U.S. patent application number 12/503123 was filed with the patent office on 2009-11-05 for antibacterial agents.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Timothy A. Johnson, Dennis J. McNamara, Debra A. Sherry, Peter Laurence Toogood.
Application Number | 20090275536 12/503123 |
Document ID | / |
Family ID | 37872452 |
Filed Date | 2009-11-05 |
United States Patent
Application |
20090275536 |
Kind Code |
A1 |
Johnson; Timothy A. ; et
al. |
November 5, 2009 |
Antibacterial Agents
Abstract
Described herein are antibacterial compounds, methods for making
the compounds, pharmaceutical compositions containing the compounds
and methods of treating bacterial infections utilizing the
compounds and pharmaceutical composition.
Inventors: |
Johnson; Timothy A.;
(Howell, MI) ; McNamara; Dennis J.; (Ann Arbor,
MI) ; Sherry; Debra A.; (Chelsea, MI) ;
Toogood; Peter Laurence; (Ann Arbor, MI) |
Correspondence
Address: |
PFIZER INC.;PATENT DEPARTMENT
Bld 114 M/S 114, EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
37872452 |
Appl. No.: |
12/503123 |
Filed: |
July 15, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11641215 |
Dec 19, 2006 |
7557100 |
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12503123 |
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60753262 |
Dec 22, 2005 |
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Current U.S.
Class: |
514/81 ;
514/229.5; 544/71 |
Current CPC
Class: |
C07D 498/22 20130101;
A61P 31/00 20180101; A61P 31/04 20180101 |
Class at
Publication: |
514/81 ; 544/71;
514/229.5 |
International
Class: |
A61K 31/675 20060101
A61K031/675; C07D 265/34 20060101 C07D265/34; A61K 31/5386 20060101
A61K031/5386; A61P 31/04 20060101 A61P031/04 |
Claims
1. (canceled)
2. The compound of of formula I: ##STR00056## or a salt, solvate,
or a hydrate thereof, wherein: R.sub.1 is a substituted or
unsubstituted pyrazine; R.sub.2 and R.sub.3 are independently H or
substituted or unsubstituted C.sub.1-6 alkyl; R.sub.4 and R.sub.5
are independently H, a substituted or unsubstituted C.sub.1-6
alkyl, a substituted or unsubstituted ether, substituted or
unsubstituted --(CH.sub.2).sub.mNR.sub.8R.sub.9, substituted or
unsubstituted benzyl, --O(CH.sub.2).sub.maryl, --Obenzyl,
--(CH.sub.2).sub.mNR.sub.8R.sub.9, --(CH.sub.2).sub.mOR.sub.6,
--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOC(.dbd.O)E, or R.sub.4nd R.sub.5 together with
the atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring; each m is independently 0, 1, 2 or
3; E is a substituted or unsubstituted ether; each R.sub.p is
independently H, C.sub.1-6 alkyl, benzyl, substituted benzyl,
phenyl, substituted phenyl, or (R.sub.p).sub.2 together with the
atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring; each R.sub.6 is independently H,
C.sub.1-6 alkyl, C.sub.1-6 acyl or benzyl; R.sub.8 and R.sub.9 are
independently H, substituted or unsubstituted C.sub.1-6 alkyl or
R.sub.8 and R.sub.9 together with the atom to which they are
attached form a substituted or unsubstituted heterocyclic ring; and
X and Y are independently H, halo, substituted or unsubstituted
C.sub.1-6 alkyl, --OR.sub.6, --CN, a substituted or unsubstituted
ether, a substituted or unsubstituted heterocyclyl, or a
substituted or unsubstituted amine wherein ##STR00057## indicates a
point of attachment; R.sub.7 is H, halo, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.3-C.sub.8 cycloalkyl, substituted or unsubstituted
heterocyclyl, a substituted or unsubstituted ether, --CN,
--NR.sub.8R.sub.9, --OR.sub.10,
--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3--(CH.sub.2).sub.mOC(-
.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOC(.dbd.O)E,
--(CH.sub.2).sub.mCO.sub.2(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mCO.sub.2(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mCO.sub.2(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mCO.sub.2E,
--(CH.sub.2).sub.mC(.dbd.O)NR.sub.6(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mC(.dbd.O)NR.sub.8R.sub.9,
--(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mPO.sub.3(R.sub.11).sub.2,
--(CH.sub.2).sub.mOR.sub.10, which is optionally substituted with
--OR.sub.11, --(CH.sub.2).sub.mC(.dbd.O)OR.sub.11,
--(CH.sub.2).sub.mNR.sub.11SO.sub.nR.sub.12,
--(CH.sub.2).sub.mSO.sub.nR.sub.12,
--(CH.sub.2).sub.mSO.sub.nNR.sub.8R.sub.9, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each n is independently is 0, 1 or 2; R.sub.10 is H, substituted or
unsubstituted C.sub.1-6 alkyl, --PO.sub.3H.sub.2,
C(.dbd.O)R.sub.13, C(.dbd.O)OR.sub.13 or C(.dbd.O)NR.sub.8R.sub.9
and R.sub.11, R.sub.12 and R.sub.13 are independently H,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted aminoalkyl, substituted or unsubstituted benzyl,
substituted or unsubstituted phenyl, an amino acid residue or a
peptide residue.
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. The compound of formula I: ##STR00058## or a salt, solvate, or
a hydrate thereof, wherein: R.sub.1 is a substituted or
unsubstituted pyrazine; R.sub.2 and R.sub.3 are independently H or
substituted or unsubstituted C.sub.1-6 alkyl; R.sub.4 and R.sub.5
are independently H, a substituted or unsubstituted C.sub.1-6
alkyl, a substituted or unsubstituted ether, substituted or
unsubstituted --(CH.sub.2).sub.maryl, substituted or unsubstituted
benzyl, --O(CH.sub.2).sub.maryl, --Obenzyl,
--(CH.sub.2).sub.mNR.sub.8R.sub.9, --(CH.sub.2).sub.mOR.sub.6,
--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOC(.dbd.O)E, or R.sub.4nd R.sub.5 together with
the atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring; each m is independently 0, 1, 2 or
3; E is a substituted or unsubstituted ether; each R.sub.p is
independently H, C.sub.1-6 alkyl, benzyl, substituted benzyl,
phenyl, substituted phenyl, or (R.sub.p).sub.2 together with the
atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring; each R.sub.6 is independently H,
C.sub.1-6 alkyl, C.sub.1-6 acyl or benzyl; R.sub.8 and R.sub.9, are
independently H, substituted or unsubstituted C.sub.1-6 alkyl or
R.sub.8 and R.sub.9 together with the atom to which they are
attached form a substituted or unsubstituted heterocyclic ring; and
X and Y are independently H, halo, substituted or unsubstituted
C.sub.1-6 alkyl, --OR.sub.6, --CN, a substituted or unsubstituted
ether, a substituted or unsubstituted heterocyclyl, or a
substituted or unsubstituted amine having a structure of compound
set forth in Table 1, an enantiomer or diastereomer thereof or a
salt, solvate, or hydrate thereof.
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. A bacteriostatic and/or bactericidal method comprising: (a)
contacting a bacteria with a compound of formula I: ##STR00059## or
a salt, solvate, or a hydrate thereof, wherein: R.sub.1 is a
substituted or unsubstituted pyrazine; R.sub.2 and R.sub.3 are
independently H or substituted or unsubstituted C.sub.1-6 alkyl;
R.sub.4 and R.sub.5 are independently H, a substituted or
unsubstituted C.sub.1-6 alkyl, a substituted or unsubstituted
ether, substituted or unsubstituted --(CH.sub.2).sub.maryl,
substituted or unsubstituted benzyl, --O(CH.sub.2).sub.maryl,
--Obenzyl, --(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOR.sub.6,
--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOC(.dbd.O)E, or R.sub.4nd R.sub.5 together with
the atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring; each m is independently 0, 1, 2 or
3; E is a substituted or unsubstituted ether; each R.sub.p is
independently H, C.sub.1-6 alkyl, benzyl, substituted benzyl,
phenyl, substituted phenyl, or (R.sub.p).sub.2 together with the
atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring; each R.sub.6 is independently H,
C.sub.1-6 alkyl, C.sub.1-6 acyl or benzyl; R.sub.8 and R.sub.9, are
independently H, substituted or unsubstituted C.sub.1-6 alkyl or
R.sub.8 and R.sub.9 together with the atom to which they are
attached form a substituted or unsubstituted heterocyclic ring; and
X and Y are independently H, halo, substituted or unsubstituted
C.sub.1-6 alkyl, --OR.sub.6, --CN, a substituted or unsubstituted
ether, a substituted or unsubstituted heterocyclyl, or a
substituted or unsubstituted amine.
16. The method of claim 15 wherein (a) occurs in vitro or in
vivo.
17. A method of treating a bacterial infection in a mammal
comprising administering an effective amount a compound of formula
I: ##STR00060## or a salt, solvate, or a hydrate thereof, wherein:
R.sub.1 is a substituted or unsubstituted pyrazine; R.sub.2 and
R.sub.3 are independently H or substituted or unsubstituted
C.sub.1-6 alkyl; R.sub.4 and R.sub.5 are independently H, a
substituted or unsubstituted C.sub.1-6 alkyl, a substituted or
unsubstituted ether, substituted or unsubstituted
--(CH.sub.2).sub.maryl, substituted or unsubstituted benzyl,
--O(CH.sub.2).sub.maryl, --Obenzyl,
--(CH.sub.2).sub.mNR.sub.8R.sub.9, --(CH.sub.2).sub.mOR.sub.6,
--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOC(.dbd.O)E, or R.sub.4nd R.sub.5 together with
the atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring; each m is independently 0, 1, 2 or
3; E is a substituted or unsubstituted ether; each R.sub.p is
independently H, C.sub.1-6 alkyl, benzyl, substituted benzyl,
phenyl, substituted phenyl, or (R.sub.p).sub.2 together with the
atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring; each R.sub.6 is independently H,
C.sub.1-6 alkyl, C.sub.1-6 acyl or benzyl; R.sub.8 and R.sub.9, are
independently H, substituted or unsubstituted C.sub.1-6 alkyl or
R.sub.8 and R.sub.9 together with the atom to which they are
attached form a substituted or unsubstituted heterocyclic ring; and
X and Y are independently H, halo, substituted or unsubstituted
C.sub.1-6 alkyl, --OR.sub.6, --CN, a substituted or unsubstituted
ether, a substituted or unsubstituted heterocyclyl, or a
substituted or unsubstituted amine.
18. The method of claim 17 comprising preventing a bacterial
infection in a mammal by administering the effective amount of the
compound of formula I: ##STR00061## or a salt, solvate, or a
hydrate thereof, wherein: R.sub.1 is a substituted or unsubstituted
pyrazine; R.sub.2 and R.sub.3 are independently H or substituted or
unsubstituted C.sub.1-6 alkyl; R.sub.4 and R.sub.5 are
independently H, a substituted or unsubstituted C.sub.1-6 alkyl, a
substituted or unsubstituted ether, substituted or unsubstituted
--(CH.sub.2).sub.maryl, substituted or unsubstituted benzyl,
--O(CH.sub.2).sub.maryl, --Obenzyl,
--(CH.sub.2).sub.mNR.sub.8R.sub.9, --(CH.sub.2).sub.mOR.sub.6,
--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOC(.dbd.O)E, or R.sub.4nd R.sub.5 together with
the atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring; each m is independently 0, 1, 2 or
3; E is a substituted or unsubstituted ether; each R.sub.p is
independently H, C.sub.1-6 alkyl, benzyl, substituted benzyl,
phenyl, substituted phenyl, or (R.sub.p).sub.2 together with the
atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring; each R.sub.6 is independently H,
C.sub.1-6 alkyl, C.sub.1-6 acyl or benzyl; R.sub.8 and R.sub.9, are
independently H, substituted or unsubstituted C.sub.1-6 alkyl or
R.sub.8 and R.sub.9 together with the atom to which they are
attached form a substituted or unsubstituted heterocyclic ring; and
X and Y are independently H, halo, substituted or unsubstituted
C.sub.1-6 alkyl, --OR.sub.6, --CN, a substituted or unsubstituted
ether, a substituted or unsubstituted heterocyclyl, or a
substituted or unsubstituted amine.
19. (canceled)
20. (canceled)
21. (canceled)
22. (canceled)
23. The method of making the compound of formula IIIa comprising:
(b) reacting a compound of formula V with a compound of formula VI
a to make the compound of formula IIIa, ##STR00062##
24. The method of claim 23 wherein (b) occurs in the presence of a
non-protic organic solvent and/or in the presence of a base.
25. The method of claim 24 wherein the base is an organic base or
an inorganic base.
26. The method of claim 25 wherein the temperature of (b) is about
20 to about 100.degree. C.
27. The method of claim 26 further comprising: (c)(i) performing a
halogen metal exchange or deprotonation reaction on a compound of
formula VII; and (c)(ii) reacting the product of (c)(i) with a
carbonyl donor to make the compound of formula V, ##STR00063##
wherein Ha is hydrogen or a halogen.
28. The method of claim 27 wherein (c)(i) comprises contacting the
compound of formula VII with a strong base.
29. The method of claim 28 wherein the strong base comprises alkyl
lithium.
30. The method of claim 29 wherein (c)(i) comprises contacting the
compounds of formula VII with a Grignard reagent in a non-protic
organic solvent.
31. The method of claim 30 wherein the temperature of (c)(i) is
about -78 to about 50.degree. C.
32. The method of claim 31 wherein the carbonyl donor comprises one
or more of dimethylformamide, N-formylmorpholine, or
para-nitrophenylformate.
33. The method of claim 26 further comprising: (c) oxidizing a
compound of formula VIII to make the compound of formula V,
##STR00064##
34. A method of making the compound of formula XVII comprising (a)
reacting a compound of formula XVIII with a compound of formula VI
a to make the compound of formula XVII, ##STR00065## wherein
R.sub.14 is a halogen, boronic acid, a boronate ester or a
substituted or unsubstituted pyrazine; and R.sub.2 and R.sub.3 are
independently H or substituted or unsubstituted C.sub.1-6 alkyl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Non-provisional
application Ser. No. 11/641,215, filed Dec. 19, 2006, which claims
the priority of U.S. Provisional Application Ser. No. 60/753,262
filed on Dec. 22, 2005.
FIELD OF THE INVENTION
[0002] Described herein are antibacterial compounds, their use as
antibacterial agents, pharmaceutical compositions containing these
compounds, and methods for their preparation.
BACKGROUND OF THE INVENTION
[0003] Antibacterial resistance is a global clinical and public
health problem that has emerged with alarming rapidity in recent
years and undoubtedly will increase in the near future. Resistance
is a problem in the community as well as in health care settings,
where transmission of bacteria is greatly amplified. Because
multiple drug resistance is a growing problem, physicians are now
confronted with infections for which there is no effective therapy.
The morbidity, mortality, and financial costs of such infections
pose an increasing burden for health care systems worldwide.
Strategies to address these issues emphasize enhanced surveillance
of drug resistance, increased monitoring and improved usage of
antimicrobial drugs, professional and public education, development
of new drugs, and assessment of alternative therapeutic
modalities.
[0004] As a result, alternative and improved agents are needed for
the treatment of bacterial infections, particularly for the
treatment of infections caused by resistant strains of bacteria,
e.g. penicillin-resistant, methicillin-resistant,
ciprofloxacin-resistant, and/or vancomycin-resistant strains.
SUMMARY OF THE INVENTION
[0005] One embodiment provides a compound having formula I:
##STR00001##
or a salt, solvate, hydrate or prodrug thereof.
[0006] In the above formula, R.sub.1 is a substituted or
unsubstituted pyrazine;
[0007] R.sub.2 and R.sub.3 are independently H or substituted or
unsubstituted C.sub.1-6 alkyl;
[0008] R.sub.4 and R.sub.5 are independently H, a substituted or
unsubstituted C.sub.1-6 alkyl, a substituted or unsubstituted
ether, substituted or unsubstituted --(CH.sub.2).sub.maryl,
substituted or unsubstituted --O(CH.sub.2).sub.maryl,
--(CH.sub.2).sub.mNR.sub.8R.sub.9, --(CH.sub.2).sub.mOR.sub.6,
--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6--(CH.sub.2).s-
ub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOC(.dbd.O)E or R.sub.4 and R.sub.5 together with
the atoms to which they are attached form a substituted or
unsubstituted heterocyclic ring;
[0009] each m is independently 0, 1, 2 or 3;
[0010] E is a substituted or unsubstituted ether;
[0011] each R.sub.p is independently H, C.sub.1-6 alkyl, benzyl,
substituted benzyl, phenyl, substituted phenyl, or (R.sub.p).sub.2
together with the atoms to which they are attached form a
substituted or unsubstituted heterocyclic ring;
[0012] each R.sub.6 is independently H, substituted or
unsubstituted C.sub.1-6 alkyl, C.sub.1-6 acyl or benzyl;
[0013] R.sub.8 and R.sub.9 are independently H, substituted or
unsubstituted C.sub.1-6 alkyl or R.sub.8 and R.sub.9 together with
the atom to which they are attached form a substituted or
unsubstituted heterocyclic ring; and
[0014] X and Y are independently H, halo, substituted or
unsubstituted C.sub.1-6 alkyl, --OR.sub.6, --CN, a substituted or
unsubstituted ether, a substituted or unsubstituted heterocyclyl,
or a substituted or unsubstituted amine.
[0015] Forms of the compounds can include salts, such as
pharmaceutically acceptable salts, solvates, hydrates or prodrugs
of the described compounds. The described compounds can also be
part of a pharmaceutical composition, which can additionally
include a pharmaceutically acceptable carrier, diluent or
excipient.
[0016] Such compounds and compositions exhibit antibacterial
activity and can be used accordingly.
DETAILED DESCRIPTION
[0017] Provided herein are compounds of Formula I. When describing
the compounds of Formula I, for example when naming the compounds,
the ring system is numbered as follows:
##STR00002##
[0018] In some compounds R.sub.1 is:
##STR00003##
for example
##STR00004##
[0019] In these embodiments, indicates a point of attachment and
the pyrazine can be substituted with one, two, three or more
R.sub.7 groups;
[0020] R.sub.7 is H, halo, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl,
substituted or unsubstituted heterocyclyl, a substituted or
unsubstituted ether,
--CN--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOC(.dbd.O)E,
--(CH.sub.2).sub.mCO.sub.2(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mCO.sub.2(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mCO.sub.2(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mCO.sub.2E,
--(CH.sub.2).sub.mC(.dbd.O)NR.sub.6(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mC(.dbd.O)NR.sub.8R.sub.9,
--(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mPO.sub.3(R.sub.11).sub.2,
--(CH.sub.2).sub.mOR.sub.10, which is optionally substituted with
--OR.sub.11, --(CH.sub.2).sub.mC(.dbd.O)OR.sub.11,
--(CH.sub.2).sub.mNR.sub.11SO.sub.nR.sub.12,
--(CH.sub.2).sub.mSO.sub.nR.sub.12,
--(CH.sub.2).sub.mSO.sub.nNR.sub.8R.sub.9, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0021] each m is as above, each n is independently 0, 1 or 2;
[0022] R.sub.10 is H, substituted or unsubstituted C.sub.1-6 alkyl,
--PO.sub.3H.sub.2, C(.dbd.O)R.sub.13, C(.dbd.O)OR.sub.13 or
C(.dbd.O)NR.sub.8R.sub.9; and
[0023] R.sub.11, R.sub.12 and R.sub.13 are independently H,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted aminoalkyl, an amino acid residue or a peptide
residue. Examples of amino acid residues include alanine, aspartic
acid, glycine, glutamic acid, histidine, lysine or valine.
[0024] In some instances, a nitrogen of the pyrazine ring can be
substituted, for example with an oxygen in
##STR00005##
which can also be depicted as
##STR00006##
[0025] In certain compounds, X is H, Y is H or both X and Y are H.
In other compounds X is F, Y is F or both X and Y are F. In these
and other compounds, R.sub.2 and R.sub.3 can be methyl. In some
compounds X can be substituted or unsubstituted --OR.sub.6, and in
some instances R.sub.6 can be ethyl. Alternatively, X can be a
substituted or unsubstituted ether or an amine.
[0026] In some embodiments, X, Y or both can be a substituted or
unsubstituted ether. In the compounds, none, one or both of R.sub.4
and R.sub.5 can be H. R.sub.4 and R.sub.5 can also independently be
ethers.
[0027] Alternatively, independently X, Y or both can be a
substituted or unsubstituted amine. When X or Y is a substituted or
unsubstituted amine, then the group can independently have the
formula --(CH.sub.2).sub.mNR.sub.8R.sub.9 and each m, R.sub.8 and
R.sub.9 is independent of any other m, R.sub.8 and R.sub.9 values
at other positions. When any R.sub.8 and R.sub.9 together with the
atom to which they are attached form a substituted or unsubstituted
heterocyclic ring, the ring can be a monocyclic ring system, for
example containing three to eight ring atoms, or the ring system
can be a bi- or polyheterocyclic ring system. Additionally, one or
more ring atoms, in addition to the N to which R.sub.8 and R.sub.9
are attached, can be selected from non-carbon atoms, for example N,
O or S.
[0028] In some embodiments R.sub.4 and R.sub.5 are the same, for
example where both are H. R.sub.4 or R.sub.5 can also be
substituted or unsubstituted --(CH.sub.2).sub.maryl or
--O(CH.sub.2).sub.maryl, such as substituted or unsubstituted
benzyl or substituted or unsubstituted --Obenzyl.
[0029] In certain compounds, when R.sub.8 and R.sub.9 together with
the atom to which they are attached form a substituted or
unsubstituted heterocyclic ring, the heterocyclic ring can have
three, four, five, six, seven, eight or more ring members and
include one, two, three or more heteroatoms, such as N, O or S.
Specific examples of such heterocyclic rings include morpholine and
piperazine or a substituted piperazine.
[0030] In certain embodiments, R.sub.11, R.sub.12 or R.sub.13 can
be an amino acid residue. Amino acid residues are molecules that
contain both amino and carboxylic acid functional groups. Some
amino acids can be represented by the formula
--C(.dbd.O)CH(Z)NHR.sub.a, where Z alone can be a side chain of a
naturally or non-naturally occurring amino acid. In cyclic amino
acids, such as proline, Z in combination with R.sub.a can be a side
chain of a naturally or non-naturally occurring amino acid. When
R.sub.a is not part of the amino acid side chain, then generally
R.sub.a is H. Amino acids and peptides can be C- or N-linked.
Examples of amino acids include alanine, arginine, asparagine,
aspartic acid, cysteine, glutamic acid, glutamine, glycine,
histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
proline, serine, threonine, tryptophan, tyrosine and valine. Other
amino acids include gamma-aminobutyric acid (GABA), carnitine,
ornithine, citrulline, homocysteine, hydroxyproline, hydroxylysine,
and sarcosine. The amino acids can be in the L- or
D-configuration.
[0031] Alternatively, R.sub.11, R.sub.12 or R.sub.13 can be a
peptide residue, which can be C- or N-linked. Peptides are amino
acids linked together via peptide bonds and can be straight-chained
or branched. Suitable peptides can include dipeptides, tripeptides,
tetrapeptides or more in which the amino acid residues making up
the peptide can be the same or different.
[0032] In some embodiments, (R.sub.p).sub.2 together with the atoms
to which they are attached form a substituted or unsubstituted
heterocyclic ring. In some compounds the oxygen atoms can be
connected via an alkyl, aryl, or alkyl-aryl-alkyl bridge, such as
in
##STR00007##
[0033] In some of the compounds each E or ether independently has
the formula [(CV.sub.2).sub.pO(CV.sub.2).sub.p].sub.qCH.sub.3
wherein each p is independently 0, 1, 2, 3, 4, 5 or 6, each q is
independently 1, 2, 3, 4, 5 or 6, each V is independently H or
another [(CV.sub.2).sub.pO(CV.sub.2).sub.p].sub.qCH.sub.3. Examples
of these compounds include where each E or ether independently has
the formula --[(CH.sub.2).sub.p--O--(CH.sub.2).sub.p].sub.qCH.sub.3
where each p is independently 0, 1, 2, 3 or 4 and each q is
independently 1, 2, 3 or 4.
[0034] In some specific embodiments, X and Y are F, R.sub.2 and
R.sub.3 are methyl, and R.sub.4 and R.sub.5 are H. In additional
specific embodiments, X is F, Y is H, R.sub.2 and R.sub.3 are
methyl, and R.sub.4 and R.sub.5 are H. In further specific
embodiments, X is H, Y is F, R.sub.2 and R.sub.3 are methyl, and
R.sub.4 and R.sub.5 are H. In some specific embodiments, X and Y
are H, R.sub.2 and R.sub.3 are methyl, and R.sub.4 and R.sub.5 are
H. In further specific embodiments, X and Y are F, R.sub.2 and
R.sub.3 are methyl, and R.sub.4 and R.sub.5 are a substituted or
unsubstituted ether, --(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOR.sub.6,
--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9, or
--(CH.sub.2).sub.mOC(.dbd.O)E. In certain of these embodiments, m
is 1 or 2. In other specific embodiments, X is F, Y is H, R.sub.2
and R.sub.3 are methyl, and R.sub.4 and R.sub.5 are a substituted
or unsubstituted ether, --(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOR.sub.6,
--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9, or
--(CH.sub.2).sub.mOC(.dbd.O)E. In certain of these embodiments, m
is 1 or 2. In some of these compounds R.sub.7 can be H, C.sub.1-6
alkyl, such as a methyl, --NR.sub.8R.sub.9 or --OR.sub.10. In other
embodiments, R.sub.7 is a substituted or unsubstituted ether,
--(CH.sub.2).sub.mOPO.sub.3(R.sub.p).sub.2,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mOC(.dbd.O)(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mOC(.dbd.O)E,
--(CH.sub.2).sub.mCO.sub.2(CH.sub.2).sub.mCH.sub.3,
--(CH.sub.2).sub.mCO.sub.2(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mCO.sub.2(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mCO.sub.2E,
--(CH.sub.2).sub.mC(.dbd.O)NR.sub.6(CH.sub.2).sub.mCO.sub.2R.sub.6,
--(CH.sub.2).sub.mC(.dbd.O)NR.sub.8R.sub.9,
--(CH.sub.2).sub.mNR.sub.8R.sub.9,
--(CH.sub.2).sub.mPO.sub.3(R.sub.11).sub.2,
--(CH.sub.2).sub.mC(.dbd.O)OR.sub.11,
--(CH.sub.2).sub.mNR.sub.11SO.sub.nR.sub.12,
--(CH.sub.2).sub.mSO.sub.nR.sub.12, or
--(CH.sub.2).sub.mSO.sub.nNR.sub.8R.sub.9. In certain of these
embodiments, m is 1 or 2.
[0035] In a subset of the compounds of Formula I, the compounds can
have the stereochemistry shown in Formula Ib below:
##STR00008##
[0036] Any embodiment described herein can be combined with any
other suitable embodiment described herein to provide additional
embodiments. For example, where one embodiment individually or
collectively describes possible groups for R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, etc., and a separate embodiment
describes possible R.sub.7 groups, it is understood that these
embodiments can be combined to provide an embodiment describing
possible groups for R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
etc. with the possible R.sub.7 groups, etc. With respect to the
above compounds, and throughout the application and claims, the
following terms have the meanings defined below.
[0037] The phrase "acyl" refers to groups having a carbon
double-bonded to an oxygen atom, such as in the structure
--C(.dbd.O)R. Examples of R can include H, such as in aldehydes, a
hydrocarbon, such as in a ketone, --NR.sub.8R.sub.9, such as in an
amide, --OR.sub.6 such as in a carboxylic acid or ester,
--OOCR.sub.2, such as in an acyl anhydride or a halo, such as in an
acyl halide.
[0038] The phrase "alkenyl" refers to straight and branched chain
hydrocarbons, such as those described with respect to alkyl groups
described herein, that include at least one double bond existing
between two carbon atoms. Examples include vinyl,
--CH.dbd.C(H)(CH.sub.3), --CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.C(H).sub.2, --C(CH.sub.3).dbd.C(H)(CH.sub.3),
--C(CH.sub.2CH.sub.3).dbd.CH.sub.2, cyclohexenyl, cyclopentenyl,
cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among
others. An alkenyl group can optionally be substituted, for example
where 1, 2, 3, 4, 5, 6, 7, 8 or more hydrogen atoms are replaced by
a substituent selected from the group consisting of halogen,
haloalkyl, hydroxy, thiol, cyano, and --NR.sub.8R.sub.9.
[0039] The phrase "alkyl" refers to hydrocarbon chains, for example
C.sub.1-6 chains, that do not contain heteroatoms. Thus, the phrase
includes straight chain alkyl groups such as methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl
and the like. The phrase also includes branched chain isomers of
straight chain alkyl groups, including but not limited to, the
following which are provided by way of example:
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH(CH.sub.2CH.sub.3).sub.2, --C(CH.sub.3).sub.3,
--C(CH.sub.2CH.sub.3).sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3)(CH.sub.2 CH.sub.3),
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2, --CH.sub.2C(CH.sub.3).sub.3,
--CH.sub.2C(CH.sub.2CH.sub.3).sub.3,
--CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3).sub.2,
--CH.sub.2CH.sub.2C(CH.sub.3),
--CH.sub.2CH.sub.2C(CH.sub.2CH.sub.3).sub.3,
--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2,
--CH(CH.sub.3)CH(CH.sub.3)CH(CH.sub.3).sub.2,
--CH(CH.sub.2CH.sub.3)CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2CH.sub.3),
and others. The phrase includes primary alkyl groups, secondary
alkyl groups, and tertiary alkyl groups. Alkyl groups can be bonded
to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s),
and/or sulfur atom(s) in the parent compound. An alkyl group can
optionally be substituted, for example where 1, 2, 3, 4, 5, 6 or
more hydrogen atoms are replaced by a substituent selected from the
group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and
--NR.sub.8R.sub.9.
[0040] The phrase "alkylene" refers to a straight or branched chain
divalent hydrocarbon radical, generally having from two to ten
carbon atoms.
[0041] The phrase "alkynyl" refers to straight and branched chain
hydrocarbon groups, such as those described with respect to alkyl
groups as described herein, except that at least one triple bond
exists between two carbon atoms. Examples include --C.ident.C(H),
--C.ident.C(CH.sub.3), --C.ident.C(CH.sub.2CH.sub.3),
--C(H.sub.2)C.ident.C(H), --C(H).sub.2C.ident.C(CH.sub.3), and
--C(H).sub.2C.ident.C(CH.sub.2CH.sub.3) among others. An alkynyl
group can optionally be substituted, for example where 1, 2, 3, 4,
5, 6, 7, 8 or more hydrogen atoms are replaced by a substituent
selected from the group consisting of halogen, haloalkyl, hydroxy,
thiol, cyano, and --NR.sub.8R.sub.9.
[0042] The phrase "aminoalkyl" refers to an alkyl group as above
attached to an amino group, which can ultimately be a primary,
secondary or tertiary amino group. An example of an amino alkyl
group is the --NR.sub.8R.sub.9 where one or both of R.sub.8 and
R.sub.9 is a substituted or unsubstituted C.sub.1-6 alkyl or
R.sub.8 and R.sub.9 together with the atom to which they are
attached form a substituted or unsubstituted heterocyclic ring.
Specific aminoalkyl groups include --NHCH.sub.3,
--N(CH.sub.3).sub.2, --NHCH.sub.2CH.sub.3,
--N(CH.sub.3)CH.sub.2CH.sub.3, --N(CH.sub.2CH.sub.3).sub.2,
--NHCH.sub.2CH.sub.2CH.sub.3, --N(CH.sub.2CH.sub.2CH.sub.3).sub.2,
and the like. Additional aminoalkyl groups include:
##STR00009##
An aminoalkyl group can optionally be substituted with 1, 2, 3, 4
or more non-hydrogen substituents, for example where each
substituent is independently selected from the group consisting of
halogen, cyano, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-2 alkyl substituted with one or more halogens, C.sub.1-2
alkoxy substituted with one or more halogens, --C(O)R.sub.6,
--C(O)OR.sub.6, --S(O).sub.nR.sub.6 and --NR.sub.8R.sub.9. These
substituents may be the same or different and may be located at any
position of the ring that is chemically permissible.
[0043] The phrase "aryl" refers to cyclic or polycyclic aromatic
rings, generally having from 5 to 12 carbon atoms. Thus the phrase
includes, but is not limited to, groups such as phenyl, biphenyl,
anthracenyl, naphthenyl by way of example. The phrase
"unsubstituted aryl" includes groups containing condensed rings
such as naphthalene. Unsubstituted aryl groups can be bonded to one
or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or
sulfur atom(s) in the parent compound. Substituted aryl groups
include methoxyphenyl groups, such as para-methoxyphenyl.
[0044] Substituted aryl groups include aryl groups in which one or
more aromatic carbons of the aryl group is bonded to a substituted
and/or unsubstituted alkyl, alkenyl, alkynyl group or a heteroatom
containing group as described herein. This includes bonding
arrangements in which two carbon atoms of an aryl group are bonded
to two suitable haloalkyls include chloromethyl, difluoromethyl,
trifluoromethyl, 1-fluoro-2-chloro-ethyl, 5-fluoro-hexyl,
3-difluoro-isopropyl, 3-chloro-isobutyl, etc.
[0045] The phrases "heterocyclyl" or "heterocyclic ring" refers to
aromatic, nonaromatic, saturated and unsaturated ring compounds
including monocyclic, bicyclic, and polycyclic ring compounds,
including fused, bridged, or spiro systems, such as, but not
limited to, quinuclidyl, containing 1, 2, 3 or more ring members of
which one or more is a heteroatom such as, but not limited to, N,
O, P and S. Unsubstituted heterocyclyl groups include condensed
heterocyclic rings such as benzimidazolyl. Examples of heterocyclyl
groups include: unsaturated 3 to 8 membered rings containing 1 to 4
nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl,
imidazolyl, imidazolidinyl, pyrazolyl, pyridyl, dihydropyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.),
tetrazolyl, (e.g. 1H-tetrazolyl, 2H tetrazolyl, etc.); saturated 3
to 8 membered rings containing 1 to 4 nitrogen atoms such as, but
not limited to, pyrrolidinyl, piperidinyl, piperazinyl; condensed
unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms
such as, but not limited to, indolyl, isoindolyl, indolinyl,
indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,
benzotriazolyl; saturated 3 to 8 membered rings containing 1 to 3
oxygen atoms such as, but not limited to, tetrahydrofuran;
unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms
and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl,
isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,5-oxadiazolyl, etc.); saturated 3 to 8 membered rings
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as,
but not limited to, morpholinyl; unsaturated condensed heterocyclic
groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms,
for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g.
2H-1,4-benzoxazinyl etc.); unsaturated 3 to 8 membered rings
containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as,
but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g.
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, etc.); saturated 3 to 8 membered rings
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as,
but not limited to, thiazolodinyl; saturated and unsaturated 3 to 8
membered rings containing 1 to 2 sulfur atoms such as, but not
limited to, thienyl, dihydrodithiinyl, dihydrodithionyl,
tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed
heterocyclic rings containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms such as, but not limited to, benzothiazolyl,
benzothiadiazolyl, benzothiazinyl (e.g. 2H-1,4-benzothiazinyl,
etc.), dihydrobenzothiazinyl (e.g. 2H-3,4-dihydrobenzothiazinyl,
etc.), unsaturated 3 to 8 membered rings containing oxygen atoms
such as, but not limited to furyl; unsaturated condensed
heterocyclic rings containing 1 to 2 oxygen atoms such as
benzodioxolyl (e.g. 1,3-benzodioxoyl, etc.); unsaturated 3 to 8
membered rings containing an oxygen atom and 1 to 2 sulfur atoms
such as; but not limited to, dihydrooxathiinyl; saturated 3 to 8
membered rings containing 1 to 2 oxygen atoms, and 1 to 2 sulfur
atoms such as 1,4-oxathiane; unsaturated condensed rings containing
1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and
unsaturated condensed heterocyclic rings containing an oxygen atom
and 1 to 2 oxygen atoms such as benzoxathiinyl. Heterocyclyl groups
also include those described herein in which one or more S atoms in
the ring is double-bonded to one or two oxygen atoms (sulfoxides
and sulfones). For example, heterocyclyl groups include
tetrahydrothiophene, tetrahydrothiophene oxide, and
tetrahydrothiophene 1,1-dioxide. Heterocyclyl groups can contain 5
or 6 ring members. Examples of heterocyclyl groups include
morpholine, piperazine, piperidine, pyrrolidine, imidazole,
pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,
thiomorpholine, thiomorpholine in which the S atom of the
thiomorpholine is bonded to one or more O atoms, pyrrole,
homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole,
quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.
[0046] A heterocyclyl group can be optionally substituted, for
example where 1, 2, 3, 4 or more hydrogen atoms are replaced by a
substituent selected from the group consisting of halogen, cyano,
hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-2 alkyl
substituted with one or more halogens, C.sub.1-2 alkoxy substituted
with one or more halogens, --C(O)R.sub.6, --C(O)OR.sub.6,
--S(O).sub.nR.sub.6 and --NR.sub.8R.sub.9. Examples of "substituted
heterocyclyl" rings include 2-methylbenzimidazolyl,
5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, 1-methylpiperazinyl,
and 2-chloropyridyl among others. Any nitrogen atom within a
heterocyclic ring can optionally be substituted with C.sub.1-6
alkyl, if chemically permissible.
[0047] Heterocyclyl groups include heteroaryl groups as a subgroup.
The phrase "heteroaryl" refers to a monovalent aromatic ring
radical, generally having 5 to 10 ring atoms, containing 1, 2, 3,
or more heteroatoms independently selected from S, O, or N. The
term heteroaryl also includes bicyclic groups in which the
heteroaryl ring is fused to a benzene ring, heterocyclic ring, a
cycloalkyl ring, or another heteroaryl ring. Examples of heteroaryl
include 7-benzimidazolyl, benzo[b]thienyl, benzofuryl,
benzothiazolyl, benzothiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl,
furanyl, furyl, imidazolyl, indolyl, indazolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,
pyrrolyl, quinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,
thiophenyl, triazolyl and the like. Heteroaryl rings can also be
optionally fused to one or more of another heterocyclic ring(s),
heteroaryl ring(s), aryl ring(s), cycloalkenyl ring(s), or
cycloalkyl rings. A heteroaryl group can be optionally substituted,
for example where 1, 2, 3, 4 or more hydrogen atoms are replaced by
a substituent selected from the group consisting of halogen, cyano,
hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-2 alkyl
substituted with one or more halogens, C.sub.1-2 alkoxy substituted
with one or more halogens, --C(O)R.sub.6, --C(O)OR.sub.6,
--S(O).sub.nR.sub.6 and --NR.sub.8R.sub.9.
[0048] The phrase "heterocyclyloxy" refers to a group in which an
oxygen atom is bound to a ring atom of a heterocyclyl group as
described herein.
[0049] "Pharmaceutically acceptable" means suitable for use in
mammals. A "pharmaceutically acceptable salt" includes a salt with
an inorganic base, organic base, atoms of an alkyl, alkenyl, or
alkynyl group to define a fused ring system (e.g. dihydronaphthyl
or tetrahydronaphthyl). Thus, the phrase "substituted aryl"
includes, but is not limited to tolyl, and hydroxyphenyl among
others. An aryl moiety can optionally be substituted with 1, 2, 3,
4 or more non-hydrogen substituents, for example where each
substituent is independently selected from the group consisting of
halogen, cyano, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-2 alkyl substituted with one or more halogens, C.sub.1-2
alkoxy substituted with one or more halogens, --C(O)R.sub.6,
--C(O)OR.sub.6, --S(O).sub.nR.sub.6 and --NR.sub.8R.sub.9. These
substituents may be the same or different and may be located at any
position of the ring that is chemically permissible.
[0050] The phrase "cycloalkyl" refers to cyclic hydrocarbon chains,
generally having from 3 to 12 carbon atoms, and includes cyclic
alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted
with straight and branched chain alkyl groups as described herein.
The phrase also includes polycyclic alkyl groups such as, but not
limited to, adamantly, norbornyl, and bicyclo[2.2.2]octyl and such
rings substituted with straight and branched chain alkyl groups as
described herein. Cycloalkyl groups can be saturated or unsaturated
and can be bonded to one or more carbon atom(s), oxygen atom(s),
nitrogen atom(s), and/or sulfur atom(s) in the parent compound. A
cycloalkyl group can be optionally substituted, for example where
1, 2, 3, 4 or more hydrogen atoms are replaced by a substituent
selected from the group consisting of halogen, cyano, hydroxy,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-2 alkyl substituted with
one or more halogens, C.sub.1-2 alkoxy substituted with one or more
halogens, --C(O)R.sub.6, --C(O)OR.sub.6, --S(O).sub.nR.sub.6 and
--NR.sub.8R.sub.9.
[0051] Ethers, as used herein, generically encompass monoethers,
polyethers, straight chain ethers, branched ethers and cyclic
ethers. Straight chain ethers can have the structure
--[(CH.sub.2).sub.p--O--(CH.sub.2).sub.p].sub.qCH.sub.3 where each
p is independently 0, 1, 2, 3, 4, 5 or 6 and q is 1, 2, 3, 4, 5 or
6. Branched ethers can have the formula
--[(CV.sub.2).sub.pO(CV.sub.2).sub.p].sub.qCH.sub.3 where each V is
independently H or another
--[(CV.sub.2).sub.pO(CV.sub.2).sub.p].sub.qCH.sub.3 group. Cyclic
ethers can have the formula
##STR00010##
where p and q are as above and indicates a point of attachment.
Specifically, as ether compounds, there are -dimethyl ether,
-methyl ethyl ether, -methoxy ethyl ether, -diethyl ether, -methyl
t-butyl ether, -methyl cellosolve, -ethylene glycol dimethyl ether,
-diethylene glycol dimethyl ether, -triethylene glycol dimethyl
ether, -tetraethylene glycol dimethyl ether, -tetrahydrofuran,
-1,4-dioxane, and the like.
[0052] The phrase "halo" refers to fluorine, chlorine, bromine or
iodine.
[0053] The phrase "haloalkyl" refers to an alkyl group in which at
least one, for example 1, 2, 3, 4, 5 or more, hydrogen atom(s)
is/are replaced with a halogen. Examples of inorganic acid, organic
acid, or basic or acidic amino acid. As salts of inorganic bases,
the invention includes, for example, alkali metals such as sodium
or potassium; alkaline earth metals such as calcium and magnesium
or aluminum; and ammonia. As salts of organic bases, the invention
includes, for example, trimethylamine, triethylamine, pyridine,
picoline, ethanolamine, diethanolamine, and triethanolamine. As
salts of inorganic acids, the instant invention includes, for
example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric
acid, and phosphoric acid. As salts of organic acids, the instant
invention includes, for example, formic acid, acetic acid,
trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid,
maleic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic
acid. As salts of basic amino acids, the instant invention
includes, for example, arginine, lysine and ornithine. Acidic amino
acids include, for example, aspartic acid and glutamic acid.
Examples of pharmaceutically acceptable salts are described in
Berge, S. M. et al., "Pharmaceutical Salts," Journal of
Pharmaceutical Science, 1977; 66:1 19.
[0054] A "prodrug" is a compound that can be transformed in vivo
into an active therapeutic compound, such as a compound described
herein. Transformation of the prodrug compound can be accomplished
chemically, enzymatically, or by action with other endogenous
materials, e.g. amino acids, peptides and proteins. Prodrugs are
discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery
Systems," Vol. 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987.
Examples of prodrugs can include esters and amides of polar groups,
such as carboxylate groups.
[0055] The term "protected" with respect to hydroxyl groups, amine
groups, and sulfhydryl groups refers to forms of these
functionalities which are protected from undesirable reaction with
a protecting group known to those skilled in the art such as those
set forth in Protective Groups in Organic Synthesis, Greene, T. W.;
Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd
Edition, 1999) which can be added or removed using the procedures
set forth therein. Examples of protected hydroxyl groups include
silyl ethers such as those obtained by reaction of a hydroxyl group
with a reagent such as, but not limited to,
t-butyldimethyl-chlorosilane, trimethylchlorosilane,
triisopropylchlorosilane, triethylchlorosilane; substituted methyl
and ethyl ethers such as, but not limited to methoxymethyl ether,
methylthiomethyl ether, benzyloxymethyl ether, t-butoxymethyl
ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers,
1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but
not limited to, benzoylformate, formate, acetate, trichloroacetate,
and trifluoracetate. Examples of protected amine groups include
amides such as, formamide, acetamide, trifluoroacetamide, and
benzamide; imides, such as phthalimide, and dithiosuccinimide; and
others. Examples of protected sulfhydryl groups include thioethers
such as S-benzyl thioether, and S-4-picolyl thioether; substituted
S-methyl derivatives such as hemithio, dithio and aminothio
acetals; and others.
[0056] A "salt" refers to all salt forms of a compound, including
salts suitable for use in industrial processes, such as the
preparation of the compound, and pharmaceutically acceptable
salts.
[0057] "Substituted" refers to a group in which one or more bonds
to a hydrogen atom contained therein are replaced by a bond to
non-hydrogen atom. In some instances the bond will also be replaced
by non-carbon atoms such as, but not limited to: a halogen atom
such as F, Cl, Br, and I; a nitrogen atom in groups such as amines,
amides, alkylamines, dialkylamines, arylamines, alkylarylamines,
diarylamines, heterocyclylamine, (alkyl)(heterocyclyl)amine,
(aryl)(heterocyclyl)amine, or diheterocyclylamine groups,
isonitrile, N-oxides, imides, and enamines; an oxygen atom in
groups such as hydroxyl groups, alkoxy groups, aryloxy groups,
ester groups, and heterocyclyloxy groups; a silicon atom in groups
such as in trialkylsilyl groups, dialkylarylsilyl groups,
alkyldiarylsilyl groups, and triarylsilyl groups; a sulfur atom in
groups such as thiol groups, alkyl and aryl sulfide groups, sulfone
groups, sulfonyl groups, and sulfoxide groups; and other
heteroatoms in various other groups. Substituted alkyl groups and
substituted cycloalkyl groups also include groups in which one or
more bonds to one or more carbon or hydrogen atoms are replaced by
a bond to a heteroatom such as oxygen in carbonyl, carboxyl, and
ether groups; nitrogen in groups such as imines, oximes and
hydrazones. Substituted cycloalkyl, substituted aryl, substituted
heterocyclyl and substituted heteroaryl also include rings and
fused ring systems which can be substituted with alkyl groups as
described herein. Substituted arylalkyl groups can be substituted
on the aryl group, on the alkyl group, or on both the aryl and
alkyl groups. All groups included herein, such as alkyl, alkenyl,
alkylene, alkynyl, aryl, heterocyclyl, heterocyclyloxy, and the
like, can be substituted. Representative examples of substituents
for substitution include one or more, for example one, two or
three, groups independently selected from halogen, --OH,
--C.sub.1-6 alkyl, C.sub.1-6 alkoxy, trifluoromethoxy,
--S(O).sub.nC.sub.1-6 alkyl, amino, haloalkyl, thiol, cyano,
--OR.sub.10 and --NR.sub.8R.sub.9, and trifluoromethyl.
[0058] "Treating" means an alleviation of symptoms associated with
an infection, halt of further progression or worsening of those
symptoms, or prevention or prophylaxis of the infection. Treatment
can also include administering the pharmaceutical formulations of
the present invention in combination with other therapies. For
example, the compounds and pharmaceutical formulations of the
present invention can be administered before, during, or after
surgical procedure and/or radiation therapy. The compounds of the
invention can also be administered in conjunction with other
antibacterial drugs.
[0059] In some instances, compounds described herein can be
provided ex vivo or produced in vivo, for example where a prodrug
of a compound is administered.
[0060] Generally, reference to a certain element such as hydrogen
or H is meant to include all isotopes of that element. For example,
if an R group is defined to include hydrogen or H, it also includes
deuterium and tritium. Chemical formulas throughout are designated
with capital Roman numerals for simplified identification. Roman
numerals used in conjunction with a small letter, for example Ia,
indicate that the structure set forth is an enantiomer of the
compound identified by the Roman numeral. Roman numerals used in
conjunction with a prime symbol, for example III', indicate that
the structure set forth can have one or more protected groups which
are included in atoms groups identified with the prime symbol, for
example where O' indicates an oxygen atom or a protected aldehyde
group.
[0061] General Synthesis of Compounds. The described compounds can
be made according to the following general synthetic schemes, in
which all R, X and Y have the values described above, B' is a is
boronic acid or a boronate ester, such as
##STR00011##
and O' is oxygen, giving an aldehyde, or a protected aldehyde
group.
##STR00012##
[0062] In some cases it may be necessary to protect the aldehyde
prior to performing a coupling reaction, such as the conversions of
XII' to III', X' to III' or XII' to X'. In these instances, the
aldehyde may be protected for example as an acetal by reaction with
a diol such as ethylene diol, propane-1,3-diol or
2,2-dimethylpropane-1,3-diol. More specifically, the aldehyde may
be reacted with a diol in a non-polar solvent by warming to
60-140.degree. C. for 2 to 24 hours in the presence of a catalytic
amount of protic acid such as para-toluenesulfonic acid or
pyridinium para-toluene sulfonate. Alternative methods of masking
the aldehyde, including alternative protecting groups or reduction
to the corresponding alcohol and protection of the alcohol will be
known to one skilled in the art.
[0063] In one embodiment, a substituted or unsubstituted pyrazine
ring having an attached boron group, such as B', is coupled with
compound XII', for example via an organometallic cross-coupling
reaction, to give the compound of formula III'. The compound of
formula I can be obtained from compound III' by condensation with a
compound of formula IV, such as barbituric acid, and cyclization.
Alternatively, compound IX can be obtained by condensation of
compounds IV and XII' and cyclization. The compound of formula I
can be obtained from compound IX by coupling a substituted or
unsubstituted pyrazine ring having an attached boron group, for
example via an organometallic cross-coupling reaction. In this
scheme, formation of compound X' from compound XII or compound III'
from compound X' may require the use of a protected aldehyde. In
the above, reaction, Ha is hydrogen or a halogen, for example
bromine. Ha can also be chlorine or iodine.
[0064] In another embodiment, compound X', containing a B' group,
is coupled to a substituted or unsubstituted pyrazine ring having
an attached halogen, to give the compound of formula III'.
Alternatively, compound X' can be converted to compound II by
condensation with a compound of formula IV, such as barbituric
acid, and cyclization. Compound II can also be obtained from
compound IX by substituting the halogen with a B' group by reaction
with a borane as described herein. The compound of formula I can be
made from compound II by coupling a substituted or unsubstituted
pyrazine ring as described herein. In some embodiments, compound X'
can be made from compound XII' by substituting the halogen with a
B' group by reaction with a borane as described herein.
Accordingly, the cross-coupling reaction may be performed either
before condensation with compound IV and cyclization, or subsequent
to introduction of compound IV.
[0065] When introduction of the pyrazine ring by cross-coupling is
performed subsequent to introduction of the compound IV, in some
cases it is desirable to protect the amide groups in the compound,
particularly when R.sub.4 and R.sub.5 are H. The protecting group
may take the form of a transient group that is removed after the
cross-coupling reaction, or it may be a prodrug moiety that is
retained or further modified for use in modulating the potency
and/or delivery of the compound. An illustration of this protection
scheme is shown below.
##STR00013##
[0066] Also provided is a method for making the compounds of
formula Ia shown below. This method can be performed by (a)
reacting a compound of formula IIIa with a compound of formula IV
at a temperature sufficient to produce a compound of formula
Ia:
##STR00014##
[0067] According to this method, specific groups can be defined as
elsewhere herein. Reaction to form Ia can occur in an aqueous or
organic solvent. Typically temperatures for this reaction will be
about 60 to about 180.degree. C., for example from about 80 to
100.degree. C., 100 to 140.degree. C. or 140 to 180.degree. C., and
can occur from about 0.5 to about 24 hours, for example 0.5, 1,
1.5, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours. Examples
of solvents that can be used include acetic acid, glacial or mixed
with water, DMSO, methanol, isopropanol, butanol, toluene, water
and combinations thereof. In a specific example, temperatures can
range from about 80.degree. C. to about 120.degree. C. In a
specific example, reaction times can range from about 5 to 24 h.
When the reaction occurs in acetic acid or acetic acid/water
mixtures, typical temperatures for this reaction will be about 80
to about 110.degree. C., for example from about 80 to 90.degree.
C., 90 to 100.degree. C. or 100 to 110.degree. C., and can occur
from about 0.5 to about 4 hours, for example 0.5, 1, 1.5 2, or 4.
This reaction can also be used to make compounds of formula I from
compounds of formula III.
[0068] These methods can also involve (b) reacting a compound of
formula V with a compound of formula VI a, optionally in a
non-protic organic solvent and/or in the presence of a base, to
make the compound of formula IIIa:
##STR00015##
[0069] In this reaction, when present, the base can be an organic
or inorganic base. In some instances compound VI a can act as a
base. Typically, the reaction will take place at a temperature of
about 20 to about 100.degree. C., for example from about 40 to
100.degree. C., 60 to 80.degree. C. or 80 to 100.degree. C. This
reaction can also be performed alone to provide the compound of
formula IIIa. Examples of solvents that can be used include
acetonitrile and dimethylformamide. Temperature ranges for the
reaction can also be about 70 to 90.degree. C. Bases that can be
used in the reaction include triethylamine, diisopropylethylamine
and potassium carbonate. Reaction times can range from about 2 to
24 hours, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24
hours. This reaction can also be used to make a compound of formula
III using a compound of formula VI.
[0070] Compound V can be made by: [0071] (c)(i) performing a
halogen metal exchange or deprotonation reaction on a compound of
formula VII, and [0072] (c)(ii) reacting the product of (c)(i) with
a carbonyl donor to make the compound of formula V:
##STR00016##
[0073] In the above, reaction, Ha is hydrogen or a halogen, for
example bromine. Ha can also be chlorine or iodine. In this
reaction, (c)(i) can include contacting the compound of formula VII
with a strong base, such as an alkyl lithium. Alternatively, (c)(i)
can include contacting the compounds of formula VII with a Grignard
reagent in a non-protic organic solvent. These reactions typically
occur at a temperature from about -78 to about 50.degree. C., for
example from about -78 to about 0.degree. C. In (c)(ii) the
carbonyl donor can include one or more of dimethylformamide,
N-formylmorpholine, or para-nitrophenylformate. Examples of
reaction times can be from about 1 to about 18 hours, for example
2, 4, 6, 8, 10, 12, 14, 16 or 18 hours.
[0074] Compound V can also be synthesized by (d) oxidizing a
compound of formula VIII to make the compound of formula V:
##STR00017##
[0075] One synthesis can combine several of these steps as
follows:
##STR00018##
[0076] Described compounds and intermediates can also be produced
according to the following reaction:
##STR00019##
[0077] In this reaction, B' is boronic acid or a boronate ester,
such as
##STR00020##
and halo is a halogen, such as iodine. Accordingly, compound III is
made by reacting compounds X and XI. This coupling reaction can
also be performed with reverse polarity wherein the boron is
attached to R.sub.1 and the halogen is attached to compound X at
the position indicated by B' (see structure XII below). In general,
the coupling reaction can be performed under standard Suzuki
cross-coupling conditions employing 0.01-0.1 equivalents of a
palladium catalyst with appropriate ligands, such as
Pd(PPh.sub.3).sub.4 or Pd(dppf) Cl.sub.2, in an organic solvent or
solvent mixture containing organic solvents, such as toluene and an
alcohol, and water. The reaction can be performed in the presence
of a base such as potassium carbonate, sodium carbonate, potassium
phosphate, cesium carbonate or sodium acetate for example, at
temperatures, e.g. from about 20 to 120.degree. C. for about 2 to
24 h. This route can also be used to make compounds of formula IIIa
when a trans-morpholine compound is used in the reaction. Compounds
III or IIIa can be used to make compounds of formula I or Ia
according to the methods described herein.
[0078] Compound X can be made by reacting compound XII to provide
compound X, where halo is a halogen, such as bromine, chlorine or
iodine:
##STR00021##
[0079] Conversion of compounds XII to compound X can be performed
by reaction with a borane such as for example,
bis(pinacolato)diboron, under palladium catalysis employing a
palladium(II) or palladium(0) species with appropriate ligands, for
example Pd(PPh.sub.3).sub.4, Pd(dppf)Cl.sub.2,
Pd(Pcy).sub.2Cl.sub.2, in an organic solvent such as
tetrahydrofuran, methyl-tetrahydrofuran, or toluene, and in the
presence of an inorganic base such as, for example, potassium
acetate, potassium phosphate, sodium carbonate, cesium carbonate.
The reaction typically proceeds at elevated temperatures from 80 to
120.degree. C. over about 12 h to 5 days.
[0080] In turn, compound XII can be made by reacting compounds VI
and XIV, where halo is a halogen, such as bromine, chlorine or
iodine:
##STR00022##
[0081] The method can involve (a) reacting a compound of formula
XIV with a compound of formula VI, optionally in a non-protic
organic solvent and/or in the presence of a base, to make the
compound of formula XII. In this reaction, when present, the base
can be an organic or inorganic base. In some instances compound VI
can act as a base. Typically, the reaction will take place at a
temperature of about 20 to about 100.degree. C., for example from
about 40 to 100.degree. C., 60 to 80.degree. C. or 80 to
100.degree. C.
[0082] Compound XIV can be made from compound XV as follows, where
halo is a halogen, such as bromine or iodine:
##STR00023##
[0083] In one embodiment, compound XIV can be made by: [0084]
(b)(i) performing a deprotonation reaction on a compound of formula
XV; and [0085] (b)(ii) reacting the product of (b)(i) with a
carbonyl donor to make the compound of formula XIV: In the above,
reaction, Ha is hydrogen. In this reaction, (b)(i) can include
contacting the compound of formula XV with a strong base, such as
alkyl lithium. These reactions typically occur at a temperature
from about -78 to about 50.degree. C. In (b)(ii) the carbonyl donor
can include one or more of dimethylformamide, N-formylmorpholine,
or para-nitrophenylformate.
[0086] Also provided is a method of making the compound of formula
XVIIa that includes (a) reacting a compound of formula VI a with a
compound of formula XVIII, optionally in a non-protic organic
solvent and/or in the presence of a base, to make the compound of
formula XVII.
##STR00024##
[0087] In this reaction, R.sub.14 is a halogen, such as bromine or
iodine, boronic acid, a boronate ester, such as
##STR00025##
or a substituted or unsubstituted pyrazine, as in R.sub.1.
[0088] In this reaction, when present, the base can be an organic
or inorganic base. In some instances compound VI a can act as a
base. Typically, the reaction will take place at a temperature of
about 20 to about 100.degree. C., for example from about 40 to
100.degree. C., 60 to 80.degree. C. or 80 to 100.degree. C.
Examples of solvents that can be used include acetonitrile and
dimethylformamide. Temperatures ranges for the reaction can also be
about 70 to 90.degree. C. Bases that can be used in the reaction
include triethylamine, diisopropylethylamine or potassium
carbonate. Reaction times can range from about 2 to 24 hours, for
example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
[0089] When R.sub.14 is a halogen, such as bromine, compound XVII
can be used to make compound XVII where R.sub.14 is boronic acid or
a boronate ester using the same reaction as set forth for making
compound X.
[0090] When R.sub.14 is a halogen, such as iodine, compound XVII
can also be used to make the compound of formula IIIa by coupling
compound XVII with a compound of formula R.sub.1--B', where B' is
boronic acid or a boronate ester, such as
##STR00026##
The compound of formula IIIa can also be produced when R.sub.14 is
boronic acid or a boronate ester, by reaction compound XVII with
compound XI (R.sub.1-halo) by the method set forth for making
compound III described herein.
##STR00027##
[0091] In general, this coupling reaction can be performed under
standard Suzuki cross-coupling conditions employing 0.01-0.1 or
more equivalents of a palladium catalyst with appropriate ligands,
such as Pd(PPh.sub.3).sub.4 or Pd(dppf) Cl.sub.2, in an organic
solvent or solvent mixture containing organic solvents, such as
toluene and an alcohol, and water. The reaction can be performed in
the presence of a base, such as potassium carbonate, sodium
carbonate, potassium phosphate, cesium carbonate or sodium acetate
for example, at temperatures, e.g. from about 20 to 120.degree. C.
for about 2 to 24 h. Compound III can then be used to produce
compounds of Formula Ia as described herein.
[0092] Compound XVIII can be made by: [0093] (b)(i) performing a
halogen metal exchange or deprotonation reaction on a compound of
formula XIX, and [0094] (c)(ii) reacting the product of (c)(i) with
a carbonyl donor to make the compound of formula XVIII:
##STR00028##
[0095] In the above, reaction, Ha is hydrogen or a halogen, for
example bromine. Ha can also be chlorine or iodine. In this
reaction, (c)(i) can include contacting the compound of formula XIX
with a strong base, such as alkyl lithium. Alternatively, (c)(i)
can include contacting the compounds of formula XIX with a Grignard
reagent in a non-protic organic solvent. These reactions typically
occur at a temperature from about -78 to about 50.degree. C., for
example from about -78 to about 0.degree. C. In (c)(ii) the
carbonyl donor can include one or more of dimethylformamide,
N-formylmorpholine or para-nitrophenylformate. Examples of reaction
times can be from about 1 to about 18 hours, for example 2, 4, 6,
8, 10, 12, 14, 16 or 18 hours.
[0096] Compound XVIII can also be synthesized by (d) oxidizing a
compound of formula XX to make the compound of formula XVIII:
##STR00029##
[0097] The compounds described herein can also be synthesized by
appropriately modifying the protocols set forth in WO
2004/031195.
[0098] Certain compounds described herein are also useful as
intermediates for preparing other described compounds and such
intermediates are included within the scope of the present
invention.
[0099] Specific compounds are described throughout with particular
reference to the Examples and the following table, in which
compounds starting with "rel-" or denoted by .+-.are racemic
compounds:
TABLE-US-00001 TABLE 1 Compound/ Example No. Name Structure 1
rel-(2S,4R,4aR)-9,10- difluoro-2,4-dimethyl-8-
pyrazin-2-yl-1,2,4,4a- tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3-
a]quinoline-5,5'- pyrimidine]- 2',4',6'(1'H,3'H)-trione
##STR00030## 2 (2R,4S,4aS)-9,10- difluoro-2,4-dimethyl-8-
pyrazin-2-yl-1,2,4,4a- tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3-
a]quinoline-5,5'- pyrimidine]- 2',4',6'(1'H,3'H)-trione
##STR00031## 3 (2S,4R,4aR)-9,10- difluoro-2,4-dimethyl-8-
pyrazin-2-yl-1,2,4,4a- tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3-
a]quinoline-5,5'- pyrimidine]- 2',4',6'(1'H,3'H)-trione
##STR00032## 4 (2R,4S,4aS)-9,10- difluoro-2,4-dimethyl-
1',3'-bis(morpholin-4- ylmethyl)-8-pyrazin-2-
yl-1,2,4,4a-tetrahydro- 2'H,6H-spiro[1,4- oxazino[4,3-a]quinoline-
5,5'-pyrimidine]- 2',4',6'(1'H,3'H)-trione ##STR00033## 5
(2R,4S,4aS)-9,10- difiuoro-2,4-dimethyl- 1',3'-bis[(4-
methylpiperazin-1- yl)methyl]-8-pyrazin-2- yl-1,2,4,4a-tetrahydro-
2'H,6H-spiro[1,4- oxazino[4,3-a]quinoline- 5,5'-pyrimidine]-
2',4',6'(1'H,3'H)-trione ##STR00034## 6 (2R,4S,4aS)-9,10-
difluoro-2,4-dimethyl-8- (4-oxidopyrazinpyrazin- 2-yl)-1,2,4,4a-
tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3- a]quinoline-5,5'-
pyrimidine]- 2',4',6'(1'H,3'H)-trione ##STR00035## 7
rel-(2S,4R,4aR)-9,10- difluoro-2,4-dimethyl-
2',4',6'-trioxo-8-pyrazin- 2-yl-1,2,4,4a- tetrahydro-2'H,6H-
spiro[1,4-oxazino[4,3- a]quinoline-5,5'- pyrimidine]-
1',3'(4'H,6'H)-diyl] bis(methylene) diacetate ##STR00036## 8
(2S,4R,4aR)-9,10- difluoro-2,4-dimethyl- 2',4',6'-trioxo-8-pyrazin-
2-yl-1,2,4,4a- tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3-
a]quinoline-5,5'- pyrimidine]- 1',3'(4'H,6'H)-diyl] bis(methylene)
diacetate ##STR00037## 9 rel-(2S,4R,4aR)-9,10- difluoro-1',3'-
bis(hydroxymethyl)-2,4- dimethyl-8-pyrazin-2-yl-
1,2,4,4a-tetrahydro- 2'H,6H-spiro[1,4- oxazino[4,3-a]quinoline-
5,5'-pyrimidine]- 2',4'6'(1'H,3'H)trione ##STR00038## 10
(2S,4R,4aR)-9,10- difluoro-1',3'- bis(hydroxymethyl)-2,4-
dimethyl-8-pyrazin-2-yl- 1,2,4,4a-tetrahydro- 2'H,6H-spiro[1,4-
oxazino[4,3-a]quinoline- 5,5'-pyrimidine]- 2',4',6'(1'H,3'H)-trione
##STR00039## 11 rel-(2S,4R,4aR)-1',3'- bis(chloromethyl)-9,10-
difluoro-2,4-dimethyl-8- pyrazin-2-yl-1,2,4,4a- tetrahydro-2'H,6H-
spiro[1,4-oxazino[4,3- a]quinoline-5,5'- pyrimidine]-
2',4',6'(1'H,3'H)-trione ##STR00040## 12 rel-tetrabenzyl
[(2S,4R,4aR)-9,10- difluoro-2,4-dimethyl-
2',4',6'-trioxo-8-pyrazin- 2-yl-1,2,4,4a- tetrahydro-2'H,6H-
spiro[1,4-oxazino[4,3- a]quinoline-5,5'- pyrimidine]-
1',3'(4'H,6'H)- diyl]bis(methylene) bis(phosphate) ##STR00041## 13
(2S,4R,4aR)-1',3'- bis(bromomethyl)-9,10- difluoro-2,4-dimethyl-8-
pyrazin-2-yl-1,2,4,4a- tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3-
a]quinoline-5,5'- pyrimidine]- 2',4',6'(1'H,3'H)-trione
##STR00042## 14 tetra-tert-butyl [(2S,4R,4aR)-9,10-
difluoro-2,4-dimethyl- 2',4',6'-trioxo-8-pyrazin- 2-yl-1,2,4,4a-
tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3- a]quinoline-5,5'-
pyrimidine]- 1',3'(4'H,6'H)- diyl]bis(methylene) bis(phosphate)
##STR00043## 15 rel-(2S,4R,4aR)-10- fluoro-2,4-dimethyl-8-
pyrazin-2-yl-1,2,4,4a- tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3-
a]quinoline-5,5'- pyrimidine]- 2'4'6'(1'H,3'H)-trione ##STR00044##
16 rel-(2S,4R,4aR)-10- fluoro-2,4-dimethyl-9- morpholin-4-yl-8-
pyrazin-2-yl-1,2,4,4a- tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3-
a]quinoline-5,5'- pyrimidine]- 2',4',6'(1'H,3'H)-trione
##STR00045## 17 rel-(2S,4R,4aR)-10- fluoro-9-(2-
methoxyethoxy)-2,4- dimethyl-8-pyrazin-2-yl- 1,2,4,4a-tetrahydro-
2'H,6H-spiro[1,4- oxazino[4,3-a]quinoline- 5,5'-pyrimidine]-
2',4',6'(1'H,3'H)-trione ##STR00046## 18 rel-(2S,4R,4aR)-10-
fluoro-9-(2- fluoroethoxy)-2,4- dimethyl-8-pyrazin-2-yl-
1,2,4,4a-tetrahydro- 2'H,6H-spiro[1,4- oxazino[4,3-a]quinoline-
5,5'-pyrimidine]- 2',4',6'(1'H,3'H)-trione ##STR00047## 19
rel-(2S,4R,4aR)-9- fluoro-2,4-dimethyl-8- pyrazin-2-yl-1,2,4,4a-
tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3- a]quinoline-5,5'-
pyrimidine]- 2',4',6'(1'H,3'H)-trione ##STR00048## 20
rel-(2S,4R,4aR)-2,4- dimethyl-8-pyrazin-2-yl- 1,2,4,4a-tetrahydro-
2'H,6H-spiro[1,4- oxazino[4,3-a]quinoline- 5,5'-pyrimidine]-
2',4',6'(1'H,3'H)-trione ##STR00049## 21 rel-(2S,4R,4aR)-8-(3-
methoxypyrazin-2-yl)- 2,4-dimethyl-1,2,4,4a- tetrahydro-2',6H-
spiro[1,4-oxazino[4,3- a]quinoline-5,5'- pyrimidine]-
2',4'6'(1'H,3'H)-trione ##STR00050## 22 (2R,4S,4aS)-8-(5-
aminopyrazin-2-yl)- 9,10-difluoro-2,4- dimethyl-1,2,4,4a-
tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3- a]quinoline-5,5'-
pyrimidine]- 2',4',6'(1'H,3'H)-trione ##STR00051## 23
(2R,4S,4aS)-9,10- difluoro-2,4-dimethyl-8- (5-methylpyrazin-2-yl)-
1,2,4,4a-tetrahydro- 2'H,6H-spiro[1,4- oxazino[4,3-a]quinoline-
5,5'-pyrimidine]- 2',4',6'(1'H,3'H)-trione ##STR00052## 24
(2R,4S,4aS)-8-(5- bromopyrazin-2-yl)- 9,10-difluoro-2,4-
dimethyl-1,2,4,4a- tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3-
pyrimidine]- 2',4',6'(1'H,3'H)-trione ##STR00053## 25
(2R,4S,4aS)-9,10- difluoro-8-(5- methoxypyrazin-2-yl)-
2,4-dimethyl-1,2,4,4a- tetrahydro-2'H,6H- spiro[1,4-oxazino[4,3-
a]quinoline-5,5'- pyrimidine]- 2',4',6'(1'H,3'H)-trione
##STR00054## 26 (2R,4S,4aS)-8-(5- ethoxypyrazin-2-yl)-
9,10-difluoro-2,4- dimethyl-1,2,4,4a- tetrahydro-2'H,6H-
spiro[1,4-oxazino[4,3- a]quinoline-5,5'- pyrimidine]-
2',4',6'(1'H,3'H)-trione ##STR00055##
[0100] Also provided are compositions that can be prepared by
mixing one or more compounds described herein, or pharmaceutically
acceptable salts or tautomers thereof, with pharmaceutically
acceptable carriers, excipients, binders, diluents or the like, to
treat or ameliorate a variety of bacterial infections. A
therapeutically effective dose or amount refers to that amount of
one or more compounds described herein sufficient to result in
amelioration of symptoms of the infection. The pharmaceutical
compositions of the instant invention can be manufactured by
methods well known in the art such as conventional granulating,
mixing, dissolving, encapsulating, lyophilizing, emulsifying or
levigating processes, among others. The compositions can be in the
form of, for example, granules, powders, tablets, capsule syrup,
suppositories, injections, emulsions, elixirs, suspensions or
solutions. The instant compositions can be formulated for various
routes of administration, for example, by oral administration, by
transmucosal administration, by rectal administration, or
subcutaneous administration as well as intrathecal, intravenous,
intramuscular, intraperitoneal, intranasal, intraocular or
intraventricular injection. The compound or compounds of the
instant invention can also be administered in a local rather than a
systemic fashion, such as injection as a sustained release
formulation. The following dosage forms are given by way of example
and should not be construed as limiting the instant invention.
[0101] For oral, buccal, and sublingual administration, powders,
suspensions, granules, tablets, pills, capsules, gelcaps, and
caplets are acceptable as solid dosage forms. These can be
prepared, for example, by mixing one or more compounds of the
instant invention, or pharmaceutically acceptable salts or
tautomers thereof, with at least one additive or excipient such as
a starch or other additive. Suitable additives or excipients are
sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran,
sorbitol, starch, agar, alginates, chitins, chitosans, pectins,
tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,
synthetic or semi-synthetic polymers or glycerides, methyl
cellulose, hydroxypropylmethyl-cellulose, and/or
polyvinylpyrrolidone. Optionally, oral dosage forms can contain
other ingredients to aid in administration, such as an inactive
diluent, or lubricants such as magnesium stearate, or preservatives
such as paraben or sorbic acid, or anti-oxidants such as ascorbic
acid, tocopherol or cysteine, a disintegrating agent, binders,
thickeners, buffers, sweeteners, flavoring agents or perfuming
agents. Additionally, dyestuffs or pigments can be added for
identification. Tablets and pills can be further treated with
suitable coating materials known in the art.
[0102] Liquid dosage forms for oral administration can be in the
form of pharmaceutically acceptable emulsions, syrups, elixirs,
suspensions, slurries and solutions, which can contain an inactive
diluent, such as water. Pharmaceutical formulations can be prepared
as liquid suspensions or solutions using a sterile liquid, such as,
but not limited to, an oil, water, an alcohol, and combinations of
these. Pharmaceutically suitable surfactants, suspending agents,
emulsifying agents, can be added for oral or parenteral
administration.
[0103] As noted above, suspensions can include oils. Such oils
include peanut oil, sesame oil, cottonseed oil, corn oil, olive oil
and mixtures of oils. Suspension preparation can also contain
esters of fatty acids such as ethyl oleate, isopropyl myristate,
fatty acid glycerides and acetylated fatty acid glycerides.
Suspension formulations can include alcohols, such as, but not
limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol
and propylene glycol. Ethers, such as but not limited to,
poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil
and petrolatum; and water can also be used in suspension
formulations.
[0104] For nasal administration, the pharmaceutical formulations
can be a spray or aerosol containing and appropriate solvents and
optionally other compounds such as, but not limited to,
stabilizers, antimicrobial agents, antioxidants, pH modifiers,
surfactants, bioavailability modifiers and combinations of these. A
propellant for an aerosol formulation can include compressed air,
nitrogen, carbon dioxide, or a hydrocarbon based low boiling
solvent. The compound or compounds of the instant invention are
conveniently delivered in the form of an aerosol spray presentation
from a nebulizer or the like.
[0105] Injectable dosage forms generally include aqueous
suspensions or oil suspensions which can be prepared using a
suitable dispersant or wetting agent and a suspending agent.
Injectable forms can be in solution phase or in the form of a
suspension, which is prepared with a solvent or diluent. Acceptable
solvents or vehicles include sterilized water, Ringer's solution,
or an isotonic aqueous saline solution. Alternatively, sterile oils
can be employed as solvents or suspending agents. Generally, the
oil or fatty acid is non-volatile, including natural or synthetic
oils, fatty acids, mono-, di- or tri-glycerides.
[0106] For injection, the pharmaceutical formulation can be a
powder suitable for reconstitution with an appropriate solution as
described above. Examples of these include freeze dried, rotary
dried or spray dried powders, amorphous powders, granules,
precipitates, or particulates. For injection, the formulations can
optionally contain stabilizers, pH modifiers, surfactants,
bioavailability modifiers and combinations of these.
[0107] The compounds can be formulated for parenteral
administration by injection such as by bolus injection or
continuous infusion. A unit dosage form for injection can be in
ampoules or in multi-dose containers.
[0108] For rectal administration, the pharmaceutical formulations
can be in the form of a suppository, an ointment, an enema, a
tablet or a cream for release of compound in the intestines,
sigmoid flexure and/or rectum. Rectal suppositories are prepared by
mixing one or more compounds of the instant invention, or
pharmaceutically acceptable salts or tautomers of the compound,
with acceptable vehicles, for example, cocoa butter or polyethylene
glycol, which is present in a solid phase at normal storing
temperatures, and present in a liquid phase at those temperatures
suitable to release a drug inside the body, such as in the rectum.
Oils can also be employed in the preparation of formulations of the
soft gelatin type and suppositories. Water, saline, aqueous
dextrose and related sugar solutions, and glycerols can be employed
in the preparation of suspension formulations which can also
contain suspending agents such as pectins, carbomers, methyl
cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as
well as buffers and preservatives.
[0109] Besides those representative dosage forms described above,
pharmaceutically acceptable excipients and carries are generally
known to those skilled in the art and are thus included in the
instant invention. Such excipients and carriers are described, for
example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New
Jersey (1991).
[0110] The formulations of the invention can be designed for to be
short-acting, fast-releasing, long-acting, and sustained-releasing.
Thus, the pharmaceutical formulations can also be formulated for
controlled release or for slow release.
[0111] The instant compositions can also comprise, for example,
micelles or liposomes, or some other encapsulated form, or can be
administered in an extended release form to provide a prolonged
storage and/or delivery effect. Therefore, the pharmaceutical
formulations can be compressed into pellets or cylinders and
implanted intramuscularly or subcutaneously as depot injections or
as implants such as stents. Such implants can employ known
materials such as silicones and biodegradable polymers.
[0112] The compositions can contain, for example, from about 0.1%
by weight, to about 90% or more by weight, of the active material,
depending on the method of administration. Where the compositions
comprise dosage units, each unit can contain, for example, from
about 5 to 500 mg or more of the active ingredient. The dosage as
employed for adult human treatment can range, for example, from
about 10 to 3000 mg per day, depending on the route and frequency
of administration.
[0113] Specific dosages can be adjusted depending on conditions of
infection, the age, body weight, general health conditions, sex,
and diet of the subject, dose intervals, administration routes,
excretion rate, and combinations of drugs. Any of the above dosage
forms containing effective amounts are well within the bounds of
routine experimentation and therefore, well within the scope of the
instant invention. Generally, the total daily dose can typically
range from about 0.1 mg/kg/day to about 500 mg/kg/day in single or
in divided doses. Typically, dosages for humans can range from
about 10 mg to about 3000 mg per day, in a single or multiple
doses.
[0114] A therapeutically effective dose or amount can vary
depending upon the route of administration and dosage form. Some
compositions of the instant invention provide a formulation that
exhibits a high therapeutic index. The therapeutic index is the
dose ratio between toxic and therapeutic effects which can be
expressed as the ratio between LD.sub.50 and ED.sub.50. The
LD.sub.50 is the dose lethal to 50% of the population and the
ED.sub.50 is the dose therapeutically effective in 50% of the
population. The LD.sub.50 and ED.sub.50 can be determined by
standard pharmaceutical procedures in animal cell cultures or
experimental models.
[0115] In one embodiment, the invention provides methods of
treating or preventing a bacterial infection in a subject, such as
a mammal, e.g., a human or non-human mammal, comprising
administering an effective amount of one or more compounds
described herein to the subject. Suitable subjects that can be
treated include domestic or wild animals, companion animals, such
as dogs, cats and the like; livestock, including horses, cows and
other ruminants, pigs, poultry, rabbits and the like; primates, for
example monkeys, such as rhesus monkeys and cynomolgus (also known
as crab-eating or long-tailed) monkeys, marmosets, tamarins,
chimpanzees, macaques and the like; and rodents, such as rats,
mice, gerbils, guinea pigs and the like. In one embodiment, the
compound is administered in a pharmaceutically acceptable form,
optionally in a pharmaceutically acceptable carrier. The compounds
described herein can be used for the treatment or prevention of
infectious disorders caused by a variety of bacterial organisms,
including infections by pathogenic bacterial species. Examples
include Gram positive and Gram negative aerobic and anaerobic
bacteria, such as Staphylococci, e.g. S. aureus; Enterococci, e.g.
E. faecalis; Streptococci, e.g. S. pyogenes and S. pneumoniae;
Escherichia species, e.g. E. coli, including enterotoxigenic,
enteropathogenic, enteroinvasive, enterohemorrhagic and
enteroaggregative E. coli strains; Haemophilus, e.g. H. influenza;
Moraxella, e.g. M. catarrhalis. Other examples include
Mycobacteria, e.g. M. tuberculosis, M. avian-intracellulare, M.
kansasii, M. bovis, M. africanum, M. genavense, M. Ieprae, M.
xenopi, M. simiae, M. scrofulaceum, M. malmoense, M. celatum, M.
abscessus, M. chelonae, M. szulgai, M. gordonae, M. haemophilum, M.
fortuni and M. marinum; Corynebacteria, e.g. C. diphtheriae; Vibrio
species, e.g. V. cholerae; Campylobacter species, e.g. C. jejuni;
Helicobacter species, e.g. H. pylori; Pseudomonas species, e.g. P.
aeruginosa; Legionella species, e.g. L. pneumophila; Treponema
species, e.g. T. pallidum; Borrelia species, e.g. B. burgdorferi;
Listeria species, e.g. L. monocytogenes; Bacillus species, e.g. B.
cereus; Bordatella species, e.g. B. pertussis; Clostridium species,
e.g. C. perfringens, C. tetani, C. difficile and C. botulinum;
Neisseria species, e.g. N. meningitidis and N. gonorrhoeae;
Chlamydia species, e.g. C. psittaci, C. pneumoniae and C.
trachomatis; Rickettsia species, e.g. R. rickettsi and R.
prowazekii; Shigella species, e.g. S. sonnet, Salmonella species,
e.g. S. typhimurium; Yersinia species, e.g. Y. enterocolitica and
Y. pseudotuberculosis; Klebsiella species, e.g. K. pneumoniae; and
Mycoplasma, e.g. M. pneumoniae.
[0116] Infections that can be treated with the described compounds
include central nervous system infections, external ear infections,
infections of the middle ear, such as acute otitis media,
infections of the cranial sinuses, eye infections, infections of
the oral cavity, such as infections of the teeth, gums and mucosa,
upper respiratory tract infections, lower respiratory tract
infections, genitourinary infections, gastrointestinal infections,
gynecological infections, septicemia, bone and joint infections,
skin and skin structure infections, bacterial endocarditis, burns,
antibacterial prophylaxis of surgery, and antibacterial prophylaxis
in immunosuppressed patients, such as patients receiving cancer
chemotherapy, or organ transplant patients. These infections can be
treated in hospital or community settings via various routes of
administration as described herein.
[0117] The compounds or compositions described herein can also be
used prophylactically. Accordingly, one or more of the present
compounds or compositions can be administered to an individual
deemed to be at risk for developing a microbial infection.
Individuals at risk for developing a microbial infection include
individuals who have been exposed to a particular microorganism,
such as a pathogenic bacterial species; individuals having a
compromised immune system, such as individuals suffering from an
immunodeficiency disease or taking immunocompromising medication;
and individuals having a history of repeated or chronic infection,
such as children who have repeated infections of the middle
ear.
[0118] Another embodiment provides a method of killing or
preventing the growth of bacteria that includes contacting a
bacteria with either a non-therapeutic amount or a therapeutically
effective amount of one or more of the present compounds. Such
methods can occur in vivo or in vitro. In vitro contact can involve
a screening assay to determine the efficacy of the one or more
compounds against selected bacteria at various amounts or
concentrations. In vivo contact with a therapeutically effective
amount of the one or more compounds can involve treatment or
prophylaxis of a bacterial infection in the animal in which the
contact occurs. The effect of the one or more compounds on the
bacteria and/or host animal can also be determined or measured.
[0119] Included within the scope of the invention are all isomers
(e.g. stereoisomers, diastereoisomers, epimers, geometrical
isomers) of the compounds described herein as well as any wholly or
partially equilibrated mixtures thereof (e.g. racemic or optically
active mixtures). The present invention also covers the individual
isomers of the compounds represented by the formulas herein as
mixtures with isomers thereof in which one or more chiral centers
are inverted.
[0120] Stereoisomeric mixtures, e.g. mixtures of diastereomers, can
be separated into their corresponding isomers in a known manner by
means of suitable separation methods. Diastereomeric mixtures for
example can be separated into their individual diastereomers by
means of fraction crystallization, chromatography, solvent
distribution, and similar procedures. This separation can take
place either at the level of one of the starting compounds or in a
compound of formula I itself. Enantiomers can be separated through
the formation of diastereomeric salts, for example by salt
formation with an enantiomerically pure chiral acid, or by means of
chromatography, for example by HPLC, using chiral chromatographic
media.
[0121] It is understood that the compounds described herein can
exhibit the phenomenon of tautomerism. As the chemical structures
sometimes only represent one of the possible tautomeric forms, it
should be understood that the invention encompasses any tautomeric
form of the represented structure.
[0122] In addition, the compounds described herein can exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of the present invention.
EXAMPLES
Example 1
[0123] Step 1: 2-Bromo-3,4,5-trifluorobenzaldehyde. A 3-L 4-neck
flask was dried by heating with a hot air gun to 94-95.degree. C.
After cooling to room temperature, 74.48 grams (1.47 mol)
diisopropylamine was added to the flask and dissolved in 600 ml dry
THF. The solution was cooled to -75.degree. C. and n-butyllithium
(2.5 M in hexane, 320 ml) was added dropwise over 70 minutes while
maintaining the temperature between -75 to -60.degree. C. The
mixture was allowed to warm to -10.4.degree. C. to 0.2.degree. C.
for 13 minutes. The reaction was cooled to -73.7.degree. C. and 140
grams (0.665 mol) of 1-bromo-2,3,4-trifluorobenzene dissolved in
860 ml THF was added dropwise over 2 hours while maintaining the
temperature between -73.7.degree. C. to -66.degree. C. The reaction
was allowed to stir for 5 hours between -76.3.degree. C. to
-71.7.degree. C. DMF (146 ml) was added over 40 minutes at -70.2 to
-64.8.degree. C. The reaction was allowed to warm to 13.degree. C.
overnight. The reaction was cooled to -25.6.degree. C. before
adding dropwise a solution of 259 ml concentrated hydrochloric acid
in 538 ml distilled water. The addition was complete in 30 minutes
with the temperature getting no higher than -9.degree. C. The
layers were separated and the aqueous portion extracted three times
with ml ethyl acetate. The combined organic portions were washed
successively with 500 ml saturated NaHCO.sub.3 solution and 500 ml
brine. After drying over sodium sulfate, the mixture was filtered
and rotary evaporated to give 148.4 grams of a brown liquid. The
liquid was vacuum distilled and the product collected at
47.9-51.3.degree. C. (1.6 torr), giving 110.17 grams product with
91% purity (HPLC). This was taken up in heptane and chilled in the
freezer to yield 80.23 grams of white to light yellow solid. The
solid was combined with a subsequent crop and material from an
earlier pilot reaction to give 106.21 grams which was vacuum dried
to remove heptane, yielding 104.95 grams with 98.8% purity, mp
36.8-38.degree. C. HPLC analysis done on a Chromolith Performance,
RP-18e, 100-4.6 mm. Mobil Phase: A=Methanol, B=0.1 N TEAA (pH=7).
Gradient from 50% to 90% methanol over 5 minutes. Detector at 254
nm. Retention time: 1.79 minutes.
[0124] Step 2:
3-Bromo-6-(2,6-cis-dimethylmorpholin-4-yl)-4,5-difluorobenzaldehyde.
2-Bromo-3,4,5-trifluorobenzaldehyde (133.15 grams, 0.56 mol) was
dissolved in 1000 ml dry acetonitrile. Triethylamine (118.65 ml,
0.85 mol) was added, followed by cis-2,6-dimethylmorpholine
(Lancaster, 71.64 grams, 0.62 mol), and 125 ml additional
acetonitrile. The mixture was refluxed for 24 hours, then cooled to
room temperature, and poured into 1500 ml saturated sodium
bicarbonate solution. The phases were separated and the aqueous
phase extracted twice with 500 ml ethyl acetate. The combined
organic portions were washed twice with 500 ml brine and then dried
over magnesium sulfate. After filtering and rotary evaporation,
199.7 grams of oil was recovered. The oil was diluted to .about.300
ml with heptane to induce solidification and placed in the freezer
overnight. The resulting yellow solid was filtered to yield 111.7
grams, 99.8% purity (HPLC) of title compound. Mp 88.1-92.0.degree.
C. HPLC analysis done on a Chromolith Performance column, RP-18e,
100-4.6 mm; Mobile phase: A=MeOH, B=0.1N TEAA (pH=7); Gradient: 60%
A to 100% A over 5 minutes; wavelength: 254 nm; Retention time:
1.94 minutes.
[0125] Step 3:
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolan-2-yl)-benzaldehyde. Potassium acetate (179.7 grams,
1.83 mol), Pd(PCy.sub.3).sub.2Cl.sub.2 (Aldrich, 32.0 grams, 0.043
mol), bis-(pinacolato)diboron (Aldrich, 149.7 grams, 0.59 mol), and
3-Bromo-6-(2,6-cis-dimethylmorpholin-4-yl)-4,5-difluorobenzaldehyde
(147.0 grams, 0.538 mol) were placed in a 5 L 4-neck flask. The
solids were evacuated and flushed with argon six times.
Methyltetrahydrofuran (3300 ml) was added. The mixture was
mechanically stirred as it was evacuated until bubbling stopped.
The reactants were flushed with argon, then evacuated and flushed
with argon again. Argon was bubbled through the mixture for 2 hours
and 16 minutes. The mixture was evacuated until bubbling ceased,
flushed with argon, evacuated, and flushed with argon again. The
mixture was heated to reflux for 4.7 days, when NMR indicated that
all
3-bromo-6-(2,6-cis-dimethylmorpholin-4-yl)-4,5-difluorobenzaldeh-
yde had been consumed. The mixture was cooled to room temperature,
filtered, and rinsed with ethyl acetate. The filtrate was rotary
evaporated to give a sticky solid which was taken up in ethyl
acetate and filtered. This yielded 101.9 grams of solid. The solids
were mixed with .about.800 ml warm ethyl acetate and filtered to
remove catalyst. Rotary evaporation yielded 94.4 grams of product
with satisfactory NMR. The initial ethyl acetate filtrate was
concentrated, heptane was added to induce solidification, and the
resulting mixture placed in a freezer. This was filtered to yield
45.45 grams of additional product. This was taken up with
.about.400 ml warm ethyl acetate, filtered to remove a white
impurity, and then rotary evaporated. The residue was treated with
hot heptane to yield fine particles and then filtered to collect
additional product. Total product collected was 121 grams, mp
142.9-143.8.degree. C. Anal. calcd.: 59.86%; C, 6.87%; H, 3.67%; N.
Found: 59.81%; C, 7.03%; H, 3.66%; N.
[0126] Step 4:
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-pyrazin-2-yl-benzaldehyde.
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolan-2-yl)-benzaldehyde (16 grams, 41 mmol),
2-iodopyrazine (Aldrich, 6 grams, 29.1 mmol), sodium carbonate (9.3
grams, 87 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (Aldrich, 0.82
gram, 1.2 mmol) were suspended in a 1:1 mixture of
CH.sub.3CN/H.sub.2O. The reaction mixture was then purged with
nitrogen and heated at 85.degree. C. overnight. Upon completion the
reaction was partitioned between H.sub.2O and ethyl acetate and the
aqueous layer was extracted twice with ethyl acetate. The combined
extracts were dried over MgSO.sub.4, filtered and concentrated. The
crude product was purified by column chromatography eluting with
5-40% ethyl acetate in hexanes to obtain 6.6 grams of the desired
product. 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.19 (d, J=6.2
Hz, 6H), 3.09 (m, 4H), 3.84 (m, 1H), 8.28 (dd, J=8.1, 2.1 Hz, 1H),
8.53 (d, J=2.5 Hz, 1H), 8.66 (dd, J=2.4, 1.7 Hz, 1H), 9.01 (s, 1H),
10.22 (s, 1H); MS (APCI+) m/z 334 (MH+).
[0127] Step 5: Compound 1. A stirring slurry of
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-pyrazin-2-yl-benzaldehyde
(6.6 grams, 19.9 mmol) in MeOH was treated with barbituric acid
(Aldrich, 2.7 grams, 20.9 mmol). The reaction was refluxed
overnight and cooled to room temperature. A solid precipitate
resulted which was filtered and dried under vacuum to afford 7.2
grams of a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) .delta. ppm
0.85 (d, J=6.4 Hz, 3H), 1.08 (d, J=6.2 Hz, 3H), 2.87 (d, J=14.4 Hz,
1H), 3.02 (m, 1H), 3.52 (d, J=14.8 Hz, 1H), 3.60 (dd, J=8.7, 6.3
Hz, 1H), 3.72 (m, 1H), 3.82 (d, J=8.8 Hz, 1H), 4.04 (dd, J=13.5,
2.1 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.63
(dd, J=2.4, 1.7 Hz, 1H), 8.88 (m, 1H), 11.44 (s, 1H), 11.78 (s,
1H); MS (APCI+) m/z 444 (MH+). Anal. calcd for
C.sub.21H.sub.19F.sub.2N.sub.5O.sub.4.0.27H.sub.2O: C, 56.27; H,
4.39; N, 15.62. Found: C, 55.88; H, 4.28; N, 15.39.
Example 2A
[0128] Compound 2: The enantiomers of compound 1 were separated by
reverse phase HPLC. The more retained enantiomer 2:
[alphaD]=-239.degree.. Anal. calcd for
C.sub.21H.sub.19F.sub.2N.sub.5O.sub.4.0.22H.sub.2O: C, 56.38; H,
4.38; N, 15.65. Found: C, 56.66; H, 4.21; N, 15.26.
Example 2B
[0129] Step 1: K.sub.2CO.sub.3 was added to a vigorously stirred
mixture of 2R,6R-(trans)-dimethyl-morpholine (from BASF) in acetone
(100 ml). Benzyl bromide was added dropwise to the mixture
resulting in an exothermic reaction. The reaction was allowed to
cool and stirred 18 h at rt. A majority of the acetone was removed
under vacuum and portioned with water (100 ml) and EtOAc (100 ml).
The aqueous layer was extracted with EtOAc (100 ml), dried over
Na.sub.2SO.sub.4 and concentrated. The product was distilled under
reduced pressure at 120.degree. C. (75-80 at 0.5 torr) providing a
colorless oil of 4-Benzyl-2R,6R-(trans)-dimethyl-morpholine.
[0130] Step 2: 2,6-Dimethyl-morpholine, HCl Salt.
4-Benzyl-2R,6R-(trans)-dimethyl-morpholine (15 g, 73 mmol) was
charged to an autoclave and MeOH (800 mL) added. Pd/C (3.5 g) was
added and the mixture was stirred at room temperature overnight
under 3.5 bars of pressure of H.sub.2. The mixture was then
filtered through celite followed by the addition of HCl 2M in
Et.sub.2O (47 mL, 1.3 eq, 95 mmol). This filtrate was then
concentrated to give the 8.3 g of the morpholine salt. .sup.1H-NMR
(500 MHz, CDCl.sub.3) .delta. 4.26 (m, 2H), 3.25 (m, 2H), 2.94 (m,
2H), 1.39 (m, 6H).
[0131] Step 3:
5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde.
To a solution of 5-bromo-2,3,4-trifluoro-benzaldehyde (11.5 g, 48
mmol) in dry acetonitrile (180 mL) was added Et.sub.3N (16.7 mL,
120 mmol) and 2,6-dimethylmorpholine, HCl Salt (8.3 g, 53 mmol).
The reaction mixture was refluxed for 24 h. The solution was
allowed to cool to room temperature and then poured into a
saturated solution of NaHCO.sub.3. The phases were separated and
the aqueous phase was extracted with EtOAc. The combined organic
layers were washed with brine, dried over MgSO.sub.4 and
concentrated to give an orange oil (15 g). Slurry of the crude in
heptane yielded 11.92 g of a yellow solid. .sup.1H-NMR (500 MHz,
CDCl.sub.3) .delta. 10.36 (s, 1H), 7.82 (dd, 1H), 4.19 (m, 2H), 3.3
(d, 2H), 2.97 (dd, 2H), 1.30 (d, 6H).
[0132] Step 4:
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolan-2-yl)-benzaldehyde.
5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde
(18.7 g, 55.6 mmol), bis-(pinacolato)-diboron (19.0 g, 74.4 mmol),
potassium acetate (22.8 g, 231 mmol) and
bis-(tricyclohexylphosphine)-dichloropalladium (4.0 g, 5.41 mmol)
were placed in a 1 L-3-necked flask. The solids were flushed with
argon and degassed anhydrous 2-methyl-THF (470 mL) was added with a
cannula. The reaction mixture was refluxed for 5 days, cooled to
room temperature, filtered through celite and evaporated to give a
sticky solid which was taken up in EtOAc and filtered. The mother
liquor was evaporated and the residue triturated in heptane.
Filtration via a sinter funnel gave 5.05 g. The mother liquor was
evaporated again; the residue was triturated in heptane and cooled
to +4.degree. C. Filtration via a sinter funnel gave 5.69 g. The
mother liquor was evaporated again, the residue was triturated in a
little heptane and cooled to -18.degree. C. Filtration using a
sinter funnel gave 0.779 g. .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta. 10.25 (s, 1H), 7.98 (dd, 1H), 4.20 (m, 2H), 3.38 (dt, 2H),
3.00 (m, 2H), 1.35 (s, 12H), 1.29 (d, 6H).
[0133] Step 5:
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-pyrazin-2-yl-benzaldehyde.
To a suspension of
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolan-2-yl)-benzaldehyde (11.5 g, 29.1 mmol) and sodium
carbonate (8.8 g, 83.1 mmol) in previously degassed
acetonitrile/water (1/1) mixture (140 mL) was added iodopyrazine
(5.7 g, 27.7 mmol) under nitrogen.
Bis-(triphenylphosphine)-dichloro-palladium-(II) (758 mg, 1.08
mmol) was added at room temperature and the reaction was heated
overnight at 85.degree. C. The mixture was cooled to room
temperature, diluted with EtOAc and water. The phases were
separated and the aqueous phase was re-extracted with EtOAc
(.times.2). The combined organic layers were dried over MgSO.sub.4
and concentrated to give a brown oil. Purification on silica gel
(hexane/EtOAc 9/1, 8/2 then 7/3) yielded 3.65 g of an off-white
solid. .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 10.35 (s, 1H),
9.06 (t, 1H), 8.70 (dd, 1H), 8.57 (d, 1H) 8.32 (dd, 1H), 4.24 (m,
2H), 3.43 (dt, 2H), 3.05 (m, 2H), 1.32 (d, 6H).
[0134] Step 6: Compound 2:
(2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-pyrazin-2-yl-1,2,4,4a-tetrahydro-
-2'H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(1'H,3'-
H)-trione (2.65 g, 8 mmol) and barbituric acid (1.07 g, 8.4 mmol)
were heated in IPA (350 mL) at 85.degree. C. over 91/2 days. A
sample of the heterogeneous mixture was taken and evaporated to
dryness. IPA (100 mL) was added and the reaction mixture was heated
at 85.degree. C. for further 2 days. A sample of the heterogeneous
mixture was taken and evaporated to dryness. Further IPA (600 mL)
was added to obtain a clear yellow solution and the reaction
mixture was heated at 85.degree. C. for an additional day. The
solvent was then removed under reduced pressure affording 4 g of a
yellow solid. The resulting solid was slurried in MeOH (100 mL)
overnight and filtered to give 1.79 g of a yellow solid as a
mixture of isomers. The mother liquor was evaporated to dryness and
the resulting solid (2.17 g) was dissolved in MeCN (50 mL).
Precipitation was achieved by adding water and filtration afforded
pure product as a yellow solid (914 mg). .sup.1H-NMR (500 MHz,
DMSO-D6) .delta. 11.83 (s, 1H), 11.49 (s, 1H), 8.94 (t, 1H), 8.68
(dd, 1H), 8.54 (d, 1H), 7.44 (d, 1H), 4.09 (dd, 1H), 3.88 (d, 1H),
3.77 (m, 1H), 3.66 (m, 1H), 3.57 (d, 1H), 3.07 (t, 1H), 2.92 (d,
1H), 1.13 (d, 3H), 0.91 (d, 3H); MS (APCI+, m/z) 443.1;
Microanalysis: expected C, 55.88%; H, 4.32%; N, 15.79%. found C,
56.21%; H, 4.17%; N, 15.24%. The mixture of isomers (1.79 g) was
suspended in IPA (700 mL) and heated at 85.degree. C. for 5% days.
The solvent was then removed under reduced pressure affording an
orange solid as a more enriched mixture of isomers. A combination
of similar work-up as before (MeOH then MeCN/water) afforded two
more batches of product (358 mg) and (150 mg) respectively.
Example 3
[0135] Compound 3: The enantiomers of compound 1 were separated by
reverse phase HPLC. The less retained enantiomer 3:
[alphaD]=+202.degree.. Anal. calcd for
C.sub.21H.sub.19F.sub.2N.sub.5O.sub.4.0.05H.sub.2O: C, 56.77; H,
4.33; N, 15.76. Found: C, 56.38; H, 4.17; N, 15.43.
Example 4
[0136] Compound 4: Compound 2 (0.300 gram, 0.677 mmol) was
suspended in dry acetonitrile (5 mL) and treated with formaldehyde
(37% aqueous solution, 0.151 mL, 2.03 mmol) and morpholine (0.177
mL, 2.03 mmol). The suspension was heated at reflux overnight. The
resulting solution was cooled and filtered to give a white solid.
NMR indicated that starting material remained so the solid material
was resuspended in acetonitrile and an additional amount of
formaldehyde and morpholine was added. The reaction mixture was
heated to reflux overnight. The solution was then cooled and the
precipitate was filtered and dried to give a white solid (0.101
gram). 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.98 (d, J=6.2
Hz, 3H), 1.19 (d, J=6.2 Hz, 3H), 2.48 (m, 4H), 2.69 (m, 4H), 3.00
(d, J=14.3 Hz, 1H), 3.08 (m, 1H), 3.18 (d, J=14.3 Hz, 1H), 3.51 (m,
4H), 3.62 (m, 4H), 3.77 (m, 1H), 3.90 (m, 1H), 4.09 (d, J=8.6 Hz,
1H), 4.18 (dd, J=13.5, 2.0 Hz, 1H), 4.67 (d, J=13.1 Hz, 1H), 4.86
(dd, J=16.3, 13.0 Hz, 2H), 5.01 (d, J=13.1 Hz, 1H), 7.40 (d, J=6.8
Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.51 (m, 1H), 9.00 (s, 1H).
Example 5
[0137] Compound 5: Compound 2 (0.400 gram, 0.902 mmol) was
suspended in dry acetonitrile (5 mL) and treated with formaldehyde
(37% aqueous solution, 0.403 mL, 5.41 mmol)) and N-methylpiperazine
(0.600 mL, 5.41 mmol). The suspension was heated under reflux for 5
hours. The resulting solution was cooled and concentrated to an
oil. The oily residue was triturated several times with MTBE
(tert-butyl methyl ether) and hexane to afford a precipitate that
was filtered and dried under vacuum to obtain a yellow solid (0.438
gram). 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.96 (d, J=6.4
Hz, 3H), 1.18 (d, J=6.2 Hz, 3H), 2.12 (s, 3H), 2.22 (s, 3H), 2.46
(m, 8H), 2.69 (m, 4H), 3.12 (m, 3H), 3.77 (m, 1H), 3.89 (m, 1H),
4.08 (d, J=8.8 Hz, 1H), 4.17 (dd, J=13.5, 2.0 Hz, 1H), 4.69 (d,
J=12.9 Hz, 1H), 4.87 (dd, J=14.1, 13.3 Hz, 2H), 5.02 (d, J=12.9 Hz,
1H), 7.41 (d, J=7.6 Hz, 1H), 8.37 (d, J=2.5 Hz, 1H), 8.51 (m, 1H),
8.99 (s, 1H). Anal. calcd for
C.sub.33H.sub.43F.sub.2N.sub.9O.sub.4.0.55H.sub.2O.0.20(CH.sub.3).sub.3CO-
CH.sub.3: C, 58.59; H, 6.76; N, 18.19. Found: C, 58.33; H, 7.23; N,
18.59.
Example 6
[0138] Compound 6: Compound 2 (0.400 gram, 0.90 mmol) was suspended
in CH.sub.2Cl.sub.2 (40 mL) followed by the addition of
3-chloroperoxybenzoic acid (77% in H.sub.2O). Reaction was stirred
at room temperature for 2 days. Saturated sodium bicarbonate was
then added. After stirring for 1 hour a yellow solid precipitate
resulted which was filtered to obtain 0.188 gram of desired
product. 1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.84 (d, J=6.4 Hz,
3H), 1.07 (d, J=6.2 Hz, 3H), 2.83 (d, J=14.8 Hz, 1H), 3.00 (m, 1H),
3.36 (d, J=14.4 Hz, 1H), 3.62 (dd, J=8.8, 6.4 Hz, 1H), 3.70 (m,
1H), 3.84 (d, J=8.8 Hz, 1H), 4.03 (dd, J=13.7, 2.1 Hz, 1H), 7.40
(d, J=7.8 Hz, 1H), 8.19 (dd, J=4.1, 1.6 Hz, 1H), 8.43 (s, 1H), 8.49
(dd, J=4.1, 0.8 Hz, 1H), 11.38 (s, 2H); MS (APCI+) m/z 460 (MH+).
Anal. calcd for
C.sub.21H.sub.19F.sub.2N.sub.5O.sub.5.1.80H.sub.2O0.30CH.sub.2Cl.sub.2:
C, 49.45; H, 4.52; N, 13.54. Found: C, 49.26; H, 4.17; N,
13.15.
Example 7
[0139] Compound 7. Compound 1 (1.0 gram, 2.3 mmol) was dissolved in
dry DMF (5 mL) and triethylamine (0.943 mL, 6.77 mmol) was added
followed by bromomethyl acetate (Aldrich, 0.487 mL, 4.96 mmol). The
resulting solution was stirred at room temperature overnight then
diluted with ethyl acetate and washed with water. The organic layer
was dried over MgSO.sub.4, concentrated and purified by column
chromatography eluting with 35-80% ethyl acetate in hexanes to give
a yellow oil (0.942 gram) that was dried under vacuum. 1H NMR (400
MHz, DMSO-d6) .delta. ppm 0.85 (d, J=6.2 Hz, 3H), 1.09 (d, J=6.2
Hz, 3H), 1.84 (s, 3H), 2.00 (s, 3H), 3.00 (d, J=14.1 Hz, 1H), 3.06
(dd, J=14.1, 9.2 Hz, 1H), 3.55 (d, J=14.3 Hz, 1H), 3.61 (dd, J=8.8,
6.4 Hz, 1H), 3.74 (m, 1H), 3.92 (d, J=8.6 Hz, 1H), 4.05 (dd,
J=13.6, 2.2 Hz, 1H), 5.57 (q, J=10 Hz, 2 H), 5.79 (q, J=10 Hz, 2H),
7.36 (d, J=7.8 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.62 (dd, J=2.5,
1.6 Hz, 1H), 8.90 (m, 1H).
Example 8
[0140] Compound 8: To a cooled solution of compound 3 (2.0 gram,
4.5 mmol) in dry DMF (7 mL) was added triethylamine (1.89 mL, 13.5
mmol) followed by bromomethyl acetate (Aldrich, 1.42 mL, 14.4
mmol). The resulting solution was then heated to 50.degree. C. for
3 hours. The reaction mixture was allowed to cool and then added
drop wise to a stirring amount of water which afforded a
precipitate that was filtered and dried under vacuum. 1H NMR (400
MHz, DMSO-d6) .delta. ppm 0.85 (d, J=6.2 Hz, 3H), 1.09 (d, J=6.2
Hz, 3H), 1.84 (s, 3H), 2.00 (s, 3H), 2.99 (d, J=14.8 Hz, 1H), 3.06
(m, 1H), 3.55 (d, J=14.3 Hz, 1H), 3.62 (m, 1H), 3.74 (m, 1H), 3.92
(d, J=8.6 Hz, 1H), 4.05 (dd, J=13.6, 2.2 Hz, 1H), 5.57 (m, 2H),
5.79 (m, 2H), 7.36 (d, J=7.8 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.62
(dd, J=2.5, 1.6 Hz, 1H), 8.90 (m, 1H).
Example 9
[0141] Compound 9: A solution of compound 7 (0.940 gram, 1.60 mmol)
in MeOH (20 mL) was treated with HCl (20 mL of a 1M solution in
diethylether). The yellow solution was stirred for 1 hour resulting
in a precipitate. The reaction mixture was concentrated. Ether was
added and the resulting yellow solid was filtered and washed with
ether. The solid material (0.755 gram) was dried under vacuum. 1H
NMR (400 MHz, DMSO-d6) .delta. ppm 0.84 (d, J=6.2 Hz, 3H), 1.09 (d,
J=6:1 Hz, 3H), 2.96 (d, J=14.6 Hz, 1H), 3.03 (m, 1H), 3.40 (d,
J=14.4 Hz, 1H), 3.62 (dd, J=8.7, 6.3 Hz, 1H), 3.73 (m, 1H), 3.89
(d, J=8.8 Hz, 1H), 4.06 (dd, J=13.5, 2.1 Hz, 1H), 4.95 (d, J=10.0
Hz, 1H), 5.04 (m, 1H), 5.21 (m, 2H), 5.86 (br. s., 2H), 7.32 (d,
J=7.8 Hz, 1H), 8.49 (d, J=2.1 Hz, 1H), 8.63 (s, 1H), 8.89 (s,
1H).
Example 10
[0142] Compound 10: A solution of compound 8 (2.5 gram, 4.25 mmol)
in MeOH (30 mL) was treated with HCl (30 mL of a 1M solution in
diethylether). The solution was stirred for 3 hours then
concentrated and triturated several times with tert-butyl methyl
ether to isolate a red solid. 1H NMR (400 MHz, DMSO-d6) .delta. ppm
0.84 (d, J=6.2 Hz, 3H), 1.09 (d, J=6.1 Hz, 3H), 2.96 (d, J=14.6 Hz,
1H), 3.01 (m, 1H), 3.40 (d, J=14.4 Hz, 1H), 3.62 (dd, J=8.7, 6.3
Hz, 1H), 3.73 (m, 1H), 3.89 (d, J=8.8 Hz, 1H), 4.06 (dd, J=13.5,
2.1 Hz, 1H), 4.95 (d, J=10.0 Hz, 1H), 5.04 (m, 1H), 5.21 (m, 2H),
5.86 (br. s., 2H), 7.32 (d, J=7.8 Hz, 1H), 8.49 (d, J=2.1 Hz, 1H),
8.63 (s, 1H), 8.89 (s, 1H).
Example 11
[0143] Compound 11: A solution of compound 9 (0.750 gram, 1.5 mmol)
in CH.sub.2Cl.sub.2 was treated with thionyl chloride (1.1 mL). The
reaction was stirred for 1 hour becoming a red solution. The
solution was carefully quenched with water and stirred for 5
minutes. The organic layer was separated and the aqueous was
extracted with CH.sub.2Cl.sub.2. The combined organics were dried
over MgSO.sub.4. Concentration provided the compound (0.657 gram)
as a beige foam. 1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.86 (d,
J=6.3 Hz, 3H), 1.12 (d, J=5.5 Hz, 3H), 3.08 (m, 2H), 3.59 (m, 2H),
3.78 (m, 1H), 3.95 (d, J=8.6 Hz, 1H), 4.09 (dd, J=13.6, 2.2 Hz,
1H), 5.51 (m, 2H), 5.73 (s, 2H), 7.35 (d, J=8.0 Hz, 1H), 8.52 (d,
J=2.3 Hz, 1H), 8.65 (dd, J=2.3, 1.6 Hz, 1H), 8.92 (m, 1H).
Example 12
[0144] Compound 12: To a mixture of dibenzyl phosphate (Aldrich,
0.770 gram, 2.8 mmol) and silver carbonate (0.383 gram, 1.4 mmol)
in toluene (1 mL) was added compound 11 (0.600 gram, 1.1 mmol). The
reaction mixture was heated to 70.degree. C. for 2 hours then
cooled to room temperature. The crude reaction mixture was loaded
directly onto the column and purified by column chromatography
eluting with 40-100% ethyl acetate in hexanes to obtain 0.439 g. 1H
NMR (400 MHz, DMSO-d6) .delta. ppm 0.82 (d, J=6.4 Hz, 3H), 1.11 (d,
J=6.1 Hz, 3H), 2.98 (d, J=14.7 Hz, 1H), 3.07 (m, 1H), 3.44 (d,
J=14.1 Hz, 1H), 3.59 (dd, J=8.6, 6.4 Hz, 1H), 3.73 (m, 1H), 3.94
(d, J=8.8 Hz, 1H), 4.07 (dd, J=13.3, 1.8 Hz, 1H), 4.84 (m, 4H),
5.04 (dd, J=8.0, 2.0 Hz, 4H), 5.47 (m, 1H), 5.55 (t, J=9.9 Hz, 1H),
5.71 (t, J=9.8 Hz, 1H), 5.80 (m, 1H), 7.19 (m, 4H), 7.30 (m, 16H),
8.44 (d, J=2.5 Hz, 1H), 8.55 (m, 2H), 8.78 (s, 1H).
Example 13
[0145] Compound 13: To a stirring solution of compound 10 (0.10
gram, 0.20 mmol) and triphenylphosphine (0.16 gram, 0.60 mmol) in
DMF (2 mL) was slowly added N-bromosuccinimide (NBS) (0.11 gram,
0.60 mmol) in dichloromethane (1 mL). The reaction mixture was
stirred overnight at room temperature. The reaction was partitioned
between water and dichloromethane. The combined organics were dried
over MgSO.sub.4. Purified by column chromatography eluting with
ethyl acetate in hexanes (20-70%). Product was confirmed by the
downfield shift of the methylene protons in the 1H NMR (400 MHz,
DMSO-d6) .delta. ppm 5.47 (m, 2H), 5.69 (m, 2H).
Example 14
[0146] Compound 14: To a stirring solution of compound 10 (0.10
gram, 0.20 mmol) and triphenylphosphine (PL-TPP (Polymer
Laboratories): 0.18 gram, 0.70 mmol) in THF (5 mL) was slowly added
NBS (0.12 gram, 0.70 mmol). Reaction was stirred at room
temperature for 1.5 hours then NaI (0.006 g, 0.04 mmol) was added
followed by di-tertbutyl phosphate, potassium salt (Digital
Specialty, 0.200 g, 0.79 mmol). Reaction was heated to 55.degree.
C. and a slurry resulted. An additional amount of THF (2 mL) was
added and the reaction was heated for 3.5 hours. Filtered the
reaction mixture and washed resin with CH.sub.2Cl.sub.2 and
concentrated to a yellow oil. The oil was partitioned between
CH.sub.2Cl.sub.2 and aqueous sodium bicarbonate then dried over
MgSO.sub.4. Triturated solid with hexane/MTBE and filtered light
orange colored solid. 1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.85
(d, J=6.2 Hz, 3H), 1.09 (d, J=6.1 Hz, 3H), 1.24 (d, J=4.9 Hz, 18H),
1.39 (s, 18 H), 3.05 (m, 2H), 3.47 (d, J=14.8 Hz, 1H), 3.59 (dd,
J=8.3, 6.2 Hz, 1H), 3.74 (m, 1H), 3.94 (d, J=8.4 Hz, 1H), 4.06 (dd,
J=13.2, 1.5 Hz, 1H), 5.30 (m, 1H), 5.40 (m, 1H), 5.55 (m, 2H), 7.32
(d, J=7.0 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.63 (m, 1H), 8.90 (s,
1H); MS (APCI+) m/z 888 (MH+).
Example 15
[0147] Step 1.
5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-3-fluoro-benzaldehyde.
4-(4-Bromo
2-[1,3]dioxolan-2-yl-6-fluoro-phenyl)-2,6-dimethyl-morpholine (1.0
grams, 2.8 mmol) was dissolved in THF (4 mL) and 1N HCl (3 mL).
Stirred overnight at room temperature then heated to 50.degree. C.
for 5 hours. Reaction was partitioned between ethyl acetate and
sodium bicarbonate. Dried the organic layer over MgSO.sub.4,
filtered and concentrated to obtain 0.847 gram of a yellow solid.
1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.19 (d, J=6.3 Hz, 6H),
2.90 (m, 2H), 3.01 (m, 2H), 3.81 (m, 2H), 7.43 (dd, J=11.5, 2.2 Hz,
1H), 7.73 (dd, J=2.4, 1.2 Hz, 1H), 10.37 (s, 1H); MS (APCI+) m/z
316, 318 (MH+).
[0148] Step 2.
2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]di-
oxaborolan-2-yl)-benzaldehyde.
5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-3-fluoro-benzaldehyde
(0.827 gram, 2.6 mmol) and bis(pinacolato)diboron (0.72 gram, 2.9
mmol) were dissolved in anhydrous 2-methyl-THF (20 mL). To this was
added potassium acetate (0.770 gram, 7.8 mmol) and
Pd(PCy.sub.3).sub.2Cl.sub.2 (0.058 gram, 0.08 mmol). The reaction
mixture was ran under nitrogen and heated to 80.degree. C.
overnight. The reaction mixture was filtered and the filtrate was
concentrated to a yellow solid. The crude product was purified by
column chromatography eluting with ethyl acetate in hexanes to
obtain 0.688 gram of the desired product. 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.18 (d, J=6.3 Hz, 6H), 1.31 (s, 12H),
3.02 (m, 4H), 3.83 (m, 2H), 7.63 (dd, J=12.9, 1.5 Hz, 1H), 8.01 (d,
J=1.5 Hz, 1H), 10.32 (s, 1H); MS (APCI+) m/z 364 (MH+).
[0149] Step 3.
2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-pyrazin-2-yl-benzaldehyde.
2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]di-
oxaborolan-2-yl)-benzaldehyde (0.40 gram, 1.1 mmol),
2-chloropyrazine (0.115 gram, 1.0 mmol), sodium carbonate (0.32
gram, 3.0 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (0.03 gram, 0.04
mmol) were suspended in a 1:1 mixture of CH.sub.3CN/H.sub.2O. The
reaction mixture was then purged with Nitrogen and heated at
95.degree. C. overnight. Upon completion the reaction was
partitioned between H.sub.2O and ethyl acetate and the aqueous
layer was extracted twice with ethyl acetate. The combined extracts
were dried over MgSO.sub.4, filtered and concentrated. The crude
product was purified by column chromatography eluting with 10-55%
ethyl acetate in hexanes to obtain 0.230 gram of the desired
product. 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.21 (d, J=6.3
Hz, 6H), 3.08 (m, 4H), 3.86 (m, 2H), 8.04 (dd, J=13.4, 2.2 Hz, 1H),
8.23 (d, J=1.5 Hz, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.62 (dd, J=2.6,
1.6 Hz, 1H), 9.04 (d, J=1.5 Hz, 1H), 10.41 (s, 1H); MS (APCI+) m/z
316 (MH+).
[0150] Step 4. Compound 15: A stirring slurry of
2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-pyrazin-2-yl-benzaldehyde
(0.221 gram, 0.70 mmol) in MeOH (4 mL) was treated with barbituric
acid (0.094 gram, 0.74 mmol). The reaction was refluxed overnight
and cooled to room temperature. A solid precipitate resulted which
was filtered and dried under vacuum to afford 0.246 gram of desired
product. 1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.87 (d, J=6.3 Hz,
3H), 1.09 (d, J=6.1 Hz, 3H), 2.98 (m, 2H), 3.48 (d, J=13.9 Hz, 1H),
3.62 (dd, J=8.7, 6.5 Hz, 1H), 3.74 (m, 1H), 3.84 (d, J=8.8 Hz, 1H),
4.06 (dd, J=13.1, 1.8 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.77 (dd,
J=15.4, 2.0 Hz, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.55 (dd, J=2.6, 1.6
Hz, 1H), 9.08 (d, J=1.5 Hz, 1H), 11.45 (s, 1H), 11.81 (s, 1H); MS
(APCI+) m/z 426 (MH+). Anal. calcd for
C.sub.21H.sub.20FN.sub.5O.sub.4.0.52H.sub.2O: C, 58.01; H, 4.88; N,
16.11. Found: C, 57.62; H, 4.85; N, 15.88.
Example 16
[0151] Step 1a.
2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-morpholin-4-yl-5-pyrazin-2-yl--
benzaldehyde. To morpholine dissolved in CH.sub.3CN was added
K.sub.2CO.sub.3 followed by
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-pyrazin-2-yl-benzaldehyde
(Example 1, step 4). The reaction mixture was heated overnight.
Partitioned between sodium bicarbonate and ethyl acetate. Extracted
with ethyl acetate (3.times.), dried over MgSO.sub.4 and
concentrated. The crude product was purified by column
chromatography eluting with 10-70% ethyl acetate in hexanes to
obtain 0.099 gram of the desired product. 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.21 (d, J=6.3 Hz, 6H), 3.06 (m, 8H),
3.60 (m, 4H), 3.85 (m, 2H), 7.75 (d, J=1.6 Hz, 1H), 8.50 (d, J=2.5
Hz, 1H), 8.64 (m, 1H), 8.91 (s, 1H), 10.26 (s, 1H); MS (APCI+) m/z
401 (MH+).
[0152] Step 2. Compound 16: A stirring slurry of
2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-morpholin-4-yl-5-pyrazin-2-yl--
benzaldehyde (0.099 gram, 0.25 mmol) in MeOH was treated with
barbituric acid (0.033 gram, 0.26 mmol). The reaction was refluxed
overnight and cooled to room temperature. A solid precipitate
resulted which was filtered and dried under vacuum to afford 0.105
gram of desired product. 1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.87
(d, J=6.4 Hz, 3H), 1.10 (d, J=6.3 Hz, 3H), 2.92 (m, 6H), 3.46 (m,
5H), 3.64 (dd, J=8.8, 6.4 Hz, 1H), 3.78 (m, 2H), 4.01 (dd, J=13.1,
2.1 Hz, 1H), 7.00 (s, 1H), 8.43 (d, J=2.5 Hz, 1H), 8.57 (dd, J=2.5,
1.6 Hz, 1H), 8.94 (d, J=1.6 Hz, 1H), 11.40 (s, 1H), 11.74 (s, 1H);
MS (APCI+) m/z 511 (MH+). Anal. calcd for
C.sub.25H.sub.27FN.sub.6O.sub.5.0.80H.sub.2O: C, 57.20; H, 5.49; N,
16.01. Found: C, 57.14; H, 5.32; N, 15.61.
Example 17
[0153] Step 1a.
2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-(2-methoxy-ethoxy)-5-pyrazin-2-
-yl-benzaldehyde. NaH was suspended in THF (4 mL) and cooled to
0.degree. C. To this suspension was slowly added 2-methoxy-ethanol
and the reaction was stirred for 15 minutes at room temperature.
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-pyrazin-2-yl-benzaldehyde
(Example 1, step 4) was dissolved up into THF and was slowly added
to the reaction. The reaction was heated to 50.degree. C. for 1
hour then stirred at room temperature overnight. The reaction
mixture was partitioned between sodium bicarbonate and ethyl
acetate. Extracted with ethyl acetate (3.times.), dried over
MgSO.sub.4, and concentrated. The crude product was purified by
column chromatography eluting with 10-70% ethyl acetate in hexanes
to obtain 0.099 gram of the desired product. 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.20 (d, J=6.3 Hz, 6H), 3.08 (m, 4H),
3.27 (s, 3H), 3.60 (m, 2H), 3.86 (m, 2H), 4.31 (m, 2H), 8.14 (d,
J=1.8 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.66 (s, 1H), 9.19 (s, 1H),
10.28 (s, 1H); MS (APCI+) m/z 390 (MH+).
[0154] Step 2. Compound 17: A stirring slurry of
2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-(2-methoxy-ethoxy)-5-pyrazin-2-
-yl-benzaldehyde (0.092 gram, 0.24 mmol) in MeOH was treated with
barbituric acid (0.032 gram, 0.25 mmol). The reaction was refluxed
overnight, cooled to room temperature and concentrated. Solid was
triturated with MeOH, filtered and dried under vacuum to afford
0.044 gram of desired product. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. ppm 0.87 (d, J=6.3 Hz, 3H), 1.10 (d, J=6.3 Hz, 3H), 2.88
(d, J=14.3 Hz, 1H), 2.98 (m, 1H), 3.10 (s, 3H), 3.47 (m, 3H), 3.63
(dd, J=8.6, 6.4 Hz, 1H), 3.75 (m, 1H), 3.81 (d, J=8.6 Hz, 1H), 4.04
(m, 2H), 4.12 (m, 1H), 7.29 (s, 1H), 8.43 (d, J=2.5 Hz, 1H), 8.58
(m, 1H), 9.09 (d, J=1.6 Hz, 1H), 11.41 (s, 1H), 11.76 (s, 1H); MS
(APCI+) m/z 500 (MH+). Anal. calcd for
C.sub.24H.sub.26FN.sub.5O.sub.6.0.07H.sub.2O: C, 57.56; H, 5.26; N,
13.99. Found: C, 57.17; H, 5.02; N, 13.70.
Example 18
[0155] Step 1a.
2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-(2-fluoro-ethoxy)-5-pyrazin-2--
yl-benzaldehyde. NaH was suspended in THF (4 mL) and cooled to
0.degree. C. To this suspension was slowly added 2-fluoroethanol
and the reaction was stirred for 15 minutes at room temperature.
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-pyrazin-2-yl-benzaldehyde
(Example 1, step 4) was dissolved up into THF and was slowly added
to the reaction. The reaction was heated to 50.degree. C. for 1
hour then stirred at room temperature overnight. The reaction
mixture was partitioned between sodium bicarbonate and ethyl
acetate. Extracted with ethyl acetate (3.times.), which was dried
over MgSO.sub.4, and concentrated. The crude product was purified
by column chromatography eluting with 10-50% ethyl acetate in
hexanes to obtain 0.103 gram of the desired product. 1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.21 (d, J=6.3 Hz, 6H), 3.09 (m,
4H), 3.87 (m, 2H), 4.40 (m, 2H), 4.61 (m, 2H), 8.12 (d, J=2.0 Hz,
1H), 8.52 (m, 1H), 8.66 (m, 1H), 9.10 (s, 1H), 10.28 (s, 1H); MS
(APCI+) m/z 378 (MH+).
[0156] Step 2. Compound 18: A stirring slurry of
2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-(2-fluoro-ethoxy)-5-pyrazin-2--
yl-benzaldehyde (0.103 gram, 0.27 mmol) in MeOH was treated with
barbituric acid (0.036 gram, 0.29 mmol). The reaction was refluxed
overnight, cooled to room temperature and concentrated. Solid was
triturated with MeOH, filtered and dried under vacuum to afford
0.081 gram of desired product. 1H NMR (400 MHz, DMSO-d6) .delta.
ppm 0.87 (d, J=6.3 Hz, 3H), 1.10 (d, J=6.3 Hz, 3H), 2.88 (d, J=14.3
Hz, 1H), 2.98 (m, 1H), 3.10 (s, 3H), 3.47 (m, 3H), 3.63 (dd, J=8.6,
6.4 Hz, 1H), 3.75 (m, 1H), 3.81 (d, J=8.6 Hz, 1H), 4.04 (m, 2H),
4.12 (m, 1H), 7.29 (s, 1H), 8.43 (d, J=2.5 Hz, 1H), 8.58 (m, 1H),
9.09 (d, J=1.6 Hz, 1H), 11.41 (s, 1H), 11.76 (s, 1H); MS (APCI+)
m/z 488 (MH+). Anal. calcd for
C.sub.23H.sub.23F.sub.2N.sub.5O.sub.5.0.71H.sub.2O: C, 55.22; H,
4.92; N, 14.0. Found: C, 54.84; H, 4.66; N, 13.84.
Example 19
[0157] Step 1.
5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-4-fluoro-benzaldehyde.
4-(4-Bromo
2-[1,3]dioxolan-2-yl-5-fluoro-phenyl)-2,6-dimethyl-morpholine (3.5
grams, 9.7 mmol) was dissolved in THF and 1N HCl (3 mL). Reaction
was stirred overnight at 50.degree. C. The reaction was partitioned
between ethyl acetate and sodium bicarbonate. The organic layer was
dried over MgSO.sub.4, filtered and concentrated to obtain 2.9 gram
of a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.21
(d, J=6.3 Hz, 6H), 2.60 (dd, J=12.0, 10.3 Hz, 2H), 3.05 (m, 2H),
3.88 (m, 2H), 6.81 (d, J=10.4 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H),
10.10 (s, 1H); MS (APCI+) m/z 316, 318 (MH+).
[0158] Step 2.
2-(2,6-Dimethyl-morpholin-4-yl)-4-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]di-
oxaborolan-2-yl)-benzaldehyde.
5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-4-fluoro-benzaldehyde (2.99
gram, 9.5 mmol) and bis(pinacolato)diboron (2.4 gram, 9.5 mmol)
were dissolved in anhydrous 2-methyl-THF. To this was added
potassium acetate (2.8 gram, 28 mmol) and
Pd(PCy.sub.3).sub.2Cl.sub.2 (0.28 gram, 0.04 mmol). The reaction
mixture was run under nitrogen and heated to 80.degree. C.
overnight. The reaction mixture was filtered and the filtrate was
concentrated to a yellow solid. The crude product was purified by
column chromatography eluting with ethyl acetate in hexanes to
obtain 2.1 gram of product. 1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 1.21 (d, J=6.3 Hz, 6H), 1.33 (s, 12H), 2.61 (dd, J=12.1, 10.4
Hz, 2H), 3.18 (m, 2H), 3.90 (m, 2H), 6.62 (d, J=11.5 Hz, 1H), 8.19
(d, J=7.2 Hz, 1H), 10.03 (s, 1H); MS (APCI+) m/z 364 (MH+).
[0159] Step 3.
2-(2,6-Dimethyl-morpholin-4-yl)-4-fluoro-5-pyrazin-2-yl-benzaldehyde.
2-(2,6-Dimethyl-morpholin-4-yl)-4-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]di-
oxaborolan-2-yl)-benzaldehyde (0.35 gram, 0.96 mmol),
2-iodopyrazine (79 .mu.L, 0.80 mmol), potassium phosphate (0.34
gram, 1.6 mmol), Buchwald ligand:
2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (Strem
Chemicals) (0.04 gram, 0.10 mmol), and Pd(OAc).sub.2 (Aldrich, 0.01
gram, 0.04 mmol) were suspended in Toluene (1.6 mL). The reaction
mixture was then purged with Nitrogen and heated at 85.degree. C.
overnight. Upon completion the reaction was partitioned between
H.sub.2O and ethyl acetate and the aqueous layer was extracted
twice with ethyl acetate. The combined extracts were dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified by column chromatography eluting with 5-45% ethyl acetate
in hexanes to obtain 0.230 gram of the desired product. 1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.24 (d, J=6.3 Hz, 6H), 2.68 (dd,
J=11.9, 10.4 Hz, 2H), 3.21 (m, 2H), 3.94 (m, 2H), 6.82 (d, J=13.3
Hz, 1H), 8.53 (d, J=9.0 Hz, 2H), 8.67 (s, 1H), 9.05 (s, 1H), 10.14
(s, 1H); MS (APCI+) m/z 316 (MH+).
[0160] Step 4. Compound 19: A stirring slurry of
2-(2,6-Dimethyl-morpholin-4-yl)-4-fluoro-5-pyrazin-2-yl-benzaldehyde
(0.115 gram, 0.36 mmol) in MeOH (4 mL) was treated with barbituric
acid (0.049 gram, 0.38 mmol). The reaction was refluxed overnight,
cooled to room temperature and concentrated. Solid was triturated
with MeOH, filtered and dried under vacuum to afford 0.098 gram of
desired product. 1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.90 (d,
J=6.4 Hz, 3H), 1.12 (d, J=6.1 Hz, 3H), 2.86 (m, 2H), 3.45 (d,
J=14.8 Hz, 1H), 3.50 (dd, J=8.9, 6.3 Hz, 1H), 3.57 (m, 1H), 3.76
(d, J=9.0 Hz, 1H), 4.12 (dd, J=12.8, 1.7 Hz, 1H), 6.87 (d, J=15.4
Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 8.43 (d, J=2.5 Hz, 1H), 8.61 (dd,
J=2.5, 1.6 Hz, 1H), 8.88 (m, 1H), 11.45 (s, 1H), 11.75 (s, 1H); MS
(APCI+) m/z 426 (MH+). Anal. calcd for
C.sub.21H.sub.20FN.sub.5O.sub.4.1.23H.sub.2O: C, 55.96; H, 4.99; N,
15.78. Found: C, 56.35; H, 5.06; N, 15.65.
Example 20
[0161] Step 1.
2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde.
4-Fluoro-3-formylphenylboronic acid (Lancaster, 3.1 grams, 18 mmol)
and pinacol (2.4 grams, 21 mmol) were stirred under nitrogen in
anhydrous THF that contained activated 4 .ANG. molecular sieves.
Reaction was stirred overnight. The reaction mixture was filtered
and the filtrate was concentrated in vacuo to give 4.5 grams of a
white solid. 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.32 (s,
12H), 7.14 (dd, J=10.5, 8.3 Hz, 1H), 8.00 (m, 1H), 8.31 (dd, J=7.4,
1.6 Hz, 1H), 10.34 (s, 1H); MS (APCI+) m/z 251 (MH+).
[0162] Step 2.
2-(2,6-Dimethyl-morpholin-4-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborola-
n-2-yl)-benzaldehyde.
2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde
(4.6 grams, 18 mmol) and potassium carbonate (3.8 grams, 27 mmol)
were suspended in DMF (3 mL). Dimethyl morpholine (2.6 mL, 21 mmol)
was then added and mixture was heated overnight at 105.degree. C.
Reaction mixture was cooled and filtered to remove salts. The
dropwise addition of water induced formation of a precipitate. The
yellow precipitate was filtered off and collected. Dried in vacuum
oven to obtain 4.26 grams of desired product. 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.21 (d, J=6.1 Hz, 6H), 1.32 (s, 12H),
2.65 (m, 2H), 3.16 (d, J=11.5 Hz, 2H), 3.93 (m, 2H), 7.03 (d, J=8.3
Hz, 1H), 7.90 (dd, J=8.2, 1.6 Hz, 1H), 8.22 (d, J=1.5 Hz, 1H),
10.17 (s, 1H); MS (APCI+) m/z 346 (MH+).
[0163] Step 3.
2-(2,6-dimethyl-morpholin-4-yl)-5-pyrazin-2-yl-benzaldehyde.
2-(2,6-dimethyl-morpholin-4-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborola-
n-2-yl)-benzaldehyde (0.250 grams, 0.72 mmol), 2-iodopyrazine
(0.135 gram, 0.65 mmol), sodium carbonate (0.350 gram, 3.3 mmol)
and Pd(PPh.sub.3).sub.2Cl.sub.2 (0.014 gram, 0.02 mmol) were
suspended in a 1:1 mixture of CH.sub.3CN/H.sub.2O. The reaction
mixture was then purged with Nitrogen and heated at 95.degree. C.
overnight. Upon completion the reaction was partitioned between
H.sub.2O and ethyl acetate and the aqueous layer was extracted
twice with ethyl acetate. The combined extracts were dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified by column chromatography eluting with 15-60% ethyl acetate
in hexanes to obtain 0.157 gram of the desired product. 1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.25 (d, J=6.3 Hz, 6H), 2.73 (m,
2H), 3.20 (m, 2H), 3.95 (m, 2H), 7.20 (d, J=8.5 Hz, 1H), 8.24 (dd,
J=8.5, 2.4 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.50 (d, J=2.4 Hz, 1H),
8.62 (m, 1H), 9.04 (d, J=1.5 Hz, 1H), 10.30 (s, 1H); MS (APCI+) m/z
298 (MH+).
[0164] Step 4. Compound 20: A stirring slurry of
2-(2,6-dimethyl-morpholin-4-yl)-5-pyrazin-2-yl-benzaldehyde (0.155
gram, 0.52 mmol) in IPA (4 mL) was treated with barbituric acid
(0.070 gram, 0.55 mmol). The reaction was refluxed overnight and
cooled to room temperature. A solid precipitate resulted which was
filtered and dried under vacuum to afford 0.171 gram of desired
product. 1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.90 (d, J=6.3 Hz,
3H), 1.13 (d, J=6.1 Hz, 3H), 2.85 (dd, J=13.3, 10.4 Hz, 1H), 2.92
(d, J=15.1 Hz, 1H), 3.37 (d, J=14.9 Hz, 1H), 3.52 (dd, J=9.0, 6.3
Hz, 1H), 3.60 (m, 1H), 3.75 (d, J=9.0 Hz, 1H), 4.15 (dd, J=13.1,
2.1 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.87
(dd, J=8.8, 2.2 Hz, 1H), 8.37 (d, J=2.7 Hz, 1H), 8.52 (dd, J=2.4,
1.5 Hz, 1H), 9.04 (d, J=1.5 Hz, 1H), 11.45 (s, 1H), 11.77 (s, 1H);
MS (APCI+) m/z 408 (MH+). Anal. calcd for
C.sub.21H.sub.21N.sub.5O.sub.4: C, 61.91; H, 5.20; N, 17.19. Found:
C, 61.81; H, 5.13; N, 17.10.
Example 21
[0165] Step 1.
2-(2,6-Dimethyl-morpholin-4-yl)-5-(3-methoxy-pyrazin-2-yl)-benzaldehyde.
2-(2,6-dimethyl-morpholin-4-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborola-
n-2-yl)-benzaldehyde (Example 18, step 2) (0.250 gram, 0.72 mmol),
2-chloro-3-methoxypyrazine (0.095 gram, 0.66 mmol), sodium
carbonate (0.350 gram, 3.3 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2
(0.014 gram, 0.02 mmol) were suspended in a 1:1 mixture of
CH.sub.3CN/H.sub.2O. The reaction mixture was then purged with
Nitrogen and heated at 95.degree. C. overnight. Upon completion the
reaction was partitioned between H.sub.2O and ethyl acetate and the
aqueous layer was extracted twice with ethyl acetate. The combined
extracts were dried over MgSO.sub.4, filtered and concentrated. The
crude product was purified by column chromatography eluting with
15-45% ethyl acetate in hexanes to obtain 0.127 gram of the desired
product. 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.24 (d, J=6.3
Hz, 6H), 2.70 (m, 2H), 3.16 (m, 2H), 3.94 (m, 2H), 4.06 (s, 3H),
7.15 (d, J=8.5 Hz, 1H), 8.05 (d, J=2.7 Hz, 1H), 8.22 (d, J=2.7 Hz,
1H), 8.27 (dd, J=8.5, 2.2 Hz, 1H), 8.57 (d, J=2.2 Hz, 1H), 10.28
(s, 1H); MS (APCI+) m/z 328 (MH+).
[0166] Step 2. Compound 21: A stirring slurry of
2-(2,6-Dimethyl-morpholin-4-yl)-5-(3-methoxy-pyrazin-2-yl)-benzaldehyde
(0.125 gram, 0.38 mmol) in nBuOH (4 mL) was treated with barbituric
acid (0.051 gram, 0.40 mmol). The reaction was refluxed overnight,
cooled to room temperature and concentrated. Triturated with MeOH
and the precipitate was filtered and dried under vacuum to afford
0.071 gram of desired product. 1H NMR (400 MHz, DMSO-d6) .delta.
ppm 0.90 (d, J=6.3 Hz, 3H), 1.13 (d, J=6.1 Hz, 3H), 2.84 (m, 1H),
2.91 (d, J=15.1 Hz, 1H), 3.38 (d, J=14.9 Hz, 1H), 3.52 (dd, J=8.4,
6.5 Hz, 1H), 3.60 (m, 1H), 3.73 (d, J=8.8 Hz, 1H), 3.94 (s, 3H),
4.13 (d, J=13.7 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 7.89
(d, J=8.1 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 8.16 (d, J=2.7 Hz, 1H),
11.42 (s, 1H), 11.74 (s, 1H); MS (APCI+) m/z 438 (MH+). Anal. calcd
for C.sub.22H.sub.23N.sub.5O.sub.5.2.13H.sub.2O: C, 55.93; H, 5.77;
N, 14.72. Found: C, 55.93; H, 4.88; N, 14.14.
Example 22
[0167] Step 1:
5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde.
5-Bromo-2,3,4-trifluoro-benzaldehyde (10 g, 41.8 mmol) was
dissolved in dry acetonitrile (70 mL). Triethylamine (6.4 mL, 46.0
mmol) was added, followed by trans-2,6-dimethylmorpholine (BASF,
5.3 g, 46 mmol). The mixture was refluxed for 24 hours, then cooled
to room temperature, and treated with 1N HCl (58 mL). The
acetonitrile was removed by rotoevaporation and the resulting
solids were filtered, washed with water then dissolved in THF (100
mL). The solution was dried over MgSO.sub.4 and concentrated to a
yellow oil. Hexanes were added and the mixture was re-concentrated
to give 12.66 g of a yellow powder. 1H NMR (400 MHz, CHLOROFORM-d)
d ppm 1.26 (d, J=6.4 Hz, 6H), 2.92 (m, 2H), 3.28 (d, J=111.7 Hz,
2H), 4.15 (m, 2H), 7.78 (dd, J=7.2, 2.3 Hz, 2H), 10.32 (s, 4H).
[0168] Step 2:
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolan-2-yl)-benzaldehyde. A solution of
5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde
(11.6 g, 34.9 mmol) and bis-(pinacolato)diboron (9.3 g, 36.7 mmol)
in anhydrous 2-methyl THF (120 mL) was treated with potassium
acetate (10 g, 105 mmol) and degassed with argon for 25 minutes.
The catalyst Pd(PCy.sub.3).sub.2Cl.sub.2 (1 g, 1.4 mmol) was then
added to the reaction mixture and heated to 80.degree. C.
overnight. The reaction was cooled to room temperature and the
solids were filtered and washed with THF. The combined filtrate
washings were concentrated and dissolved in warm methanol and
cooled in the refrigerator overnight. The solids that formed were
filtered, washed with cold methanol, and dried to give 4.2 g of a
yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.24 (d, J=6.4
Hz, 6H), 1.1 (s, 12H), 2.95 (m, 2H), 3.35 (m, 2H), 4.16 (m, 2H),
7.94 (dd, J=6.2, 2.0 Hz, 1H), 10.21 (s, 1H).
[0169] Step 3:
5-(5-Amino-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-ben-
zaldehyde. To a suspension of
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolan-2-yl)-benzaldehyde (0.500 g, 1.3 mmol) and cesium
carbonate (1.2 g, 3.6 mmol) in previously degassed
toluene/IPA/water (4/4/1) mixture (2.5 mL) was added
5-bromo-pyrazin-2-ylamine (Maybridge, 0.208 g, 1.2 mmol) under
nitrogen. Tetrakis(triphenylphosphine)palladium-(0) (0.055 g, 0.05
mmol) was added at room temperature and the reaction was heated at
85.degree. C. for 3.5 hrs. The mixture was cooled to room
temperature, diluted with EtOAc and water then neutralized. The
phases were separated and the aqueous phase was re-extracted with
EtOAc (.times.2). The combined organic layers were dried over
MgSO.sub.4 and concentrated. Purified by column chromatography
eluting with ethyl acetate in hexanes (10-60%) to obtain 150 mgs of
product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz,
6H), 2.97 (m, 2H), 3.34 (m, 2H), 4.18 (m, 2H), 4.78 (s, 2H), 8.08
(d, J=1.6 Hz, 1H), 8.19 (dd, J=8.4, 2.1 Hz, 1H), 8.44 (m, 1H),
10.37 (s, 1H); MS (APCI+) m/z 349 (MH+).
[0170] Step 4: Compound 22. A stirring slurry of
5-(5-Amino-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-ben-
zaldehyde (0.148 g, 0.425 mmol) in nBuOH was treated with
barbituric acid (0.057 g, 0.446 mmol). The reaction mixture was
stirred at room temperature for 30 minutes then heated to reflux
overnight. Upon cooling a solid precipitate resulted which was
filtered. Further analysis indicated that neither the filtrate nor
the solid material was pure. The solids and the filtrate were
recombined and concentrated then purified by column chromatography
eluting with MeOH in DCM (1-12%) to give 112 mgs as an enriched
mixture of isomers. 1H NMR (400 MHz, DMSO-d6) Major isomer: d ppm
0.84 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.0 Hz, 3H), 2.84 (d, J=14.4 Hz,
1H), 2.96 (m, 1H), 3.44 (d, J=14.6 Hz, 1H), 3.59 (dd, J=8.6, 6.2
Hz, 1H), 3.71 (m, 1H), 3.77 (d, J=8.8 Hz, 1H), 3.99 (dd, J=13.7,
2.4 Hz, 1H), 6.50 (s, 2H), 7.20 (d, J=8.2 Hz, 1H), 7.88 (d, J=1.6
Hz, 1H), 8.16 (dd, J=2.4, 1.5 Hz, 1H), 11.40 (s, 1H), 11.74 (s,
1H); MS (APCI+) m/z 459 (MH+).
Example 23
[0171] Step 1:
5-(5-Bromo-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-ben-
zaldehyde. To a suspension of
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolan-2-yl)-benzaldehyde (Example 22, step 2) (1.5 g, 3.9
mmol) and sodium carbonate (1.1 g, 11 mmol) in previously degassed
acetonitrile/water (1/1) mixture (4 mL) was added
2-bromo-5-iodo-pyrazine (1.0 g, 3.5 mmol) under nitrogen.
Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.099 g, 0.14
mmol) was added at room temperature and the reaction was heated
overnight at 55.degree. C. The mixture was cooled to room
temperature, diluted with EtOAc and water then neutralized. The
phases were separated and the aqueous phase was re-extracted with
EtOAc (.times.2). The combined organic layers were dried over
MgSO.sub.4 and concentrated. Purified by column chromatography
eluting with ethyl acetate in hexanes (5-40%) to obtain 931 mgs of
product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz,
6H), 3.02 (m, 2H), 3.40 (m, 2H), 4.19 (m, 2H), 8.28 (dd, J=8.2, 2.1
Hz, 1H), 8.74 (d, J=1.4 Hz, 1H), 8.78 (m, 1H), 10.29 (s, 1H); MS
(APCI+) m/z 412, 414 (MH+).
[0172] Step 2:
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-pyrazin-2-yl)-be-
nzaldehyde. To a suspension of
5-(5-Bromo-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-ben-
zaldehyde (0.375 g, 0.91 mmol) and sodium carbonate (0.29 g, 2.7
mmol) in previously degassed acetonitrile/water (1/1) mixture (4
mL) was added methyl boronic acid (0.11 g, 1.8 mmol) under
nitrogen. Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.026
g, 0.036 mmol) was added at room temperature and the reaction was
heated for 5 hours at 85.degree. C. Analysis indicated that
starting material had not fully been consumed so an additional 1
equivalent of methyl boronic acid was added to the reaction and
stirred overnight at 85.degree. C. The mixture was cooled to room
temperature, diluted with EtOAc and water then neutralized. The
phases were separated and the aqueous phase was re-extracted with
EtOAc (.times.2). The combined organic layers were dried over
MgSO.sub.4 and concentrated. Purified by column chromatography
eluting with ethyl acetate in hexanes (5-35%) to obtain 132 mgs of
product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz,
6H), 2.61 (s, 3H), 3.00 (m, 2H), 3.38 (m, 2H), 4.19 (m, 2H), 8.26
(dd, J=8.2, 2.1 Hz, 1H), 8.54 (d, J=1.2 Hz, 1H), 8.89 (dd, J=2.3,
1.6 Hz, 1H), 10.33 (s, 1H); MS (APCI+) m/z 348 (MH+).
[0173] Step 3: Compound 23. A stirring solution of
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-pyrazin-2-yl)-be-
nzaldehyde (0.185 g, 0.533 mmol) in acetic acid, glacial (4 mL) was
treated with barbituric acid (0.072 g, 0.559 mmol). The reaction
mixture was stirred for 1 hour at 110.degree. C. then slowly cooled
to room temperature. Reaction mixture was azeotroped and
concentrated using toluene. Purified by column chromatography
eluting with ethyl acetate in hexanes (25-80%) to obtain 99 mgs of
product. 1H NMR (400 MHz, DMSO-d6) d ppm 0.85 (d, J=6.4 Hz, 3H),
1.08 (d, J=6.2 Hz, 3H), 2.45 (s, 3H), 2.86 (d, J=14.4 Hz, 1H), 3.01
(m, 1H), 3.51 (d, J=14.4 Hz, 1H), 3.60 (dd, J=8.8, 6.4 Hz, 1H),
3.72 (m, 1H), 3.81 (d, J=8.8 Hz, 1H), 4.03 (dd, J=13.5, 2.0 Hz,
1H), 7.36 (d, J=7.2 Hz, 1H), 8.53 (d, J=1.2 Hz, 1H), 8.75 (m, 1H),
11.44 (s, 1H), 11.77 (s, 1H); MS (APCI+) m/z 458 (MH+). Anal. calcd
for C.sub.22H.sub.21F.sub.2N.sub.5O.sub.4.0.14H.sub.2O: C, 57.45;
H, 4.66; N, 15.23. Found: C, 57.14; H, 4.55; N, 14.83.
Example 24
[0174] Compound 24. A stirring slurry of
5-(5-Bromo-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-ben-
zaldehyde (Example 23, step 1) (0.274 g, 0.665 mmol) in nBuOH was
treated with barbituric acid (0.089 g, 0.698 mmol). The reaction
mixture was stirred at room temperature for 30 minutes then heated
to 105.degree. C. overnight. The dark red solution was concentrated
in vacuo to a reddish oil which was azeotroped with toluene to give
an enriched mixture of isomers. 1H NMR (400 MHz, DMSO-d6) Major
isomer: d ppm 0.85 (d, J=6.4 Hz, 3H), 1.08 (d, J=6.2 Hz, 3H), 2.86
(d, J=14.6 Hz, 1H), 3.02 (m, 1H), 3.53 (d, J=14.6 Hz, 1H), 3.60
(dd, J=8.7, 6.5 Hz, 1H), 3.72 (m, 1H), 3.83 (d, J=8.8 Hz, 1H), 4.04
(dd, J=13.6, 1.9 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 8.71 (t, J=1.7
Hz, 1H), 8.82 (d, J=1.6 Hz, 1H), 11.45 (s, 1H), 11.78 (s, 1H); MS
(APCI+) m/z 522, 524 (MH+).
Example 25
[0175] Step 1. 2-iodo-5-methoxy-pyrazine. Sodium methoxide (25% wt.
in MeOH, 0.321 mL, 1.4 mmol) was combined with N-methylpyrrolidine
(NMP) (1.28 mL) and warmed to 60.degree. C. 2-bromo-5-iodo-pyrazine
(0.40 g, 1.4 mmol) was added. The suspension was stirred at
60.degree. C. for 1 hour. Combined with an additional 100 mg
previously run reaction prior to work-up. Reaction mixture was
partitioned between H.sub.2O and ethyl acetate and the aqueous
layer was extracted (3.times.) with ethyl acetate. The combined
extracts were dried over MgSO.sub.4, filtered and concentrated to
give a brown oil which solidified to obtain 406 mgs of crude
material. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 3.90 (s, 3H), 8.03
(d, J=1.4 Hz, 1H), 8.29 (d, J=1.4 Hz, 1H); MS (APCI+, m/z) 237.
[0176] Step 2.
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methoxy-pyrazin-2-yl)-b-
enzaldehyde. To a suspension of
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolan-2-yl)-benzaldehyde (0.78 g, 2.0 mmol) and sodium
carbonate (0.54 g, 5.1 mmol) in previously degassed
acetonitrile/water (3 mL/3 mL) mixture was added
2-iodo-5-methoxy-pyrazine (0.40 g, 1.69 mmol) under nitrogen.
Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.048 g, 0.068
mmol) was added at room temperature and the reaction was heated
overnight at 60.degree. C. The mixture was cooled to room
temperature, diluted with EtOAc and water. The phases were
separated and the aqueous phase was re-extracted with EtOAc
(3.times.). The combined extracts were dried over MgSO.sub.4 and
purified by column chromatography 0-5% EA/Hex to obtain 386 mgs of
solid. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H),
2.98 (m, 2H), 3.35 (m, 2H), 3.99 (s, 3H), 4.18 (m, 2H), 8.22 (dd,
J=8.2, 2.1 Hz, 1H), 8.29 (d, J=1.4 Hz, 1H), 8.53 (dd, J=2.2, 1.5
Hz, 1H), 10.35 (s, 1H); MS (APCI+, m/z) 364.
[0177] Step 3. Compound 25. A stirring solution of
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methoxy-pyrazin-2-yl)-b-
enzaldehyde (0.386 g, 1.06 mmol) was dissolved in acetic acid (3
mL):H.sub.2O (2 mL) treated with barbituric acid (0.143 g, 1.12
mmol). The reaction mixture was stirred for 1 hour at 110.degree.
C. then slowly cooled to room temperature. The precipitate was
filtered to obtain 388 mgs of a light brown solid. 1H NMR (400 MHz,
DMSO-d6) d ppm 0.85 (d, J=6.4 Hz, 3H), 1.08 (d, J=6.2 Hz, 3H), 2.86
(d, J=14.2 Hz, 1H), 2.99 (m, 1H), 3.48 (d, J=113.6 Hz, 1H), 3.60
(dd, J=8.8, 6.4 Hz, 1H), 3.71 (m, 1H), 3.80 (d, J=8.8 Hz, 1H), 3.89
(s, 3H), 4.01 (dd, J=13.5, 2.2 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H),
8.31 (d, J=1.6 Hz, 1H), 8.44 (dd, J=2.2, 1.5 Hz, 1H), 11.42 (s,
1H), 11.76 (s, 1H); MS (APCI+, m/z) 474. Anal. calcd for
C.sub.22H.sub.21F.sub.2N.sub.5O.sub.5.0.08CH.sub.3CO.sub.2H: C,
55.65; H, 4.49; N, 14.64. Found: C, 55.49; H, 4.22; N, 14.25.
Example 26
[0178] Step 1. 2-ethoxy-5-iodo-pyrazine. Sodium ethoxide (21% wt.,
0.524 mL, 1.4 mmol) was combined with NMP (2 mL) and warmed to
60.degree. C. 2-bromo-5-iodo-pyrazine (0.40 g, 1.4 mmol) was then
added. The suspension was stirred at 60.degree. C. for 1 hour.
Reaction mixture was partitioned between H.sub.2O and ethyl acetate
and the aqueous layer was extracted (3.times.) with ethyl acetate.
The combined extracts were dried over MgSO.sub.4, filtered and
concentrated to give a brown oil (362 mgs). 1H NMR (400 MHz,
CHLOROFORM-d) d ppm 1.36 (t, J=7.1 Hz, 3H), 4.31 (q, J=7.0 Hz, 2H),
8.00 (d, J=1.6 Hz, 1H), 8.26 (d, J=1.6 Hz, 1H); MS (APCI+, m/z)
251.
[0179] Step 2.
2-(2,6-Dimethyl-morpholin-4-yl)-5-(5-ethoxy-pyrazin-2-yl)-3,4-difluoro-be-
nzaldehyde. To a suspension of
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,-
2]dioxaborolan-2-yl)-benzaldehyde (0.66 g, 1.7 mmol) and sodium
carbonate (0.61 g, 5.8 mmol) in previously degassed
acetonitrile/water (3 mL/3 mL) mixture was added
2-ethoxy-5-iodo-pyrazine (0.362 g, 1.45 mmol) under nitrogen.
Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.041 g, 0.058
mmol) was added at room temperature and the reaction was heated
overnight at 60.degree. C. The mixture was cooled to room
temperature, diluted with EtOAc and water. The phases were
separated and the aqueous phase was re-extracted with EtOAc
(3.times.). The combined extracts were dried over MgSO.sub.4 and
purified by column chromatography 0-5% EA/Hex to obtain 313 mgs of
solid. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H),
1.41 (t, J=7.1 Hz, 3H), 2.98 (m, 2H), 3.36 (m, 2H), 4.18 (m, 2H),
4.41 (q, J=7.1 Hz, 2H), 8.22 (dd, J=8.2, 2.1 Hz, 1H), 8.26 (d,
J=1.4 Hz, 1H), 8.51 (dd, J=2.3, 1.6 Hz, 1H), 10.36 (s, 1H); MS
(APCI+, m/z) 378.
[0180] Step 3. Compound 26. A stirring solution of
2-(2,6-Dimethyl-morpholin-4-yl)-5-(5-ethoxy-pyrazin-2-yl)-3,4-difluoro-be-
nzaldehyde (0.312 g, 0.829 mmol) dissolved in acetic acid (2.48
mL):H.sub.2O (1.65 mL) was treated with barbituric acid (0.112 g,
0.871 mmol). The reaction mixture was stirred for 1 hour at
110.degree. C. then slowly cooled to room temperature. The reaction
mixture was azeotroped, concentrated using toluene. The mixture was
purified by column chromatography eluting with ethyl acetate in
hexanes to obtain 320 mgs of product. 1H NMR (400 MHz, DMSO-d6) d
ppm 0.85 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.0 Hz, 3H), 1.31 (t, J=7.1
Hz, 3H), 2.86 (d, J=14.4 Hz, 1H), 2.99 (m, 1H), 3.48 (d, J=14.2 Hz,
1H), 3.60 (dd, J=8.7, 6.3 Hz, 1H), 3.71 (m, 1H), 3.79 (d, J=8.8 Hz,
1H), 4.01 (dd, J=13.5, 2.2 Hz, 1H), 4.33 (q, J=7.0 Hz, 2H), 7.28
(d, J=8.0 Hz, 1H), 8.28 (d, J=1.4 Hz, 1H), 8.42 (m, 1H), 11.42 (s,
1H), 11.76 (s, 1H); MS (APCI+, m/z) 488. Anal. calcd for
C.sub.22H.sub.21F.sub.2N.sub.5O.sub.5.0.11CH.sub.3CO.sub.2H: C,
56.45; H, 4.78; N, 14.18. Found: C, 56.21; H, 4.68; N, 13.79.
Example 27
[0181] In this example, the in vitro antibacterial activity of
selected compounds was determined against S. aureus and H.
influenzae. Except for clarifying or modifying statements, MIC
testing followed procedures recommended by the NCCLS.sup.1-2 or
followed the descriptions cited below.
[0182] Bacterial Cultures At least the following organisms are
included in the screen: Staphylococcus aureus SA-1 (UC-76) and H.
influenzae HI-3542. Incubations were at 35.degree. C. Stock
bacterial cultures were maintained on Tryptic Soy Agar containing
5% Sheep Blood (BD, Becton Dickinson Microbiology Systems,
Cockeysville, Md.), anaerobes were maintained on Anaerobic Blood
Agar plates--CDC Formulation (BD), and fastidious organisms were
maintained on Chocolate Agar II Plates (BD). Specific conditions of
handling are listed below.
[0183] Permanent Stock Culture Collection Stock cultures are stored
as frozen suspensions at -70.degree. C. Most cultures are routinely
suspended in 10% skim milk (BD) prior to snap freezing in dry
ice/ethanol and then placed in a -70.degree. C. freezer.
Haemophilus were suspended in inactivated horse serum (Colorado
Serum Company, Denver, Colo.) containing 7.5% glucose prior to snap
freezing.
[0184] Maintenance of Stock Cultures Most cultures were maintained
on Tryptic Soy Agar containing 5% Sheep Blood at room temperature
(20.degree. C.). Each culture was recovered from frozen and
transferred an additional time before MIC testing. Fresh plates
were inoculated the day before testing, incubated overnight, and
checked to confirm purity and identity.
[0185] Haemophilus was maintained on Chocolate Agar II Plates at
room temperature in a candle jar providing a 35% CO.sub.2
atmosphere.
[0186] Confirming Identity of Cultures Culture identifications were
confirmed by standard microbiological methods.sup.3. Cultures were
streaked onto appropriate agar plates for visualization of purity,
expected colony morphology, and hemolytic patterns. Gram stains
were also utilized.
[0187] The identities of recent isolates used in this test were
confirmed using a MicroScan WalkAway 40 SI Instrument (Dade
Behring, West Sacramento, Calif.). This device utilizes an
automated incubator, reader, and computer to assess for
identification purposes the biochemical reactions carried out by
each organism. Using this machine, organism identification
(confirmation) and an initial antibiogram was generated for each
strain.
[0188] Standardized Organism Inocula Frozen stock cultures were
used as the initial source of organisms for performing microbroth
dilution MIC testing. Stock cultures were passed on their standard
growth medium for at least 1 growth cycle (18 24 hours) prior to
their use.
[0189] Most bacteria, unless otherwise noted, were prepared
directly from agar plates in 10 mL aliquots of the appropriate
broth medium. Bacterial cultures were adjusted to the opacity of a
0.5 McFarland Standard (optical density value of 0.28-0.33 on a
Perkin-Elmer Lambda EZ150 Spectrophotometer Wellesley, Mass., set
at a wavelength of 600 nm)). The adjusted cultures were diluted 400
fold (0.25 mL inoculum+100 mL broth) in growth media to produce a
starting suspension of approximately 5.times.10.sub.5 colony
forming units (CFU)/mL. Unless otherwise noted, bacterial strains
were tested in cation adjusted Mueller Hinton Broth (CAMHB).
[0190] Haemophilus influenzae strains were grown on Chocolate Agar
II Plates and tested in Haemophilus Test Medium (Remel, Lenexa,
Kans.).
[0191] Test Compound ("Drug") Preparation Compounds were
solubilized in DMSO. Drug stock solutions were prepared on the day
of testing. Drugs were weight corrected for assay content where
necessary.
[0192] Drug Dilution Tray Preparation Microbroth dilution stock
plates were prepared in two dilution series, 64 to 0.06 .mu.g
drug/mL and 0.25 to 0.00025 .mu.g drug/mL. For the high
concentration series, 200 .mu.L of stock solution (2 mg/mL) was
added to duplicate rows of a 96-well microtiter plate. This was
used as the first well in the dilution series. Serial two-fold
decremental dilutions were made using a BioMek FX robot (Beckman
Coulter Inc., Fullerton, Calif.) with 10 of the remaining 11 wells,
each of which contained 100 .mu.L of the appropriate
solvent/diluent. Row 12 contained solvent/diluent only and served
as the control. For tube one of the low concentration series, 200
.mu.L of an 8 .mu.g/mL stock was added to duplicate rows of a
96-well plate. Serial two-fold dilutions were made as described
above.
[0193] Daughter plates were spotted (3.2 .mu.L/well) from the stock
plates listed above using the BioMek FX robot and were either used
immediately or frozen at -70.degree. C. until use.
[0194] Plate Inoculation Aerobic organisms were inoculated (100
.mu.L volumes) into the thawed plates using the BioMek FX robot.
The inoculated plates were placed in stacks of no more than 5 and
covered with an empty plate. These plates were incubated 16 to 24
hours in ambient atmosphere according to CLSI guidelines.sup.2.
[0195] Reading the Test After inoculation and incubation, the
degree of bacterial growth was estimated visually with the aid of a
Test Reading Mirror (Dynex Technologies 220 16) in a darkened room
with a single light shining directly through the top of the
microbroth tray. The MIC was the lowest concentration of drug that
prevented macroscopically visible growth under the conditions of
the test. Testing was performed in duplicate. When the MIC values
in duplicate tests varied by 1 well (2 fold), the lower values were
reported. If the MICs varied by 2 dilutions, the middle value was
reported. Greater than this 4 fold variance called for the test to
be repeated, after which a similar determination was applied to all
values.
REFERENCES
[0196] 1. National Committee for Clinical Laboratory Standards.
Performance Standards for Antimicrobial Susceptibility Testing;
Fourteenth Informational Supplement. NCCLS document M100-S14 {ISBN
1-56238-516-X}, NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pa.
19087-1898 USA, 2004. [0197] 2. National Committee for Clinical
Laboratory Standards. Methods for Dilution Antimicrobial Tests for
Bacteria That Grow Aerobically; Approved Standard-Sixth Edition.
NCCLS document M7-A6 {ISBN 1-56238-486-4}, NCCLS, 940 West Valley
Road, Suite 1400, Wayne, Pa. 19087-1898 USA, 2003. [0198] 3. Murray
P R, Baron E J, Jorgensen J H, Pfaller M A, Yolken R H. Manual of
Clinical Microbiology, Eighth Edition. ASM Press {ISBN
1-55581-255-4}, American Society for Microbiology, 1752 N Street
NW, Washington, D.C. 20036-2904 USA, 2003.
[0199] Using this protocol, the following results were
generated:
TABLE-US-00002 TABLE 2 Minimum Inhibitory Concentration (.mu.g/ml)
Compound/ Example S. aureus H. influenzae No. UC76 3542 1 0.25 1 2
0.125 0.5 3 32 >64 4 0.25 0.5 5 0.5 1 6 0.5 0.25 7 ND* ND 8 ND
ND 9 ND ND 10 ND ND 11 ND ND 12 ND ND 13 ND ND 14 ND ND 15 1 4 16
>64 >64 17 >64 >64 18 >64 >64 19 2 2 20 4 2 21 16
32 22 0.5 0.5 23 0.125 1 24 ND ND 25 0.125 0.5 26 0.25 1 *ND--not
determined
[0200] Relative stereochemistry for racemic compounds was assigned
based on the R or S designation of the structures as set forth in
Table 1.
[0201] As used herein, reference to "a" or "an" means "one or
more." Throughout, the plural and singular should be treated as
interchangeable, other than the indication of number.
[0202] As will be understood by one skilled in the art, for any and
all purposes, particularly in terms of providing a written
description, all ranges disclosed herein also encompass any and all
possible subranges and combinations of subranges thereof as well as
the individual values making up the range, particularly integer
values. Any listed range can be easily recognized as sufficiently
describing and enabling the same range being broken down into at
least equal halves, thirds, quarters, fifths, tenths, etc. As a
non-limiting example, each range discussed herein can be readily
broken down into a lower third, middle third and upper third, etc.
For example, the range C.sub.1-C.sub.6, includes the subranges
C.sub.2-C.sub.6, C.sub.3-C.sub.6, C.sub.3-C.sub.5, C.sub.4-C.sub.6,
etc., as well as C.sub.1 (methl), C.sub.2 (ethyl), C.sub.3
(propyl), C.sub.4 (butyl), C.sub.5 (pentyl) and C.sub.6 (hexyl)
individually. As will also be understood by one skilled in the art,
all language such as "up to," "at least," "greater than," "less
than," "more than," "or more" and the like include the number
recited and refer to ranges which can be subsequently broken down
into subranges as discussed above. In the same manner, all ratios
disclosed herein also include all subratios falling within the
broader ratio.
[0203] One skilled in the art will also readily recognize that
where members are grouped together in a common manner, such as in a
Markush group, the present invention encompasses not only the
entire group listed as a whole, but each member of the group
individually and all possible subgroups of the main group.
Additionally, for all purposes, the present invention encompasses
not only the main group, but also the main group absent one or more
of the group members. The present invention also envisages the
explicit exclusion of one or more of any of the group members in
the claimed invention.
[0204] As will be understood by the skilled artisan, all numbers,
including those expressing quantities of ingredients, properties
such as molecular weight, reaction conditions, and so forth, are
approximations and understood as being modified in all instances by
the term "about." These values can vary depending upon the desired
properties sought to be obtained by those skilled in the art
utilizing the present teachings of the present invention. It is
also understood that such values inherently contain variability
necessarily resulting from the standard deviations found in their
respective testing measurements.
[0205] All references disclosed herein are specifically
incorporated herein by reference thereto.
[0206] While specific embodiments have been illustrated and
described, it should be understood that these embodiments do not
limit the scope of the invention and that changes and modifications
can be made in accordance with ordinary skill in the art without
departing from the invention in its broader aspects as defined in
the following claims. Reference to a "step" in the application is
used for convenience purposes only and does not categorize, define
or limit the invention as set forth herein.
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