U.S. patent application number 15/993825 was filed with the patent office on 2018-09-27 for boron-containing small molecules as antiprotozoal agents.
The applicant listed for this patent is MMV MEDICINES FOR MALARIA VENTURE. Invention is credited to ROBERT T. JACOBS, JACOB J. PLATTNER, YONG-KANG ZHANG.
Application Number | 20180273553 15/993825 |
Document ID | / |
Family ID | 55806821 |
Filed Date | 2018-09-27 |
United States Patent
Application |
20180273553 |
Kind Code |
A1 |
ZHANG; YONG-KANG ; et
al. |
September 27, 2018 |
BORON-CONTAINING SMALL MOLECULES AS ANTIPROTOZOAL AGENTS
Abstract
This invention provides, among other things, novel compounds
useful for treating protozoal infections, pharmaceutical
compositions containing such compounds, as well as combinations of
these compounds with at least one additional therapeutically
effective agent.
Inventors: |
ZHANG; YONG-KANG; (SAN JOSE,
CA) ; PLATTNER; JACOB J.; (BERKELEY, CA) ;
JACOBS; ROBERT T.; (PALO ALTO, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MMV MEDICINES FOR MALARIA VENTURE |
Geneva |
|
CH |
|
|
Family ID: |
55806821 |
Appl. No.: |
15/993825 |
Filed: |
May 31, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15562099 |
Sep 27, 2017 |
10011616 |
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PCT/US2016/026772 |
Apr 8, 2016 |
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15993825 |
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62145422 |
Apr 9, 2015 |
|
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62152605 |
Apr 24, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 241/18 20130101;
C07F 5/025 20130101; A61P 33/06 20180101; A61P 33/02 20180101 |
International
Class: |
C07F 5/02 20060101
C07F005/02 |
Claims
1. A compound having a structure according to formula (I) and/or
(II): ##STR00134## wherein Y substituted or unsubstituted
C.sub.1-C.sub.3 alkyl or substituted or unsubstituted
C.sub.3-C.sub.5 cycloalkyl or substituted or unsubstituted
C.sub.1-C.sub.3 alkyloxy, and R.sup.1 and R.sup.2 are each
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl, and wherein R.sup.1
and R.sup.2, along with the nitrogen to which they are attached,
can be optionally joined to form a substituted or unsubstituted 3
to 8 membered ring, or a salt, prodrug, or a hydrate, or a solvate
thereof.
2. The compound of claim 1 having a structure according to formula
(Ia) and/or (IIa): ##STR00135## wherein Y is substituted or
unsubstituted C.sub.1-C.sub.3 alkyl or substituted or unsubstituted
C.sub.3-C.sub.5 cycloalkyl or substituted or unsubstituted
C.sub.1-C.sub.3 alkyloxy, A is a substituted or unsubstituted 3 to
8 membered ring, or a salt, prodrug, or a hydrate, or a solvate
thereof.
3. The compound of claim 2, wherein the compound is according to
formula (Ia).
4. The compound of claim 2, wherein the compound is according to
formula (IIa).
5. The compound of claim 1, wherein Y is substituted or
unsubstituted C.sub.1-C.sub.3 alkyl.
6. The compound of claim 1, wherein Y is substituted or
unsubstituted methyl.
7. The compound of claim 2, wherein the group and ##STR00136##
wherein R.sup.8 is H or substituted or unsubstituted alkyl and
R.sup.4 or R.sup.5 or R.sup.6 are each independently selected from
H, substituted or unsubstituted C.sub.1-C.sub.6 alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, and wherein R.sup.4 and
R.sup.5, along with the atoms to which they are attached, can be
optionally joined to form a substituted or unsubstituted 3 to 8
membered ring, and wherein R.sup.5 and R.sup.6, along with the
atoms to which they are attached, can be optionally joined to form
a substituted or unsubstituted 3 to 8 membered ring, wherein
R.sup.6 and R.sup.8, along with the atoms to which they are
attached, can be optionally joined to form a substituted or
unsubstituted 3 to 8 membered ring.
8. The compound of claim 7, wherein R.sup.8 is H.
9. The compound of claim 7, wherein R.sup.6 is unsubstituted
C.sub.1-C.sub.4 alkyl or halosubstituted C.sub.1-C.sub.4 alkyl or
unsubstituted C.sub.3-C.sub.5 cycloalkyl.
10. The compound of claim 7, wherein R.sup.6 is methyl or ethyl or
propyl or isopropyl or trifluoromethyl or difluoromethyl or
trifluoroethyl or cyclopropyl.
11. The compound of claim 7, wherein R.sup.5 is H.
12. The compound of claim 7, wherein R.sup.4 is H.
13. The compound of claim 1, selected from the following group:
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(2-hy-
droxyethyl) pyrazine-2-carboxamide;
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-meth-
oxyethyl)pyrazine-2-carboxamide;
N-(1-hydroxy-2-methylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
N-(2-hydroxy-2-methylpropyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,-
2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydr-
oxypropan-2-yl)pyrazine-2-carboxamide;
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N,N-bis(2-
-hydroxyethyl)pyrazine-2-carboxamide;
N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c-
][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
N-(1-hydroxy-4-methylpentan-2-yl)-5-((1-hydroxy-7-methyl-1,3-dihydrobenzo-
[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide;
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-hydr-
oxypropyl) pyrazine-2-carboxamide;
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-hydr-
oxyethyl)-N-methylpyrazine-2-carboxamide;
((R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-
-hydroxypropan-2-yl)pyrazine-2-carb oxamide;
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypropan-2-yl)pyrazine-2-carboxamide;
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypentan-2-yl)pyrazine-2-carboxamide;
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypentan-2-yl)pyrazine-2-carboxamide;
N-(1-hydroxy-3-phenylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
N-(2-hydroxy-1-phenylethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2-
]oxaborol-6-yloxy)pyrazine-2-carboxamide;
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(1-(h-
ydroxymethyl)cyclopropyl)pyrazine-2-carboxamide;
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydr-
oxybutan-2-yl)pyrazine-2-carboxamide;
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxybutan-2-yl)pyrazine-2-carboxamide;
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydr-
oxybut-3-en-2-yl)pyrazine-2-carboxamide;
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxybutan-2-yl)pyrazine-2-carboxamide;
N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c-
][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
(S)--N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
(R)--N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
(R)--N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
(R)--N-(2-hydroxy-1-phenylethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c-
][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
(R)--N-(1-hydroxy-3-phenylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrob-
enzo[c][1,2]oxaborol-6-yloxy) pyrazine-2-carboxamide;
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxyhexan-2-yl) pyrazine-2-carboxamide;
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxybut-3-en-2-yl)pyrazine-2-carboxamide;
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxybut-3-en-2-yl)pyrazine-2-carboxamide;
(S)--N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
(S)--N-(1-hydroxy-3-methoxypropan-2-yl)-5-((1-hydroxy-7-methyl-1,3-dihydr-
obenzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide;
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,-
4,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide;
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,-
4,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide;
(S)--N-(1-hydroxy-3-(methylthio)propan-2-yl)-5-((1-hydroxy-7-methyl-1,3-d-
ihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide;
(S)--N-(1-hydroxy-3-(methylsulfonyl)propan-2-yl)-5-(1-hydroxy-7-methyl-1,-
3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,-
5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide;
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,-
5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide;
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(3-hydr-
oxybutan-2-yl)pyrazine-2-carboxamide;
(3-hydroxy-3-methylpyrrolidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydroben-
zo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;
(3-hydroxy-3-methylazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo-
[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-((1R,-
2R)-2-hydroxycyclopentyl)pyrazine-2-carboxamide;
(R)--N-(2-hydroxy-2-methylhexan-3-yl)-5-((1-hydroxy-7-methyl-1,3-dihydrob-
enzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide;
(S)--N-(2-hydroxy-2-methylhexan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
(R)--N-(2-hydroxy-2-methylpentan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrob-
enzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-((1S,2S-
)-2-hydroxycyclopentyl)pyrazine-2-carboxamide;
(S)--N-(3-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
(R)--N-(3-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(cis--
2-hydroxycyclopentyl)pyrazine-2-carboxamide;
(S)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyraz-
in-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone;
(R)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyraz-
in-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone;
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypentan-2-yl)-N-methylpyrazine-2-carboxamide;
(S)--N-(2-hydroxy-2-methylpentan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrob-
enzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;
(3-ethyl-3-hydroxyazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;
(3-cyclopropyl-3-hydroxyazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydro-
benzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;
(3-hydroxy-3-propylazetidine-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenz-
o[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;
(3-hydroxy-3-isopropylazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone; and
(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-d-
ihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone, or a
salt, prodrug, or a hydrate, or a solvate thereof.
14. The compound of claim 2, selected from the following group:
(3-hydroxy-3-methylpyrrolidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydroben-
zo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;
(3-hydroxy-3-methylazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo-
[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;
(S)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyraz-
in-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone;
(R)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyraz-
in-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone;
(3-ethyl-3-hydroxyazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;
(3-cyclopropyl-3-hydroxyazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydro-
benzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;
(3-hydroxy-3-propylazetidine-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenz-
o[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;
(3-hydroxy-3-isopropylazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone; and
(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-d-
ihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone; or a
salt, prodrug, or a hydrate, or a solvate thereof.
15. A pharmaceutical formulation comprising: a) the compound of
claim 1; and b) a pharmaceutically acceptable excipient.
16. A combination comprising the compound of claim 1, together with
at least one additional therapeutic agent.
17. The combination of claim 16, wherein said at least one
additional therapeutic agent is an antimalarial.
18. The combination of claim 16, wherein said antimalarial is
artemisinin or an artemisinin derivative selected from artesunate
or artemether or artemotil or dihydroartemisinin or lumefantrine,
artemether-lumefantrine, amodiaquine, artesunate-amodiaquine,
artesunate-mefloquine, artesunate-sulfadoxine/pyrimethamine,
atovaquone-proguanil, quinine, chloroquine, cotrifazid,
doxycycline, mefloquine, primaquine, proguanil,
sulfadoxine-pyrimethamine, hydroxychloroquine,
sulfalene-pyrimethamine, dapsone, proguanil-dapsone,
chloroproguanil-dapsone, halofantrine,
dihydroartemisinin-piperaquine, piperaquine, pyronaridine and
tetracycline.
19. A method of killing the growth of a protozoa, comprising:
contacting the protozoa with an effective amount of the compound of
claim 1, thereby killing the growth of the protozoa.
20. The method of claim 19, wherein the protozoa is a member of the
Plasmodium genus, in particular Plasmodium falciparum.
21. The method of claim 19, wherein the disease is malaria.
22. A method for preparing a compound according to claim 1, wherein
said method comprises reacting an intermediate of formula:
##STR00137## under amide formation conditions with an intermediate
of formula ##STR00138## to lead to a compound of Formula (I) or
(II): ##STR00139##
23. An intermediate for the preparation of a compound of claim 1,
said intermediate having the following formula: ##STR00140## in
particular
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 15/562,099, filed Sep. 27, 2017, which is a United States
National Stage Application filed under 35 U.S.C. .sctn. 371 of
International Patent Application No. PCT/US2016/026772, filed Apr.
8, 2016 and published as WO 2016/164814 A1, which claims priority
to U.S. Provisional Application No. 62/145,422, filed Apr. 9, 2015
and U.S. Provisional Patent Application No. 62/152,605, filed Apr.
24, 2015, the entire contents of which applications is incorporated
herein for all purposes by this reference.
BACKGROUND OF THE INVENTION
[0002] The global rise of protozoa resistant to antimicrobials in
general, poses a major threat. Deployment of massive quantities of
antimicrobial agents into the ecosphere during the past 60 years
has introduced a powerful selective pressure for the emergence and
spread of antimicrobial-resistant pathogens. Thus, there is a need
to discover new broad spectrum antimicrobials, such as
antiprotozoals, useful in combating microorganisms, especially
those with multidrug-resistance.
[0003] Boron-containing molecules, such as oxaboroles, useful as
antimicrobials have been described previously, such as in U.S. Pat.
Pubs. US20060234981 and US20070155699. Generally speaking, an
oxaborole has the following structure and substituent numbering
system:
##STR00001##
[0004] It has now been discovered that certain classes of
oxaboroles which are surprisingly effective antiprotozoals. This,
and other uses of these oxaboroles are described herein.
SUMMARY OF THE INVENTION
[0005] This invention provides, among other things, novel compounds
useful for treating protozoa infections, pharmaceutical
compositions containing such compounds, as well as combinations of
these compounds with at least one additional therapeutically
effective agent.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions and Abbreviations
[0006] As used herein, the singular forms "a," "an", and "the"
include plural references unless the context clearly dictates
otherwise. For example, reference to "an active agent" includes a
single active agent as well as two or more different active agents
in combination. It is to be understood that present teaching is not
limited to the specific dosage forms, carriers, or the like,
disclosed herein and as such may vary.
[0007] The abbreviations used herein generally have their
conventional meaning within the chemical and biological arts.
[0008] The following abbreviations have been used: Ac is acetyl;
AcOH is acetic acid; ACTBr is cetyltrimethylammonium bromide; AIBN
is azobisisobutyronitrile or 2,2 azobisisobutyronitrile; aq. is
aqueous; Ar is aryl; B.sub.2pin.sub.2 is bis(pinacolato)diboron; Bn
is, in general, benzyl [see Cbz for one example of an exception];
(BnS).sub.2 is benzyl disulfide; BnSH is benzyl thiol or benzyl
mercaptan; BnBr is benzyl bromide; Boc is tert-butoxy carbonyl;
Boc.sub.2O is di-tert-butyl dicarbonate; Bz is, in general,
benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl
or carboxybenzyl; Cs.sub.2CO.sub.3 is cesium carbonate; CSA is
camphor sulfonic acid; CTAB is cetyltrimethylammonium bromide; Cy
is cyclohexyl; DABCO is 1,4-diazabicyclo[2.2.2]octane; DCM is
dichloromethane or methylene chloride; DHP is dihydropyran; DIAD is
diisopropyl azodicarboxylate; DIEA or DIPEA is
N,N-diisopropylethylamine; DMAP is 4-(dimethylamino)pyridine; DME
is 1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is
dimethylsulfoxide; equiv or eq. is equivalent; EtOAc is ethyl
acetate; EtOH is ethanol; Et.sub.2O is diethyl ether; EDCI is
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; ELS
is evaporative light scattering; equiv or eq is equivalent; h is
hours; HATU is
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate; HOBt is N-hydroxybenzotriazole; HCl is
hydrochloric acid; HPLC is high pressure liquid chromatography;
ISCO Companion is automated flash chromatography equipment with
fraction analysis by UV absorption available from Presearch; KOAc
or AcOK is potassium acetate; K.sub.2CO.sub.3 is potassium
carbonate; LiAlH.sub.4 or LAH is lithium aluminum hydride; LDA is
lithium diisopropylamide; LHMDS is lithium bis(trimethylsilyl)
amide; KHMDS is potassium bis(trimethylsilyl) amide; LiOH is
lithium hydroxide; m-CPBA is 3-chloroperoxybenzoic acid; MeCN or
ACN is methyl cyanide or cyanomethane or ethanenitrile or
acetonitrile which are all names for the same compound; MeOH is
methanol; MgSO.sub.4 is magnesium sulfate; mins or min is minutes;
Mp or MP is melting point; NaCNBH.sub.3 is sodium cyanoborohydride;
NaOH is sodium hydroxide; Na.sub.2SO.sub.4 is sodium sulfate; NBS
is N-bromosuccinimide; NH.sub.4Cl is ammonium chloride; NIS is
N-iodosuccinimide; N.sub.2 is nitrogen; NMM is N-methylmorpholine;
n-BuLi is n-butyllithium; overnight is O/N; PdCl.sub.2(pddf) is
1,1'-Bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd/C
is the catalyst known as palladium on carbon; Pd.sub.2(dba).sub.3
is an organometallic catalyst known as tris(dibenzylideneacetone)
dipalladium(0); Ra Ni or Raney Ni is Raney nickel; Ph is phenyl;
PMB is p-methoxybenzyl; PrOH is 1-propanol; iPrOH is 2-propanol;
POCl.sub.3 is phosphorus chloride oxide; PTSA is para-toluene
sulfonic acid; Pyr. or Pyr or Py as used herein means pyridine; RT
or rt or r.t. is room temperature; sat. is saturated; Si-amine or
Si--NH.sub.2 is amino-functionalized silica, available from
SiliCycle; Si-pyr is pyridyl-functionalized silica, available from
SiliCycle; TEA or Et.sub.3N is triethylamine; TFA is
trifluoroacetic acid; Tf.sub.2O is trifluoromethanesulfonic
anhydride; THF is tetrahydrofuran; TFAA is trifluoroacetic
anhydride; THP is tetrahydropyranyl; TMSI is trimethylsilyl iodide;
H.sub.2O is water; diNO.sub.2PhSO.sub.2Cl is dinitrophenyl sulfonyl
chloride; 3-F-4-NO.sub.2-PhSO.sub.2Cl is
3-fluoro-4-nitrophenylsulfonyl chloride;
2-MeO-4-NO.sub.2-PhSO.sub.2Cl is 2-methoxy-4-nitrophenylsulfonyl
chloride; and (EtO).sub.2POCH.sub.2COOEt is a triethylester of
phosphonoacetic acid known as triethyl phosphonoacetate.
[0009] "Compound of the invention," as used herein refers to the
compounds discussed herein, salts (e.g. pharmaceutically acceptable
salts), prodrugs, solvates and hydrates of these compounds.
[0010] "Combination of the invention," as used herein refers to the
compounds and antiprotozoals discussed herein as well as acids,
bases, salt forms (such as pharmaceutically acceptable salts),
prodrugs, solvates and hydrates of these compounds and
antiprotozoals.
[0011] "Boron containing compounds", as used herein, refers to the
compounds of the invention that contain boron as part of their
chemical formula.
[0012] Where substituent groups are specified by their conventional
chemical formulae, written from left to right, they equally
encompass the chemically identical substituents, which would result
from writing the structure from right to left, e.g., --CH.sub.2O--
is intended to also recite --OCH.sub.2--.
[0013] The term "poly" as used herein means at least 2. For
example, a polyvalent metal ion is a metal ion having a valency of
at least 2.
[0014] "Moiety" refers to a radical of a molecule that is attached
to the remainder of the molecule.
[0015] The symbol , whether utilized as a bond or displayed
perpendicular to a bond, indicates the point at which the displayed
moiety is attached to the remainder of the molecule.
[0016] The term "alkyl," by itself or as part of another
substituent, means, unless otherwise stated, a straight or branched
chain, or cyclic hydrocarbon radical, or combination thereof, which
may be fully saturated, mono- or polyunsaturated and can include
di- and multivalent radicals, having the number of carbon atoms
designated (i.e. C.sub.1-C.sub.10 means one to ten carbons). In
some embodiments, the term "alkyl" means a straight or branched
chain, or combinations thereof, which may be fully saturated, mono-
or polyunsaturated and can include di- and multivalent radicals.
Examples of saturated hydrocarbon radicals include, but are not
limited to, groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for
example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An
unsaturated alkyl group is one having one or more double bonds or
triple bonds. Examples of unsaturated alkyl groups include, but are
not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,
2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-
and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
[0017] The term "alkylene" by itself or as part of another
substituent means a divalent radical derived from an alkane, as
exemplified, but not limited, by
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and further includes those
groups described below as "heteroalkylene." Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those
groups having 10 or fewer carbon atoms being preferred in the
invention. A "lower alkyl" or "lower alkylene" is a shorter chain
alkyl or alkylene group, generally having eight or fewer carbon
atoms.
[0018] The term "alkenylene" by itself or as part of another
substituent means a divalent radical derived from an alkene.
[0019] The term "cycloalkylene" by itself or as part of another
substituent means a divalent radical derived from a
cycloalkane.
[0020] The term "heteroalkylene" by itself or as part of another
substituent means a divalent radical derived from an
heteroalkane.
[0021] The term "heterocycloalkylene" by itself or as part of
another substituent means a divalent radical derived from an
heterocycloalkane.
[0022] The term "arylene" by itself or as part of another
substituent means a divalent radical derived from an aryl.
[0023] The term "heteroarylene" by itself or as part of another
substituent means a divalent radical derived from heteroaryl.
[0024] The terms "alkoxy," "alkylamino" and "alkylthio" (or
thioalkoxy) are used in their conventional sense, and refer to
those alkyl groups attached to the remainder of the molecule via an
oxygen atom, an amino group, or a sulfur atom, respectively.
[0025] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a stable straight or
branched chain, or cyclic hydrocarbon radical, or combinations
thereof, consisting of the stated number of carbon atoms and at
least one heteroatom. In some embodiments, the term "heteroalkyl,"
by itself or in combination with another term, means a stable
straight or branched chain, or combinations thereof, consisting of
the stated number of carbon atoms and at least one heteroatom. In
an exemplary embodiment, the heteroatoms can be selected from the
group consisting of B, O, N and S, and wherein the nitrogen and
sulfur atoms may optionally be oxidized and the nitrogen heteroatom
may optionally be quaternized. The heteroatom(s) B, O, N and S may
be placed at any interior position of the heteroalkyl group or at
the position at which the alkyl group is attached to the remainder
of the molecule. Examples include, but are not limited to,
--CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3. Up to two heteroatoms may be
consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3.
Similarly, the term "heteroalkylene" by itself or as part of
another substituent means a divalent radical derived from
heteroalkyl, as exemplified, but not limited by,
--CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For
heteroalkylene groups, heteroatoms can also occupy either or both
of the chain termini (e.g., alkyleneoxy, alkylenedioxy,
alkyleneamino, alkylenediamino, and the like). Still further, for
alkylene and heteroalkylene linking groups, no orientation of the
linking group is implied by the direction in which the formula of
the linking group is written. For example, the formula
--C(O).sub.2R'-- represents both --C(O).sub.2R'-- and --R'
C(O).sub.2--.
[0026] The terms "cycloalkyl" and "heterocycloalkyl", by themselves
or in combination with other terms, represent, unless otherwise
stated, cyclic versions of "alkyl" and "heteroalkyl", respectively.
Additionally, for heterocycloalkyl, a heteroatom can occupy the
position at which the heterocycle is attached to the remainder of
the molecule. Examples of cycloalkyl include, but are not limited
to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,
cycloheptyl, and the like. Examples of heterocycloalkyl include,
but are not limited to, 1-(1,2,5,6-tetrahydropyridyl),
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,
3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,
2-piperazinyl, and the like.
[0027] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.
For example, the term "halo(C.sub.1-C.sub.4)alkyl" is mean to
include, but not be limited to, trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0028] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, substituent that can be a single ring or
multiple rings (preferably from 1 or 2 or 3 rings), which are fused
together or linked covalently. The term "heteroaryl" refers to aryl
groups (or rings) that contain from one to four heteroatoms. In an
exemplary embodiment, the heteroatom is selected from B, N, O, and
S, wherein the nitrogen and sulfur atoms are optionally oxidized,
and the nitrogen atom(s) are optionally quaternized. A heteroaryl
group can be attached to the remainder of the molecule through a
heteroatom. Non-limiting examples of aryl and heteroaryl groups
include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,
pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,
5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,
purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
Substituents for each of the above noted aryl and heteroaryl ring
systems are selected from the group of acceptable substituents
described below.
[0029] For brevity, the term "aryl" when used in combination with
other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both
aryl and heteroaryl rings as defined above. Thus, the term
"arylalkyl" is meant to include those radicals in which an aryl
group is attached to an alkyl group (e.g., benzyl, phenethyl,
pyridylmethyl and the like) including those alkyl groups in which a
carbon atom (e.g., a methylene group) has been replaced by, for
example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl,
3-(1-naphthyloxy)propyl, and the like).
[0030] Each of the above terms (e.g., "alkyl," "heteroalkyl,"
"aryl" and "heteroaryl") are meant to include both substituted and
unsubstituted forms of the indicated radical. Preferred
substituents for each type of radical are provided below.
[0031] Substituents for the alkyl and heteroalkyl radicals
(including those groups often referred to as alkylene, alkenyl,
heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are
generically referred to as "alkyl group substituents," and they can
be one or more of a variety of groups selected from, but not
limited to: --R', --OR', .dbd.O, .dbd.NR', .dbd.N--OR', --NR'R'',
--SR', -halogen, --SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R',
--CONR'R'', --OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O).sub.2R', --NR'''''--C(NR'R''R''').dbd.NR'''',
--NR''''--C(NR'R'').dbd.NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NR''SO.sub.2R', --CN, --NO.sub.2, --N.sub.3,
--CH(Ph).sub.2, fluoro(C.sub.1-C.sub.4)alkoxy, and
fluoro(C.sub.1-C.sub.4)alkyl, in a number ranging from zero to
(2m'+1), where m' is the total number of carbon atoms in such
radical. R', R'', R''', R'''' and R''''' each preferably
independently refer to hydrogen, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, e.g., aryl
substituted with 1-3 halogens, substituted or unsubstituted alkyl,
alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound
of the invention includes more than one R group, for example, each
of the R groups is independently selected as are each R', R'',
R''', R'''' and R''''' groups when more than one of these groups is
present. When R' and R'' are attached to the same nitrogen atom,
they can be combined with the nitrogen atom to form a 5-, 6-, or
7-membered ring. For example, --NR'R'' is meant to include, but not
be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above
discussion of substituents, one of skill in the art will understand
that the term "alkyl" is meant to include groups including carbon
atoms bound to groups other than hydrogen groups, such as haloalkyl
(e.g., --CF.sub.3 and --CH.sub.2CF.sub.3) and acyl (e.g.,
--C(O)CH.sub.3, --C(O)CF.sub.3, --C(O)CH.sub.2OCH.sub.3, and the
like).
[0032] Similar to the substituents described for the alkyl radical,
substituents for the aryl and heteroaryl groups are generically
referred to as "aryl group substituents." The substituents are
selected from, for example: --R', --OR', .dbd.O, .dbd.NR',
.dbd.N--OR', --NR'R'', --SR', -halogen, --SiR'R''R''', --OC(O)R',
--C(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R',
--NR'--C(O)NR''R''', --NR''C(O).sub.2R',
--NR'''''--C(NR'R''R''').dbd.NR'''', --NR''''--C(NR'R'').dbd.NR''',
--S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'', --NR''SO.sub.2R',
--CN, --NO.sub.2, --N.sub.3, --CH(Ph).sub.2,
fluoro(C.sub.1-C.sub.4)alkoxy, and fluoro(C.sub.1-C.sub.4)alkyl, in
a number ranging from zero to the total number of open valences on
the aromatic ring system; and where R', R'', R''', R'''' and R'''''
are preferably independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heteroaryl. When a compound of the invention includes more than one
R group, for example, each of the R groups is independently
selected as are each R', R'', R''', R'''' and R''''' groups when
more than one of these groups is present.
[0033] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula -T-C(O)--(CRR').sub.q--U--, wherein T and U are
independently --NR--, --O--, --CRR'-- or a single bond, and q is an
integer of from 0 to 3. Alternatively, two of the substituents on
adjacent atoms of the aryl or heteroaryl ring may optionally be
replaced with a substituent of the formula
-A-(CH.sub.2).sub.r--B--, wherein A and B are independently
--CRR'--, --O--, --NR--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2NR'-- or a single bond, and r is an integer of from 1
to 4. One of the single bonds of the new ring so formed may
optionally be replaced with a double bond. Alternatively, two of
the substituents on adjacent atoms of the aryl or heteroaryl ring
may optionally be replaced with a substituent of the formula
--(CRR').sub.s--X--(CR''R''').sub.d--, where s and d are
independently integers of from 0 to 3, and X is --O--, --NR'--,
--S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The
substituents R, R', R'' and R''' are preferably independently
selected from hydrogen or substituted or unsubstituted C.sub.1 or
C.sub.2 or C.sub.3 or C.sub.4 or C.sub.5 or C.sub.6 alkyl.
[0034] "Ring" as used herein, means a substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl. A ring includes fused ring moieties. The number of
atoms in a ring is typically defined by the number of members in
the ring. For example, a "5- to 7-membered ring" means there are 5
or 6 or 7 atoms in the encircling arrangement. Unless otherwise
specified, the ring optionally includes a heteroatom. Thus, the
term "5 to 7-membered ring" or "5 or 6 or 7 membered ring"
includes, for example phenyl, pyridinyl and piperidinyl. The term
"5 to 7-membered heterocycloalkyl ring" "5 or 6 or 7-membered
heterocycloalkyl ring", on the other hand, would include pyridinyl
and piperidinyl, but not phenyl. The term "ring" further includes a
ring system comprising more than one "ring", wherein each "ring" is
independently defined as above.
[0035] As used herein, the term "heteroatom" includes atoms other
than carbon (C) and hydrogen (H). Examples include oxygen (O),
nitrogen (N) sulfur (S), silicon (Si), germanium (Ge), aluminum
(Al) and boron (B).
[0036] The term "leaving group" means a functional group or atom
which can be displaced by another functional group or atom in a
substitution reaction, such as a nucleophilic substitution
reaction. By way of example, representative leaving groups include
triflate, chloro, bromo and iodo groups; sulfonic ester groups,
such as mesylate, tosylate, brosylate, nosylate and the like; and
acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
[0037] The symbol "R" is a general abbreviation that represents a
substituent group that is selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl and substituted
or unsubstituted heterocycloalkyl groups.
[0038] By "effective" amount of a drug, formulation, or permeant is
meant a sufficient amount of an active agent to provide the desired
local or systemic effect. A "Topically effective,"
"pharmaceutically effective," or "therapeutically effective" amount
refers to the amount of drug needed to effect the desired
therapeutic result.
[0039] "Topically effective" refers to a material that, when
applied to the skin, nail, hair, claw or hoof produces a desired
pharmacological result either locally at the place of application
or systemically as a result of transdermal passage of an active
ingredient in the material.
[0040] The term "pharmaceutically acceptable salt" is meant to
include a salt of a compound of the invention which is prepared
with relatively nontoxic acids or bases, depending on the
particular substituents found on the compounds described herein.
When compounds of the invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable base addition salts include sodium,
potassium, calcium, ammonium, organic amino (such as choline or
diethylamine or amino acids such as d-arginine, l-arginine,
d-lysine, or l-lysine), or magnesium salt, or a similar salt. When
compounds of the invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include those
derived from inorganic acids like hydrochloric, hydrobromic,
nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, lactic, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like glucuronic or galactunoric acids and the like (see, for
example, Berge et al., "Pharmaceutical Salts", Journal of
Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds
of the invention contain both basic and acidic functionalities that
allow the compounds to be converted into either base or acid
addition salts.
[0041] The neutral forms of the compounds are preferably
regenerated by contacting the salt with a base or acid and
isolating the parent compounds in the conventional manner. The
parent form of the compound differs from the various salt forms in
certain physical properties, such as solubility in polar
solvents.
[0042] In addition to salt forms, the invention provides compounds
which are in a prodrug form. Prodrugs of the compounds described
herein readily undergo chemical changes under physiological
conditions to provide the compounds of the invention. Additionally,
prodrugs can be converted to the compounds of the invention by
chemical or biochemical methods in an ex vivo environment.
[0043] Certain compounds of the invention can exist in unsolvated
forms as well as solvated forms, including hydrated forms. In
general, the solvated forms are equivalent to unsolvated forms and
are encompassed within the scope of the invention. Certain
compounds of the invention may exist in multiple crystalline or
amorphous forms.
[0044] Certain compounds of the invention possess asymmetric carbon
atoms (optical centers) or double bonds; the racemates,
diastereomers, geometric isomers and individual isomers are
encompassed within the scope of the invention. The graphic
representations of racemic, ambiscalemic and scalemic or
enantiomerically pure compounds used herein are taken from Maehr,
J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to
denote the absolute configuration of a stereocenter unless
otherwise noted. When the compounds described herein contain
olefinic double bonds or other centers of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers. Likewise, all tautomeric
forms are included.
[0045] Compounds of the invention can exist in particular geometric
or stereoisomeric forms. The invention contemplates all such
compounds, including cis- and trans-isomers, (-)- and
(+)-enantiomers, (R)- and (S)-enantiomers, diastereomers,
(D)-isomers, (L)-isomers, the racemic mixtures thereof, and other
mixtures thereof, such as enantiomerically or diastereomerically
enriched mixtures, as falling within the scope of the invention.
Additional asymmetric carbon atoms can be present in a substituent
such as an alkyl group. All such isomers, as well as mixtures
thereof, are intended to be included in this invention.
[0046] Optically active (R)- and (S)-isomers and d and l isomers
can be prepared using chiral synthons or chiral reagents, or
resolved using conventional techniques. If, for instance, a
particular enantiomer of a compound of the invention is desired, it
can be prepared by asymmetric synthesis, or by derivatization with
a chiral auxiliary, where the resulting diastereomeric mixture is
separated and the auxiliary group cleaved to provide the pure
desired enantiomers. Alternatively, where the molecule contains a
basic functional group, such as an amino group, or an acidic
functional group, such as a carboxyl group, diastereomeric salts
can be formed with an appropriate optically active acid or base,
followed by resolution of the diastereomers thus formed by
fractional crystallization or chromatographic means known in the
art, and subsequent recovery of the pure enantiomers. In addition,
separation of enantiomers and diastereomers is frequently
accomplished using chromatography employing chiral, stationary
phases, optionally in combination with chemical derivatization
(e.g., formation of carbamates from amines).
[0047] The compounds of the invention may also contain unnatural
proportions of atomic isotopes at one or more of the atoms that
constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the invention, whether
radioactive or not, are intended to be encompassed within the scope
of the invention.
[0048] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable vehicle" refers to any formulation or
carrier medium that provides the appropriate delivery of an
effective amount of an active agent as defined herein, does not
interfere with the effectiveness of the biological activity of the
active agent, and that is sufficiently non-toxic to the host or
patient. Representative carriers include water, oils, both
vegetable and mineral, cream bases, lotion bases, ointment bases
and the like. These bases include suspending agents, thickeners,
penetration enhancers, and the like. Their formulation is well
known to those in the art of cosmetics and topical pharmaceuticals.
Additional information concerning carriers can be found in
Remington: The Science and Practice of Pharmacy, 21st Ed.,
Lippincott, Williams & Wilkins (2005) which is incorporated
herein by reference.
[0049] "Pharmaceutically acceptable topical carrier" and equivalent
terms refer to pharmaceutically acceptable carriers, as described
herein above, suitable for topical application. An inactive liquid
or cream vehicle capable of suspending or dissolving the active
agent(s), and having the properties of being nontoxic and
non-inflammatory when applied to the skin, nail, hair, claw or hoof
is an example of a pharmaceutically-acceptable topical carrier.
This term is specifically intended to encompass carrier materials
approved for use in topical cosmetics as well.
[0050] The term "pharmaceutically acceptable additive" refers to
preservatives, antioxidants, fragrances, emulsifiers, dyes and
excipients known or used in the field of drug formulation and that
do not unduly interfere with the effectiveness of the biological
activity of the active agent, and that is sufficiently non-toxic to
the host or patient. Additives for topical formulations are
well-known in the art, and may be added to the topical composition,
as long as they are pharmaceutically acceptable and not deleterious
to the epithelial cells or their function. Further, they should not
cause deterioration in the stability of the composition. For
example, inert fillers, anti-irritants, tackifiers, excipients,
fragrances, opacifiers, antioxidants, gelling agents, stabilizers,
surfactant, emollients, coloring agents, preservatives, buffering
agents, other permeation enhancers, and other conventional
components of topical or transdermal delivery formulations as are
known in the art.
[0051] The terms "enhancement," "penetration enhancement" or
"permeation enhancement" relate to an increase in the permeability
of the skin, nail, hair, claw or hoof to a drug, so as to increase
the rate at which the drug permeates through the skin, nail, hair,
claw or hoof. The enhanced permeation effected through the use of
such enhancers can be observed, for example, by measuring the rate
of diffusion of the drug through animal skin, nail, hair, claw or
hoof using a diffusion cell apparatus. A diffusion cell is
described by Merritt et al. Diffusion Apparatus for Skin
Penetration, J of Controlled Release, 1 (1984) pp. 161-162. The
term "permeation enhancer" or "penetration enhancer" intends an
agent or a mixture of agents, which, alone or in combination, act
to increase the permeability of the skin, nail, hair or hoof to a
drug.
[0052] The term "excipients" is conventionally known to mean
carriers, diluents and/or vehicles used in formulating drug
compositions effective for the desired use.
[0053] The term "topical administration" refers to the application
of a pharmaceutical agent to the external surface of the skin,
nail, hair, claw or hoof, such that the agent crosses the external
surface of the skin, nail, hair, claw or hoof and enters the
underlying tissues. Topical administration includes application of
the composition to intact skin, nail, hair, claw or hoof, or to a
broken, raw or open wound of skin, nail, hair, claw or hoof.
Topical administration of a pharmaceutical agent can result in a
limited distribution of the agent to the skin and surrounding
tissues or, when the agent is removed from the treatment area by
the bloodstream, can result in systemic distribution of the
agent.
[0054] The term "transdermal delivery" refers to the diffusion of
an agent across the barrier of the skin, nail, hair, claw or hoof
resulting from topical administration or other application of a
composition. The stratum corneum acts as a barrier and few
pharmaceutical agents are able to penetrate intact skin. In
contrast, the epidermis and dermis are permeable to many solutes
and absorption of drugs therefore occurs more readily through skin,
nail, hair, claw or hoof that is abraded or otherwise stripped of
the stratum corneum to expose the epidermis. Transdermal delivery
includes injection or other delivery through any portion of the
skin, nail, hair, claw or hoof or mucous membrane and absorption or
permeation through the remaining portion. Absorption through intact
skin, nail, hair, claw or hoof can be enhanced by placing the
active agent in an appropriate pharmaceutically acceptable vehicle
before application to the skin, nail, hair, claw or hoof. Passive
topical administration may consist of applying the active agent
directly to the treatment site in combination with emollients or
penetration enhancers. As used herein, transdermal delivery is
intended to include delivery by permeation through or past the
integument, i.e. skin, nail, hair, claw or hoof.
[0055] The terms "effective amount" or a "therapeutically effective
amount" of a drug or pharmacologically active agent refers to a
nontoxic but sufficient amount of the drug or agent to provide the
desired effect. In the oral dosage forms of the present disclosure,
an "effective amount" of one active of the combination is the
amount of that active that is effective to provide the desired
effect when used in combination with the other active of the
combination. The amount that is "effective" will vary from subject
to subject, depending on the age and general condition of the
individual, the particular active agent or agents, and the
appropriate "effective" amount in any individual case may be
determined by one of ordinary skill in the art using routine
experimentation.
[0056] The phrases "active ingredient", "therapeutic agent",
"active", or "active agent" mean a chemical entity which can be
effective in treating a targeted disorder, disease or
condition.
[0057] The phrase "pharmaceutically acceptable" means moieties or
compounds that are, within the scope of medical judgment, suitable
for use in humans without causing undesirable biological effects
such as undue toxicity, irritation, allergic response, and the
like, for example.
[0058] The phrase "oral dosage form" means any pharmaceutical
composition administered to a subject via the oral cavity.
Exemplary oral dosage forms include tablets, capsules, films,
powders, sachets, granules, solutions, solids, suspensions or as
more than one distinct unit (e.g., granules, tablets, and/or
capsules containing different actives) packaged together for
co-administration, and other formulations known in the art. An oral
dosage form can be one, two, three, four, five or six units. When
the oral dosage form has multiple units, all of the units are
contained within a single package, (e.g. a bottle or other form of
packaging such as a blister pack). When the oral dosage form is a
single unit, it may or may not be in a single package. In a
preferred embodiment, the oral dosage form is one, two or three
units. In a particularly preferred embodiment, the oral dosage form
is one unit.
[0059] The phrase "unit", as used herein, refers to the number of
discrete objects to be administered which comprise the dosage form.
In some embodiments, the dosage form includes a compound of the
invention in one capsule. This is a single unit. In some
embodiments, the dosage form includes a compound of the invention
as part of a therapeutically effective dosage of a cream or
ointment. This is also a single unit. In some embodiments, the
dosage form includes a compound of the invention and another active
ingredient contained within one capsule, or as part of a
therapeutically effective dosage of a cream or ointment. This is a
single unit, whether or not the interior of the capsule includes
multiple discrete granules of the active ingredient. In some
embodiments, the dosage form includes a compound of the invention
in one capsule, and the active ingredient in a second capsule. This
is a two unit dosage form, such as two capsules or tablets, and so
such units are contained in a single package. Thus the term `unit`
refers to the object which is administered to the animal, not to
the interior components of the object.
[0060] The term, "prodrug", as defined herein, is a derivative of a
parent drug molecule that exerts its pharmacological effect only
after chemical and/or enzymatic conversion to its active form in
vivo. Prodrugs include those designed to circumvent problems
associated with delivery of the parent drug. This may be due to
poor physicochemical properties, such as poor chemical stability or
low aqueous solubility, and may also be due to poor pharmacokinetic
properties, such as poor bioavailability or poor half-life. Thus,
certain advantages of prodrugs may include improved chemical
stability, absorption, and/or PK properties of the parent
carboxylic acids. Prodrugs may also be used to make drugs more
"patient friendly," by minimizing the frequency (e.g., once daily)
or route of dosing (e.g., oral), or to improve the taste or odor if
given orally, or to minimize pain if given parenterally.
[0061] In some embodiments, the prodrugs are chemically more stable
than the active drug, thereby improving formulation and delivery of
the parent drug, compared to the drug alone.
[0062] Prodrugs for carboxylic acid analogs of the invention may
include a variety of esters. In an exemplary embodiment, the
pharmaceutical compositions of the invention include a carboxylic
acid ester. In an exemplary embodiment, the prodrug is suitable for
treatment/prevention of those diseases and conditions that require
the drug molecule to cross the blood brain barrier. In an exemplary
embodiment, the prodrug enters the brain, where it is converted
into the active form of the drug molecule. In one embodiment, a
prodrug is used to enable an active drug molecule to reach the
inside of the eye after topical application of the prodrug to the
eye. Additionally, a prodrug can be converted to its parent
compound by chemical or biochemical methods in an ex vivo
environment. For example, a prodrug can be slowly converted to its
parent compound when placed in a transdermal patch reservoir with a
suitable enzyme or chemical reagent.
[0063] "Antibiotic", as used herein, is a compound which can kill
or inhibit the growth of bacteria. The term antibiotic is broad
enough to encompass acids, bases, salt forms (such as
pharmaceutically acceptable salts), prodrugs, solvates and hydrates
of the antibiotic compound.
[0064] "Antiprotozoal" or "antiprotozoa", as used herein, is a
compound which can kill or inhibit the growth of protozoa. The term
anti-protozoal or anti-protozoa is broad enough to encompass acids,
bases, salt forms (such as pharmaceutically acceptable salts),
prodrugs, solvates and hydrates of the antiprotozoal or
antiprotozoa compound.
[0065] The term "microbial infection" or "infection by a
microorganism" refers to any infection of a host by an infectious
agent including, but not limited to, viruses, bacteria,
mycobacteria, fungus and parasites (see, e.g., Harrison's
Principles of Internal Medicine, pp. 93-98 (Wilson et al., eds.,
12th ed. 1991); Williams et al., J. of Medicinal Chem. 42:1481-1485
(1999), herein each incorporated by reference in their
entirety).
[0066] "Biological medium," as used herein refers to both in vitro
and in vivo biological milieus. Exemplary in vitro "biological
media" include, but are not limited to, cell culture, tissue
culture, homogenates, plasma and blood. In vivo applications are
generally performed in mammals, preferably humans.
[0067] "Inhibiting" and "blocking," are used interchangeably herein
to refer to the partial or full blockade of an enzyme, such as a
beta-lactamase or a leucyl t-RNA synthetase.
[0068] Boron is able to form additional covalent or dative bonds
with oxygen, sulfur or nitrogen under some circumstances in this
invention.
[0069] Embodiments of the invention also encompass compounds that
are poly- or multivalent species, including, for example, species
such as dimers, trimers, tetramers and higher homologs of the
compounds of use in the invention or reactive analogues
thereof.
[0070] "Salt counterion", as used herein, refers to positively
charged ions that associate with a compound of the invention when
the boron is fully negatively or partially negatively charged.
Examples of salt counterions include H.sup.+, H.sub.3O.sup.+,
ammonium, potassium, calcium, magnesium, organic amino (such as
choline or diethylamine or amino acids such as d-arginine,
l-arginine, d-lysine, l-lysine), and sodium.
[0071] The compounds comprising a boron bonded to a carbon and
three heteroatoms (such as three oxygens described in this section)
can optionally contain a fully negatively charged boron or
partially negatively charged boron. Due to the negative charge, a
positively charged counterion may associate with this compound,
thus forming a salt. Examples of positively charged counterions
include H.sup.+, H.sub.3O.sup.+, ammonium, potassium, calcium,
magnesium, organic amino (such as choline or diethylamine or amino
acids such as d-arginine, l-arginine, d-lysine, l-lysine), and
sodium. These salts of the compounds are implicitly contained in
descriptions of these compounds.
II. Introduction
[0072] The invention provides novel boron compounds. The novel
compounds, as well as pharmaceutical compositions containing such
compounds or combinations of these compounds with at least one
additional therapeutically effective agent, can be used for, among
other things, treating protozoal infections.
III. The Compounds
[0073] III.a) Cyclic Boronic Esters
[0074] In one aspect, the invention provides a compound of the
invention. In an exemplary embodiment, the invention is a compound
described herein. In an exemplary embodiment, the invention is a
compound according to a formula described herein.
[0075] In another aspect, the invention provides a compound having
a structure according to formula (I) and/or (II):
##STR00002##
[0076] wherein Y is H or substituted or unsubstituted
C.sub.1-C.sub.3 alkyl or substituted or unsubstituted
C.sub.3-C.sub.8 cycloalkyl or substituted or unsubstituted
C.sub.1-C.sub.3 alkyloxy, and R.sup.1 and R.sup.2 are each
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl, and wherein R.sup.1
and R.sup.2, along with the nitrogen to which they are attached,
can be optionally joined to form a substituted or unsubstituted 3
to 8 membered ring, or a salt, or a hydrate, or a solvate
thereof.
[0077] In an exemplary embodiment, the compound is according to
formula (I), or a salt, or a hydrate, or a solvate thereof, wherein
Y, R.sup.1, and R.sup.2 are each as described herein. In an
exemplary embodiment, the compound is according to formula (II), or
a salt, or a hydrate, or a solvate thereof, wherein Y, R.sup.1, and
R.sup.2 are each as described herein.
[0078] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein R.sup.1 and R.sup.2 are each as
described herein, and Y is H. In an exemplary embodiment, the
compound is according to formula (I) and/or (II), wherein R.sup.1
and R.sup.2 are each as described herein, and Y is methyl. In an
exemplary embodiment, the compound is according to formula (I)
and/or (II), wherein R.sup.1 and R.sup.2 are each as described
herein, and Y is ethyl. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein R.sup.1 and R.sup.2
are each as described herein, and Y is propyl. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein R.sup.1 and R.sup.2 are each as described herein, and Y is
isopropyl. In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein R.sup.1 and R.sup.2 are each as
described herein, and Y is cyclopropyl. In an exemplary embodiment,
the compound is according to formula (I) and/or (II), wherein
R.sup.1 and R.sup.2 are each as described herein, and Y is
cyclobutyl. In an exemplary embodiment, the compound is according
to formula (I) and/or (II), wherein R.sup.1 and R.sup.2 are each as
described herein, and Y is cyclopentyl. In an exemplary embodiment,
the compound is according to formula (I) and/or (II), wherein
R.sup.1 and R.sup.2 are each as described herein, and Y is
cyclohexyl. In an exemplary embodiment, the compound is according
to formula (I) and/or (II), wherein R.sup.1 and R.sup.2 are each as
described herein, and Y is methoxy. In an exemplary embodiment, the
compound is according to formula (I) and/or (II), wherein R.sup.1
and R.sup.2 are each as described herein, and Y is ethoxy. In an
exemplary embodiment, the compound is according to formula (I)
and/or (II), wherein R.sup.1 and R.sup.2 are each as described
herein, and Y is propoxy. In an exemplary embodiment, the compound
is according to formula (I) and/or (II), wherein R.sup.1 and
R.sup.2 are each as described herein, and Y is isopropoxy.
[0079] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y and R.sup.1 are as described
herein, and R.sup.2 is H or unsubstituted C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 alkyl substituted with hydroxy. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y and R.sup.1 are as described herein, and R.sup.2 is H. In
an exemplary embodiment, the compound is according to formula (I)
and/or (II), wherein Y and R.sup.1 are as described herein, and
R.sup.2 is methyl. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y and R.sup.1 are as
described herein, and R.sup.2 is ethyl. In an exemplary embodiment,
the compound is according to formula (I) and/or (II), wherein Y and
R.sup.1 are as described herein, and R.sup.2 is unsubstituted
C.sub.3 alkyl. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y and R.sup.1 are as
described herein, and R.sup.2 is hydroxymethyl. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y and R.sup.1 are as described herein, and R.sup.2 is
hydroxyethyl. In an exemplary embodiment, the compound is according
to formula (I) and/or (II), wherein Y and R.sup.1 are as described
herein, and R.sup.2 is hydroxypropyl or hydroxyisopropyl.
[0080] In an exemplary embodiment, the compound is according to
formula (I) wherein R.sup.1 is as described herein, R.sup.2 is H,
and Y is CH.sub.3. In an exemplary embodiment, the compound is
according to formula (I) wherein R.sup.1 is as described herein,
R.sup.2 is CH.sub.3, and Y is CH.sub.3. In an exemplary embodiment,
the compound is according to formula (II) wherein R.sup.1 is as
described herein, R.sup.2 is H, and Y is CH.sub.3. In an exemplary
embodiment, the compound is according to formula (II) wherein
R.sup.1 is as described herein, R.sup.2 is CH.sub.3, and Y is
CH.sub.3.
[0081] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y and R.sup.2 are as described
herein, and R.sup.1 is according to formula (III)
##STR00003##
[0082] (III), wherein R.sup.8 is H or substituted or unsubstituted
alkyl, and R.sup.4 or R.sup.5 or R.sup.6 or R.sup.7 are each
independently selected from H, substituted or unsubstituted
C.sub.1-C.sub.6 alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl, and wherein R.sup.4 and R.sup.5, along with the atoms
to which they are attached, can be optionally joined to form a
substituted or unsubstituted 3 to 8 membered ring, and wherein
R.sup.6 and R.sup.7, along with the atoms to which they are
attached, can be optionally joined to form a substituted or
unsubstituted 3 to 8 membered ring, and wherein R.sup.5 and
R.sup.6, along with the atoms to which they are attached, can be
optionally joined to form a substituted or unsubstituted 3 to 8
membered ring, wherein R.sup.6 and R.sup.8, along with the atoms to
which they are attached, can be optionally joined to form a
substituted or unsubstituted 3 to 8 membered ring.
[0083] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y and R.sup.2 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.8
is H, and R.sup.4 or R.sup.5 or R.sup.6 or R.sup.7 are as described
herein. In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y and R.sup.2 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.8
is --CH.sub.3, and R.sup.4 or R.sup.5 or R.sup.6 or R.sup.7 are as
described herein. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y and R.sup.2 are as
described herein, and R.sup.1 is according to formula (III),
wherein R.sup.8 is --CH.sub.2CH.sub.3, and R.sup.4 or R.sup.5 or
R.sup.6 or R.sup.7 are as described herein. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y and R.sup.2 are as described herein, and R.sup.1 is
according to formula (III), wherein R.sup.8 is C.sub.3 alkyl, and
R.sup.4 or R.sup.5 or R.sup.6 or R.sup.7 are as described
herein.
[0084] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y and R.sup.2 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.8
is H or substituted or unsubstituted alkyl, and R.sup.4 or R.sup.5
or R.sup.6 or R.sup.7 are each independently selected from H or
methyl or ethyl or ethenyl or unsubstituted C.sub.3-C.sub.6 alkyl,
or C.sub.1-C.sub.6 alkyl substituted with one or more halogen, or
C.sub.1-C.sub.6 alkyl substituted with phenyl, or unsubstituted
C.sub.3-C.sub.6 cycloalkyl, or unsubstituted phenyl, or
C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3 alkoxy, or
C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3 alkylthio,
or C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3
alkylsulfonyl. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y and R.sup.2 are as
described herein, and R.sup.1 is according to formula (III),
wherein R.sup.8 is H, and R.sup.4 or R.sup.5 or R.sup.6 or R.sup.7
are each independently selected from H or methyl or ethyl or
trifluoromethyl or propyl or isopropyl or butyl or isobutyl or
secbutyl or t-butyl or phenyl or benzyl or 2-phenylethyl or
1-phenylethyl or ethenyl or cyclopropyl or cyclobutyl or
cyclopentyl or cyclohexyl or methoxymethyl or methylthiomethyl or
methylsulfonylmethyl or 2,2,2 trifluoroethyl. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y and R.sup.2 are as described herein, and R.sup.1 is
according to formula (III), wherein R.sup.8 is H, and R.sup.4 or
R.sup.5 or R.sup.6 or R.sup.7 are each independently selected from
H or methyl or ethyl or propyl or isopropyl or butyl or isobutyl or
secbutyl or t-butyl or phenyl or benzyl or 2-phenylethyl or
1-phenylethyl or ethenyl or cyclopropyl or cyclobutyl or
cyclopentyl or cyclohexyl or methoxymethyl or methylthiomethyl or
methylsulfonylmethyl or 2,2,2 trifluoroethyl.
[0085] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y and R.sup.2 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.8
is H or substituted or unsubstituted alkyl, R.sup.7 is H; and
R.sup.4 or R.sup.5 or R.sup.6 are each independently selected from
H or methyl or ethyl or ethenyl or unsubstituted C.sub.3-C.sub.6
alkyl, or C.sub.1-C.sub.6 alkyl substituted with one or more
halogen, or C.sub.1-C.sub.6 alkyl substituted with phenyl, or
unsubstituted C.sub.3-C.sub.6 cycloalkyl, or unsubstituted phenyl,
or C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3 alkoxy,
or C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3
alkylthio, or C.sub.1-C.sub.3 alkyl substituted with
C.sub.1-C.sub.3 alkylsulfonyl. In an exemplary embodiment, the
compound is according to formula (I) and/or (II), wherein Y and
R.sup.2 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.8 is H, R.sup.7 is H; and R.sup.4 or
R.sup.5 or R.sup.6 are each independently selected from H or methyl
or ethyl or trifluoromethyl or propyl or isopropyl or butyl or
isobutyl or secbutyl or t-butyl or phenyl or benzyl or
2-phenylethyl or 1-phenylethyl or ethenyl or cyclopropyl or
cyclobutyl or cyclopentyl or cyclohexyl or methoxymethyl or
methylthiomethyl or methylsulfonylmethyl or 2,2,2 trifluoroethyl.
In an exemplary embodiment, the compound is according to formula
(I) and/or (II), wherein Y and R.sup.2 are as described herein, and
R.sup.1 is according to formula (III), wherein R.sup.8 is H,
R.sup.7 is H; and R.sup.4 or R.sup.5 or R.sup.6 are each
independently selected from H or methyl or ethyl or propyl or
isopropyl or butyl or isobutyl or secbutyl or t-butyl or phenyl or
benzyl or 2-phenylethyl or 1-phenylethyl or ethenyl or cyclopropyl
or cyclobutyl or cyclopentyl or cyclohexyl or methoxymethyl or
methylthiomethyl or methylsulfonylmethyl or 2,2,2
trifluoroethyl.
[0086] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y and R.sup.2 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.8
is H or substituted or unsubstituted alkyl, R.sup.5 is H; and
R.sup.4 or R.sup.6 or R.sup.7 are each independently selected from
H or methyl or ethyl or ethenyl or unsubstituted C.sub.3-C.sub.6
alkyl, or C.sub.1-C.sub.6 alkyl substituted with one or more
halogen, or C.sub.1-C.sub.6 alkyl substituted with phenyl, or
unsubstituted C.sub.3-C.sub.6 cycloalkyl, or unsubstituted phenyl,
or C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3 alkoxy,
or C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3
alkylthio, or C.sub.1-C.sub.3 alkyl substituted with
C.sub.1-C.sub.3 alkylsulfonyl. In an exemplary embodiment, the
compound is according to formula (I) and/or (II), wherein Y and
R.sup.2 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.8 is H, R.sup.5 is H; and R.sup.4 or
R.sup.6 or R.sup.7 are each independently selected from H or methyl
or ethyl or trifluoromethyl or propyl or isopropyl or butyl or
isobutyl or secbutyl or t-butyl or phenyl or benzyl or
2-phenylethyl or 1-phenylethyl or ethenyl or cyclopropyl or
cyclobutyl or cyclopentyl or cyclohexyl or methoxymethyl or
methylthiomethyl or methylsulfonylmethyl or 2,2,2 trifluoroethyl.
In an exemplary embodiment, the compound is according to formula
(I) and/or (II), wherein Y and R.sup.2 are as described herein, and
R.sup.1 is according to formula (III), wherein R.sup.8 is H,
R.sup.5 is H; and R.sup.4 or R.sup.6 or R.sup.7 are each
independently selected from H or methyl or ethyl or propyl or
isopropyl or butyl or isobutyl or secbutyl or t-butyl or phenyl or
benzyl or 2-phenylethyl or 1-phenylethyl or ethenyl or cyclopropyl
or cyclobutyl or cyclopentyl or cyclohexyl or methoxymethyl or
methylthiomethyl or methylsulfonylmethyl or 2,2,2
trifluoroethyl.
[0087] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y and R.sup.2 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.8
is H or substituted or unsubstituted alkyl, R.sup.6 is H; R.sup.7
is H; and R.sup.4 or R.sup.5 are each independently selected from H
or methyl or ethyl or ethenyl or unsubstituted C.sub.3-C.sub.6
alkyl, or C.sub.1-C.sub.6 alkyl substituted with one or more
halogen, or C.sub.1-C.sub.6 alkyl substituted with phenyl, or
unsubstituted C.sub.3-C.sub.6 cycloalkyl, or unsubstituted phenyl,
or C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3 alkoxy,
or C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3
alkylthio, or C.sub.1-C.sub.3 alkyl substituted with
C.sub.1-C.sub.3 alkylsulfonyl. In an exemplary embodiment, the
compound is according to formula (I) and/or (II), wherein Y and
R.sup.2 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.8 is H, R.sup.6 is H; R.sup.7 is H;
and R.sup.4 or R.sup.5 are each independently selected from H or
methyl or ethyl or trifluoromethyl or propyl or isopropyl or butyl
or isobutyl or secbutyl or t-butyl or phenyl or benzyl or
2-phenylethyl or 1-phenylethyl or ethenyl or cyclopropyl or
cyclobutyl or cyclopentyl or cyclohexyl or methoxymethyl or
methylthiomethyl or methylsulfonylmethyl or 2,2,2 trifluoroethyl.
In an exemplary embodiment, the compound is according to formula
(I) and/or (II), wherein Y and R.sup.2 are as described herein, and
R.sup.1 is according to formula (III), wherein R.sup.8 is H,
R.sup.6 is H; R.sup.7 is H; and R.sup.4 or R.sup.5 are each
independently selected from H or methyl or ethyl or propyl or
isopropyl or butyl or isobutyl or secbutyl or t-butyl or phenyl or
benzyl or 2-phenylethyl or 1-phenylethyl or ethenyl or cyclopropyl
or cyclobutyl or cyclopentyl or cyclohexyl or methoxymethyl or
methylthiomethyl or methylsulfonylmethyl or 2,2,2
trifluoroethyl.
[0088] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y and R.sup.2 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.8
is H or substituted or unsubstituted alkyl, R.sup.5 is H; R.sup.6
is H; R.sup.7 is H; and R.sup.4 is selected from methyl or ethyl or
ethenyl or unsubstituted C.sub.3-C.sub.6 alkyl, or C.sub.1-C.sub.6
alkyl substituted with one or more halogen, or C.sub.1-C.sub.6
alkyl substituted with phenyl, or unsubstituted C.sub.3-C.sub.6
cycloalkyl, or unsubstituted phenyl, or C.sub.1-C.sub.3 alkyl
substituted with C.sub.1-C.sub.3 alkoxy, or C.sub.1-C.sub.3 alkyl
substituted with C.sub.1-C.sub.3 alkylthio, or C.sub.1-C.sub.3
alkyl substituted with C.sub.1-C.sub.3 alkylsulfonyl. In an
exemplary embodiment, the compound is according to formula (I)
and/or (II), wherein Y and R.sup.2 are as described herein, and
R.sup.1 is according to formula (III), wherein R.sup.8 is H,
R.sup.5 is H; R.sup.6 is H; R.sup.7 is H; and R.sup.4 is selected
from methyl or ethyl or trifluoromethyl or propyl or isopropyl or
butyl or isobutyl or secbutyl or t-butyl or phenyl or benzyl or
2-phenylethyl or 1-phenylethyl or ethenyl or cyclopropyl or
cyclobutyl or cyclopentyl or cyclohexyl or methoxymethyl or
methylthiomethyl or methylsulfonylmethyl or 2,2,2 trifluoroethyl.
In an exemplary embodiment, the compound is according to formula
(I) and/or (II), wherein Y and R.sup.2 are as described herein, and
R.sup.1 is according to formula (III), wherein R.sup.8 is H,
R.sup.5 is H; R.sup.6 is H; R.sup.7 is H; and R.sup.4 is selected
from methyl or ethyl or propyl or isopropyl or butyl or isobutyl or
secbutyl or t-butyl or phenyl or benzyl or 2-phenylethyl or
1-phenylethyl or ethenyl or cyclopropyl or cyclobutyl or
cyclopentyl or cyclohexyl or methoxymethyl or methylthiomethyl or
methylsulfonylmethyl or 2,2,2 trifluoroethyl.
[0089] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, and R.sup.8 are as
described herein, and R.sup.1 is according to formula (III),
wherein R.sup.4 is H; R.sup.5 is H; R.sup.6 is H; R.sup.7 is H. In
an exemplary embodiment, the compound is according to formula (I)
and/or (II), wherein Y, R.sup.2, and R.sup.8 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.4
is H; R.sup.5 is H; and R.sup.6 and R.sup.7 are each independently
selected from H and unsubstituted C.sub.1-C.sub.6 alkyl. In an
exemplary embodiment, the compound is according to formula (I)
and/or (II), wherein Y, R.sup.2, R.sup.4, R.sup.5, and R.sup.8 are
as described herein, and R.sup.1 is according to formula (III),
wherein R.sup.6 and R.sup.7 are each independently selected from H
and unsubstituted C.sub.1-C.sub.6 alkyl. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y, R.sup.2, R.sup.5, and R.sup.8 are as described herein,
and R.sup.1 is according to formula (III), wherein R.sup.4 is H,
and wherein R.sup.6 and R.sup.7 are each independently selected
from H and unsubstituted C.sub.1-C.sub.6 alkyl. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y, R.sup.2, R.sup.5, and R.sup.8 are as described herein,
and R.sup.1 is according to formula (III), wherein R.sup.4 is H,
R.sup.6 is H, and R.sup.7 is unsubstituted C.sub.1-C.sub.6 alkyl.
In an exemplary embodiment, the compound is according to formula
(I) and/or (II), wherein Y, R.sup.2, and R.sup.8 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.4
is H, R.sup.6 is H, and R.sup.5 is methyl or ethyl or propyl or
isopropyl and R.sup.7 is methyl or ethyl or propyl or isopropyl. In
an exemplary embodiment, the compound is according to formula (I)
and/or (II), wherein Y, R.sup.2, and R.sup.8 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.4
is H, R.sup.6 is H, and R.sup.5 is methyl and R.sup.7 is methyl. In
an exemplary embodiment, the compound is according to formula (I)
and/or (II), wherein Y, R.sup.2, and R.sup.8 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.4
is H; R.sup.5 is H; R.sup.6 is H; R.sup.7 is methyl or ethyl or
propyl or isopropyl. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y, R.sup.2, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.4 is H; R.sup.5 is H; R.sup.6 is H;
R.sup.7 is methyl. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y, R.sup.2, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.4 is H; R.sup.5 is H; R.sup.6 is
methyl or ethyl; and R.sup.7 is methyl or ethyl. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y, R.sup.2, and R.sup.8 are as described herein, and
R.sup.1 is according to formula (III), wherein R.sup.4 is H;
R.sup.5 is H; R.sup.6 is methyl; and R.sup.7 is methyl. In an
exemplary embodiment, the compound is according to formula (I)
and/or (II), wherein Y, R.sup.2, and R.sup.8 are as described
herein, and R.sup.1 is according to formula (III), wherein R.sup.4
is H; R.sup.5 is H; and R.sup.6 and R.sup.7 are each independently
selected from H and unsubstituted C.sub.1-C.sub.6 alkyl.
[0090] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, and R.sup.8 are as
described herein, and R.sup.1 is according to formula (III),
wherein R.sup.6 is H; R.sup.7 is H; and R.sup.4 and R.sup.5 are
each independently selected from H and unsubstituted
C.sub.1-C.sub.6 alkyl. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y, R.sup.2, R.sup.6,
R.sup.7, and R.sup.8 are as described herein, and R.sup.1 is
according to formula (III), wherein R.sup.4 and R.sup.5 are each
independently selected from H and unsubstituted C.sub.1-C.sub.6
alkyl. In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, R.sup.7, and R.sup.8
are as described herein, and R.sup.1 is according to formula (III),
wherein R.sup.6 is H, and wherein R.sup.4 and R.sup.5 are each
independently selected from H and unsubstituted C.sub.1-C.sub.6
alkyl. In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, R.sup.7, and R.sup.8
are as described herein, and R.sup.1 is according to formula (III),
wherein R.sup.4 is H, R.sup.6 is H, and R.sup.5 is unsubstituted
C.sub.1-C.sub.6 alkyl. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y, R.sup.2, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.6 is H; R.sup.7 is H; R.sup.4 is H;
R.sup.5 is ethyl. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y, R.sup.2, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.6 is H; R.sup.7 is H; R.sup.4 is H;
R.sup.5 is propyl or isopropyl. In an exemplary embodiment, the
compound is according to formula (I) and/or (II), wherein Y,
R.sup.2, and R.sup.8 are as described herein, and R.sup.1 is
according to formula (III), wherein R.sup.6 is H; R.sup.7 is H;
R.sup.4 is H; R.sup.5 is butyl or isobutyl or secbutyl or
tert-butyl. In an exemplary embodiment, the compound is according
to formula (I) and/or (II), wherein Y, R.sup.2, and R.sup.8 are as
described herein, and R.sup.1 is according to formula (III),
wherein R.sup.6 is H; R.sup.7 is H; R.sup.4 is H; R.sup.5 is
methyl. In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, and R.sup.8 are as
described herein, and R.sup.1 is according to formula (III),
wherein R.sup.6 is H; R.sup.7 is H; R.sup.4 is methyl or ethyl; and
R.sup.5 is methyl or ethyl. In an exemplary embodiment, the
compound is according to formula (I) and/or (II), wherein Y,
R.sup.2, and R.sup.8 are as described herein, and R.sup.1 is
according to formula (III), wherein R.sup.6 is H; R.sup.7 is H;
R.sup.4 is methyl; and R.sup.5 is methyl. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y, R.sup.2, and R.sup.8 are as described herein, and
R.sup.1 is according to formula (III), wherein R.sup.6 is H;
R.sup.7 is H; and R.sup.4 and R.sup.5 are each independently
selected from H and unsubstituted C.sub.1-C.sub.6 alkyl.
[0091] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, R.sup.6, R.sup.7, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), and wherein R.sup.4 and R.sup.5, along with the
atoms to which they are attached, are joined to form a substituted
or unsubstituted 3 or 4 or 5 membered ring. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y, R.sup.2, R.sup.6, R.sup.7, and R.sup.8 are as described
herein, and R.sup.1 is according to formula (III), and wherein
R.sup.4 and R.sup.5, along with the atoms to which they are
attached, are joined to form a substituted or unsubstituted 6 or 7
or 8 membered ring. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y, R.sup.2, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.6 is H; R.sup.7 is H; and R.sup.4 and
R.sup.5, along with the atoms to which they are attached, are
joined to form a substituted or unsubstituted 3 or 4 or 5 or 6 or 7
or 8 membered ring. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y, R.sup.2, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.6 is H; R.sup.7 is H; and R.sup.4 and
R.sup.5, along with the atoms to which they are attached, are
joined to form a cyclopropyl ring.
[0092] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, R.sup.4, R.sup.5, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), and wherein R.sup.6 and R.sup.7, along with the
atoms to which they are attached, are joined to form a substituted
or unsubstituted 3 or 4 or 5 membered ring. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y, R.sup.2, R.sup.4, R.sup.5, and R.sup.8 are as described
herein, and R.sup.1 is according to formula (III), and wherein
R.sup.6 and R.sup.7, along with the atoms to which they are
attached, are joined to form a substituted or unsubstituted 6 or 7
or 8 membered ring. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y, R.sup.2, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.4 is H; R.sup.5 is H; and R.sup.6 and
R.sup.7, along with the atoms to which they are attached, are
joined to form a substituted or unsubstituted 3 or 4 or 5 or 6 or 7
or 8 membered ring. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y, R.sup.2, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.4 is H; R.sup.5 is H; and R.sup.6 and
R.sup.7, along with the atoms to which they are attached, are
joined to form a cyclopropyl ring.
[0093] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, R.sup.4, R.sup.7, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), and R.sup.5 and R.sup.6, along with the atoms to
which they are attached, are joined to form a substituted or
unsubstituted 3 or 4 or 5 membered ring. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y, R.sup.2, R.sup.4, R.sup.7, and R.sup.8 are as described
herein, and R.sup.1 is according to formula (III), and R.sup.5 and
R.sup.6, along with the atoms to which they are attached, are
joined to form a substituted or unsubstituted 6 or 7 or 8 membered
ring. In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, and R.sup.8 are as
described herein, and R.sup.1 is according to formula (III),
wherein R.sup.4 is H; R.sup.7 is H; and wherein R.sup.5 and
R.sup.6, along with the atoms to which they are attached, are
joined to form a substituted or unsubstituted 3 or 4 or 5 or 6 or 7
or 8 membered ring. In an exemplary embodiment, the compound is
according to formula (I) and/or (II), wherein Y and R.sup.2, and
R.sup.1 is according to formula (III), wherein R.sup.4 is H;
R.sup.7 is H; R.sup.8 is H; and wherein R.sup.5 and R.sup.6, along
with the atoms to which they are attached, are joined to form a
substituted or unsubstituted 3 or 4 or 5 or 6 or 7 or 8 membered
ring. In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, and R.sup.8 are as
described herein, and R.sup.1 is according to formula (III),
wherein R.sup.4 is H; R.sup.7 is H; and wherein R.sup.5 and
R.sup.6, along with the atoms to which they are attached, are
joined to form a 3 or 4 or 5 or 6 or 7 or 8 membered ring
substituted with hydroxy. In an exemplary embodiment, the compound
is according to formula (I) and/or (II), wherein Y, R.sup.2, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), wherein R.sup.4 is H; R.sup.7 is H; and wherein
R.sup.5 and R.sup.6, along with the atoms to which they are
attached, are joined to form a cyclopentyl ring.
[0094] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, R.sup.4, R.sup.5, and
R.sup.8 are as described herein, and R.sup.1 is according to
formula (III), and R.sup.6 and R.sup.8, along with the atoms to
which they are attached, are joined to form a substituted or
unsubstituted 3 or 4 or 5 membered ring. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y, R.sup.2, R.sup.4, R.sup.5, and R.sup.8 are as described
herein, and R.sup.1 is according to formula (III), and R.sup.6 and
R.sup.8, along with the atoms to which they are attached, are
joined to form a substituted or unsubstituted 6 or 7 or 8 membered
ring. In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein Y, R.sup.2, and R.sup.5 are as
described herein, and R.sup.1 is according to formula (III),
wherein R.sup.4 is H; R.sup.7 is H; and wherein R.sup.6 and
R.sup.8, along with the atoms to which they are attached, are
joined to form a substituted or unsubstituted 3 or 4 or 5 or 6 or 7
or 8 membered ring.
[0095] In an exemplary embodiment, the compound is according to
formula (I), wherein Y is as described herein, and R.sup.1 and
R.sup.2, along with the nitrogen to which they are attached, are
joined to form a substituted or unsubstituted 3 to 8 membered ring.
In an exemplary embodiment, the compound is according to formula
(I), wherein Y is --CH.sub.3, and R.sup.1 and R.sup.2, along with
the nitrogen to which they are attached, are joined to form a
substituted or unsubstituted 3 to 8 membered ring.
[0096] In an exemplary embodiment, the compound is according to
formula (II), wherein Y is as described herein, and R.sup.1 and
R.sup.2, along with the nitrogen to which they are attached, are
joined to form a substituted or unsubstituted 3 to 8 membered ring.
In an exemplary embodiment, the compound is according to formula
(II), wherein Y is --CH.sub.3, and R.sup.1 and R.sup.2, along with
the nitrogen to which they are attached, are joined to form a
substituted or unsubstituted 3 to 8 membered ring. In an exemplary
embodiment, the compound is according to formula (I) and/or (II),
wherein Y is as described herein, and R.sup.1 and R.sup.2, along
with the nitrogen to which they are attached, are joined to form
hydroxy substituted C.sub.3-C.sub.8 heterocycloalkyl. In an
exemplary embodiment, the compound is according to formula (I)
and/or (II), wherein Y is CH.sub.3, and R.sup.1 and R.sup.2, along
with the nitrogen to which they are attached, are joined to form
hydroxy substituted C.sub.3-C.sub.8 heterocycloalkyl.
[0097] In an exemplary embodiment, the compound is according to
formula (I) wherein R.sup.1 is according to formula (III), R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are as described herein, R.sup.8 is
H, R.sup.2 is H, and Y is CH.sub.3. In an exemplary embodiment, the
compound is according to formula (I) wherein R.sup.1 is according
to formula (III), R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are as
described herein, R.sup.8 is H, R.sup.2 is CH.sub.3, and Y is
CH.sub.3. In an exemplary embodiment, the compound is according to
formula (II) wherein R.sup.1 is according to formula (III),
R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are as described herein,
R.sup.8 is H, R.sup.2 is H, and Y is CH.sub.3. In an exemplary
embodiment, the compound is according to formula (II) wherein
R.sup.1 is according to formula (III), R.sup.4, R.sup.5, R.sup.6,
and R.sup.7 are as described herein, R.sup.8 is H, R.sup.2 is
CH.sub.3, and Y is CH.sub.3.
[0098] In an exemplary embodiment, the compound is according to
formula (I) and/or (II), wherein R.sup.2, R.sup.8, are as described
herein, and R.sup.1 is according to formula (III), wherein Y is
CH.sub.3, R.sup.4 is H; R.sup.5 is H; R.sup.6 is H; R.sup.7 is H.
In an exemplary embodiment, the compound is according to formula
(I) and/or (II), wherein Y, R.sup.8, are as described herein, and
R.sup.1 is according to formula (III), wherein R.sup.2 is H,
R.sup.4 is H; R.sup.5 is H; R.sup.6 is H; R.sup.7 is H.
[0099] In another aspect, the invention provides a compound having
a structure according to formula (Ia) and/or (IIa):
##STR00004##
[0100] wherein Y is H or substituted or unsubstituted
C.sub.1-C.sub.3 alkyl or substituted or unsubstituted
C.sub.3-C.sub.8 cycloalkyl or substituted or unsubstituted
C.sub.1-C.sub.3 alkyloxy, A is a substituted or unsubstituted 3 to
8 membered ring, or a salt, or a hydrate, or a solvate thereof. In
an exemplary embodiment, the compound is according to formula (Ia),
wherein Y is as described herein, and A is a substituted or
unsubstituted 3 to 8 membered ring. In an exemplary embodiment, the
compound is according to formula (IIa), wherein Y is as described
herein, and A is a substituted or unsubstituted 3 to 8 membered
ring. In an exemplary embodiment, the compound is according to
formula (Ia), wherein Y is CH.sub.3, and A is a substituted or
unsubstituted 3 to 8 membered ring. In an exemplary embodiment, the
compound is according to formula (IIa), wherein Y is CH.sub.3, and
A is a substituted or unsubstituted 3 to 8 membered ring.
[0101] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein, and A
is an unsubstituted 3 membered ring. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is CH.sub.3, and A is an unsubstituted 3 membered ring. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is an
unsubstituted 4 membered ring. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y is
CH.sub.3, and A is an unsubstituted 4 membered ring. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is an
unsubstituted 5 membered ring. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y is
CH.sub.3, and A is an unsubstituted 5 membered ring. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is an
unsubstituted 6 membered ring. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y is
CH.sub.3, and A is an unsubstituted 6 membered ring. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is an
unsubstituted 7 membered ring. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y is
CH.sub.3, and A is an unsubstituted 7 membered ring. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is an
unsubstituted 8 membered ring. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y is
CH.sub.3, and A is an unsubstituted 8 membered ring.
[0102] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein, and A
is substituted with hydroxy. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y is as
described herein, and A is substituted with substituted or
unsubstituted alkyl. In an exemplary embodiment, the compound is
according to formula (Ia) and/or (IIa), wherein Y is as described
herein, and A is substituted with unsubstituted C.sub.1-C.sub.6
alkyl. In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein, and A
is substituted with substituted C.sub.1-C.sub.6 alkyl. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is
substituted with halosubstituted C.sub.1-C.sub.6 alkyl. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is
substituted with fluorosubstituted C.sub.1-C.sub.6 alkyl. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is
substituted with halosubstituted methyl. In an exemplary
embodiment, the compound is according to formula (Ia) and/or (IIa),
wherein Y is as described herein, and A is substituted with
fluorosubstituted methyl. In an exemplary embodiment, the compound
is according to formula (Ia) and/or (IIa), wherein Y is as
described herein, and A is substituted with trifluoromethyl. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is
substituted with unsubstituted C.sub.6-C.sub.8 cycloalkyl. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is
substituted with substituted C.sub.6-C.sub.8 cycloalkyl. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and A is
substituted with unsubstituted cyclopropyl. In an exemplary
embodiment, the compound is according to formula (Ia) and/or (IIa),
wherein Y is as described herein, and A is substituted with
substituted cyclopropyl. In an exemplary embodiment, the compound
is according to formula (Ia) and/or (IIa), wherein Y is as
described herein, and A is substituted with unsubstituted
cyclobutyl. In an exemplary embodiment, the compound is according
to formula (Ia) and/or (IIa), wherein Y is as described herein, and
A is substituted with substituted cyclobutyl. In an exemplary
embodiment, the compound is according to formula (Ia) and/or (IIa),
wherein Y is as described herein, and A is substituted with
unsubstituted cyclopentyl. In an exemplary embodiment, the compound
is according to formula (Ia) and/or (IIa), wherein Y is as
described herein, and A is substituted with substituted
cyclopentyl.
[0103] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00005##
R.sup.8 is H or substituted or unsubstituted alkyl, and R.sup.4 or
R.sup.5 or R.sup.6 are each independently selected from H,
substituted or unsubstituted C.sub.1-C.sub.6 alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, and wherein R.sup.4 and
R.sup.5, along with the atoms to which they are attached, can be
optionally joined to form a substituted or unsubstituted 3 to 8
membered ring, and wherein R.sup.5 and R.sup.6, along with the
atoms to which they are attached, can be optionally joined to form
a substituted or unsubstituted 3 to 8 membered ring, wherein
R.sup.6 and R.sup.8, along with the atoms to which they are
attached, can be optionally joined to form a substituted or
unsubstituted 3 to 8 membered ring. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y is as
described herein, and
##STR00006##
wherein R.sup.8 is H or substituted or unsubstituted alkyl, and
R.sup.4 or R.sup.5 or R.sup.6 are each independently selected from
H or methyl or ethyl or ethenyl or unsubstituted C.sub.3-C.sub.6
alkyl, or C.sub.1-C.sub.6 alkyl substituted with one or more
halogen, or C.sub.1-C.sub.6 alkyl substituted with phenyl, or
unsubstituted C.sub.3-C.sub.6 cycloalkyl, or unsubstituted phenyl,
or C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3 alkoxy,
or C.sub.1-C.sub.3 alkyl substituted with C.sub.1-C.sub.3
alkylthio, or C.sub.1-C.sub.3 alkyl substituted with
C.sub.1-C.sub.3 alkylsulfonyl. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y and
R.sup.2 are as described herein, and
##STR00007##
wherein R.sup.8 is substituted or unsubstituted alkyl, and R.sup.4
or R.sup.5 or R.sup.6 are each independently selected from H or
methyl or ethyl or trifluoromethyl or propyl or isopropyl or butyl
or isobutyl or secbutyl or t-butyl or phenyl or benzyl or
2-phenylethyl or 1-phenylethyl or ethenyl or cyclopropyl or
cyclobutyl or cyclopentyl or cyclohexyl or methoxymethyl or
methylthiomethyl or methylsulfonylmethyl or 2,2,2 trifluoroethyl.
In an exemplary embodiment, the compound is according to formula
(I) and/or (II), wherein Y and R.sup.2 are as described herein,
and
##STR00008##
wherein R.sup.8 is H, and R.sup.4 or R.sup.5 or R.sup.6 are each
independently selected from H or methyl or ethyl or propyl or
isopropyl or butyl or isobutyl or secbutyl or t-butyl or phenyl or
benzyl or 2-phenylethyl or 1-phenylethyl or ethenyl or cyclopropyl
or cyclobutyl or cyclopentyl or cyclohexyl or methoxymethyl or
methylthiomethyl or methylsulfonylmethyl or 2,2,2
trifluoroethyl.
[0104] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00009##
is substituted
##STR00010##
In an exemplary embodiment, the compound is according to formula
(Ia) and/or (IIa), wherein Y is as described herein, and
##STR00011##
substituted with hydroxy or substituted with C.sub.1-C.sub.4 alkyl
or combinations thereof.
[0105] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00012##
is substituted
##STR00013##
In an exemplary embodiment, the compound is according to formula
(Ia) and/or (IIa), wherein Y is as described herein, and
##STR00014##
is substituted with hydroxy or substituted with C.sub.1-C.sub.4
alkyl or combinations thereof.
[0106] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00015##
is substituted
##STR00016##
In an exemplary embodiment, the compound is according to formula
(Ia) and/or (IIa), wherein Y is as described herein, and
##STR00017##
is substituted with hydroxy or substituted with C.sub.1-C.sub.4
alkyl or combinations thereof.
[0107] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00018##
is substituted
##STR00019##
In an exemplary embodiment, the compound is according to formula
(Ia) and/or (IIa), wherein Y is as described herein, and
##STR00020##
is substituted with hydroxy or substituted with C.sub.1-C.sub.4
alkyl or combinations thereof.
[0108] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00021##
is substituted
##STR00022##
In an exemplary embodiment, the compound is according to formula
(Ia) and/or (IIa), wherein Y is as described herein, and
##STR00023##
is substituted with hydroxy or substituted with C.sub.1-C.sub.4
alkyl or combinations thereof.
[0109] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00024##
is substituted
##STR00025##
In an exemplary embodiment, the compound is according to formula
(Ia) and/or (IIa), wherein Y is as described herein, and
##STR00026##
substituted with hydroxy or substituted with C.sub.1-C.sub.4 alkyl
or combinations thereof.
[0110] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00027##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00028##
In an exemplary embodiment, the compound is according to formula
(Ia) and/or (IIa), wherein Y is as described herein, and
##STR00029##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00030##
wherein R.sup.4 or R.sup.5 or R.sup.6 or R.sup.8 are as described
herein. In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00031##
wherein R.sup.4 or R.sup.5 are as described herein, R.sup.8 is H,
and R.sup.6 is unsubstituted C.sub.1-C.sub.4 alkyl or
halosubstituted C.sub.1-C.sub.4 alkyl or unsubstituted
C.sub.3-C.sub.5 cycloalkyl, R.sup.8 are as described herein. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and
##STR00032##
wherein R.sup.6 or R.sup.8 are as described herein.
[0111] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00033##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00034##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00035##
wherein R.sup.4 or R.sup.5 or R.sup.6 or R.sup.8 are as described
herein. In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00036##
wherein R.sup.4 or R.sup.5 or R.sup.8 are as described herein,
R.sup.8 is H, and R.sup.6 is unsubstituted C.sub.1-C.sub.4 alkyl or
halosubstituted C.sub.1-C.sub.4 alkyl or unsubstituted
C.sub.3-C.sub.5 cycloalkyl. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y is as
described herein, and
##STR00037##
wherein R.sup.4 or R.sup.5 or R.sup.8 are as described herein, and
R.sup.6 is methyl or ethyl or propyl or isopropyl or
trifluoromethyl or difluoromethyl or trifluoroethyl or cyclopropyl.
In an exemplary embodiment, the compound is according to formula
(Ia) and/or (IIa), wherein Y is as described herein, and
##STR00038##
wherein R.sup.6 or R.sup.8 are as described herein. In an exemplary
embodiment, the compound is according to formula (Ia) and/or (IIa),
wherein Y is as described herein, and
##STR00039##
wherein R.sup.8 is H and R.sup.6 is methyl or ethyl or propyl or
isopropyl or trifluoromethyl or difluoromethyl or trifluoroethyl or
cyclopropyl.
[0112] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00040##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00041##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00042##
wherein R.sup.4 or R.sup.5 or R.sup.6 or R.sup.8 are as described
herein.
[0113] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00043##
wherein R.sup.4 or R.sup.5 are as described herein, R.sup.8 is H,
and R.sup.6 is unsubstituted C.sub.1-C.sub.4 alkyl or
halosubstituted C.sub.1-C.sub.4 alkyl or unsubstituted
C.sub.3-C.sub.5 cycloalkyl, R.sup.8 are as described herein. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and
##STR00044##
wherein R.sup.6 or R.sup.8 are as described herein.
[0114] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00045##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00046##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00047##
wherein R.sup.4 or R.sup.5 or R.sup.6 or R.sup.8 are as described
herein. In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00048##
wherein R.sup.4 or R.sup.5 are as described herein, R.sup.8 is H,
and R.sup.6 is unsubstituted C.sub.1-C.sub.4 alkyl or
halosubstituted C.sub.1-C.sub.4 alkyl or unsubstituted
C.sub.3-C.sub.5 cycloalkyl, R.sup.8 are as described herein. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and
##STR00049##
is R.sup.6, wherein R.sup.6 or R.sup.8 are as described herein.
[0115] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00050##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00051##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00052##
wherein R.sup.4 or R.sup.5 or R.sup.6 or R.sup.8 are as described
herein. In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00053##
wherein R.sup.4 or R.sup.5 are as described herein, R.sup.8 is H,
and R.sup.6 is unsubstituted C.sub.1-C.sub.4 alkyl or
halosubstituted C.sub.1-C.sub.4 alkyl or unsubstituted
C.sub.3-C.sub.5 cycloalkyl, R.sup.8 are as described herein. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and
##STR00054##
wherein R.sup.6 or R.sup.8 are as described herein.
[0116] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00055##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00056##
wherein R.sup.8 is as described herein. In an exemplary embodiment,
the compound is according to formula (Ia) and/or (IIa), wherein Y
is as described herein, and
##STR00057##
wherein R.sup.4 or R.sup.5 or R.sup.6 or R.sup.8 are as described
herein. In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00058##
wherein R.sup.4 or R.sup.5 are as described herein, R.sup.8 is H,
and R.sup.6 is unsubstituted C.sub.1-C.sub.4 alkyl or
halosubstituted C.sub.1-C.sub.4 alkyl or unsubstituted
C.sub.3-C.sub.5 cycloalkyl, R.sup.8 are as described herein. In an
exemplary embodiment, the compound is according to formula (Ia)
and/or (IIa), wherein Y is as described herein, and
##STR00059##
wherein R.sup.6 or R.sup.8 are as described herein.
[0117] In an exemplary embodiment, the compound is according to
formula (Ia) and/or (IIa), wherein Y is as described herein,
and
##STR00060##
is unsubstituted piperazinyl. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y is as
described herein, and
##STR00061##
is substituted piperazinyl. In an exemplary embodiment, the
compound is according to formula (Ia) and/or (IIa), wherein Y is as
described herein, and
##STR00062##
is piperazinyl substituted with a hydroxyC.sub.1-C.sub.6alkyl.
[0118] In an exemplary embodiment, the compound is according to
formula (Ia) wherein A is as described herein, and Y is CH.sub.3.
In an exemplary embodiment, the compound is according to formula
(IIa) wherein A is as described herein, and Y is CH.sub.3.
[0119] In another embodiment, the invention provides a compound
having a structure according to formula (Ib) and/or (IIb):
##STR00063##
[0120] wherein Y, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and
R.sup.8 are as described herein, and C* is a carbon atom which is a
stereocenter having a configuration which is (R) or (S). In another
embodiment, the compound has a structure according to formula (Ib),
wherein Y, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are as described herein, and C* is a stereocenter with an (R)
configuration. In another embodiment, the compound has a structure
according to formula (Ib), wherein Y, R.sup.2, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are as described herein, and C* is a
stereocenter with an (S) configuration. In another embodiment, the
compound has a structure according to formula (IIb), wherein Y,
R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are as
described herein, and C* is a stereocenter with an (R)
configuration. In another embodiment, the compound has a structure
according to formula (IIb), wherein Y, R.sup.2, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are as described herein, and C* is a
stereocenter with an (S) configuration.
[0121] In another embodiment, the invention provides a compound
having a structure according to formula (Ic) and/or (IIc):
##STR00064##
[0122] wherein Y, R.sup.2, R.sup.4, R.sup.5, and R.sup.8 are as
described herein, and C* is a carbon atom which is a stereocenter
having a configuration which is (R) or (S). In another embodiment,
the compound has a structure according to formula (Ic), wherein Y,
R.sup.2, R.sup.4, R.sup.5, and R.sup.8 are as described herein, and
C* is a stereocenter with an (R) configuration. In another
embodiment, the compound has a structure according to formula (Ic),
wherein Y, R.sup.2, R.sup.4, R.sup.5, and R.sup.8 are as described
herein, and C* is a stereocenter with an (S) configuration. In
another embodiment, the compound has a structure according to
formula (IIc), wherein Y, R.sup.2, R.sup.4, R.sup.5, and R.sup.8
are as described herein, and C* is a stereocenter with an (R)
configuration. In another embodiment, the compound has a structure
according to formula (IIc), wherein Y, R.sup.2, R.sup.4, R.sup.5,
and R.sup.8 are as described herein, and C* is a stereocenter with
an (S) configuration.
[0123] In another embodiment, the invention provides a compound
having a structure according to formula (Id) and/or (IId):
##STR00065##
[0124] wherein Y, R.sup.6, and R.sup.8 are as described herein, and
C* is a carbon atom which is a stereocenter having a configuration
which is (R) or (S). In another embodiment, the compound has a
structure according to formula (Id), wherein Y, R.sup.6, and
R.sup.8 are as described herein, and C* is a stereocenter with an
(R) configuration. In another embodiment, the compound has a
structure according to formula (Id), wherein Y, R.sup.6, and
R.sup.8 are as described herein, and C* is a stereocenter with an
(S) configuration. In another embodiment, the compound has a
structure according to formula (IId), wherein Y, R.sup.6, and
R.sup.8 are as described herein, and C* is a stereocenter with an
(R) configuration. In another embodiment, the compound has a
structure according to formula (IId), wherein Y, R.sup.6, and
R.sup.8 are as described herein, and C* is a stereocenter with an
(S) configuration.
[0125] In another embodiment, the invention provides a compound
having a structure according to formula (Ie) and/or (IIe) and/or
(If) and/or (IIf):
##STR00066##
[0126] wherein Y, R.sup.2, R.sup.4, R.sup.5, R.sup.6, and R.sup.8
are as described herein, and C* is a carbon atom which is a
stereocenter having a configuration which is (R) or (S). In another
embodiment, the compound has a structure according to formula (Ie),
wherein Y, R.sup.2, R.sup.4, R.sup.5, R.sup.6, and R.sup.8 are as
described herein, and C* is a stereocenter with an (R)
configuration. In another embodiment, the compound has a structure
according to formula (Ie), wherein Y, R.sup.2, R.sup.4, R.sup.5,
R.sup.6, and R.sup.8 are as described herein, and C* is a
stereocenter with an (S) configuration. In another embodiment, the
compound has a structure according to formula (IIe), wherein Y,
R.sup.2, R.sup.4, R.sup.5, R.sup.6, and R.sup.8 are as described
herein, and C* is a stereocenter with an (R) configuration.
[0127] In another embodiment, the compound has a structure
according to formula (IIe), wherein Y, R.sup.2, R.sup.4, R.sup.5,
R.sup.6, and R.sup.8 are as described herein, and C* is a
stereocenter with an (S) configuration. In another embodiment, the
compound has a structure according to formula (If), wherein Y,
R.sup.2, R.sup.4, R.sup.5, R.sup.6, and R.sup.8 are as described
herein, and C* is a stereocenter with an (R) configuration. In
another embodiment, the compound has a structure according to
formula (If), wherein Y, R.sup.2, R.sup.4, R.sup.5, R.sup.6, and
R.sup.8 are as described herein, and C* is a stereocenter with an
(S) configuration. In another embodiment, the compound has a
structure according to formula (IIf), wherein Y, R.sup.2, R.sup.4,
R.sup.5, R.sup.6, and R.sup.8 are as described herein, and C* is a
stereocenter with an (R) configuration. In another embodiment, the
compound has a structure according to formula (IIf), wherein Y,
R.sup.2, R.sup.4, R.sup.5, R.sup.6, and R.sup.8 are as described
herein, and C* is a stereocenter with an (S) configuration.
[0128] In an exemplary embodiment, alkyl is linear alkyl. In
another exemplary embodiment, alkyl is branched alkyl.
[0129] In an exemplary embodiment, heteroalkyl is linear
heteroalkyl. In another exemplary embodiment, heteroalkyl is
branched heteroalkyl.
[0130] In an exemplary embodiment, the invention provides a
compound described herein, or a salt, hydrate or solvate thereof,
or a combination thereof. In an exemplary embodiment, the invention
provides a compound described herein, or a salt, hydrate or solvate
thereof. In an exemplary embodiment, the invention provides a
compound described herein, or a salt thereof. In an exemplary
embodiment, the salt is a pharmaceutically acceptable salt. In an
exemplary embodiment, the invention provides a compound described
herein, or a hydrate thereof. In an exemplary embodiment, the
invention provides a compound described herein, or a solvate
thereof. In an exemplary embodiment, the invention provides a
compound described herein, or a prodrug thereof. In an exemplary
embodiment, the invention provides a salt of a compound described
herein. In an exemplary embodiment, the invention provides a
pharmaceutically acceptable salt of a compound described herein. In
an exemplary embodiment, the invention provides a hydrate of a
compound described herein. In an exemplary embodiment, the
invention provides a solvate of a compound described herein. In an
exemplary embodiment, the invention provides a prodrug of a
compound described herein.
[0131] III.b) Compositions Involving Stereoisomers
[0132] As used herein, the term "chiral", "enantiomerically
enriched" or "diastereomerically enriched" refers to a composition
having an enantiomeric excess (ee) or a diastereomeric excess (de)
of greater than about 50%, preferably greater than about 70% and
more preferably greater than about 90%. In general, higher than
about 90% enantiomeric or diastereomeric excess is particularly
preferred, e.g., those compositions with greater than about 95%,
greater than about 97% and greater than about 99% ee or de.
[0133] When a first compound and a second compound are present in a
composition, and the first compound is a non-superimposable mirror
image of the second compound, and the first compound is present in
the composition in a greater amount than the second compound, then
the first compound is referred to herein as being present in
"enantiomeric excess".
[0134] The term "enantiomeric excess" of a compound z, as used
herein, is defined as:
ee z = ( conc . of z - conc . of y conc . of z + conc . of y )
.times. 100 ##EQU00001##
[0135] wherein z is a first compound in a composition, y is a
second compound in the composition, and the first compound is a
non-superimposable mirror image of the second compound.
[0136] The term "enantiomeric excess" is related to the older term
"optical purity" in that both are measures of the same phenomenon.
The value of ee will be a number from 0 to 100, zero being racemic
and 100 being enantiomerically pure. A composition which in the
past might have been called 98% optically pure is now more
precisely characterized by 96% ee. A 90% ee reflects the presence
of 95% of one enantiomer and 5% of the other(s) in the material in
question.
[0137] When a first compound and at least one additional compound
are present in a composition, and the first compound and each of
the additional compounds are stereoisomers, but not mirror images,
of one another, and the first compound is present in the
composition in a greater amount than each of the additional
compounds, then the first compound is referred to herein as being
present in "diastereomeric excess".
[0138] When dealing with mixtures of diastereomers, the term
"diastereomeric excess" or "de" is defined analogously to
enantiomeric excess. Thus:
de w = ( conc . of major diastereomer - conc . of min or
diastereomer ( s ) conc . of major diastereomer + conc . of min or
diastereomer ( s ) ) .times. 100 ##EQU00002##
[0139] wherein the major diastereomer is a first compound in a
composition, and the minor diastereomer(s) is at least one
additional compound in the composition, and the major diastereomer
and minor diastereomer(s) are stereoisomers, but not mirror images,
of one another.
[0140] The value of de will likewise be a number from 0 to 100,
zero being an equal mixture of a first diastereomer and the
remaining diastereomer(s), and 100 being 100% of a single
diastereomer and zero % of the other(s)--i.e. diastereomerically
pure. Thus, 90% de reflects the presence of 95% of one diastereomer
and 5% of the other diastereomer(s) in the material in
question.
[0141] Hence, in one embodiment, the invention provides a
composition including a first compound of the invention, wherein
the first compound of the invention has at least one stereocenter,
and at least one stereoisomer of the first compound of the
invention. In another embodiment, the invention provides a
composition including a first compound of the invention, wherein
the first compound of the invention has at least one stereocenter,
and a second compound of the invention, wherein the first compound
of the invention is a stereoisomer of the second compound of the
invention. In another embodiment, the invention provides a
composition including a first compound of the invention, wherein
the first compound of the invention has at least one stereocenter,
and only one stereoisomer of the first compound of the
invention.
[0142] In another embodiment, the invention provides a composition
including a first compound of the invention, wherein the first
compound of the invention has only one stereocenter, and an
enantiomer of the first compound of the invention. In another
embodiment, the invention provides a composition including a first
compound of the invention, wherein the first compound of the
invention has two stereocenters, and an enantiomer of the first
compound of the invention. In another embodiment, the invention
provides a composition including a first compound of the invention,
wherein the first compound of the invention has two stereocenters,
and at least one diastereomer of the first compound of the
invention. In another embodiment, the invention provides a
composition including a first compound of the invention, wherein
the first compound of the invention has two stereocenters, and only
one diastereomer of the first compound of the invention.
[0143] In situations where the first compound of the invention and
its enantiomer are present in a composition, the first compound of
the invention can be present in an enantiomeric excess of at least
about 80%, or at least about 90%, or at least about 92% or at least
about 95%. In another embodiment, where the first compound of the
invention and its enantiomer are present in a composition, the
first compound of the invention can be present in an enantiomeric
excess of at least about 96%, at least about 97%, at least about
98%, at least about 99% or at least about 99.5%. In another
embodiment, the first compound of the invention has at least one
stereocenter and is enantiomerically pure (enantiomeric excess is
about 100%).
[0144] In situations where the first compound of the invention and
at least one diastereomer of the first compound of the invention
are present in a composition, the first compound of the invention
can be present in a diastereomeric excess of at least about 80%, or
at least about 90%, or at least about 92% or at least about 95%. In
situations where the first compound of the invention and at least
one diastereomer of the first compound of the invention are present
in a composition, the first compound of the invention can be
present in a diastereomeric excess of at least about 96%, at least
about 97%, at least about 98%, at least about 99% or at least about
99.5%. In another embodiment, the first compound of the invention
has at least two stereocenters and is diastereomerically pure
(diastereomeric excess is about 100%).
[0145] Enantiomeric or diastereomeric excess can be determined
relative to exactly one other stereoisomer, or can be determined
relative to the sum of at least two other stereoisomers. In an
exemplary embodiment, enantiomeric or diastereomeric excess is
determined relative to all other detectable stereoisomers, which
are present in the mixture. Stereoisomers are detectable if a
concentration of such stereoisomer in the analyzed mixture can be
determined using common analytical methods, such as chiral
HPLC.
[0146] As used herein, and unless otherwise indicated, a
composition that is "substantially free" of a compound means that
the composition contains less than about 20% by weight, or less
than about 15% by weight, or less than about 10% by weight, or less
than about 5% by weight, or less than about 3% by weight, or less
than about 2% by weight, or less than about 1% by weight of the
compound.
[0147] As used herein, the term "substantially free of the (or its)
enantiomer" means that a composition contains a significantly
greater proportion of a first compound of the invention than a
second compound of the invention, wherein the first compound is a
non-superimposable mirror image of the second compound. In one
embodiment of the invention, the term "substantially free of the
enantiomer" means that the composition is made up of at least about
90% by weight of a first compound of the invention, and about 10%
by weight or less of a second compound of the invention, wherein
the first compound is a non-superimposable mirror image of the
second compound. In one embodiment of the invention, the term
"substantially free of the (R) enantiomer" means that the
composition is made up of at least about 90% by weight of a first
compound of the invention which has only one stereocenter and the
stereocenter is in an (S) configuration, and about 10% by weight or
less of a second compound of the invention, wherein the second
compound is the enantiomer of the first compound. In one embodiment
of the invention, the term "substantially free of the enantiomer"
means that the composition is made up of at least about 95% by
weight of a first compound of the invention, and about 5% by weight
or less of a second compound of the invention, wherein the first
compound is a non-superimposable mirror image of the second
compound. In one embodiment of the invention, the term
"substantially free of the (R) enantiomer" means that the
composition is made up of at least about 95% by weight of a first
compound of the invention which has only one stereocenter and the
stereocenter is in an (S) configuration, and about 5% by weight or
less of a second compound of the invention, wherein the second
compound is the enantiomer of the first compound. In one embodiment
of the invention, the term "substantially free of the enantiomer"
means that the composition is made up of at least about 98% by
weight of a first compound of the invention, and about 2% by weight
or less of a second compound of the invention, wherein the first
compound is a non-superimposable mirror image of the second
compound. In one embodiment of the invention, the term
"substantially free of the (R) enantiomer" means that the
composition is made up of at least about 98% by weight of a first
compound of the invention which has only one stereocenter and the
stereocenter is in an (S) configuration, and about 2% by weight or
less of a second compound of the invention, wherein the second
compound is the enantiomer of the first compound. In one embodiment
of the invention, the term "substantially free of the enantiomer"
means that the composition is made up of at least about 99% by
weight of a first compound of the invention, and about 1% by weight
or less of a second compound of the invention, wherein the first
compound is a non-superimposable mirror image of the second
compound. In one embodiment of the invention, the term
"substantially free of the (R) enantiomer" means that the
composition is made up of at least about 99% by weight of a first
compound of the invention which has only one stereocenter and the
stereocenter is in an (S) configuration, and about 1% by weight or
less of a second compound of the invention, wherein the second
compound is the enantiomer of the first compound.
[0148] In an exemplary embodiment, the invention provides a
composition comprising a) first compound described herein; and b)
the enantiomer of the first compound, wherein the first compound
described herein is present in an enantiomeric excess of at least
80%. In an exemplary embodiment, the enantiomeric excess is at
least 92%.
[0149] III.c) Combinations Comprising Additional Therapeutic
Agents
[0150] The compounds of the invention may also be used in
combination with additional therapeutic agents. The invention thus
provides, in a further aspect, a combination comprising a compound
of the invention together with at least one additional therapeutic
agent. In an exemplary embodiment, the combination comprises a
compound described herein or a pharmaceutically acceptable salt
thereof together with at least one additional therapeutic agent. In
an exemplary embodiment, the additional therapeutic agent is a
compound of the invention. In an exemplary embodiment, the
additional therapeutic agent includes a boron atom. In an exemplary
embodiment, the additional therapeutic agent does not contain a
boron atom. In an exemplary embodiment, the combination comprises:
a) a compound of the invention and b) a first additional
therapeutic agent. In an exemplary embodiment, the combination
comprises: a) a compound of the invention; b) a first additional
therapeutic agent; and c) a second additional therapeutic agent. In
an exemplary embodiment, the combination comprises: a) a compound
of the invention; b) a first additional therapeutic agent; c) a
second additional therapeutic agent; and d) a third additional
therapeutic agent.
[0151] When a compound of the invention is used in combination with
at least one additional therapeutic agent active against the same
disease state, the dose of each compound may differ from that when
the compound is used alone. Appropriate doses will be readily
appreciated by those skilled in the art. It will be appreciated
that the amount of a compound of the invention required for use in
treatment will vary with the nature of the condition being treated
and the age and the condition of the patient and will be ultimately
at the discretion of the attendant physician or veterinarian. In an
exemplary embodiment, the additional therapeutic agent is berenil.
In an exemplary embodiment, the additional therapeutic agent is
diminazene. In an exemplary embodiment, the additional therapeutic
agent is an antiprotozoal. In an exemplary embodiment, the
additional therapeutic agent is selected from the group consisting
of benznidazole, buparvaquone, carbarsone, clioquinol, disulfiram,
eflornithine, emetine, etofamide, furazolidone, meglumine
antimoniate, melarsoprol, metronidazole, miltefosine, nifurtimox,
nimorazole, nitazoxanide, ornidazole, paromomycin sulfate,
pentamidine, pyrimethamine, secnidazole and tinidazole. In an
exemplary embodiment, the additional therapeutic agent is
pentamidine. In an exemplary embodiment, the additional therapeutic
agent is suramin. In an exemplary embodiment, the additional
therapeutic agent is eflornithine. In an exemplary embodiment, the
additional therapeutic agent is melarsoprol. In an exemplary
embodiment, the additional therapeutic agent is nifurtimox. In an
exemplary embodiment, the additional therapeutic agent contains a
5-nitrofuran moiety. In an exemplary embodiment, the additional
therapeutic agent contains a 5-nitroimidazolyl moiety. In an
exemplary embodiment, the additional therapeutic agent is
fexinidazole. In an exemplary embodiment, the additional
therapeutic agent is an antiparasitic. In an exemplary embodiment,
the additional therapeutic agent is selected from the group
consisting of amitraz, avermectin, carbadox, diethylcarbamazine,
dimetridazole, diminazene, ivermectin, macrofilaricide, malathion,
mitaban, organophosphate, oxamniquine, permethrin, praziquantel,
pyrantel pamoate, selamectin, sodium stibogluconate and
thiabendazole. In an exemplary embodiment, the additional
therapeutic agent is selected from the group consisting of
antimony, meglumine antimoniate, sodium stibogluconate,
amphotericin, miltefosine and paromomycin.
[0152] In an exemplary embodiment, the additional therapeutic agent
is an antimalarial. In an exemplary embodiment, the additional
therapeutic agent is artemisinin. In an exemplary embodiment, the
additional therapeutic agent is an artemisinin derivative. In an
exemplary embodiment, the additional therapeutic agent is an
artemisinin derivative which is artesunate or artemether or
artemotil or dihydroartemisinin. In an exemplary embodiment, the
additional therapeutic agent is a member selected from
lumefantrine, artemether-lumefantrine, amodiaquine,
artesunate-amodiaquine, artesunate-mefloquine,
artesunate-sulfadoxine/pyrimethamine, atovaquone-proguanil,
quinine, chloroquine, cotrifazid, doxycycline, mefloquine,
primaquine, proguanil, sulfadoxine-pyrimethamine,
hydroxychloroquine, sulfalene-pyrimethamine, dapsone,
proguanil-dapsone and chloroproguanil-dapsone. In an exemplary
embodiment, the additional therapeutic agent is a member selected
from amodiaquine, chloroquine and sulfadoxine-pyrimethamine. In an
exemplary embodiment, the additional therapeutic agent is
mefloquine. In an exemplary embodiment, the additional therapeutic
agent is a member selected from halofantrine,
dihydroartemisinin-piperaquine, piperaquine, pyronaridine and
tetracycline.
[0153] The compounds of the invention, or pharmaceutical
formulations thereof may also be used in combination with other
therapeutic agents, for example immune therapies [e.g. interferon,
such as interferon alfa-2a (ROFERON.RTM.-A; Hoffmann-La Roche),
interferon alpha-2b (INTRON.RTM.-A; Schering-Plough), interferon
alfacon-1 (INFERGEN.RTM.; Intermune), peginterferon alpha-2b
(PEGINTRON.TM.; Schering-Plough) or peginterferon alpha-2a
(PEGASYS.RTM.; Hoffmann-La Roche)], therapeutic vaccines,
antifibrotic agents, anti-inflammatory agents [such as
corticosteroids or NSAIDs], bronchodilators [such as beta-2
adrenergic agonists and xanthines (e.g. theophylline)], mucolytic
agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell
adhesion [e.g. ICAM antagonists], anti-oxidants [e.g.
N-acetylcysteine], cytokine agonists, cytokine antagonists, lung
surfactants and/or antimicrobial. The compositions according to the
invention may also be used in combination with gene replacement
therapy.
[0154] The individual components of such combinations may be
administered either simultaneously or sequentially in a unit dosage
form. The unit dosage form may be a single or multiple unit dosage
forms. In an exemplary embodiment, the invention provides a
combination in a single unit dosage form. An example of a single
unit dosage form is a capsule wherein both the compound of the
invention and the additional therapeutic agent are contained within
the same capsule. In an exemplary embodiment, the invention
provides a combination in a two unit dosage form. An example of a
two unit dosage form is a first capsule which contains the compound
of the invention and a second capsule which contains the additional
therapeutic agent. Thus the term `single unit` or `two unit` or
`multiple unit` refers to the object which the patient ingests, not
to the interior components of the object. Appropriate doses of
known therapeutic agents will be readily appreciated by those
skilled in the art.
[0155] The combinations referred to herein may conveniently be
presented for use in the form of a pharmaceutical formulation.
Thus, an exemplary embodiment of the invention is a pharmaceutical
formulation comprising a) a compound of the invention; b) an
additional therapeutic agent and c) a pharmaceutically acceptable
excipient. In an exemplary embodiment, the pharmaceutical
formulation is a unit dosage form. In an exemplary embodiment, the
pharmaceutical formulation is a single unit dosage form. In an
exemplary embodiment, the pharmaceutical formulation is a two unit
dosage form. In an exemplary embodiment, the pharmaceutical
formulation is a two unit dosage form comprising a first unit
dosage form and a second unit dosage form, wherein the first unit
dosage form includes a) a compound of the invention and b) a first
pharmaceutically acceptable excipient; and the second unit dosage
form includes c) an additional therapeutic agent and d) a second
pharmaceutically acceptable excipient.
[0156] It is to be understood that the invention covers all
combinations of aspects and/or embodiments, as well as suitable,
convenient and preferred groups described herein.
[0157] III.d) Preparation of Boron-Containing Compounds
[0158] Compounds of use in the invention can be prepared using
commercially available starting materials, known intermediates, or
by using the synthetic methods described herein, or published in
references described and incorporated by reference herein, such as
U.S. Prov. Pat. App. 60/654,060; Filed Feb. 16, 2005 (Attorney
Docket No. 064507-5014PR); U.S. patent application Ser. No.
11/357,687, Filed Feb. 16, 2006 (Attorney Docket No.
064507-5014US); U.S. patent application Ser. No. 11/505,591, Filed
Aug. 16, 2006 (Attorney Docket No. 064507-5014US01), U.S. Prov.
Pat. App. 60/823,888 filed on Aug. 29, 2006 and 60/774,532 filed on
Feb. 16, 2006 (Attorney Docket No. 064507-5016PR and
064507-5016PR01, respectively); U.S. patent application Ser. No.
11/676,120, Filed Feb. 16, 2007 (Attorney Docket No.
064507-5016US); U.S. patent application Ser. No. 12/142,692, Filed
Jun. 19, 2008 (Attorney Docket No. 064507-5026US); U.S. patent
application Ser. No. 12/399,015, Filed Mar. 5, 2009 (Attorney
Docket No. 064507-5029US); U.S. patent application Ser. No.
12/464,829, Filed May 12, 2009 (Attorney Docket No. 064507-5033US);
which are herein incorporated by reference in their entirety for
all purposes. Methods of producing the compounds of the invention
are also described in these patent applications.
[0159] The compounds in this invention can be prepared as shown in
the reaction schemes below.
[0160] In an aspect of the invention, compounds of the invention
can be synthesized according to at least one of the following
schemes:
[0161] General Synthetic Scheme:
##STR00067##
[0162] Alternative General Synthetic Scheme:
##STR00068##
[0163] General Synthetic Scheme:
##STR00069##
[0164] Alternative General Synthetic Scheme:
##STR00070##
[0165] General Synthetic Scheme:
##STR00071##
[0166] wherein the E-ring is substituted or unsubstituted
cycloalkoxy (ring sizes from 3 to 8).
[0167] General Synthetic Scheme:
##STR00072##
[0168] wherein the G-ring is substituted or unsubstituted
cycloalkyl (ring sizes from 3 to 8).
[0169] Compounds described herein can be converted into hydrates
and solvates by methods similar to those described herein.
IV. Methods of Inhibiting Microorganism Growth or Killing
Microorganisms
[0170] The compounds of the invention exhibit potency against
microorganisms, such as protozoa, and therefore have the potential
to kill and/or inhibit the growth of microorganisms.
[0171] In a further aspect, the invention provides a method of
killing and/or inhibiting the growth of a microorganism, said
method comprising: contacting said microorganism with an effective
amount of a compound of the invention, thereby killing and/or
inhibiting the growth of the microorganism. In an exemplary
embodiment, the microorganism is a protozoa. In an exemplary
embodiment, the microorganism is a kinetoplastid. In another
exemplary embodiment, the protozoa is a Trypanosoma. In an
exemplary embodiment, the Trypanosoma is a member selected from T.
avium, T. boissoni, T. brucei, T. carassii, T. cruzi, T.
congolense, T. equinum, T. equiperdum, T. evansi, T. hosei, T.
levisi, T. melophagium, T. parroti, T. percae, T. rangeli, T.
rotatorium, T. rugosae, T. sergenti, T. simiae, T. sinipercae, T.
suis, T. theileri, T. triglae and T. vivax. In another exemplary
embodiment, the protozoa is a Trypanosoma brucei. In another
exemplary embodiment, the protozoa is a member selected from
Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and
Trypanosoma brucei gambiense. In another exemplary embodiment, the
protozoa is a member selected from Trypanosoma brucei rhodesiense
and Trypanosoma brucei gambiense. In another exemplary embodiment,
the protozoa is Trypanosoma cruzi. In another exemplary embodiment,
the protozoa is a member of the genus Leishmania. In another
exemplary embodiment, the protozoa is a member of Leishmania
Viannia. In an exemplary embodiment, the protozoa is a member
selected from L. donovani, L. infantum, L. chagasi; L. mexicana, L.
amazonensis, L. venezuelensis, L. tropica, L. major, L. aethiopica,
L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and
L. (V.) peruviana. In an exemplary embodiment, the protozoa is L.
donovani. In an exemplary embodiment, the protozoa is L. infantum.
In another exemplary embodiment, the protozoa is a member of the
genus Plasmodium. In another exemplary embodiment, the protozoa is
a member selected from Plasmodium falciparum, Plasmodium vivax,
Plasmodium ovale, Plasmodium vivax, Plasmodium malariae and
Plasmodium knowlesi. In another exemplary embodiment, the protozoa
is Plasmodium vivax. In another exemplary embodiment, the protozoa
is Plasmodium ovale. In another exemplary embodiment, the protozoa
is Plasmodium malariae. In another exemplary embodiment, the
protozoa is Plasmodium falciparum. In another exemplary embodiment,
the protozoa is transmitted to the animal described herein by a
mosquito infected with the protozoa. In another exemplary
embodiment, wherein the protozoa is transmitted to the animal
described herein by an Anopheles mosquito containing the protozoa.
In an exemplary embodiment, the compound is described herein, or a
salt, prodrug, hydrate or solvate thereof, or a combination
thereof. In an exemplary embodiment, the invention provides a
compound described herein, or a salt, hydrate or solvate thereof.
In an exemplary embodiment, the invention provides a compound
described herein, or a prodrug thereof. In an exemplary embodiment,
the invention provides a compound described herein, or a salt
thereof. In another exemplary embodiment, the compound of the
invention is a compound described herein, or a pharmaceutically
acceptable salt thereof. In another exemplary embodiment, the
compound is described by a formula listed herein, or a
pharmaceutically acceptable salt thereof. In an exemplary
embodiment, the compound is part of a pharmaceutical formulation
described herein. In another exemplary embodiment, the contacting
occurs under conditions which permit entry of the compound into the
organism. Such conditions are known to one skilled in the art and
specific conditions are set forth in the Examples appended
hereto.
[0172] In another aspect, the microorganism is inside, or on the
surface of an animal. In an exemplary embodiment, the animal is a
member selected from human, cattle, deer, reindeer, goat, honey
bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit,
cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose,
guinea fowl, pigeon, swan, and turkey. In another exemplary
embodiment, the animal is a human.
[0173] In an exemplary embodiment, the microorganism is killed or
its growth is inhibited through oral administration of the compound
of the invention. In an exemplary embodiment, the microorganism is
killed or its growth is inhibited through intravenous
administration of the compound of the invention. In an exemplary
embodiment, the microorganism is killed or its growth is inhibited
through topical administration of the compound of the invention. In
an exemplary embodiment, the microorganism is killed or its growth
is inhibited through intraperitoneal administration of the compound
of the invention. In an exemplary embodiment, the compound is
administered in a topically effective amount. In an exemplary
embodiment, the compound is administered in a cosmetically
effective amount. In an exemplary embodiment, the pharmaceutical
formulation is administered in an orally effective amount.
V. Methods of Treating and/or Preventing Disease
[0174] The compounds of the invention exhibit potency against
microorganisms, such as protozoa, and therefore have the potential
to achieve therapeutic efficacy in the animals described
herein.
[0175] In another aspect, the invention provides a method of
treating and/or preventing a disease. The method includes
administering to the animal a therapeutically effective amount of
the compound of the invention, sufficient to treat and/or prevent
the disease. In another aspect, the invention provides a method of
treating a disease in an animal comprising administering to the
animal a therapeutically effective amount of the compound of the
invention, wherein the animal is in need of treatment, sufficient
to treat the disease. In another aspect, the invention provides a
method of treating a disease in an animal comprising administering
to the animal a therapeutically effective amount of the compound of
the invention, wherein the animal is not otherwise in need of
treatment with the compound of the invention, sufficient to treat
the disease. In another aspect, the invention provides a method of
preventing a disease in an animal comprising administering to the
animal a therapeutically effective amount of the compound of the
invention, sufficient to prevent the disease. In an exemplary
embodiment, the compound of the invention can be used in human or
veterinary medical therapy, particularly in the treatment or
prophylaxis of protozoa-associated disease. In an exemplary
embodiment, the compound of the invention can be used in human or
veterinary medical therapy, particularly in the treatment or
prophylaxis of kinetoplastid-associated disease. In an exemplary
embodiment, the disease is associated with a Trypanosoma. In an
exemplary embodiment, the Trypanosoma is a member selected from T.
avium, T. boissoni, T. brucei, T. carassii, T. cruzi, T.
congolense, T. equinum, T. equiperdum, T. evansi, T. hosei, T.
levisi, T. melophagium, T. parroti, T. percae, T. rangeli, T.
rotatorium, T. rugosae, T. sergenti, T. simiae, T. sinipercae, T.
suis, T. theileri, T. triglae and T. vivax. In an exemplary
embodiment, the disease is associated with a Trypanosoma brucei. In
an exemplary embodiment, the disease is associated with a member
selected from Trypanosoma brucei brucei, Trypanosoma brucei
rhodesiense and Trypanosoma brucei gambiense. In an exemplary
embodiment, the disease is associated with Trypanosoma brucei
rhodesiense. In an exemplary embodiment, the disease is associated
with Trypanosoma brucei gambiense. In an exemplary embodiment, the
disease is associated with Trypanosoma cruzi. In an exemplary
embodiment, the disease is a trypanosomiasis. In an exemplary
embodiment, the disease is a human trypanosomiasis. In an exemplary
embodiment, the disease is an animal trypanosomiasis. In an
exemplary embodiment, the disease is a member selected from nagana,
surra, mal de caderas, murrina de caderas, dourine, cachexial
fevers, Gambian horse sickness, baleri, kaodzera, tahaga, galziekte
or galzietzke and peste-boba. In an exemplary embodiment, the
disease is a member selected from Chagas disease (or Human American
trypanosomiasis), nagana, surra, Covering sickness (or dourine) and
sleeping sickness (or African sleeping sickness or Human African
trypanosomiasis). In an exemplary embodiment, the disease is Chagas
disease. In an exemplary embodiment, the disease is sleeping
sickness (or African sleeping sickness). In an exemplary
embodiment, the disease is acute phase sleeping sickness. In an
exemplary embodiment, the disease is chronic phase sleeping
sickness. In an exemplary embodiment, the disease is an acute phase
of a trypanosomiasis. In an exemplary embodiment, the disease is a
chronic phase of a trypanosomiasis. In an exemplary embodiment, the
disease is the non-CNS form of a trypanosomiasis. In an exemplary
embodiment, the disease is the CNS form of a trypanosomiasis. In an
exemplary embodiment, the disease is the non-CNS form of sleeping
sickness. In an exemplary embodiment, the disease is the CNS form
of sleeping sickness. In an exemplary embodiment, the disease is
early stage Human African trypanosomiasis. In an exemplary
embodiment, the disease is late stage Human African
trypanosomiasis. In another exemplary embodiment, the disease is
associated with a member of the genus Leishmania. In another
exemplary embodiment, the disease is associated with a member of
Leishmania Viannia. In an exemplary embodiment, the disease is
associated with a member selected from L. donovani, L. infantum, L.
chagasi; L. mexicana, L. amazonensis, L. venezuelensis, L. tropica,
L. major, L. aethiopica, L. (V.) braziliensis, L. (V) guyanensis,
L. (V.) panamensis, and L. (V.) peruviana. In an exemplary
embodiment, the disease is associated with L. donovani. In an
exemplary embodiment, the disease is associated with L. infantum.
In an exemplary embodiment, the disease is leishmaniasis. In an
exemplary embodiment, the disease is visceral leishmaniasis. In an
exemplary embodiment, the disease is cutaneous leishmaniasis. In an
exemplary embodiment, the disease is diffuse cutaneous
leishmaniasis and/or mucocutaneous leishmaniasis. In another
exemplary embodiment, the disease is associated with a member of
the genus Plasmodium. In another exemplary embodiment, the disease
is associated with a member selected from Plasmodium falciparum,
Plasmodium vivax, Plasmodium ovale, Plasmodium vivax, Plasmodium
malariae and Plasmodium knowlesi. In another exemplary embodiment,
the disease is associated with a member selected from Plasmodium
vivax, Plasmodium ovale, Plasmodium vivax and Plasmodium malariae.
In another exemplary embodiment, the disease is associated with
Plasmodium falciparum. In another exemplary embodiment, the disease
is transmitted to the animal described herein by a mosquito
infected with the protozoa. In another exemplary embodiment, the
disease is transmitted to the animal described herein by an
Anopheles mosquito containing the protozoa. In another exemplary
embodiment, the disease is malaria. In another exemplary
embodiment, the disease is cerebral malaria. In another exemplary
embodiment, the disease is chronic malaria. In an exemplary
embodiment, the compound is described herein, or a salt, prodrug,
hydrate or solvate thereof, or a combination thereof. In an
exemplary embodiment, the invention provides a compound described
herein, or a salt, hydrate or solvate thereof. In an exemplary
embodiment, the invention provides a compound described herein, or
a prodrug thereof. In an exemplary embodiment, the invention
provides a compound described herein, or a salt thereof. In another
exemplary embodiment, the compound of the invention is a compound
described herein, or a pharmaceutically acceptable salt thereof. In
another exemplary embodiment, the compound is described by a
formula listed herein, or a pharmaceutically acceptable salt
thereof. In an exemplary embodiment, the compound is part of a
pharmaceutical formulation described herein. In another exemplary
embodiment, the contacting occurs under conditions which permit
entry of the compound into the organism. Such conditions are known
to one skilled in the art and specific conditions are set forth in
the Examples appended hereto.
[0176] In another exemplary embodiment, the animal is a member
selected from human, cattle, deer, reindeer, goat, honey bee, pig,
sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat,
camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea
fowl, pigeon, swan, and turkey. In another exemplary embodiment,
the animal is a human. In another exemplary embodiment, the animal
is a mouse. In another exemplary embodiment, the animal is a member
selected from a human, cattle, goat, pig, sheep, horse, cow, bull,
dog, guinea pig, gerbil, rabbit, cat, chicken and turkey. In
another exemplary embodiment, the animal is a human.
[0177] In an exemplary embodiment, the disease is treated through
oral administration of the compound of the invention. In an
exemplary embodiment, the disease is treated through intravenous
administration of the compound of the invention. In an exemplary
embodiment, the disease is treated through topical administration
of the compound of the invention. In an exemplary embodiment, the
disease is treated through intraperitoneal administration of the
compound of the invention. In an exemplary embodiment, the compound
is administered in a topically effective amount. In an exemplary
embodiment, the compound is administered in a cosmetically
effective amount. In an exemplary embodiment, the pharmaceutical
formulation is administered in an orally effective amount.
[0178] In an exemplary embodiment, the disease is associated with
an infection by a microorganism described herein. In an exemplary
embodiment, the disease is associated with an infection by a
protozoa described herein.
VI. Pharmaceutical Formulations
[0179] In another aspect, the invention is a pharmaceutical
formulation which includes: (a) a pharmaceutically acceptable
excipient; and (b) a compound of the invention. In another aspect,
the pharmaceutical formulation includes: (a) a pharmaceutically
acceptable excipient; and (b) a compound according to a formula
described herein. In another aspect, the pharmaceutical formulation
includes: (a) a pharmaceutically acceptable excipient; and (b) a
compound described herein, or a salt, prodrug, hydrate or solvate
thereof, or a combination thereof. In another aspect, the
pharmaceutical formulation includes: (a) a pharmaceutically
acceptable excipient; and (b) a compound described herein, or a
salt, hydrate or solvate thereof, or a combination thereof. In
another aspect, the pharmaceutical formulation includes: (a) a
pharmaceutically acceptable excipient; and (b) a compound described
herein, or a salt, hydrate or solvate thereof. In another aspect,
the pharmaceutical formulation includes: (a) a pharmaceutically
acceptable excipient; and (b) a salt of a compound described
herein. In an exemplary embodiment, the salt is a pharmaceutically
acceptable salt. In another aspect, the pharmaceutical formulation
includes: (a) a pharmaceutically acceptable excipient; and (b) a
prodrug of a compound described herein. In another exemplary
embodiment, the pharmaceutical formulation includes: (a) a
pharmaceutically acceptable excipient; and (b) a compound described
herein. In an exemplary embodiment, the pharmaceutical formulation
is a unit dosage form. In an exemplary embodiment, the
pharmaceutical formulation is a single unit dosage form.
[0180] The pharmaceutical formulations of the invention can take a
variety of forms adapted to the chosen route of administration.
Those skilled in the art will recognize various synthetic
methodologies that may be employed to prepare non-toxic
pharmaceutical formulations incorporating the compounds described
herein. Those skilled in the art will recognize a wide variety of
non-toxic pharmaceutically acceptable solvents that may be used to
prepare solvates of the compounds of the invention, such as water,
ethanol, propylene glycol, mineral oil, vegetable oil and
dimethylsulfoxide (DMSO).
[0181] The pharmaceutical formulation of the invention may be
administered orally, topically, intraperitoneally, parenterally, by
inhalation or spray or rectally in unit dosage forms containing
conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles. It is further understood that the best
method of administration may be a combination of methods. Oral
administration in the form of a pill, capsule, elixir, syrup,
lozenge, troche, or the like is particularly preferred. The term
parenteral as used herein includes subcutaneous injections,
intradermal, intravascular (e.g., intravenous), intramuscular,
spinal, intrathecal injection or like injection or infusion
techniques. In an exemplary embodiment, the pharmaceutical
formulation is administered orally. In an exemplary embodiment, the
pharmaceutical formulation is administered intravenously. In an
exemplary embodiment, the pharmaceutical formulation is
administered in a topically effective dose. In an exemplary
embodiment, the pharmaceutical formulation is administered in a
cosmetically effective dose. In an exemplary embodiment, the
pharmaceutical formulation is administered in an orally effective
dose.
[0182] The pharmaceutical formulations containing compounds of the
invention are preferably in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or
soft capsules, or syrups or elixirs.
[0183] Compositions intended for oral use may be prepared according
to any method known in the art for the manufacture of
pharmaceutical formulations, and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving agents in
order to provide pharmaceutically elegant and palatable
preparations. Tablets may contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients
that are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed.
[0184] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0185] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing
or wetting agents, which may be a naturally-occurring phosphatide,
for example, lecithin, or condensation products of an alkylene
oxide with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0186] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide palatable oral preparations. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0187] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0188] Pharmaceutical formulations of the invention may also be in
the form of oil-in-water emulsions and water-in-oil emulsions. The
oily phase may be a vegetable oil, for example olive oil or arachis
oil, or a mineral oil, for example liquid paraffin or mixtures of
these. Suitable emulsifying agents may be naturally-occurring gums,
for example gum acacia or gum tragacanth; naturally-occurring
phosphatides, for example soy bean, lecithin, and esters or partial
esters derived from fatty acids and hexitol; anhydrides, for
example sorbitan monooleate; and condensation products of the said
partial esters with ethylene oxide, for example polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.
[0189] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative, and
flavoring and coloring agents. The pharmaceutical formulations may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents, which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parenterally acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0190] The composition of the invention may also be administered in
the form of suppositories, e.g., for rectal administration of the
drug. These compositions can be prepared by mixing the drug with a
suitable non-irritating excipient that is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are cocoa butter and polyethylene glycols.
[0191] Alternatively, the compositions can be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives and buffering agents can be dissolved in
the vehicle.
[0192] For administration to non-human animals, the composition
containing the therapeutic compound may be added to the animal's
feed or drinking water. Also, it will be convenient to formulate
animal feed and drinking water products so that the animal takes in
an appropriate quantity of the compound in its diet. It will
further be convenient to present the compound in a composition as a
premix for addition to the feed or drinking water. The composition
can also added as a food or drink supplement for humans.
[0193] Dosage levels of the order of from about 5 mg to about 250
mg per kilogram of body weight per day and more preferably from
about 25 mg to about 150 mg per kilogram of body weight per day,
are useful in the treatment of the above-indicated conditions. The
amount of active ingredient that may be combined with the carrier
materials to produce a unit dosage form will vary depending upon
the condition being treated and the particular mode of
administration. Unit dosage forms will generally contain between
from about 1 mg to about 500 mg of an active ingredient.
[0194] Frequency of dosage may also vary depending on the compound
used and the particular disease treated. However, for treatment of
most disorders, a dosage regimen of 4 times daily or less is
preferred. It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of
factors including the activity of the specific compound employed,
the age, body weight, general health, sex, diet, time of
administration, route of administration and rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
[0195] In an exemplary embodiment, the unit dosage form contains
from about 1 mg to about 800 mg of a compound of the invention. In
an exemplary embodiment, the unit dosage form contains from about 1
mg to about 500 mg of an active ingredient. In an exemplary
embodiment, the unit dosage form contains from about 100 mg to
about 800 mg of a compound of the invention. In an exemplary
embodiment, the unit dosage form contains from about 200 mg to
about 500 mg of a compound of the invention. In an exemplary
embodiment, the unit dosage form contains from about 500 mg to
about 800 mg of a compound of the invention. In an exemplary
embodiment, the unit dosage form contains from about 1 mg to about
100 mg of a compound of the invention. In an exemplary embodiment,
the unit dosage form contains from about 10 mg to about 100 mg of a
compound of the invention. In an exemplary embodiment, the unit
dosage form contains from about 50 mg to about 100 mg of a compound
of the invention. In an exemplary embodiment, the unit dosage form
contains from about 25 mg to about 75 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 40 mg to about 60 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 75 mg to about 200 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 1 mg to about 5 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 10 mg to about 25 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 50 mg to about 350 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 200 mg to about 400 mg of a compound of the
invention.
[0196] In an exemplary embodiment, the daily dosage contains from
about 1 mg to about 800 mg of a compound of the invention. In an
exemplary embodiment, the daily dosage contains from about 1 mg to
about 500 mg of an active ingredient. In an exemplary embodiment,
the daily dosage contains from about 100 mg to about 800 mg of a
compound of the invention. In an exemplary embodiment, the daily
dosage contains from about 200 mg to about 500 mg of a compound of
the invention. In an exemplary embodiment, the daily dosage
contains from about 500 mg to about 800 mg of a compound of the
invention. In an exemplary embodiment, the daily dosage contains
from about 1 mg to about 100 mg of a compound of the invention. In
an exemplary embodiment, the daily dosage contains from about 10 mg
to about 100 mg of a compound of the invention. In an exemplary
embodiment, the daily dosage contains from about 50 mg to about 100
mg of a compound of the invention. In an exemplary embodiment, the
daily dosage contains from about 75 mg to about 200 mg of a
compound of the invention. In an exemplary embodiment, the daily
dosage contains from about 1 mg to about 5 mg of a compound of the
invention. In an exemplary embodiment, the daily dosage contains
from about 10 mg to about 25 mg of a compound of the invention. In
an exemplary embodiment, the daily dosage contains from about 50 mg
to about 350 mg of a compound of the invention. In an exemplary
embodiment, the daily dosage contains from about 200 mg to about
400 mg of a compound of the invention.
[0197] Preferred compounds of the invention will have desirable
pharmacological properties that include, but are not limited to,
oral bioavailability, low toxicity, low serum protein binding and
desirable in vitro and in vivo half-lives. Penetration of the blood
brain barrier for compounds used to treat CNS disorders is
necessary, while low brain levels of compounds used to treat
peripheral disorders are often preferred.
[0198] Assays may be used to predict these desirable
pharmacological properties. Assays used to predict bioavailability
include transport across human intestinal cell monolayers,
including Caco-2 cell monolayers. Toxicity to cultured hepatocytes
may be used to predict compound toxicity. Penetration of the blood
brain barrier of a compound in humans may be predicted from the
brain levels of laboratory animals that receive the compound
intravenously.
[0199] Serum protein binding may be predicted from albumin binding
assays. Such assays are described in a review by Oravcova, et al.
(Journal of Chromatography B (1996) volume 677, pages 1-27).
[0200] Compound half-life is inversely proportional to the
frequency of dosage of a compound. In vitro half-lives of compounds
may be predicted from assays of microsomal half-life as described
by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998)
volume 26, pages 1120-1127).
[0201] The amount of the composition required for use in treatment
will vary not only with the particular compound selected but also
with the route of administration, the nature of the condition being
treated and the age and condition of the patient and will
ultimately be at the discretion of the attendant physician or
clinician.
[0202] VI. a) Testing
[0203] Preferred compounds for use in the pharmaceutical
formulations described herein will have certain pharmacological
properties. Such properties include, but are not limited to, low
toxicity, low serum protein binding and desirable in vitro and in
vivo half-lives. Assays may be used to predict these desirable
pharmacological properties. Assays used to predict bioavailability
include transport across human intestinal cell monolayers,
including Caco-2 cell monolayers. Serum protein binding may be
predicted from albumin binding assays. Such assays are described in
a review by Oravcova et al. (1996, J. Chromat. B677: 1-27).
Compound half-life is inversely proportional to the frequency of
dosage of a compound. In vitro half-lives of compounds may be
predicted from assays of microsomal half-life as described by Kuhnz
and Gleschen (Drug Metabolism and Disposition, (1998) volume 26,
pages 1120-1127).
[0204] Toxicity and therapeutic efficacy of such compounds can be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., for determining the LD50 (the dose
lethal to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between toxic and therapeutic effects is the therapeutic index and
it can be expressed as the ratio between LD.sub.50 and ED.sub.50.
Compounds that exhibit high therapeutic indices are preferred. The
data obtained from these cell culture assays and animal studies can
be used in formulating a range of dosage for use in humans. The
dosage of such compounds lies preferably within a range of
circulating concentrations that include the ED.sub.50 with little
or no toxicity. The dosage can vary within this range depending
upon the unit dosage form employed and the route of administration
utilized. The exact formulation, route of administration and dosage
can be chosen by the individual physician in view of the patient's
condition. (See, e.g. Fingl et al., 1975, in "The Pharmacological
Basis of Therapeutics", Ch. 1, p. 1).
[0205] VI. b) Administration
[0206] For any compound used in the method of the invention, the
therapeutically effective dose can be estimated initially from cell
culture assays, as disclosed herein. For example, a dose can be
formulated in animal models to achieve a circulating concentration
range that includes the EC.sub.50 (effective dose for 50% increase)
as determined in cell culture, i.e., the concentration of the test
compound which achieves a half-maximal inhibition of protozoa cell
growth. Such information can be used to more accurately determine
useful doses in humans.
[0207] In general, the compounds prepared by the methods, and from
the intermediates, described herein will be administered in a
therapeutically or cosmetically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of
factors including the activity of the specific compound employed,
the age, body weight, general health, sex, diet, time of
administration, route of administration, and rate of excretion,
drug combination, the severity of the particular disease undergoing
therapy and the judgment of the prescribing physician. The drug can
be administered from once or twice a day, or up to 3 or 4 times a
day.
[0208] Dosage amount and interval can be adjusted individually to
provide plasma levels of the active moiety that are sufficient to
maintain protozoa cell growth inhibitory effects. Usual patient
dosages for systemic administration range from 0.1 to 1000 mg/day,
preferably, 1-500 mg/day, more preferably 10-200 mg/day, even more
preferably 100-200 mg/day. Stated in terms of patient body surface
areas, usual dosages range from 50-91 mg/m.sup.2/day.
[0209] The amount of the compound in a formulation can vary within
the full range employed by those skilled in the art. Typically, the
formulation will contain, on a weight percent (wt %) basis, from
about 0.01-10 wt % of the drug based on the total formulation, with
the balance being one or more suitable pharmaceutical excipients.
Preferably, the compound is present at a level of about 0.1-3.0 wt
%, more preferably, about 1.0 wt %.
[0210] Exemplary embodiments are summarized herein below.
[0211] In an exemplary embodiment, the invention is a compound
having a structure according to formula (I) and/or (II):
##STR00073##
[0212] wherein Y is substituted or unsubstituted C.sub.1-C.sub.3
alkyl or substituted or unsubstituted C.sub.1-C.sub.3 alkyloxy, and
R.sup.1 and R.sup.2 are each independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl,
and wherein R.sup.1 and R.sup.2, along with the nitrogen to which
they are attached, can be optionally joined to form a substituted
or unsubstituted 3 to 8 membered ring, or a salt, or a hydrate, or
a solvate thereof.
[0213] In an exemplary embodiment, according to the above
paragraph, R.sup.1 is according to formula (III):
##STR00074##
[0214] wherein R.sup.8 is H or substituted or unsubstituted alkyl,
and R.sup.4 or R.sup.5 or R.sup.6 or R.sup.7 are each independently
selected from H, substituted or unsubstituted C.sub.1-C.sub.6
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted C.sub.3-C.sub.8 cycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl, and
wherein R.sup.4 and R.sup.5, along with the atoms to which they are
attached, can be optionally joined to form a substituted or
unsubstituted 3 to 8 membered ring, and wherein R.sup.7 and
R.sup.8, along with the atoms to which they are attached, can be
optionally joined to form a substituted or unsubstituted 3 to 8
membered ring, and wherein R.sup.5 and R.sup.6, along with the
atoms to which they are attached, can be optionally joined to form
a substituted or unsubstituted 3 to 8 membered ring.
[0215] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure according to formula (Ia)
and/or (IIa):
##STR00075##
[0216] wherein A is a substituted or unsubstituted 3 to 8 membered
ring.
[0217] In an exemplary embodiment, the invention provides a
combination comprising the compound according to any of the above
paragraphs, together with at least one additional therapeutic
agent.
[0218] In an exemplary embodiment, the invention provides a
pharmaceutical formulation comprising: a) the compound according to
any of the above paragraphs, or a salt thereof; and b) a
pharmaceutically acceptable excipient.
[0219] In an exemplary embodiment, according to any of the above
paragraphs, the pharmaceutical formulation is a unit dosage
form.
[0220] In an exemplary embodiment, according to any of the above
paragraphs, the salt of the compound according to any of the above
paragraphs is a pharmaceutically acceptable salt.
[0221] In an exemplary embodiment, the invention provides a method
of killing and/or preventing the growth of a protozoa, comprising:
contacting the protozoa with an effective amount of the compound of
the invention, thereby killing and/or preventing the growth of the
protozoa.
[0222] In an exemplary embodiment, according to any of the above
paragraphs, the protozoa is a member of the trypanosome genus.
[0223] In an exemplary embodiment, according to any of the above
paragraphs, the protozoa is a member of the leishmania genus.
[0224] In an exemplary embodiment, according to any of the above
paragraphs, the protozoa is a member of the plasmodium genus.
[0225] In an exemplary embodiment, according to any of the above
paragraphs, the protozoa is Trypanosoma brucei.
[0226] In an exemplary embodiment, according to any of the above
paragraphs, the Trypanosoma brucei is a member selected from
Trypanosoma brucei brucei, Trypanosoma brucei gambiense and
Trypanosoma brucei rhodesiense.
[0227] In an exemplary embodiment, according to any of the above
paragraphs, the protozoa is a member selected from Leishmania
donovani, Leishmania infantum, Leishmania chagasi, Leishmania
mexicana, Leishmania amazonensis, Leishmania venezuelensis,
Leishmania tropica, Leishmania major, Leishmania aethiopica.
[0228] In an exemplary embodiment, according to any of the above
paragraphs, the protozoa is Leishmania donovani.
[0229] In an exemplary embodiment, according to any of the above
paragraphs, the protozoa is a member selected from Plasmodium
falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium vivax,
Plasmodium malariae and Plasmodium knowlesi.
[0230] In another exemplary embodiment, according to any of the
above paragraphs, the protozoa is Plasmodium falciparum.
[0231] In an exemplary embodiment, the invention provides a method
of treating and/or preventing a disease in an animal, comprising:
administering to the animal a therapeutically effective amount of
the compound of the invention, thereby treating and/or preventing
the disease.
[0232] In an exemplary embodiment, according to any of the above
paragraphs, the disease is African sleeping sickness.
[0233] In an exemplary embodiment, according to any of the above
paragraphs, the disease is leishmaniasis.
[0234] In an exemplary embodiment, according to any of the above
paragraphs, the leishmaniasis is a member selected from visceral
leishmaniasis, cutaneous leishmaniasis, diffuse cutaneous
leishmaniasis and mucocutaneous leishmaniasis.
[0235] In an exemplary embodiment, according to any of the above
paragraphs, the leishmaniasis is visceral leishmaniasis.
[0236] In an exemplary embodiment, according to any of the above
paragraphs, the leishmaniasis is cutaneous leishmaniasis.
[0237] In an exemplary embodiment, according to any of the above
paragraphs, the disease is malaria.
[0238] In an exemplary embodiment, according to any of the above
paragraphs, the disease is cerebral malaria.
[0239] In an exemplary embodiment, according to any of the above
paragraphs, the animal is a human.
[0240] In an exemplary embodiment, according to any of the above
paragraphs, the invention is a use of a compound of the invention
or a combination of the invention in the manufacture of a
medicament for the treatment and/or prophylaxis of protozoal
infection.
[0241] The invention is further illustrated by the Examples that
follow. The Examples are not intended to define or limit the scope
of the invention.
EXAMPLES
[0242] The following Examples illustrate the synthesis of
representative compounds used in the invention and the following
Reference Examples illustrate the synthesis of intermediates in
their preparation. These examples are not intended, nor are they to
be construed, as limiting the scope of the invention. It will be
clear that the invention may be practiced otherwise than as
particularly described herein. Numerous modifications and
variations of the invention are possible in view of the teachings
herein and, therefore, are within the scope of the invention.
[0243] All temperatures are given in degrees Centigrade. Room
temperature means 20 to 25.degree. C. Reagents were purchased from
commercial sources or prepared following standard literature
procedures. Unless otherwise noted, reactions were carried out
under a positive pressure of nitrogen. Reaction vessels were sealed
with either rubber septa or Teflon screw caps. Nitrogen was
introduced through Tygon tubing, fitted with a large bore syringe
needle. Concentration under vacuum refers to the removal of solvent
on a Buchi Rotary Evaporator.
[0244] Analytical HPLC was performed using a Supelco discovery
C.sub.18 15 cm.times.4.6 mm/5 .mu.m column coupled with an Agilent
1050 series VWD UV detector at 210 nm. Conditions: Solvent A:
H.sub.2O/1% acetonitrile/0.1% HCO.sub.2H; Solvent B: methanol.
[0245] Proton magnetic resonance (.sup.1H NMR) spectra were
recorded on a Varian INOVA NMR spectrometer [400 MHz (.sup.1H) or
500 MHz (.sup.1H)]. All spectra were determined in the solvents
indicated. Although chemical shifts are reported in ppm downfield
of tetramethylsilane, they are referenced to the residual proton
peak of the respective solvent peak for .sup.1H NMR. Interproton
coupling constants are reported in Hertz (Hz).
[0246] LCMS spectra were obtained using a ThermoFinnigan AQA MS ESI
instrument utilizing a Phenomenex Aqua 5 micron C.sub.18 125 .ANG.
50.times.4.60 mm column. The spray setting for the MS probe was at
350 .mu.L/min with a cone voltage at 25 mV and a probe temperature
at 450.degree. C. The spectra were recorded using ELS and UV (254
nm) detection. Alternatively, LCMS spectra were obtained using an
Agilent 1200SL HPLC equipped with a 6130 mass spectrometer
operating with electrospray ionization.
[0247] Silica gel chromatography was carried out on either a
Teledyne ISCO CombiFlash Companion or Companion Rf Flash
Chromatography System with a variable flow rate from 5-100 mL/min.
The columns used were Teledyne ISCO RediSep Disposable Flash
Columns (4, 12, 40, 80, or 120 g prepacked silica gel), which were
run with a maximum capacity of 1 g crude sample per 10 g silica
gel. Samples were preloaded on Celite in Analogix Sample Loading
Cartridges with frits (1/in, 1/out). The eluent was 0-100% EtOAc in
heptane or 0-10% MeOH in CH.sub.2Cl.sub.2 as a linear gradient over
the length of the run (14-20 minutes). Peaks were detected by
variable wavelength UV absorption (200-360 nm). The resulting
fractions were analyzed, combined as appropriate, and evaporated
under reduced pressure to provide purified material.
[0248] HPLC purification was performed using a 50 mm Varian Dynamax
HPLC 21.4 mm Microsorb Guard-8 C.sub.18 column, Dyonex Chromeleon
operating system coupled with a Varian Prostar 320 UV-vis detector
(254 nm) and a Sedex55 ELS detector. Conditions: Solvent A:
H.sub.2O/1% acetonitrile/0.1% HCO.sub.2H; Solvent B: MeOH. The
appropriate solvent gradient for purification was determined based
on the results of analytical HPLC experiments. The resulting
fractions were analyzed, combined as appropriate, and evaporated
under reduced pressure to provide purified material.
[0249] The following experimental sections illustrate procedures
for the preparation of intermediates and methods for the
preparation of products according to this invention. It should be
evident to those skilled in the art that appropriate substitution
of both the materials and methods disclosed herein will produce the
examples illustrated below and those encompassed by the scope of
the invention.
[0250] All solvents used were commercially available and were used
without further purification. Reactions were typically run using
anhydrous solvents under an inert atmosphere of N.sub.2.
[0251] Compounds are named using the AutoNom 2000 add-on for MDL
ISIS.TM. Draw 2.5 SP2 or their catalogue name if commercially
available.
[0252] Starting materials used were either available from
commercial sources or prepared according to literature procedures
and had experimental data in accordance with those reported.
6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (C50), for example, can be
synthesized according to the methods described in U.S. Pat. Pubs.
US20060234981 and US20070155699.
Example 1
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(2-hyd-
roxyethyl)pyrazine-2-carboxamide
##STR00076##
[0253] Step 1: Preparation of
5-chloro-N-(2-hydroxyethyl)pyrazine-2-carboxamide
[0254] To a solution of 5-chloropyrazine-2-carboxylic acid (600 mg,
4 mmol, 1 eq), 2-aminoethanol (300 mg, 4.8 mmol, 1.2 eq), HOBT (700
mg, 5.2 mmol, 1.3 eq) and EDC (Ig, 5.2 mmol, 1.3 eq) in DCM (25 mL,
c=0.16) was added TEA (1.2 g, 12 mmol, 3 eq). The reaction was
stirred at room temperature for 30 min. The mixture was washed with
1N HCl, saturated NaHCO.sub.3, brine, dried over MgSO.sub.4,
filtered and evaporated to give the desired product (610 mg, 80%
yield) as yellow oil.
2: Preparation of 3-(benzyloxy)-6-formyl-2-methylphenyl
trifluoromethanesulfonate
[0255] 4-(benzyloxy)-2-hydroxy-3-methylbenzaldehyde (180 g, 742.97
mmol, 1.0 eq) in DCM (2000 mL) was charged into a 3-L 3-necked
flask and pyridine (176.31 g, 2.23 mol, 3.0 eq) was then added.
Trifluoromethanesulfonic anhydride (314.43 g, 1.114 mol, 1.5 eq)
was added dropwise at <25.degree. C. for 2.5 h and then the
mixture was stirred at 10-25.degree. C. for 3 h. HPLC showed that
the reaction was completed. 1 N HCl (750 mL) was added to the
mixture. The separated organic layer was washed by water
(2.times.1000 mL) and concentrated to give the desired product as
light yellow solid (240.1 g, yield 86.3%, HPLC purity 98%).
Step 3: Preparation of
4-(benzyloxy)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zaldehyde
[0256] 3-(Benzyloxy)-6-formyl-2-methylphenyl
trifluoromethanesulfonate (110.25 g, 294.53 mmol, 1.0 eq),
Pin.sub.2B.sub.2 (82.26 g, 323.98 mmol, 1.1 eq), potassium acetate
(57.84 g, 589.05 mmol, 2.0 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (14.47
g, 20.62 mmol, 0.07 eq) and 1,4-dioxane (1100 mL) were added to a
2-L 3-necked flask and N.sub.2 gas was purged. The resulting
mixture was stirred at 90-95.degree. C. for 4 h. TLC showed that
the reaction was completed. It was filtered and the filtrate was
concentrated at 50.degree. C. to give crude product. EA (600 mL)
was charged into the crude product and the solution was washed with
water (600 mL.times.2). The EA layer was concentrated at 40.degree.
C. to about 400 g solution of crude product in EA. The solution was
charged into a 2 L 3-necked flask and then heated to 60-65.degree.
C. Heptane (850 mL) was added dropwise into the solution, which was
then cooled slowly to 10-20.degree. C. It was stirred at
10-20.degree. C. for 2 h and then filtered. The solid cake was
dried at 40.degree. C. to give the desired product as light yellow
solid. (82.2 g, yield 79.3%). .sup.1H NMR (500 MHz, DMSO-d.sub.6):
.delta. 9.75 (s, 1H), 7.77 (d, 1H), 7.48-7.21 (m, 6H), 5.27 (s,
2H), 2.23 (s, 3H), 1.37 (s, 12H) ppm; HPLC purity 95%.
Step 4: Preparation of
6-(benzyloxy)-7-methylbenzo[c][1,2]oxaborol-1 (3H)-ol
[0257]
4-(Benzyloxy)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)benzaldehyde (179 g, 508.19 mmol, 1.0 eq), DCM (540 mL) and EtOH
(1080 mL) were added into a 3-L 3-necked flask. NaBH.sub.4 (19.21
g, 508.19 mmol, 1.0 eq) was added in portions for 1 h and the
resulting mixture was stirred at 10-25.degree. C. for another 1 h.
TLC showed that the reaction was completed and then 350 mL 1N HCl
was added into the reaction mixture. It was stirred for 20 min and
some solid was precipitated. The mixture was concentrated at
30.degree. C. to remove the DCM and then 960 mL water was added
into the mixture. Solid was precipitated. It was filtered and the
solid cake was dissolved in 2.8 L EA and washed with water (100
mL.times.2). The organic layer was separated and concentrated to
give crude product. A mixed solvent of DCM and PE (750 ml, v/v=2:3)
was added into the crude product and it was stirred at room
temperature for 1 h. It was filtered and the solid cake was dried
at 40.degree. C. in vacuum for 2 h to give the pure product as
light gray solid (94.1 g, yield 72.9%, and purity 98%). .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 8.91 (s, 1H), 7.48-7.32 (m, 5H),
7.14 (s, 2H) 5.12 (s, 2H), 4.88 (s, 2H), 2.35 (s, 3H) ppm.
Step 5: Preparation of
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol
[0258] 6-(Benzyloxy)-7-methylbenzo[c][1,2]oxaborol-1(3H)-ol (69.0
g, 271.56 mmol, 1.0 eq), Pd/C (6.9 g, 0.1 w/w) and MeOH (1050 mL)
were charged into a 2-L 3-necked flask under N.sub.2 with
mechanical stirring. The flask was set under vacuum (-0.085 MPa)
and then H.sub.2 gas was purged. The resulting mixture was stirred
at 30-35.degree. C. for 6 h. TLC showed that the reaction was
completed. It was filtered and the filtrate was concentrated at
40.degree. C. to remove MeOH. Water (150 mL) was added into the
mixture. It was stirred at room temperature for 1 h and filtered.
The cake was dried at 40.degree. C. in vacuum for 2 h to give the
pure product as white solid (35.1 g, yield 79.1%). .sup.1H NMR (300
MHz, DMSO-d.sub.6): .delta. 9.03 (s, 1H), 8.76 (s, 1H), 6.98 (d,
J=8.1 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 4.83 (s, 2H), 2.25 (s, 3H)
ppm; HPLC purity: 97.3% at 220 nm.
Step 6: Preparation of
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(2-hy-
droxyethyl)pyrazine-2-carboxamide
[0259] 7-Methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (10.0 g, 60.99
mmol, 1.0 eq), 5-chloro-N-(2-hydroxyethyl)pyrazine-2-carboxamide
(12.29 g, 60.99 mmol, 1.0 eq), Cs.sub.2CO.sub.3 (49.68 g, 152.47
mmol, 2.5 eq) and DMF (80 mL) were added into a 250-mL 3-necked
flask with mechanical stirring. It was stirred at 35-40.degree. C.
for 24 h and HPLC showed that the reaction was completed. Water
(100 mL) was added and then 700 mL 0.35N HCl was added into the
reaction mixture dropwise while white solid was precipitated. The
mixture was stirred for 20 min and then filtered. The solid cake
was stirred in water (200 mL) for 30 min and filtered. And then the
solid was stirred in acetone (300 mL) and filtered. The solid was
dissolved in 100 ml DMF at 65.degree. C. and then MeCN (200 mL) was
slowly added. The resulting mixture was cooled to room temperature
with stirring while light yellow solid was precipitated. It was
filtered and the solid cake was stirred again in acetone (300 mL)
for 30 min. After filtration, the solid was dried under high vacuum
to give the desired product as off-white solid (10.3 g, yield
51.3%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.05 (s, 1H),
8.65 (s, 1H), 8.59 (s, 1H), 8.58-8.55 (m, 1H), 7.28 (d, J=8.1 Hz,
1H), 7.24 (d, J=8.1 Hz, 1H), 4.98 (s, 2H), 4.76 (t, J=5.4 Hz, 1H),
3.54-3.48 (m, 2H), 3.39-3.30 (m, 2H), 2.21 (s, 3H) ppm; HPLC
purity: 99.6% at 220 nm and 99.3% at 254 nm; Mass: m/z=330
(M+1).
Example 2
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-metho-
xyethyl)pyrazine-2-carboxamide
##STR00077##
[0260] Step 1: Preparation of
5-chloro-N-(2-methoxyethyl)pyrazine-2-carboxamide
[0261] To a solution of 5-chloropyrazine-2-carbonyl chloride (600
mg, 3.16 mmol, 1 eq) in DCM (25 mL) were added 2-methoxyethanamine
(285 mg, 3.8 mmol, 1.2 eq) and TEA (960 mg, 4.1 mmol, 2.5 eq) at
room temperature. The reaction was stirred at room temperature for
2 h. After completion, the reaction was poured into H.sub.2O (100
mL) and extracted with DCM (2.times.20 mL). The combined organic
phases were washed with brine, dried over MgSO.sub.4, filtered and
concentrated in vacuum. The residue was purified by column
chromatography to give the desired product (350 mg, 51% yield) as a
yellow solid.
Step 2: Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-meth-
oxyethyl)pyrazine-2-carboxamide
[0262] To a solution of
5-chloro-N-(2-methoxyethyl)pyrazine-2-carboxamide (216 mg, 1 mmol,
1 eq) in DMF (2 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (164 mg, 1 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (812 mg, 2.5 mmol, 2.5 eq) at room
temperature. The reaction was stirred at 50.degree. C. for 2 h.
After completion, the reaction was poured into 2N HCl (20 mL) and
extracted with EA (2.times.10 mL). The combined organic phases were
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuum. The residue was purified by column chromatography to
give the desired product (45 mg, 13% yield) as a white solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.07 (s, 1H), 8.66 (s,
1H), 8.62-8.59 (m, 1H), 8.60 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.25
(d, J=8.1 Hz, 1H), 4.98 (s, 2H), 3.47-3.46 (m, 4H), 3.26 (s, 3H),
2.22 (s, 3H) ppm. HPLC purity: 98.2% at 220 nm and 96.9% at 254 nm;
Mass: m/z=344 (M+1, ESI+).
Example 3
N-(1-hydroxy-2-methylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c-
][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00078##
[0263] Step 1: Preparation of
5-chloro-N-(1-hydroxy-2-methylpropan-2-yl)pyrazine-2-carboxamide
[0264] To a solution of 5-chloropyrazine-2-carboxylic acid (1 g,
6.33 mmol, 1 eq), HOBT (1.11 g, 8.23 mmol, 1.3 eq), and EDC-HCl
(1.58 g, 8.23 mmol, 1.3 eq) in DCM (48 mL, c=0.13) were added TEA
(1.9 g, 19.0 mmol, 3 eq) and 2-amino-2-methylpropan-1-ol (676 mg,
7.60 mmol, 1.2 eq). The solution was stirred for 2 h. After
completion, the reaction was poured into 1N HCl (60 mL) and
extracted with DCM (1.times.20 mL). The combined organic phases
were washed with brine, dried over MgSO.sub.4, filtered and
concentrated in vacuum. The residue was purified by column
chromatography to give the
5-chloro-N-(1-hydroxy-2-methylpropan-2-yl)pyrazine-2-carboxamide
(200 mg, 14% yield).
Step 2: Preparation of
N-(1-hydroxy-2-methylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0265] To a solution of
5-chloro-N-(1-hydroxy-2-methylpropan-2-yl)pyrazine-2-carboxamide
(100 mg, 0.437 mmol, 1.1 eq) in DMF (1.3 mL, c=0.3) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (65 mg, 0.397 mmol, 1
eq) and Cs.sub.2CO.sub.3 (258 mg, 0.794 mmol, 2 eq) at room
temperature. The reaction was stirred at 50.degree. C. for 2 h.
Then the reaction was poured into water (15 mL), adjusted to pH=5
with 2N HCl. The precipitated solid was filtered. The filter cake
was washed with PE. Then the filter cake was dried in vacuum to
give the desired product (54 mg, 38% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 9.04 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H),
7.94 (s, 1H), 7.29 (d, J=8 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 5.13 (t,
J=5 Hz, 1H) 4.98 (s, 2H), 3.45 (d, J=5 Hz, 2H), 2.21 (s, 3H), 1.35
(s, 6H) ppm. HPLC purity: 97.8% at 220 nm and 96.8% at 254 nm;
Mass: m/z=358.3 (M+1, ESI+).
Example 4
N-(2-hydroxy-2-methylpropyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2-
]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00079##
[0266] Step 1: Preparation of
5-chloro-N-(2-hydroxy-2-methylpropyl)pyrazine-2-carboxamide
[0267] To a solution of 5-chloropyrazine-2-carboxylic acid (1 g,
6.33 mmol, 1 eq), HOBT (1.11 g, 8.23 mmol, 1.3 eq), and EDC-HCl
(1.58 g, 8.23 mmol, 1.3 eq) in DCM (48 mL) were added TEA (1.9 g,
19.0 mmol, 3 eq) and 1-amino-2-methylpropan-2-ol (676 mg, 7.60
mmol, 1.2 eq). The solution was stirred for 4 h. After completion,
the reaction was poured into 1N HCl (10 mL) and extracted with DCM
(1.times.10 mL). The organic phase was dried over MgSO.sub.4,
filtered and concentrated in vacuum. The residue was purified by
column chromatography to give the
5-chloro-N-(2-hydroxy-2-methylpropyl)pyrazine-2-carboxamide (1.1 g,
75% yield).
Step 2: Preparation of
N-(2-hydroxy-2-methylpropyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,-
2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0268] To a solution of
5-chloro-N-(2-hydroxy-2-methylpropyl)pyrazine-2-carboxamide (115
mg, 0.5 mmol, 1 eq) in DMF (1.67 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (82 mg, 0.5 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (326 mg, 1 mmol, 2 eq) at room temperature.
The reaction was stirred at 50.degree. C. for 2 h. Then the
reaction was poured into water (20 mL), adjusted to pH=4 with 2N
HCl. The precipitated solid was filtered. The filter cake was
washed with PE. Then the filter cake was dried in vacuum to give
the desired product (123 mg, 68% yield). .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 9.10 (s, 1H), 8.68 (s, 1H), 8.64 (s, 1H),
8.25-8.40 (m, 1H), 7.30 (d, J=8 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 4.99
(s, 2H), 4.73 (s, 1H), 3.28 (d, J=6.3 Hz, 2H), 2.22 (s, 3H), 1.11
(s, 6H), ppm. HPLC purity: 99.5% at 220 nm and 99.2% at 254 nm;
Mass: m/z=358.5 (M+1, ESI+).
Example 5
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydro-
xypropan-2-yl)pyrazine-2-carboxamide
##STR00080##
[0269] Step 1: Preparation of
5-chloro-N-(1-hydroxypropan-2-yl)pyrazine-2-carboxamide
[0270] To a solution of 5-chloropyrazine-2-carboxylic acid (1 g,
6.33 mmol, 1 eq) and TEA (704 mg, 6.96 mmol, 1.1 eq) in DCM (31.6
mL) was added isobutyl chloroformate (944 mg, 6.96 mmol, 1.1 eq) at
0.degree. C. The reaction was stirred for 20 min. Then
2-aminopropan-1-ol (523 mg, 6.96 mmol, 1.1 eq) was added and
stirred for 1 h. After completion, the reaction was added 1N HCl (4
mL) and extracted with DCM (2.times.8 mL). The combined organic
phases were dried over MgSO.sub.4, filtered, evaporated and
purified by column chromatography to give the
5-chloro-N-(1-hydroxypropan-2-yl)pyrazine-2-carboxamide (0.8 g, 58%
yield).
Step 2: Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydr-
oxypropan-2-yl)pyrazine-2-carboxamide
[0271] To a solution of
5-chloro-N-(1-hydroxypropan-2-yl)pyrazine-2-carboxamide (150 mg,
0.7 mmol, 1.1 eq) in DMF (2.1 mL, c=0.3) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (104 mg, 0.63 mmol, 1
eq) and Cs.sub.2CO.sub.3 (413 mg, 12.7 mmol, 2 eq) at room
temperature. The reaction was stirred at 50.degree. C. for 1 h.
Then the reaction was poured into water (30 mL), adjusted to pH=4
with 2N HCl. The precipitated solid was filtered. The filter cake
was washed with PE. Then the filter cake was dried in vacuum to
give the product (124 mg, 57% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 9.04 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H),
8.27 (d, J=8.5 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.25 (d, J=8.5 Hz,
1H), 4.98 (s, 2H), 4.80 (t, J=5.5 Hz, 1H), 4.10-4.00 (m, 1H),
3.50-3.40 (m, 2H), 2.22 (s, 3H), 1.15 (d, J=7 Hz, 3H) ppm. HPLC
purity: 96.5% at 220 nm and 95.1% at 254 nm; Mass: m/z=344 (M+1,
ESI+).
Example 6
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N,N-bis(2--
hydroxyethyl)pyrazine-2-carboxamide
##STR00081##
[0272] Step 1: Preparation of
5-chloro-N,N-bis(2-hydroxyethyl)pyrazine-2-carboxamide
[0273] To a solution of 5-chloropyrazine-2-carboxylic acid (1 g,
6.33 mmol, 1 eq) and TEA (704 mg, 6.96 mmol, 1.1 eq) in DCM (31.6
mL) was added isobutyl chloroformate (944 mg, 6.96 mmol, 1.1 eq) at
0.degree. C. The reaction was stirred for 20 min. Then
2,2'-azanediyldiethanol (732 mg, 6.96 mmol, 1.1 eq) was added and
stirred for 1 h. After completion, the reaction was added 1N HCl (4
mL) and extracted with DCM (2.times.8 mL). The combined organic
phase was dried over MgSO.sub.4, filtered, evaporated and purified
by column chromatography to
5-chloro-N,N-bis(2-hydroxyethyl)pyrazine-2-carboxamide (700 mg, 45%
yield).
Step 2: Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N,N-bis(2-
-hydroxyethyl)pyrazine-2-carboxamide
[0274] To a solution of
5-chloro-N,N-bis(2-hydroxyethyl)pyrazine-2-carboxamide (123 mg, 0.5
mmol, 1 eq) in DMF (1.67 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (82 mg, 0.5 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (326 mg, 1 mmol, 2 eq) at room temperature.
The reaction was stirred at 50.degree. C. for 2 h. Then the
reaction was poured into water (30 mL), adjusted to pH=4 with 2N
HCl and extracted with EA (2.times.10 mL). The combined organic
phase was washed with brine, dried over MgSO.sub.4, filtered and
concentrated in vacuum. The residue was purified by column
chromatography to give the desired product (16 mg, 8% yield).
.sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 9.02 (s, 1H), 8.49 (s,
1H), 8.30 (s, 1H), 7.27 (d, J=8 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 4.97
(s, 2H), 4.76 (t, J=5 Hz, 1H), 4.55-4.70 (m, 1H), 3.61-3.59 (m,
2H), 3.54-3.51 (m, 2H), 3.49 (s, 4H), 2.22 (s, 3H) ppm. HPLC
purity: 96.7% at 254 nm; Mass: m/z=374 (M+1, ESI+).
Example 7
N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c]-
[1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00082##
[0275] Step 1: Preparation of
5-chloro-N-(1-hydroxy-3-methylbutan-2-yl)pyrazine-2-carboxamide
[0276] To a solution of 5-chloropyrazine-2-carboxylic acid (500 mg,
3.16 mmol, 1 eq) and TEA (352 mg, 3.48 mmol, 1.1 eq) in DCM (15.8
mL, c=0.20) was added isobutyl chloroformate (472 mg, 3.48 mmol,
1.1 eq) at 0.degree. C. The solution was stirred for 0.5 h. Then
2-amino-3-methylbutan-1-ol (359 mg, 3.48 mmol, 1.1 eq) was added
and stirred for 1 h. After completion, the reaction was poured into
2N HCl (20 mL) and extracted with DCM (2.times.5 mL). The combined
organic phase was dried over MgSO.sub.4, filtered, evaporated and
purified by column chromatography to give
5-chloro-N-(1-hydroxy-3-methylbutan-2-yl)pyrazine-2-carboxamide
(270 mg, 35% yield).
Step 2: Preparation of
N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c-
][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0277] To a solution of
5-chloro-N-(1-hydroxy-3-methylbutan-2-yl)pyrazine-2-carboxamide
(134 mg, 0.55 mmol, 1.1 eq) in DMF (2.5 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (82 mg, 0.5 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (325 mg, 1 mmol, 2 eq) at room temperature.
The reaction was stirred at 50.degree. C. for 2 h. Then the
reaction was poured into water (20 mL), adjusted to pH=4 with 2N
HCl. The precipitated solid was filtered. The filter cake was
washed with EA/PE (1/2 mixture). Then the filter cake was dried in
vacuum to give the desired product (74 mg, 20% yield). .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 9.04 (s, 1H), 8.67 (s, 1H), 8.61
(s, 1H), 8.11 (d, J=9.5 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.25 (d, J=8
Hz, 1H), 4.99 (s, 2H), 4.70 (t, J=5 Hz, 1H), 3.78-3.76 (m, 1H),
3.61-3.56 (m, 1H), 3.53-3.29, 2.23 (s, 3H), 1.97-1.92 (m, 1H), 0.92
(d, J=7 Hz, 3H), 0.87 (d, J=7 Hz, 3H) ppm. HPLC purity: 96.3% at
220 nm and 97.8% at 254 nm; Mass: m/z=372 (M+1, ESI+).
Example 8
N-(1-hydroxy-4-methylpentan-2-yl)-5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide
##STR00083##
[0278] Step 1: Preparation of 2-amino-4-methylpentan-1-ol
[0279] To a solution of 2-amino-4-methylpentanoic acid (10 g, 76
mmol, 1 eq) in THF (200 mL) were added NaBH.sub.4 (6.92 g, 183
mmol, 2.4 eq) and then a solution of I.sub.2 (19.3 g, 76 mmol, 1
eq) in THF (50 mL) dropwise at 0.degree. C. After addition, the
reaction was allowed to warm to room temperature. Once no bubble
was emerged from the mixture, the reaction mixture was allowed to
reflux overnight. Then the reaction was quenched slowly with MeOH
(25 mL) and concentrated directly to give a residue. 20% KOH (150
mL) was added and extracted with DCM (3.times.150 mL). The combined
organic phase was washed with brine, dried over Na.sub.2SO.sub.4,
filtered and evaporated to give the desired product (8.67 g, 97%
yield) as oil.
Step 2: Preparation of
5-chloro-N-(1-hydroxy-4-methylpentan-2-yl)pyrazine-2-carboxamide
[0280] To a solution of 5-chloropyrazine-2-carboxylic acid (1 g,
6.3 mmol, 1 eq) in DCM (31 mL, c=0.2) were added TEA (703 mg, 6.96
mmol, 1.1 eq) and a solution of isobutyl chloroformate (943 mg,
6.96 mmol, 1.1 eq) in DCM (3 mL) dropwise at -10.degree. C. In 15
min, 2-amino-4-methylpentan-1-ol (814 mg, 6.96 mmol, 1.1 eq) was
added and the reaction was monitored by TLC. The reaction was
quenched with 1N HCl (10 mL), poured into water (20 mL) and
extracted with DCM (2.times.30 mL). The combined organic phase was
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuum. The residue was purified by column chromatography to
give the desired product (380 mg, 23% yield) as a solid.
Step 3: Preparation of
N-(1-hydroxy-4-methylpentan-2-yl)-5-((1-hydroxy-7-methyl-1,3-dihydrobenzo-
[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide
[0281] To a solution of
5-chloro-N-(1-hydroxy-4-methylpentan-2-yl)pyrazine-2-carboxamide
(100 mg, 0.4 mmol, 1 eq) in DMF (1 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (65 mg, 0.4 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (325 mg, 1 mmol, 2.5 eq) at room temperature.
The reaction was stirred at 40.degree. C. for 2 h. After
completion, the reaction was poured into 1N HCl (20 mL) and
extracted with EA (2.times.10 mL). The combined organic phase was
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuum. The residue was purified by column chromatography to
give the desired product (50 mg, 33% yield) as a solid. .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 9.05 (s, 1H), 8.66 (s, 1H), 8.59
(s, 1H), 8.20 (d, J=9.3 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.25 (d, J=8
Hz, 1H), 4.99 (s, 2H), 4.73 (t, J=7.8 Hz, 1H), 4.06-4.04 (m, 1H),
3.47-3.39 (m, 2H), 2.23 (s, 3H), 1.55-1.48 (m, 2H), 1.40-1.37 (m,
1H), 0.88 (d, J=6.3 Hz, 6H) ppm. HPLC purity: 97.3% at 220 nm and
97.2% at 254 nm; Mass: m/z=386 (M+1, ESI+).
Example 9
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-hydro-
xypropyl)pyrazine-2-carboxamide
##STR00084##
[0282] Preparation of
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(2-hy-
droxypropyl) pyrazine-2-carboxamide
[0283] 5-chloro-N-(2-hydroxypropyl)pyrazine-2-carboxamide was
synthesized from 5-chloropyrazine-2-carboxylic acid and
1-aminopropan-2-ol by using the method in the previous example. To
a solution of the obtained amide (130 mg, 0.60 mmol, 1 eq) in DMF
(1.2 mL) were added 7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol
(100 mg, 0.6 mmol, 1 eq) and Cs.sub.2CO.sub.3 (495 mg, 1.5 mmol,
2.5 eq) at room temperature. The reaction was stirred at 40.degree.
C. for 2 h, poured into 1N HCl (20 mL) and extracted with EA
(2.times.20 mL). The combined organic phase was washed with brine,
dried over MgSO.sub.4, filtered and concentrated in vacuum. The
residue was purified by column chromatography to give the desired
product (65 mg, 29% yield) as a solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 9.06 (s, 1H), 8.66 (s, 1H), 8.60 (s, 1H),
8.48 (t, J=6.0 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.25 (d, J=8 Hz, 1H),
4.98 (s, 2H), 4.82 (d, J=4.8 Hz, 1H), 3.83-3.76 (m, 1H), 3.28-3.19
(m, 2H), 2.22 (s, 3H), 1.06 (d, J=6.0 Hz, 3H) ppm. HPLC purity:
99.1% at 220 nm and 98.9% at 254 nm; Mass: m/z=344 (M+1, ESI+), 366
(M+23, ESI+).
Example 10
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-hydro-
xyethyl)-N-methylpyrazine-2-carboxamide
##STR00085##
[0284] Step 1: Preparation of
5-chloro-N-(2-hydroxyethyl)-N-methylpyrazine-2-carboxamide
[0285] To a solution of 5-chloropyrazine-2-carboxylic acid (500 mg,
3.16 mmol, 1 eq) and TEA (352 mg, 3.48 mmol, 1.1 eq) in DCM (158
mL) was added isobutyl chloroformate (472 mg, 3.48 mmol, 1.1 eq) at
0.degree. C. The solution was stirred for 20 min. Then
2-(methylamino)ethan-1-ol (261 mg in 5 mL DCM) was added and
stirred for 20 min. After completion, the reaction was poured into
2N HCl (10 mL) and extracted with DCM (2.times.5 mL). The combined
organic phase was dried over MgSO.sub.4, filtered, evaporated and
purified by column chromatography to give
5-chloro-N-(2-hydroxyethyl)pyrazine-2-carboxamide (480 mg, 70%
yield).
Step 2: Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-hydr-
oxyethyl)-N-methylpyrazine-2-carboxamide
[0286] To a solution of
5-chloro-N-(2-hydroxyethyl)-N-methylpyrazine-2-carboxamide (236 mg,
1.1 mmol, 1.1 eq) in DMF (5 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (164 mg, 1 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (650 mg, 2 mmol, 2 eq) at room temperature.
The reaction was stirred at 50.degree. C. for 1 h. After
completion, the reaction was poured into water (30 mL), adjusted to
pH=4 with 2N HCl and extracted with EA (2.times.15 mL). The
combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum. The residue was
purified by column chromatography to give the desired product (90
mg, 26% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.07
(s, 1H), 8.60-8.45 (m, 1H), 8.40-8.25 (m, 1H), 7.35-7.20 (m, 2H),
4.98 (s, 2H), 4.82-4.62 (m, 1H), 3.70-3.30 (m, 4H), 3.12-2.95 (m,
3H), 2.24 (s, 3H) ppm, HPLC purity: 100% at 220 nm and 98% at 254
nm; Mass: m/z=344 (M+1, ESI+), 366 (M+23, ESI+).
Example 11
((R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypropan-2-yl)pyrazine-2-carboxamide
##STR00086##
[0287] Step 1: Preparation of
(R)-5-chloro-N-(1-hydroxypropan-2-yl)pyrazine-2-carboxamide
[0288] To a solution of 5-chloropyrazine-2-carboxylic acid (1.5 g,
9.5 mmol, 1.0 eq) in DCM (48 mL, c=0.20) were added TEA (1.06 g,
10.4 mmol, 1.1 eq) and isobutyl chloroformate (1.4 g, 10.4 mmol,
1.1 eq) in ice-water bath. (R)-2-aminopropan-1-ol (784 mg, 10.4
mmol, 1.1 eq) was added after 10 min. The reaction was stirred at
room temperature for 20 min. After completion, the reaction mixture
was adjusted to pH=4 with 1N HCl. The mixture was extracted with
DCM (2.times.50 mL). The combined organic phase was washed with
brine, dried over MgSO.sub.4, filtered and concentrated to give a
residue. The residue was purified by column chromatography to give
the desired product (1.1 g, 55% yield) as a white solid.
Step 2: Preparation of
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypropan-2-yl)pyrazine-2-carboxamide
[0289] To a solution of
(R)-5-chloro-N-(1-hydroxypropan-2-yl)pyrazine-2-carboxamide (550
mg, 2.5 mmol, 1.0 eq) and
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (420 mg, 2.5 mmol, 1.0
eq) in DMF (8.5 mL) was added Cs.sub.2CO.sub.3 (1.65 g, 5.1 mmol,
2.0 eq) under nitrogen. The solution was stirred at 30.degree. C.
for 1 h. After completion, the reaction mixture was adjusted to
pH=6 slowly with 1N HCl and then filtered to give the desired
product (340 mg, 40% yield) as a white solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.66 (s, 1H), 8.60 (s, 1H),
8.30 (d, J=8.4 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.25 (d, J=8 Hz, 1H),
4.99 (s, 2H), 4.83 (t, 1H), 4.04 (m, 1H), 3.43-3.45 (m, 2H), 2.22
(s, 3H), 1.15 (d, J=6.6 Hz, 3H) ppm. HPLC purity: 99.3% at 220 nm
and 99.7% at 254 nm; Mass: m/z=344 (M+1, ESI+).
Example 12
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-h-
ydroxypropan-2-yl)pyrazine-2-carboxamide
##STR00087##
[0290] Step 1: Preparation of
(S)-5-chloro-N-(1-hydroxypropan-2-yl)pyrazine-2-carboxamide
[0291] To a solution of 5-chloropyrazine-2-carboxylic acid (500 mg,
3.2 mmol, 1.0 eq) in DCM (16 mL) was added TEA (352 mg, 3.5 mmol,
1.1 eq) and isobutyl chloroformate (472 mg, 3.5 mmol, 1.1 eq) in
ice-water bath under nitrogen. (S)-2-aminopropan-1-ol (261 mg, 3.5
mmol, 1.1 eq) was added after 10 min. The solution was stirred at
room temperature for 2 h. After completion, the reaction mixture
was adjusted to pH=3 with 1N HCl. The mixture was extracted with
DCM (2.times.30 mL) to give a residue. The residue was purified by
column chromatography to give the desired product (500 mg, 73%
yield).
Step 2: Preparation of
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypropan-2-yl)pyrazine-2-carboxamide
[0292] To a solution of
(S)-5-chloro-N-(1-hydroxypropan-2-yl)pyrazine-2-carboxamide (100
mg, 0.46 mmol, 1.0 eq) and
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (76 mg, 0.46 mmol, 1.0
eq) in DMF (1.5 mL) was added Cs.sub.2CO.sub.3 (303 mg, 0.93 mmol,
2 eq). The solution was stirred at room temperature for 1 h and
then at 30.degree. C. for 1 h. After completion, the reaction
mixture was adjusted to pH=3 with 1N HCl. The aqueous phase was
extracted with DCM (2.times.30 mL). The combined organic phase was
washed with brine, dried over MgSO.sub.4, filtered and concentrated
to give a residue. The residue was purified by column
chromatography to give the desired product (77 mg, 10% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.66 (s,
1H), 8.60 (s, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.29 (d, J=8 Hz, 1H),
7.25 (d, J=8 Hz, 1H), 4.99 (s, 2H), 4.83 (t, J=5.7 Hz, 1H),
4.10-4.00 (m, 1H), 3.47-3.40 (m, 2H), 2.22 (s, 3H), 1.15 (d, J=6.6
Hz, 3H) ppm. HPLC purity: 99.3% at 220 nm and 99.6% at 254 nm;
Mass: m/z=344 (M+1, ESI+).
Example 13
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-h-
ydroxypentan-2-yl)pyrazine-2-carboxamide
##STR00088##
[0293] Step 1: Preparation of (S)-2-aminopentan-1-ol
hydrochloride
[0294] To a solution of NaBH.sub.4 (7.75 g, 205 mmol, 2.4 eq) in
THF (200 mL) was added (S)-2-aminobutanoic acid (10 g, 85.4 mmol, 1
eq) at -10.degree. C. A solution of I.sub.2 (21.7 g, 83.4 mole, 1
eq) in THF (85 mL) was added dropwise into the reaction with
stirring at -10.degree. C. After no gas released, the reaction was
stirred at 68.degree. C. for 21 h. MeOH (40 mL) was added dropwise
into the reaction with stirring at 0.degree. C. until the reaction
was clarified and then concentrated directly. The residue was
dissolved in 4M KOH/H.sub.2O (150 mL), stirred at room temperature
for 4 h and extracted with DCM (3.times.150 mL). The combined
organic phase was washed with brine, dried over MgSO.sub.4,
filtered and evaporated to give the (S)-2-aminopentan-1-ol (8 g,
91% yield). To a solution of (S)-2-aminopentan-1-ol (8 g, 77.5
mmol, 1 eq) in MeOH (75 mL) was added 4N HCl (80 mL). The reaction
was stirred at room temperature for 2 h and then concentrated
directly. The residue was washed with EA/PE (1/3 mixture), dried in
vacuo to give the (S)-2-aminopentan-1-ol hydrochloride (8.5 g, 78%
yield).
Step 2: Preparation of
(S)-5-chloro-N-(1-hydroxypentan-2-yl)pyrazine-2-carboxamide
[0295] To a solution of 5-chloropyrazine-2-carboxylic acid (500 mg,
3.16 mol, 1 eq) in NMP (21 mL) was added
2-chloro-1-methylpyridinium iodide (CMPI, 2.02 g, 7.91 mmol, 2.5
eq). The reaction was stirred at room temperature for 1 h. Then
(S)-2-aminopentan-1-ol hydrochloride (442 mg, 3.16 mmol, 1 eq) and
DIPEA (2.45 g, 19.0 mmol, 6 eq) were added and stirred for 1 h.
After completion, the reaction was poured into water (250 mL),
adjusted to pH=4 with 2N HCl and extracted with EA (2.times.90 mL).
The combined organic phase was washed with brine, dried over MgSO4,
filtered and concentrated in vacuum. The residue was purified by
column chromatography to give
(S)-5-chloro-N-(1-hydroxypentan-2-yl)pyrazine-2-carboxamide (710
mg, yield 90%).
Step 3: Preparation of
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypentan-2-yl)pyrazine-2-carboxamide
[0296] To a solution of
(S)-5-chloro-N-(1-hydroxypentan-2-yl)pyrazine-2-carboxamide (700
mg, 2.87 mmol, 1 eq) in DMF (14.4 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (471 mg, 2.87 mmol, 1
eq) and Cs.sub.2CO.sub.3 (1.87 g, 5.75 mmol, 2 eq) at room
temperature. The reaction was stirred at 50.degree. C. for 2 h.
After completion, the reaction was poured into water (150 mL),
adjusted to pH=4 with 2N HCl. The precipitated solid was filtered.
The filter cake was purified by column chromatography to give the
desired product (330 mg, 31% yield). .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.66 (s, 1H), 8.60 (s, 1H),
8.22 (d, J=9 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.26 (d, J=8 Hz, 1H),
4.99 (s, 2H), 4.72-4.82 (m, 1H), 4.05-3.90 (m, 1H), 3.55-3.35 (m,
2H), 2.22 (s, 3H), 1.68-1.40 (m, 2H), 1.40-1.20 (m, 2H), 0.87 (t,
J=7.2 Hz, 3H) ppm. HPLC purity: 99.7% at 220 nm and 99.5% at 254
nm; Mass: m/z=372 (M+1, ESI+).
Example 14
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-h-
ydroxypentan-2-yl)pyrazine-2-carboxamide
##STR00089##
[0297] Step 1: Preparation of
(R)-5-chloro-N-(1-hydroxypentan-2-yl)pyrazine-2-carboxamide
[0298] To a solution of 5-chloropyrazine-2-carboxylic acid (500 mg,
3.2 mmol, 1.0 eq) in DCM (16 mL) were added TEA (352 mg, 3.5 mmol,
1.1 eq) and isobutyl chloroformate (472 mg, 3.5 mmol, 1.1 eq) at
0.degree. C. under nitrogen. After 10 min, (R)-2-aminopentan-1-ol
(359 mg, 3.5 mmol, 1.1 eq) was added in portions. The solution was
stirred at room temperature for 2 h. After completion, the reaction
mixture was adjusted to pH=3 with 1N HCl and extracted with DCM
(2.times.30 mL). The combined organic phase was washed with brine,
dried over MgSO.sub.4, filtered and concentrated to give a residue.
The residue was purified by column chromatography to give the
desired product (500 mg, 73% yield).
Step 2: Preparation of
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypentan-2-yl)pyrazine-2-carboxamide
[0299] To a solution of
(R)-5-chloro-N-(1-hydroxypentan-2-yl)pyrazine-2-carboxamide (63 mg,
0.26 mmol, 1.0 eq) and 7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol
(42 mg, 0.26 mmol, 1.0 eq) in DMF (1.5 mL, c=0.30) was added
Cs.sub.2CO.sub.3 (168 mg, 0.52 mmol, 2 eq). The mixture was stirred
at 30.degree. C. for 1 h. After completion, the reaction mixture
was adjusted to pH=3 with 1N HCl and filtered. The filtered cake
was dissolved by EA (1 mL), dried over MgSO.sub.4, filtered and
concentrated to give a residue. The residue was purified by column
chromatography to give the desired product (60 mg, 63% yield) as a
white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 9.09 (s,
1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.24 (d, J=9.0 Hz, 1H), 7.30 (d,
J=8 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 4.99 (s, 2H), 4.78 (t, J=5.5 Hz,
1H), 4.01-3.94 (m, 1H), 3.51-3.45 (m, 1H), 3.45-3.40 (m, 1H), 2.22
(s, 3H), 1.61-1.45 (m, 2H), 1.40-1.20 (m, 2H), 0.87 (t, J=6.9 Hz,
3H) ppm. HPLC purity: 99.2% at 220 nm and 99.3% at 254 nm; Mass:
m/z=372 (M+1, ESI+).
Example 15
N-(1-hydroxy-3-phenylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c-
][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00090##
[0300] Step 1: Preparation of
6-chloro-N-(1-hydroxy-3-phenylpropan-2-yl)pyrazine-2-carboxamide
[0301] To a solution of 5-chloropyrazine-2-carboxylic acid (500 mg,
3.2 mmol, 1 eq) in NMP (21 mL) was added
2-chloro-1-methylpyridinium iodide (CMPI, 352 mg, 3.5 mmol, 1.1 eq)
with stirring for 30 min. And then to the reaction mixture were
added 2-amino-3-phenylpropan-1-ol (478 mg, 3.16 mmol, 1 eq) and
DIPEA (2.78 g, 21.5 mmol, 6 eq) for 5 min. The solution was stirred
at room temperature for 2 h. After completion, the reaction mixture
was adjusted pH=3 with 2N HCl, extracted with DCM (2.times.30 mL).
The organic phase was washed with brine (50 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum.
The residue was purified by column chromatography to give the
desired product (650 mg, 71% yield) as a white solid.
Step 2: Preparation of
N-(1-hydroxy-3-phenylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0302] To a solution of
6-chloro-N-(1-hydroxy-3-phenylpropan-2-yl)pyrazine-2-carboxamide
(293 mg, 1.0 mmol, 1.1 eq) and
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (150 mg, 0.91 mmol, 1.0
eq) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (0.74 g, 2.27 mmol,
2.5 eq). The solution was stirred at 50.degree. C. for 2 h. After
completion, the reaction was poured into 1N HCl (50 mL) and
extracted with EA (3.times.30 mL). The combined organic phase was
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuum. The residue was purified by column
chromatography to give the desired product (145 mg, 38% yield) as a
white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.08 (s,
1H), 8.60 (s, 2H), 8.39 (d, J=9.0 Hz, 1H), 7.30-7.10 (m, 7H), 4.98
(s, 2H), 4.95-4.90 (m, 1H), 4.30-4.10 (m, 1H), 3.55-3.40 (m, 2H),
3.00-2.80 (m, 2H), 2.21 (s, 3H) ppm. HPLC purity: 96.2% at 220 nm
and 96.1% at 254 nm; Mass: m/z=420 (M+1, ESI+).
Example 16
N-(2-hydroxy-1-phenylethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]-
oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00091##
[0303] Step 1: Preparation of
5-chloro-N-(2-hydroxy-1-phenylethyl)pyrazine-2-carboxamide
[0304] To a solution of 5-chloropyrazine-2-carboxylic acid (500 mg,
3.16 mmol, 1 eq) in NMP (21 mL) was added CMPI (2.02 g, 7.91 mmol,
2.5 eq). The reaction was stirred at room temperature for 1 h. Then
2-amino-2-phenylethanol (434 mg, 3.16 mmol, 1 eq) and DIPEA (2.78
g, 21.5 mmol, 6.8 eq) were added and stirred for 1 h. After
completion, the reaction was poured into water (200 mL), adjusted
to pH=4 with 2N HCl and extracted with EA (2.times.20 mL). The
combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum to give
5-chloro-N-(2-hydroxy-1-phenylethyl)pyrazine-2-carboxamide (600 mg,
68% yield).
Step 2: Preparation of
N-(2-hydroxy-1-phenylethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2-
]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0305] To a solution of
5-chloro-N-(2-hydroxy-1-phenylethyl)pyrazine-2-carboxamide (277 mg,
1 mmol, 1 eq) in DMF (3.33 mL, c=0.3) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (164 mg, 1 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (650 mg, 2 mmol, 2 eq) at room temperature.
The reaction was stirred at 40.degree. C. for 1 h. After
completion, the reaction was poured into water (30 mL), adjusted to
pH=4 with 2N HCl. The precipitated solid was filtered. The filter
cake was washed with EA/PE (1/1 mixture). Then the filter cake was
dried in vacuo to give the desired product (130 mg, 32% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.07 (s, 1H), 8.90 (d,
J=9 Hz, 1H), 8.65 (s, 2H), 7.45-7.20 (m 7H), 5.10-5.00 (m, 2H),
4.98 (s, 2H), 3.85-3.65 (m, 2H), 2.22 (s, 3H) ppm. HPLC purity:
96.7% at 220 nm and 95.7% at 254 nm; Mass: m/z=406 (M+1, ESI+).
Example 17
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(1-(hy-
droxymethyl)cyclopropyl)pyrazine-2-carboxamide
##STR00092##
[0306] Step 1: Preparation of
5-chloro-N-(1-(hydroxymethyl)cyclopropyl)pyrazine-2-carboxamide
[0307] To a solution of 5-chloropyrazine-2-carboxylic acid (157 mg,
1 mmol, 1 eq) in NMP (10 mL) was added CMPI (637 mg, 2.5 mmol, 2.5
eq) and then stirred for 0.5 h at room temperature. A solution of
(1-aminocyclopropyl)methanol hydrochloride (123 mg, 1 mmol, 1 eq)
in NMP (3 mL) and DIPEA (903 mg, 6.8 mmol, 6.8 eq) was added. After
completion, the reaction mixture was poured into water (100 mL),
adjusted to pH=3 by 1N HCl and extracted with EA (3.times.50 mL).
The combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum. The residue was
purified by column chromatography to give the desired product (100
mg, 44% yield)
Step 2: Preparation of 5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][,
2]oxaborol-6-yl)oxy)-N-(1-(hydroxymethyl)cyclopropyl)pyrazine-2-carboxami-
de
[0308] To a solution of
5-chloro-N-(1-(hydroxymethyl)cyclopropyl)pyrazine-2-carboxamide
(100 mg, 0.4 mmol, 1 eq) in DMF (1.0 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (72 mg, 0.4 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (360 mg, 1.1 mmol, 2.5 eq) at room
temperature. The reaction was stirred at 40.degree. C. for 2 h.
After completion, the reaction was poured into 1N HCl (20 mL) and
extracted with EA (2.times.20 mL). The combined organic phase was
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuum. The residue was purified by column chromatography to
give the desired product (38 mg, 24% yield) as a solid. .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 9.07 (s, 1H), 8.67 (s, 1H), 8.64
(s, 1H), 8.57 (s, 1H), 7.30 (d, J=8 Hz, 1H), 7.25 (d, J=8 Hz, 1H),
4.99 (s, 2H), 4.71 (t, J=5.7 Hz, 1H), 3.52 (d, J=5.7 Hz, 2H), 2.21
(s, 3H), 0.78 (s, 4H) ppm. HPLC purity: 96.5% at 220 nm and 99.2%
at 254 nm; Mass: m/z=356 (M+1, ESI+).
Example 18
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydro-
xybutan-2-yl)pyrazine-2-carboxamide
##STR00093##
[0309] Step 1: Preparation of
5-chloro-N-(1-hydroxybutan-2-yl)pyrazine-2-carboxamide
[0310] To a solution of 5-chloropyrazine-2-carboxylic acid (500 mg,
3.16 mmol, 1 eq), TEA (352 mg, 3.47 mmol, 1.1 eq) in DCM (15.8 mL)
was added isobutyl chloroformate (944 mg, 10.4 mmol, 1.1 eq). After
10 min, 2-aminobutan-1-ol (338 mg, 3.79 mmol, 1.2 eq) was added at
0.degree. C. The reaction mixture was stirred at room temperature
for 10 min. After completion, the reaction was poured into water
(100 mL) and extracted with DCM (2.times.20 mL). The combined
organic phase was washed with brine, dried over MgSO.sub.4,
filtered and concentrated in vacuum. The residue was purified by
column chromatography to give the desired product (480 mg, 66%
yield) as solid.
Step 2: Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydr-
oxybutan-2-yl)pyrazine-2-carboxamide
[0311] To a solution of
5-chloro-N-(1-hydroxybutan-2-yl)pyrazine-2-carboxamide (211 mg,
0.92 mmol, 1 eq) in DMF (3 mL, c=0.3) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (166 mg, 1.0 mmol, 1.1
eq) and Cs.sub.2CO.sub.3 (748 mg, 2.3 mmol, 2.5 eq) at room
temperature. The reaction mixture was stirred at 50.degree. C. for
4 h. After completion, the reaction was poured into 2N HCl (20 mL)
and extracted with EA (2.times.10 mL). The combined organic phase
was washed with brine, dried over MgSO.sub.4, filtered and
concentrated in vacuum. The residue was purified by column
chromatography to give the desired product (247 mg, 75% yield) as a
white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.08 (s,
1H), 8.66 (s, 1H), 8.60 (s, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.40-7.20
(m, 2H), 4.98 (s, 2H), 4.77 (s, 1H), 4.00-3.80 (m, 1H), 3.60-3.40
(m, 2H), 2.22 (s, 3H), 1.75-1.40 (m, 2H), 1.00-0.80 (m, 3H) ppm.
HPLC purity: 95.2% at 220 nm and 97.4% at 254 nm; Mass: m/z=358
(M+1, ESI+).
Example 19
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-h-
ydroxybutan-2-yl)pyrazine-2-carboxamide
##STR00094##
[0312] Step 1: Preparation of
(R)-5-chloro-N-(1-hydroxybutan-2-yl)pyrazine-2-carboxamide
[0313] To a solution of 5-chloropyrazine-2-carboxylic acid (Ig,
9.49 mmol, 1 eq), TEA (704 mg, 10.4 mmol, 1.1 eq) in DCM (31.6 mL)
were added isobutyl chloroformate (944 mg, 10.4 mmol, 1.1 eq).
After 10 min, (R)-2-aminobutan-1-ol (676 mg, 11.4 mmol, 1.2 eq) was
added at 0.degree. C. The reaction mixture was stirred at room
temperature for 10 min. After completion, the reaction was poured
into water (100 mL) and extracted with DCM (2.times.40 mL). The
combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum. The residue was
purified by column chromatography to give the desired product (740
mg, 51% yield) as a colorless solid.
Step 2: Preparation of
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxybutan-2-yl)pyrazine-2-carboxamide
[0314] To a solution of
(R)-5-chloro-N-(1-hydroxybutan-2-yl)pyrazine-2-carboxamide (500 mg,
2.18 mmol, 1 eq) in DMF (7.3 mL, c=0.3) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (394 mg, 2.4 mmol, 1.1
eq) and Cs.sub.2CO.sub.3 (1.77 g, 5.45 mmol, 2.5 eq) at room
temperature. The reaction was stirred at 50.degree. C. for 3 h.
After completion, the reaction was poured into 2N HCl (50 mL) and
extracted with EA (2.times.20 mL). The combined organic phase was
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuum. The residue was purified by column chromatography to
give the desired product (460 mg, 59% yield) as a white solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.66 (s,
1H), 8.61 (s, 1H), 8.23 (d, J=9 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H),
7.25 (d, J=8.4 Hz, 1H), 4.99 (s, 2H), 4.77 (t, J=5.6 Hz, 1H),
3.95-3.80 (m, 1H), 3.50-3.35 (m, 2H), 2.22 (s, 3H), 1.75-1.45 (m,
2H), 0.86 (t, J=7.5 Hz, 3H) ppm. HPLC purity: 100% at 220 nm and
100% at 254 nm; Mass: m/z=358 (M+1, ESI+).
Example 20
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydro-
xybut-3-en-2-yl)pyrazine-2-carboxamide
##STR00095##
[0315] Step 1: Preparation of
2-(tert-butyldimethylsilyloxy)ethanol
[0316] To a solution of NaH (3.8 g, 159.2 mmol, 1.2 eq) in THF (265
mL) was added ethane-1,2-diol (9.88 g, 159.2 mmol, 1.2 eq). Then
the reaction was stirred for 1.5 h. TBSCl (20 g, 132.7 mmol, 1 eq)
was added and stirred for 1.5 h. After completion, the reaction was
poured into water (150 mL), added 0.8 M K2CO3 (40 mL), extracted
with Et.sub.2O. The organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum. The residue was
purified by column chromatography to give
2-(tert-butyldimethylsilyloxy)ethanol (8.6 g, 36% yield).
Step 2: Preparation of
2-(tert-butyldimethylsilyloxy)acetaldehyde
[0317] To a solution of DMSO (7.73 mL, 109 mmol, 2.4 eq) in DCM
(130 mL) was added (COCl).sub.2 (4.6 mL in 8 mL DCM) at -78.degree.
C. Then reaction was stirred for 30 min. To the reaction mixture
was added a solution of pyridine (7.36 mL, 90.85 mmol, 2 eq) and
2-(tert-butyldimethylsilyloxy)ethanol (8 g, 45.42 mmol, 1 eq) in
DCM (10 mL). After completion, Et.sub.3N (31.6 mL, 227 mmol, 5 eq)
was added and stirred for 30 min. Then the reaction was poured into
water (100 mL), adjusted to pH=3 with 1N HCl and extracted with EA
(3.times.50 mL). The combined organic phase was washed with brine,
dried over MgSO.sub.4, filtered and concentrated in vacuum to give
2-(tert-butyldimethylsilyloxy)acetaldehyde (8.3 g, 100% yield).
Step 3: Preparation of
(E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfin-
amide
[0318] To a solution of 2-(tert-butyldimethylsilyloxy)acetaldehyde
(7.9, 45.4 mmol, 1.1 eq) and 2-methylpropane-2-sulfinamide (5 g,
41.25 mmol, 1 eq) in DCM (83 mL) was added Ti(OEt).sub.4 (11.3 g in
20 mL DCM) at room temperature. Then reaction was stirred at
40.degree. C. overnight. After completion, the reaction was poured
into sodium bicarbonate solution (200 mL), added diatomite (20 g)
and stirred for 0.5 h. The mixture was filtered and extracted with
DCM (2.times.50 mL). The combined organic phase was washed with
brine, dried over MgSO.sub.4, concentrated in vacuum. The residue
was purified by column chromatography to give
(E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfin-
amide (5.1 g, 44% yield).
Step 4: Preparation of
N-(1-(tert-butyldimethylsilyloxy)but-3-en-2-yl)-2-methylpropane-2-sulfina-
mide
[0319] To a solution of
(E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfin-
amide (2 g, 7.22 mmol, 1 eq) in DCM (36 mL) was added
vinylmagnesium bromide (5.4 mL, 10.82 mmol, 1.5 eq) at -78.degree.
C. The reaction was stirred for 1 h. After completion, a solution
of ammonium chloride was added dropwise, and the mixture was
extracted with DCM (2.times.10 mL). The combined organic phase was
washed with brine, dried over MgSO4, filtered and concentrated in
vacuum. The residue was purified by column chromatography to give
N-(1-(tert-butyldimethylsilyloxy)but-3-en-2-yl)-2-methylpropane-2-sulfina-
mide (1.2 g, yield 54%).
Step 5: Preparation of 2-aminobut-3-en-1-ol hydrochloride
[0320] To a solution of
N-(1-(tert-butyldimethylsilyloxy)but-3-en-2-yl)-2-methylpropane-2-sulfina-
mide (12 g, 3.93 mmol, 1 eq) in MeOH (19.7 mL) was added 4N
HCl/MeOH (10 mL). The reaction was stirred at room temperature for
1 h. After completion, the reaction was concentrated directly,
washed with EA/PE (1/1 mixture) and dried in vacuum to give
2-aminobut-3-en-1-ol hydrochloride (370 mg, 76% yield).
Step 6: Preparation of
5-chloro-N-(1-hydroxybut-3-en-2-yl)pyrazine-2-carboxamide
[0321] To a solution of 5-chloropyrazine-2-carboxylic acid (473 mg,
3.0 mol, 1 eq) in NMP (19.9 mL) was added CMPI (1.91 g, 7.5 mmol,
2.5 eq). The reaction was stirred at room temperature for 1 h. Then
2-aminobut-3-en-1-ol hydrochloride (370 mg, 3.0 mmol, 1 eq) and
DIPEA (2.32 g, 18.0 mmol, 6 eq) were added and stirred for 1.5 h.
And then the reaction was poured into water (200 mL), adjusted to
pH=4 with 2N HCl and extracted with EA (2.times.80 mL). The
combined organic phase was washed with brine, dried over MgSO4,
filtered and concentrated in vacuum. The residue was purified by
column chromatography to give
5-chloro-N-(1-hydroxybut-3-en-2-yl)pyrazine-2-carboxamide (455 mg,
yield 66%).
Step 7: Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydr-
oxybut-3-en-2-yl)pyrazine-2-carboxamide
[0322] To a solution of
5-chloro-N-(1-hydroxybut-3-en-2-yl)pyrazine-2-carboxamide (455 mg,
2.0 mmol, 1 eq) in DMF (10 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (328 mg, 2.0 mmol, 1
eq) and Cs.sub.2CO.sub.3 (1.3 g, 4 mmol, 2 eq). The reaction was
stirred at 40.degree. C. for 2 h. After completion, the reaction
was poured into water (120 mL), adjusted to pH=3 with 2N HCl and
extracted with EA (2.times.40 mL). The combined organic phase was
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuum. The residue was purified by column chromatography to
give the desired product (260 mg, 36% yield). .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.67 (s, 1H), 8.63 (s, 1H),
8.46 (d, J=8.7 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz,
1H), 6.00-5.85 (m, 1H), 5.19-5.10 (m, 2H), 4.99 (s, 2H), 4.92 (t,
J=5.6 Hz, 1H), 4.60-4.50 (m, 1H), 3.60-3.50 (m, 2H), 2.22 (s, 3H)
ppm. HPLC purity: 99.3% at 220 nm and 99.5% at 254 nm; Mass:
m/z=356 (M+1, ESI+).
Example 21
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-h-
ydroxybutan-2-yl)pyrazine-2-carboxamide
##STR00096##
[0323] Step 1: Preparation of
(S)-5-chloro-N-(1-hydroxybutan-2-yl)pyrazine-2-carboxamide
[0324] To a solution of 5-chloropyrazine-2-carboxylic acid (1 g,
9.49 mmol, 1 eq) and TEA (704 mg, 10.4 mmol, 1.1 eq) in DCM (31.6
mL) was added isobutyl chloroformate (944 mg, 10.4 mmol, 1.1 eq).
The reaction mixture was stirred for 30 min at 0.degree. C., and
then (S)-2-aminobutan-1-ol (676 mg, 11.4 mmol, 1.2 eq) was added at
0.degree. C. The reaction mixture was stirred at room temperature
for 10 min. After completion, the reaction was poured into water
(100 mL) and extracted with DCM (2.times.40 mL). The combined
organic phase was washed with brine, dried over MgSO.sub.4,
filtered and concentrated in vacuum. The residue was purified by
column chromatography to give the desired product (740 mg, 51%
yield) as a colorless solid.
Step 2: Preparation of
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxybutan-2-yl)pyrazine-2-carboxamide
[0325] To a solution of
(S)-5-chloro-N-(1-hydroxybutan-2-yl)pyrazine-2-carboxamide (500 mg,
2.18 mmol, 1 eq) in DMF (7.3 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (394 mg, 2.4 mmol, 1.1
eq) and Cs.sub.2CO.sub.3 (1.77 g, 5.45 mmol, 2.5 eq) at room
temperature. The reaction was stirred at 50.degree. C. for 3 h.
After completion, the reaction was poured into 2N HCl (50 mL) and
extracted with EA (2.times.20 mL). The combined organic phase was
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuum. The residue was purified by column chromatography to
give the desired product (460 mg, 59% yield) as a white solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.66 (s,
1H), 8.61 (s, 1H), 8.23 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H),
7.25 (d, J=8.4 Hz, 1H), 4.99 (s, 2H), 4.78 (t, J=5 Hz, 1H),
3.95-3.80 (m, 1H), 3.60-3.40 (m, 2H), 2.22 (s, 3H), 1.75-1.45 (m,
2H), 0.86 (t, J=7.4 Hz, 3H) ppm. HPLC purity: 100% at 220 nm and
100% at 254 nm; Mass: m/z=358 (M+1, ESI+).
Example 22
N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c]-
[1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00097##
[0326] Step 1: Preparation of
(E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide
[0327] To a solution of cyclopropanecarbaldehyde (7.0 g, 99.12
mmol, 1.2 eq) in DCM (138 mL) were added Ti(OEt).sub.4 (22.6 g,
99.12 mmol, 1.2 eq) and 2-methylpropane-2-sulfinamide (10 g, 82.6
mmol, 1 eq) at room temperature. The reaction was stirred at
50.degree. C. overnight. After completion, the reaction was poured
into Sq NaHCO.sub.3 (138 mL) and diatomite (30 g) with good
stirring for 0.5 h. The reaction mixture was filtered and
separated. Then, the organic phase was washed with brine, dried
over MgSO.sub.4, filtered and concentrated in vacuum to give the
desired product (12.5 g, 87% yield) as oil.
Step 2 and 3: Preparation of
N-(1-cyclopropyl-2-(isopropoxydimethylsilyl)ethyl)-2-methylpropane-2-sulf-
inamide
[0328] To a mixture of Mg (2.86 g, 119.16 mmol, 1.65 eq) in THF (75
mL) were added I.sub.2 (40 mg) and
(chloromethyl)(isopropoxy)dimethylsilane (6.0 g, 36.11 mmol, 0.5
eq) under N.sub.2. The reaction was stirred at 100.degree. C. for 1
h, and then additional (chloromethyl)(isopropoxy)dimethylsilane (12
g, 72.22 mmol, 1.0 eq) was added. The reaction was stirred at
85.degree. C. for 2 h. After completion, a solution of
(E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (12.5 g,
72.22 mmol, 1.0 eq) in THF (37.5 mL) was added into the reaction
mixture at -20.degree. C. under N.sub.2. The reaction was stirred
at room temperature for 1 h. After completion, the reaction was
poured into water (300 mL) and extracted with EA (3.times.100 mL).
The combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum to give the desired
product (22.5 g, 100% yield) as oil.
Step 4: Preparation of
N-(1-cyclopropyl-2-hydroxyethyl)-2-methylpropane-2-sulfinamide
[0329] To a solution of
N-(1-cyclopropyl-2-(isopropoxydimethylsilyl)ethyl)-2-methylpropane-2-sulf-
inamide (22.3 g, 73.07 mmol, 1 eq) in mixed solution (MeOH: 53.5
mL; THF: 53.5 mL) were added KHCO.sub.3 (7.32 g, 73.07 mmol, 1 eq),
KF (8.5 g, 146.14 mmol, 2 eq) and H.sub.2O.sub.2 (22.3 mL) under
N.sub.2 at 0.degree. C. The reaction was stirred at 45.degree. C.
for 2 h. After completion, the reaction was poured into water (300
mL) and extracted with EA (3.times.100 mL). The combined organic
phase was washed with brine, dried over MgSO.sub.4, filtered and
concentrated in vacuum. The residue was purified by column
chromatography to give the desired product (10 g, 67% yield) as a
white solid.
Step 5: Preparation of 2-amino-2-cyclopropylethanol
hydrochloride
[0330] To a solution of
N-(1-cyclopropyl-2-hydroxyethyl)-2-methylpropane-2-sulfinamide (2
g, 9.75 mmol) in MeOH (48.7 mL) was added HCl (24 mL) at 0.degree.
C. The reaction was stirred at room temperature for 2 h. After
completion, the reaction was concentrated in vacuum to give the
desired product (1.3 g, 100% yield) as a white solid.
Step 6: Preparation of
5-chloro-N-(1-cyclopropyl-2-hydroxyethyl)pyrazine-2-carboxamide
[0331] To a solution of 5-chloropyrazine-2-carboxylic acid (1.73 g,
10.95 mmol, 1 eq) and CMPI (7 g, 27.375 mmol, 2.5 eq) in NMP (50
mL) was added a solution of DIPEA (8.5 g, 65.7 mmol, 6 eq) and
2-amino-2-cyclopropylethanol hydrochloride (1.8 g, 13.13 mmol, 1.2
eq) in NMP (23 mL) at room temperature. The reaction was stirred at
room temperature overnight. After completion, the reaction was
poured into water (600 mL) and extracted with EA (3.times.200 mL).
The combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum. The residue was
purified by column chromatography to give the desired product (1.3
g, 50% yield) as a white solid.
Step 7: Preparation of
N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c-
][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0332] To a solution of
5-chloro-N-(1-cyclopropyl-2-hydroxyethyl)pyrazine-2-carboxamide
(150 mg, 0.91 mmol, 1 eq) in DMF (5 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (250 mg, 1.0 mmol, 1.1
eq) and Cs.sub.2CO.sub.3 (0.74 g, 2.27 mmol, 2.5 eq) at room
temperature. The reaction mixture was stirred at 50.degree. C. for
2 h. After completion, the reaction was poured into 2N HCl (50 mL)
and extracted with EA (3.times.20 mL). The combined organic phase
was washed with brine, dried over MgSO.sub.4, filtered and
concentrated in vacuum. The residue was purified by column
chromatography to give the desired product (20 mg, 7% yield) as a
white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.08 (s,
1H), 8.66 (s, 1H), 8.62 (s, 1H), 8.45-8.35 (m, 1H), 7.40-7.20 (m,
2H), 4.99 (s, 2H), 4.85-4.75 (m, 1H), 3.70-3.50 (m, 2H), 3.50-3.30
(m, 1H), 2.22 (s, 3H), 1.10-1.00 (m, 1H), 0.50-0.20 (m, 4H) ppm.
HPLC purity: 95.8% at 220 nm and 96.4% at 254 nm; Mass: m/z=370
(M+1, ESI+).
Example 23
(S)--N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydroben-
zo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00098##
[0333] Step 1: Preparation of
(S)-5-chloro-N-(1-hydroxy-3-methylbutan-2-yl)pyrazine-2-carboxamide
[0334] To a solution of 5-chloropyrazine-2-carboxylic acid (250 mg,
1.58 mmol, 1 eq) in NMP (7.9 mL) was added CMPI (1.1 g, 3.96 mmol,
2.5 eq). The reaction was stirred at room temperature for 2 h. Then
(S)-2-amino-3-methylbutan-1-ol (163 mg, 1.58 mmol, 1 eq) and DIPEA
(1.23 g, 9.49 mmol, 6 eq) were added and stirred for 1 h. After
completion, the reaction was poured into water (400 mL), adjusted
to pH=4 with 2N HCl and extracted with EA (2.times.100 mL). The
combined organic phase was washed with brine, dried over
MgSO.sub.4, evaporated and purified by column chromatography to
give
(S)-5-chloro-N-(1-hydroxy-3-methylbutan-2-yl)pyrazine-2-carboxamide
(245 mg, 64% yield).
Step 2: Preparation of
(S)--N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0335] To a solution of
(S)-5-chloro-N-(1-hydroxy-3-methylbutan-2-yl)pyrazine-2-carboxamide
(134 mg, 0.55 mmol, 1.1 eq) in DMF (5 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (82 mg, 0.5 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (325.8 mg, 1 mmol, 2 eq) at room temperature.
The reaction was stirred at 50.degree. C. for 1 h. After
completion, the reaction was poured into water (250 mL), adjusted
to pH=4 with 2N HCl. The precipitated solid was filtered. The
filtrate was purified by column chromatography and then
recrystallized to give the desired product (48 mg, 36% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.67 (s,
1H), 8.62 (s, 1H), 8.20-8.10 (m, 1H), 7.40-7.20 (m, 2H), 4.99 (s,
2H), 4.80-4.70 (m, 1H), 3.85-3.70 (m, 1H), 3.65-3.45 (m, 2H), 2.22
(s, 3H), 2.02-1.88 (m, 1H), 0.92 (d, J=6.6 Hz, 3H), 0.87 (d, J=6.6
Hz, 3H) ppm. HPLC purity: 99.8% at 220 nm and 99.6% at 254 nm;
Mass: m/z=372 (M+1, ESI+).
Example 24
(R)--N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydroben-
zo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00099##
[0336] Step 1: Preparation of
(S,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide
[0337] To a solution of cyclopropanecarbaldehyde (7.0 g, 99.12
mmol, 1.2 eq) in DCM (138 mL) were added Ti(OEt).sub.4 (22.6 g,
99.12 mmol, 1.2 eq) and (S)-2-methylpropane-2-sulfinamide (10 g,
82.6 mmol, 1 eq) at room temperature. The reaction was stirred at
50.degree. C. overnight. After completion, the reaction was poured
into saturated NaHCO.sub.3 (138 mL) and diatomite (30 g) with good
stirring for 0.5 h. The mixture was filtered and separated. Then,
the organic phase was washed with brine, dried over MgSO.sub.4,
filtered and concentrated in vacuum to give the desired product
(12.5 g, 87% yield) as oil.
Step 2 and 3: Preparation of
(S)--N--((R)-1-cyclopropyl-2-(isopropoxydimethylsilyl)ethyl)-2-methylprop-
ane-2-sulfinamide
[0338] To a mixture of Mg (2.86 g, 119.16 mmol, 1.65 eq) in THF (75
mL) were added I.sub.2 (40 mg) and
(chloromethyl)(isopropoxy)dimethylsilane (6.0 g, 36.11 mmol, 0.5
eq) under N.sub.2. The reaction was stirred at 100.degree. C. for 1
h, and then additional (chloromethyl)(isopropoxy)dimethylsilane (12
g, 72.22 mmol, 1.0 eq) was added dropwise slowly. The reaction was
stirred at 85.degree. C. for 2 h. After completion, a solution of
(S,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (12.5
g, 72.22 mmol, 1.0 eq) in THF (37.5 mL) was added into the reaction
mixture at -20.degree. C. under N.sub.2. The mixture was stirred at
room temperature for 1 h. After completion, the reaction mixture
was poured into water (300 mL) and extracted with EA (3.times.100
mL). The combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum to give the desired
product (22.5 g, 100% yield) as oil.
Step 4: Preparation of
(S)--N--((R)-1-cyclopropyl-2-hydroxyethyl)-2-methylpropane-2-sulfinamide
[0339] To a solution of
(S)--N--((R)-1-cyclopropyl-2-(isopropoxydimethylsilyl)ethyl)-2-methylprop-
ane-2-sulfinamide (22.3 g, 73.07 mmol, 1 eq) in mixed solution
(MeOH: 53.5 mL; THF: 53.5 mL) were added KHCO.sub.3 (7.32 g, 73.07
mmol, 1 eq), KF (8.5 g, 146.14 mmol, 2 eq) and H.sub.2O.sub.2 (22.3
mL) under N.sub.2 at 0.degree. C. The reaction was stirred at
45.degree. C. for 2 h. After completion, the reaction was poured
into water (300 mL) and extracted with EA (3.times.100 mL). The
combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum. The residue was
purified by column chromatography to give the desired product (10
g, 67% yield) as a white solid.
Step 5: Preparation of (R)-2-amino-2-cyclopropylethanol
hydrochloride
[0340] To a solution of
(S)--N--((R)-1-cyclopropyl-2-hydroxyethyl)-2-methylpropane-2-sulfinamide
(2 g, 9.75 mmol, 1 eq) in MeOH (48.7 mL) was added HCl (24 mL) at
0.degree. C. The reaction was stirred at room temperature for 2 h.
After completion, the reaction was concentrated in vacuum to give
the desired product (1.3 g, 100% yield) as a white solid that was
used in the next step without further purification.
Step 6: Preparation of
(R)-5-chloro-N-(1-cyclopropyl-2-hydroxyethyl)pyrazine-2-carboxamide
[0341] To a solution of 5-chloropyrazine-2-carboxylic acid (1.73 g,
10.95 mmol, 1 eq) and CMPI (7 g, 27.375 mmol, 2.5 eq) in NMP (73
mL) was added a solution of DIPEA (8.5 g, 65.7 mmol, 6 eq). In 30
min, (R)-2-amino-2-cyclopropylethanol hydrochloride (1.8 g, 13.13
mmol, 1.2 eq) was added at room temperature. The reaction was
stirred overnight, poured into water (600 mL) and extracted with EA
(3.times.200 mL). The combined organic phase was washed with brine,
dried over MgSO.sub.4, filtered and concentrated in vacuum. The
residue was purified by column chromatography to give the desired
product (1.3 g, 50% yield) as a white solid.
Step 7: Preparation of
(R)--N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0342] To a solution of
(R)-5-chloro-N-(1-cyclopropyl-2-hydroxyethyl)pyrazine-2-carboxamide
(1.0 g, 4.15 mmol, 1 eq) in DMF (21 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (0.75 g, 4.57 mmol, 1.1
eq) and Cs.sub.2CO.sub.3 (3.4 g, 10.38 mmol, 2.5 eq) at room
temperature. The reaction was stirred at 50.degree. C. for 2 h.
After completion, the reaction was poured into 2N HCl (200 mL) and
extracted with EA (3.times.60 mL). The combined organic phase was
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuum. The residue was purified by column chromatography and
prep-HPLC to give the desired product (180 mg, 12% yield) as a
white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.07 (s,
1H), 8.64 (s, 1H), 8.60 (s, 1H), 8.37 (d, J=9.0 Hz, 1H), 7.28 (d,
J=8.1 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 4.97 (s, 2H), 4.78 (t, 1H),
3.65-3.50 (m, 2H), 3.40-3.30 (m, 1H), 2.20 (s, 3H), 1.10-1.00 (m,
1H), 0.50-0.20 (m, 4H) ppm. HPLC purity: 99.6% at 220 nm and 99.7%
at 254 nm; Chiral HPLC purity: 100% at 240 nm; Mass: m/z=370 (M+1,
ESI+) and 392 (M+23, ESI+).
Example 25
(R)--N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydroben-
zo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00100##
[0343] Step 1: Preparation of
(R)-5-chloro-N-(1-hydroxy-3-methylbutan-2-yl)pyrazine-2-carboxamide
[0344] To a solution of 5-chloropyrazine-2-carboxylic acid (250 mg,
1.58 mmol, 1 eq) in NMP (7.9 mL, c=0.20) was added CMPI (1.1 g,
3.96 mmol, 2.5 eq). The reaction was stirred at room temperature
for 2 h. Then (R)-2-amino-3-methylbutan-1-ol (163 mg, 1.58 mmol, 1
eq) and DIPEA (1.23 g, 9.49 mmol, 6 eq) were added and stirred for
1.5 h. After completion, the reaction was poured into water (80 mL)
and extracted with EA (3.times.25 mL). The combined organic phase
was washed with brine, dried over MgSO.sub.4, evaporated and
purified by column chromatography to give the
(R)-5-chloro-N-(1-hydroxy-3-methylbutan-2-yl)pyrazine-2-carboxamide
(250 mg, 65% yield).
Step 2: Preparation of
(R)--N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0345] To a solution of
(R)-5-chloro-N-(1-hydroxy-3-methylbutan-2-yl)pyrazine-2-carboxamide
(243 mg, 1 mmol, 1 eq) in DMF (5 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (164 mg, 1 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (650 mg, 2 mmol, 2 eq) at room temperature.
The reaction mixture was stirred at 50.degree. C. for 1 h. After
completion, the mixture was poured into water (50 mL), adjusted to
pH=5 with 2N HCl and extracted with EA (3.times.50 mL). The
combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum. The residue was
purified by column chromatography and recrystallized to give the
desired product (74 mg, 20% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H),
8.13 (d, J=9.5 Hz, 1H), 7.29 (d, J=8 Hz 1H), 7.26 (d, J=8 Hz, 1H),
4.99 (s, 2H), 4.72 (t, J=5.5 Hz, 1H), 3.82-3.77 (m, 1H), 3.65-3.49
(m, 2H), 2.22 (s, 3H), 1.98-1.92 (m, 1H), 0.92 (d, J=6.5 Hz, 3H),
0.87 (s, J=6.5 Hz, 3H) ppm. HPLC purity: 100% at 220 nm and 100% at
254 nm; Chiral purity: 100% at 240 nm; Mass: m/z=372 (M+1,
ESI+).
Example 26
(R)--N-(2-hydroxy-1-phenylethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c]-
[1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00101##
[0346] Step 1: Preparation of
(R)-5-chloro-N-(2-hydroxy-1-phenylethyl)pyrazine-2-carboxamide
[0347] To a solution of 5-chloropyrazine-2-carboxylic acid (500 mg,
3.16 mmol, 1 eq) in NMP (21.1 mL) was added CMPI (2.02 g, 7.91
mmol, 2.5 eq). The reaction was stirred at room temperature for 2
h. Then (R)-2-amino-2-phenylethanol (434 mg, 3.16 mmol, 1 eq) and
DIPEA (2.45 g, 19 mmol, 6 eq) were added and stirred for 1.5 h.
After completion, the reaction was poured into water (500 mL),
adjusted to pH=4 with 2N HCl and extracted with EA (2.times.150
mL). The combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum to give
(R)-5-chloro-N-(2-hydroxy-1-phenylethyl)pyrazine-2-carboxamide (640
mg, 72% yield).
Step 2: Preparation of
(R)--N-(2-hydroxy-1-phenylethyl)-5-(1-hydroxy-7-methyl-1,3
dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0348] To a solution of
(R)-5-chloro-N-(2-hydroxy-1-phenylethyl)pyrazine-2-carboxamide (554
mg, 2 mmol, 1 eq) in DMF (10 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (316 mg, 2 mmol, 1 eq)
and Cs.sub.2CO.sub.3 (977 mg, 3 mmol, 1.5 eq) at room temperature.
The reaction was stirred at 50.degree. C. for 0.5 h. After
completion, the reaction was poured into ice-water (150 mL),
adjusted to pH=4 with 2N HCl and extracted with EA (2.times.50 mL).
The combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum. The residue was
purified by column chromatography to give the desired product (270
mg, 33% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.08
(s, 1H), 8.92 (d, J=8.4 Hz, 1H), 8.65 (s, 1H), 8.64 (s, 1H),
7.40-7.23 (m, 7H), 5.10-5.00 (m, 2H) 4.98 (s, 2H), 3.85-3.70 (m,
2H), 2.22 (s, 3H) ppm. HPLC purity: 99.9% at 220 nm and 99.8% at
254 nm; Chiral HPLC purity: 100% at 240 nm; Mass: m/z=406 (M+1,
ESI+).
Example 27
(R)--N-(1-hydroxy-3-phenylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy) pyrazine-2-carboxamide
##STR00102##
[0349] Step 1: Preparation of
(R)-6-chloro-N-(1-hydroxy-3-phenylpropan-2-yl)pyrazine-2-carboxamide
[0350] To a solution of 5-chloropyrazine-2-carboxylic acid (500 mg,
3.2 mmol, 1 eq) in NMP (21 mL) was added CMPI (352 mg, 3.5 mmol,
1.1 eq) with stirring for 30 min. And then
(R)-2-amino-3-phenylpropan-1-ol (478 mg, 3.16 mmol, 1 eq) and DIPEA
(2.78 g, 21.5 mmol, 6 eq) were added. The solution was stirred at
room temperature for 2 h. After completion, the reaction mixture
was adjusted to pH=3 by 2N HCl and extracted with DCM (2.times.30
mL). The combined organic phase was washed with brine (50 mL),
dried over anhydrous Na.sub.2SO.sub.4 and filtered. The residue
after rotary evaporation was purified by column chromatography to
give the desired product (650 mg, 71% yield) as a white solid.
Step 2: Preparation of
(R)--N-(1-hydroxy-3-phenylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrob-
enzo[c][1,2]oxaborol-6-yloxy) pyrazine-2-carboxamide
[0351] To a solution of
(R)-6-chloro-N-(1-hydroxy-3-phenylpropan-2-yl)pyrazine-2-carboxamide
(145 mg, 0.5 mmol, 1.0 eq) and
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (79 mg, 0.46 mmol, 1.0
eq) in DMF (2.5 mL, c=0.2) was added Cs.sub.2CO.sub.3 (244 mg, 0.75
mmol, 1.5 eq). The reaction mixture was stirred at 50.degree. C.
for 2 h. After completion, the mixture was adjusted to pH=3 using
1N HCl and extracted with DCM (2.times.30 mL). The combined organic
phase was washed with brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4 and filtered. The residue after rotary evaporation
was purified by column chromatography to give the desired product
(126 mg, 60% yield) as a white solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.60 (s, 2H), 8.39 (d, J=8.4
Hz, 1H), 7.33-7.22 (m, 6H), 7.21-7.13 (m, 1H), 4.98 (s, 2H), 4.93
(t, 1H), 4.25-4.15 (m, 1H), 3.52-3.41 (m, 2H), 2.98-2.84 (m, 2H),
2.21 (s, 3H) ppm. HPLC purity: 98.7% at 220 nm and 100% at 254 nm;
Chiral Purity: 100% at 240 nm; Mass: m/z=420 (M+1, ESI+).
Example 28
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-h-
ydroxyhexan-2-yl) pyrazine-2-carboxamide
##STR00103##
[0352] Step 1: Preparation of (R)-2-aminohexan-1-ol
[0353] To a solution of (R)-2-aminohexanoic acid (10 g, 76.2 mmol,
1 eq) in THF (200 mL) was added NaBH.sub.4 (6.9 g, 182.9 mmol, 2.4
eq) at 0.degree. C. under N.sub.2. A solution of I.sub.2 (19.3 g,
76.2 mmol, 1 eq) in THF (54 mL) was added dropwise into reaction
for 40 min until no gas was produced. The reaction mixture was
stirred overnight at 70.degree. C. After completion, MeOH was added
dropwise into the reaction mixture until it was clear. The reaction
was added 20% KOH (150 mL) and stirred for 4 h. The reaction was
diluted with H.sub.2O (100 mL), extracted with DCM (3.times.150
mL). The organic phase was washed with brine and dried over
anhydrous Na.sub.2SO.sub.4. The reaction mixture was concentrated
to give the desired product (R)-2-aminohexan-1-ol (8.8 g, 99%
yield).
Step 2: Preparation of (R)-2-aminohexan-1-ol hydrochloride
[0354] To a solution of (R)-2-aminohexan-1-ol (9 g, 76.2 mmol, 1
eq) in MeOH (160 mL) was added 4N HCl/MeOH (42 mL), stirred at room
temperature for 40 min. The residue after rotary evaporation was
wished with 40% EA/PE. The precipitated solid was filtered to give
(R)-2-aminohexan-1-ol hydrochloride (11 g, 95% yield).
Step 3: Preparation of
(R)-5-chloro-N-(1-hydroxyhexan-2-yl)pyrazine-2-carboxamide
[0355] To a solution of 5-chloropyrazine-2-carboxylic acid (1.278
g, 8.1 mmol, 1 eq) in NMP (54 mL) was added CMPI (5.17 g, 20.2
mmol, 2.5 eq) with stirring under N.sub.2. In 30 min, a solution of
(R)-2-aminohexan-1-ol hydrochloride (Ig, 8.1 mmol, 1 eq) in NMP (4
mL) was added. The reaction was stirred at room temperature for 2
hours. After completion, the reaction was diluted with H.sub.2O
(800 mL), adjusted to pH 3-4 with 1N HCl, extracted with EA
(2.times.150 mL). The organic phase was washed with brine
(3.times.600 mL) and dried over anhydrous Na.sub.2SO.sub.4. The
residue after rotary evaporation was purified by column
chromatography to give the desired product (1.73 g, 99% yield).
Step 4: Preparation of
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxyhexan-2-yl) pyrazine-2-carboxamide
[0356] To a solution of (R)-5-chloro-N-(1-hydroxyhexan-2-yl)
pyrazine-2-carboxamide (500 mg, 1.8 mmol, 1 eq) in DMF (9 mL,
c=0.2) were added Cs.sub.2CO.sub.3 (1.17 g, 3.6 mmol, 2 eq),
benzo[c][1,2]oxaborole-1,6(3H)-diol (1.17 g, 7.16 mmol, 1 eq). The
reaction was stirred at 50.degree. C. for 2 h. After completion,
the reaction was diluted with H.sub.2O (200 mL), adjusted to pH
3.about.4 with 1N HCl to give a solid precipitation, filtered. The
residue after rotary evaporation was purified by column
chromatography to give the desired product (600 mg, 23% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.07 (s, 1H), 8.66 (s,
1H), 8.60 (s, 1H), 8.23 (d, J=9 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H),
7.25 (d, J=8.4 Hz, 1H), 4.99 (s, 2H), 4.77 (t, 1H), 3.98-3.85 (m,
1H), 3.55-3.35 (m, 2H), 2.22 (s, 3H), 1.70-1.42 (m, 2H), 1.35-1.15
(m, 4H), 0.84 (m, 3H) ppm; HPLC purity: 99.2% at 220 nm and 98.9%
at 254 nm; Chiral HPLC purity: 100% at 240 nm; Mass: m/z=386.2
(M+1, ESI+).
Example 29
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-h-
ydroxybut-3-en-2-yl)pyrazine-2-carboxamide
##STR00104##
[0358] The racemic mixture
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydr-
oxybut-3-en-2-yl)pyrazine-2-carboxamide (330 mg) was separated by
chiral column chromatography to give the desired product
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxybut-3-en-2-yl)pyrazine-2-carboxamide (110 mg) and the other
enantiomer. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.07 (s,
1H), 8.65 (s, 1H), 8.61 (s, 1H), 8.44 (d, J=8.7 Hz, 1H), 7.28 (d,
J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 5.98-5.86 (m, 1H), 5.19-5.06
(m, 2H), 4.97 (s, 2H), 4.94-4.87 (t, 1H), 4.60-4.40 (m, 1H),
3.45-3.54 (m, 2H), 2.20 (s, 3H) ppm; HPLC purity: 99% at 220 nm and
98.4% at 254 nm; Chiral HPLC purity: 100% at 240 nm; Mass: m/z=356
(M+1, ESI+).
Example 30
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-h-
ydroxybut-3-en-2-yl)pyrazine-2-carboxamide
##STR00105##
[0360] The racemic mixture
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydr-
oxybut-3-en-2-yl)pyrazine-2-carboxamide (330 mg) was separated by
chiral column chromatography to give the desired product
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxybut-3-en-2-yl)pyrazine-2-carboxamide (110 mg) and the other
enantiomer. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.07 (s,
1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.45 (d, J=8.7 Hz, 1H), 7.29 (d,
J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 5.97-5.90 (m, 1H), 5.17-5.10
(m, 2H), 4.99 (s, 2H), 4.91 (t, J=5.5 Hz, 1H), 4.55-4.52 (m, 1H),
3.58-3.53 (m, 2H), 2.22 (s, 3H) ppm; HPLC purity: 99% at 220 nm and
98.4% at 254 nm; Chiral HPLC purity: 100% at 240 nm; Mass: m/z=356
(M+1, ESI+), 353.9 (M-1, ESI-).
Example 31
(S)--N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydroben-
zo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00106##
[0361] Step 1: Preparation of
(R,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide
[0362] To a solution of cyclopropanecarbaldehyde (7.0 g, 99.12
mmol, 1.2 eq) in DCM (138 mL) were added Ti(OEt).sub.4 (22.6 g,
99.12 mmol, 1.2 eq) and (R)-2-methylpropane-2-sulfinamide (10 g,
82.6 mmol, 1 eq) at room temperature. The reaction was stirred at
50.degree. C. overnight. After completion, the reaction was poured
into Sq NaHCO.sub.3 (138 mL) and diatomite (30 g) with good
stirring for 0.5 h. The reaction mixture was filtered and
separated. Then, the organic phase was washed with brine, dried
over MgSO.sub.4, filtered and concentrated in vacuum to give the
desired product (12.5 g, 87% yield) as oil.
Step 2 and 3: Preparation of
(R)--N--((S)-1-cyclopropyl-2-(isopropoxydimethylsilyl)ethyl)-2-methylprop-
ane-2-sulfinamide
[0363] To a mixture of Mg (2.86 g, 119.16 mmol, 1.65 eq) in THF (75
mL) were added I.sub.2 (40 mg) and
(chloromethyl)(isopropoxy)dimethylsilane (6.0 g, 36.11 mmol, 0.5
eq) under N.sub.2. The reaction was stirred at 100.degree. C. for 1
h, then additional (chloromethyl)(isopropoxy)dimethylsilane (12 g,
72.22 mmol, 1.0 eq) was added. The reaction was stirred at
85.degree. C. for 2 h. After completion, A solution of
(R,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (12.5
g, 72.22 mmol, 1.0 eq) in THF (37.5 mL) was added into the reaction
at -20.degree. C. under N.sub.2. The reaction was stirred at room
temperature for 1 h. After completion, the reaction was poured into
water (300 mL) and extracted with EA (3.times.100 mL). The combined
organic phase was washed with brine, dried over MgSO.sub.4,
filtered and concentrated in vacuum to give the desired product
(22.5 g, 102% yield) as oil.
Step 4: Preparation of
(R)--N--((S)-1-cyclopropyl-2-hydroxyethyl)-2-methylpropane-2-sulfinamide
[0364] To a solution of
(R)--N--((S)-1-cyclopropyl-2-(isopropoxydimethylsilyl)ethyl)-2-methylprop-
ane-2-sulfinamide (22.3 g, 73.07 mmol, 1 eq) in mixed solution
(MeOH: 53.5 mL; THF: 53.5 mL) were added KHCO.sub.3 (7.32 g, 73.07
mmol, 1 eq), KF (8.5 g, 146.14 mmol, 2 eq) and H.sub.2O.sub.2 (22.3
mL) under N.sub.2 at 0.degree. C. The reaction was stirred at
45.degree. C. for 2 h. After completion, the reaction was poured
into water (300 mL) and extracted with EA (3.times.100 mL). The
combined organic phase was washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuum. The residue was
purified by column chromatography to give the desired product (10
g, 67% yield) as a white solid.
Step 5: Preparation of (S)-2-amino-2-cyclopropylethanol
hydrochloride
[0365] To a solution of
(R)--N--((S)-1-cyclopropyl-2-hydroxyethyl)-2-methylpropane-2-sulfinamide
(2 g, 9.75 mmol, 1 eq) in MeOH (48.7 mL) was added HCl (24 mL) at
0.degree. C. The reaction was stirred at room temperature for 2 h.
After completion, the reaction was concentrated in vacuum to give
the desired product (1.3 g, 100% yield) as a white solid.
Step 6: Preparation of
(S)-5-chloro-N-(1-cyclopropyl-2-hydroxyethyl)pyrazine-2-carboxamide
[0366] To a solution of 5-chloropyrazine-2-carboxylic acid (1.73 g,
10.95 mmol, 1 eq) and CMPI (7 g, 27.375 mmol, 2.5 eq) in NMP (73
mL) was added a solution of DIPEA (8.5 g, 65.7 mmol, 6 eq) and
(S)-2-amino-2-cyclopropylethanol hydrochloride (1.8 g, 13.13 mmol,
1.2 eq) at room temperature. The reaction was stirred overnight.
After completion, the reaction was poured into water (600 mL) and
extracted with EA (3.times.200 mL). The combined organic phase was
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuum. The residue was purified by column chromatography to
give the desired product (1.3 g, 50% yield) as a white solid.
Step 7: Preparation of
(S)--N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0367] To a solution of
(S)-5-chloro-N-(1-cyclopropyl-2-hydroxyethyl)pyrazine-2-carboxamide
(1.0 g, 4.15 mmol, 1 eq) in DMF (21 mL) were added
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (0.75 g, 4.57 mmol, 1.1
eq) and Cs.sub.2CO.sub.3 (3.4 g, 10.38 mmol, 2.5 eq) at room
temperature. The reaction mixture was stirred at 50.degree. C. for
2 h. After completion, the reaction was poured into 2N HCl (200 mL)
and extracted with EA (3.times.60 mL). The combined organic phase
was washed with brine, dried over MgSO.sub.4, filtered and
concentrated in vacuum. The residue was purified by column
chromatography and prep-HPLC to give the desired product (98 mg, 6%
yield) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 9.07 (s, 1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.37 (d, J=9.0
Hz, 1H), 7.24-7.31 (m, 2H), 4.99 (s, 2H), 4.77-4.81 (m, 1H),
3.59-3.61 (m, 2H), 3.32-3.50 (m, 1H), 2.22 (s, 3H), 1.00-1.20 (m,
1H), 0.20-0.50 (m, 4H) ppm. HPLC purity: 96.6% at 220 nm and 95.9%
at 254 nm; Mass: m/z=370 (M+1, ESI+).
Example 32
(S)--N-(1-hydroxy-3-methoxypropan-2-yl)-5-((1-hydroxy-7-methyl-1,3-dihydro-
benzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide
##STR00107##
[0368] Step 1: Preparation of ethyl benzimidate
[0369] To a solution of benzonitrile (10 g, 97 mmol) in
CH.sub.3CH.sub.2OH (54 g, 1164 mmol) was added acetyl chloride (61
g, 776 mmol) at 0.degree. C. The reaction mixture was stirred at
25.degree. C. overnight. After removing the solvent, aq NaHCO.sub.3
solution was added until no gas generated at 0.degree. C. The
solution was extracted with ether (100 mL*3). The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give ethyl
benzimidate (11 g, crude) as a yellow oil which was used for next
step without further purification. MS: m/z=150.0 (M+1, ESI+).
Step 2: Preparation of (S)-methyl
2-phenyl-4,5-dihydrooxazole-4-carboxylate
[0370] To a solution of ethyl benzimidate (8.3 g, 55.8 mmol) in
ClCH.sub.2CH.sub.2Cl (30 mL) was added (S)-methyl
2-amino-3-hydroxypropanoate hydrochloride (9.52 g, 61.38 mmol). The
reaction mixture was stirred at 84.degree. C. overnight. The
solvent was removed under the reduced pressure to give methyl
(S)-2-phenyl-4,5-dihydrooxazole-4-carboxylate (10.6 g, crude) as a
yellow oil which was used for next step without further
purification. MS: m/z=206.0 (M+1, ESI+).
Step 3: Preparation of
(R)-(2-phenyl-4,5-dihydrooxazol-4-yl)methanol
[0371] To a solution of LiAlH.sub.4 (2.9 g, 77.5 mmol) in THF (70
mL) was added methyl (S)-2-phenyl-4,5-dihydrooxazole-4-carboxylate
(10.6 g, 51.7 mmol) in THF (70 mL) at 0.degree. C. The reaction
mixture was stirred at 70.degree. C. for 2 h, and then several drop
of H.sub.2O was added until no gas generated, filtered off and the
filtered cake was washed with EA. The combined organic phase was
concentrated in vacuum and the residue was purified by Combiflash
(EA) to give (R)-(2-phenyl-4,5-dihydrooxazol-4-yl)methanol (2.0 g,
16%, over 3 steps) as a white solid. MS: m/z=178.0 (M+1, ESI+).
Step 4: Preparation of
(R)-4-(methoxymethyl)-2-phenyl-4,5-dihydrooxazole
[0372] To a solution of
(R)-(2-phenyl-4,5-dihydrooxazol-4-yl)methanol (2.0 g, 11.2 mmol) in
THF (60 mL) was added NaH (542 mg, 22.4 mmol) at 0.degree. C. After
being stirred at 0.degree. C. for 15 min, CH.sub.3I (3.98 g, 28.0
mmol) was added. The reaction mixture was stirred at rt overnight.
The solvent was removed and the residue was purified by silica gel
column chromatography using PE:EA=5:1 to give
(R)-4-(methoxymethyl)-2-phenyl-4,5-dihydrooxazole (1.9 g, yield
88%) as a white solid. MS: m/z=192.0 (M+1, ESI+).
Step 5: Preparation of (S)-2-amino-3-methoxypropan-1-ol
hydrochloride
[0373] A solution of
(R)-4-(methoxymethyl)-2-phenyl-4,5-dihydrooxazole (1.9 g, 11.8
mmol) in aq HCl (4N, 60 mL) was refluxed overnight. After cooled to
room temperature, filtered off and the filtrate washed by ether (50
mL*3), then the water layer was lyophilizated to give
(S)-2-amino-3-methoxypropan-1-ol hydrochloride (1.5 g, yield 83%)
as a white solid. MS: m/z=106.0 (M+1, ESI+).
Step 6: Preparation of
(S)-5-chloro-N-(1-hydroxy-3-methoxypropan-2-yl)pyrazine-2-carboxamide
[0374] A solution of 5-chloropyrazine-2-carboxylic acid (187 mg,
1.18 mmol) and HATU (537 mg, 1.41 mmol) in DMF (5 mL) was stirred
at rt for 30 min. Then (S)-2-amino-3-methoxypropan-1-ol
hydrochloride (200 mg, 1.41 mmol) and DIPEA (304 mg, 2.35 mmol)
were added. The resulting mixture was stirred at rt for 1 h, water
(20 mL) was added and the solution was extracted with EA (30 mL*2).
The combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under the reduced
pressure. The residue was purified by Combiflash (PE:EA=1:1) to
give
(S)-5-chloro-N-(1-hydroxy-3-methoxypropan-2-yl)pyrazine-2-carboxamid-
e (230 mg, yield 66%) as a yellow solid. MS: m/z=246.0 (M+1,
ESI+).
Step 7: Preparation of
(S)--N-(1-hydroxy-3-methoxypropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydro-
benzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0375] To a solution of
(S)-5-chloro-N-(1-hydroxy-3-methoxypropan-2-yl)pyrazine-2-carboxamide
(100 mg, 0.408 mmol) and
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (67 mg, 0.408 mmol) in
DMF (5 mL) was added Cs.sub.2CO.sub.3 (265 mg, 0.816 mmol). The
reaction mixture was stirred at 60.degree. C. for 2 h. The mixture
was filtered off and the filtrate was purified by Prep-HPLC to give
(S)--N-(1-hydroxy-3-methoxypropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-di-
hydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide (80 mg,
yield 52.5%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.10 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.25 (d, J=8.8
Hz, 1H), 7.30 (d, J=9 Hz, 2H), 7.26 (d, J=9 Hz, 2H), 4.99 (s, 2H),
4.91 (t, J=5.2 Hz, 1H), 4.17-4.09 (m, 1H), 3.55-3.44 (m, 4H), 3.27
(s, 3H), 2.22 (s, 3H) ppm; HPLC purity: 100% at 220 nm and 100% at
254 nm; Chiral HPLC purity: 100% at 200 nm; MS: m/z=374.1 (M+1,
ESI+).
Example 33
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,4-
,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide
##STR00108##
[0376] Step 1: Preparation of
5-chloro-N-(4,4,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide
[0377] To a solution of 5-chloropyrazine-2-carboxylic acid (372 mg,
2.348 mmol) and HATU (1.07 g, 2.817 mmol) in DMF (10 mL) was added
DIPEA (606 mg, 4.969 mmol). The mixture was stirred at rt for 30
min, then 2-amino-4,4,4-trifluorobutan-1-ol hydrochloride (506 mg,
2.817 mmol) was added. The resulting mixture was stirred at rt for
1 h. Water (30 mL) was added and the solution was extracted with EA
(50 mL*3). The combined organic layers were washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by Combiflash
(PE:EA=1:1) to give
5-chloro-N-(4,4,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide
(435 mg, 65%) as a white solid. MS: m/z=284.0 (M+1, ESI+).
Step 2: Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,4,4--
trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide
[0378] To a solution of
5-chloro-N-(4,4,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide
(435 mg, 1.537 mmol) and
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (252 mg, 1.537 mmol) in
DMF (10 mL) was added Cs.sub.2CO.sub.3 (999 mg, 3.074 mmol). The
reaction mixture was stirred at 60.degree. C. overnight, then
filtered off and the filtrate was purified by prep-HPLC to give
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,4,4--
trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide (360 mg, yield
57%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.09 (s, 1H), 8.72 (d, J=9.2 Hz, 1H), 8.67 (s, 1H), 8.63 (s, 1H),
7.30 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 5.11 (t, J=6.0 Hz,
1H), 4.99 (s, 2H), 4.39-4.30 (m, 1H), 3.50-3.34 (m, 2H), 2.74-2.56
(m, 2H), 2.23 (s, 3H) ppm; MS: m/z=412.1 (M+1, ESI+).
Step 3: Preparation of
((R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4-
,4,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide
[0379] The racemic compound
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,4,4--
trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide (360 mg) was
separated by chiral HPLC method to give
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,-
4,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide (170 mg)
and
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,-
4,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide (33.2 mg)
as white solid respectively. Analytical data for the (R)-isomer is
shown as following. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.10 (s, 1H), 8.74 (d, J=8.8 Hz, 1H), 8.67 (d, J=1.2 Hz, 1H), 8.63
(d, J=1.6 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H),
5.12 (t, J=6.0 Hz, 1H), 4.99 (s, 2H), 4.36-4.32 (m, 1H), 3.50-3.46
(m, 1H), 3.45-3.39 (m, 1H), 2.74-2.60 (m, 2H), 2.22 (s, 3H) ppm;
HPLC purity: 100% at 220 nm and 100% at 254 nm; Chiral purity: 100%
at 230 nm; MS: m/z=412.1 (M+1, ESI+).
Example 34
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,4-
,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide
##STR00109##
[0381] The title (S)-isomer compound was obtained by a chiral HPLC
separation from its racemic mixture as described above in the
section for another enantiomer. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.10 (s, 1H), 8.73 (d, J=9.6 Hz, 1H), 8.67
(d, J=1.6 Hz, 1H), 8.63 (d, J=1.2 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H),
7.26 (d, J=8.0 Hz, 1H), 5.11 (t, J=6.0 Hz, 1H), 4.99 (s, 2H),
4.39-4.30 (m, 1H), 3.49-3.45 (m, 1H), 3.43-3.38 (m, 1H), 2.72-2.59
(m, 2H), 2.22 (s, 3H) ppm; HPLC purity: 100% at 220 nm and 100% at
254 nm; Chiral purity: 98.8% at 230 nm; MS: m/z=412.1 (M+1,
ESI+).
Example 35
(S)--N-(1-hydroxy-3-(methylthio)propan-2-yl)-5-((1-hydroxy-7-methyl-1,3-di-
hydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide
##STR00110##
[0382] Step 1: Preparation of (S)-methyl
2-amino-3-mercaptopropanoate hydrochloride
[0383] To a solution of (S)-2-amino-3-mercaptopropanoic acid
hydrochloride hydrate (3.0 g, 17.0 mmol) in CH.sub.3OH (50 mL) was
added SOCl.sub.2 (4.1 g, 34.0 mmol) at 0.degree. C. The reaction
mixture was stirred at 60.degree. C. overnight. Then concentrated
under the reduced pressure to give (S)-methyl
2-amino-3-mercaptopropanoate hydrochloride (2.3 g, crude) as a
white solid which was used for next step without further
purification. MS: m/z=136.0 (M+1, ESI+).
Step 2: Preparation of (S)-methyl
2-(tert-butoxycarbonylamino)-3-mercaptopropanoate
[0384] To a solution of (S)-methyl 2-amino-3-mercaptopropanoate
hydrochloride (2.0 g, 11.4 mmol) in DCM (50 mL) was added
(Boc).sub.2O (3.7 g, 17.1 mmol). The reaction mixture was stirred
at rt for 2 h. After cooled to room temperature, EA (150 mL) and
ammonia water (50 mL) were added. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated under the reduced
pressure to give (S)-methyl
2-(tert-butoxycarbonylamino)-3-mercaptopropanoate (4 g, crude) as a
white solid which was used for next step without further
purification. MS: m/z=136.0 (M-99, ESI+).
Step 3: Preparation of (S)-methyl
2-(tert-butoxycarbonylamino)-3-(methylthio)propanoate
[0385] To a solution of (S)-methyl
2-(tert-butoxycarbonylamino)-3-mercaptopropanoate (4.0 g, 17.0
mmol) in DCM (50 mL) was added MeI (4.8 g, 34.0 mmol) and DIPEA
(4.4 g, 34.0 mmol). The reaction mixture was stirred at 25.degree.
C. overnight. The solvent was removed and the residue was purified
by silica gel column chromatography using PE:EA=2:1 to give
(S)-methyl 2-(tert-butoxycarbonylamino)-3-(methylthio)propanoate
(2.34 g, yield 54%) as a colorless oil. MS: m/z=150.0 (M-99,
ESI+)
Step 4: Preparation of (S)-methyl 2-amino-3-(methylthio)propanoate
hydrochloride
[0386] To a solution of (S)-methyl
2-(tert-butoxycarbonylamino)-3-(methylthio)propanoate (1.2 g, 3.4
mmol) in 1,4-dioxane (30 mL) was added HCl/1,4-dioxane (4N, 30 mL).
The reaction mixture was stirred at 25.degree. C. overnight. The
mixture was concentrated under the reduced pressure to give crude
(S)-methyl 2-amino-3-(methylthio)propanoate hydrochloride (1.4 g)
as a white solid which was used for next step without further
purification. MS: m/z=150.0 (M+1, ESI+).
Step 5: Preparation of (S)-2-amino-3-(methylthio)propan-1-ol
hydrochloride
[0387] To a solution of LiAlH.sub.4 (0.53 g, 14.0 mmol) in THF (25
mL) was added (S)-methyl 2-amino-3-(methylthio)propanoate
hydrochloride (1.4 g, 9.3 mmol) in THF (5 mL) at 0.degree. C. The
reaction mixture was stirred at 70.degree. C. for 2 h, and then
several drop of H.sub.2O was added until no gas generated. It was
filtered off and the filtered cake was washed with EA. The combined
organic phase was concentrated in vacuum. Then HCl/1,4-dioxane (4N,
20 mL) was added and the resulting mixture was stirred at rt for 30
min. After removed the solvent, H.sub.2O (30 mL) was added, washed
with EA (3*30 mL) and the water layer was lyophilized to give
(S)-2-amino-3-(methylthio)propan-1-ol hydrochloride (880 mg, yield
58%) as a colorless oil. MS: m/z=122.0 (M+1, ESI+).
Step 6: Preparation of
(S)-5-chloro-N-(1-hydroxy-3-(methylthio)propan-2-yl)pyrazine-2-carboxamid-
e
[0388] To a solution of 5-chloropyrazine-2-carboxylic acid (200 mg,
1.26 mmol) and HATU (575 mg, 1.51 mmol) in DMF (5 mL) was added
DIPEA (326 mg, 2.52 mmol). The mixture was stirred at rt for 30
min, and then (S)-2-amino-3-(methylthio)propan-1-ol hydrochloride
(239 mg, 1.51 mmol) was added. The resulting mixture was stirred at
rt for 1 h, water (20 mL) was added and the solution was extracted
with EA (30 mL*2). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
the reduced pressure. The residue was purified by Combiflash
(PE:EA=1:1) to give
(S)-5-chloro-N-(1-hydroxy-3-(methylthio)propan-2-yl)pyrazine-2-carboxamid-
e (207 mg, 62.6%) as a yellow solid. MS: m/z=262.0 (M+1, ESI+).
Step 7: Preparation of
(S)--N-(1-hydroxy-3-(methylthio)propan-2-yl)-5-(1-hydroxy-7-methyl-1,3-di-
hydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0389] To a solution of
(S)-5-chloro-N-(1-hydroxy-3-(methylthio)propan-2-yl)pyrazine-2-carboxamid-
e (100 mg, 0.383 mmol) and
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (63 mg, 0.383 mmol) in
DMF (10 mL) was added Cs.sub.2CO.sub.3 (249 mg, 0.766 mmol). The
reaction mixture was stirred at 60.degree. C. for 2 h, and then
filtered off. The filtrate was purified by prep-HPLC to give
(S)--N-(1-hydroxy-3-(methylthio)propan-2-yl)-5-(1-hydroxy-7-methyl-1,3-di-
hydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide (70 mg,
yield 47%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.09 (s, 1H), 8.68 (s, 1H), 8.63 (s, 1H), 8.41 (d, J=9.2
Hz, 1H), 7.28 (q, J=8.4 Hz, 2H), 4.99 (s, 2H), 4.95 (t, J=5.2 Hz,
1H), 4.16-4.08 (m, 1H), 3.62-3.47 (m, 2H), 2.79-2.65 (m, 2H), 2.50
(s, 3H), 2.22 (s, 3H) ppm; HPLC purity: 100% at 220 nm and 100% at
254 nm; Chiral HPLC purity: 100% at 230 nm; MS: m/z=390.0 (M+1,
ESI+).
Example 36
(S)--N-(1-hydroxy-3-(methylsulfonyl)propan-2-yl)-5-(1-hydroxy-7-methyl-1,3-
-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00111##
[0390] Step 1: Preparation of
(S)-5-chloro-N-(1-hydroxy-3-(methylsulfonyl)propan-2-yl)pyrazine-2-carbox-
amide
[0391] To a solution of
(S)-5-chloro-N-(1-hydroxy-3-(methylthio)propan-2-yl)pyrazine-2-carboxamid-
e (100 mg, 0.383 mmol) in DCM (10 mL) was added mCPBA (132 mg,
0.766 mmol) at 0.degree. C. The mixture was stirred at rt for 90
min, water (20 mL) was added and the solution was extracted with
DCM (30 mL*2). The combined organic layers were washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by Combiflash
(PE:EA=1:8) to give
((S)-5-chloro-N-(1-hydroxy-3-(methylsulfonyl)propan-2-yl)pyrazine-2-carbo-
xamide (89 mg, yield 79%) as a yellow solid. MS: m/z=294.0 (M+1,
ESI+).
Step 2: Preparation of
(S)--N-(1-hydroxy-3-(methylsulfonyl)propan-2-yl)-5-(1-hydroxy-7-methyl-1,-
3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0392] To a solution of
(S)-5-chloro-N-(1-hydroxy-3-(methylsulfonyl)propan-2-yl)pyrazine-2-carbox-
amide (84 mg, 0.287 mmol) and
7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (47 mg, 0.287 mmol) in
DMF (3 mL) was added Cs.sub.2CO.sub.3 (186 mg, 0.574 mmol). The
reaction mixture was stirred at 60.degree. C. for 2 h and filtered
off. The filtrate was purified by prep-HPLC to give
(S)--N-(1-hydroxy-3-(methylsulfonyl)propan-2-yl)-5-(1-hydroxy-7-methyl-1,-
3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide (54
mg, yield 45%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.10 (s, 1H), 8.78 (d, J=9.2 Hz, 1H), 8.68
(d, J=1.2 Hz, 1H), 8.64 (d, J=1.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H),
7.26 (d, J=8.4 Hz, 1H), 5.15 (t, J=5.6 Hz, 1H), 4.99 (s, 2H),
4.53-4.51 (m, 1H), 3.61-3.31 (m, 4H), 2.97 (s, 3H), 2.22 (s, 3H)
ppm; Chiral purity: 100% at 230 nm; HPLC purity: 100% at 220 nm and
100% at 254 nm; MS: m/z=422.1 (M+1, ESI+).
Example 37
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,5-
,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide
##STR00112##
[0393] Step 1: Preparation of 3,3,3-trifluoropropyl
trifluoromethanesulfonate
[0394] At -25.degree. C., 2,6-lutidine (1.41 g, 13.2 mmol) in DCM
(50 mL) was mixed with Tf.sub.2O (3.47 g, 12.3 mmol), and the
mixture was stirred for 5 min. To the mixture was added
3,3,3-trifluoropropan-1-ol (1.0 g, 8.8 mmol). After 2 h, it was
warmed to rt and stirred for 1 h. The solvent was removed and the
residue was purified by silica gel column chromatography using
PE:EA=2:1 to give 3,3,3-trifluoropropyl trifluoromethanesulfonate
(460 mg, yield 21%) as a yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 4.73-4.70 (m, 2H), 2.72-2.65 (m, 2H) ppm.
Step 2: Preparation of tert-butyl
2-(diphenylmethyleneamino)-5,5,5-trifluoropentanoate
[0395] A solution of tert-butyl 2-(diphenylmethyleneamino)acetate
(424 mg, 1.44 mmol) in THF (20 mL) was cooled to -78.degree. C. and
treated dropwise with LDA (2M in THF, 1.08 mL, 2.16 mmol), and then
added 3,3,3-trifluoropropyl trifluoromethanesulfonate (460 mg, 1.87
mmol) in THF (2 mL) dropwise. The reaction mixture was gradually
warmed to rt and stirred for 4 h. The reaction was quenched with 50
mL saturated NH.sub.4Cl at 0.degree. C. and then extracted with
ethyl acetate (100 mL.times.2). The organic layers were dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography using
PE:EA=40:1 to give tert-butyl
2-(diphenylmethyleneamino)-5,5,5-trifluoropentanoate (400 mg, yield
71%) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.66-7.16 (m, 10H), 3.98 (t, 1H), 2.18-2.07 (m, 4H), 1.43 (s, 9H)
ppm.
Step 3: Preparation of 2-amino-5,5,5-trifluoropentanoic Acid
hydrochloride
[0396] A solution of tert-butyl
2-(diphenylmethyleneamino)-5,5,5-trifluoropentanoate (400 mg, 1.02
mmol) in 50% HCl (5 mL) was refluxed overnight. Water was removed
to give 2-amino-5,5,5-trifluoropentanoic acid hydrochloride (210
mg, yield 99%) as a white solid. MS: m/z=172.3 (M+1, ESI+).
Step 4: Preparation of 2-amino-5,5,5-trifluoropentan-1-ol
hydrochloride
[0397] To a solution of 2-amino-5,5,5-trifluoropentanoic acid
hydrochloride (210 mg, 1.0 mmol) in THF (10 mL) was added LAH (76
mg, 2.0 mmol). The mixture was stirred at 70.degree. C. overnight.
Several drop of water was added and filtered. The filtrate was
concentrated under reduced pressure. 2 mL of 4M HCl/1,4-dioxane was
added at rt and stirred for 30 min. Water (10 mL) was added and
then the mixture was extracted with EtOAc (10 mL.times.2). The
aqueous layer was freeze-dried to give
2-amino-5,5,5-trifluoropentan-1-ol hydrochloride (150 mg, yield
77%) as a white solid. MS: m/z=158.3 (M+1, ESI+).
Step 5: Preparation of
5-chloro-N-(5,5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide
[0398] A solution of 5-chloropyrazine-2-carboxylic acid (123 mg,
0.78 mmol), HATU (593 mg, 1.56 mmol) and DIPEA (302 mg, 2.34 mmol)
in DMF (5 mL) was stirred at rt for 30 min. Then
2-amino-5,5,5-trifluoropentan-1-ol hydrochloride (150 mg, 0.78
mmol) was added and the reaction mixture was continued to be
stirred at rt overnight. The crude obtained from a normal work-up
was purified by prep-HPLC to give
5-chloro-N-(5,5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide
(60 mg, yield 26%) as a white solid. MS: m/z=298.1 (M+1, ESI+).
Step 6: Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,5,5--
trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide
[0399] A solution of
5-chloro-N-(5,5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide
(60 mg, 0.2 mmol), 7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (33
mg, 0.2 mmol) and Cs.sub.2CO.sub.3 (131 mg, 0.4 mmol) in DMF (4 mL)
was stirred at 50.degree. C. for 4 h. After cooled to room
temperature, the crude was purified by Prep-HPLC to give
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,5,5--
trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide (32 mg, yield
27%) as a white solid. MS: m/z=426.1 (M+1, ESI+).
Step 7: Preparation of
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,-
5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide and
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,-
5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide
[0400] The racemic mixture
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,5,5--
trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide (40 mg) was
separated by chiral HPLC method using the following condition:
instrument SFC-80 (Thar, Waters), column CHIRALPAK AD 20*250 mm, 5
um, column temperature 35.degree. C., mobile phase
CO.sub.2/Methanol=70/30, flow rate 80 g/min, back pressure 100 bar,
detection wavelength 214 nm or 230 nm, cycle time 6.0 min, sample
solution 300 mg in 60 mL MeOH, and injection volume 4.5 mL (loading
23 mg/injection).
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,-
5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide (11.9 mg,
yield 30%) was obtained as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.09 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H),
8.49 (d, J=9.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.26 (d, J=8.2 Hz,
1H), 4.99 (s, 2H), 4.93 (t, J=6.0 Hz, 1H), 4.05-4.01 (m, 1H),
3.51-3.45 (m, 2H), 2.30-2.22 (m, 5H), 1.88-1.74 (m, 2H) ppm; HPLC
purity: 100% at 214 nm and 100% at 254 nm; MS: m/z=426.2 (M+1,
ESI+); Chiral purity: 100% at 230 nm.
Example 38
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,5-
,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide
##STR00113##
[0402] The title (S)-isomer compound was obtained by a chiral HPLC
separation from its racemic mixture as described above in the
section for another enantiomer.
(S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,-
5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide (11.2 mg,
yield 28%) was obtained as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.10 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H),
8.49 (d, J=9.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.26 (d, J=8.4 Hz,
1H), 4.99 (s, 2H), 4.94 (t, J=6.0 Hz, 1H), 4.05-4.01 (m, 1H),
3.51-3.45 (m, 2H), 2.30-2.22 (m, 5H), 1.88-1.74 (m, 2H) ppm; HPLC
purity: 100% at 214 nm and 100% at 254 nm; MS: m/z=426.2 (M+1,
ESI+); Chiral purity: 98.1% at 239 nm.
Example 39
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(3-hydro-
xybutan-2-yl)pyrazine-2-carboxamide
##STR00114##
[0403] Step 1: Preparation of 3-aminobutan-2-ol
[0404] The solution of 3-nitrobutan-2-ol (1.0 g, 8.4 mmol) in MeOH
(30 mL) was hydrogenated using 10% Pd/C (100 mg) as catalyst under
H.sub.2 overnight. The catalyst was removed by filtration on Celite
and the solvent was evaporated under reduced pressure to give
3-aminobutan-2-ol (740 mg, yield 99%) as colorless oil. It was used
in next step without further purification.
Step 2: Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(3-hydr-
oxybutan-2-yl)pyrazine-2-carboxamide
[0405] To a solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (100 mg, 0.35 mmol) and DIPEA (135 mg, 1.05 mmol)
in DMF (3 mL) was added HATU (200 mg, 0.53 mmol). The reaction
mixture was stirred at rt for 30 min, and then 3-aminobutan-2-ol
(250 mg, 0.35 mmol) was added. The reaction mixture was stirred at
rt overnight. The crude product obtained from a normal work-up was
purified by prep-HPLC to give
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (50 mg, yield 41%) as a white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.11 (s, 1H), 8.67 (s, 1H), 8.61
(s, 1H), 8.33-8.09 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0
Hz, 1H), 4.99 (s, 2H), 3.89-3.64 (m, 2H), 2.22 (s, 3H), 1.16-1.11
(m, 3H), 1.07-1.03 (m, 3H) ppm; HPLC purity: 99.0% at 220 nm and
100% at 254 nm; MS: m/z=358 (M+1, ESI+).
Example 40
(3-hydroxy-3-methylpyrrolidin-1-yl)
(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-
-2-yl)methanone
##STR00115##
[0406] Preparation of (3-hydroxy-3-methylpyrrolidin-1-yl)
(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-
-yl)methanone
[0407] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (80 mg, 0.28 mmol), HATU (213 mg, 0.56 mmol) and
DIPEA (144 mg, 1.12 mmol) in DMF (3 mL) was stirred at rt for 30
min, and then 3-methylpyrrolidin-3-ol hydrochloride (58 mg, 0.42
mmol) was added. The reaction mixture was continued to be stirred
at rt overnight. The crude product obtained from a normal work-up
was purified by prep-HPLC to give
(3-hydroxy-3-methylpyrrolidin-1-yl)(5-(1-hydroxy-7-methyl-1,3-dihydrobenz-
o[c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)methanone (12 mg, yield 12%)
as a white solid. The ratio of the two stereo-isomers in this
racemic product is about 60:40 according by .sup.1HNMR. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.57-8.56 (m, 1H),
8.50-8.48 (m, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H),
4.99 (s, 2H), 4.85-4.79 (m, 1H), 3.62-3.49 (m, 4H), 2.23 (s, 3H),
1.85-1.81 (m, 2H), 1.33-1.27 (m, 3H) ppm; HPLC purity: 100% at 220
nm and 100% at 254 nm; MS: m/z=370.1 (M+1, ESI+).
Example 41
(3-hydroxy-3-methylazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone
##STR00116##
[0408] Step 1: Preparation of
1-benzhydryl-3-methylazetidin-3-ol
[0409] To a solution of 1-benzhydrylazetidin-3-one (7.11 g, 30
mmol) in dry THF (150 mL) was added methylmagnesium bromide (3M, 30
mL, 90 mmol) dropwise at -78.degree. C. After stirred at
-78.degree. C. for 2 h, the reaction mixture was gradually warmed
to rt and stirred overnight. Saturated NH.sub.4Cl (100 mL) was
added and extracted with EA (100 mL.times.3). The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated under the reduced pressure. The residue
was purified by silica gel column chromatography using PE:EA (4:1)
as elution to give 1-benzhydryl-3-methylazetidin-3-ol (7.0 g, yield
92%) as a yellow solid. MS: m/z=254.1 (M+1, ESI+).
Step 2: Preparation of 3-methylazetidin-3-ol hydrochloride
[0410] To a solution of 1-benzhydryl-3-ethylazetidin-3-ol (7.0 g,
27.7 mmol) and HCl (1N, 28 mL) in MeOH (100 mL) was hydrogenated
using 10% Pd/C (800 mg) as catalyst under atmospheric pressure of
H.sub.2 overnight. The catalyst was removed and the solvent was
evaporated to give 3-methylazetidin-3-ol hydrochloride (3.0 g,
yield 88%) as a light yellow solid. It was used in next step
without further purification.
Step 3: Preparation of (3-hydroxy-3-methylazetidin-1-yl)
(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-
-yl)methanone
[0411] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (1.08 g, 3.78 mmol), HATU (2.87 g, 7.56 mmol) and
DIPEA (1.95 g, 15.12 mmol) in DMF (15 mL) was stirred at rt for 30
min. 3-Methylazetidin-3-ol hydrochloride (558 mg, 4.54 mmol) was
added and the reaction mixture was stirred at rt overnight. The
crude sample obtained from a normal work-up was purified by
prep-HPLC to give
(3-hydroxy-3-methylazetidin-1-yl)(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)methanone (630 mg, yield 47%)
as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.10
(s, 1H), 8.62 (d, J=1.2 Hz, 1H), 8.57 (d, J=1.2 Hz, 1H), 7.29 (d,
J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 5.71 (s, 1H), 4.99 (s, 2H),
4.41 (d, J=9.6 Hz, 1H), 4.35 (d, J=9.6 Hz, 1H), 3.95 (d, J=9.6 Hz,
1H), 3.90 (d, J=9.6 Hz, 1H), 2.21 (s, 3H), 1.40 (s, 3H) ppm; HPLC
purity: 100% at 214 nm and 100% at 254 nm; MS: m/z=356.1 (M+1,
ESI+).
Example 42
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-((1R,2-
R)-2-hydroxycyclopentyl)pyrazine-2-carboxamide
##STR00117##
[0412] Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-((1R,2R-
)-2-hydroxycyclopentyl)pyrazine-2-carboxamide
[0413] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (50 mg, 0.17 mmol), HATU (100 mg, 0.26 mmol) and
DIPEA (88 mg, 0.68 mmol) in DMF (3 mL) was stirred at rt for 30
min. (1R,2R)-2-aminocyclopentanol (26 mg, 0.26 mmol) was added and
the reaction mixture was stirred at rt overnight. The crude product
obtained from a normal work-up was purified by prep-HPLC to give
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-((1R,-
2R)-2-hydroxycyclopentyl)pyrazine-2-carboxamide (20.1 mg, yield
31%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.09 (s, 1H), 8.65 (d, J=1.2 Hz, 1H), 8.61 (d, J=1.2 Hz, 1H), 8.48
(d, J=7.2 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.26 (d, J=8 Hz, 1H), 4.99
(s, 2H), 4.03-4.00 (m, 2H), 2.21 (s, 3H), 1.99-1.95 (m, 1H),
1.86-1.83 (m, 1H), 1.67-1.61 (m, 2H), 1.54-1.45 (m, 2H) ppm; HPLC
purity: 100% at 214 nm and 100% at 254 nm; MS: m/z=370.0 (M+1,
ESI+).
Example 43
(R)--N-(2-hydroxy-2-methylhexan-3-yl)-5-((1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide
##STR00118##
[0414] Step 1: Preparation of (R)-methyl 2-aminopentanoate
hydrochloride
[0415] To a solution of (R)-2-aminopentanoic acid (2.0 g, 17.1
mmol) in MeOH (50 mL) was added SOCl.sub.2 (4.0 g, 34.2 mmol)
dropwise at 0.degree. C. The reaction mixture was stirred at
70.degree. C. for 2 h, and then concentrated under the reduced
pressure to give (R)-methyl 2-aminopentanoate hydrochloride (2.0 g,
yield 70%) as a white solid. MS: m/z=132.1 (M+1, ESI+).
Step 2: Preparation of (R)-3-amino-2-methylhexan-2-ol
[0416] To a solution of (R)-methyl 2-aminopentanoate hydrochloride
(2.0 g, 12.0 mmol) in dry THF (100 mL) was added methylmagnesium
bromide (16 mL, 48 mmol, 3M in ether) at 0.degree. C. The reaction
mixture was stirred at room temperature overnight. The mixture was
quenched with saturated NH.sub.4Cl and extracted with EtOAc (20
mL.times.3). The combined organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel eluted with DCM: MeOH: TEA (10:1:0.01) to give
(R)-3-amino-2-methylhexan-2-ol (800 mg, yield 51%). MS: m/z=132.1
(M+1, ESI+).
Step 3: Preparation of
(R)--N-(2-hydroxy-2-methylhexan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0417] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (200 mg, 0.7 mmol), HATU (400 mg, 1.05 mmol) and
DIPEA (361 mg, 2.8 mmol) in DMF (5 mL) was stirred at rt for 30
min. And then (R)-3-amino-2-methylhexan-2-ol (100 mg, 0.84 mmol)
was added and the reaction mixture was stirred at rt overnight. The
crude residue obtained from a normal work-up was purified by
prep-HPLC to give
(R)--N-(2-hydroxy-2-methylhexan-3-yl)-5-(1-hydroxy-7-methyl-3-dihydrobenz-
o[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide (29 mg, yield 10%)
as a white solid. .sup.1HNMR (400 MHz, DMSO-d6): .delta. 9.07 (s,
1H), 8.66 (d, J=0.8 Hz, 1H), 8.61 (d, J=0.8 Hz, 1H), 7.97 (d,
J=10.0 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H),
4.98 (s, 2H), 4.58 (s, 1H), 3.87-3.81 (m, 1H), 2.22 (s, 3H),
1.70-1.62 (m, 1H), 1.52-1.42 (m, 1H), 1.34-1.16 (m, 2H), 1.14 (s,
3H), 1.05 (s, 3H), 0.85 (t, J=7.6 Hz, 3H) ppm; HPLC purity: 100% at
214 nm and 100% at 254 nm; MS: m/z=400.0 (M+1, ESI+); Chiral
purity: 100% at 230 nm.
Example 44
(S)--N-(2-hydroxy-2-methylhexan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydroben-
zo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00119##
[0418] Step 1: Preparation of (S)-methyl 2-aminopentanoate
[0419] To a solution of (S)-2-aminopentanoic acid (2.0 g, 17.1
mmol) in MeOH (50 mL) was added SOCl.sub.2 (4.0 g, 34.2 mmol)
dropwise at 0.degree. C. The reaction mixture was stirred at
70.degree. C. for 2 h, and then concentrated under the reduced
pressure to give (S)-methyl 2-aminopentanoate hydrochloride (2.0 g,
yield 70%) as a white solid. MS: m/z=132.1 (M+1, ESI+).
Step 2: Preparation of (S)-3-amino-2-methylhexan-2-ol
[0420] To a solution of (S)-methyl 2-aminopentanoate hydrochloride
(2.0 g, 12.0 mmol) in dry THF (100 mL) was added methylmagnesium
bromide (16 mL, 48 mmol, 3M in ether) at 0.degree. C. The reaction
mixture was stirred at room temperature overnight. The mixture was
quenched with saturated NH.sub.4Cl and extracted with EtOAc (20
mL.times.3). The combined organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel eluted with DCM: MeOH: TEA (10:1:0.01) to give
(S)-3-amino-2-methylhexan-2-ol (800 mg, yield 51%). MS: m/z=132.1
(M+1, ESI+).
Step 3: Preparation of
(S)--N-(2-hydroxy-2-methylhexan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0421] To a solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (200 mg, 0.70 mmol) in DMF (5.0 mL) was added HATU
(400 mg, 1.04 mmol) and DIPEA (360 mg, 2.78 mmol). After the
reaction mixture was stirred at room temperature for 15 min,
(S)-3-amino-2-methylhexan-2-ol (100 mg, 0.84 mmol) was added. Then,
the mixture was stirred at room temperature overnight. The mixture
was quenched with water and extracted with EtOAc (20 mL.times.3).
The combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude residue was purified by prep-HPLC to give
(S)--N-(2-hydroxy-2-methylhexan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide (29.0 mg, Yield
10%). .sup.1HNMR (400 MHz, DMSO-d6): .delta. 9.06 (s, 1H), 8.66 (s,
1H), 8.60 (s, 1H), 7.98 (d, J=10.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H),
7.24 (d, J=8.4 Hz, 1H), 4.97 (s, 2H), 4.59 (s, 1H), 3.85-3.81 (m,
1H), 2.21 (s, 3H), 1.69-1.61 (m, 1H), 1.50-1.45 (m, 1H), 1.34-1.16
(m, 2H), 1.14 (s, 3H), 1.04 (s, 3H), 0.84 (t, J=8.0 Hz, 3H) ppm.
HPLC purity: 100% at 214 nm and 100% at 254 nm; MS: m/z=400.1 (M+1,
ESI+). Chiral HPLC purity: 100% at 230 nm.
Example 45
(R)--N-(2-hydroxy-2-methylpentan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00120##
[0422] Step 1: Preparation of (R)-methyl 2-aminobutanoate
hydrochloride
[0423] To a solution of (R)-2-aminobutanoic acid (2.0 g, 19.4 mmol)
in MeOH (50 mL) was added SOCl.sub.2 (4.6 g, 38.8 mmol) dropwise at
0.degree. C. The reaction mixture was stirred at 70.degree. C. for
2 h, and then concentrated under the reduced pressure to give
(R)-methyl 2-aminobutanoate hydrochloride (2.0 g, yield 67%) as a
white solid. .sup.1H NMR (400 Hz, DMSO-d6): .delta. 8.82 (s, 3H),
4.12 (s, 1H), 3.83 (s, 3H), 2.15-2.08 (m, 2H), 1.12 (t, J=8.0 Hz,
3H) ppm; MS: m/z=118.1 (M+1, ESI+).
Step 2: Preparation of (R)-3-amino-2-methylpentan-2-ol
[0424] To a solution of (R)-methyl 2-aminobutanoate hydrochloride
(2.0 g, 13.1 mmol) in dry THF (100 mL) was added methylmagnesium
bromide (17.5 mL, 52.4 mmol, 3M in ether) at 0.degree. C. The
reaction mixture was stirred at room temperature overnight. The
mixture was quenched with saturated NH.sub.4Cl and extracted with
EtOAc (20 mL.times.3). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel eluted with DCM: MeOH: TEA (10:1:0.01) to give
(R)-3-amino-2-methylpentan-2-ol (800 mg, yield 52%). MS: m/z=118.1
(M+1, ESI+).
Step 3: Preparation of
(R)--N-(2-hydroxy-2-methylpentan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrob-
enzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0425] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (1.0 g, 3.5 mmol), HATU (2.0 g, 5.25 mmol) and
DIPEA (1.8 g, 13.95 mmol) in DMF (10 mL) was stirred at rt for 30
min. Then (R)-3-amino-2-methylpentan-2-ol (500 mg, 4.2 mmol) was
added and the reaction mixture was stirred at rt overnight. The
crude product obtained from a normal work-up was purified by
prep-HPLC to give
(R)--N-(2-hydroxy-2-methylpentan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrob-
enzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide (248 mg, yield
18%) as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta.
9.08 (s, 1H), 8.68 (s, 1H), 8.62 (s, 1H), 7.97 (d, J=8.0 Hz, 1H),
7.30 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 4.99 (s, 2H), 4.59
(s, 1H), 3.78-3.73 (m, 1H), 2.23 (s, 3H), 1.79-1.77 (m, 1H),
1.47-1.45 (m, 1H), 1.15 (s, 3H), 1.06 (s, 3H), 0.81 (t, J=6.0 Hz,
3H) ppm; HPLC purity: 100% at 214 nm and 100% at 254 nm; MS:
m/z=386.3 (M+1, ESI+); Chiral HPLC purity: 100% at 230 nm.
Example 46
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-((1S,2S)-
-2-hydroxycyclopentyl)pyrazine-2-carboxamide
##STR00121##
[0426] Preparation of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-((1S,2S-
)-2-hydroxycyclopentyl)pyrazine-2-carboxamide
[0427] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (50 mg, 0.17 mmol), HATU (100 mg, 0.26 mmol) and
DIPEA (88 mg, 0.68 mmol) in DMF (3 mL) was stirred at rt for 30
min. Then (1R,2R)-2-aminocyclopentanol (26 mg, 0.26 mmol) was added
and the reaction mixture was stirred at rt overnight. The crude
product obtained from a normal work-up was purified by prep-HPLC to
give
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-((1S,-
2S)-2-hydroxycyclopentyl)pyrazine-2-carboxamide (9.7 mg, yield 15%)
as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.09
(s, 1H), 8.65 (d, J=0.8 Hz, 1H), 8.60 (d, J=0.8 Hz, 1H), 8.48 (d,
J=7.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 4.99
(s, 2H), 4.79 (d, J=4.4 Hz, 1H), 4.04-4.00 (m, 2H), 2.21 (s, 3H),
1.99-1.95 (m, 1H), 1.86-1.83 (m, 1H), 1.67-1.62 (m, 2H), 1.54-1.46
(m, 2H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS:
m/z=370.0 (M+1, ESI+); Chiral HPLC purity: 100% at 230 nm.
Example 47
(S)--N-(3-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydroben-
zo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00122##
[0428] Step 1: Preparation of (S)-methyl 2-aminopropanoate
hydrochloride
[0429] To a solution of (S)-2-aminopropanoic acid (1.0 g, 11.23
mmol) in MeOH (30 mL) at 0.degree. C. was added dropwise SOCl.sub.2
(2.67 g, 22.47 mmol). The reaction mixture was refluxed for 2 h,
and then solvent was removed to give crude (S)-methyl
2-aminopropanoate hydrochloride (1.6 g) as a white solid. It was
used in next step without further purification.
Step 2: Preparation of (S)-3-amino-2-methylbutan-2-ol
[0430] To a solution of crude (S)-methyl 2-aminopropanoate
hydrochloride (1.6 g, 11.51 mmol) in THF (30 mL) at 0.degree. C.
was added MeMgBr (3M, 15 mL, 46.04 mmol) dropwise. The reaction
mixture was stirred at rt overnight. The mixture was quenched with
saturated NH.sub.4Cl and extracted with EtOAc (20 mL.times.3). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
eluted with MeOH:DCM:Et.sub.3N (10:80:3) to give crude
(S)-3-amino-2-methylbutan-2-ol (100 mg) as a colorless oil. It was
used in next step without further purification. MS: m/z=104.1 (M+1,
ESI+).
Step 3: Preparation of
(S)--N-(3-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0431] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (60 mg, 0.21 mmol), HATU (120 mg, 0.31 mmol) and
DIPEA (81 mg, 0.63 mmol) in DMF (3 mL) was stirred at rt for 30
min. Then (S)-3-amino-2-methylbutan-2-ol (26 mg, 0.25 mmol) was
added and the reaction mixture was stirred at rt overnight. The
crude product was purified by prep-HPLC to give
(S)--N-(3-hydroxy-3-methylbutan-2-yl)-5-((1-hydroxy-7-methyl-1,3-dihydrob-
enzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide (8.6 mg, yield
11%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.08 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.11 (d, J=9.2 Hz, 1H),
7.30 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 4.99 (s, 2H), 4.72
(s, 1H), 3.92-3.87 (m, 1H), 2.22 (s, 3H), 1.15 (s, 3H), 1.12 (d,
J=6.4 Hz, 3H), 1.09 (s, 3H) ppm; HPLC purity: 100% at 214 nm and
100% at 254 nm; MS: m/z=372.1 (M+1, ESI+); Chiral purity: 100% at
230 nm.
Example 48
[0432]
(R)--N-(3-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dih-
ydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00123##
Step 1: Preparation of (R)-methyl 2-aminopropanoate
hydrochloride
[0433] To a solution of (R)-2-aminopropanoic acid (1.0 g, 11.23
mmol) in MeOH (30 mL) at 0.degree. C. was added dropwise SOCl.sub.2
(2.67 g, 22.47 mmol). The reaction mixture was refluxed for 2 h,
and then solvent was removed to give crude (R)-methyl
2-aminopropanoate hydrochloride (1.7 g) as a white solid. It was
used in next step without further purification.
Step 2: Preparation of (R)-3-amino-2-methylbutan-2-ol
[0434] To a solution of crude (R)-methyl 2-aminopropanoate
hydrochloride (1.7 g, 12.23 mmol) in THF (30 mL) at 0.degree. C.
was added dropwise MeMgBr (3M, 16 mL, 48.92 mmol). The reaction
mixture was stirred at rt overnight. The mixture was quenched with
saturated NH.sub.4Cl and extracted with EtOAc (20 mL.times.3). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography over silica gel
by eluted with MeOH:DCM:Et.sub.3N (10:80:3) to give
(R)-3-amino-2-methylbutan-2-ol (80 mg) as a colorless oil. It was
used in next step without further purification. MS: m/z=104.1 (M+1,
ESI+).
Step 3: Preparation of
(R)--N-(3-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0435] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (60 mg, 0.21 mmol), HATU (120 mg, 0.31 mmol) and
DIPEA (81 mg, 0.63 mmol) in DMF (3 mL) was stirred at rt for 30
min. Then (R)-3-amino-2-methylbutan-2-ol (26 mg, 0.25 mmol) was
added and the reaction mixture was stirred at rt overnight. The
crude product obtained from a normal work-up was purified by
prep-HPLC to give
(R)--N-(3-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide (7.6 mg, yield
10%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.09 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.12 (d, J=9.2 Hz, 1H),
7.30 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 4.99 (s, 2H), 4.72
(s, 1H), 3.92-3.87 (m, 1H), 2.22 (s, 3H), 1.15 (s, 3H), 1.12 (d,
J=6.4 Hz, 3H), 1.09 (s, 3H) ppm; HPLC purity: 100% at 214 nm and
100% at 254 nm; MS: m/z=372.1 (M+1, ESI+); Chiral purity: 100% at
220 nm.
Example 49
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(cis-2-
-hydroxycyclopentyl)pyrazine-2-carboxamide
##STR00124##
[0436] Preparation of
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(cis--
2-hydroxycyclopentyl)pyrazine-2-carboxamide
[0437] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (80 mg, 0.28 mmol), HATU (213 mg, 0.56 mmol) and
DIPEA (144 mg, 1.12 mmol) in DMF (3 mL) was stirred at rt for 30
min. Then cis-2-aminocyclopentan-1-ol hydrochloride (42 mg, 0.42
mmol) was added and the reaction mixture was stirred at rt
overnight. The crude compound obtained from a normal work-up was
purified by prep-HPLC to give the final product. Since the starting
material 2-aminocyclopentan-1-ol was a mixture of the two
cis-isomers [(1R,2S)-2-aminocyclopentan-1-ol and
(1S,2R)-2-aminocyclopentan-1-ol], the final product contains
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-((1S,-
2R)-2-hydroxycyclopentyl)pyrazine-2-carboxamide and
5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-((1R,-
2S)-2-hydroxycyclopentyl)pyrazine-2-carboxamide with a 50:50 ratio
(19 mg, yield 18%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.67 (d, J=0.8 Hz, 1H), 8.62
(d, J=0.8 Hz, 1H), 8.18 (d, J=7.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H),
7.26 (d, J=8.0 Hz, 1H), 5.12 (d, J=4.4 Hz, 1H), 4.99 (s, 2H), 4.03
(d, J=6.0 Hz, 2H), 2.21 (s, 3H), 2.00-1.85 (m, 1H), 1.85-1.70 (m,
2H), 1.70-1.50 (m, 3H) ppm; HPLC purity: 100% at 220 nm and 100% at
254 nm; MS: m/z=370.0 (M+1, ESI+).
Example 50
(S)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazi-
n-2-yl) (2-(hydroxymethyl)piperazin-1-yl)methanone Hydrochloric
Acid Salt
##STR00125##
[0438] Step 1: Preparation of (S)-tert-butyl
4-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-
e-2-carbonyl)-3-(hydroxymethyl)piperazine-1-carboxylate
[0439] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (100 mg, 0.35 mmol), HATU (200 mg, 0.52 mmol) and
DIPEA (135 mg, 1.05 mmol) in DMF (5 mL) was stirred at rt for 30
min. Then (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate
(90 mg, 0.42 mmol) was added and the reaction mixture was stirred
at rt overnight. The crude compound obtained from a normal work-up
was purified by prep-HPLC to give (S)-tert-butyl
4-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-
e-2-carbonyl)-3-(hydroxymethyl)piperazine-1-carboxylate (65 mg,
yield 38%) as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6):
.delta. 9.07 (s, 1H), 8.53 (s, 1H), 8.34-8.31 (m, 1H), 7.30 (d,
J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 4.97 (s, 2H), 4.90-4.80 (m,
1H), 4.22-4.19 (m, 1H), 4.04-3.71 (m, 3H), 3.49 (s, 1H), 3.21-2.92
(m, 4H), 2.23 (s, 3H), 1.39 (s, 9H) ppm; MS: m/z=429.1 (M-55,
ESI+).
Step 2: Preparation of
(S)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyraz-
in-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone
[0440] To a solution of (S)-tert-butyl
4-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-
e-2-carbonyl)-3-(hydroxymethyl)piperazine-1-carboxylate (65 mg,
0.134 mmol) in DCM (5 mL) was added HCl (0.34 mL, 1.34 mmol, 4
mol/L in 1,4-dioxane). The reaction mixture was stirred at room
temperature for 2 h. The solvent was removed by vacuum and the
residue was purified by prep-HPLC to give
(S)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyraz-
in-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone (6.8 mg, yield
13%) as a white solid. HPLC purity: 98.4% at 214 nm and 100% at 254
nm; MS: m/z=385.1 (M+1, ESI+); Chiral purity: 98.7%.
Example 51
(R)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazi-
n-2-yl) (2-(hydroxymethyl)piperazin-1-yl)methanone Hydrochloric
Acid Salt
##STR00126##
[0441] Step 1: Preparation of (R)-tert-butyl
4-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-
e-2-carbonyl)-3-(hydroxymethyl)piperazine-1-carboxylate
[0442] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (100 mg, 0.35 mmol), HATU (200 mg, 0.52 mmol) and
DIPEA (135 mg, 1.05 mmol) in DMF (5 mL) was stirred at rt for 30
min. (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (90
mg, 0.42 mmol) was added and the reaction mixture was stirred at rt
overnight. The crude product after a normal work-up was purified by
prep-HPLC to give (R)-tert-butyl
4-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-
e-2-carbonyl)-3-(hydroxymethyl)piperazine-1-carboxylate (65 mg,
yield 38%) as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 9.07 (s, 1H), 8.53 (s, 1H), 8.35-8.29 (m, 1H), 7.29 (d,
J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 4.97 (s, 2H), 4.90-4.79 (m,
1H), 4.23-4.20 (m, 1H), 4.02-3.68 (m, 3H), 3.48 (s, 2H), 3.05-2.91
(m, 3H), 2.23 (s, 3H), 1.39 (s, 9H) ppm; MS: m/z=429.1 (M-55,
ESI+).
Step 2: Preparation of
(R)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][,
22]oxaborol-6-yloxy)pyrazin-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methano-
ne
[0443] To a solution of (R)-tert-butyl
4-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-
e-2-carbonyl)-3-(hydroxymethyl)piperazine-1-carboxylate (65 mg,
0.134 mmol) in DCM (5 mL) was added HCl (0.34 mL, 1.34 mmol, 4
mol/L in 1,4-dioxane). The reaction mixture was stirred at room
temperature for 2 h. The solvent was removed by vacuum and the
residue was purified by prep-HPLC to give
(R)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyraz-
in-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone (6.2 mg, 12%) as
a white solid. HPLC purity: 100% at 214 nm and 100% at 254 nm; MS:
m/z=385.0 (M+1, ESI+); Chiral HPLC purity: 100% at 230 nm.
Example 52
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-h-
ydroxypentan-2-yl)-N-methylpyrazine-2-carboxamide
##STR00127##
[0444] Step 1: Preparation of (R)-methyl
2-(tert-butoxycarbonylamino)pentanoate
[0445] To a solution of (R)-methyl 2-aminopentanoate hydrochloride
(1.6 g) and Et.sub.3N (3.7 mL, 25.65 mmol) in DCM (20 mL) was added
(Boc).sub.2O (3.7 g, 17.09 mmol). The reaction mixture was stirred
at rt overnight. Solvent was removed and the residue was purified
by silica gel column chromatography using PE:EA (8:1) as eluent to
give (R)-methyl 2-(tert-butoxycarbonylamino)pentanoate (1.8 g,
yield 91%) as a colorless oil. MS: m/z=254.2 (M+23, ESI+).
Step 2: Preparation of (R)-2-(methylamino)pentan-1-ol
[0446] To a solution of (R)-methyl
2-(tert-butoxycarbonylamino)pentanoate (500 mg, 2.16 mmol) in THF
(30 mL) was added LiAlH.sub.4 (247 mg, 6.49 mmol). The reaction
mixture was refluxed overnight. Water (0.3 mL) was added. The solid
was removed by filtration. The filtrate was concentrated and the
residue was purified by silica gel column chromatography using
DCM:MeOH:Et.sub.3N (80:10:3) as eluent to give
(R)-2-(methylamino)pentan-1-ol (100 mg) as a colorless oil. MS:
m/z=118.2 (M+1, ESI+).
Step 3: Preparation of
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypentan-2-yl)-N-methylpyrazine-2-carboxamide
[0447] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (600 mg, 2.1 mmol), HATU (1.6 g, 4.2 mmol) and
DIPEA (1.1 g, 8.4 mmol) in DMF (10 mL) was stirred at rt for 30
min. (R)-2-(methylamino)pentan-1-ol (269 mg, 2.3 mmol) was added
and the reaction mixture was stirred at rt overnight. The crude
product after a normal work-up was purified by prep-HPLC to give
(R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1--
hydroxypentan-2-yl)-N-methylpyrazine-2-carboxamide (284 mg, yield
35%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.08 (s, 1H), 8.56-8.54 (m, 1H), 8.30-8.23 (m, 1H), 7.29 (d, J=8.4
Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 4.98 (s, 2H), 4.77-4.74 (m, 1H),
4.60-4.50 (m, 0.35H), 3.75-3.65 (m, 0.65H), 3.55-3.31 (m, 2H), 2.83
(s, 3H), 2.23 (s, 3H), 1.48-1.23 (m, 4H), 0.92-0.80 (m, 3H) ppm;
HPLC purity: 100% at 214 nm and 100% at 254 nm; MS: m/z=386.2 (M+1,
ESI+); Chiral purity 100% at 230 nm.
Example 53
(S)--N-(2-hydroxy-2-methylpentan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
##STR00128##
[0448] Step 1: Preparation of (S)-methyl 2-aminobutanoate
[0449] To a solution of (S)-2-aminobutanoic acid (2.0 g, 19.42
mmol) in MeOH (50 mL) was added SOCl.sub.2 (4.6 g, 38.8 mmol)
dropwise at 0.degree. C. The reaction mixture was stirred at
70.degree. C. for 2 h, and then concentrated under reduced pressure
to give (S)-methyl 2-aminobutanoate hydrochloride (2.0 g, yield
67%) as a white solid. .sup.1H NMR (400 Hz, DMSO-d.sub.6): .delta.
8.82 (s, 3H), 4.12 (s, 1H), 3.83 (s, 3H), 2.15-2.08 (m, 2H), 1.12
(t, J=8.0 Hz, 3H) ppm; MS: m/z=118.1 (M+1, ESI+).
Step 2: Preparation of (S)-3-amino-2-methylpentan-2-ol
[0450] To a solution of (S)-methyl 2-aminobutanoate hydrochloride
(2.0 g, 13.1 mmol) in dry THF (100 mL) was added methylmagnesium
bromide (17.5 mL, 52.4 mmol, 3M in ether) at 0.degree. C. The
reaction mixture was stirred at room temperature overnight. The
mixture was quenched with saturated NH.sub.4Cl and extracted with
EtOAc (20 mL.times.3). The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography
over silica gel eluted with DCM: MeOH: TEA (10:1:0.01) to give
(S)-3-amino-2-methylpentan-2-ol (800 mg, yield 52%). MS: m/z=118.1
(M+1, ESI+).
Step 3: Preparation of
(S)--N-(2-hydroxy-2-methylpentan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrob-
enzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide
[0451] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (200 mg, 0.7 mmol), HATU (400 mg, 1.05 mmol) and
DIPEA (360 mg, 2.78 mmol) in DMF (5 mL) was stirred at rt for 30
min. Then (S)-3-amino-2-methylpentan-2-ol (100 mg, 0.84 mmol) was
added and the reaction mixture was stirred at rt overnight. The
crude compound obtained after a normal work-up was purified by
prep-HPLC to give
(S)--N-(2-hydroxy-2-methylpentan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrob-
enzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide (27.3 mg, yield
10%) as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta.
9.08 (s, 1H), 8.68 (d, J=1.2 Hz, 1H), 8.62 (d, J=1.2 Hz, 1H), 7.98
(d, J=10.4 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.26 (d, J=8 Hz, 1H),
4.99 (s, 2H), 4.59 (s, 1H), 3.77-3.72 (m, 1H), 2.23 (s, 3H),
1.79-1.76 (m, 1H), 1.47-1.45 (m, 1H), 1.15 (s, 3H), 1.06 (s, 3H),
0.81 (t, J=6.4 Hz, 3H) ppm; HPLC purity: 100% at 214 nm and 100% at
254 nm; MS: m/z=386.1 (M+1, ESI+); Chiral purity: 100% at 230
nm.
Example 54
(3-ethyl-3-hydroxyazetidine-1-yl)
(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-
-2-yl)methanone
##STR00129##
[0452] Step 1: Preparation of 1-benzhydryl-3-ethylazetidin-3-ol
[0453] To a solution of 1-benzhydrylazetidin-3-one (2.37 g, 10
mmol) in dry THF (50 mL) was added ethylmagnesium bromide (3M, 10
mL, 30 mmol) dropwise at -78.degree. C. After being stirred at
-78.degree. C. for 2 h, the reaction mixture was gradually warmed
to rt and stirred overnight. Saturated NH.sub.4Cl (50 mL) was added
and the mixture was extracted with EA (100 mL.times.3). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under the reduced
pressure. The residue was purified by silica gel column
chromatography using PE:EA (4:1) as eluent to give
1-benzhydryl-3-ethylazetidin-3-ol (2.5 g, yield 94%) as a yellow
solid. MS: m/z=268.1 (M+1, ESI+).
Step 2: Preparation of 3-ethylazetidin-3-ol hydrochloride
[0454] A solution of 1-benzhydryl-3-ethylazetidin-3-ol (1.3 g, 4.9
mmol) and HCl (1N, 4.9 mL) in MeOH (20 mL) was hydrogenated using
10% Pd/C (150 mg) as catalyst under atmospheric pressure of H.sub.2
overnight. The catalyst was removed and the solvent was evaporated
to give 3-ethylazetidin-3-ol hydrochloride (0.52 g, yield 78%) as a
light yellow solid. It was used in next step without further
purification.
Step 3: Preparation of (3-ethyl-3-hydroxyazetidine-1-yl)
(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-
-yl)methanone
[0455] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (800 mg, 2.8 mmol), HATU (2.13 g, 5.6 mmol) and
DIPEA (1.44 g, 11.2 mmol) in DMF (10 mL) was stirred at rt for 30
min. Then 3-ethylazetidin-3-ol hydrochloride (466 mg, 3.4 mmol) was
added and the reaction mixture was stirred at rt overnight. The
crude compound obtained after a normal work-up was purified by
prep-HPLC to give
(3-ethyl-3-hydroxyazetidine-1-yl)(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)methanone (386 mg, yield 37%)
as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.09
(s, 1H), 8.61 (d, J=1.2 Hz, 1H), 8.57 (d, J=1.2 Hz, 1H), 7.29 (d,
J=8 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 5.61 (s, 1H), 4.99 (s, 2H), 4.41
(d, J=9.6 Hz, 1H), 4.30 (d, J=10.4 Hz, 1H), 3.96 (d, J=10.0 Hz,
1H), 3.84 (d, J=10.4 Hz, 1H), 2.22 (s, 3H), 1.67 (q, J=7.2 Hz, 2H),
0.88 (t, J=7.2 Hz, 3H) ppm; HPLC purity: 100% at 214 nm and 100% at
254 nm; MS: m/z=370.2 (M+1, ESI+).
Example 55
(3-cyclopropyl-3-hydroxyazetidine-1-yl)
(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-
-2-yl)methanone
##STR00130##
[0456] Step 1: Preparation of
1-benzhydryl-3-cyclopropylazetidin-3-ol
[0457] To a solution of 1-benzhydrylazetidin-3-one (1.5 g, 6.3
mmol) in dry THF (50 mL) was added cyclopropylmagnesium bromide
(0.5M, 25.2 mL, 12.6 mmol) dropwise at -78.degree. C. After being
stirred at -78.degree. C. for 2 h, the reaction mixture was
gradually warmed to rt and stirred overnight. Saturated NH.sub.4Cl
(50 mL) was added and extracted with EA (3.times.100 mL). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under the reduced
pressure. The residue was purified by silica gel column
chromatography eluted with PE:EA (4:1, v/v) to give
1-benzhydryl-3-cyclopropylazetidin-3-ol (1.0 g, yield 57%) as a
yellow solid. MS: m/z=280.1 (M+1, ESI+).
Step 2: Preparation of 3-cyclopropylazetidin-3-ol hydrochloride
[0458] A solution of 1-benzhydryl-3-cyclopropylazetidin-3-ol (1.0
g, 3.6 mmol) and HCl (1N, 3.6 mL) in MeOH (20 mL) was hydrogenated
using 10% Pd/C (150 mg) as catalyst under atmospheric pressure of
H.sub.2 overnight. The catalyst was removed by filtration and the
solvent was evaporated to give 3-cyclopropylazetidin-3-ol
hydrochloride (0.4 g, yield 75%) as a light yellow solid. It was
used in next step without further purification.
Step 3: Preparation of (3-cyclopropyl-3-hydroxyazetidine-1-yl)
(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-
-yl)methanone
[0459] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (700 mg, 2.45 mmol), HATU (1.86 g, 4.9 mmol) and
DIPEA (1.26 g, 9.8 mmol) in DMF (10 mL) was stirred at rt for 30
min. Then 3-cyclopropylazetidin-3-ol hydrochloride (438 mg, 2.94
mmol) was added and the reaction mixture was stirred at rt
overnight. The crude product was purified by prep-HPLC to give
(3-cyclopropyl-3-hydroxyazetidine-1-yl)(5-(1-hydroxy-7-methyl-1,3-dihydro-
benzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)methanone (300.9 mg,
yield 32%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.09 (s, 1H), 8.61 (d, J=1.2 Hz, 1H), 8.56 (d, J=1.2 Hz,
1H), 7.29 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 5.66 (s, 1H),
4.99 (s, 2H), 4.35 (d, J=10.4 Hz, 1H), 4.29 (d, J=10.4 Hz, 1H),
3.89 (d, J=10.4 Hz, 1H), 3.82 (d, J=10.4 Hz, 1H), 2.21 (s, 3H),
1.22-1.18 (m, 1H), 0.43-0.40 (m, 2H), 0.34-0.31 (m, 2H) ppm; HPLC
purity: 100% at 214 nm and 100% at 254 nm; MS: m/z=382.3 (M+1,
ESI+).
Example 56
(3-hydroxy-3-propylazetidine-1-yl)
(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-
-2-yl)methanone
##STR00131##
[0460] Step 1: Preparation of
1-benzhydryl-3-propylazetidine-3-ol
[0461] To a solution of 1-benzhydrylazetidin-3-one (2.37 g, 10
mmol) in dry THF (50 mL) was added propylmagnesium chloride (2M, 15
mL, 30 mmol) dropwise at -78.degree. C. After being stirred at
-78.degree. C. for 2 h, the reaction mixture was gradually warmed
to rt and stirred overnight. Saturated NH.sub.4Cl (50 mL) was added
and extracted with EA (3.times.100 mL). The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under the reduced pressure. The residue was purified
by silica gel column chromatography eluted with PE:EA (4:1) to give
1-benzhydryl-3-propylazetidine-3-ol (2.2 g, yield 78%) as a yellow
solid. MS: m/z=282 (M+1, ESI+).
Step 2: Preparation of 3-propylazetidine-3-ol hydrochloride
[0462] A solution of 1-benzhydryl-3-propylazetidine-3-ol (2.2 g,
7.8 mmol) and HCl (1N, 7.8 mL) in MeOH (30 mL) was hydrogenated
using 10% Pd/C (250 mg) as catalyst under atmospheric pressure of
H.sub.2 overnight. The catalyst was removed by filtration and the
solvent was evaporated to give 3-propylazetidine-3-ol hydrochloride
(0.8 g, yield 68%) as a light yellow solid. It was used in next
step without further purification.
Step 3: Preparation of (3-hydroxy-3-propylazetidine-1-yl)
(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-
-yl)methanone
[0463] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (800 mg, 2.8 mmol), HATU (2.13 g, 5.6 mmol) and
DIPEA (1.44 g, 11.2 mmol) in DMF (10 mL) was stirred at rt for 30
min. Then 3-propylazetidine-3-ol hydrochloride (507 mg, 3.4 mmol)
was added and the reaction mixture was stirred at rt overnight. The
crude product obtained from a normal work-up was purified by
prep-HPLC to give
(3-hydroxy-3-propylazetidine-1-yl)(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo-
[c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)methanone (384 mg, yield 36%)
as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.08
(s, 1H), 8.61 (d, J=0.8 Hz, 1H), 8.56 (d, J=0.8 Hz, 1H), 7.29 (d,
J=6.4 Hz, 1H), 7.25 (d, J=6.4 Hz, 1H), 5.60 (s, 1H), 4.99 (s, 2H),
4.41 (d, J=8.0 Hz, 1H), 4.31 (d, J=8.0 Hz, 1H), 3.96 (d, J=8.4 Hz,
1H), 3.85 (d, J=8.4 Hz, 1H), 2.22 (s, 3H), 1.63 (t, J=6.4 Hz, 2H),
1.39-1.35 (m, 2H), 0.90 (t, J=6.0 Hz, 3H) ppm; HPLC purity: 100% at
214 nm and 100% at 254 nm; MS: m/z=384.2 (M+1, ESI+).
Example 57
(3-hydroxy-3-isopropylazetidin-1-yl)
(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-
-2-yl)methanone
##STR00132##
[0464] Step 1: Preparation of
1-benzhydryl-3-isopropylazetidin-3-ol
[0465] To a solution of 1-benzhydrylazetidin-3-one (2.37 g, 10
mmol) in dry THF (50 mL) was added isopropylmagnesium chloride (2M,
15 mL, 30 mmol) dropwise at -78.degree. C. After being stirred at
-78.degree. C. for 2 h, the reaction mixture was gradually warmed
to rt and stirred overnight. Saturated NH.sub.4Cl (50 mL) was added
and extracted with EA (3.times.100 mL). The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under the reduced pressure. The residue was purified
by silica gel column chromatography using PE:EA (4:1) as eluent to
give 1-benzhydryl-3-isopropylazetidin-3-ol (1.55 g, yield 55%) as a
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.40 (d,
J=7.2 Hz, 4H), 7.26 (t, J=7.2 Hz, 4H), 7.18 (t, J=7.2 Hz, 2H), 4.93
(s, 1H), 4.41 (s, 1H), 3.12 (d, J=8.0 Hz, 2H), 2.79 (d, J=8.0 Hz,
2H), 1.99 (m, 1H), 0.86 (d, J=6.8 Hz, 6H) ppm; MS: m/z=282.3 (M+1,
ESI+).
Step 2: Preparation of 3-isopropylazetidin-3-ol hydrochloride
[0466] A solution of 1-benzhydryl-3-isopropylazetidin-3-ol (1.55 g,
5.5 mmol) and HCl (1N, 5.5 mL) in MeOH (25 mL) was hydrogenated
using 10% Pd/C (200 mg) as catalyst under atmospheric pressure of
H.sub.2 overnight. The catalyst was removed and the solvent was
evaporated to give 3-isopropylazetidin-3-ol hydrochloride (860 mg,
yield 98%) as a light yellow solid. It was used in next step
without further purification. MS: m/z=116.2 (M+1, ESI+).
Step 3: Preparation of (3-hydroxy-3-isopropylazetidin-1-yl)
(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-
-yl)methanone
[0467] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (700 mg, 2.45 mmol), HATU (1.86 g, 4.9 mmol) and
DIPEA (1.26 g, 9.8 mmol) in DMF (10 mL) was stirred at rt for 30
min. Then 3-isopropylazetidin-3-ol hydrochloride (444 mg, 2.94
mmol) was added and the reaction mixture was stirred at rt
overnight. The crude material was purified by prep-HPLC to give
(3-hydroxy-3-isopropylazetidin-1-yl)(5-(1-hydroxy-7-methyl-1,3-dihydroben-
zo[c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)methanone (342 mg, yield
36%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.10 (s, 1H), 8.62 (d, J=1.2 Hz, 1H), 8.57 (d, J=1.2 Hz, 1H), 7.29
(d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 5.55 (s, 1H), 4.99 (s,
2H), 4.45 (d, J=10.4 Hz, 1H), 4.27 (d, J=10.4 Hz, 1H), 4.01 (d,
J=10.4 Hz, 1H), 3.80 (d, J=10.4 Hz, 1H), 2.21 (s, 3H), 1.85-1.82
(m, 1H), 0.87-0.85 (m, 6H) ppm; HPLC purity: 100% at 214 nm and
100% at 254 nm; MS: m/z=384.2 (M+1, ESI+).
Example 58
(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)
(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-
-2-yl)methanone
##STR00133##
[0468] Step 1: Preparation of
l-benzhydryl-3-(trifluoromethyl)azetidin-3-ol
[0469] To a solution of 1-benzhydrylazetidin-3-one (2.0 g, 8.45
mmol) in THF (25 mL) was added trimethyl(trifluoromethyl)silane
(1.80 g, 12.65 mmol) and cesium fluoride (1.95 g, 12.85 mmol). The
reaction mixture was stirred at room temperature for 1 h and
quenched with saturated NH.sub.4Cl solution. The mixture was
extracted with EtOAc (3.times.20 mL). The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuum. The crude product was purified by column
chromatography on silica gel using PE:EA (4:1) as eluent to give
1-benzhydryl-3-(trifluoromethyl)azetidin-3-ol (1.55 g, yield 60%)
as a yellow solid. MS: m/z=308.1 (M+1, ESI+).
Step 2: Preparation of 3-(trifluoromethyl)azetidin-3-ol
hydrochloride
[0470] A solution of 1-benzhydryl-3-(trifluoromethyl)azetidin-3-ol
(1.55 g, 5.04 mmol) and HCl (1N, 5 mL) in MeOH (30 mL) was
hydrogenated using 10% Pd/C (200 mg) as catalyst under atmospheric
pressure of H.sub.2 overnight. The catalyst was removed by
filtration and the solvent was evaporated to give
3-(trifluoromethyl)azetidin-3-ol hydrochloride (800 mg, yield 89%)
as a light yellow solid. It was used in next step without further
purification. MS: m/z=142.1 (M+1, ESI+).
Step 3: Preparation of (3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)
(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-
-yl)methanone
[0471] A solution of
5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-
-carboxylic acid (568 mg, 1.99 mmol), HATU (1.51 g, 3.98 mmol) and
DIPEA (1.03 g, 7.96 mmol) in DMF (7 mL) was stirred at rt for 30
min. Then 3-(trifluoromethyl)azetidin-3-ol hydrochloride (423 mg,
2.39 mmol) was added and the reaction mixture was stirred at rt
overnight. The crude product was purified by prep-HPLC to give
(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)(5-(1-hydroxy-7-methyl-1,3-di-
hydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)methanone (200.8
mg, yield 25%) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.08 (s, 1H), 8.65 (d, J=1.2 Hz, 1H), 8.57
(d, J=1.6 Hz, 1H), 7.48 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.24 (d,
J=8.0 Hz, 1H), 4.98 (s, 2H), 4.80 (d, J=10.8 Hz, 1H), 4.55 (d,
J=11.6 Hz, 1H), 4.31 (d, J=10.8 Hz, 1H), 4.07 (d, J=11.2 Hz, 1H),
2.21 (s, 3H) ppm; HPLC purity: 100% at 214 nm and 100% at 254 nm;
MS: m/z=410.1 (M+1, ESI+).
Example 2
[0472] In Vitro Activity Against Plasmodium falciparum
[0473] a) Against 3D7 Strain of Plasmodium falciparum
[0474] Inhibition of 3D7 strain parasites was assessed using the
[.sup.3H]-hypoxanthine incorporation assay (Desjardins, et al.
Antimicrob. Agents Chemother. 1979, 16, 710-718). Briefly,
parasites were cultured in human erythrocytes (from the Spanish Red
Cross blood bank) using RPMI-1640 culture media (Gibco)
supplemented with 0.5% Albumax II (Invitrogen), 2% D-sucrose
(Sigma-Aldrich), 0.3% glutamine (Sigma-Aldrich), and 5 mM
hypoxanthine (Sigma-Aldrich). Cultures were maintained at
37.degree. C. at an atmosphere of 5% O.sub.2, 5% CO.sub.2, and 95%
N.sub.2. To assess inhibition, asynchronous parasite cultures with
0.5% parasitemia and 2% hematocrit were exposed to 3-fold serial
dilutions of test compounds for 24 hours in 96 well plate cultures
(Costar #3894). After 24 hours, [.sup.3H]-hypoxanthine was added,
plates were incubated for an additional 24 hours, and parasites
were harvested on glass fiber filters (Wallac #1450-421) using a
cell harvester 96 (TOMTEC, Perkin Elmer). Filters were dried on
scintillator sheets (MeltiLex A, PerkinElmer #1450-441) to
determine incorporation of [.sup.3H]-hypoxanthine. Radioactivity
was measured using a microbeta counter (Perkin Elmer). Data are
normalized using the incorporation of the positive control
(infected erythrocytes without drug). IC.sub.50 values were
determined using Excel and Grafit 5 software. Values were
determined from at least three independent experiments, and
standard deviations were calculated.
[0475] b) Against W2 Strain of Plasmodium falciparum
[0476] W2 strain P. falciparum parasites were cultured in human
erythrocytes and RPMI-1640 culture media with either 10% human
serum or 0.5% Albumax serum substitute under 3% O.sub.2, 5%
CO.sub.2, and 92% N.sub.2. Parasites synchronized to ring stage by
treatments with 5% D-sorbitol were cultured with serial dilutions
of benzoxaboroles from 5 to 10 mM stocks in 96 well microplate
cultures including 200 .mu.L of media/well, 2% hematocrit, and 1%
parasitemia. At the completion of 48 h incubations, when untreated
cultures contained new rings, parasites were fixed with 2%
formaldehyde for 48 h, and 5 .mu.L aliquots were transferred to
another 96 well plate containing 150 .mu.L/well of staining
solution (100 mM NH.sub.4Cl, 0.1% Triton X-100, and 1 nM YOYO-1 in
PBS). Parasites per erythrocyte were then determined by flow
cytometry from plots of forward scatter against fluorescence
(excitation 488 nm, emission 520 nm) using a FacSort flow cytometer
(Beckton Dickinson) equipped with an AMS Loader (Cytek
Development). All values were normalized to percent control
activity, and ICsos were calculated using the Prism 3.0 program
(GRAPHPAD Software). Goodness of fit was assessed by R.sup.2
values, and meaningful dose-response curves yielded R.sup.2 values
>0.95.
[0477] C log D
[0478] c) C log D
[0479] C log D (pH=7.4) was calculated using ChemAxon software
under the condition of pH=7.4.
[0480] Data for exemplary compounds of the invention are provided
below.
TABLE-US-00001 IC50: I Org. Growth IC50: I Org. Growth P.
falciparum P. falciparum 3D7, 2 d W2, 2 d Ex# (LPS_00570) [uM]
(LPS_00451) [uM] Clog D 1 1.08 0.372 0.25 2 0.644 0.788 0.83 3
0.425 0.29 0.74 4 0.554 0.334 0.74 5 0.317 0.0923 0.66 6 0.184
0.328 -0.25 7 0.0965 0.115 1.54 8 0.937 0.93 1.86 9 1.1 1.28 0.66
10 0.437 0.262 0.5 11 0.848 0.944 0.66 12 0.808 0.844 0.66 13 0.715
0.297 1.53 14 0.201 0.161 1.53 15 0.407 0.297 2.35 16 0.38 0.223
2.1 17 1.5 2.01 0.38 18 0.725 0.622 1.13 19 0.403 0.136 1.13 20
0.786 0.535 1.06 21 0.801 0.704 1.13 22 1.15 0.458 1.03 23 1.99
0.774 1.54 24 0.587 0.492 1.03 25 0.466 0.149 1.54 26 0.161 0.103
2.1 27 0.505 0.115 2.35 28 0.215 0.0849 1.93 29 0.764 0.828 1.06 30
0.536 0.317 1.06 31 1.09 0.643 1.03 32 0.796 0.512 0.16 33 0.149
0.0822 1.54 34 0.452 0.35 1.54 35 0.0737 0.37 0.99 36 0.472 0.201
-.097 37 0.48 0.23 1.79 38 0.959 0.352 1.79 39 1.46 0.513 1.08 40
0.314 0.139 0.52 41 0.0706 0.0326 0.47 42 0.245 0.133 1.11 43 0.553
0.26 2.02 44 0.217 0.129 2.02 45 0.222 0.0918 1.62 46 0.537 0.149
1.11 47 0.327 0.202 1.16 48 0.374 0.265 1.16 49 0.181 0.292 1.11 50
0.171 0.0982 -0.29 51 0.151 0.103 -0.29 52 0.252 0.0481 1.78 53
0.829 0.279 1.62 54 0.087 0.0289 0.94 55 0.234 0.0517 0.84 56 0.137
0.0159 1.33 57 0.369 0.0407 1.34 58 0.0139 0.0066 1.10
[0481] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
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