 2.25-2.09 (m, 2H),
1.97-1.95 (m, 1H), 1.83-1.71 (m, 2H), 1.54-1.44 (m, 7H), 1.43-1.20
(m, 11H), 1.12 (s, 1H), 0.91-0.87 (m, 1H), 0.74 (s, 6H)
[0458] LCMS Rt=3.033 min in 4.0 min chromatography, 10-80AB.lcm,
purity 100%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.4
[M+H].sup.+ 524, found 524.
Example 10. Syntheses of Compounds 18, 19, and 20
##STR00157##
[0460] To a solution of H1 (200 mg, 0.439 mmol) in acetone (5 mL)
was added 5-methoxy-2H-benzo[d][1,2,3]triazole (98.1 mg, 0.658
mmol), followed by adding K.sub.2CO.sub.3 (121 mg, 0.878 mmol) at
25.degree. C. The resulting reaction mixture was stirred at
25.degree. C. for 16 hours, treated with water (20 mL), extracted
with EtOAc (3.times.20 mL). The combined organic solution was
washed with brine (20 mL), dried over Na.sub.2SO.sub.4 and
concentrated in vacuum to give the crude product, which was
purified by flash column (0.about.30% of EtOAc in PE) to give
Compound 18 (10 mg, 4%) as a solid and a mixture of Compound 19 and
Compound 20 (100 mg, crude). The mixture of Compound 19 and
Compound 20 was purified by SFC separation (column:OD (250 mm*30
mm, 5 um)), gradient: 40-40% B (A=0.1% NH.sub.3H.sub.2O, B=ETOH),
flow rate: 50 mL/min) to give Compound 19 (32 mg, 13%) as a solid
and Compound 20 (27 mg, 12%) as a solid.
[0461] Compound 18:
[0462] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.74-7.71 (m, 1H),
7.08-7.06 (m, 2H), 5.48-5.38 (m, 2H), 3.88 (s, 3H), 3.55-3.50 (m,
1H), 3.42-3.38 (m, 1H), 3.32 (s, 3H), 2.64-2.60 (m, 1H), 2.29-2.18
(m, 1H), 2.14-2.06 (m, 1H), 1.92 (m, 1H), 1.68 (m, 5H), 1.53-1.41
(m, 4H), 1.41-1.19 (m, 12H), 1.09-1.02 (m, 1H), 0.79 (s, 3H), 0.73
(s, 3H) LCMS Rt=3.215 min in 4.0 min chromatography, 10-80AB.lcm,
purity 100%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.4
[M+H].sup.+ 524, found 524.
[0463] Compound 19:
[0464] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92 (d, J=8.0 Hz,
1H), 7.01 (m, 1H), 6.61-6.59 (m, 1H), 5.37-5.28 (m, 2H), 3.86 (s,
3H), 3.53 (t, J=8.0 Hz, 1H), 3.43-3.37 (m, 1H), 3.32 (s, 3H), 2.68
(t, J=8.0 Hz, 1H), 2.27-2.17 (m, 1H), 2.13-2.070 (m, 1H), 1.97-1.82
(m, 2H), 1.77-1.68 (m, 3H), 1.55-1.27 (m, 12H), 1.21 (s, 3H),
1.10-1.05 (m, 1H), 0.94 (s, 2H), 0.79 (s, 3H), 0.72 (s, 3H).
[0465] LCMS Rt=2.344 min in 3.0 min chromatography, 10-80AB.lcm,
purity 96.15%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.4
[M+H].sup.+ 524, found 524.
[0466] Compound 20:
[0467] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (d, J=4.0 Hz,
1H), 7.23-7.11 (m, 2H), 5.36 (s, 2H), 3.89 (s, 3H), 3.53 (t, J=8.0
Hz, 1H), 3.42-3.37 (m, 1H), 3.32 (s, 3H), 2.67 (t, J=8.0 Hz, 1H),
2.26-2.17 (m, 1H), 2.12-2.06 (m, 1H), 1.97-1.81 (m, 2H), 1.77-1.67
(m, 3H), 1.55-1.46 (m, 4H), 1.46-1.22 (m, 9H), 1.21 (s, 3H), 1.12
(s, 1H), 1.09-1.02 (m, 1H), 0.79 (s, 3H), 0.71 (s, 3H).
[0468] LCMS Rt=1.095 min in 2.0 min chromatography, 30-90AB_2 MIN_E
M, purity 100%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.4
[M+H].sup.+ 524, found 524.
Example 11. Syntheses of Compounds 21 and 22
##STR00158##
[0470] To a solution of the G1 (150 mg, 0.329 mmol) and
1H-pyrazolo[3,4-c]pyridine (41 mg, 0.345 mmol) in acetone (3 mL)
was added K.sub.2CO.sub.3 (26.1 g, 0.658 mmol) at 25.degree. C.
After stirring at 25.degree. C. for 10 hrs, the mixture was poured
into water (50 mL) and extracted with EtOAc (3.times.20 mL). The
combined organic layer was washed with brine (50 mL), dried over
with Na.sub.2SO.sub.4, filtered and concentrated to afford crude
product, which was purified by prep. HPLC (column: YMC-Actus Triart
C18 150*30 mm*5 um)), gradient: 30-60% B (A=0.1% HCl, B=ACN), flow
rate: 25 mL/min) to afford Compound 22 (3 mg, impure) as a solid
and Compound 21 (20 mg, impure). Compound 21 (20 mg, impure) was
purified by flash column (0.about.30% of EtOAc in PE) to give
Compound 21 (9 mg, 6%) as a solid.
[0471] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.26 (s, 1H), 8.17
(d, J=4.8 Hz, 1H), 7.98 (s, 1H), 7.53 (d, J=6.8 Hz, 1H), 5.36-5.20
(m, 2H), 3.38-3.36 (m, 1H), 3.32-3.31 (m, 1H), 3.27 (s, 3H),
2.70-2.61 (m, 1H), 2.30-2.19 (m, 1H), 2.17-2.13 (m, 1H), 2.04-1.95
(m, 1H), 1.85-1.74 (m, 2H), 1.56-1.49 (m, 6H), 1.45-1.22 (m, 12H),
1.17-1.14 (m, 1H), 0.93-0.88 (m, 1H), 0.73 (s, 6H).
[0472] LCMS Rt=1.771 min in 3.0 min chromatography, 10-80AB, purity
100%, MS ESI calcd. For C.sub.30H.sub.44N.sub.3O.sub.3 [M+H].sup.+
494, found 494.
Example 12. Syntheses of Compounds 23 and 24
##STR00159##
[0474] To a mixture of H1 (150 mg, 0.329 mmol) and K.sub.2CO.sub.3
(90.9 mg, 0.658 mmol) in acetone (3 mL) was added
1H-pyrazolo[3,4-c]pyridine (41 mg, 0.345 mmol) at 25.degree. C.
After stirring at 25.degree. C. for 12 h, the mixture was poured
into water (50 mL) and extracted with EtOAc (3.times.20 mL). The
combined organic layer was washed with brine (50 mL), dried over
with Na.sub.2SO.sub.4, filtered and concentrated to afford crude
product, which was purified by preparative HPLC (column: YMC-Actus
Triart C18 150*30 mm*5 um)), gradient: 35-65% B (A=0.1% HCl,
B=ACN), flow rate: 25 mL/min) to afford Compound 23 (50 mg, 31%) as
a solid and Compound 24 (20 mg, impure). Compound 24 (20 mg,
impure) was purified by SFC separation (column: AD (250 mm*30 mm,
10 um)), gradient: 45-45% B (A=0.1% NH.sub.3H.sub.2O, B=EtOH), flow
rate: 80 mL/min) to afford Compound 24 (8 mg, 5%) as a solid.
[0475] Compound 23:
[0476] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.79 (s, 1H), 8.34
(d, J=5.6 Hz, 1H), 8.09 (s, 1H), 7.66-7.63 (m, 1H), 5.23-5.30 (m,
2H), 3.56-3.48 (m, 1H), 3.42-3.37 (m, 1H), 3.33 (s, 3H), 2.69-2.66
(m, 1H), 2.27-2.17 (m, 1H), 2.14-2.07 (m, 1H), 1.97-1.84 (m, 2H),
1.80-1.65 (m, 4H), 1.55-1.28 (m, 13H), 1.21 (s, 3H), 1.10-1.04 (m,
1H), 0.80 (s, 3H), 0.71 (s, 3H).
[0477] LCMS Rt=2.290 min in 4.0 min chromatography, 10-80AB, purity
99.1%, MS ESI calcd. For C.sub.30H.sub.44N.sub.3O.sub.3 [M+H].sup.+
494, found 494.
[0478] Compound 24:
[0479] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.26 (s, 1H), 8.17
(d, J=6.4 Hz, 1H), 7.98 (s, 1H), 7.56-7.50 (m, 1H), 5.35-5.19 (m,
2H), 3.56-3.50 (m, 1H), 3.44-3.39 (m, 1H), 3.33 (s, 3H), 2.66 (t,
J=8.8 Hz, 1H), 2.25-2.22 (m, 1H), 2.10-2.07 (m, 1H), 1.97-1.67 (m,
6H), 1.52-1.38 (m, 7H), 1.36-1.25 (m, 6H), 1.21 (s, 3H), 1.15-1.03
(m, 1H), 0.79 (s, 3H), 0.70 (s, 3H).
[0480] LCMS Rt=2.155 min in 4.0 min chromatography, 10-80AB, purity
100%, MS ESI calcd. For C.sub.30H.sub.44N.sub.3O.sub.3 [M+H].sup.+
494, found 494.
Example 13. Synthesis of Compound 25
##STR00160##
[0482] Step 1. To a solution of A2 (20 g, 57.7 mmol) in THF (100
mL) was added dropwise K-selectride (57.7 mL, 57.7 mmol, 1M in THF)
at -70.degree. C. The reaction mixture was stirred 2 h at
-70.degree. C. The mixture was quenched with sat.NH.sub.4Cl (20 mL)
at -20.degree. C. and extracted with EtOAc (3.times.50 mL). The
combined organic phase was washed with brine (2.times.30 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated and purified by
flash column (0.about.30% of EtOAc in PE) to give 11 (12.5 g, 62%)
as a solid.
[0483] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.75-4.65 (m, 1H),
4.02-3.90 (m, 1H), 2.51-2.40 (m, 1H), 2.22-2.01 (m, 1H), 1.98-1.40
(m, 15H), 1.40-1.08 (m, 7H), 1.08-0.78 (m, 6H).
[0484] Step 2. To a solution of 11 (12 g, 34.4 mmol) in DCM (100
mL) was added TBSOTf (11.8 mL, 51.6 mmol) and 2,6-dimethylpyridine
(7.37 g, 68.8 mmol) in one portion at 15.degree. C. The mixture was
refluxed at 15.degree. C. for 7 hrs. Then sat.NH.sub.4Cl (50 mL)
was added to the reaction mixture. The aqueous phase was extracted
with DCM (3.times.50 mL). The combined organic phase was washed
with brine (2.times.50 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to give residue, which was purified by
flash column (0.about.5% of EtOAc in PE) to afford 12 (8.35 g,
crude) combined with another batch of I2-A (7.5 g, crude,
I2-A/I2=1/1) as an oil, which was used directly for the next
step.
[0485] Step 3. To a suspension of PPh.sub.3EtBr (37.8 g, 102 mmol)
in THF (100 mL) was added t-BuOK (11.4 g, 102 mmol) at 10.degree.
C. The color of the suspension turned dark red. After stirring at
40.degree. C. for 1 h, a solution of 12 (15.85 g, crude, containing
I2-A) in THF (20 mL) was added at 40.degree. C. and the reaction
mixture was stirred at 40.degree. C. for 16 h. To the mixture was
added saturated NH.sub.4Cl solution (20 mL) and EtOAc (60 mL). The
organic layer was separated and the aqueous phase was extracted
with EtOAc (2.times.50 mL). The combined organic phase was washed
with brine (2.times.20 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, concentrated and purified by flash column (0.about.20% of
EtOAc in PE) to give 13 (10 g, crude) as colorless oil.
[0486] Step 4. To a solution of 13 (12 g, 27.7 mmol) in DCM (100
mL) was added DMP (23.4 g, 55.4 mmol) followed by H.sub.2O (2.48
mg, 0.138 mmol). The reaction mixture was stirred at 15.degree. C.
for 30 min. The reaction mixture was added aqueous saturated
NaHCO.sub.3 (50 mL) solution, aqueous saturated
Na.sub.2S.sub.2O.sub.3 (50 mL) solution, extracted with DCM
(2.times.50 mL). The combined organic layer was washed with aqueous
saturated NaHCO.sub.3 (2.times.20 mL) solution and brine (20 mL),
dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuum and
purified by flash column (0.about.10% of EtOAc in PE) to give 14 (6
g, 50%) as a solid.
[0487] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.20-5.00 (m, 1H),
3.88 (s, 1H), 2.48-1.97 (m, 10H), 1.80-1.35 (m, 8H), 1.35-1.11 (m,
2H), 1.11-0.80 (m, 18H), 0.02 (s, 6H).
[0488] Step 5. Under nitrogen atmosphere, anhydrous THF (20 mL) was
cooled to 15.degree. C. and anhydrous LiCl (2.35 g, 55.6 mmol) was
added in one portion. The mixture was stirred for 30 min to obtain
a clear solution. To the solution was added anhydrous FeCl.sub.3
(4.94 g, 30.5 mmol) in one portion. The resulting mixture was
stirred for additional 30 mins. The reaction mixture was cooled to
-35.degree. C. and methyl magnesium bromide (3 M in diethyl ether,
37.0 mL, 111 mmol) was added dropwise maintaining the internal
temperature between -35.degree. C. and -30.degree. C. The above
mixture was stirred for 30 min at -30.degree. C. 14 (6 g, 13.9
mmol) in THF (20 mL) was added in one portion. The internal
temperature was allowed to 15.degree. C. and the reaction mixture
was stirred for 2 hrs. The reaction mixture was poured into
ice-cooled aqueous HCl (1 M, 20 mL), extracted with EtOAc
(2.times.20 mL). The combined organic layer was washed with water
(20 mL), aqueous NaOH (10%, 2.times.20 mL) and brine (20 mL), dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by flash column (0.about.5% of EtOAc in PE) to
give 15 (3.5 g, 56%) as a solid.
[0489] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.15-5.00 (m, 1H),
3.87 (s, 1H), 2.41-2.00 (m, 4H), 1.80-1.49 (m, 7H), 1.49-1.25 (m,
7H), 1.25-1.08 (m, 6H), 1.08-0.81 (m, 14H), 0.81-0.69 (m, 4H),
0.05-0.01 (m, 6H).
[0490] Step 6. To a solution of 15 (3.5 g, 7.83 mmol) in THF (20
mL) was added dropwise BH.sub.3.Me.sub.2S (7.83 mL, 10M, 78.3 mmol)
at 0.degree. C. The resulting solution was stirred at 15.degree. C.
for 3 h. After cooling to 0.degree. C., a solution of aqueous NaOH
(46.9 mL, 93.9 mmol, 2 M) was added very slowly. After the
addition, H.sub.2O.sub.2 (7.84 mL, 78.3 mmol, 30% in water) was
added slowly and the inner temperature was maintained below
10.degree. C. The resulting solution was stirred at 15.degree. C.
for 1 h. Then saturated aqueous Na.sub.2S.sub.2O.sub.3 (20 mL) was
added until the reaction solution became clear.
[0491] The mixture was extracted with EtOAc (3.times.20 mL). The
combined organic layer was washed with saturated aqueous
Na.sub.2S.sub.2O.sub.3 (2.times.10 mL), brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give 16
(3.4 g, crude) as a solid, which was used in next step without
further purification.
[0492] Step 7. To a solution of 16 (3.4 g, 7.31 mmol) in DCM (20
mL) was added DMP (6.19 g, 14.6 mmol) followed by H.sub.2O (2.62
mg, 0.146 mmol). The reaction mixture was stirred at 15.degree. C.
for 30 min. To the reaction mixture was added aqueous saturated
NaHCO.sub.3 (50 mL) solution and aqueous saturated
Na.sub.2S.sub.2O.sub.3 (10 mL) solution. The mixture was extracted
with DCM (2.times.20 mL). The combined organic layer was washed
with saturated NaHCO.sub.3 (2.times.20 mL) and brine (20 mL), dried
over Na.sub.2SO.sub.4, filtered, concentrated in vacuum and
purified by flash column (0.about.10% of EtOAc in PE) to give 17
(2.2 g, 65%) as a solid.
[0493] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.83-3.80 (m, 1H),
2.59-2.50 (m, 1H), 2.21-1.90 (m, 6H), 1.78-1.49 (m, 9H), 1.49-1.09
(m, 12H), 0.90 (s, 9H), 0.73 (s, 3H), 0.58 (s, 3H), 0.06-0.01 (m,
6H).
[0494] Step 8. To a solution of 17 (1.80 g, 3.88 mmol) in
CH.sub.3OH (50 mL) was added concentrated HCl (0.966 mL, 12 M)
15.degree. C. under N.sub.2. The mixture was stirred at 15.degree.
C. for 16 hrs. To the mixture was added saturated NaHCO.sub.3 (5
mL) and stirred for 20 min. The aqueous phase was extracted with
EtOAc (3.times.50 mL). The combined organic phase was washed with
brine (2.times.50 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to give a solid, which was purified by
flash column (0.about.70% of EtOAc in PE) to give Compound 25 (1.20
g, impure) as a solid. The impure Compound 25 (600 mg, impure) was
triturated with hexane (30 mL) at 68.degree. C. to give Compound 25
(510 mg, 64%) as a solid.
[0495] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.85 (brs, 1H),
2.58-2.52 (m, 1H), 2.21-2.06 (m, 4H), 2.03-1.92 (m, 2H), 1.85-1.58
(m, 3H), 1.58-1.45 (m, 4H), 1.45-1.14 (m, 15H), 0.75 (s, 3H), 0.61
(s, 3H).
[0496] LCMS Rt=0.893 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for C.sub.22H.sub.33O
[M+H-2H.sub.2O].sup.+313, found 313.
Example 14. Synthesis of Compound 26
##STR00161##
[0498] Step 1. To a solution of Compound 25 (497 mg, 1.42 mmol) in
MeOH (10 ml) was added HBr (57.2 mg, 0.284 mmol, 40% in water) and
Br.sub.2 (230 mg, 1.75 mmol) at 15.degree. C. After stirring at
15.degree. C. for 4 hrs, the mixture was quenched by NaHCO.sub.3
(10 mL), treated with water (20 mL), extracted with EtOAc
(3.times.20 mL). The combined organic phase was washed with brine
(40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered,
concentrated in vacuum to give J1 (600 mg, crude) as a solid.
[0499] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.95-3.86 (m, 2H),
2.86-2.80 (m, 1H), 2.40-2.05 (m, 3H), 2.05-1.57 (m, 6H), 1.55-1.13
(m, 16H), 1.05-0.95 (m, 1H), 0.75 (s, 3H), 0.65-0.55 (m, 3H).
[0500] Step 2. To a suspension of TEA (35.2 mg, 0.348 mmol) and
1H-pyrazole-4-carbon (12.9 mg, 0.139 mmol) in DMF (5 mL) was added
J1 (50 mg, 0.116 mmol) at 25.degree. C. under N.sub.2. The mixture
was stirred at 25.degree. C. for 16 h. The mixture was concentrated
to give a light yellow solid. The solid was purified by pre-HPLC
(Column:YMC-Actus Triart C18 100*30 mm*5 um; Condition: water(0.05%
HCl)-ACN; Gradient 53%-83% B; Gradient Time (min):9.5) to afford
Compound 26 (22 mg, 43%) as a solid.
[0501] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (s, 1H), 7.81
(s, 1H), 5.05-4.87 (m, 2H), 3.88-3.82 (m, 1H), 2.70-2.58 (m, 1H),
2.28-2.15 (m, 1H), 2.05-1.56 (m, 7H), 1.48-1.15 (m, 17H), 0.76 (s,
3H), 0.66 (s, 3H).
[0502] LCMS Rt=0.828 min in 1.5 min chromatography, 5-95 AB, purity
100%, MS ESI calcd. for C.sub.26H.sub.34N.sub.3O
[M+H-2H.sub.2O].sup.+404, found 404.
Example 15. Syntheses of Compounds 27 and 28
##STR00162##
[0504] To a suspension of 2H-pyrazolo[3,4-c]py (125 mg, 1.05 mmol)
and K.sub.2CO.sub.3 (193 mg, 1.40 mmol) in acetone (10 mL) was
added J1 (300 mg, 0.701 mmol) at 15.degree. C. under N.sub.2. The
mixture was stirred at 15.degree. C. for 16 hrs. The mixture was
filtered and concentrated to give a solid, which was purified by
pre-HPLC (Column:Xtimate C18 150*25 mm*5 um; Condition: water(0.05%
HCl)-ACN; Gradient 16%-41% B; Gradient Time (min):9.5) to afford
Compound 27 (8.00 mg, 2%) as a solid and Compound 28 (6.00 mg, 2%)
as a solid.
[0505] Compound 27:
[0506] .sup.1H NMR (400 MHz, CDCl3) .delta. 9.25 (s, 1H), 8.19-8.14
(m, 1H), 7.98 (s, 1H), 7.55-7.50 (m, 1H), 5.36-5.20 (m, 2H),
3.87-3.85 (m, 1H), 2.75-2.70 (m, 1H), 2.33-1.72 (m, 5H), 1.50-1.12
(m, 19H), 0.90-0.77 (m, 4H), 0.71 (s, 3H).
[0507] LCMS Rt=0.725 min in 1.5 min chromatography, 5-95 AB, purity
100%, MS ESI calcd. for C.sub.28H.sub.40N.sub.3O.sub.3 [M+H].sup.+
466, found 466.
[0508] Compound 28:
[0509] .sup.1H NMR (400 MHz, CDCl3) .delta. 8.80 (s, 1H), 8.36-8.32
(m, 1H), 8.09 (s, 1H), 7.65-7.60 (m, 1H), 5.32-5.20 (m, 2H),
3.87-3.85 (m, 1H), 2.75-2.68 (m, 1H), 2.33-1.68 (m, 7H), 1.50-1.18
(m, 18H), 0.77 (s, 3H), 0.72 (s, 3H).
[0510] LCMS Rt=0.748 min in 1.5 min chromatography, 5-95 AB, purity
100%, MS ESI calcd. for C.sub.28H.sub.40N.sub.3O.sub.3 [M+H].sup.+
466, found 466.
Example 16. Synthesis of Compound 29
##STR00163## ##STR00164##
[0512] Step 1. To a solution of A3 (82 g, 269 mmol) in DCM (500 mL)
was added imidazole (27.4 g, 403 mmol) and TBSCl (60.7 g, 403 mmol)
at 25.degree. C. The reaction mixturewas stirred at 25.degree. C.
for 5 hours. The reaction mixture was concentrated under reduced
pressure. The residue was triturated from MeOH (500 mL) to give K1
(102 g, 91%) as a solid.
[0513] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.62-3.50 (m, 1H),
2.65-2.29 (m, 4H), 2.20-2.01 (m, 2H), 1.85-1.63 (m, 6H), 1.56-1.38
(m, 6H), 1.26-0.93 (m, 5H), 0.92-0.80 (m, 12H), 0.04 (s, 6H).
[0514] Step 2. To a solution of K1 (25 g, 59.7 mmol) in THF (50 mL)
was added L-selectride (65.6 mL, 1 M in THF, 65.6 mmol) at
-70.degree. C. under N.sub.2, The reaction mixture was stirred at
-70.degree. C. for 5 hours. The reaction mixture was quenched by
water (50 mL). The mixture was extracted with EtOAc (3.times.150
mL). The combined organic phase was washed with saturated brine
(2.times.150 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified by silica gel
chromatography (PE/EtOAc=30/1 to 3/1) to afford K2 (16 g, crude) as
a solid.
[0515] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.97 (s, 1H),
3.64-3.52 (m, 1H), 2.52-2.38 (m, 1H), 2.18-1.97 (m, 2H), 1.86-1.43
(m, 11H), 1.42-1.13 (m, 6H), 1.08-0.96 (m, 1H), 0.93-0.79 (m, 15H),
0.044 (s, 6H).
[0516] Step 5. To a solution of EtPPh.sub.3Br (39.3 g, 106 mmol) in
THF (100 mL) was added t-BuOK (11.8 g, 106 mmol) at 25.degree. C.
under N.sub.2. The reaction mixture was stirred at 25.degree. C.
for 0.5 hour. K2 (15 g, 35.6 mmol) was added to the reaction
mixture under N.sub.2. The reaction mixture was stirred at
50.degree. C. for 5 hours. The reaction mixture was quenched by
water (50 mL). The mixture was extracted with EtOAc (3.times.150
mL). The combined organic phase was washed with brine (2.times.50
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuum. The residue was purified by silica gel chromatography
(PE/EtOAc=30/1 to 10/1) to afford K3 (5.5 g, 36%) and K3 (6 g,
crude) as a solid.
[0517] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.19-5.05 (m, 1H),
3.88 (s, 1H), 3.63-3.52 (m, 1H), 2.45-2.17 (m, 3H), 1.79-1.51 (m,
10H), 1.51-1.23 (m, 10H), 1.10-0.99 (m, 1H), 0.91-0.83 (m, 12H),
0.83-0.78 (m, 3H), 0.07-0.02 (m, 6H).
[0518] Step 6. To a solution of K3 (5 g, 11.5 mmol) in THF (50 mL)
was added NaH (2.28 g, 60%, 57.4 mmol) at 0.degree. C. The reaction
mixture was stirred at 0.degree. C. for 0.5 hour under N.sub.2. MeI
(44 g, 309 mmol) was added to the reaction mixture at 0.degree. C.
The reaction mixture was stirred at 40.degree. C. for 20 hours. The
reaction mixture was quenched with ice-water (30 mL) and stirred
for 20 mins. The aqueous phase was extracted with EtOAc (3.times.50
mL). The combined organic phase was washed with brine (2.times.50
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by silica gel chromatography
(PE/EtOAc=50/1 to 10/1) to afford K4 (1.8 g, 35%) as a solid.
[0519] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.15-5.07 (m, 1H),
3.64-3.54 (m, 1H), 3.28 (s, 3H), 3.26-3.21 (m, 1H), 2.41-2.12 (m,
3H), 1.72-1.51 (m, 10H), 1.49-1.15 (m, 9H), 1.06-0.97 (m, 1H),
0.97-0.77 (m, 15H), 0.05 (s, 6H).
[0520] Step 7. To a solution of K4 (1.8 g, 4.02 mmol) in THF (30
mL) was added TBAF (12 mL, 1M in THF, 12.0 mmol) at 25.degree. C.,
the reaction mixture was stirred at 40.degree. C. for 15 hours. The
reaction mixture was quenched with water (20 mL), The aqueous phase
was extracted with EtOAc (3.times.50 mL). The combined organic
phase was washed with brine (2.times.30 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
triturated from water (40 mL) at 80.degree. C. to give K5 (1.6 g,
crude) as a solid.
[0521] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.13-5.03 (m, 1H),
3.64-3.50 (m, 1H), 3.26-3.20 (m, 4H), 2.40-2.10 (m, 3H), 1.84-1.73
(m, 1H), 1.68-1.58 (m, 14H), 1.35-1.14 (m, 5H), 1.11-1.03 (m, 1H),
0.86-0.81 (m, 6H).
[0522] Step 8. To a solution of K5 (1.3 g, 3.90 mmol) in DCM (20
mL) was added silica gel (4 g) and PCC (1.68 g, 7.8 mmol)
25.degree. C. The mixture was stirred at 25.degree. C. for 3 hrs.
The mixture was filtered though a pad of silica gel and the solid
was washed with EtOAc/DCM (30/30 mL). filtered and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (PE/EtOAc=10/1 to 1/1) to afford K6 (1 g, 78%) as a
solid.
[0523] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.16-5.07 (m, 1H),
3.32-3.19 (m, 4H), 2.48-2.09 (m, 6H), 2.09-1.87 (m, 3H), 1.78-1.10
(m, 14H), 1.00 (s, 3H), 0.87 (s, 3H).
[0524] Step 9. Under nitrogen atmosphere, anhydrous THF (30 mL) was
cooled to 10.degree. C. and anhydrous LiCl (508 mg, 12.0 mmol) was
added in one portion. The mixture was stirred for 30 mins to obtain
a clear solution. To this solution was added anhydrous FeCl.sub.3
(1.07 g, 6.64 mmol) in one portion. The resulting mixture was
stirred for additional 30 mins. The reaction mixture was cooled to
-35.degree. C. and methyl magnesium bromide (8.03 mL, 3 M in ether,
24.1 mmol) was added dropwise maintaining the internal temperature
between -35.degree. C. and -30.degree. C. The above mixture was
stirred for 30 mins at -30.degree. C. K6 (1 g, 3.02 mmol) in THF
(10 mL) was added in one portion. The internal temperature was
allowed to -20.degree. C. and held between -15.degree. C. and
-20.degree. C. for 2 hrs. The reaction mixture was poured into
ice-cooled aqueous HCl (1 M, 50 mL), extracted with EtOAc
(2.times.100 mL). The combined organic layer was washed with water
(50 mL), aqueous NaOH (10%, 2.times.100 mL) and brine (100 mL),
dried over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by column chromatography on silica gel
(PE/EtOAc=20/1 to 2/1) to give K7 (800 mg, 77%) as a solid.
[0525] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.17-5.07 (m, 1H),
3.25 (s, 4H), 2.42-2.15 (m, 3H), 1.90-1.80 (m, 1H), 1.67-1.57 (m,
6H), 1.55-1.37 (m, 7H), 1.35-1.14 (m, 10H), 0.84 (s, 3H), 0.76 (s,
3H).
[0526] Step 10. To a solution of K7 (0.8 g, 2.3 mmol) in THF (25
mL) was added BH.sub.3.Me.sub.2S (2.3 mL, 10 M in THF, 23 mmol)
slowly at 0.degree. C. under N.sub.2. The reaction mixture was
stirred at 25.degree. C. for 12 hrs. After the mixture was cooled
to 0.degree. C., a solution of NaOH (7.66 mL, 3 M in H.sub.2O, 23.0
mmol) was added into the mixture very slowly. After the addition
was complete, H.sub.2O.sub.2 (2.6 g, 30%) was added slowly and the
inner temperature was maintained below 10.degree. C. The mixture
was stirred at 25.degree. C. for 2 hrs. The resulting solution was
extracted with EtOAc (3.times.150 mL). The combined organic layers
were washed with aqueous Na.sub.2S.sub.2O.sub.3 (40 mL), brine (50
mL), dried over Na.sub.2SO.sub.4. The mixture was filtered. The
filtrate was concentrated in vacuum to give K8 (650 mg, crude) as a
solid. The crude product was used next step without further
purification.
[0527] Step 11. To a solution of K8 (0.65 g, 1.78 mmol) in DCM (20
mL) was added silica gel (1.71 g) and PCC (0.765 g, 3.56 mmol) at
25.degree. C. The reaction mixture was stirred at 25.degree. C. for
4 hours. The solution was filtered and the filter cake was washed
with EtOAc (10 mL). The solution was filtered and the filter cake
was washed with EtOAc (30 mL). The solution was concentrated in
vacuo. The residue was purified by silica gel chromatography
(PE/EtOAc=50/1 to 1/1) to afford Compound 29 (0.12 g, 19%) as a
solid.
[0528] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.26 (s, 3H),
3.24-3.19 (m, 1H), 2.62-2.54 (m, 1H), 2.12-2.14 (m, 1H), 2.11 (s,
3H), 2.03-1.84 (m, 2H), 1.74-1.59 (m, 5H), 1.56-1.35 (m, 7H),
1.32-1.11 (m, 9H), 0.75 (s, 3H), 0.59 (s, 3H).
[0529] LCMS Rt=0.991 min in 2 min chromatography, 30-90AB_ELSD,
purity 97.6.0%, MS ESI calcd. for C.sub.22H.sub.33O
[M-H.sub.2O--CH.sub.3OH].sup.+313, found 313.
Example 17. Syntheses of Compounds 30 and 31
##STR00165## ##STR00166##
[0531] Step 1. To a solution of K1 (15 g, 35.8 mmol) in THF (100
mL) was added LiA1H(t-BuO).sub.3 (27.2 g, 107 mmol) at -70.degree.
C., the reaction mixture was stirred at -70.degree. C. for 5 hours.
The reaction mixture was poured into ice-water (50 mL) and stirred
for 20 min. The organic layer was separated. The aqueous phase was
extracted with EtOAc (2.times.50 mL). The combined organic phase
was washed with saturated brine (2.times.30 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified by flash column (0.about.10% of EtOAc in PE) to afford
L1 (8 g, crude) as a solid.
[0532] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.65-3.41 (m, 2H),
2.53-2.38 (m, 1H), 2.30-1.95 (m, 2H), 1.95-1.65 (m, 6H), 1.65-1.38
(m, 8H), 1.38-0.99 (m, 4H), 0.99-0.78 (m, 14H), 0.78-0.65 (m, 1H),
0.046 (m, 6H).
[0533] Step 2. To a solution of bromo(ethyl)triphenylphosphorane
(28.2 g, 76.0 mmol) in THF (100 mL) was added t-BuOK (8.52 g, 76.0
mmol) at 25.degree. C. The mixture was heated to 60.degree. C. and
stirred for 1 h. A solution of L1 (8 g, 19.0 mmol) in THF (20 mL)
was added. The mixture was stirred at 60.degree. C. for 16 hrs. The
mixture was treated with NH.sub.4Cl (50 mL, sat. aq.). The organic
layer was separated. The aqueous phase was extracted with EtOAc
(2.times.50 mL). The combined organic phase was washed with
saturated brine (2.times.50 mL), dried over anhydrous Na2SO4,
filtered, concentrated. The residue was purified by flash column
(0.about.5% of EtOAc in PE) to give L2 (5 g, 61%) as a solid.
[0534] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.22-5.05 (m, 1H),
3.65-3.49 (m, 1H), 3.49-3.30 (m, 1H), 2.48-2.35 (m, 1H), 2.35-2.19
(m, 2H), 1.98-1.85 (m, 1H), 1.75-1.55 (m, 11H), 1.55-1.25 (m, 9H),
1.25-1.10 (m, 1H), 0.95-0.80 (m, 14H), 0.047 (s, 6H).
[0535] Step 3. To a solution of L2 (5 g, 11.5 mmol) in THF (50 mL)
was added NaH (2.28 g, 57.4 mmol, 60% in mineral oil) in one
portion at 0.degree. C. under N.sub.2. After 30 min, MeI (16.1 g,
114 mmol) was added dropwise at 20.degree. C. The reaction mixture
was stirred for 6 hours at 40.degree. C. The mixture was quenched
with saturated aqueous NH.sub.4Cl (20 mL, sat. aq.) at 0.degree. C.
The organic layer was separated. The aqueous phase was extracted
with EtOAc (2.times.20 mL). The combined organic phases was washed
with saturated brine (2.times.20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to afford L3 (5 g,
crude) as a solid which used directly for the next step.
[0536] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.20-5.10 (m, 1H),
3.60-3.55 (m, 1H), 3.28 (s, 3H), 2.90-2.75 (m, 1H), 2.41-2.05 (m,
3H), 1.85-1.35 (m, 14H), 1.35-1.00 (m, 6H), 1.00-0.65 (m, 15H),
0.05 (m, 6H).
[0537] Step 4. To a solution L3 (5 g, 11.1 mmol) in THF (10 mL) was
added TBAF (55.5 mL, 55.5 mmol, 1 M in THF). The reaction mixture
was stirred at 80.degree. C. for 16 h. The reaction mixture was
poured into water (50 mL). The organic layer was separated. The
aqueous phase was extracted with EtOAc (2.times.20 mL). The
combined organic phase was washed with saturated brine (2.times.20
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to give L4 (3.6 g, impure) as a solid.
[0538] Step 5. To a solution of L4 (3.6 g, 10.8 mmol) in DCM (20
mL) was added silica gel (3 g) and PCC (4.64 g, 21.6 mmol) at
20.degree. C. The mixture was stirred at 20.degree. C. for 2 hrs.
The mixture was filtered and the filter cake was washed with DCM
(2.times.10 mL). The combined filtrate was concentrated in vacuum
to give L5 (3 g, crude) as a solid.
[0539] Step 6. Under N.sub.2, anhydrous THF (10 mL) was cooled to
15.degree. C. and anhydrous LiCl (1.53 g, 36.2 mmol) was added in
one portion. The mixture was stirred for 30 min to obtain a clear
solution. To this solution was added anhydrous FeCl.sub.3 (3.22 g,
19.9 mmol) in one portion. The resulting mixture was stirred for
additional 30 mins. The reaction mixture was cooled to -35.degree.
C. and methyl magnesium bromide (3 M in diethyl ether, 12.0 mL,
36.2 mmol) was added dropwise maintaining the internal temperature
between -35.degree. C. and -30.degree. C. The above mixture was
stirred for 30 min at -30.degree. C. L5 (3 g, 9.07 mmol) in THF (10
mL) was added in one portion. The internal temperature was allowed
to -20.degree. C. and held between -15.degree. C. and -20.degree.
C. for 2 hrs. The reaction mixture was poured to ice-cooled aqueous
HCl (1 M, 20 mL), extracted with EtOAc (2.times.20 mL). The organic
layer was separated. The combined organic layer was washed with
water (20 mL), aqueous NaOH (10%, 2.times.20 mL) and brine (20 mL),
dried over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by flash column (0.about.10% of EtOAc in PE)
to give L6 (2.8 g, 89%) as a solid.
[0540] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.20-5.00 (m, 1H),
3.27 (s, 3H), 2.90-2.80 (m, 1H), 2.45-2.10 (m, 4H), 2.90-1.45 (m,
11H), 1.45-1.05 (m, 11H), 0.95-0.72 (m, 7H).
[0541] Step 7. To a solution of L6 (2.8 g, 8.07 mmol) in THF (15
mL) was added dropwise a solution of BH.sub.3.Me.sub.2S (8.07 mL,
10M, 80.7 mmol) at 0.degree. C. The solution was stirred at
15.degree. C. for 3 h. After cooling to 0.degree. C., a solution of
NaOH solution (48.4 mL, 2M, 96.8 mmol) was added very slowly. After
addition, H.sub.2O.sub.2 (8.07 mL, 80.7 mmol, 30% in water) was
added slowly and the inner temperature was maintained below
10.degree. C. The resulting solution was stirred at 15.degree. C.
for 2 h. Then saturated aqueous Na.sub.2S.sub.2O.sub.3 (20 mL) was
added until the reaction solution became clear. The mixture was
extracted with EtOAc (3.times.20 mL). The combined organic solution
was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3
(2.times.10 mL), brine (20 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to give L7 (3.1 g, crude) as a
solid which was used in next step without further purification.
[0542] Step 8. To a solution of L7 (3.1 g, 8.50 mmol) in DCM (20
mL) was added PCC (3.65 g, 17.0 mmol) and silica gel (3 g) at
25.degree. C. The solution was stirred at 25.degree. C. for 3 h.
The reaction mixture was filtered and the filter cake was washed
with anhydrous DCM (2.times.20 mL). The combined filtrate was
concentrated in vacuum. The residue purified by flash column
(0.about.20% of EtOAc in PE) to give Compound 30 (2 g, impure) as a
solid. The residue Compound 30 (2 g, 5.51 mmol) was re-crystallized
from MeCN (20 mL) at 65.degree. C. to give Compound 30 (24 mg, 1%,
pure) as a solid. The mother liquid was concentrated to give
Compound 30 (1776 mg, impure) as a solid.
[0543] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.26 (s, 3H),
2.90-2.80 (m, 1H), 2.50-2.41 (m, 1H), 2.20-2.08 (m, 4H), 2.08-1.95
(m, 1H), 1.82-1.70 (m, 2H), 1.70-1.60 (m, 3H), 1.60-1.45 (m, 5H),
1.45-1.20 (m, 9H), 1.20-1.05 (m, 2H), 0.90-0.80 (m, 1H), 0.76 (s,
3H), 0.62 (s, 3H).
[0544] LCMS t.sub.R=0.905 min in 2 min chromatography,
30-90AB_ELSD, purity 100.0%, MS ESI calcd. for C.sub.22H.sub.33O
[M-H.sub.2O--CH.sub.3O].sup.+ 313, found 313.
[0545] Step 9. To a solution of Compound 30 (200 mg, 551 .mu.mol)
in MeOH (10 mL) was added HBr (11.1 mg, 0.0551 mmol, 40% in water)
and Br.sub.2 (105 mg, 0.661 mmol) at 25.degree. C. The mixture was
stirred at 25.degree. C. for 2 hrs. The mixture was quenched by
sat.aq NaHCO.sub.3 (10 mL), treated with water (20 mL). The mixture
was extracted with DCM (2.times.20 mL). The combined organic phase
was washed with brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered, concentrated in vacuum to afford L8
(230 mg, crude) as a pale yellow oil, which was used directly in
next step without further purification.
[0546] Step 10. To a solution of L8 (230 mg, 0.521 mmol) in acetone
(5 mL) was added K.sub.2CO.sub.3 (143 mg, 1.04 mmol) and
1H-pyrazole-4-carbonitrile (58.1 mg, 0.625 mmol) at 25.degree. C.
The mixture was stirred at 25.degree. C. for 16 hrs. The mixture
was treated with water (20 mL). The mixture was extracted with DCM
(2.times.10 mL). The combined organic phase was washed with brine
(10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered,
concentrated. The residue was purified by flash column (0.about.50%
of EtOAc in PE) to give Compound 31 (63 mg, 27%) as a solid.
[0547] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (s, 1H), 7.80
(s, 1H), 5.08-4.85 (m, 2H), 3.27 (s, 3H), 2.85-2.75 (m, 1H),
2.55-2.45 (m, 1H), 2.22-2.12 (m, 1H), 2.12-2.00 (m, 1H), 1.90-1.65
(m, 5H), 1.65-1.1.28 (m, 11H), 1.28-1.20 (m, 3H), 1.20-1.05 (m,
2H), 0.90-0.80 (m, 1H), 0.77 (s, 3H), 0.68 (s, 3H).
[0548] LCMS t.sub.R=0.912 min in 2 min chromatography,
30-90AB_ELSD, purity 100.0%, MS ESI calcd. for
C.sub.27H.sub.40N.sub.3O.sub.3 [M+H].sup.+ 454, found 454.
Example 18. Syntheses of Compounds 32 and 33
##STR00167##
[0550] Step 1. To a solution of Compound 6 (1 g, 2.88 mmol) in MeOH
(10 ml) was added HBr (0.1 mL, 40% in water) and Br.sub.2 (551 mg,
3.45 mmol) at 25.degree. C. The mixture was stirred at 25.degree.
C. for 3 hrs. The mixture was quenched with saturated aqueous
NaHCO.sub.3 (10 mL), treated with water (20 mL) and extracted with
EtOAc (2.times.30 mL). The combined organic phase was washed with
Sat Na.sub.2S.sub.2O.sub.3 (50 mL) and brine (50 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum.
The residue was purified by flash chromatography eluting with
(petroleum ether/ethyl acetate=5/1) to give M1 (800 mg, 66%) as a
solid.
[0551] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.95-3.88 (m, 2H),
2.76 (t, J=8 Hz, 1H), 2.20-2.11 (m, 1H), 1.95-1.84 (m, 2H),
1.78-1.67 (m, 2H), 1.53-1.43 (m, 4H), 1.42-1.38 (m, 1H), 1.34-1.08
(m, 13H), 1.03-0.93 (m, 4H), 0.87-0.80 (m, 1H), 0.71 (s, 3H), 0.65
(s, 3H).
[0552] Step 2. To a solution of M1 (200 mg, 0.47 mmol) in acetone
(2 mL) was added K.sub.2CO.sub.3 (161 mg, 1.17 mmol) and
5-methyl-2H-tetrazole (59.2 mg, 0.705 mmol). The mixture was
stirred at 25.degree. C. for 16 hours. To the mixture was added
water (10 mL) and ethyl acetate (20 mL). The organic layer was
separated. The aqueous phase was extracted with ethyl acetate (50
mL). The combined organic layers was washed with brine (100 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum.
The residue was purified by flash chromatography eluting with
(petroleum ether/ethyl acetate=2/1) to give Compound 32 (56 mg,
28%) and Compound 33 (82 mg, 41%) as a solid.
[0553] Compound 32:
[0554] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 5.40-5.31 (m, 2H),
2.59-2.54 (m, 4H), 2.23-2.13 (m, 1H), 2.10-2.02 (m, 1H), 1.98-1.85
(m, 1H), 1.82-1.68 (m, 2H), 1.54-1.39 (m, 5H), 1.37-1.15 (m, 13H),
1.04-0.94 (m, 4H), 0.90-0.81 (m, 1H), 0.72 (s, 6H).
[0555] LCMS Rt=1.103 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. For C.sub.25H.sub.41N.sub.4O.sub.2
[M+H].sup.+429, found 429.
[0556] Compound 33:
[0557] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 5.17-5.03 (m, 2H),
2.60 (t, J=8 Hz, 1H), 2.46 (s, 3H), 2.25-2.13 (m, 1H), 2.07-1.87
(m, 1H), 1.83-1.70 (m, 2H), 1.56-1.42 (m, 6H), 1.40-1.11 (m, 13H),
1.05-0.95 (m, 4H), 0.90-0.81 (m, 1H), 0.73 (s, 3H), 0.69 (s,
3H).
[0558] LCMS Rt=1.043 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. For C.sub.25H.sub.41N.sub.4O.sub.2
[M+H].sup.+429, found 429.
Example 19. Syntheses of Compounds 34, 35, 36, and 37
##STR00168##
[0560] Step 1. To a solution of Compound 5 (1.1 g, 3.17 mmol) in
MeOH (20 mL) was added HBr (126 mg, 0.634 mmol, 40% in water) and
Br.sub.2 (608 mg, 3.80 mmol) at 25.degree. C. The mixture was
stirred at 25.degree. C. for 1 h. The mixture was quenched by
sat.NaHCO.sub.3 (20 mL), and treated with water (20 mL). The
mixture was extracted with DCM (2.times.30 mL). The combined
organic phase was washed with brine (2.times.20 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered, concentrated in vacuum to
afford N3 (1.2 g, impure) as a solid used directly for the next
step.
[0561] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.95-3.85 (m, 2H),
2.85-2.75 (m, 1H), 2.25-2.10 (m, 1H), 1.95-1.69 (m, 7H), 1.69-1.41
(m, 8H), 1.41-0.98 (m, 12H), 0.98-0.75 (m, 3H), 0.63 (s, 3H).
[0562] Step 2. To a solution of N3 (350 mg, 0.822 mmol) in acetone
(10 mL) was added K.sub.2CO.sub.3 (226 mg, 1.64 mmol) and
5-methyl-2H-tetrazole (137 mg, 1.64 mmol) at 25.degree. C. The
mixture was stirred at 25.degree. C. for 16 hrs. The reaction
mixture was treated with water (20 mL). The mixture was extracted
with CH.sub.2Cl.sub.2 (2.times.20 mL). The combined organic phase
was washed with brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered, concentrated in vacuum. The residue was
purified by flash column (0.about.100% of EtOAc in PE) to afford
Compound 35 (5 mg, 1%) as a solid, Compound 34 (49 mg, 14%) as a
solid, Compound 37 (6 mg, 2%) as a solid and Compound 36 (41 mg,
12%) as a solid.
[0563] Compound 34:
[0564] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.40-5.30 (m, 2H),
2.65-2.60 (m, 1H), 2.56 (s, 3H), 2.30-2.15 (m, 1H), 2.09-2.00 (m,
1H), 1.89-1.55 (m, 6H), 1.55-1.01 (m, 17H), 1.01-0.90 (m, 3H), 0.77
(s, 3H), 0.70 (s, 3H).
[0565] LCMS Rt=1.084 min in 2 min chromatography, 30-90AB_ELSD,
purity 100.0%, MS ESI calcd. for C.sub.25H.sub.41N.sub.4O.sub.2
[M+H].sup.+ 429, found 429.
[0566] Compound 35:
[0567] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.45-5.25 (m, 2H),
2.80-2.70 (m, 1H), 2.57 (s, 3H), 2.00-1.65 (m, 7H), 1.50-1.40 (m,
5H), 1.40-1.22 (m, 6H), 1.22-1.15 (m, 5H), 1.15-1.00 (m, 2H), 0.94
(s, 3H), 0.94-0.89 (m, 3H), 0.75 (s, 3H).
[0568] LCMS Rt=1.094 min in 2 min chromatography, 30-90AB_ELSD,
purity 100.0%, MS ESI calcd. for C.sub.25H.sub.39N.sub.4O
[M+H--H.sub.2O].sup.+411, found 411.
[0569] Compound 36:
[0570] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.20-5.00 (m, 2H),
2.70-2.60 (m, 1H), 2.47 (s, 3H), 2.25-2.15 (m, 1H), 2.10-2.00 (m,
1H), 1.90-1.65 (m, 5H), 1.65-1.25 (m, 10H), 1.25-1.11 (m, 7H),
1.11-1.05 (m, 1H), 1.05-0.95 (m, 3H), 0.77 (s, 3H), 0.67 (s,
3H).
[0571] LCMS Rt=1.007 min in 2 min chromatography, 30-90AB_ELSD,
purity 100.0%, MS ESI calcd. for C.sub.25H.sub.41N.sub.4O.sub.2
[M+H].sup.+ 429, found 429.
[0572] Compound 37:
[0573] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.30-5.20 (m, 1H),
.delta. 5.00-4.90 (m, 1H), 2.90-2.80 (m, 1H), 2.48 (s, 3H),
1.95-1.65 (m, 7H), 1.45-1.40 (m, 3H), 1.40-1.22 (m, 7H), 1.22-1.10
(m, 6H), 1.10-1.06 (m, 2H), 0.97 (s, 3H), 0.96-0.93 (m, 3H), 0.75
(s, 3H).
[0574] LCMS Rt=1.021 min in 2 min chromatography, 30-90AB_ELSD,
purity 100.0%, MS ESI calcd. for C.sub.25H.sub.39N.sub.4O
[M+H--H2O].sup.+411, found 411.
Example 20. Syntheses of Compounds 38 and 39
##STR00169##
[0576] Step 1. To a solution of D6 (500 mg, 1.17 mmol) in acetone
(10 mL) was added K.sub.2CO.sub.3 (322 mg, 2.34 mmol) and
1H-pyrazole-4-carbonitrile (162 mg, 1.75 mmol). After stirring at
25.degree. C. for 12 hours, the mixture was poured in to water (50
mL) and extracted with ethyl acetate (3.times.50 mL). The combined
organic layers was washed with brine (150 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue
was purified by flash column (0.about.15% of EtOAc in PE) to afford
O1 (340 mg, 60%) as a solid.
[0577] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.99-7.78 (m, 2H),
5.07-4.84 (m, 2H), 2.67-2.49 (m, 1H), 2.26-2.13 (m, 1H), 2.02-1.81
(m, 2H), 1.64-1.38 (m, 10H), 1.34-0.99 (m, 12H), 0.98-0.91 (m, 3H),
0.76 (s, 2H), 0.72 (s, 1H), 0.69-0.63 (m, 3H).
[0578] Step 2. O1 (340 mg, 0.77 mmol) was purified by SFC (column:
OD (250 mm*30 mm, 5 um)), gradient: 45-45% B (A=0.1%
NH.sub.3/H.sub.2O, B=EtOH), flow rate: 50 mL/min) to give Compound
38 (145 mg, 43%) and Compound 39 (84 mg, 24%) as a solid.
[0579] Compound 38:
[0580] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.88-7.78 (d,
J=19.2 Hz, 2H), 5.06-4.84 (m, 2H), 2.64-2.56 (m, 1H), 2.26-2.15 (m,
1H), 2.04-1.96 (m, 1H), 1.84-1.64 (m, 5H), 1.55-1.24 (m, 11H),
1.22-1.09 (m, 6H), 1.07-0.99 (m, 1H), 0.96-0.89 (m, 3H), 0.76 (s,
3H), 0.66 (s, 3H).
[0581] LCMS Rt=1.037 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.27H.sub.40N.sub.3O.sub.2
[M+H].sup.+ 438, found 438.
[0582] SFC Rt=4.998 min in 10 min chromatography,
OD_3_EtOH_DEA_5_40_25 ML, purity: 99.8%.
[0583] Note: The structure of Compound 38 was confirmed by
X-ray.
[0584] Compound 39:
[0585] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.87-7.78 (d,
J=17.2 Hz, 2H), 5.07-4.86 (m, 2H), 2.57-2.49 (m, 1H), 2.23-2.13 (m,
1H), 2.06-1.99 (m, 1H), 1.97-1.86 (m, 1H), 1.79-1.67 (m, 2H),
1.55-1.36 (m, 6H), 1.35-1.13 (m, 12H), 1.05-0.92 (m, 4H), 0.89-0.81
(m, 1H), 0.72 (s, 3H), 0.68 (s, 3H).
[0586] LCMS Rt=1.051 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.27H.sub.39N.sub.3O.sub.2Na
[M+Na].sup.+460, found 460.
[0587] SFC Rt=6.270 min in 10 min chromatography,
OD_3_EtOH_DEA_5_40_25 ML, purity: 100%.
Example 21. Synthesis of Compound 40
##STR00170##
[0589] Step 1. To a solution of P1 (2 g, 6.56 mmol) in toluene (20
mL) was added p-toluenesulfonic acid (20 mg, 0.116 mmol) and
pyridin-2-ylmethanamine (1.55 g, 14.4 mmol) at 25.degree. C. The
reaction mixture was heated to 130.degree. C. in a Dean-Stark
apparatus for 16 h. The reaction was cooled to 25.degree. C. and
diluted with EtOAc (30 mL). The organic layer was washed
sequentially with sat. NH.sub.4Cl (2.times.20 mL), sat. NaHCO.sub.3
(20 mL), brine (20 mL) and dried over Na.sub.2SO.sub.4, then
concentrated in vacuum to give crude product P2 (3 g, crude) as
yellow oil, which was used directly for the next.
[0590] Step 2. P2 (1 g, 2.53 mmol), Cu(OTf).sub.2 (1.18 g, 3.28
mmol) and L-ascorbic acid, sodium salt (1 g, 5.06 mmol) were added
to a round-bottom-flask under N.sub.2. Acetone (dry, 8 mL) and MeOH
(dry, 8 mL) were added at 25.degree. C. and stirred for 5 min
(reaction mixture may turn brown). O.sub.2 from a balloon was
bubbled through the reaction mixture for 5 min (resulting in a
blue/green solution). After that, the reaction was heated to
50.degree. C. under an O.sub.2 atmosphere for 1.5 h. The reaction
mixture was then cooled to 25.degree. C., EtOAc (30 mL) and sat.
Na.sub.4EDTA (30 mL, pH.about.10) were added and the reaction
mixture was stirred for 1 h. The layers were separated. The aqueous
layer was extracted with EtOAc (2.times.30 mL), dried over
Na.sub.2SO.sub.4 and concentrated in vacuum to give crude product,
which was purified by a silica gel column (PE/EtOAc=3/1) to give P3
(230 mg, 28%) as a solid which was triturated with MeCN (5 mL) at
25.degree. C. to give P3 (110 mg, 48% yield) as a solid and P3 (100
mg, impure) as a solid.
[0591] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.78-3.73 (m, 1H),
2.98 (d, J=1.4 Hz, 1H), 2.49-2.41 (m, 1H), 2.16-2.03 (m, 1H),
2.02-1.92 (m, 1H), 1.87-1.76 (m, 2H), 1.68-1.56 (m, 1H), 1.55-1.45
(m, 5H), 1.42-1.22 (m, 7H), 1.21 (s, 3H), 1.11 (s, 1H), 1.04-0.86
(m, 5H), 0.78 (s, 3H).
[0592] Step 3. Into a over-dried bottom was added t-BuOH (2 mL) and
t-BuOK (348 mg, 3.11 mmol). It was degassed and filled with
N.sub.2. A solution of P3 (100 mg, 0.312 mmol) in DME (2 mL) was
added into the suspension. After 30 min, a solution of TosMIC (121
mg, 0.624 mmol) in DME (2 mL) was added. The mixture became yellow.
The resulting mixture was stirred at 25.degree. C. for 16 h. Water
was added and the mixture was stirred and the mixture was extracted
with ethyl acetate (3.times.30 mL). The combined organic layer was
washed with brine. The combined organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
purified by flash chromatography eluting with (petroleum
ether/ethyl acetate=4/1) to give Compound 40 (60 mg, 58% yield) as
a pale solid, which was triturated with MeCN (2 mL) to give
Compound 40 (30 mg) as a solid.
[0593] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.51-3.44 (m, 1H),
2.46-2.37 (m, 1H), 2.23-2.11 (m, 1H), 2.00-1.91 (m, 1H), 1.84-1.74
(m, 2H), 1.70-7.67 (m, 1H), 1.62-1.57 (m, 1H), 1.53-1.31 (m, 8H),
1.30-1.22 (m, 4H), 1.21-1.15 (s, 3H), 1.09 (s, 1H), 1.04-0.84 (m,
6H), 0.77 (s, 3H) LCMS Rt=0.747 min in 2 min chromatography, 30-90
AB, purity 100%, MS ESI calcd. For C.sub.21H.sub.30N
[M+H-2H.sub.2O].sup.+296, found 296.
[0594] Note: the structure of Compound 40 was confirmed by
X-ray.
Example 23. Synthesis of Compound 41
##STR00171##
[0596] Step 1. To a solution of P3 (1.2 g, 3.74 mmol) in THF (12
mL) was added KOH (632 mg, 11.3 mmol) and Me.sub.2SO.sub.4 (966 mg,
0.725 mL, 7.66 mol) at 0.degree. C. Then the mixture was warmed to
25.degree. C. and stirred at the same temperature for 16 h. The
mixture was quenched with the addition of 50 mL of water and
extracted with EtOAc (2.times.30 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuum to give crude product, which was purified by a silica gel
column (PE/EtOAc=10/1-5:1) to give Q1 (600 mg, 48%) as a solid and
the starting material P3 (600 mg) as a solid.
[0597] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.49 (s, 3H),
3.20-3.15 (m, 1H), 2.48-2.40 (m, 1H), 2.12-1.90 (m, 3H), 1.83-1.75
(m, 1H), 1.59-1.46 (m, 8H), 1.38-1.26 (m, 4H), 1.23-1.15 (m, 5H),
1.01-0.91 (m, 4H), 0.86-0.76 (m, 4H).
[0598] Step 2. Into an over-dried bottom was added t-BuOH (2 mL)
and t-BuOK (334 mg, 2.98 mmol). It was evaporated and filled with
N.sub.2. Q1 (100 mg, 0.299 mmol) in DME (1 mL) was added into the
suspension. After 30 min, TosMIC (116 mg, 0.598 mmol) in DME (1 mL)
was added. The mixture became yellow. The resulting mixture was
stirred at 25.degree. C. for 16 h. Water was added and the mixture
was stirred. Then it was extracted with ethyl acetate (3.times.30
mL). The combined organic layer was washed with brine. The combined
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by flash chromatography
eluting with (petroleum ether: ethyl acetate=4/1) to give Compound
41 (25 mg, impure) as a pale yellow oil, which was triturated with
MeCN (1 mL) to give Compound 41 (10 mg, 10%) as a solid.
[0599] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.41 (s, 3H),
2.92-2.88 (m, 1H), 2.43-2.35 (m, 1H), 2.23-2.09 (m, 1H), 2.02-1.89
(m, 2H), 1.81-1.64 (m, 2H), 1.49-1.32 (m, 5H), 1.27-1.24 (m, 5H),
1.22-1.20 (m, 4H), 1.00-0.85 (m, 7H), 0.83-0.79 (m, 1H), 0.77 (s,
3H).
[0600] LCMS Rt=0.903 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.22H.sub.32N [M+H-2H.sub.2O].sup.+296,
found 296.
Example 24. Synthesis of Compound 42
##STR00172##
[0602] Step 1. To a solution of P3 (200 mg, 0.624 mmol) in MeOH (5
mL) was added NaBH.sub.4 (46.9 mg, 1.24 mmol) at 25.degree. C. The
reaction was stirred at 25.degree. C. for 30 mins. The reaction was
quenched with water (10 mL) and extracted with DCM (2.times.20 mL).
The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to give R1 (180 mg, crude) as a
colourless oil, which was used directly for next step without
further purification.
[0603] Step 2. To a solution of R1 (200 mg, 0.620 mmol) in THF (3
mL) was added KOH (211 mg, 3.77 mmol) and Me.sub.2SO.sub.4 (320 mg,
0.24 mL, 2.54 mmol) at 0.degree. C. Then the mixture was warmed to
25.degree. C. and stirred at the same temperature for 16 h. The
mixture was quenched with the addition of 50 mL of water and
extracted with EtOAc (2.times.30 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuum to give crude product which was purified by a silica gel
column (PE/EtOAc=10/1-5:1) to give Compound 42 (30 mg, 14%) as a
solid, which was triturated with n-hexane (3 mL) at 25.degree. C.
to give Compound 42 (6 mg, 3%) as a solid.
[0604] .sup.1H NMR (400 MHz, CDCl3) .delta. 3.39-3.33 (m, 7H),
2.91-2.86 (m, 1H), 2.08-2.02 (m, 1H), 1.91-1.86 (m, 5H), 1.55-1.20
(m, 7H), 1.18-1.14 (m, 8H), 0.92-0.79 (m, 3H), 0.77 (s, 6H).
[0605] LCMS Rt=0.952 min in 2 min chromatography, 30-90 AB, purity
99%, MS ESI calcd. For
C.sub.22H.sub.38O.sub.3Na.sup.+[M+Na].sup.+373, found 373.
Example 25. Synthesis of Compound 43
##STR00173##
[0607] Step 1. To a suspension of EtPPh.sub.3Br (3.32 g, 8.95 mmol)
in THF (40 mL) was added t-BuOK (1 g, 8.95 mmol) at 25.degree. C.
under N.sub.2. After stirring at 60.degree. C. for 30 min, a
solution of Q1 (600 mg, 1.79 mmol) in THF (10 mL) was added at
60.degree. C. The mixture was stirred at 60.degree. C. for 16 h.
The mixture was quenched with NH.sub.4Cl (80 mL). The organic layer
was separated, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuum to give a crude product, which was purified
by a silica gel column (PE/EtOAc=10/1-5/1) to give S1 (340 mg, 55%)
as a solid.
[0608] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.25-5.18 (m, 1H),
3.33 (s, 3H), 3.17-3.12 (m, 1H), 2.42-2.36 (m, 1H), 2.25-2.10 (m,
2H), 1.79-1.76 (m, 6H), 1.75-1.56 (m, 5H), 1.54-1.23 (m, 6H),
1.21-0.98 (m, 5H), 0.90-0.84 (m, 5H), 0.77 (s, 3H).
[0609] Step 2. To a solution of S1 (340 mg, 0.981 mmol) in THF (4
mL) was added 9-BBN dimer (597 mg, 2.45 mmol) at 0.degree. C. under
N.sub.2. The solution was stirred at 60.degree. C. for 16 h. After
cooling to 0.degree. C., a solution of EtOH (15 mL) and NaOH (1.96
mL, 5M, 9.81 mmol) was added very slowly. After addition,
H.sub.2O.sub.2 (0.981 ml, 9.81 mmol, 30% in water) was added slowly
and the inner temperature was maintained below 10.degree. C. The
mixture was stirred at 60.degree. C. under N.sub.2 for 1 hour. The
mixture was re-cooled to 30.degree. C. Water washed (100 mL) was
added to the solution and extracted with EtOAc (2.times.50 mL). The
combined organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuum to give S2 (400 mg, crude) as colorless
oil which was directly used for next step.
[0610] Step 3. To a solution of S2 (350 mg, 0.960 mmol) in DCM (10
mL) was added PCC (413 mg, 1.92 mmol) and silica gel (454 mg) at
25.degree. C. Then the solution was stirred at 25.degree. C. for 3
h. The reaction mixture was filtered and the residue was washed
with anhydrous DCM (2.times.30 mL). The combined filtrate was
concentrated in vacuum to give a crude product, which was purified
by a silica gel column (PE/EtOAc=8/1.about.4/1) to give Compound 43
(270 mg, impure) as pale solid. The solid was triturated with MeCN
(5 mL) at 25.degree. C. to give Compound 45 (10 mg, 4%) as a solid
for delivery and Compound 43 (250 mg, crude) as pale yellow
oil.
[0611] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.33 (s, 3H),
3.08-3.03 (m, 1H), 2.71-2.66 (m, 1H), 2.21 (s, 3H), 2.17-1.97 (m,
2H), 1.58-1.55 (m, 3H), 1.54-1.21 (m, 12H), 1.20-1.00 (m, 5H),
0.98-0.75 (m, 5H), 0.65 (s, 3H).
[0612] LCMS Rt=0.960 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.23H.sub.39O.sub.3[M+H].sup.+ 363,
found 363.
Example 26. Synthesis of Compound 44
##STR00174##
[0614] Step 1. To a solution of Compound 43 (1 g, 2.75 mmol) in
MeOH (15 ml) was added HBr (44.5 mg, 0.55 mmol, 40% in water) and
Br.sub.2 (439 mg, 0.140 mmol) at 25.degree. C. The mixture was
stirred at 25.degree. C. for 16 hrs. The mixture was quenched by
sat.aq NaHCO.sub.3 (10 mL), treated with water (20 mL), extracted
with EtOAc (2.times.20 mL). The combined organic phase was washed
with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, concentrated in vacuum to afford T1 (1.3 g, crude) as
light yellow oil which was used directly for the next step.
[0615] Step 2. To a mixture of T1 (300 mg, 0.680 mmol) and
K.sub.2CO.sub.3 (186 mg, 1.35 mmol) in acetone (5 mL) was added
1H-pyrazole-4-carbonitrile (94 mg, 1.01 mmol) at 25.degree. C. The
reaction mixture was stirred at the 25.degree. C. for 16 h. The
reaction mixture was filtered and the filtrate was concentrated in
vacuum to give crude product, which was purified by a silica gel
column (PE/EtOAc=2/1) to give Compound 44 (37 mg, 12%) as a
solid.
[0616] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.80 (s, 2H), 5.45
(d, J=17.8 Hz, 1H), 4.93 (d, J=17.8 Hz, 1H), 3.38 (s, 3H),
3.19-3.14 (m, 1H), 2.73-2.67 (m, 1H), 2.20-2.02 (m, 2H), 1.80-1.65
(m, 3H), 1.50-1.32 (m, 5H), 1.31-1.11 (m, 11H), 1.00-0.80 (m, 3H),
0.77 (s, 3H), 0.66 (s, 3H)
[0617] LCMS Rt=1.113 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For
C.sub.27H.sub.39N.sub.3O.sub.3Na.sup.+[M+Na].sup.+476, found
476.
Example 27. Syntheses of Compounds 45 and 46
##STR00175##
[0619] Step 1. To a suspension of EtPPh.sub.3Br (11.5 g, 31.2 mmol)
in THF (50 mL) was added t-BuOK (3.50 g, 31.2 mmol) at 25.degree.
C. under N.sub.2. After stirring at 60.degree. C. for 30 min, a
solution of P3 (2 g, 6.24 mmol) in THF (20 mL) was added at
60.degree. C. The mixture was stirred at 60.degree. C. for 16 h and
quenched with NH.sub.4Cl (100 mL). The organic layer was separated,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to
give crude product which was purified by a silica gel column
(PE/EtOAc=10/1-5/1) to give U1 (1.8 g, 87%) as a solid.
[0620] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.18-5.14 (m, 1H),
3.68-3.63 (m, 1H), 2.47-2.35 (m, 1H), 2.21-2.09 (m, 1H), 1.89-1.70
(m, 5H), 1.69-1.59 (m, 1H), 1.51-1.45 (m, 4H), 1.41-1.19 (m, 8H),
1.16 (s, 3H), 1.12-0.88 (m, 2H), 1.12-0.88 (m, 1H), 1.12-0.88 (m,
1H), 0.86 (s, 3H), 0.84-0.81 (m, 1H), 0.80 (s, 3H).
[0621] Step 2. To a solution of U1 (1.8 g, 5.41 mmol) in DCM (40
mL) was added TBSCl (1.22 g, 8.11 mmol) and 1H-Imidazole (735 mg,
10.8 mmol) at 25.degree. C. The reaction was stirred at 50.degree.
C. for 16 h, quenched by water (30 mL) and extracted with DCM
(2.times.20 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give crude
product which was purified by a silica gel column
(PE/EtOAc=10/1-5/1) to give U2 (1.6 g, 66%) as a solid.
[0622] Step 3. To a solution of U2 (1.6 g, 3.58 mmol) in THF (40
mL) was added 9-BBN dimer (4.36 g, 17.9 mmol) at 0.degree. C. under
N.sub.2. The solution was stirred at 60.degree. C. for 16 h. After
cooling to 0.degree. C., a solution of EtOH (40 mL) and NaOH (7.15
mL, 5M, 35.8 mmol) was added very slowly. After addition,
H.sub.2O.sub.2 (3.56 ml, 35.8 mmol, 30% in water) was added slowly
and the inner temperature was maintained below 10.degree. C. The
mixture was stirred at 60.degree. C. under N.sub.2 for 1 hour. The
mixture was re-cooled to 30.degree. C., treated with water (100 mL)
and extracted with EtOAc (2.times.50 mL). The combined organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuum to give U3 (2.3 g, crude) as colourless oil, which was
directly used for next step.
[0623] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.15-4.06 (m, 1H),
3.40-3.30 (m, 1H), 1.76-1.68 (m, 3H), 1.56-1.43 (m, 6H), 1.40-1.30
(m, 4H), 1.29-1.15 (m, 13H), 1.04-0.80 (m, 4H), 0.78-0.73 (m,
6H).
[0624] Step 4. To a solution of U3 (300 mg, 1.72 mmol) in DCM (15
mL) was added silica gel (404 mg) and PCC (368 mg, 1.71 mmol) at
25.degree. C. The reaction was stirred at 25.degree. C. for 1 h.
The mixture was filtered and the filtrate was concentrated in
vacuum to give crude product which was purified by a silica gel
column (PE/EtOAc=6/1-2/1) to give Compound 46 (10 mg, 3%) and
Compound 45 (10 mg, 3%) as a solid.
[0625] Compound 45:
[0626] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.86 (s, 1H),
3.45-3.40 (m, 1H), 2.50-2.34 (m, 1H), 2.21-2.05 (m, 4H), 2.03-1.89
(m, 1H), 1.88-1.63 (m, 3H), 1.48-1.22 (m, 9H), 1.21-1.12 (m, 6H),
1.11-0.98 (m, 1H), 0.97-0.80 (m, 3H), 0.75-0.70 (m, 6H).
[0627] LCMS Rt=0.969 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For
C.sub.22H.sub.35O.sub.2[M+H--H.sub.2O].sup.+331, found 331.
[0628] Compound 46:
[0629] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.35-3.10 (m, 1H),
2.54-2.38 (m, 1H), 2.34-2.09 (m, 5H), 1.89-1.62 (m, 4H), 1.60-1.53
(m, 2H), 1.47-1.24 (m, 9H), 1.21-1.12 (m, 4H), 1.09 (s, 1H),
1.03-0.89 (m, 4H), 0.83 (s, 3H).
[0630] LCMS Rt=0.977 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.22H.sub.35O.sub.3[M+H].sup.+ 347,
found 347.
Example 28. Synthesis of Compound 47
##STR00176##
[0632] Step 1. To a solution of Compound 45 (560 mg, 1.60 mmol) in
MeOH (15 ml) was added HBr (25.9 mg, 0.32 mmol, 40% in water) and
Br.sub.2 (255 mg, 1.60 mmol) at 25.degree. C. The mixture was
stirred at 25.degree. C. for 16 hrs. The mixture was quenched by
sat.aq NaHCO.sub.3 (10 mL), treated with water (20 mL), extracted
with EtOAc (2.times.20 mL). The combined organic phase was washed
with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, concentrated in vacuum to afford V1 (700 mg, crude) as
light yellow oil which was used directly for the next step.
[0633] Step 2. To a mixture of V1 (150 mg, 0.351 mmol) and
K.sub.2CO.sub.3 (96.9 mg, 0.702 mmol) in acetone (5 mL) was added
1H-pyrazole-4-carbonitrile (48.9 mg, 0.526 mmol) at 25.degree. C.
The reaction mixture was stirred at the 25.degree. C. for 16 h. The
reaction mixture was quenched by water (20 mL) and extracted with
EtOAc (2.times.20 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give crude
product (50 mg) which was triturated with MeCN (5 mL) to give
Compound 47 (41 mg, 27%) as a solid.
[0634] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.31 (s, 1H),
8.05 (s, 1H), 5.87 (d, J=18.2 Hz, 1H), 5.22 (d, J=18.2 Hz, 1H),
4.92-4.88 (m, 1H), 3.88 (s, 1H), 3.56-3.49 (m, 1H), 2.86-2.76 (m,
1H), 1.96-1.92 (m, 1H), 1.73-1.58 (m, 4H), 1.57-1.44 (m, 1H),
1.42-1.22 (m, 7H), 1.19-1.11 (m, 5H), 1.07 (s, 3H), 0.92-0.77 (m,
2H), 0.70 (s, 3H), 0.54 (s, 3H)
[0635] LCMS Rt=0.980 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For
C.sub.26H.sub.37N.sub.3O.sub.3Na.sup.+[M+Na].sup.+462, found
462.
Example 29. Synthesis of Compound 48
##STR00177##
[0637] To a solution of Compound 47 (50 mg, 0.114 mmol) in DCM (10
mL) was added PCC (98.0 mg, 0.455 mmol) and silica gel (150 mg) at
25.degree. C. Then the solution was stirred at 25.degree. C. for 5
h. The reaction mixture was filtered and the residue was washed
with anhydrous DCM (2.times.30 mL). The combined filtrate was
concentrated in vacuum to give a crude product, which was purified
by a silica gel column (PE/EtOAc=1/1) to give Compound 48 (13 mg,
26%) as a solid.
[0638] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.83-7.79 (m, 2H),
5.55 (d, J=18.4 Hz, 1H), 5.08 (d, J=18.4 Hz, 1H), 3.27 (t, J=9.0
Hz, 1H), 2.52-2.39 (m, 1H), 2.39-2.29 (m, 1H), 2.26-2.14 (m, 1H),
1.89-1.68 (m, 3H), 1.58-1.43 (m, 4H), 1.40-1.23 (m, 9H), 1.21 (s,
3H), 1.07-0.99 (m, 1H), 1.07-0.99 (m, 1H), 0.96 (s, 3H), 0.84 (s,
3H).
[0639] LCMS Rt=0.983 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.26H.sub.36N.sub.3O.sub.3 [M+H].sup.+
438, found 438.
Example 30. Syntheses of Compounds 49 and 50
##STR00178##
[0641] To a mixture of VI (400 mg, 0.936 mmol) and K.sub.2CO.sub.3
(258 mg, 1.87 mmol) in acetone (5 mL) was added
1H-pyrazole-4-carbonitrile (166 mg, 1.40 mmol) at 25.degree. C. The
reaction mixture was stirred at the 25.degree. C. for 16 h. The
reaction mixture was quenched with water (20 mL) and extracted with
EtOAc (2.times.20 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give crude
product, which was purified by prep.
[0642] HPLC (column: Boston Green ODS 150*30 5 u, gradient: 34-44%
B (A=0.1% TFA-ACN, B=acetonitrile), flow rate: 30 mL/min) to give
mixture of Compound 49 and Compound 50 (120 mg, crude) as yellow
oil. The oil was purified by SFC (column: OD (250 mm*30 mm, 5 um);
Mobile phase: Supercritical CO.sub.2/MeOH+NH.sub.3H.sub.2O=40/40;
Flow rate: 50 ml/min; Wavelength: 220 nm) to give Compound 49 (20
mg, 17%) as a solid and Compound 50 (50 mg, 42%) as a solid.
[0643] Compound 49:
[0644] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.28 (s, 1H), 8.17
(d, J=5.6 Hz, 1H), 7.99 (s, 1H), 7.52 (d, J=5.6 Hz, 1H), 5.81 (d,
J=17.6 Hz, 1H), 5.37 (d, J=17.6 Hz, 1H), 3.61-3.56 (m, 1H),
2.66-2.60 (m, 2H), 2.21-2.08 (m, 1H), 1.92-1.64 (m, 4H), 1.54-1.44
(m, 4H), 1.42-1.31 (m, 4H), 1.30-1.25 (m, 3H), 1.21 (s, 3H),
1.18-1.05 (m, 3H), 0.97-0.85 (m, 2H), 0.77 (s, 3H), 0.73 (s,
3H).
[0645] LCMS Rt=0.655 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.28H.sub.40N.sub.3O.sub.3 [M+H].sup.+
466, found 466.
[0646] Compound 50:
[0647] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.92 (s, 1H),
8.33-8.31 (m, 1H), 8.11 (s, 1H), 7.65-7.63 (m, 1H), 5.91 (d, J=18.4
Hz, 1H), 5.35 (d, J=18.4 Hz, 1H), 3.65-3.61 (m, 1H), 2.73-2.67 (m,
1H), 2.62-2.60 (m, 1H), 2.19-2.07 (m, 1H), 1.90-1.64 (m, 4H),
1.54-1.44 (m, 4H), 1.43-1.32 (m, 4H), 1.31-1.22 (m, 4H), 1.21 (s,
3H), 1.19-1.07 (m, 2H), 0.97-0.86 (m, 2H), 0.77 (s, 3H), 0.73 (s,
3H).
[0648] LCMS Rt=0.690 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.28H.sub.40N.sub.3O.sub.3 [M+H].sup.+
466, found 466.
Example 31. Syntheses of Compounds 51 and 52
##STR00179## ##STR00180## ##STR00181##
[0650] Step 1. To a solution of W1 (50 g, 172 mmol) in toluene (400
mL) was added p-toluenesulfonic acid (532 mg, 3.09 mmol) and
pyridin-2-ylmethanamine (40.8 g, 378 mmol) at 25.degree. C. The
reaction mixture was heated to 140.degree. C. with a Dean-Stark
apparatus for 16 hrs. The reaction mixture was cooled to 25.degree.
C. and then diluted with EtOAc (300 mL) and water (200 mL). The
combined organic layer was washed sequentially with sat. NH.sub.4Cl
(2.times.200 mL), sat. NaHCO.sub.3 (200 mL), brine (200 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give the crude product, which was triturated
from (EtOAc, 200 mL) at 25.degree. C. to give W2 (54 g, 83%) as a
pale solid.
[0651] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.50-8.43 (m, 1H),
7.60-7.55 (m, 1H), 7.36-7.33 (m, 1H), 7.21-7.06 (m, 1H), 7.18-7.11
(m, 2H), 4.58-4.45 (m, 2H), 3.61-3.40 (m, 1H), 2.40-2.34 (m, 1H),
2.22-2.18 (m, 1H), 1.98-1.95 (m, 2H), 1.93-1.60 (m, 5H), 1.57-1.33
(m, 4H), 1.21-1.17 (m, 3H), 1.05-0.96 (m, 2H), 0.95-0.84 (m, 2H),
0.82 (s, 3H), 0.78 (s, 3H), 0.70-0.65 (s, 1H).
[0652] Step 2. W2 (20 g, 52.5 mmol), Cu(OTf).sub.2 (24.6 g, 68.2
mmol) and L-ascorbic acid sodium salt (20.8 g, 105 mmol) were added
to a round-bottom-flask under N.sub.2. Acetone (160 mL) and MeOH
(160 mL) were added at 25.degree. C. and stirred for 5 mins
(reaction mixture may turn brown). O.sub.2 from a balloon was
bubbled through the reaction mixture for 5 mins (resulting in a
blue/green solution), after which the reaction was heated to
60.degree. C. under an O.sub.2 atmosphere for 18 hrs. The reaction
mixture was cooled to 25.degree. C., EtOAc (300 mL) and sat.
Na.sub.4EDTA (300 mL, PH.about.10) were added and the reaction
mixture was stirred for 2 hrs. The layer was separated. The aqueous
layer was extracted with EtOAc (2.times.300 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give crude
product which was purified by a silica gel column (PE/EtOAc=1/1) to
give W3 (12.5 g, 77%) as a solid.
[0653] .sup.1H NMR (400 MHz, MeOD) .delta.3.74-3.64 (m, 1H),
3.60-3.47 (m, 1H), 2.48-2.41 (m, 1H), 2.14-2.05 (m, 1H), 2.01-1.91
(m, 1H), 1.89-1.62 (m, 6H), 1.62-1.51 (m, 2H), 1.49-1.28 (m, 7H),
1.22-1.11 (m, 1H), 1.10-0.97 (m, 2H), 0.94 (s, 3H), 0.89 (s, 3H),
0.87-0.80 (m, 1H).
[0654] Step 3. To a solution of W3 (10.3 g, 33.6 mmol) in DCM (150
mL) was added TBDPSCl (13.8 g, 50.4 mmol) and imidazole (4.57 g,
67.2 mmol) at 25.degree. C. The reaction was stirred at 25.degree.
C. for 16 h. The reaction was quenched with H.sub.2O (100 mL) and
extracted with DCM (2.times.100 mL). The combined organic layer was
washed with saturated brine solution (100 mL). The organic phase
was then dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuum and the resulting solid was purified by
column chromatography (PE/EtOAc=15/1-10/1) to give W4 (6 g, 33%) as
a solid.
[0655] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.68-7.65 (m, 4H),
7.45-7.33 (m, 6H), 3.70-3.65 (m, 1H), 3.60-3.53 (m, 1H), 2.94 (d,
J=0.8 Hz, 1H), 2.46-2.39 (m, 1H), 2.13-2.05 (m, 1H), 2.04-2.01 (m,
2H), 1.98-1.87 (m, 2H), 1.78-1.68 (m, 2H), 1.68-1.57 (m, 2H),
1.54-1.38 (m, 4H), 1.23-1.11 (m, 3H), 1.04 (s, 9H), 0.91 (s, 3H),
0.90-0.84 (m, 1H), 0.82 (s, 3H), 0.79-0.63 (m, 2H).
[0656] Step 4. To a suspension of EtPh.sub.3PBr (16.7 g, 45.2 mmol)
in anhydrous THF (60 mL) under N.sub.2 was added t-BuOK (5.07 g,
45.2 mmol) at 25.degree. C. The color of the suspension turned dark
red. Then the reaction mixture was heated to 40.degree. C. After
stirring at 40.degree. C. for 30 mins, W4 (6.2 g, 11.3 mmol) was
added. The reaction mixture was stirred at 40.degree. C. for 1.5
hrs. The reaction mixture was quenched with aq.NH.sub.4Cl solution
(100 mL) and then extracted with EtOAc (2.times.100 mL). The
combined organic phase was washed with brine (100 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to get the
crude product, which was purified with flash column (0.about.20% of
EtOAc in PE) to give W5 (6 g, 95%) as a solid.
[0657] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.71-7.63 (m, 4H),
7.45-7.31 (m, 6H), 5.20-5.14 (m, 1H), 3.71-3.65 (m, 1H), 3.59-3.54
(m, 1H), 2.48-2.34 (m, 1H), 2.16-2.12 (m, 1H), 1.83-1.80 (m, 4H),
1.78-1.70 (m, 1H), 1.69-1.57 (m, 4H), 1.45-1.40 (m, 2H), 1.29-1.21
(m, 3H), 1.20-1.14 (m, 2H), 1.04 (s, 9H), 1.00-0.93 (m, 1H),
0.91-0.85 (m, 2H), 0.83 (s, 3H), 0.80 (s, 3H), 0.79-0.68 (m, 2H),
0.67-0.57 (m, 1H).
[0658] Step 5. To a solution of W5 (6 g, 10.7 mmol) in DCM (60 mL)
was added silica gel (10 g) and PCC (9.22 g, 42.8 mmol) at
25.degree. C. Then the reaction was stirred at 25.degree. C. for 2
hrs. The reaction mixture was filtered and the residue was washed
with DCM (2.times.80 mL). The combined filtrate was concentrated in
vacuum to give crude product which was purified by a silica gel
column (PE/EtOAc=10/1) to give W6 (5 g, 84%) as a solid.
[0659] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.71-7.61 (m, 4H),
7.46-7.31 (m, 6H), 5.46-5.42 (m, 1H), 3.60-3.54 (m, 1H), 2.57 (t,
J=13.2 Hz, 1H), 2.39-2.12 (m, 3H), 1.90-1.71 (m, 2H), 1.71-1.62 (m,
3H), 1.61-1.56 (m, 4H), 1.52-1.33 (m, 6H), 1.32-1.22 (m, 2H), 1.20
(s, 3H), 1.04 (s, 9H), 0.92-0.75 (m, 5H).
[0660] Step 6. To a solution of W6 (5 g, 9.01 mmol) in THF (50 mL)
was added lithium tri-tert-butoxyaluminum hydride (11.4 g, 45 mmol)
in THF (100 mL) was added dropwise at 0.degree. C. The reaction was
warmed to 25.degree. C. and stirred at 25.degree. C. for 16 hrs.
The reaction was quenched by adding aqueous HCl (1 M, 100 mL) and
the mixture was diluted with EtOAc (100 mL). The phases were
separated and the organic phase was washed sequentially with water
(100 mL) and saturated brine solution (100 mL). The organic phase
was then dried over anhydrous Na.sub.2SO.sub.4 and filtered. The
filtrate was concentrated under vacuum to give W7 (5 g, crude) as
pale yellow oil.
[0661] Step 7. To a solution of W7 (5 g, 8.97 mmol) in THF (50 mL)
was added NaH (1.07 g, 26.9 mmol, 60%) in one portion at 0.degree.
C. under N.sub.2. After 30 mins, MeI (12.7 g, 5.57 mL, 89.7 mmol,
actual dosage: 13.6 g) was added dropwise at 25.degree. C. The
reaction mixture was stirred for 16 hrs at 40.degree. C. The
mixture was quenched with saturated aqueous NH.sub.4Cl (100 mL).
Then the mixture was extracted with EtOAc (200 mL) and H.sub.2O
(2.times.150 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, and the solvent was evaporated to afford crude
product. The crude product was purified by column chromatography on
silica gel (PE/EtOAc=20/1-10/1) to give W8 (4.7 g, 92%) as an
oil.
[0662] .sup.1H NMR (400 MHz, CDCl3) .delta. 7.70-7.65 (m, 4H),
7.45-7.34 (m, 6H), 5.23-5.18 (m, 1H), 3.83-3.77 (m, 1H), 3.63-3.55
(m, 1H), 3.26 (s, 3H), 2.46-2.09 (m, 2H), 1.92-1.85 (m, 1H),
1.76-1.73 (m, 6H), 1.54-1.30 (m, 8H), 1.23-1.09 (m, 6H), 1.05 (m,
9H), 0.86 (s, 3H), 0.80 (s, 3H).
[0663] Step 8. To a solution of W8 (4.7 g, 8.23 mmol) in THF (50
mL) was added dropwise a solution of BH.sub.3-Me.sub.2S (8.22 mL,
82.3 mmol) at 0.degree. C. The solution was stirred at 25.degree.
C. for 16 hrs. After cooling to 0.degree. C., a solution of EtOH
(4.79 mL, 82.3 mmol) and NaOH solution (39.4 g, 10% in water) was
added very slowly. After addition, H.sub.2O.sub.2 (8.23 mL, 82.3
mmol, 30% in water) was added slowly and the inner temperature was
maintained below 10.degree. C. The resulting solution was stirred
at 25.degree. C. for 1 h. The mixture was quenched with saturated
aqueous Na.sub.2S.sub.2O.sub.3 (50 mL) and extracted with EtOAc
(3.times.50 mL). The combined organic layer was washed with
saturated aqueous Na.sub.2S.sub.2O.sub.3 (2.times.50 mL), brine (50
mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give
W9 (5.1 g, crude) as a solid, which was used directly for next step
without further purification.
[0664] Step 9. To a solution of W9 (5.1 g, 8.65 mmol) in THF (10
mL) was added TBAF (43.2 mL, 1 M in THF) at 25.degree. C. The
reaction was stirred at 40.degree. C. for 48 hrs. The reaction was
quenched with water (50 mL) and extracted with EtOAc (2.times.100
mL). The combined organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to give W10 (5 g, crude) as
pale yellow oil which was used directly for next step without
further purification.
[0665] Step 10. To a solution of W10 (5 g, crude) in DCM (50 mL)
was added silica gel (13.4 g) and PCC (12.2 g, 56.8 mmol) at
25.degree. C. The reaction was stirred at 25.degree. C. for 4 hrs.
The reaction mixture was filtered and the filtrate was concentrated
in vacuum to give crude product which was purified by a silica gel
column (PE/EtOAc=5/1) to give W11 (1.2 g, impure) as a pale yellow
oil.
[0666] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.42-3.38 (m, 1H),
3.13 (s, 3H), 2.56-2.52 (dd, J=8.8 Hz, 1H), 2.43-2.21 (m, 4H), 2.05
(s, 3H), 2.04-1.65 (m, 8H), 1.55-1.23 (m, 5H), 1.18-1.01 (m, 3H),
1.00 (s, 3H), 0.94 (s, 3H).
[0667] Step 11. A suspension of LiCl (307 mg, 7.26 mmol, anhydrous)
in THF (20 mL, anhydrous) was stirred at 10.degree. C. for 30 mins
under N.sub.2. FeCl.sub.3 (616 mg, 3.80 mmol, anhydrous) was added
at 10.degree. C. The mixture was cooled to -30.degree. C. To the
mixture was added MeMgBr (4.60 mL, 13.8 mmol, 3M in diethyl ether)
dropwise at -30.degree. C. The mixture was stirred at -30.degree.
C. for 10 mins. W11 (1.2 g, impure) was added at -30.degree. C. The
mixture was stirred at -15.degree. C. for 2 hrs. To the mixture was
added citric acid (40 mL, 10% aq.). The mixture was extracted with
EtOAc (2.times.60 mL). The combined organic phase was washed with
saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to give crude product which was
purified by a silica gel column (PE/EtOAc= 1/10-1/5) to give
Compound 51 (650 mg, 52%) as a solid.
[0668] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.38-3.36 (m, 1H),
3.11 (s, 3H), 2.53-2.48 (dd, J=8.8 Hz, 1H), 2.04 (s, 3H), 2.01-1.94
(m, 1H), 1.70-1.59 (m, 4H), 1.55-1.46 (m, 4H), 1.42-1.23 (m, 6H),
1.19 (s, 3H), 1.18-0.98 (m, 6H), 0.91 (s, 3H), 0.74 (s, 3H).
[0669] LCMS Rt=1.058 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.23H.sub.39O.sub.3[M+H].sup.+ 363,
found 363.
[0670] The stereochemistry at C17 of Compound 51 was confirmed by
NOE.
[0671] Step 12. To a solution of Compound 51 (600 mg, 1.65 mmol) in
MeOH (6 mL) was added CH.sub.3ONa (891 mg, 16.5 mmol) at 25.degree.
C. The reaction was stirred at 50.degree. C. for 16 hrs. The
reaction mixture was quenched with HCl (2 mL, 2 M) to adjust the pH
to about 7, diluted with water (20 mL) and extracted with DCM
(2.times.20 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give crude
product which was purified by a silica gel column
(PE/EtOAc=5/1-3/1) to give Compound 52 (420 mg, 70%, 10 mg for
delivery) as a solid.
[0672] .sup.1H NMR (400 MHz, CDCl3) .delta. 3.45-3.42 (m, 1H), 3.35
(s, 3H), 3.27 (t, J=9.2 Hz, 1H), 2.08 (s, 3H), 2.01-1.94 (m, 1H),
1.70-1.59 (m, 4H), 1.55-1.46 (m, 4H), 1.42-1.23 (m, 6H), 1.20 (s,
3H), 1.19-1.17 (m, 3H), 1.16-0.92 (m, 3H), 0.75 (s, 3H), 0.63 (s,
3H).
[0673] LCMS Rt=1.033 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For
C.sub.22H.sub.35O.sub.2[M-CH.sub.3OH+H].sup.+331, found 331.
[0674] The stereochemistry at C17 of Comound 52 was confirmed by
NOE during the pilot reaction.
Example 32. Synthesis of Compound 53
##STR00182##
[0676] Step 1. To a solution of Compound 51 (400 mg, 1.10 mmol) in
MeOH (4 mL) was added HBr (44.5 mg, 0.220 mmol, 40% in water) and
the solution of Br.sub.2 (0.06 mL, 1.21 mmol) in MeOH (4 mL) at
25.degree. C. The mixture was stirred at 25.degree. C. for 16 hrs.
The mixture was quenched by sat.aq NaHCO.sub.3 (10 mL) and treated
with water (20 mL). The reaction mixture was filtered and the
residue was washed with water (10 mL), concentrated in vacuum to
give X1 (430 mg, 89%) as a solid.
[0677] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.96-3.82 (m, 2H),
3.47 (t, J=8.8 Hz, 1H), 3.38-3.36 (m, 1H), 3.35 (s, 3H), 2.19-1.93
(m, 2H), 1.78-1.60 (m, 4H), 1.53-1.45 (m, 3H), 1.45-1.33 (m, 3H),
1.32-1.22 (m, 5H), 1.20 (s, 3H), 1.15 (s, 1H), 1.13-0.91 (m, 3H),
0.75 (s, 3H), 0.67 (s, 3H).
[0678] Step 2. To a solution of 1H-pyrazole-4-carbonitrile (31.6
mg, 0.3397 mmol) and K.sub.2CO.sub.3 (78.2 mg, 0.5662 mmol) in
acetone (2 mL) was added X1 (100 mg, 0.2265 mmol) at 25.degree. C.
The mixture was stirred at 25.degree. C. for 2 h. The mixture was
poured into water (10 mL) and extracted with EtOAc (2.times.10 mL).
The combined organic layer was washed with saturated brine
(2.times.10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated in vacuum to give Compound 53 (106 mg, crude) as a
solid, which was further purified by HPLC (column: Gemini 150*25 5
u, gradient: 56-81% B, condition: water(0.05% HCl)-ACN, flow rate:
30 mL/min) to give Compound 53 (57 mg, 54%) as solid.
[0679] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (s, 1H), 7.79
(s, 1H), 5.00-4.80 (m, 2H), 3.53-3.50 (m, 1H), 3.41-3.36 (m, 4H),
2.20-2.05 (m, 2H), 1.80-1.65 (m, 4H), 1.60-1.50 (m, 7H), 1.48-0.90
(m, 11H), 0.75 (s, 3H), 0.67 (s, 3H).
[0680] LCMS Rt=1.053 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.27H.sub.40N.sub.3O.sub.3
[M+H].sup.+ 454, found 454.
Example 33. Syntheses of Compounds 54 and 55
##STR00183##
[0682] To a solution of X1 (150 mg, 0.339 mmol) in acetone (2 mL)
was added 2H-pyrazolo [3,4-c]pyridine (60.5 mg, 0.508 mmol) and
K.sub.2CO.sub.3 (92.8 mg, 0.678 mmol). After stirring at 15.degree.
C. for 16 hrs, the reaction mixture was treated with water (5 mL)
and extracted with EtOAc (2.times.10 mL). The combined organic
layer was washed with brine (5 mL). The organic layer was dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by HPLC (column: Waters Xbridge 150*25 5 u), water (10 mM
NH4HCO3)-ACN, gradient: 45-65% B, flow rate: 25 mL/min)) to give
Compound 55 (20 mg, 12%) as a solid and Compound 54 (15 mg, impure)
as a solid, which was combined with another batch prepared from 50
mg of X1. The impure sample was further purified by prep-TLC
(PE/EtOAc=1/1) to give Compuond 54 (8 mg) as a solid.
[0683] Compound 54:
[0684] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.40-9.20 (m, 1H),
8.25-8.10 (m, 1H), 8.10-8.00 (m, 1H), 7.70-7.55 (m, 1H), 5.39-5.12
(m, 2H), 3.63-3.10 (m, 1H), 3.52-3.48 (m, 1H), 3.42 (s, 3H),
2.34-2.01 (m, 3H), 2.00-1.62 (m, 10H), 1.62-1.48 (m, 5H), 1.48-0.97
(m, 6H), 0.82-0.63 (m, 6H).
[0685] LCMS Rt=0.766 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.29H.sub.42N.sub.3O.sub.3
[M+H].sup.+ 480 found 480.
[0686] Compound 55:
[0687] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.81-8.78 (m, 1H),
8.36-8.32 (m, 1H), 8.08 (s, 1H), 7.65-7.61 (m, 1H), 5.28-5.12 (m,
2H), 3.70-3.60 (m, 1H), 3.52-3.48 (m, 1H), 3.41 (s, 3H), 2.21-2.01
(m, 2H), 1.84-1.65 (m, 4H), 1.65-1.48 (m, 6H), 1.48-1.19 (m, 10H),
1.19-0.98 (m, 2H), 0.82-0.70 (m, 6H).
[0688] LCMS Rt=0.793 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.29H.sub.42N.sub.3O.sub.3
[M+H].sup.+ 480 found 480.
Example 34. Syntheses of Compounds 56, 57, 58, and 59
##STR00184## ##STR00185## ##STR00186##
[0690] Step 1. To a solution of Y1 (10 g, 34.4 mmol) in toluene
(100 mL) was added p-toluenesulfonic acid (106 mg, 0.6 mmol) and
pyridin-2-ylmethanamine (8.17 g, 75.6 mmol) at 25.degree. C. The
reaction mixture was heated to 140.degree. C. with a Dean-Stark
apparatus for 16 hrs. The reaction was cooled to 25.degree. C. and
diluted with EtOAc (200 mL). The organic layer was washed
sequentially with sat. NH.sub.4Cl (2.times.200 mL), sat.
NaHCO.sub.3 (200 mL), brine (200 mL), dried over Na.sub.2SO.sub.4,
filtered, and then concentrated in vacuum to give a crude product.
The residual was triturated with EtOAc (20 mL) to give Y2 (8.7 g,
66%) as a solid.
[0691] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.57-8.49 (m,
1H), 7.72-7.61 (m, 1H), 7.44-7.38 (m, 1H), 7.17-7.09 (m, 1H),
4.69-4.52 (m, 2H), 2.49-2.22 (m, 2H), 2.06-1.63 (m, 8H), 1.54-1.44
(m, 3H), 1.41 (s, 3H), 1.40-1.32 (m, 3H), 1.30-1.24 (m, 5H),
1.21-1.07 (m, 3H), 0.90 (s, 3H).
[0692] Step 2. Y2 (8.7 g, 22.8 mmol), Cu(OTf).sub.2 (10.6 g, 29.6
mmol) and L-ascorbic acid sodium salt (9.03 g, 45.6 mmol) were
added to a round-bottom-flask under N.sub.2. Acetone (dry, 50 mL)
and MeOH (dry, 50 mL) were added at 25.degree. C. and stirred for 5
mins (reaction mixture may turn brown). O.sub.2 from a balloon was
bubbled through the reaction mixture for 5 min (resulting in a
blue/green solution). The reaction mixture was heated at 50.degree.
C. under an O.sub.2 atmosphere for 24 hrs. The reaction mixture was
then cooled to 25.degree. C. EtOAc (100 mL) and sat. Na.sub.4ETDA
(200 mL, pH-10) were added and the reaction mixture was stirred for
1 h. The layers were separated. The aqueous layer was extracted
with EtOAc (2.times.200 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuum to give crude product, which was
purified by flash column (0-40% of EtOAc in PE) to give Y3 (4 g,
57%) as a solid.
[0693] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 3.82-3.74 (m,
1H), 2.98 (brs, 1H), 2.49-2.40 (m, 1H), 2.17-2.03 (m, 1H),
2.01-1.71 (m, 5H), 1.67-1.29 (m, 12H), 1.26 (s, 3H), 1.23-1.01 (m,
3H), 0.93 (s, 3H).
[0694] Step 3. To a solution of Y3 (2 g, 6.52 mmol) in THF (20 mL)
was added KOH (2.21 g, 39.6 mmol) and Me.sub.2SO.sub.4 (1.85 g,
14.6 mmol) at 0.degree. C. Then the mixture was warmed to
25.degree. C. and stirred at the same temperature for 16 hrs.
Me.sub.2SO.sub.4 (4.08 g, 32.4 mmol) was added at 0.degree. C. and
the mixture was stirred at 40.degree. C. for 16 hrs. The mixture
was quenched with the addition of 50 mL of water and extracted with
EtOAc (2.times.30 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give crude
product, which was purified by a silica gel column
(PE/EtOAc=10/1-5/1) to give Y4 (1.2 g, 58%) as a solid.
[0695] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 3.50 (m, 1H),
3.19 (dd, J=6.8 Hz, J=4.8 Hz, 1H), 2.48-2.40 (m, 1H), 2.12-2.00 (m,
2H), 1.98-1.51 (m, 7H), 1.48-1.28 (m, 10H), 1.27 (s, 3H), 1.23-1.01
(m, 4H), 0.93 (s, 3H).
[0696] Step 4. To a suspension of EtPPh.sub.3Br (4.15 g, 11.2 mmol)
in THF (20 mL) was added t-BuOK (1.25 g, 11.2 mmol) at 25.degree.
C. under N.sub.2. The mixture was stirred at 50.degree. C. for 30
mins. To the mixture was added Y4 (1.2 g, 3.74 mmol) in THF (12 mL)
at 50.degree. C. The mixture was stirred at 50.degree. C. for 16
hrs. The mixture was quenched with sat.NH.sub.4Cl solution (50 mL)
and extracted with EtOAc (2.times.100 mL). The combined organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuum to give crude product which was purified by a silica gel
column (PE/EtOAc=5/1-3/1) to give Y5 (1.1 g, 89%) as colourless
oil.
[0697] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.26-5.18 (m, 1H),
3.34 (s, 3H), 3.16 (dd, J=10.6 Hz, J=5.0 Hz, 1H), 2.44-2.39 (m,
1H), 2.20-2.15 (m, 4H), 1.80-1.76 (m, 5H), 1.75-1.23 (m, 9H), 1.27
(s, 3H), 1.25-0.95 (m, 6H), 0.86 (s, 3H).
[0698] Step 5. To a solution of Y5 (1.1 g, 3.30 mmol) in THF (30
mL) was added 9-BBN dimer (2.01 g, 8.25 mmol) at 25.degree. C.
under N.sub.2. The solution was stirred at 50.degree. C. for 16
hrs. After cooling to 0.degree. C., a solution of EtOH (30 mL) and
NaOH (6.60 mL, 5M in H.sub.2O, 33.0 mmol) was added very slowly.
After the addition, H.sub.2O.sub.2 (3.30 mL, 33.0 mmol, 30% in
water) was added slowly and the inner temperature was maintained
below 10.degree. C. The mixture was stirred at 50.degree. C. under
N.sub.2 for 1 h. The mixture was re-cooled to 30.degree. C. Water
(100 mL) was added to the solution and extracted with EtOAc
(2.times.100 mL). The combined organic layer was washed sat.
Na.sub.2S.sub.2O.sub.3 (100 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to give Y6 (3 g, crude) as
colorless oil, which was used directly for the next step.
[0699] Step 6. To a solution of Y6 (3 g, 8.55 mmol) in DCM (30 mL)
was added silica gel (6.1 g) and PCC (5.51 g, 25.6 mmol) at
25.degree. C. The reaction was stirred at 25.degree. C. for 2 hrs.
The reaction mixture was filtered and the filtrate was concentrated
in vacuum to give crude product, which was purified by a silica gel
column (PE/EtOAc=5/1) to give Compound 56 (1.2 g, impure) as
colourless oil. Compound 56 (1.2 g, impure) was purified by
combi-flash (DCM/acetone=30/1-20/1) to give Compound 56 (250 mg,
pure) as a solid and Compound 56 (420 mg, impure) as a solid.
Compound 56 (250 mg, 0.717 mmol) was triturated with (PE/EtOAc=3/1,
120 mL) to afford Compound 56 (240 mg, 96%) as a solid.
[0700] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.34 (m, 1H), 3.08
(dd, J=10.8 Hz, J=4.4 Hz, 1H), 2.69 (t, J=8.8 Hz, 1H), 2.22 (s,
3H), 2.11-2.05 (m, 2H), 1.80-1.55 (m, 8H), 1.53-1.29 (m, 5H), 1.28
(s, 3H), 1.19-0.85 (m, 9H), 0.66 (s, 3H).
[0701] LCMS Rt=0.924 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.22H.sub.37O.sub.3[M+H].sup.+ 349,
found 349.
[0702] Step 7. To a solution of Compound 56 (420 mg, 1.20 mmol) in
MeOH (8 ml) was added HBr (48.5 mg, 0.240 mmol, 40% in water) and
Br.sub.2 (210 mg, 1.32 mmol) in MeOH (8 mL) at 25.degree. C. The
mixture was stirred at 25.degree. C. for 16 hrs. The mixture was
quenched by sat.NaHCO.sub.3 (10 mL) and water (20 mL), extracted
with EtOAc (2.times.20 mL). The combined organic phase was washed
with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated in vacuum to afford Y8 (500 mg, 98%) as light
yellow oil, which was used directly for the next step.
[0703] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.15-3.99 (m, 2H),
3.34 (s, 3H), 3.11 (dd, J=11.0 Hz, J=4.6 Hz, 1H), 3.01 (t, J=9.2
Hz, 1H), 2.58 (s, 1H), 2.19-2.05 (m, 3H), 1.90-1.59 (m, 6H),
1.51-1.32 (m, 7H), 1.28 (s, 3H), 1.13-1.01 (m, 3H), 0.94-0.82 (m,
2H), 0.65 (s, 3H).
[0704] Step 8. To a mixture of Y8 (250 mg, 0.585 mmol) and
K.sub.2CO.sub.3 (160 mg, 1.16 mmol) in acetone (4 mL) was added
1H-pyrazole-4-carbonitrile (81.6 mg, 0.877 mmol) at 25.degree. C.
The reaction mixture was stirred at the 25.degree. C. for 16 hrs.
The reaction mixture was filtered and the filtrate was concentrated
in vacuum to give crude product, which was purified by a silica gel
column (PE/EtOAc=2/1-1/1) to give Compound 57 (125 mg, 49%) as a
solid.
[0705] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.81 (s, 2H), 5.45
(d, J=17.6 Hz, 1H), 4.94 (d, J=17.6 Hz, 1H), 3.40 (s, 3H), 3.19
(dd, J=11 Hz, J=4.6 Hz, 1H), 2.75-2.65 (m, 1H), 2.22-2.07 (m, 2H),
1.92-1.59 (m, 6H), 1.52-1.41 (m, 7H), 1.40-1.30 (m, 3H), 1.29 (s,
3H), 1.15-1.04 (m, 2H), 0.99-0.82 (m, 2H), 0.67 (s, 3H).
[0706] LCMS Rt=0.981 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.26H.sub.37N.sub.3O.sub.3Na
[M+Na].sup.+462, found 462.
[0707] Step 9. To a solution of Y8 (250 mg, 0.585 mmol) in acetone
(5 mL) was added 5-methyl-2H-tetrazole (73.7 mg, 0.877 mmol),
followed by K.sub.2CO.sub.3 (160 mg, 1.16 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 16 hrs. The
mixture was filtered and the filtrate was concentrated in vacuum to
give crude product, which was purified by a silica gel column
(PE/EtOAc=3/1-1/1) to give Compound 58 (60 mg, impure) as a solid
and Compound 59 (54 mg, 22%) as a solid. Compound 58 (60 mg,
impure) was re-purified by combi-flash (EtOAc in PE, 40%-50%) to
afford Compound 58 (45 mg, 75%) as a solid.
[0708] Compound 58:
[0709] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.89 (d, J=16.8
Hz, 1H), 5.35 (d, J=17.2 Hz, 1H), 3.45 (s, 3H), 3.18 (dd, J=11 Hz,
J=4.2 Hz, 1H), 2.74-2.64 (m, 1H), 2.56 (s, 3H), 2.23-2.06 (m, 2H),
1.91-1.67 (m, 6H), 1.53-1.36 (m, 8H), 1.37-1.29 (m, 3H), 1.28 (s,
3H), 1.15-1.02 (m, 2H), 0.99-0.87 (m, 1H), 0.69 (s, 3H).
[0710] LCMS Rt=0.951 min in 2 min chromatography, 30-90 AB, purity
99.42%, MS ESI calcd. For C.sub.23H.sub.33N.sub.4O
[M+H--CH.sub.3OH--H.sub.2O].sup.+381, found 381.
[0711] Compound 59:
[0712] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.62 (d, J=18.0
Hz, 1H), 5.24 (d, J=18.4 Hz, 1H), 3.42 (s, 3H), 3.24 (dd, J=11.2
Hz, J=4.4 Hz, 1H), 2.84-2.72 (m, 1H), 2.45 (s, 3H), 2.22-2.06 (m,
2H), 1.91-1.72 (m, 5H), 1.52-1.37 (m, 7H), 1.38-1.30 (m, 3H), 1.29
(s, 3H), 1.17-1.03 (m, 3H), 1.01-0.83 (m, 2H), 0.69 (s, 3H).
[0713] LCMS Rt=0.912 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.24H.sub.39N.sub.4O.sub.3 [M+H].sup.+
431, found 431.
Example 35. Syntheses of Compounds 60 and 61
##STR00187## ##STR00188##
[0715] Step 1. To a solution of P3 (2 g, 6.24 mmol) in THF (20 mL)
was added KOH (1.05 g, 18.9 mmol) and Me.sub.2SO.sub.4 (1.60 g,
1.20 mL, 12.7 mmol) at 0.degree. C. Then the mixture was warmed to
25.degree. C. and stirred at this temperature for 16 hrs.
Me.sub.2SO.sub.4 (1.60 g, 1.20 mL, 12.7 mmol) at 0.degree. C. was
added and the mixture was stirred at 25.degree. C. for 16 hrs. The
mixture was quenched with 50 mL of water and extracted with EtOAc
(2.times.30 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give crude
product, which was purified by a silica gel column
(PE/EtOAc=10/1-5/1) to give Q1 (1.7 g, 82%) as a solid.
[0716] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.49 (s, 3H), 3.17
(dd, J=11.2 Hz, J=4.8 Hz, 1H), 2.48-2.39 (m, 1H), 2.12-1.88 (m,
3H), 1.84-1.74 (m, 1H), 1.54-1.49 (m, 3H), 1.42-1.33 (m, 2H),
1.32-1.22 (m, 6H), 1.21 (s, 3H), 1.14-1.11 (m, 2H), 1.13 (s, 1H),
1.02-0.94 (m, 1H), 0.93 (s, 3H), 0.87-0.79 (m, 1H), 0.77 (s,
3H).
[0717] Step 2. To a suspension of EtPPh.sub.3Br (5.64 g, 15.2 mmol)
in THF (60 mL) was added t-BuOK (1.70 g, 15.2 mmol) at 25.degree.
C. under N.sub.2. The mixture was stirred at 50.degree. C. for 30
mins. To the mixture was added Q1 (1.7 g, 5.08 mmol) in THF (20 mL)
at 50.degree. C. The mixture was stirred at 50.degree. C. for 16
hrs. The reaction was cooled to 25.degree. C. and the mixture was
quenched with sat.NH.sub.4Cl (100 mL) and extracted with EtOAc
(2.times.100 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give crude
product, which was purified by a silica gel column
(PE/EtOAc=5/1-3/1) to give S1 (1.6 g, 91%) as a solid.
[0718] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.27-5.16 (m, 1H),
3.33 (s, 3H), 3.14 (dd, J=10.4 Hz, J=4.8 Hz, 1H), 2.46-2.33 (m,
1H), 2.26-2.06 (m, 2H), 1.80-1.75 (m, 3H), 1.73-1.70 (m, 1H),
1.55-1.51 (m, 2H), 1.42-1.32 (m, 3H), 1.28-1.22 (m, 5H), 1.20 (s,
3H), 1.19-1.16 (m, 2H), 1.15-1.02 (m, 2H), 0.97-0.87 (m, 1H), 0.86
(s, 3H), 0.82-0.78 (m, 1H), 0.82-0.78 (m, 1H), 0.77 (s, 3H).
[0719] Step 3. To a solution of S1 (1.6 g, 4.61 mmol) in THF (20
mL) was added 9-BBN dimer (2.80 g, 11.5 mmol) at 0.degree. C. under
N.sub.2. The solution was stirred at 50.degree. C. for 16 hrs.
After cooling to 0.degree. C., a solution of EtOH (30 mL) and NaOH
(9.22 mL, 5M in H.sub.2O, 46.1 mmol) was added in sequence very
slowly. After the addition, H.sub.2O.sub.2 (4.60 mL, 46.1 mmol, 30%
in water) was added slowly and the inner temperature was maintained
below 10.degree. C. The mixture was stirred at 50.degree. C. under
N.sub.2 for 1 h. The mixture was cooled to 30.degree. C., diluted
with water (100 mL) and extracted with EtOAc (2.times.100 mL). The
combined organic layer was washed with sat. Na.sub.2S.sub.2O.sub.3
(50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuum to give S2 (3.5 g, crude) as colorless oil, which was
directly used in next step without further purification.
[0720] Step 4. To a solution of S2 (3.5 g, 9.60 mmol) in DCM (35
mL) was added silica gel (5.6 g) and PCC (5.15 g, 23.9 mmol) at
25.degree. C. The reaction was stirred at 25.degree. C. for 2 hrs.
The reaction mixture was filtered and the filtrate was concentrated
in vacuum to give crude product which was purified by a silica gel
column (PE/EtOAc=5/1) to give Compound 56 (950 mg, 27%) as a
solid.
[0721] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.33 (s, 3H), 3.06
(dd, J=10.8 Hz, J=4.4 Hz, 1H), 2.68 (t, J=9.0 Hz, 1H), 2.21 (s,
3H), 2.11-1.95 (m, 2H), 1.74-1.62 (m, 3H), 1.54-1.43 (m, 3H),
1.42-1.22 (m, 7H), 1.21 (s, 3H), 1.18-1.02 (m, 4H), 0.96-0.78 (m,
2H), 0.76 (s, 3H), 0.65 (s, 3H).
[0722] Step 5. To a solution of Compound 56 (200 mg, 0.552 mmol) in
MeOH (4 ml) was added HBr (22.3 mg, 0.11 mmol, 40% in water) and
Br.sub.2 (96.9 mg, 0.607 mmol) in MeOH (4 mL) at 25.degree. C. The
mixture was stirred at 25.degree. C. for 16 hrs. The mixture was
quenched by sat.NaHCO.sub.3 (10 mL), treated with water (20 mL),
extracted with EtOAc (2.times.20 mL). The combined organic phase
was washed with brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered, concentrated in vacuum to afford T1
(230 mg, crude) as light yellow oil, which was used directly for
the next step.
[0723] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.18-4.09 (m, 1H),
4.06-3.97 (m, 1H), 3.32 (s, 3H), 3.08 (dd, J=10.8 Hz, J=4.4 Hz,
1H), 3.03-2.96 (m, 1H), 2.15-1.97 (m, 4H), 1.79-1.64 (m, 6H),
1.54-1.49 (m, 5H), 1.21 (s, 3H), 1.19-1.01 (m, 6H), 0.76 (s, 3H),
0.64 (s, 3H).
[0724] Step 6. To a solution of T1 (230 mg, 0.521 mmol) in acetone
(5 mL) was added 5-methyl-2H-tetrazole (65.7 mg, 0.782 mmol),
followed by K.sub.2CO.sub.3 (143 mg, 1.04 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 16 hrs. The
mixture was filtered and the filtrate was concentrated in vacuum to
give crude product which was purified by a silica gel column
(PE/EtOAc=3/1-1/1) to give Compound 60 (70 mg, 30%, impure) as
colourless oil and Compound 61 (45 mg, 19%, impure) as colourless
oil. Compound 60 (70 mg, impure) was purified by a silica gel
column (PE/EtOAc=3/1) to give Compound 61 (54 mg, 77%) as a solid.
Compound 61 (45 mg, impure) was purified by a silica gel column
(PE/EtOAc=2/1-1/1) to give Compound 61 (28 mg, 62%) as a solid.
[0725] Compound 60:
[0726] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.92-5.86 (m, 1H),
5.37-5.32 (m, 1H), 3.44 (s, 3H), 3.16 (dd, J=10.8 Hz, J=4.4 Hz,
1H), 2.68 (t, J=8.8 Hz, 1H), 2.56 (s, 3H), 2.23-2.03 (m, 2H), 2.01
(s, 1H), 1.74-1.66 (m, 3H), 1.54-1.49 (m, 3H), 1.39-1.24 (m, 6H),
1.21 (s, 3H), 1.19-1.09 (m, 3H), 0.98-0.80 (m, 3H), 0.77 (s, 3H),
0.68 (s, 3H).
[0727] LCMS Rt=1.030 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.24H.sub.37N.sub.4O.sub.2
[M+H--CH3OH].sup.+413, found 413.
[0728] Compound 61:
[0729] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.65-5.59 (m, 1H),
5.26-5.20 (m, 1H), 3.41 (s, 3H), 3.22 (dd, J=11.2 Hz, J=4.4 Hz,
1H), 2.76 (t, J=8.4 Hz, 1H), 2.44 (s, 3H), 2.20-2.04 (m, 2H),
1.84-1.65 (m, 3H), 1.54-1.50 (m, 2H), 1.46-1.24 (m, 8H), 1.22 (s,
3H), 1.20-1.07 (m, 3H), 1.00-0.81 (m, 3H), 0.78 (s, 3H), 0.68 (s,
3H).
[0730] LCMS Rt=0.983 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.25H.sub.41N.sub.4O.sub.3 [M+H].sup.+
445, found 445.
Example 52. Syntheses of Compounds 62 and 63
##STR00189##
[0732] To a mixture of T1 (500 mg, 1.13 mmol) and K.sub.2CO.sub.3
(312 mg, 2.26 mmol) in acetone (5 mL) was added
1H-pyrazolo[3,4-b]pyridine (201 mg, 1.69 mmol) at 25.degree. C. The
reaction mixture was stirred at the 25.degree. C. for 16 h. The
reaction mixture was filtered and the filtrate was concentrated in
vacuum to give crude product which was purified by prep. HPLC
(column: Agela Durashell C18 150*25 5 u, gradient: 30-60% B
(A=0.05% HCl-ACN, B=acetonitrile), flow rate: 30 mL/min) to give
Compound 62 (30 mg, impure) as a solid and Compound 63 (10 mg, 2%)
as a solid. The impure Compound 62 (30 mg, impure) was purified by
SFC separation (Column: AS (250 mm*30 mm, 5 um), Mobile phase:
Supercritical CO.sub.2/MeOH+NH.sub.3H.sub.2O=25/25, Flow rate: 50
ml/min, Wavelength: 220 nm) to give Compound 62 (5 mg, 1%) as a
solid.
[0733] Compound 62:
[0734] .sup.1H NMR (400 MHz, CDCl3) .delta. 9.28-9.26 (m, 1H),
8.20-8.14 (m, 1H), 7.95 (s, 1H), 7.64-7.43 (m, 1H), 5.74 (d, J=17.4
Hz, 1H), 5.29 (d, J=17.4 Hz, 1H), 3.46 (s, 3H), 3.25-3.20 (m, 1H),
2.82-2.73 (m, 1H), 2.22-2.06 (m, 2H), 1.80-1.67 (m, 4H), 1.43-1.33
(m, 4H), 1.30-1.11 (m, 11H), 1.00-0.82 (m, 3H), 0.78 (s, 3H), 0.71
(s, 3H) LCMS Rt=0.794 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.29H.sub.42N.sub.3O.sub.3 [M+H].sup.+
480, found 480.
[0735] Compound 63: .sup.1H NMR (400 MHz, CDCl3) .delta. 9.52-9.30
(m, 1H), 8.45-8.32 (m, 1H), 8.20-8.12 (m, 1H), 6.13-6.09 (m, 1H),
5.80-5.60 (m, 1H), 3.50 (s, 3H), 3.35-3.30 (m, 1H), 2.96-2.92 (m,
1H), 2.15-2.08 (m, 2H), 1.90-1.67 (m, 4H), 1.43-1.33 (m, 6H),
1.30-1.11 (m, 10H), 1.00-0.82 (m, 3H), 0.78 (s, 3H), 0.71 (s,
3H)
[0736] LCMS Rt=0.816 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.29H.sub.42N.sub.3O.sub.3 [M+H].sup.+
480, found 480.
Example 36. Synthesis of Compound 64
##STR00190##
[0738] Step 1. To a stirred slurry of CuI (13.7 g, 72.2 mmol) in
dry THF (90 mL) at 0.degree. C. was added a solution of MeLi (87
mL, 1.6 M in ether) in ether until the initially formed yellow
precipitate just rediseolved to give a dear solution. Then a
solution of Z1 (10 g. 27.8 mmol) in dry THF (200 mL) was added at
0.degree. C., during which a bright yellow precipitate formed in
the solution. 5 The mixture was stirred at 0.degree. C. for 30 mins
and quenched with NH.sub.4Cl (300 mL). The aqueous phase was
extracted with EtOAc (3.times.400 mL). The combined organic phase
was washed with saturated brine (2.times.400 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified by flash column (0.about.30% of EtOAc in PE) to give
Z2 (7.1 g, 68%) as a solid.
[0739] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 5.38-5.36 (m, 1H),
4.62-4.58 (m, 1H), 2.68-2.66 (m, 1H), 2.33-2.27 (m, 2H), 2.12 (s,
4H), 2.03 (s, 3H), 2.00-1.95 (m, 2H), 1.96-1.85 (m, 2H), 1.65-1.50
(m, 2H), 1.50-1.45 (m, 5H), 1.47-1.35 (m, 4H), 1.01 (s, 3H), 0.93
(t, J=7.2 Hz, 3H), 0.65 (s, 3H).
[0740] The stereochemistry at C16 of Z2 was confirmed by NOE.
[0741] Step 2. To a solution of Z2 (7 g, 18.7 mmol) in MeOH (50 mL)
and THF (50 mL) was added dry Pd/C (2 g) under N.sub.2. The mixture
was degassed under vacuum and purged with H.sub.2 several times.
The mixture was stirred for 20 hrs at 25.degree. C. under 30 psi of
H.sub.2. The reaction mixture was filtered and the filtrate was
concentrated in vacuum to give Z3 (6.5 g, 92%) as a solid.
[0742] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 4.77-4.64 (m, 1H),
2.65-2.60 (m, 1H), 2.11-2.10 (m, 4H), 2.00 (s, 3H), 1.95-1.70 (m,
4H), 1.69-1.48 (m, 9H), 1.40-1.10 (m, 8H), 1.10-0.95 (m, 5H), 0.61
(s, 3H).
[0743] Step 3. To a solution of Z3 (6.5 g, 17.3 mmol) in MeOH (50
mL) was added K.sub.2CO.sub.3 (4.77 g, 34.6 mmol) at 20.degree. C.
under N.sub.2. The mixture was stirred at 20.degree. C. for 2 hrs
and quenched with water (40 mL). The aqueous phase was extracted
with DCM (3.times.60 mL). The combined organic phase was washed
with saturated brine (2.times.60 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to give Z4 (4.7 g,
crude) as a solid.
[0744] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 3.65-3.55 (m, 1H),
2.65-2.62 (m, 1H), 2.14-2.11 (m, 4H), 1.93-1.90 (m, 1H), 1.85-1.80
(m, 1H), 1.70-1.55 (m, 1H), 1.50-1.45 (m, 4H), 1.43-1.30 (m, 3H),
1.20-1.19 (m, 7H), 1.15-1.05 (m, 1H), 1.05-1.00 (m, 1H), 1.00-0.80
(m, 4H), 0.82 (s, 3H), 0.64 (m, 4H).
[0745] Step 4. To a solution of Z4 (4.7 g, 14.1 mmol) in DCM (70
mL) was added silica gel (7.2 g) and PCC (6.07 g, 28.2 mmol) at
20.degree. C. After stirring at 20.degree. C. for 1 h, the
resulting mixture was filtered and the filtrate concentrated by
vacuum. The crude product was re-dissolved in DCM (80 mL) and
treated with silica gel (20 g) and PE (80 mL). The mixture was
stirred at 20.degree. C. for 30 mins and filtered. The filtrate was
concentrated in vacuum to give Z5 (3.4 g, crude) as a solid.
[0746] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.65-2.62 (m, 1H),
2.45-2.20 (m, 3H), 2.15-2.10 (m, 5H), 2.10-1.90 (m, 2H), 1.70-1.15
(m, 12H), 1.00 (s, 3H), 0.94-0.92 (m, 4H), 0.80-0.70 (m, 1H), 0.65
(s, 3H).
[0747] Step 5. Under nitrogen atmosphere, anhydrous THF (40 mL) was
cooled to 10.degree. C. and anhydrous LiCl (907 mg, 21.4 mmol) was
added in one portion. The mixture was stirred for 30 min after
which a clear solution was obtained. To this mixture was added
anhydrous FeCl.sub.3 (1.81 g, 11.2 mmol) in one portion. The
resulting mixture was stirred for additional 30 min. The reaction
mixture was cooled to -35.degree. C. and methyl magnesium bromide
(3 M in diethyl ether, 13.6 mL, 40.8 mmol) was added dropwise
maintaining the internal temperature between -35.degree. C. and
-30.degree. C. The above mixture was stirred for 30 min at
-30.degree. C. Z5 (3.4 g, 10.2 mmol) was added in one portion. The
internal temperature was allowed to -20.degree. C. and held between
-15.degree. C. and -20.degree. C. for 2 hours. TLC showed the
reaction was completed. The reaction mixture was quenched with
aqueous HCl (2 M, 20 mL), extracted with CH.sub.2Cl.sub.2
(2.times.50 mL). The combined organic layer was washed with aqueous
NaOH (10%, 2.times.30 mL) and brine (30 mL), dried over anhydrous
sodium sulfate, filtered and concentrated. The residue was purified
by flash column (0.about.20% of EtOAc in PE) to give Compound 64
(0.56 g, 13%) as a solid and 2.5 g impure product. The 2.5 g impure
product was purified by flash column (5%-20% of EtOAc in PE) to
give Compound 64 (2.4 g, 56%) as a solid.
[0748] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.64-2.62 (m, 1H),
2.27-2.10 (m, 4H), 1.93-1.89 (m, 1H), 1.70-1.60 (m, 3H), 1.59-1.30
(m, 6H), 1.30-1.10 (m, 12H), 0.94-0.92 (m, 4H), 0.80-0.75 (m, 1H),
0.74 (m, 3H), 0.62 (m, 3H).
[0749] LCMS Rt=1.263 min in 2 min chromatography, 30-90 AB, purity
98%, MS ESI calcd. For C.sub.23H.sub.37O [M+H--H.sub.2O].sup.+329,
found 329.
Example 37. Synthesis of Compound 65
##STR00191##
[0751] Step 1. A solution of copper(II) acetate (503 mg, 2.78 mmol)
in anhydrous THF (350 mL) was cooled to 0.degree. C. After adding
ethyl magnesium bromide (27 mL, 8.10 mmol) dropwise, a solution of
Z1 (10 g, 27.8 mmol) together with chlorotrimethyl silane (15 g,
139 mmol) in THF (50 mL) was added dropwise, keeping the
temperature below 10.degree. C. After an hour at 0.degree. C.,
ethyl magnesium bromide (10 mL, 30 mmol) was added and the reaction
was stirred for 30 mins. The reaction was quenched by the addition
of NH.sub.4Cl (300 mL). extracted with EtOAc (3.times.400 mL). The
combined organic phase was washed with saturated brine (2.times.800
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by flash column (0.about.25%
of EtOAc in PE) to give AA1 (4.8 g, 44%) as a solid.
[0752] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 5.36-5.34 (m, 1H),
4.60-4.56 (m, 1H), 2.50-2.48 (m, 1H), 2.31-2.28 (m, 2H), 2.21-2.20
(m, 1H), 2.01 (s, 3H), 2.00-1.83 (m, 6H), 1.56-1.50 (m, 7H),
1.47-1.45 (m, 3H), 1.30-1.10 (m, 3H), 1.05-0.95 (m, 4H), 0.79 (t,
J=6.8 Hz, 3H), 0.63 (s, 3H).
[0753] Step 2. To a solution of AA1 (4.8 g, 12.8 mmol) in MeOH (80
mL) was added K.sub.2CO.sub.3 (3.52 mg, 25.6 mmol) at 20.degree. C.
under N.sub.2. The mixture was stirred at 20.degree. C. for 2 hrs
and quenched with water (40 mL). The aqueous phase was extracted
with DCM (3.times.60 mL). The combined organic phase was washed
with saturated brine (2.times.60 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to give AA2 (3.6 g,
84%) as a solid.
[0754] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 5.36-5.34 (m, 1H),
3.53-3.51 (m, 1H), 2.60-2.45 (m, 1H), 2.30-2.20 (m, 3H), 2.12 (s,
3H), 1.97-1.95 (m, 2H), 1.87-1.83 (m, 2H), 1.60-1.30 (m, 9H),
1.25-1.10 (m, 4H), 1.05-0.95 (m, 4H), 0.83-0.79 (m, 3H), 0.65 (s,
3H).
[0755] Step 3. To a solution of AA2 (3.6 g, 10.4 mmol) in MeOH (100
mL) and THF (100 mL) was added dry Pd/C (1 g) under N.sub.2. The
mixture was degassed under vacuum and purged with H.sub.2 several
times. The mixture was stirred for 20 hrs at 30.degree. C. under 30
psi of H.sub.2. The reaction mixture was filtered and the filtrate
was concentrated in vacuum to give AA3 (3.5 g, 96%) as a solid.
[0756] .sup.1H NMR (methanol-d4, 400 MHz) .delta. 3.54-3.52 (m,
1H), 2.47-2.46 (m, 1H), 2.34-2.33 (m, 1H), 2.14 (s, 3H), 1.98-1.94
(m, 1H), 1.80-1.65 (m, 4H), 1.60-1.20 (m, 14H), 1.10-0.90 (m, 3H),
0.85-0.70 (m, 7H), 0.65 (s, 3H).
[0757] Step 4. To a solution of AA3 (3.5 g, 10.5 mmol) in DCM (50
mL) was added silica gel (5 g) and PCC (4.52 g, 21 mmol) at
20.degree. C. After stirring at 20.degree. C. for 1 h, the
resulting mixture was filtered and the filtrate concentrated by
vacuum. The crude product was re-dissolved in DCM (50 mL) and
treated with silica gel (30 g) and PE (50 mL). The mixture was
stirred at 20.degree. C. for 30 mins and filtered. The filtrate was
concentrated in vacuum to give AA4 (2.89 g, 83%) as a solid.
[0758] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.55-2.20 (m, 5H),
2.12 (s, 3H), 2.00-2.93 (m, 3H), 1.65-1.55 (m, 2H), 1.50-1.20 (m,
12H), 1.00 (s, 3H), 0.98-0.85 (m, 1H), 0.82-0.78 (m, 4H), 0.65 (s,
3H).
[0759] Step 5. Under nitrogen atmosphere, anhydrous THF (40 mL) was
cooled to 10.degree. C. and anhydrous LiCl (741 mg, 17.5 mmol) was
added in one portion. The mixture was stirred for 30 min after
which a clear solution was obtained. To this mixture was added
anhydrous FeCl.sub.3 (1.49 g, 9.21 mmol) in one portion. The
resulting mixture was stirred for an additional 30 min. The
reaction mixture was cooled to -35.degree. C. and methyl magnesium
bromide (3 M in diethyl ether, 11.1 mL, 33.5 mmol) was added
dropwise maintaining the internal temperature between -35.degree.
C. and -30.degree. C. The above mixture was stirred for 30 min at
-30.degree. C. AA4 (2.89 g, 8.38 mmol) was added in one portion.
The internal temperature was allowed to -20.degree. C. and held
between -15.degree. C. and -20.degree. C. for 2 hours. The reaction
mixture was quenched with aqueous HCl (2 M, 20 mL), extracted with
CH.sub.2Cl.sub.2 (2.times.50 mL). The combined organic layer was
washed with aqueous NaOH (10%, 2.times.30 mL) and brine (30 mL),
dried over anhydrous sodium sulfate, filtered and concentrated. The
residue was triturated from EtOAc to give Compound 65 (0.25 g, 8%)
as a solid, and 2 g of impure product.
[0760] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.51-2.44 (m, 1H),
2.21-2.18 (m, 1H), 2.11 (s, 3H), 1.91-1.88 (m, 1H), 1.70-1.60 (m,
3H), 1.60-1.78 (m, 4H), 1.75-1.65 (m, 5H), 1.60-1.05 (m, 11H),
1.00-1.80 (m, 1H), 0.79-0.75 (m, 4H), 0.73 (s, 3H), 0.62 (s,
3H).
[0761] LCMS Rt=1.315 min in 2 min chromatography, 30-90 AB, purity
100%, MS ESI calcd. For C.sub.24H.sub.39O [M+H--H.sub.2O].sup.+343,
found 343.
[0762] The stereochemistry at C16 of Compound 65 was confirmed by
NOE.
Example 38. Synthesis of Compound 66
##STR00192##
[0764] Step 1. To a solution of Compound 64 (900 mg, 2.59 mmol) in
MeOH (10 ml) was added HBr (103 mg, 0.518 mmol, 40% in water) and
Br.sub.2 (406 mg, 2.59 mmol) at 25.degree. C. After stirring at
25.degree. C. for 16 hrs, the mixture was quenched by sat.aq
NaHCO.sub.3 (10 mL), treated with water (20 mL), extracted with
EtOAc (2.times.20 mL). The combined organic phase was washed with
brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered,
concentrated in vacuum to afford AB1 (1.2 g) as a solid used
directly for the next step.
[0765] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.89 (d, J=12.0
Hz, 1H), 3.85 (d, J=12.0 Hz, 1H) 2.68-2.67 (m, 1H), 2.46 (d, J=12
Hz, 1H), 1.82-1.80 (m, 1H), 1.66-1.59 (m, 2H), 1.52-1.44 (m, 5H),
1.37-1.18 (m, 14H), 0.96 (d, J=8.0 Hz, 4H), 0.84-0.77 (m, 1H), 0.74
(s, 3H), 0.65 (s, 3H)
[0766] Step 2. To a mixture of AB1 (100 mg, 0.235 mmol) and
K.sub.2CO.sub.3 (64.9 mg, 0.47 mmol) in acetone (5 mL) was added
1H-pyrazole-4-carbonitrile (32.7 mg, 0.352 mmol) at 25.degree. C.
The reaction mixture was stirred at the 25.degree. C. for 16 h.
Then saturated aqueous H.sub.2O (50 mL) was added. The mixture was
extracted with EtOAc (3.times.50 mL). The combined organic solution
was washed with brine (20 mL), dried over Na.sub.2SO.sub.4 and
concentrated in vacuum to give the crude product. The crude product
was purified by flash column (0.about.30% of EtOAc in PE) to give
Compound 66 (38 mg, 37%) as a solid.
[0767] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.86 (s, 1H), 7.81
(s, 1H), 5.00 (d, J=16.0 Hz, 1H), 4.85 (d, J=16.0 Hz, 1H),
2.71-2.68 (m, 1H), 2.18-2.09 (m, 1H), 1.98-1.96 (m, 1H), 1.65-1.53
(m, 2H), 1.52-1.50 (m, 5H), 1.37-1.14 (m, 14H), 0.97 (d, J=8 Hz,
4H), 0.85-0.81 (m, 1H), 0.75 (s, 3H), 0.68 (s, 3H).
[0768] LCMS Rt=2.594 mmin in 4.0 min chromatography,
30-90AB_220&254.lcm, purity 100%, MS ESI calcd. for
C.sub.27H.sub.38N.sub.3O [M+H--H.sub.2O].sup.+420, found 420.
Example 39. Syntheses of Compounds 67, 68, and 69
##STR00193##
[0770] To a solution of AB1 (200 mg, 0.47 mmol) in acetone (2 mL)
was added 5-methoxy-2H-benzo[d][1,2,3]triazole (105 mg, 0.705
mmol), followed by K.sub.2CO.sub.3 (129 mg, 0.940 mmol) at
25.degree. C. The resulting reaction mixture was stirred at
25.degree. C. for 16 hours. To the mixture was added water (20 mL)
and then extracted with EtOAc (3.times.20 mL). The combined organic
solution was washed with brine (20 mL), dried over Na.sub.2SO.sub.4
and concentrated in vacuum to give the crude product. The crude
product was purified by per-HPLC separation (column: DYA-5 C18
150*25 mm*5 um, gradient: 60-100% B (A=0.05% HCl-ACN,
B=acetonitrile), flow rate: 25 mL/min) to give impure Compound 67
and a mixture of Compound 68 and Compound 69. The impure Compound
67 was purified by flash column (0.about.30% of EtOAc in PE) to
give Compound 67 (23 mg, 10%) as a solid. The mixture of Compound
68 and Compound 69, which were purified by SFC separation
(column:AD (250 mm*30 mm, 10 um), gradient: 40-40% B (A=0.1%
NH.sub.3H.sub.2O, B=ETOH), flow rate: 80 mL/min) to give Compound
68 (23 mg, 10%) as solid and Compound 69 (18 mg, 8%) as solid.
[0771] Compound 67:
[0772] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.73 (d, J=8.0 Hz,
1H), 7.07 (d, J=8.0 Hz, 2H), 5.41 (d, J=16 Hz, 2H), 3.88 (s, 3H),
2.76-2.78 (m, 1H), 2.22 (d, J=8.0 Hz, 1H), 2.09-2.06 (m, 1H),
1.66-1.62 (m, 2H), 1.52-1.48 (m, 5H), 1.37-1.21 (m, 14H), 0.98 (d,
J=8.0 Hz, 3H), 0.99-0.97 (m, 2H), 0.76 (s, 6H).
[0773] LCMS Rt=2.963 mmin in 4.0 min chromatography, 30-90AB.lcm,
purity 96.89%, MS ESI calcd. for C.sub.30H.sub.44N.sub.3O.sub.3
[M+H].sup.+ 494, found 494.
[0774] Compound 68:
[0775] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92 (d, J=8.0 Hz,
1H), 7.01 (dd, J=2.0, 8.0 Hz, 1H), 6.58 (d, J=2.0 Hz, 1H), 5.30 (s,
2H), 3.86 (s, 3H), 2.72-2.69 (m, 1H), 2.29 (d, J=8.0 Hz, 1H),
2.08-2.05 (m, 1H), 1.67-1.57 (m, 2H), 1.54-1.51 (m, 5H), 1.37-1.21
(m, 14H), 0.94 (d, J=8 Hz, 4H), 0.88-0.80 (m, 1H), 0.76 (s, 3H),
0.75 (s, 3H).
[0776] LCMS Rt=2.718 min in 4.0 min chromatography, 30-90AB.lcm,
purity 100%, MS ESI calcd. for C.sub.30H.sub.44N.sub.3O.sub.3
[M+H].sup.+ 494, found 494.
[0777] Compound 69:
[0778] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (d, J=2.0 Hz,
1H), 7.18-7.16 (m, 2H), 5.33 (s, 2H), 3.89 (s, 3H), 2.74-2.68 (m,
1H), 2.28 (d, J=8.0 Hz, 1H), 2.10-2.01 (m, 1H), 1.67-1.53 (m, 2H),
1.52-1.51 (m, 5H), 1.37-1.21 (m, 14H), 0.94 (d, J=8 Hz, 4H),
0.88-0.80 (m, 1H), 0.76 (s, 3H), 0.76 (s, 3H).
[0779] LCMS Rt=2.732 min in 4.0 min chromatography, 30-90AB.lcm,
purity 100%, MS ESI calcd. for C.sub.30H.sub.44N.sub.3O.sub.3
[M+H].sup.+ 494, found 494.
Example 40. Syntheses of Compounds 70, 71, and 72
##STR00194##
[0781] Step 1. To a solution of Compound 65 (1 g, 2.77 mmol) in
MeOH (10 ml) was added HBr (110 mg, 0.554 mmol, 40% in water) and
Br.sub.2 (442 mg, 2.82 mmol) at 25.degree. C. The mixture was
stirred at 25.degree. C. for 16 hrs. The mixture was quenched by
sat.aq NaHCO.sub.3 (10 mL), treated with water (20 mL), extracted
with EtOAc (2.times.20 mL). The combined organic phase was washed
with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, concentrated in vacuum to afford AC1 (1.2 g) as a solid
used directly for the next step.
[0782] Step 2. To a solution of AC1 (200 mg, 0.486 mmol) in acetone
(2 mL) was added 5-methoxy-2H-benzo[d][1,2,3]triazole (108 mg,
0.729 mmol), followed by K.sub.2CO.sub.3 (134 mg, 0.972 mmol) at
25.degree. C. The resulting reaction mixture was stirred at
25.degree. C. for 16 hours. To the mixture was added water (20 mL)
and then extracted with EtOAc (3.times.20 mL). The combined organic
solution was washed with brine (20 mL), dried over Na.sub.2SO.sub.4
and concentrated in vacuum to give the crude product, which was
purified by flash column (0.about.30% of EtOAc in PE) to give
Compound 70 (33 mg, 7%) as a solid; and 100 mg of a mixture of
Compound 71 and Compound 72. The mixture was purified by SFC
(column: OD (250 mm*30 mm, 5 um)), gradient: 45-45% B (A=0.1%
NH.sub.3H.sub.2O, B=ETOH), flow rate: 50 mL/min) to give Compound
72 (46 mg, 9%) as a solid and Compound 72 (32 mg, 7%) as a
solid.
[0783] Compound 70:
[0784] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.73 (d, J=8.0 Hz,
1H), 7.07 (d, J=8.0 Hz, 2H), 5.41 (d, J=12 Hz, 2H), 3.87 (s, 3H),
2.56-2.54 (m, 1H), 2.28 (d, J=8.0 Hz, 1H), 2.09-2.06 (m, 1H),
1.66-1.62 (m, 2H), 1.52-1.48 (m, 5H), 1.37-1.21 (m, 16H), 1.00-0.92
(m, 1H) 0.83 (d, J=8.0 Hz, 4H), 0.76 (s, 3H), 0.75 (s, 3H).
[0785] LCMS Rt=3.059 in in 4.0 min chromatography, 30-90AB.lcm,
purity 96.49%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.3
[M+H].sup.+ 508, found 508.
[0786] Compound 71:
[0787] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (d, J=4.0 Hz,
1H), 7.20-7.13 (m, 2H), 5.41-5.30 (m, 2H), 3.89 (s, 3H), 2.56-2.54
(m, 1H), 2.35 (d, J=8.0 Hz, 1H), 2.09-2.06 (m, 1H), 1.69-1.62 (m,
2H), 1.52-1.48 (m, 5H), 1.37-1.21 (m, 16H), 1.00-0.92 (m, 1H)
0.85-0.79 (m, 4H), 0.76 (s, 3H), 0.73 (s, 3H).
[0788] LCMS Rt=2.822 in in 4.0 min chromatography, 30-90AB.lcm,
purity 100%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.3
[M+H].sup.+ 508, found 508.
[0789] Compound 72:
[0790] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92 (d, J=8.0 Hz,
1H), 7.01 (dd, J=4, 8.0 Hz, 1H), 6.57 (d, J=4 Hz, 1H), 5.38-5.27
(d, J=12 Hz, 2H), 3.85 (s, 3H), 2.60-2.53 (m, 1H), 2.37 (d, J=8.0
Hz, 1H), 2.13-2.06 (m, 1H), 1.73-1.65 (m, 2H), 1.56-1.51 (m, 5H),
1.37-1.21 (m, 16H), 0.83-0.80 (m, 1H), 0.82 (d, J=8.0 Hz, 4H), 0.76
(s, 3H), 0.74 (s, 3H).
[0791] LCMS Rt=2.795 in in 4.0 min chromatography, 30-90AB.lcm,
purity 100%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.3
[M+H].sup.+ 508, found 508.
Example 41. Synthesis of Compound 73
##STR00195##
[0793] Step 1. To a solution of iPrMgCl (420 mL, 2 M in THF) in THF
(100 mL) was added a solution of Z1 (20 g, 56.1 mmol) in toluene
(400 mL) at 20.degree. C. After stirring at this temperature for 30
mins, the suspension was allowed to heat at 40.degree. C. for 18
hrs. The reaction mixture was quenched with aqueous NH.sub.4Cl (500
mL), extracted with EtOAc (2.times.600 mL). The combined organic
layer was washed with brine (500 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash column (0.about.20% of EtOAc in PE) to give AD1
(7 g, 31%) as a solid.
[0794] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 5.35-5.34 (m, 1H),
3.52 (s, 1H), 2.48-2.20 (m, 4H), 2.13 (s, 3H), 2.00-1.75 (m, 4H),
1.70-1.25 (m, 11H), 1.20-1.05 (m, 2H), 1.00 (s, 3H), 0.95-0.80 (m,
1H), 0.85-0.83 (m, 3H), 0.76-0.73 (m, 3H), 0.64 (s, 2H).
[0795] Step 2. To a solution of AD1 (4 g, 1.87 mmol) in MeOH (100
mL) and THF (100 mL) was added dry Pd(OH).sub.2/C (1 g) under
N.sub.2. The mixture was degassed under vacuum and purged with
H.sub.2 several times. The mixture was stirred for 20 hrs at
30.degree. C. under 30 psi of H.sub.2. The reaction mixture was
filtered and the filtrate was concentrated in vacuum to give AD2
(3.8 g, 95%) as a solid.
[0796] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 3.58 (s, 1H),
2.45-2.30 (m, 2H), 2.11 (s, 4H), 1.90-1.50 (m, 8H), 1.45-1.25 (m,
5H), 1.25-1.30 (m, 3H), 1.15-1.00 (m, 2H), 0.95-0.85 (m, 3H),
0.84-0.75 (m, 6H), 0.74-0.65 (m, 3H), 0.61 (s, 3H).
[0797] Step 3. To a solution of AD2 (3.8 g, 1.8 mmol) in DCM (15
mL) was added silica gel (1.03 g) and PCC (775 mg, 3.6 mmol) at
25.degree. C. After stirring at 25.degree. C. for 1 h, the
resulting mixture was filtered and the filtrate concentrated by
vacuum. The crude product was re-dissolved in DCM (20 mL) and
treated with silica gel (20 g) and PE (30 mL). The mixture was
stirred at 25.degree. C. for 30 mins and filtered. The filtrate was
concentrated in vacuum to give AD3 (3.4 g, crude) as a solid.
[0798] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.45-2.25 (m, 5H),
2.13 (s, 3H), 2.10-2.00 (m, 2H), 1.90-1.73 (m, 1H), 1.75-1.65 (m,
2H), 1.60-1.55 (m, 1H), 1.64 (m, 1H), 1.59-1.25 (m, 6H), 1.25-1.10
(m, 4H), 1.00 (s, 3H), 0.95-0.90 (m, 1H), 0.85-0.83 (m, 3H),
0.75-0.73 (m, 3H), 0.64 (s, 3H).
[0799] Step 4. Under nitrogen atmosphere, anhydrous THF (40 mL) was
cooled to 10.degree. C. and anhydrous LiCl (491 mg, 11.6 mmol) was
added in one portion. The mixture was stirred for 30 min, after
which a clear solution was obtained. To this mixture was added
anhydrous FeCl.sub.3 (992 mg, 6.12 mmol) in one portion. The
resulting mixture was stirred for additional 30 min. The reaction
mixture was cooled to -35.degree. C. and methyl magnesium bromide
(3 M in diethyl ether, 11.1 mL, 33.5 mmol) was added dropwise
maintaining the internal temperature between -35.degree. C. and
-30.degree. C. The above mixture was stirred for 30 min at
-30.degree. C. AD3 (2 g, 5.57 mmol) was added in one portion. The
internal temperature was allowed to -20.degree. C. and held between
-15.degree. C. and -20.degree. C. for 2 hours. The reaction mixture
was quenched with aqueous NH.sub.4Cl (50 mL), extracted with EtOAc
(3.times.100 mL). The combined organic layer was washed with brine
(50 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by flash column (0.about.20%
of EtOAc in PE) to give Compound 73 (310 mg) as a yellow oil, which
was lyophilized to give Compound 73 (300 mg, 14%) as white
powder.
[0800] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.35 (s, 2H), 2.12
(s, 3H), 1.90-1.86 (m, 1H), 1.70-1.60 (m, 2H), 1.54-1.45 (m, 6H),
1.45-1.25 (m, 7H), 1.20-1.15 (m, 3H), 0.94-0.85 (m, 4H), 0.85-0.82
(m, 4H), 0.80-0.70 (m, 7H), 0.62 (s, 3H).
[0801] LCMS Rt=1.318 min in 2 min chromatography, 30-90 CD, purity
100%, MS ESI calcd. For
C.sub.25H.sub.41O.sup.+[M+H--H.sub.2O].sup.+357, found 357.
Example 42. Synthesis of Compound 74
##STR00196##
[0803] To a mixture of AC1 (80 mg, 0.182 mmol) and K.sub.2CO.sub.3
(50.3 mg, 0.364 mmol) in acetone (5 mL) was added
1H-pyrazole-4-carbonitrile (25.4 mg, 0.273 mmol) at 25.degree. C.
The reaction mixture was stirred at the 25.degree. C. for 16 h and
treated with H.sub.2O (50 mL). The mixture was extracted with EtOAc
(3.times.50 mL). The combined organic solution was washed with
brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuum to give the crude product, which was
purified by flash column (0.about.30% of EtOAc in PE) to give an
impure solid (50 mg). The impure product was purified by flash
column (0.about.30% of EtOAc in PE) to give Compound 74 (32 mg,
39%) as a solid.
[0804] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (s, 1H), 7.81
(s, 1H), 5.00 (d, J=16 Hz, 1H), 4.87 (d, J=16 Hz, 1H), 2.54 (m,
1H), 2.25 (d, J=8.0 Hz, 1H), 1.96 (m, 1H), 1.65 (m, 2H), 1.53-1.47
(m, 5H), 1.38-1.12 (m, 16H), 1.01-0.92 (m, 1H), 0.81 (t, J=8.0 Hz,
4H), 0.75 (s, 3H), 0.68 (s, 3H).
[0805] LCMS Rt=2.682 in in 4.0 min chromatography, 30-90AB.lcm,
purity 100%, MS ESI calcd. for C.sub.28H.sub.40N.sub.3O
[M-H.sub.2O+H].sup.+434, found 434.
Example 44. Syntheses of Compounds 78 and 79
##STR00197##
[0807] Step 1. To a solution of compound 73 (750 mg, 2 mmol) in
MeOH (10 mL) was added HBr (80.7 mg, 0.4 mmol, 40% in water) and
Br.sub.2 (326 mg, 2.04 mmol) at 15.degree. C. After stirring at
15.degree. C. for 16 hrs, the mixture was quenched by sat.aq
NaHCO.sub.3 (10 mL) and water (20 mL), extracted with EtOAc
(3.times.20 mL). The combined organic phase was washed with brine
(40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuum. The residue was purified by flash column
(0.about.30% of EtOAc in PE) to give AE1 (660 mg, 69%) as a
solid.
[0808] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.99-3.86 (m, 2H),
2.68-2.63 (m, 1H), 1.86-1.76 (m, 1H), 1.72-1.59 (m, 2H), 1.53-1.32
(m, 8H), 1.29-1.23 (m, 4H), 1.21-1.18 (m, 4H), 1.17-1.12 (m, 2H),
1.02-0.83 (m, 6H), 0.81-0.71 (m, 8H), 0.67-0.61 (m, 3H).
[0809] Step 2. To a solution of AE1 (150 mg, 0.33 mmol) in acetone
(5 mL) was added K.sub.2CO.sub.3 (91 mg, 0.66 mmol) and
1H-pyrazolo[3,4-c]pyridine (39.3 mg, 0.33 mmol). The mixture was
stirred at 15.degree. C. for 12 hrs. Second batch of
K.sub.2CO.sub.3 (45.5 mg, 0.33 mmol) and 1H-pyrazolo[3,4-c]pyridine
(7.86 mg, 0.06 mmol) was added at 15.degree. C. The mixture was
stirred at 15.degree. C. for another 8 hrs and poured in to water
(10 mL), extracted with ethyl acetate (3.times.10 mL). The combined
organic layer was washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue
was purified by flash column (0.about.80% of EtOAc in PE) to afford
Compound 78 (70 mg, impure) as a solid and Compound 79 (31 mg, 19%)
as a solid.
[0810] The impure Compound 78 (70 mg, 0.14 mmol) was purified by
SFC (column: AS (250 mm*30 mm, 5 um)), gradient: 35-35% B (A=0.1%
NH.sub.3/H.sub.2O, B=EtOH), flow rate: 50 mL/min) to give a solid,
which was further purified by re-crystallized from MeCN (3 mL) to
give Compound 78 (36 mg, 22%) as a solid.
[0811] Compound 78:
[0812] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.77 (s, 1H),
8.38-8.29 (m, 1H), 8.09 (s, 1H), 7.66-7.61 (m, 1H), 5.33-5.21 (m,
2H), 2.53-2.42 (m, 2H), 2.13-2.04 (m, 1H), 1.75-1.65 (m, 2H),
1.56-1.23 (m, 15H), 1.21 (s, 3H), 1.21-1.14 (m, 2H), 1.03-0.91 (m,
1H), 0.88-0.79 (m, 7H), 0.76 (s, 3H), 0.71 (s, 3H).
[0813] LCMS Rt=0.968 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.2
[M+H].sup.+ 492, found 492.
[0814] Compound 79:
[0815] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.26 (s, 1H),
8.18-8.14 (d, J=6 Hz, 1H), 7.96 (s, 1H), 7.54-7.49 (m, 1H),
5.37-5.18 (m, 2H), 2.53-2.44 (m, 2H), 2.12-2.03 (m, 1H), 1.74-1.66
(m, 2H), 1.52-1.28 (m, 12H), 1.26-1.13 (m, 8H), 1.03-0.92 (m, 1H),
0.87-0.82 (m, 4H), 0.81-0.75 (m, 6H), 0.71 (s, 3H).
[0816] LCMS Rt=0.917 min in 2 min chromatography, 30-90AB, purity
100%, MS ESI calcd. for C.sub.31H.sub.46N.sub.3O.sub.2 [M+H].sup.+
492, found 492.
Example 44. Syntheses of Compounds 80, 81, and 82
##STR00198##
[0818] To a solution of AE1 (250 mg, 0.55 mmol) in acetone (10 mL)
was added K.sub.2CO.sub.3 (151 mg, 1.1 mmol) and
5-methoxy-2H-benzo[d][1,2,3]triazole (123 mg, 0.83 mmol) and the
mixture was stirred at 15.degree. C. for 12 hours. A second batch
of K.sub.2CO.sub.3 (75.5 mg, 0.55 mmol) and
5-methoxy-2H-benzo[d][1,2,3]triazole (61.5 mg, 0.41 mmol) was added
at 15.degree. C. and the mixture was stirred at 15.degree. C. for 8
hours. The mixture was poured in to water (20 mL) and extracted
with ethyl acetate (3.times.20 mL). The combined organic layers was
washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuum. The residue was purified by flash
column (0-45% of EtOAc in PE) to afford Compound 80 (44 mg, 15%) as
a solid and a mixture of Compound 81 and Compound 82 (200 mg, 69%)
as a light yellow oil.
[0819] The mixture of Compound 81 and Compound 82 (200 mg, 0.05
mmol) was purified by SFC (column: OD (250 mm*30 mm, 10 um)),
gradient: 40-40% B (A=0.1% NH3/H.sub.2O, B=MEOH), flow rate: 80
mL/min) to give Compound 81 (43 mg, 21%) as a solid and Compound 82
(26 mg, 13%) as a solid.
[0820] Compound 80:
[0821] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78-7.69 (m, 1H),
7.11-7.03 (m, 2H), 5.49-5.37 (m, 2H), 3.87 (s, 3H), 2.54-2.41 (m,
2H), 2.14-2.05 (m, 1H), 1.73-1.64 (m, 2H), 1.57-1.23 (m, 17H), 1.21
(s, 3H), 1.19-1.07 (m, 2H), 0.86-0.79 (m, 6H), 0.78-0.71 (m,
6H).
[0822] LCMS Rt=1.348 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.32H.sub.48N.sub.3O.sub.3
[M+H].sup.+ 522, found 522.
[0823] Compound 81:
[0824] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.94-7.89 (d,
J=9.6 Hz, 1H), 7.03-6.97 (m, 1H), 6.58-6.54 (m, 1H), 5.46-5.27 (m,
2H), 3.83 (s, 3H), 2.56-2.44 (m, 2H), 2.13-2.05 (m, 1H), 1.75-1.66
(m, 2H), 1.61-1.23 (m, 16H), 1.21 (s, 3H), 1.15 (s, 1H), 1.03-0.91
(m, 1H), 0.89-0.79 (m, 7H), 0.76 (s, 3H), 0.72 (s, 3H).
[0825] LCMS Rt=1.273 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.32H.sub.48N.sub.3O.sub.3
[M+H].sup.+ 522, found 522.
[0826] Compound 82:
[0827] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41-7.37 (d,
J=1.2 Hz, 1H), 7.19-7.11 (m, 2H), 5.45-5.31 (m, 2H), 3.89 (s, 3H),
2.53-2.43 (m, 2H), 2.12-2.04 (m, 1H), 1.75-1.65 (m, 2H), 1.61-1.23
(m, 15H), 1.21 (s, 3H), 1.19-0.91 (m, 3H), 0.88-0.78 (m, 7H), 0.76
(s, 3H), 0.71 (s, 3H).
[0828] LCMS Rt=1.277 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.32H.sub.48N.sub.3O.sub.3
[M+H].sup.+ 522, found 522.
Example 45. Syntheses of Compounds 83, 84, and 85
##STR00199##
[0830] To a solution of AB1 (150 mg, 0.352 mmol) and
1H-pyrazolo[3,4-c]pyridine (43.9 mg, 0.369 mmol) in acetone (3 mL)
was added K.sub.2CO.sub.3 (97.2 g, 0.704 mmol) at 25.degree. C.
After stirring at 25.degree. C. for 10 hrs, the mixture was poured
into water (50 mL) and extracted with EtOAc (3.times.20 mL). The
combined organic layer was washed with brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford crude product
(100 mg), which was purified by preparative HPLC (column: YMC-Actus
Triart C18 150*30 mm*5 um)), gradient: 40-70% B (A=0.1% HCl,
B=ACN), flow rate: 25 mL/min) to afford Compound 85 (15 mg, 9%) as
a solid, Compound 84 (17 mg, 10%) as a solid and Compound 83 (20
mg, impure). Compound 83 (20 mg, impure) was purified by SFC
separation (column: AD (250 mm*30 mm, 10 um)), gradient: 50-50% B
(A=0.1% NH.sub.3H.sub.2O, B=EtOH), flow rate: 80 mL/min) to afford
Compound 83 (3 mg, yield 15%) as a solid.
[0831] Compound 83:
[0832] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.26 (s, 1H), 8.17
(d, J=4.8 Hz, 1H), 7.98 (s, 1H), 7.53 (d, J=6.0 Hz, 1H), 5.34-5.16
(m, 2H), 2.78-2.70 (m, 1H), 2.27 (d, J=8.4 Hz, 1H), 2.07-2.01 (m,
1H), 1.73-1.59 (m, 3H), 1.54-1.45 (m, 5H), 1.42-1.24 (m, 11H), 1.21
(s, 3H), 0.98 (d, J.sup.=6.8 Hz, 3H), 0.86-0.80 (m, 1H), 0.76 (s,
3H), 0.73 (s, 3H).
[0833] LCMS Rt=2.405 mmin in 4 min chromatography, 10-80AB, purity
99%, MS ESI calcd. For C.sub.29H.sub.42N.sub.3O.sub.2 [M+H].sup.+
464, found 464.
[0834] Compound 84:
[0835] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.78 (s, 1H), 8.34
(d, J=5.6 Hz, 1H), 8.10 (s, 1H), 7.65-7.63 (m, 1H), 5.28-5.17 (m,
2H), 2.76-2.65 (m, 1H), 2.29-2.26 (m, 1H), 2.10-2.02 (m, 1H),
1.72-1.60 (m, 3H), 1.55-1.48 (m, 5H), 1.42-1.34 (m, 4H), 1.32-1.19
(m, 10H), 0.96 (d, J=7.2 Hz, 3H), 0.88-0.82 (m, 1H), 0.77 (s, 3H),
0.74 (s, 3H).
[0836] LCMS Rt=2.014 min in 3 min chromatography, 10-80AB, purity
100%, MS ESI calcd. For C.sub.29H.sub.42N.sub.3O.sub.2 [M+H].sup.+
464, found 464.
[0837] Compound 85:
[0838] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.03 (s, 1H), 8.56
(s, 1H), 7.87 (d, J=6.8 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 5.32-5.18
(m, 2H), 3.80-2.74 (m, 1H), 2.35-2.32 (m, 1H), 2.01-1.98 (m, 1H),
1.71-1.51 (m, 6H), 1.45-1.24 (m, 13H), 1.22 (s, 3H), 1.03 (d, J=7.2
Hz, 3H), 0.91-0.86 (m, 1H), 0.77 (s, 3H), 0.74 (s, 3H).
[0839] LCMS Rt=2.388 min in 4 min chromatography, 10-80AB, purity
98.7%, MS ESI calcd. For C.sub.29H.sub.42N.sub.3O.sub.2 [M+H].sup.+
464, found 464.
Example 46. Syntheses of Compounds 86 and 87
##STR00200##
[0841] To a mixture of AC1 (150 mg, 0.341 mmol) and K.sub.2CO.sub.3
(94.2 mg, 0.682 mmol) in acetone (3 mL) was added
1H-pyrazolo[3,4-c]pyridine (42.6 mg, 0.358 mmol) at 25.degree. C.
After stirring at 25.degree. C. for 12 hrs, the mixture was poured
into water (50 mL) and extracted with EtOAc (3.times.20 mL). The
combined organic layer was washed with brine (50 mL), dried over
with Na.sub.2SO.sub.4, filtered and concentrated to afford crude
product, which was purified by prep-HPLC separation (column:
YMC-Actus Triart C18 150*30 mm*5 um)), gradient: 45-75% B (A=0.1%
HCl, B=ACN), flow rate: 25 mL/min) to afford Compound 87 (36 mg,
22%) as a solid and Compound 86 (20 mg, impure). The crude Compound
86 was purified by SFC separation (column: AD (250 mm*30 mm, 10
um)), gradient: 45-45% B (A=0.1% NH.sub.3H.sub.2O, B=ETOH), flow
rate: 80 mL/min) to afford Compound 86 (11 mg, 7%) as a solid.
[0842] Compound 86:
[0843] 1H NMR (400 MHz, CDCl.sub.3) .delta. 9.28 (s, 1H), 8.25-8.1
(m, 1H), 8.02 (s, 1H), 7.65-7.55 (m, 1H), 5.37-5.19 (m, 2H),
2.58-2.5 (m, 1H), 2.33 (d, J=12 Hz, 1H), 2.10-2.05 (m, 1H),
1.72-1.65 (m, 2H), 1.53-1.45 (m, 5H), 1.42-1.23 (m, 12H), 1.21 (s,
3H), 1.16 (s, 1H), 1.01-0.93 (m, 1H), 0.83 (t, J=8.0 Hz, 4H), 0.77
(s, 3H), 0.73 (s, 3H).
[0844] LCMS Rt=2.502 min in 4.0 min chromatography, 10-80AB.lcm,
purity 100%, MS ESI calcd. for C.sub.30H.sub.44N.sub.3O.sub.2
[M+H].sup.+ 478, found 478.
[0845] Compound 87:
[0846] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.26 (s, 1H), 8.17
(d, J=4.0 Hz, 1H), 7.97 (s, 1H), 7.54-7.50 (m, 1H), 5.35-5.17 (m,
2H), 2.60-2.52 (m, 1H), 2.35-2.30 (m, 1H), 2.10-2.04 (m, 1H),
1.69-1.62 (m, 4H), 1.52-1.46 (m, 5H), 1.39-1.26 (m, 11H), 1.21 (s,
3H), 1.12-0.98 (m, 1H), 0.83 (t, J=8.0 Hz, 4H), 0.76 (s, 3H), 0.73
(s, 3H)
[0847] LCMS Rt=1.750 min in 3.0 min chromatography, 10-80AB_3
MIN_E.M, purity 100%, MS ESI calcd. for
C.sub.30H.sub.44N.sub.3O.sub.2 [M+H].sup.+ 478, found 478.
Example 47. Synthesis of Compound 88
##STR00201##
[0849] The synthesis of P1 is disclosed in WO2016/61527.
[0850] Step 1. To a suspension of MePPh.sub.3Br (14.5 g, 39.3 mol)
in THF (300 mL) was added t-BuOK (4.4 g, 39.3 mmol) at 15.degree.
C. under N.sub.2. After stirring at 50.degree. C. for 30 min, P1
(10 g, 32.8 mmol) was added in portions below 65.degree. C. The
mixture was stirred at 50.degree. C. for 1 h and treated with
NH.sub.4Cl (300 mL). The organic layer was separated, concentrated
in vacuum to give a cured which was triturated from MeOH/water (150
L, 1:1) at 50.degree. C. The mixture was filtered after cooled and
the solid was washed with MeOH/water (2.times.150 mL, 1:1), dried
in vacuum to give AF1 (8 g, 77%) as a solid.
[0851] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.15-5.05 (m, 1H),
2.40-2.10 (m, 3H), 1.80-1.55 (m, 5H), 1.54-1.40 (m, 6H), 1.39-1.25
(m, 4H), 1.24-1.10 (m, 10H), 0.77 (s, 3H), 076-0.70 (m, 4H).
[0852] Step 2. To a suspension of selenium dioxide (854 mg, 7.70
mmol) in DCM (40 mL) was added dropwise tert-butyl hydro peroxide
(3.13 mL, 23.1 mmol 70% solution in water) to give a nearly
homogeneous solution after stirring at 0.degree. C. for 1 h. Then a
solution of AF1 (4.9 g, 15.4 mmol) in DCM (10 mL) was added
dropwise to give a clear solution. The resulting mixture was
stirred 20.degree. C. for 18 h. The reaction mixture was diluted
with PE (100 mL) and a lot of white precipitate appeared. The
precipitate was collected by filtration and dried in air to give
the product AF2 (4.9 g, crude) as a solid.
[0853] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.55-5.50 (m, 1H),
4.45-4.40 (m, 1H), 2.30-2.20 (m, 1H), 1.75-1.55 (m, 8H), 1.54-1.15
(m, 17H), 1.10-1.00 (m, 1H), 0.90-0.80 (m, 4H), 0.75 (s, 3H).
[0854] Step 3. To a solution of AF2 (2.2 g, 6.61 mmol) in dry THF
(60 mL) was slowly added to a stirred suspension NaH (791 mg, 19.8
mmol) in dry THF (20 mL) at -5.degree. C. Then MeI (10.2 mL, 165
mmol) was added to reaction mixture and stirred for 24 h at
35.degree. C. The reaction mixture was quenched by water (80 mL)
and extracted with DCM (2.times.80 mL). The combined organic layer
was washed by brine and dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to give a residue (2.5 g). The
residue was purified by silica gel chromatography eluted with
PE:EtOAc=5:1 to give AF3 (1.56 g, 68%) as a solid.
[0855] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.60-5.50 (m, 1H),
4.00-3.90 (m, 1H), 3.30 (m, 3H), 2.30-2.20 (m, 1H), 1.75-1.60 (m,
6H), 1.59-1.15 (m, 18H), 1.05-0.95 (m, 1H), 0.85 (s, 3H), 0.80-0.79
(m, 1H), 0.75 (s, 3H).
[0856] Step 4. To a solution of AF3 (500 mg, 1.44 mmol) in dry THF
(5 mL) was added borane-tetrahydrofuran complex (2.88 mL of 1.0 M
solution in THF) and the reaction mixture was stirred at 20.degree.
C. for 1 hour. NaOH (4.76 mL, 14.3 mmol, 3 M in water) was slowly
added. The mixture was cooled in ice (0.degree. C.) and 30 percent
aqueous solution of H.sub.2O.sub.2 (1.62 g, 14.3 mmol) was slowly
added. The mixture was stirred at ambient temperature for 1 hour
and then extracted with DCM (3.times.50 mL). The combined DCM
extracts were washed with 10 percent aqueous Na.sub.2S.sub.2O.sub.3
(100 mL), brine (100 mL), dried over Na.sub.2SO.sub.4, filtered,
and concentrated in vacuum to afford compound AF4 (500 mg, crude)
as a solid, which was used in next step without further
purification.
[0857] Step 5. To a solution To a solution of AF4 (500 mg, 1.37
mmol) in DCM (40 mL) was added PCC (590 mg, 2.74 mmol) and silica
gel (1 g) at 25.degree. C. Then the solution was stirred at
25.degree. C. for 3 h. The reaction mixture was filtered and the
residue was washed with anhydrous DCM (2.times.30 mL). The combined
filtrate was concentrated in vacuum to give Compound 88 (200 mg,
crude) as a solid, which was purified by silica gel column
(PE/EtOAc=1/1) and lyophilization to afford Compound 88 (20 mg,
10%) as a solid.
[0858] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.40-4.30 (m, 1H),
3.20 (s, 3H), 2.55-2.50 (m, 1H), 2.16 (s, 3H), 1.95-1.90 (m, 1H),
1.70-1.55 (m, 4H), 1.50-1.40 (m, 5H), 1.39-1.15 (m, 12H), 1.05-0.95
(m, 1H), 0.90-0.85 (m, 1H), 0.74 (s, 3H), 0.60 (s, 3H).
[0859] HPLC Rt=4.28 min in 8.0 min chromatography, 30-90 AB, purity
100%.
[0860] LCMS Rt=1.061 min in 2.0 min chromatography, 30-90 AB,
purity 92%, MS ESI calcd. for C.sub.23H.sub.39O.sub.3[M+H].sup.+
363, found 363.
[0861] The stereochemistry at C16 of Compound 88 was confirmed by
NOE.
Example 48. Syntheses of Compounds 89 and 90
##STR00202##
[0863] Step 1a (Compound 89). To a solution of AB1 (80 mg, 0.188
mmol), DIEA (60.6 mg, 0.47 mmol) in DMF (2 mL) was added aniline
(26.2 mg, 0.282 mmol) at 25.degree. C. The mixture was stirred at
60.degree. C. for 16 hours. The mixture was poured into water (10
mL) and extracted with EtOAc (2.times.20 mL). The combined organic
layers was washed with brine (20 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuum. The residue was purified by
HPLC separation (column: Phenomenex Gemini C18 250*50 mm*10 um,
gradient: 87-97% B, Condition:(water (0.05% ammonia hydroxide
v/v)-ACN), flow rate: 30 mL/min) to give Compound 89 (12 mg,
impure) as a solid. The Compound 89 (12 mg, impure) was purified by
a silica gel column (PE/EtOAc=5/1) to give Compound 89 (5 mg, 6%)
as a solid.
[0864] .sup.1HNMR (400 MHz, CDCl3) .delta.7.19 (t, J=8 Hz, 2H),
6.72 (t, J=8 Hz, 1H), 6.60 (d, J=8 Hz, 2H), 4.73-4.69 (m, 1H),
4.01-3.85 (m, 2H), 2.79-2.66 (m, 1H), 2.19 (d, J=12 Hz, 1H),
1.89-1.82 (m, 1H), 1.70-1.58 (m, 3H), 1.51-1.34 (m, 6H), 1.31-1.15
(m, 11H), 1.01-0.92 (m, 4H), 0.88-0.78 (m, 2H), 0.74 (s, 3H), 0.67
(s, 3H).
[0865] LCMS Rt=4.893 mmin in 7.0 min chromatography, 30-90 CD,
purity 100%, MS ESI calcd. For C.sub.29H.sub.44NO.sub.2
[M+H].sup.+438, found 438.
[0866] Step 1b (Compound 90). To a solution of AB1 (80 mg, 0.188
mmol), DIEA (60.6 mg, 0.47 mmol) in DMF (2 mL) was added
N-methylaniline (30.2 mg, 0.282 mmol) at 25.degree. C. The mixture
was stirred at 60.degree. C. for 16 hours. The mixture was poured
into water (10 mL) and extracted with EtOAc (2.times.20 mL). The
combined organic layers was washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue
was purified by HPLC separation (column: Phenomenex Gemini C18
250*50 mm*10 um, gradient: 90-100% B, Condition: (water (0.05%
ammonia hydroxide v/v)-ACN), flow rate: 30 mL/min) to give Compound
90 (10 mg, impure) as a solid. The Compound 90 (10 mg, impure) was
purified by a silica gel column (PE/EtOAc=5/1) to give Compound 90
(3 mg, 4%) as a solid.
[0867] .sup.1HNMR (400 MHz, CDCl3) .delta. 7.20 (t, J=8 Hz, 2H),
6.71 (t, J=8 Hz, 1H), 6.61 (d, J=8 Hz, 2H), 4.73-4.69 (m, 1H),
4.06-3.95 (m, 2H), 3.01 (s, 3H), 2.75-2.63 (m, 1H), 2.24 (d, J=8
Hz, 1H), 1.91-1.61 (m, 2H), 1.52-1.38 (m, 5H), 1.36-1.15 (m, 13H),
1.01-0.88 (m, 4H), 0.86-0.78 (m, 2H), 0.75 (s, 3H), 0.68 (s,
3H).
[0868] LCMS Rt=5.041 min in 7.0 min chromatography, 30-90 CD,
purity 100%, MS ESI calcd. For C.sub.30H.sub.46NO.sub.2
[M+H].sup.+452, found 452.
Example 49. Synthesis of Compound 91
##STR00203##
[0870] To a solution of AE1 (100 mg, 0.22 mmol) in acetone (3 mL)
was added K.sub.2CO.sub.3 (60.7 mg, 0.44 mmol) and
1H-pyrazole-4-carbonitrile (30.7 mg, 0.33 mmol). The mixture was
stirred at 15.degree. C. for 12 hours. The mixture was poured in to
water (10 mL) and extracted with ethyl acetate (3.times.10 mL). The
combined organic layers was washed with brine (150 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue
was purified by flash column (0.about.30% of EtOAc in PE) to afford
Compound 91 (90 mg, 88%, impure) as a solid, which was purified by
SFC (column: OD (250 mm*30 mm, 10 um)), gradient: 40-40% B (A=0.1%
NH.sub.3/H.sub.2O, B=EtOH), flow rate: 50 mL/min) to give Compound
91 (44 mg, 48%) as a solid.
[0871] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.86-7.79 (d, J=14
Hz, 2H), 5.04-4.85 (m, 2H), 2.52-2.36 (m, 2H), 1.99-1.92 (m, 1H),
1.73-1.63 (m, 2H), 1.57-1.22 (m, 16H), 1.205 (s, 3H), 1.19-1.13 (m,
2H), 1.02-0.89 (m, 1H), 0.86-0.83 (m, 3H), 0.79-0.73 (m, 6H), 0.66
(s, 3H).
[0872] LCMS Rt=1.227 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.29H.sub.44N.sub.3O.sub.2
[M+H].sup.+ 466, found 466.
Example 50. Syntheses of Compounds 92 and 93
##STR00204##
[0874] To a solution of AB1 (550 mg, 1.29 mmol) in acetone (10 mL)
was added K.sub.2CO.sub.3 (356 mg, 2.58 mmol) and
5-methyl-1H-tetrazole (162 mg, 1.93 mmol) at 25.degree. C. The
mixture was stirred at 25.degree. C. for 16 hours. To the mixture
was added water (50 mL) and ethyl acetate (50 mL). The organic
layer was separated. The mixture was extracted with ethyl acetate
(2.times.50 mL). The combined organic layers was washed with brine
(200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuum. The residue was purified by column chromatography on silica
gel with PE:EtOAc=0:1-1:1 to give Compound 93 (233 mg, 42%) and
Compound 92 (112 mg, 20%) as solid.
[0875] Compound 92:
[0876] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 5.37-5.26 (m, 2H),
2.74-2.66 (m, 1H), 2.46 (s, 3H), 2.27-2.25 (m, 1H), 2.02-1.98 (m,
1H), 1.70-1.57 (m, 4H), 1.56-1.46 (m, 5H), 1.42-1.16 (m, 13H), 0.98
(m, 3H), 0.86-0.79 (m, 1H), 0.74 (m, 6H).
[0877] LCMS Rt=1.108 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.25H.sub.41N.sub.4O.sub.2
[M+H].sup.+ 429, found 429.
[0878] Compound 93:
[0879] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 5.16-4.97 (m, 2H),
2.74-2.68 (m, 1H), 2.46 (s, 3H), 2.27-2.25 (m, 1H), 2.00-1.97 (m,
1H), 1.72-1.63 (m, 2H), 1.60 (s, 1H), 1.54-1.41 (m, 4H), 1.41-1.15
(m, 14H), 1.0-0.90 (m, 4H), 0.87-0.81 (m, 1H), 0.76-0.70 (m,
6H).
[0880] LCMS Rt=1.043 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.25H.sub.41N.sub.4O.sub.2
[M+H].sup.+ 429, found 429.
Example 51. Syntheses of Compounds 94 and 95
##STR00205## ##STR00206##
[0882] Step 1. To a solution of Y1 (5 g, 17.2 mmol) in DCM (100 mL)
was added diethyoxalate (2.99 g, 20.5 mmol) at 20.degree. C. After
cooling to 0.degree. C., MeONa (1.39 g, 25.7 mmol) was added. The
mixture was stirred at 20.degree. C. for 18 hours and treated with
NaHCO3 (1.8 g, solid). The mixture was stirred at 20.degree. C. for
10 min and then concentrated in vacuum to give a crude product AG1
(10 g, crude) as a solid which was used for the next step
directly.
[0883] Step 2. To a solution of AG1 (10 g, crude) in acetone (150
mL) was added MeI (32.6 g, 230 mmol) at 20.degree. C. The mixture
was warmed to 60.degree. C. and stirred at 60.degree. C. for 18
hours. The mixture was concentrated in vacuum to give a crude
product (13 g, crude) as yellow oil, which was used directly for
the next step.
[0884] Step 3. To a solution of AG2 (13 g, crude) in MeOH (100 mL)
was added MeONa (1.73 g, 32.1 mmol) at 0.degree. C. The mixture was
warmed to 15.degree. C. and stirred at 15.degree. C. for 18 hours.
The reaction was treat with water (30 mL) and EtOAc (20 mL). The
mixture was extracted with EtOAc (2.times.30 mL). The combined
organic phase was washed with brine (60 mL), dried over Na2SO4,
filtered, concentrated in vacuum to give a crude product, which was
purified with flash column (EtOAc in PE=0-35%) to give AG3 (0.9 g)
as a solid.
[0885] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.60-2.41 (m, 1H),
2.24-2.18 (m, 1H), 1.91-1.72 (m, 6H), 1.70-1.60 (m, 3H), 1.60-1.49
(m, 4H), 1.49-1.39 (m, 3H), 1.39-1.12 (m, 5H), 1.12-1.08 (m, 3H),
1.08-1.02 (m, 1H), 0.99-0.94 (m, 1H), 0.94-0.80 (m, 4H).
[0886] Step 4. To suspension of Ph.sub.3PEtBr (1.82 g, 4.92 mmol)
in THF (20 mL) under nitrogen was added t-BuOK (552 mg, 4.92 mmol).
The mixture became deep orange and stirred at 15.degree. C. for 30
min. After that, AG3 (500 mg, 1.64 mmol) was added. The resulting
mixture was stirred at 45.degree. C. for 3 hrs. After cooling, the
mixture was treated with NH.sub.4Cl (200 mL), extracted with EtOAc
(2.times.200 mL). The organic phase was washed with brine (100 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to
give crude product, which was purified by a silica gel column
(PE/EtOAc=0-10%) to give AG4 (300 mg, impure) as a solid.
[0887] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.18-5.10 (m, 1H),
2.60-2.49 (m, 1H), 2.30-2.20 (m, 1H), 2.00 (s, 1H), 1.90-1.72 (m,
4H), 1.72-1.63 (m, 4H), 1.63-1.54 (m, 2H), 1.54-1.50 (m, 1H),
1.50-1.38 (m, 5H), 1.38-1.20 (m, 6H), 1.20-1.02 (m, 4H), 1.02-0.98
(m, 3H), 0.87 (s, 3H).
[0888] Step 5. To a solution of AG4 (300 mg, 0.947 mmol) in THF (10
mL) was added dropwise BH.sub.3-Me.sub.2S (2.84 mL, 2.84 mmol) at
0.degree. C. The solution was stirred at 20.degree. C. for 2 hrs.
After cooling to 0.degree. C., a solution of NaOH solution (1.81
mL, 5 M) was added very slowly. After addition, H.sub.2O.sub.2
(1.07 mL, 10.8 mmol, 30% in water) was added slowly and the inner
temperature was maintained below 10.degree. C. The resulting
solution was stirred at 20.degree. C. for 1 h. The mixture was
extracted with EtOAc (3.times.20 mL). The combined organic layer
was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3
(2.times.10 mL), brine (50 mL), dried over Na.sub.2SO.sub.4 and
concentrated in vacuum to give crude product AG5 (210 mg, crude) as
a solid.
[0889] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.94-1.98 (m, 1H),
1.98-1.71 (m, 4H), 1.71-1.50 (m, 7H), 1.50-1.33 (m, 6H), 1.33-1.19
(m, 10H), 1.19-0.58 (m, 10H).
[0890] Step 6. To a solution of AG5 (600 mg, crude) in DCM (25 mL)
was added silica gel (1.65 g) and PCC (773 mg, 3.58 mmol) at
25.degree. C. The reaction mixture was stirred for 1 h and diluted
with PE (10 mL). The resulting mixture was filtered though a pad of
silica gel. The silica was washed with PE/DCM (50/50 mL), filtered
and concentrated in vacuum. The residue was purified by flash
column (0.about.25% of EtOAc in PE) to give AG6 (520 mg, impure) as
a solid.
[0891] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.70-2.57 (m, 1H),
2.20-2.05 (m, 4H), 1.98-1.75 (m, 4H), 1.75-1.51 (m, 4H), 1.51-1.20
(m, 9H), 1.20-1.00 (m, 5H), 1.00-0.89 (m, 6H), 0.63 (s, 3H).
[0892] Step 7. To a solution of AG6 (520 mg, 1.56 mmol) in MeOH (10
mL) was added MeONa (421 mg, 7.8 mmol). After stirring at
40.degree. C. for 18 hrs, the reaction was quenched water (5 mL).
To the mixture was added water (5 mL) and EtOAc (5 mL). The mixture
was extracted with EtOAc (2.times.10 mL). The combined organic
layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by flash column
(0.about.10% of EtOAc in PE) to give Compound 94 (340 mg, impure)
as a solid. The impure Compound 94 (340 mg, impure) was
re-crystallized from MeCN to give Compound 94 (166 mg, 49%) as a
solid.
[0893] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.70-2.57 (m, 1H),
2.18-2.05 (m, 4H), 1.98-1.90 (m, 1H), 1.90-1.75 (m, 3H), 1.75-1.58
(m, 3H), 1.52-1.32 (m, 9H), 1.32-1.18 (m, 6H), 1.16-0.98 (m, 3H),
0.98-0.90 (m, 3H), 0.63 (s, 3H).
[0894] LCMS Rt=1.057 mmin in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.22H.sub.35O
[M+H--H.sub.2O].sup.+315, found 315.
[0895] The stereochemistry at C16 of Compound 94 was confirmed by
NOE.)
[0896] Step 8. To a solution of Compound 94 (140 mg, 0.421 mmol) in
MeOH (4 ml) was added HBr (17 mg, 0.0842 mmol, 40% in water) and
Br.sub.2 (73.9 mg, 0.463 mmol) in MeOH (2 mL) at 20.degree. C. The
mixture was stirred at 20.degree. C. for 2.5 hrs. The mixture was
quenched by sat.aq NaHCO.sub.3 (10 mL), treated with water (10 mL),
some solid was formed. The suspension was filtered to give AG7 (150
mg, crude) as a solid.
[0897] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.95-3.80 (m, 1H),
3.54-3.48 (m, 1H), 2.77-2.60 (m, 1H), 1.90-1.75 (m, 4H), 1.75-1.62
(m, 1H), 1.62-1.49 (m, 4H), 1.49-1.20 (m, 13H), 1.19-0.90 (m, 7H),
0.66 (s, 3H).
[0898] Step 9. To a solution of AG7 (150 mg, 0.377 mmol) in acetone
(2 mL) was added 1H-pyrazole-4-carbonitrile (38.5 mg, 0.414 mmol)
and K.sub.2CO.sub.3 (104 mg, 0.754 mmol). After stirring at
20.degree. C. for 16 hrs, the reaction mixture was quenched with
water (5 mL). The resulting mixture was extracted with EtOAc
(2.times.10 mL). The combined organic layer was washed with brine
(5 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified by flash column
(0.about.30% of EtOAc in PE) give Compound 95 (49 mg, 31%) as a
solid.
[0899] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.90-7.95 (m, 2H),
5.02-4.80 (m, 2H), 2.80-2.63 (m, 1H), 2.24-2.18 (m, 1H), 2.05-1.93
(m, 1H), 1.89-1.71 (m, 4H), 1.69-1.51 (m, 5H), 1.51-1.23 (m, 12H),
1.20-1.02 (m, 3H), 1.02-0.91 (m, 3H), 0.69 (s, 3H).
[0900] LCMS Rt=1.042 min in 2 min chromatography, 30-90AB_2 MIN_E,
purity 100%, MS ESI calcd. for C.sub.26H.sub.36N.sub.3O
[M+H--H.sub.2O].sup.+406,
TABLE-US-00003 TABLE 2 TBPS Data Compound TBPS IC.sub.50 Compound
structure number (nM) ##STR00207## 1 E ##STR00208## 2 E
##STR00209## 3 E ##STR00210## 4 E ##STR00211## 5 E ##STR00212## 6 E
##STR00213## 7 E ##STR00214## 8 E ##STR00215## 9 D ##STR00216## 10
E ##STR00217## 11 E ##STR00218## 12 E ##STR00219## 13 E
##STR00220## 14 E ##STR00221## 15 E ##STR00222## 16 E ##STR00223##
17 E ##STR00224## 18 E ##STR00225## 19 E ##STR00226## 20 E
##STR00227## 21 E ##STR00228## 23 E ##STR00229## 24 E ##STR00230##
25 E ##STR00231## 26 E ##STR00232## 27 E ##STR00233## 28 E
##STR00234## 29 E ##STR00235## 30 E ##STR00236## 31 E ##STR00237##
34 E ##STR00238## 35 E ##STR00239## 36 E ##STR00240## 37 E
##STR00241## 38 D ##STR00242## 39 D ##STR00243## 40 E ##STR00244##
41 D ##STR00245## 42 D ##STR00246## 43 D ##STR00247## 44 B
##STR00248## 45 E ##STR00249## 46 E ##STR00250## 47 E ##STR00251##
48 E ##STR00252## 49 D ##STR00253## 50 E ##STR00254## 51 E
##STR00255## 52 E ##STR00256## 53 E ##STR00257## 54 E ##STR00258##
55 E ##STR00259## 56 C ##STR00260## 58 C ##STR00261## 59 D
##STR00262## 60 D ##STR00263## 61 D ##STR00264## 62 B ##STR00265##
63 D ##STR00266## 64 D ##STR00267## 65 E ##STR00268## 66 B
##STR00269## 67 B ##STR00270## 68 B ##STR00271## 69 B ##STR00272##
70 E ##STR00273## 71 E ##STR00274## 72 E ##STR00275## 73 E
##STR00276## 74 E ##STR00277## 75 E ##STR00278## 76 E ##STR00279##
77 E ##STR00280## 78 E ##STR00281## 79 E ##STR00282## 80 D
##STR00283## 81 C ##STR00284## 82 E ##STR00285## 83 E ##STR00286##
84 E ##STR00287## 85 E ##STR00288## 86 D ##STR00289## 87 D
##STR00290## 88 E ##STR00291## 89 B ##STR00292## 90 D ##STR00293##
91 B ##STR00294## 92 B For Table 2: TBPS: A" indicates an IC.sub.50
<10 nM, "B" indicates an IC.sub.50 10 to <50 nM, "C"
indicates an IC.sub.50 50 nM to <100 nM, "D" indicates an
IC.sub.50 100 nM to <500 nM, and "E" indicates IC.sub.50 greater
than or equal to 500 nM.
EQUIVALENTS AND SCOPE
[0901] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The invention includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0902] Furthermore, the invention encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should it be understood that, in general, where the invention,
or aspects of the invention, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
invention or aspects of the invention consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates
otherwise.
[0903] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present invention that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the invention can be excluded from any claim, for any
reason, whether or not related to the existence of prior art.
[0904] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
invention, as defined in the following claims.
* * * * *