U.S. patent application number 15/247991 was filed with the patent office on 2016-12-15 for 7-oxo-thiazolopyridine carbonic acid derivatives and their use in the treatment, amelioration or prevention of a viral disease.
The applicant listed for this patent is European Molecular Biology Laboratory, F. Hoffmann-La Roche AG, Savira Pharmaceuticals GmbH. Invention is credited to Helmut BUSCHMANN, Dirk CLASSEN-HOUBEN, Stephen CUSACK, Bruno GIETHLEN, Norbert HANDLER, Thierry LANGER, Christophe MORICE, Thibault SAUVAITRE, Celine SIMON, Mark SMITH, Sung-Sau SO, Oliver SZOLAR, Andrea WOLKERSTORFER.
Application Number | 20160362423 15/247991 |
Document ID | / |
Family ID | 48669865 |
Filed Date | 2016-12-15 |
United States Patent
Application |
20160362423 |
Kind Code |
A1 |
WOLKERSTORFER; Andrea ; et
al. |
December 15, 2016 |
7-OXO-THIAZOLOPYRIDINE CARBONIC ACID DERIVATIVES AND THEIR USE IN
THE TREATMENT, AMELIORATION OR PREVENTION OF A VIRAL DISEASE
Abstract
The present invention relates to a compound having the general
formula (A), optionally in the form of a pharmaceutically
acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug,
tautomer, racemate, enantiomer, or diastereomer or mixture thereof,
##STR00001## which are useful in treating, ameloriating or
preventing a viral disease. Furthermore, specific combination
therapies are disclosed.
Inventors: |
WOLKERSTORFER; Andrea;
(Vienna, AT) ; SZOLAR; Oliver; (Vienna, AT)
; HANDLER; Norbert; (Vienna, AT) ; CUSACK;
Stephen; (Seyssinet, FR) ; SAUVAITRE; Thibault;
(Frankfurt am Main, DE) ; SIMON; Celine;
(Illkirch, FR) ; MORICE; Christophe; (Widensolen,
FR) ; GIETHLEN; Bruno; (Altorf, FR) ; LANGER;
Thierry; (Oberschaeffolsheim, FR) ; SMITH; Mark;
(Jersey City, NJ) ; SO; Sung-Sau; (Verona, NJ)
; CLASSEN-HOUBEN; Dirk; (Kramsach, AT) ;
BUSCHMANN; Helmut; (Aachen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Savira Pharmaceuticals GmbH
F. Hoffmann-La Roche AG
European Molecular Biology Laboratory |
Vienna
Basel
Heidelberg |
|
AT
CH
DE |
|
|
Family ID: |
48669865 |
Appl. No.: |
15/247991 |
Filed: |
August 26, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13900964 |
May 23, 2013 |
9434745 |
|
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15247991 |
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61650713 |
May 23, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5377 20130101;
A61K 45/06 20130101; C07D 487/04 20130101; A61P 31/22 20180101;
A61K 31/4545 20130101; A61K 31/519 20130101; A61P 31/16 20180101;
C07D 513/04 20130101; A61K 31/496 20130101; A61P 31/18 20180101;
A61P 31/12 20180101; A61K 31/437 20130101 |
International
Class: |
C07D 513/04 20060101
C07D513/04; A61K 31/5377 20060101 A61K031/5377; A61K 31/4545
20060101 A61K031/4545; A61K 31/496 20060101 A61K031/496; A61K
31/437 20060101 A61K031/437; A61K 45/06 20060101 A61K045/06 |
Claims
1. A compound having formula (A) ##STR00232## wherein R*
--X.sup.1--R.sup.1; X.sup.1 is NR.sup.4; X.sup.2 is O, S or
NR.sup.4; X.sup.3 is O or S; X.sup.4 is O or S; R.sup.1 is
--SO.sub.2--R.sup.4; R.sup.2 is a hydrocarbon group which contains
from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms
selected from O, N and S and which contains at least one ring,
wherein the hydrocarbon group can be optionally substituted;
R.sup.3 is --H, -(optionally substituted C.sub.1-6 alkyl),
-(optionally substituted C.sub.3-7 cycloalkyl), -(optionally
substituted aryl), or --C.sub.1-4 alkyl-(optionally substituted
aryl); or if X.sup.2 is NR.sup.4, then R.sup.3 can also be --OH;
R.sup.4 is --H, -(optionally substituted C.sub.1-6 alkyl),
-(optionally substituted C.sub.3-7 cycloalkyl), -(optionally
substituted aryl), --C.sub.1-4 alkyl-(optionally substituted
C.sub.3-7 cycloalkyl), or --C.sub.1-4 alkyl-(optionally substituted
aryl); or R.sup.4 and R.sup.1 can be joined together to form a 5-
to 7-membered ring, which can optionally contain O, S or further N;
or if X.sup.2 is NR.sup.4, then R.sup.4 and R.sup.3 can be joined
together to form a 5- to 7-membered ring, which can optionally
contain O, S or further N; R.sup.5 is --H, -(optionally substituted
C.sub.1-6 alkyl), -(optionally substituted C.sub.3-7 cycloalkyl),
-(optionally substituted aryl), --C.sub.1-4 alkyl-(optionally
substituted C.sub.3-7 cycloalkyl), or --C.sub.1-4 alkyl-(optionally
substituted aryl); and R.sup.6 is --H or --C.sub.1-6 alkyl; wherein
the optional substituent of the alkyl group is selected from the
group consisting of halogen, --CN, --NR.sup.6R.sup.6, --OH, and
--O--C.sub.1-6 alkyl; wherein the optional substituent of the
cycloalkyl group, the aryl group or the hydrocarbon group is
selected from the group consisting of --C.sub.1-6 alkyl, halogen,
--CF.sub.3, --CN, --X.sup.1--R.sup.5 and --C.sub.1-4 alkyl-aryl; or
a pharmaceutically acceptable salt, solvate, polymorph, cocrystal,
prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture
thereof; wherein, the prodrug is a compound where X.sup.2 is O or
S, and R.sup.3 is one of the following groups: ##STR00233## wherein
R.sup.6 is the same or different, wherein R.sup.9 is aryl or
C.sub.3-7 cycloalkyl, p is 2-8.
2. The compound according to claim 1, wherein X.sup.2 is O.
3. The compound according to claim 1, wherein X.sup.3 is O.
4. The compound according to claim 1, wherein X.sup.4 is O.
5. The compound according to claim 1, wherein R.sup.3 is --H,
--C.sub.1-6 alkyl or Bz.
6. The compound according to claim 1, wherein R.sup.4 is --H,
-(optionally substituted C.sub.1-6 alkyl), -(optionally substituted
aryl), or --C.sub.1-4 alkyl-(optionally substituted aryl).
7. The compound according to claim 1, wherein R.sup.2 is selected
from the group consisting of ##STR00234## wherein X is absent,
CH.sub.2, NH, C(O)NH, S or O; Y is CH.sub.2; or X and Y can be
joined together to form an annulated, carbo- or heterocylic 3- to
8-membered ring which can be saturated or unsaturated; and R is
independently selected from H, --C.sub.1-6 alkyl, halogen, --CN,
--OH, and --O--C.sub.1-6 alkyl.
8. The compound according to claim 1, wherein R.sup.2 is
##STR00235##
9. The compound according to claim 1, wherein R.sup.2 is
##STR00236##
10. The compound according to claim 1, wherein R.sup.2 is
##STR00237##
11. The compound according to claim 10, wherein X is absent and Y
is CH.sub.2.
12. The compound according to claim 1, wherein R is H or
halogen.
13. A pharmaceutical composition comprising: (i) a compound having
formula (A) as defined in claim 1 or a pharmaceutically acceptable
salt, solvate, polymorph, cocrystal, prodrug, tautomer, racemate,
enantiomer, or diastereomer or mixture thereof; and (ii) a
pharmaceutically acceptable excipient.
14. The pharmaceutical composition according to claim 13, further
comprising: i. at least one polymerase inhibitor which is different
from the compound having formula (A); ii. at least one
neuraminidase inhibitor; iii. at least one M2 channel inhibitor;
iv. at least one alpha glucosidase inhibitor; v. at least one
ligand of another influenza target; or vi. at least one medicament
selected from an antibiotics, an anti-inflammatory agent, an
lipoxygenase inhibitor, an EP ligand, an bradykinin ligand and a
cannabinoid ligand.
15. A method of treating or ameliorating influenza, the method
comprising administering to a patient in need thereof an effective
amount of a compound according to claim 1.
16. A method of treating or ameliorating influenza, the method
comprising administering to a patient in need thereof an effective
amount of a pharmaceutical composition according to claim 13.
17. A method of treating or ameliorating influenza, the method
comprising administering to a patient in need thereof an effective
amount of a pharmaceutical composition according to claim 14.
18. A compound selected from: ##STR00238## ##STR00239##
##STR00240## ##STR00241## ##STR00242## or a pharmaceutically
acceptable salt, solvate, polymorph, cocrystal, prodrug, tautomer,
racemate, enantiomer, or diastereomer or mixture thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 13/900,964, filed May 23, 2013 to be issued as U.S. Pat. No.
9,434,745, which claims priority from U.S. Provisional Application
No. 61/650,713, filed May 23, 2012; both of which are incorporated
by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to a compound having the
general formula (A), optionally in the form of a pharmaceutically
acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug,
tautomer, racemate, enantiomer, or diastereomer or mixture
thereof,
##STR00002##
which is useful in treating, ameloriating or preventing a viral
disease. Furthermore, specific combination therapies are
disclosed.
BACKGROUND OF THE INVENTION
[0003] In recent years the serious threat posed by influenza virus
to worldwide public health has been highlighted by, firstly, the
ongoing low level transmission to humans of the highly pathogenic
avian H5N1 strain (63% mortality in infected humans,
http://www.who.int/csr/disease/avian_influenza/en/) and secondly,
the unexpected emergence in 2009 of a novel pandemic strain A/H1N1
that has rapidly spread around the entire world
(http://www.who.int/csr/disease/swineflu/en/). Whilst the new
strain is highly contagious but currently only generally gives mild
illness, the future evolution of this virus is unpredictable. In a
much more serious, but highly plausible scenario, H5N1 could have
been more easily transmissible between humans or the new A/H1N1
could have been more virulent and could have carried the single
point mutation that confers Tamiflu resistance (Neumann et al.,
Nature, 2009 (18; 459(7249) 931-939)); as many seasonal H1N1
strains have recently done (Dharan et al., The Journal of the
American Medical Association, 2009 Mar. 11; 301 (10), 1034-1041;
Moscona et al., The New England Journal of Medicine, 2009 (March 5;
360(10) pp 953-956)). In this case, the delay in generating and
deploying a vaccine (.about.6 months in the relatively favourable
case of A/H1N1 and still not a solved problem for H5N1) could have
been catastrophically costly in human lives and societal
disruption.
[0004] It is widely acknowledged that to bridge the period before a
new vaccine becomes available and to treat severe cases, as well as
to counter the problem of viral resistance, a wider choice of
anti-influenza drugs is required. Development of new anti-influenza
drugs has therefore again become a high priority, having been
largely abandoned by the major pharmaceutical companies once the
anti-neuraminidase drugs became available.
[0005] An excellent starting point for the development of antiviral
medication is structural data of essential viral proteins. Thus,
the crystal structure determination of e.g. the influenza virus
surface antigen neuraminidase (Von Itzstein, M. et al., (1993),
Nature, 363, pp. 418-423) led directly to the development of
neuraminidase inhibitors with anti-viral activity preventing the
release of virus from the cells, however, not the virus production.
These and their derivatives have subsequently developed into the
anti-influenza drugs, zanamivir (Glaxo) and oseltamivir (Roche),
which are currently being stockpiled by many countries as a first
line of defence against an eventual pandemic. However, these
medicaments provide only a reduction in the duration of the
clinical disease. Alternatively, other anti-influenza compounds
such as amantadine and rimantadine target an ion channel protein,
i.e., the M2 protein, in the viral membrane interfering with the
uncoating of the virus inside the cell. However, they have not been
extensively used due to their side effects and the rapid
development of resistant virus mutants (Magden, J. et al., (2005),
Appl. Microbiol. Biotechnol., 66, pp. 612-621). In addition, more
unspecific viral drugs, such as ribavirin, have been shown to work
for treatment of influenza and other virus infections (Eriksson, B.
et al., (1977), Antimicrob. Agents Chemother., 11, pp. 946-951).
However, ribavirin is only approved in a few countries, probably
due to severe side effects (Furuta et al., ANTIMICROBIAL AGENTS AND
CHEMOTHERAPY, 2005, p. 981-986). Clearly, new antiviral compounds
are needed, preferably directed against different targets.
[0006] Influenza virus as well as Thogotovirus belong to the family
of Orthomyxoviridae which, as well as the family of the
Bunyaviridae, including the Hantavirus, Nairovirus,
Orthobunyavirus, and Phlebovirus, are negative stranded RNA
viruses. Their genome is segmented and comes in ribonucleoprotein
particles that include the RNA dependent RNA polymerase which
carries out (i) the initial copying of the single-stranded virion
RNA (vRNA) into viral mRNAs and (ii) the vRNA replication. This
enzyme, a trimeric complex composed of subunits PA, PB1 and PB2, is
central to the life cycle of the virus since it is responsible for
the replication and transcription of viral RNA. In previous work
the atomic structure of two key domains of the polymerase, the mRNA
cap-binding domain in the PB2 subunit (Guilligay et al., Nature
Structural & Molecular Biology 2008; May; 15(5): 500-506) and
the endonuclease-active site in the PA subunit (Dias et al., Nature
2009, 458, 914-918) have been identified and determined. These two
sites are critical for the unique cap-snatching mode of
transcription that is used by influenza virus to generate viral
mRNAs. For the generation of viral mRNA the polymerase makes use of
the so called "cap-snatching" mechanism (Plotch, S. J. et al.,
(1981), Cell, 23, pp. 847-858; Kukkonen, S. K. et al (2005), Arch.
Virol., 150, pp. 533-556; Leahy, M. B. et al, (2005), J. Virol.,
71, pp. 8347-8351; Noah, D. L. et al., (2005), Adv. Virus Res., 65,
pp. 121-145). A 5' cap (also termed an RNA cap, RNA
7-methylguanosine cap or an RNA m7G cap) is a modified guanine
nucleotide that has been added to the 5' end of a messenger RNA.
The 5' cap consists of a terminal 7-methylguanosine residue which
is linked through a 5'-5'-triphosphate bond to the first
transcribed nucleotide. The viral polymerase binds to the 5' RNA
cap of cellular mRNA molecules and cleaves the RNA cap together
with a stretch of 10 to 15 nucleotides. The capped RNA fragments
then serve as primers for the synthesis of viral mRNA.
[0007] The polymerase complex seems to be an appropriate antiviral
drug target since it is essential for synthesis of viral mRNA and
viral replication and contains several functional active sites
likely to be significantly different from those found in host cell
proteins (Magden, J. et al., (2005), Appl. Microbiol. Biotechnol.,
66, pp. 612-621). Thus, for example, there have been attempts to
interfere with the assembly of polymerase subunits by a
25-amino-acid peptide resembling the PA-binding domain within PB1
(Ghanem, A. et al., (2007), J. Virol., 81, pp. 7801-7804).
Furthermore, the endonuclease activity of the polymerase has been
targeted and a series of 4-substituted 2,4-dioxobutanoic acid
compounds has been identified as selective inhibitors of this
activity in influenza viruses (Tomassini, J. et al., (1994),
Antimicrob. Agents Chemother., 38, pp. 2827-2837). In addition,
flutimide, a substituted 2,6-diketopiperazine, identified in
extracts of Delitschia confertaspora, a fungal species, has been
shown to inhibit the endonuclease of influenza virus (Tomassini, J.
et al., (1996), Antimicrob. Agents Chemother., 40, pp. 1189-1193).
Moreover, there have been attempts to interfere with viral
transcription by nucleoside analogs, such as
2'-deoxy-2'-fluoroguanosine (Tisdale, M. et al., (1995),
Antimicrob. Agents Chemother., 39, pp. 2454-2458).
[0008] Certain heterocyclic carboxamides which are stated to be
useful in preventing or treating atherosclerosis or restenosis are
disclosed in WO 2004/019933. The compounds are stated to be useful
in these applications due to their activity against herpes viruses
because atherosclerosis is related to a number of herpes virus
infections.
[0009] WO 02/04444 discloses specific heterocyclic carboxamides as
antiviral agents.
[0010] O. Tabarrini et al. investigated the naphthyridone scaffold
and in particular identified a 1,6-naphthyridone derivative with
anti-HIV activity in ChemMedChem, 2011, 6(7), 1249-1257.
[0011] It is an object of the present invention to identify further
compounds which are effective against viral diseases and which have
improved pharmacological properties.
SUMMARY OF THE INVENTION
[0012] Accordingly, in a first embodiment, the present invention
provides a compound having the general formula (A).
[0013] It is understood that throughout the present specification
the term "a compound having the general formula (A)" encompasses
pharmaceutically acceptable salts, solvates, polymorphs, prodrugs,
tautomers, racemates, enantiomers, or diastereomers or mixtures
thereof unless mentioned otherwise.
[0014] A further embodiment of the present invention relates to a
pharmaceutical composition comprising a compound having the general
formula (A) and optionally one or more pharmaceutically acceptable
excipient(s) and/or carrier(s).
[0015] The compounds having the general formula (A) are useful for
treating, ameliorating or preventing viral diseases.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Before the present invention is described in detail below,
it is to be understood that this invention is not limited to the
particular methodology, protocols and reagents described herein as
these may vary. It is also to be understood that the terminology
used herein is for the purpose of describing particular embodiments
only, and is not intended to limit the scope of the present
invention which will be limited only by the appended claims. Unless
defined otherwise, all technical and scientific terms used herein
have the same meanings as commonly understood by one of ordinary
skill in the art.
[0017] Preferably, the terms used herein are defined as described
in "A multilingual glossary of biotechnological terms: (IUPAC
Recommendations)", Leuenberger, H. G. W, Nagel, B. and Kolbl, H.
eds. (1995), Helvetica Chimica Acta, CH-4010 Basel,
Switzerland.
[0018] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" and "comprising", will be understood
to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or
step or group of integers or steps. In the following passages
different aspects of the invention are defined in more detail. Each
aspect so defined may be combined with any other aspect or aspects
unless clearly indicated to the contrary. In particular, any
feature indicated as being preferred or advantageous may be
combined with any other feature or features indicated as being
preferred or advantageous.
[0019] Several documents are cited throughout the text of this
specification. Each of the documents cited herein (including all
patents, patent applications, scientific publications,
manufacturer's specifications, instructions, etc.), whether supra
or infra, are hereby incorporated by reference in their entirety.
Nothing herein is to be construed as an admission that the
invention is not entitled to antedate such disclosure by virtue of
prior invention.
DEFINITIONS
[0020] The term "alkyl" refers to a saturated straight or branched
carbon chain.
[0021] The term "cycloalkyl" represents a cyclic version of
"alkyl". The term "cycloalkyl" is also meant to include bicyclic,
tricyclic and polycyclic versions thereof. Unless specified
otherwise, the cycloalkyl group can have 3 to 12 carbon atoms.
[0022] "Hal" or "halogen" represents F, Cl, Br and I.
[0023] The term "aryl" preferably refers to an aromatic monocyclic
ring containing 6 carbon atoms, an aromatic bicyclic ring system
containing 10 carbon atoms or an aromatic tricyclic ring system
containing 14 carbon atoms. Examples are phenyl, naphthyl or
anthracenyl, preferably phenyl.
[0024] The term "heteroaryl" preferably refers to a five- or
six-membered aromatic ring wherein one or more of the carbon atoms
in the ring have been replaced by 1, 2, 3, or 4 (for the
five-membered ring) or 1, 2, 3, 4, or 5 (for the six-membered ring)
of the same or different heteroatoms, whereby the heteroatoms are
selected from O, N and S. Examples of the heteroaryl group include
pyrrole, pyrrolidine, oxolane, furan, imidazolidine, imidazole,
pyrazole, oxazolidine, oxazole, thiazole, piperidine, pyridine,
morpholine, piperazine, and dioxolane.
[0025] The term "hydrocarbon group which contains from 5 to 20
carbon atoms and optionally 1 to 4 heteroatoms selected from O, N
and S and which contains at least one ring" refers to any group
having 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms
selected from O, N and 2 as long as the group contains at least one
ring. The term is also meant to include bicyclic, tricyclic and
polycyclic versions thereof. If more than one ring is present, they
can be separate from each other or be annelated. The ring(s) can be
either carbocyclic or heterocyclic and can be saturated,
unsaturated or aromatic. The carbon atoms and heteroatoms can
either all be present in the one or more rings or some of the
carbon atoms and/or heteroatoms can be present outside of the ring,
e.g., in a linker group (such as --(CH.sub.2).sub.p-- with p=1 to
6). Examples of these groups include -(optionally substituted
C.sub.3-7 cycloalkyl), -(optionally substituted aryl) wherein the
aryl group can be, for example, phenyl, -(optionally substituted
biphenyl), adamantyl, --(C.sub.3-7 cycloalkyl)-aryl as well as the
corresponding compounds with a linker.
[0026] The term "(optionally substituted mono- or polycyclic group
containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms
selected from O, N and S)" refers to any mono- or polycyclic group
containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms
selected from O, N and S. This term includes monocyclic, bicyclic,
tricyclic and polycyclic versions thereof. If more than one ring is
present, they can be separate from each other or be annelated. The
ring(s) can be either carbocyclic or heterocyclic and can be
saturated, unsaturated or aromatic. The carbon atoms and
heteroatoms can either all be present in the one or more rings or
some of the carbon atoms and/or heteroatoms can be present outside
of the ring, e.g., in a linker group (such as --(CH.sub.2).sub.p--
with p=1 to 6). Examples of these groups include -(optionally
substituted C.sub.3-7 cycloalkyl), and -(optionally substituted
aryl) wherein the aryl group can be, for example, phenyl or
anthracenyl as well as the corresponding compounds with a
linker.
[0027] If a compound or moiety is referred to as being "optionally
substituted", it can in each instance include 1 or more of the
indicated substituents, whereby the substituents can be the same or
different.
[0028] The term "pharmaceutically acceptable salt" refers to a salt
of a compound of the present invention. Suitable pharmaceutically
acceptable salts include acid addition salts which may, for
example, be formed by mixing a solution of compounds of the present
invention with a solution of a pharmaceutically acceptable acid
such as hydrochloric acid, sulfuric acid, fumaric acid, maleic
acid, succinic acid, acetic acid, benzoic acid, citric acid,
tartaric acid, carbonic acid or phosphoric acid. Furthermore, where
the compound carries an acidic moiety, suitable pharmaceutically
acceptable salts thereof may include alkali metal salts (e.g.,
sodium or potassium salts); alkaline earth metal salts (e.g.,
calcium or magnesium salts); and salts formed with suitable organic
ligands (e.g., ammonium, quaternary ammonium and amine cations
formed using counteranions such as halide, hydroxide, carboxylate,
sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).
Illustrative examples of pharmaceutically acceptable salts include,
but are not limited to, acetate, adipate, alginate, ascorbate,
aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, butyrate, calcium edetate, camphorate,
camphorsulfonate, camsylate, carbonate, chloride, citrate,
clavulanate, cyclopentanepropionate, digluconate, dihydrochloride,
dodecylsulfate, edetate, edisylate, estolate, esylate,
ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate,
gluconate, glutamate, glycerophosphate, glycolylarsanilate,
hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, hydroiodide,
2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate,
lactate, lactobionate, laurate, lauryl sulfate, malate, maleate,
malonate, mandelate, mesylate, methanesulfonate, methylsulfate,
mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate,
N-methylglucamine ammonium salt, oleate, oxalate, pamoate
(embonate), palmitate, pantothenate, pectinate, persulfate,
3-phenylpropionate, phosphate/diphosphate, picrate, pivalate,
polygalacturonate, propionate, salicylate, stearate, sulfate,
subacetate, succinate, tannate, tartrate, teoclate, tosylate,
triethiodide, undecanoate, valerate, and the like (see, for
example, S. M. Berge et al., "Pharmaceutical Salts", J. Pharm.
Sci., 66, pp. 1-19 (1977)).
[0029] When the compounds of the present invention are provided in
crystalline form, the structure can contain solvent molecules. The
solvents are typically pharmaceutically acceptable solvents and
include, among others, water (hydrates) or organic solvents.
Examples of possible solvates include ethanolates and
iso-propanolates.
[0030] The term "codrug" refers to two or more therapeutic
compounds bonded via a covalent chemical bond. A detailed
definition can be found, e.g., in N. Das et al., European Journal
of Pharmaceutical Sciences, 41, 2010, 571-588.
[0031] The term "cocrystal" refers to a multiple component crystal
in which all components are solid under ambient conditions when in
their pure form. These components co-exist as a stoichiometric or
non-stoichometric ratio of a target molecule or ion (i.e., compound
of the present invention) and one or more neutral molecular
cocrystal formers. A detailed discussion can be found, for example,
in Ning Shan et al., Drug Discovery Today, 13(9/10), 2008, 440-446
and in D. J. Good et al., Cryst. Growth Des., 9(5), 2009,
2252-2264.
[0032] The compounds of the present invention can also be provided
in the form of a prodrug, namely a compound which is metabolized in
vivo to the active metabolite. Suitable prodrugs are, for instance,
esters. Specific examples of suitable groups are given, among
others, in US 2007/0072831 in paragraphs [0082] to [0118] under the
headings prodrugs and protecting groups. If X.sup.2 is O or S,
preferred examples of the prodrug include compounds in which
R.sup.3 is replaced by one of the following groups:
##STR00003##
[0033] In these formulae, R.sup.6 can be the same or different.
R.sup.9 is a cyclic group such as an aryl group or a C.sub.3-7
cycloalkyl group. p is 2 to 8.
[0034] If X.sup.2 is NR.sup.4, preferred examples of the prodrug
include compounds in which R.sup.3 and R.sup.4 are not both H.
Compounds Having the General Formula (A)
[0035] The present invention provides a compound having the general
formula (A).
##STR00004##
[0036] The present invention provides a compound having the general
formula (A) in which the following definitions apply. [0037] R* is
--H, -Hal, -(optionally substituted C.sub.1-6 alkyl), -(optionally
substituted C.sub.3-7 cycloalkyl), -(optionally substituted aryl),
--C.sub.1-4 alkyl-(optionally substituted C.sub.3-7 cycloalkyl),
--C.sub.1-4 alkyl-(optionally substituted aryl) or
--X.sup.1--R.sup.1. In a preferred embodiment, R* is -Hal,
-(optionally substituted C.sub.1-6 alkyl) (wherein the optional
substituent of the alkyl group is preferably Hal, more preferably
F); --C.sub.1-4 alkyl-(optionally substituted aryl) (wherein the
optional substituent of the aryl group is preferably halogen) or
--X.sup.1--R.sup.1. In a more preferred embodiment R* is
X.sup.1--R.sup.1. [0038] X.sup.1 is O, C(O), C(O)O, OC(O); S, SO,
SO.sub.2, NR.sup.4, N(R.sup.5)C(O), C(O)NR.sup.5, preferably
X.sup.1 is O, or NR.sup.4, more preferably X.sup.1 is NR.sup.4. In
one preferred embodiment, X.sup.1 is NR.sup.4 and R.sup.1 and
R.sup.4 are joined together to form a 5- to 7-membered ring, which
can optionally contain O, S or further N. In another preferred
embodiment, X.sup.1 is NR.sup.4 and R.sup.1 is --SO.sub.2--R.sup.4.
[0039] X.sup.2 is O, S, NR.sup.4, preferably X.sup.2 is O. [0040]
X.sup.3 is O or S, preferably X.sup.3 is O. [0041] X.sup.4 is O or
S, preferably X.sup.4 is O. [0042] R.sup.1 is --H, -(optionally
substituted C.sub.1-6 alkyl), -(optionally substituted C.sub.3-7
cycloalkyl), (optionally substituted aryl), --C.sub.1-4
alkyl-(optionally substituted C.sub.3-7 cycloalkyl), --C.sub.1-4
alkyl-(optionally substituted aryl). Preferably R.sup.1 is --H,
-(optionally substituted C.sub.1-6 alkyl), -(optionally substituted
benzyl), more preferably R.sup.1 is --H or -(optionally substituted
benzyl). Throughout the present specification, it is understood
that the definitions of the substituents of the aryl group apply
analogously to the benzyl group. [0043] R.sup.2 is a hydrocarbon
group which contains from 5 to 20 carbon atoms and optionally 1 to
4 heteroatoms selected from O, N and S and which contains at least
one ring, wherein the hydrocarbon group can be optionally
substituted. Preferably, the at least one ring is aromatic such as
an aryl or heteroaryl ring. More preferably, R.sup.2 is a
hydrocarbon group which contains from 5 to 20 carbon atoms and
optionally 1 to 4 heteroatoms and which contains at least two
rings, wherein the hydrocarbon group can be optionally substituted.
Even more preferably, at least one of the at least two rings is
aromatic such as an aryl or heteroaryl ring. Preferred examples of
R.sup.2 can be selected from the group consisting of
[0043] ##STR00005## [0044] wherein [0045] X is absent, CH.sub.2,
NH, C(O)NH, S or O. Furthermore, [0046] Y is CH.sub.2. [0047] In an
alternative embodiment, X and Y can be joined together to form an
annulated, carbo- or heterocylic 3- to 8-membered ring which can be
saturated or unsaturated. Specific examples of X-Y include
--CH.sub.2--, --CH.sub.2--CH.sub.2--, --O--, and --NH--. [0048] R
is independently selected from H, --C.sub.1-6 alkyl, halogen, --CN,
--OH, and --O--C.sub.1-6 alkyl. [0049] R.sup.3 is --H, -(optionally
substituted C.sub.1-6 alkyl), -(optionally substituted C.sub.3-7
cycloalkyl), -(optionally substituted aryl), or --C.sub.1-4
alkyl-(optionally substituted aryl) or if X.sup.2 is NR.sup.4, then
R.sup.3 can also be --OH, preferably R.sup.3 is --H, --C.sub.1-6
alkyl or Bz. [0050] R.sup.4 is --H, -(optionally substituted
C.sub.1-6 alkyl), -(optionally substituted C.sub.3-7 cycloalkyl),
--(optionally substituted aryl), --C.sub.1-4 alkyl-(optionally
substituted C.sub.3-7 cycloalkyl), or --C.sub.1-4 alkyl-(optionally
substituted aryl) or if X.sup.1 is NR.sup.4, then R.sup.4 and
R.sup.1 can be joined together to form a 5- to 7-membered ring,
which can optionally contain O, S or further N or if X.sup.2 is
NR.sup.4, then R.sup.4 and R.sup.3 can be joined together to form a
5- to 7-membered ring, which can optionally contain O, S or further
N. Preferably, R.sup.4 is --H, -(optionally substituted aryl), or
-(optionally substituted C.sub.1-6 alkyl), more preferably, R.sup.4
is --H or -(optionally substituted benzyl).
[0051] R.sup.5 is --H, -(optionally substituted C.sub.1-6 alkyl),
-(optionally substituted C.sub.3-7 cycloalkyl), -(optionally
substituted aryl), --C.sub.1-4 alkyl-(optionally substituted
C.sub.3-7 cycloalkyl), or --C.sub.1-4 alkyl-(optionally substituted
aryl). Preferably, R.sup.5 is --H. [0052] R.sup.6 is --H, or
--C.sub.1-6 alkyl.
[0053] The optional substituent of the alkyl group is selected from
the group consisting of halogen, --CN, --NR.sup.6R.sup.6, --OH, and
--O--C.sub.1-6 alkyl. Preferably the substituent is -halogen, more
preferably F.
[0054] The optional substituent of the cycloalkyl group, the aryl
group or the hydrocarbon group is selected from the group
consisting of --C.sub.1-6 alkyl, halogen, --CF.sub.3, --CN,
--X.sup.1--R.sup.5 and --C.sub.1-4 alkyl-aryl. Preferably, the
substituent is -halogen (preferably F), --OCH.sub.3 or --CN.
[0055] The present inventors have surprisingly found that the
compounds of the present invention which have a bulky moiety
R.sup.2 have improved pharmacological properties compared to
corresponding compounds which have a smaller moiety R.sup.2.
Without wishing to be bound by theory it is assumed that the viral
polymerase protein has a pocket for binding and that the bulky
moiety R.sup.2 of the compounds of the present invention fills this
pocket to a larger extent. It is further assumed that the larger
moiety R.sup.2 is able to provide more hydrophobic interaction with
the pocket than smaller moieties such as methyl.
[0056] The compounds of the present invention can be administered
to a patient in the form of a pharmaceutical composition which can
optionally comprise one or more pharmaceutically acceptable
excipient(s) and/or carrier(s).
[0057] The compounds of the present invention can be administered
by various well known routes, including oral, rectal,
intragastrical, intracranial and parenteral administration, e.g.
intravenous, intramuscular, intranasal, intradermal, subcutaneous,
and similar administration routes. Oral, intranasal and parenteral
administration are particularly preferred. Depending on the route
of administration different pharmaceutical formulations are
required and some of those may require that protective coatings are
applied to the drug formulation to prevent degradation of a
compound of the invention in, for example, the digestive tract.
[0058] Thus, preferably, a compound of the invention is formulated
as a syrup, an infusion or injection solution, a spray, a tablet, a
capsule, a capslet, lozenge, a liposome, a suppository, a plaster,
a band-aid, a retard capsule, a powder, or a slow release
formulation. Preferably, the diluent is water, a buffer, a buffered
salt solution or a salt solution and the carrier preferably is
selected from the group consisting of cocoa butter and
vitebesole.
[0059] Particular preferred pharmaceutical forms for the
administration of a compound of the invention are forms suitable
for injectionable use and include sterile aqueous solutions or
dispersions and sterile powders for the extemporaneous preparation
of sterile injectable solutions or dispersions. In all cases the
final solution or dispersion form must be sterile and fluid.
Typically, such a solution or dispersion will include a solvent or
dispersion medium, containing, for example, water-buffered aqueous
solutions, e.g. biocompatible buffers, ethanol, polyol, such as
glycerol, propylene glycol, polyethylene glycol, suitable mixtures
thereof, surfactants or vegetable oils. A compound of the invention
can also be formulated into liposomes, in particular for parenteral
administration. Liposomes provide the advantage of increased half
life in the circulation, if compared to the free drug and a
prolonged more even release of the enclosed drug.
[0060] Sterilization of infusion or injection solutions can be
accomplished by any number of art recognized techniques including
but not limited to addition of preservatives like anti-bacterial or
anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic
acid or thimersal. Further, isotonic agents, such as sugars or
salts, in particular sodium chloride, may be incorporated in
infusion or injection solutions.
[0061] Production of sterile injectable solutions containing one or
several of the compounds of the invention is accomplished by
incorporating the respective compound in the required amount in the
appropriate solvent with various ingredients enumerated above as
required followed by sterilization. To obtain a sterile powder the
above solutions are vacuum-dried or freeze-dried as necessary.
Preferred diluents of the present invention are water,
physiological acceptable buffers, physiological acceptable buffer
salt solutions or salt solutions. Preferred carriers are cocoa
butter and vitebesole. Excipients which can be used with the
various pharmaceutical forms of a compound of the invention can be
chosen from the following non-limiting list: [0062] a) binders such
as lactose, mannitol, crystalline sorbitol, dibasic phosphates,
calcium phosphates, sugars, microcrystalline cellulose,
carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl
pyrrolidone and the like; [0063] b) lubricants such as magnesium
stearate, talc, calcium stearate, zinc stearate, stearic acid,
hydrogenated vegetable oil, leucine, glycerids and sodium stearyl
fumarates, [0064] c) disintegrants such as starches,
croscarmellose, sodium methyl cellulose, agar, bentonite, alginic
acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the
like.
[0065] In one embodiment the formulation is for oral administration
and the formulation comprises one or more or all of the following
ingredients: pregelatinized starch, talc, povidone K 30,
croscarmellose sodium, sodium stearyl fumarate, gelatin, titanium
dioxide, sorbitol, monosodium citrate, xanthan gum, titanium
dioxide, flavoring, sodium benzoate and saccharin sodium.
[0066] If a compound of the invention is administered intranasally
in a preferred embodiment, it may be administered in the form of a
dry powder inhaler or an aerosol spray from a pressurized
container, pump, spray or nebulizer with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, a hydrofluoro-alkane such as
1,1,1,2-tetrafluoroethane (HFA 134A.TM.) or
1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA.TM.), carbon dioxide,
or another suitable gas. The pressurized container, pump, spray or
nebulizer may contain a solution or suspension of the compound of
the invention, e.g., using a mixture of ethanol and the propellant
as the solvent, which may additionally contain a lubricant, e.g.,
sorbitan trioleate.
[0067] Other suitable excipients can be found in the Handbook of
Pharmaceutical Excipients, published by the American Pharmaceutical
Association, which is herein incorporated by reference.
[0068] It is to be understood that depending on the severity of the
disorder and the particular type which is treatable with one of the
compounds of the invention, as well as on the respective patient to
be treated, e.g. the general health status of the patient, etc.,
different doses of the respective compound are required to elicit a
therapeutic or prophylactic effect. The determination of the
appropriate dose lies within the discretion of the attending
physician. It is contemplated that the dosage of a compound of the
invention in the therapeutic or prophylactic use of the invention
should be in the range of about 0.1 mg to about 1 g of the active
ingredient (i.e. compound of the invention) per kg body weight.
However, in a preferred use of the present invention a compound of
the invention is administered to a subject in need thereof in an
amount ranging from 1.0 to 500 mg/kg body weight, preferably
ranging from 1 to 200 mg/kg body weight. The duration of therapy
with a compound of the invention will vary, depending on the
severity of the disease being treated and the condition and
idiosyncratic response of each individual patient. In one preferred
embodiment of a prophylactic or therapeutic use, from 10 mg to 200
mg of the compound are orally administered to an adult per day,
depending on the severity of the disease and/or the degree of
exposure to disease carriers.
[0069] As is known in the art, the pharmaceutically effective
amount of a given composition will also depend on the
administration route. In general, the required amount will be
higher if the administration is through the gastrointestinal tract,
e.g., by suppository, rectal, or by an intragastric probe, and
lower if the route of administration is parenteral, e.g.,
intravenous. Typically, a compound of the invention will be
administered in ranges of 50 mg to 1 g/kg body weight, preferably
10 mg to 500 mg/kg body weight, if rectal or intragastric
administration is used and in ranges of 1 to 100 mg/kg body weight
if parenteral administration is used. For intranasal
administration, 1 to 100 mg/kg body weight are envisaged.
[0070] If a person is known to be at risk of developing a disease
treatable with a compound of the invention, prophylactic
administration of the biologically active blood serum or the
pharmaceutical composition according to the invention may be
possible. In these cases the respective compound of the invention
is preferably administered in above outlined preferred and
particular preferred doses on a daily basis. Preferably, from 0.1
mg to 1 g/kg body weight once a day, preferably 10 to 200 mg/kg
body weight. This administration can be continued until the risk of
developing the respective viral disorder has lessened. In most
instances, however, a compound of the invention will be
administered once a disease/disorder has been diagnosed. In these
cases it is preferred that a first dose of a compound of the
invention is administered one, two, three or four times daily.
[0071] The compounds of the present invention are particularly
useful for treating, ameliorating, or preventing viral diseases.
The type of viral disease is not particularly limited. Examples of
possible viral diseases include, but are not limited to, viral
diseases which are caused by Poxviridae, Herpesviridae,
Adenoviridae, Papillomaviridae, Polyomaviridae, Parvoviridae,
Hepadnaviridae, Retroviridae, Reoviridae, Filoviridae,
Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae,
Arenaviridae, Coronaviridae, Picornaviridae, Hepeviridae,
Caliciviridae, Astroviridae, Togaviridae, Flaviviridae, Deltavirus,
Bornaviridae, and prions. Preferably viral diseases which are
caused by Herpesviridae, Retroviridae, Filoviridae,
Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae,
Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae,
Flaviviridae, more preferably viral diseases which are caused by
orthomyxoviridae.
[0072] Examples of the various viruses are given in the following
table.
TABLE-US-00001 Family Virus (preferred examples) Poxviridae
Smallpox virus Molluscum contagiosum virus Herpesviridae Herpes
simplex virus Varicella zoster virus Cytomegalovirus Epstein Barr
virus Kaposi's sarcoma-associated herpesvirus Adenoviridae Human
adenovirus A-F Papillomaviridae Papillomavirus Polyomaviridae
BK-virus JC-Virsu Parvoviridae B19 virus Adeno associated virus
2/3/5 Hepadnaviridae Hepatitis B virus Retroviridae Human
immunodeficiency virus types 1/2 Human T-cell leukemia virus Human
foamy virus Reoviridae Reovirus 1/2/3 Rotavirus A/B/C Colorado tick
fever virus Filoviridae Ebola virus Marburg virus Paramyxoviridae
Parainfluenza virus 1-4 Mumps virus Measles virus Respiratory
syncytial virus Hendravirus Rhabdoviridae Vesicular stomatitis
virus Rabies virus Mokola virus European bat virus Duvenhage virus
Orthomyxoviridae Influenza virus types A-C Bunyaviridae California
encephalitis virus La Crosse virus Hantaan virus Puumala virus Sin
Nombre virus Seoul virus Crimean- Congo hemorrhagic fever virus
Sakhalin virus Rift valley virus Sandfly fever virus Uukuniemi
virus Arenaviridae Lassa virus Lymphocytic choriomeningitis virus
Guanarito virus Junin virus, Machupo virus Sabia virus
Coronaviridae Human coronavirus Picornaviridae Human enterovirus
types A-D (Poliovirus, Echovirus, Coxsackie virus A/B) Rhinovirus
types A/B/C Hepatitis A virus Parechovirus Food and mouth disease
virus Hepeviridae Hepatitis E virus Caliciviridae Norwalk virus
Sapporo virus Astroviridae Human astrovirus 1 Togaviridae Ross
River virus Chikungunya virus O'nyong-nyong virus Rubella virus
Flaviviridae Tick-borne encephalitis virus Dengue virus Yellow
Fever virus Japanese encephalitis virus Murray Valley virus St.
Louis encephalitis virus West Nile virus Hepatitis C virus
Hepatitis G virus Hepatitis GB virus Deltavirus Hepatitis
deltavirus Bornaviridae Bornavirus Prions
[0073] Preferably, the compounds of the present invention are
employed to treat influenza. Within the present invention, the term
"influenza" includes influenza A, B, C, isavirus and thogotovirus
and also covers bird flu and swine flu. The subject to be treated
is not particularly restricted and can be any vertebrate, such as
birds and mammals (including humans).
[0074] Without wishing to be bound by theory it is assumed that the
compounds of the present invention are capable of inhibiting
endonuclease activity, particularly of the influenza virus. More
specifically it is assumed that they directly interfere with the
N-terminal part of the influenza PA protein, which harbours
endonuclease activity. However, delivery of a compound into a cell
may represent a problem depending on, e.g., the solubility of the
compound or its capabilities to cross the cell membrane. The
present invention not only shows that the claimed compounds have in
vitro polymerase inhibitory activity but also in vivo antiviral
activity.
[0075] A possible measure of the in vitro polymerase inhibitory
activity of the compounds having the formula (A) and/or (C) is the
FRET endonuclease activity assay disclosed herein. Preferably, the
compounds exhibit a % reduction of at least about 50% at 25 .mu.M
in the FRET assay. In this context, the % reduction is the %
reduction of the initial reaction velocity (v0) of substrate
cleavage of compound-treated samples compared to untreated samples.
Preferably, the compounds exhibit an IC.sub.50 of at least about 40
.mu.M, more preferably at least about 20 .mu.M, in the FRET assay.
The half maximal inhibitory concentration (IC.sub.50) is a measure
of the effectiveness of a compound in inhibiting biological or
biochemical function and was calculated from the initial reaction
velocities (v0) in a given concentration series ranging from
maximum 100 .mu.M to at least 2 nM.
[0076] A possible measure of the in vivo antiviral activity of the
compounds having the formula (A) and/or (C) is the CPE assay
disclosed herein. Preferably, the compounds exhibit a % reduction
of at least about 30% at 50 .mu.M. In this connection, the
reduction in the virus-mediated cytopathic effect (CPE) upon
treatment with the compounds was calculated as follows: The cell
viability of infected-treated and uninfected-treated cells was
determined using an ATP-based cell viability assay (Promega). The
response in relative luminescent units (RLU) of infected-untreated
samples was subtracted from the response (RLU) of the
infected-treated samples and then normalized to the viability of
the corresponding uninfected sample resulting in % CPE reduction.
Preferably, the compounds exhibit an IC.sub.50 of at least about 45
.mu.M, more preferably at least about 10 .mu.M, in the CPE assay.
The half maximal inhibitory concentration (IC.sub.50) is a measure
of the effectiveness of a compound in inhibiting biological or
biochemical function and was calculated from the RLU response in a
given concentration series ranging from maximum 100 .mu.M to at
least 100 nM.
[0077] The compounds having the general formula (A) can be used in
combination with one or more other medicaments. The type of the
other medicaments is not particularly limited and will depend on
the disorder to be treated. Preferably, the other medicament will
be a further medicament which is useful in treating, ameloriating
or preventing a viral disease, more preferably a further medicament
which is useful in treating, ameloriating or preventing
influenza.
[0078] The following combinations of medicaments are envisaged as
being particularly suitable: [0079] (i) The combination of
endonuclease and cap-binding inhibitors (particularly targeting
influenza). The endonuclease inhibitors are not particularly
limited and can be any endonuclease inhibitor, particularly any
viral endonuclease inhibitor. Preferred endonuclease inhibitors are
those having the general formula (I) as defined in the US
application with the Ser. No. 61/550,045, filed on Oct. 21, 2011,
the complete disclosure of which is incorporated by reference. In
particular, all descriptions with respect to the general formula of
the compounds according to U.S. 61/550,045, the preferred
embodiments of the various substituents as well as the medical
utility and advantages of the compounds are incorporated herein by
reference. [0080] The compounds having the general formula (I) of
this reference can optionally be in the form of a pharmaceutically
acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug,
tautomer, racemate, enantiomer, or diastereomer or mixture thereof.
They are defined as follows (wherein the definitions of the various
moieties given in this earlier application apply):
[0080] ##STR00006## [0081] wherein [0082] R.sup.1 is selected from
--H, --C.sub.1-6 alkyl, --(C.sub.3-7 cycloalkyl) and
--CH.sub.2--(C.sub.3-7 cycloalkyl); [0083] R.sup.2 is selected from
--H,
[0083] ##STR00007## [0084] --C.sub.1-6 alkyl, -Hal, --(C.sub.3-7
cycloalkyl), --CH.sub.2--(C.sub.3-7 cycloalkyl),
--(CH.sub.2).sub.m-(optionally substituted aryl), -(optionally
substituted 5- or 6-membered heterocyclic ring which contains at
least one heteroatom selected from N, O and S, wherein the
substituent is selected from --C.sub.1-4 alkyl, -halogen, --CN,
--CHal.sub.3, -aryl, --NR.sup.6R.sup.7, and --CONR.sup.6R.sup.7;
[0085] R.sup.3 is selected from --H, --C.sub.1-6 alkyl, [0086]
--(CH.sub.2).sub.n--NR.sup.6R.sup.8, [0087] -(optionally
substituted 5- or 6-membered carbo- or heterocyclic ring wherein
the heterocyclic ring contains at least one heteroatom selected
from N, O and S), wherein the substituent is selected from -Hal,
--C.sub.1-4 alkyl, --NR.sup.9R.sup.10, --(CH.sub.2).sub.n--OH,
--C(O)--NR.sup.9R.sup.10, --SO.sub.2--NR.sup.9R.sup.10,
--NH--C(O)--O--R.sup.11, --C(O)--O--R.sup.11, and a 5- or
6-membered heterocyclic ring which contains at least one heteroatom
selected from N, O and S; [0088] or wherein R.sup.1 and R.sup.2
together form a phenyl ring or wherein R.sup.2 and R.sup.3 together
form a phenyl ring; [0089] R.sup.4 is --H; [0090] R.sup.5 is
selected from the group consisting of --H or
--(CH.sub.2).sub.n-(optionally substituted aryl), wherein the
substituent is selected from -Hal and --C.sub.1-4 alkyl; or wherein
R.sup.4 and R.sup.5 together form a methylene group --CH.sub.2--,
ethylene group --CH.sub.2CH.sub.2-- or ethyne group --CHCH--, which
can be optionally substituted by --C.sub.1-4 alkyl, -halogen,
--CHal.sub.3, --R.sup.6R.sup.7, --OR.sup.6, --CONR.sup.6R.sup.7,
--SO.sub.2R.sup.6R.sup.7, aryl or heteroaryl; [0091] R.sup.6 is
selected from --H and --C.sub.1-4 alkyl; [0092] R.sup.7 is selected
from --H and --C.sub.1-4 alkyl; [0093] R.sup.8 is selected from
--H, --C.sub.1-6 alkyl, --(CH.sub.2).sub.n-(optionally substituted
aryl), --SO.sub.2--(CH.sub.2).sub.n-(optionally substituted aryl),
--SO.sub.2--(CH.sub.2).sub.n-(optionally substituted 5- to
10-membered mono- or bicyclic heteroring which contains at least
one heteroatom selected from N, O and S),
--(CH.sub.2).sub.n-(optionally substituted 5- or 6-membered
heterocyclic ring which contains at least one heteroatom selected
from N, O and S), wherein the substituent is selected from -Hal,
--CF.sub.3, --C.sub.1-4 alkyl, and --(CH.sub.2).sub.n-aryl; [0094]
R.sup.9 is selected from --H, --C.sub.1-4 alkyl, and --C.sub.1-4
alkylene-NR.sup.11R.sup.11; [0095] R.sup.10 is selected from --H,
--C.sub.1-4 alkyl, and --C.sub.1-4 alkylene-NR.sup.11R.sup.11;
[0096] R.sup.11 is selected from --H, --CF.sub.3, and --C.sub.1-4
alkyl; [0097] each m is 0 or 1; and [0098] each n is independently
0, 1, 2, or 3. [0099] Further preferred endonuclease inhibitors are
those having the general formula (C) as defined in the applicant's
other patent application, namely U.S. application Ser. No.
13/900,940, filed May 23, 2013, the complete disclosure of which is
incorporated by reference. In particular, all descriptions with
respect to the general formula of the compounds having the general
formula (C), the preferred embodiments of the various substituents
as well as the medical utility and advantages of the compounds are
incorporated herein by reference. The compounds having the general
formula (C) can be optionally in the form of a pharmaceutically
acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug,
tautomer, racemate, enantiomer, or diastereomer or mixture thereof.
They are defined below.
[0100] The cap-binding inhibitors are not particularly limited
either and can be any cap-binding inhibitor, particularly any viral
cap-binding inhibitor. Preferred cap-binding inhibitors are those
having the general formula (II) as defined in U.S. application
61/550,057 and/or the compounds disclosed in WO2011/000566, the
complete disclosure of which is incorporated by reference. In
particular, all descriptions with respect to the general formula of
the compounds according to U.S. 61/550,057 or WO2011/000566, the
preferred embodiments of the various substituents as well as the
medical utility and advantages of the compounds are incorporated
herein by reference.
[0101] The compound having the general formula (II) can be
optionally in the form of a pharmaceutically acceptable salt,
solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate,
enantiomer, or diastereomer or mixture thereof. It is defined as
follows:
##STR00008## [0102] wherein [0103] Y is S; [0104] R.sup.21 is
selected from --H, --C.sub.1-6alkyl, --(CH.sub.2).sub.q-aryl,
--(CH.sub.2).sub.q-heterocyclyl, --(CH.sub.2).sub.q-cycloalkyl,
--(CH.sub.2).sub.p--OR.sup.25, and
--(CH.sub.2).sub.p--NR.sup.25R.sup.26; [0105] R.sup.22 is selected
from --H, --C.sub.1-6 alkyl, --(CH.sub.2).sub.q-cycloalkyl, -Hal,
--CF.sub.3 and --CN; [0106] R.sup.23 is selected from -aryl,
-heterocyclyl, -cycloalkyl, --C(--R.sup.28)(--R.sup.29)-aryl,
--C(--R.sup.28)(--R.sup.29)-heterocyclyl, and
--C(--R.sup.28)(--R.sup.29)-cycloalkyl; [0107] R.sup.25 is selected
from --H, --C.sub.1-6 alkyl, and --(CH.sub.2CH.sub.2O).sub.rH;
[0108] R.sup.26 is selected from --H, and --C.sub.1-6 alkyl; [0109]
R.sup.27 is independently selected from --C.sub.1-6 alkyl,
--C(O)--C.sub.1-6 alkyl, -Hal, --CF.sub.3, --CN, --COOR.sup.25,
--OR.sup.25, --(CH.sub.2).sub.qNR.sup.25R.sup.26,
--C(O)--NR.sup.25R.sup.26, and --NR.sup.25--C(O)--C.sub.1-6 alkyl;
[0110] R.sup.28 and R.sup.29 are independently selected from --H,
--C.sub.1-6 alkyl, --(CH.sub.2).sub.q-aryl,
--(CH.sub.2).sub.q-heterocyclyl, --(CH.sub.2).sub.q-cycloalkyl,
--OH, --O--C.sub.1-6 alkyl, --O--(CH.sub.2).sub.q-aryl,
--O--(CH.sub.2).sub.q-heterocyclyl, and
--O--(CH.sub.2).sub.q-cycloalkyl; [0111] or R.sup.28 and R.sup.29
are together .dbd.O, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; [0112] p is 1 to 4; [0113] q
is 0 to 4; and [0114] r is 1 to 3; [0115] wherein the aryl group,
heterocyclyl group and/or cycloalkyl group can be optionally
substituted with one or more substituents R.sup.27. [0116] The
compounds of WO2011/000566 have the general formula (XXI):
[0116] ##STR00009## [0117] or a pharmaceutically effective salt, a
solvate, a prodrug, a tautomer, a racemate, an enantiomer or a
diastereomer thereof; [0118] wherein [0119] one of Y and Z is
--XR.sup.12 and the other is R.sup.10'; [0120] R.sup.10, R.sup.10'
and R.sup.10'' are each individually selected from the group
consisting of hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.8-alkynyl,
--(CH.sub.2).sub.nC(O)OH, --(CH.sub.2).sub.nC(O)OR.sup.16,
--(CH.sub.2).sub.nOH, --(CH.sub.2).sub.nOR.sup.16, --CF.sub.3,
--(CH.sub.2).sub.n-cycloalkyl, --(CH.sub.2).sub.nC(O)NH.sub.2,
--(CH.sub.2).sub.nC(O)NHR.sup.16,
--(CH.sub.2).sub.nC(O)NR.sup.16R.sup.17,
--(CH.sub.2).sub.nS(O).sub.2NH.sub.2,
--(CH.sub.2).sub.nS(O).sub.2NHR.sup.16,
--(CH.sub.2).sub.nS(O).sub.2NR.sup.16R.sup.17,
--(CH.sub.2).sub.nS(O).sub.2R.sup.16, halogen, --CN,
--(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n-heteroaryl,
--(CH.sub.2).sub.nNH.sub.2, --(CH.sub.2).sub.nNHR.sup.16, and
--(CH.sub.2).sub.nNR.sup.16R.sup.17; optionally substituted; [0121]
R.sup.11 is selected from the group consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, --CF.sub.3, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.8-alkynyl, --(CH.sub.2).sub.n-cycloalkyl,
--(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n-heterocycloalkyl and
--(CH.sub.2).sub.n-heteroaryl; optionally substituted; [0122] X is
selected from the group consisting of CH.sub.2, C(O), C(S), CH(OH),
CH(OR.sup.16), S(O).sub.2, --S(O).sub.2--N(H)--,
--S(O).sub.2--N(R.sup.16)--, --N(H)--S(O).sub.2--,
--N(R.sup.16)--S(O).sub.2--, C(.dbd.NH), C(.dbd.N--R.sup.16),
CH(NH.sub.2), CH(NHR.sup.16), CH(NR.sup.16R.sup.17),
--C(O)--N(H)--, --C(O)--N(R.sup.16)--, --N(H)--C(O)--,
--N(R.sup.16)--C(O)--, N(H), N(--R.sup.16) and O; [0123] R.sup.12
is selected from the group consisting of C.sub.1-C.sub.6-alkyl,
--CF.sub.3, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.8-alkynyl,
--(CH.sub.2).sub.n-cycloalkyl, --(CH.sub.2).sub.n-heterocycloalkyl,
--(CH.sub.2).sub.n-aryl, --NR.sup.16R.sup.17, and
--(CH.sub.2).sub.n-heteroaryl; optionally substituted; [0124]
R.sup.16 and R.sup.17 are independently selected from the group
consisting of C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, --(CH.sub.2).sub.n-cycloalkyl,
--(CH.sub.2).sub.n-aryl, --CF.sub.3, --C(O)R.sup.18 and
--S(O).sub.2R.sup.18; optionally substituted; [0125] R.sup.18 is
independently selected from the group consisting of
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, --(CH.sub.2).sub.n-cycloalkyl and
--CF.sub.3; optionally substituted; and [0126] n is in each
instance selected from 0, 1 and 2. [0127] In the context of
WO2011/000566 the term "optionally substituted" in each instance
refers to between 1 and 10 substituents, e.g. 1, 2, 3, 4, 5, 6, 7,
8, 9, or 10 substituents which are in each instance preferably
independently selected from the group consisting of halogen, in
particular F, Cl, Br or I; --NO.sub.2, --CN, --OR', --NR'R'',
--(CO)OR', --(CO)OR''', --(CO)NR'R'', --NR'COR''', --NR'COR'',
--NR''CONR'R'', --NR''SO.sub.2A, --COR'''; --SO.sub.2NR'R'',
--OOCR''', --CR'''R''''OH, --R'''OH, .dbd.O, and -E; [0128] R' and
R'' are each independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, --OE, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a
heteroaryl, or heterocycloalkyl; optionally substituted; [0129]
R''' and R'''' are each independently selected from the group
consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and --NR'R'';
and [0130] E is selected from the group consisting of alkyl,
alkenyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an
alicyclic system, aryl and heteroaryl; optionally substituted.
[0131] Widespread resistance to both classes of licensed influenza
antivirals (M2 ion channel inhibitors (adamantanes) and
neuraminidase inhibitors (Oseltamivir)) occurs in both pandemic and
seasonal viruses, rendering these drugs to be of marginal utility
in the treatment modality. For M2 ion channel inhibitors, the
frequency of viral resistance has been increasing since 2003 and
for seasonal influenza A/H3N2, adamantanes are now regarded as
ineffective. Virtually all 2009 H1N1 and seasonal H3N2 strains are
resistant to the adamantanes (rimantadine and amantadine), and the
majority of seasonal H1N1 strains are resistant to oseltamivir, the
most widely prescribed neuraminidase inhibitor (NAI). For
oseltamivir the WHO reported on significant emergence of influenza
A/H1N1 resistance starting in the influenza season 2007/2008; and
for the second and third quarters of 2008 in the southern
hemisphere. Even more serious numbers were published for the fourth
quarter of 2008 (northern hemisphere) where 95% of all tested
isolates revealed no Oseltamivir-susceptibility. Considering the
fact that now most national governments have been stockpiling
Oseltamivir as part of their influenza pandemic preparedness plan,
it is obvious that the demand for new, effective drugs is growing
significantly. To address the need for more effective therapy,
preliminary studies using double or even triple combinations of
antiviral drugs with different mechanisms of action have been
undertaken. Adamantanes and neuraminidase inhibitors in combination
were analysed in vitro and in vivo and found to act highly
synergistically. However, it is known that for both types of
antivirals resistant viruses emerge rather rapidly and this issue
is not tackled by combining these established antiviral drugs.
[0132] Influenza virus polymerase inhibitors are novel drugs
targeting the transcription activity of the polymerase. Selective
inhibitors against the cap-binding and endonuclease active sites of
the viral polymerase severely attenuate virus infection by stopping
the viral reproductive cycle. These two targets are located within
distinct subunits of the polymerase complex and thus represent
unique drug targets. Due to the fact that both functions are
required for the so-called "cap-snatching" mechanism mandatory for
viral transcription, concurrent inhibition of both functions is
expected to act highly synergistically. This highly efficient drug
combination would result in lower substance concentrations and
hence improved dose-response-relationships and better side effect
profiles. [0133] Both of these active sites are composed of
identical residues in all influenza A strains (e.g., avian and
human) and hence this high degree of sequence conservation
underpins the perception that these targets are not likely to
trigger rapid resistant virus generation. Thus, endonuclease and
cap-binding inhibitors individually and in combination are ideal
drug candidates to combat both seasonal and pandemic influenza,
irrespectively of the virus strain. [0134] The combination of an
endonuclease inhibitor and a cap-binding inhibitor or a dual
specific polymerase inhibitor targeting both the endonuclease
active site and the cap-binding domain would be effective against
virus strains resistant against adamantanes and neuraminidase
inhibitors and moreover combine the advantage of low susceptibility
to resistance generation with activity against a broad range of
virus strains. [0135] (ii) The combination of inhibitors of
different antiviral targets (particularly targeting influenza)
focusing on the combination with (preferably influenza) polymerase
inhibitors as dual or multiple combination therapy. Influenza virus
polymerase inhibitors are novel drugs targeting the transcription
activity of the polymerase. Selective inhibitors against the
cap-binding and endonuclease active sites of the viral polymerase
severely attenuate virus infection by stopping the viral
reproductive cycle. The combination of a polymerase inhibitor
specifically addressing a viral intracellular target with an
inhibitor of a different antiviral target is expected to act highly
synergistically. This is based on the fact that these different
types of antiviral drugs exhibit completely different mechanisms of
action and pharmacokinetics properties which act advantageously and
synergistically on the antiviral efficacy of the combination.
[0136] This highly efficient drug combination would result in lower
substance concentrations and hence improved
dose-response-relationships and better side effect profiles. [0137]
Moreover, advantages described under (i) for polymerase inhibitors
would prevail for combinations of inhibitors of different antiviral
targets with polymerase inhibitors. [0138] Typically, at least one
compound selected from the first group of polymerase inhibitors is
combined with at least one compound selected from the second group
of polymerase inhibitors. [0139] The first group of polymerase
inhibitors which can be used in this type of combination therapy
includes, but is not limited to, the compounds having the formula
(A) or (C). [0140] The second group of polymerase inhibitors which
can be used in this type of combination therapy includes, but is
not limited to, the compounds having the general formula (I), the
compounds having the general formula (II), the compounds disclosed
in WO 2011/000566, WO 2010/110231, WO 2010/110409, WO 2006/030807
or U.S. Pat. No. 5,475,109 as well as flutimide and analogues,
favipiravir and analogues, epigallocatechin gallate and analogues,
as well as nucleoside analogs such as ribavirine. [0141] (iii) The
combination of polymerase inhibitors with neuramidase inhibitors
[0142] Influenza virus polymerase inhibitors are novel drugs
targeting the transcription activity of the polymerase. Selective
inhibitors against the cap-binding and endonuclease active sites of
the viral polymerase severely attenuate virus infection by stopping
the viral reproductive cycle. The combination of a polymerase
inhibitor specifically addressing a viral intracellular target with
an inhibitor of a different extracellular antiviral target,
especially the (e.g., viral) neuraminidase is expected to act
highly synergistically. This is based on the fact that these
different types of antiviral drugs exhibit completely different
mechanisms of action and pharmacokinetic properties which act
advantageously and synergistically on the antiviral efficacy of the
combination. [0143] This highly efficient drug combination would
result in lower substance concentrations and hence improved
dose-response-relationships and better side effect profiles. [0144]
Moreover, advantages described under (i) for polymerase inhibitors
would prevail for combinations of inhibitors of different antiviral
targets with polymerase inhibitors. [0145] Typically, at least one
compound selected from the above mentioned first group of
polymerase inhibitors is combined with at least one neuramidase
inhibitor. [0146] The neuraminidase inhibitor (particularly
influenza neuramidase inhibitor) is not specifically limited.
Examples include zanamivir, oseltamivir, peramivir, KDN DANA, FANA,
and cyclopentane derivatives. [0147] (iv) The combination of
polymerase inhibitors with M2 channel inhibitors [0148] Influenza
virus polymerase inhibitors are novel drugs targeting the
transcription activity of the polymerase. Selective inhibitors
against the cap-binding and endonuclease active sites of the viral
polymerase severely attenuate virus infection by stopping the viral
reproductive cycle. The combination of a polymerase inhibitor
specifically addressing a viral intracellular target with an
inhibitor of a different extracellular and cytoplasmic antiviral
target, especially the viral M2 ion channel, is expected to act
highly synergistically. This is based on the fact that these
different types of antiviral drugs exhibit completely different
mechanisms of action and pharmacokinetic properties which act
advantageously and synergistically on the antiviral efficacy of the
combination. [0149] This highly efficient drug combination would
result in lower substance concentrations and hence improved
dose-response-relationships and better side effect profiles.
Moreover, advantages described under (i) for polymerase inhibitors
would prevail for combinations of inhibitors of different antiviral
targets with polymerase inhibitors. [0150] Typically, at least one
compound selected from the above mentioned first group of
polymerase inhibitors is combined with at least one M2 channel
inhibitor. [0151] The M2 channel inhibitor (particularly influenza
M2 channel inhibitor) is not specifically limited. Examples include
amantadine and rimantadine. [0152] (v) The combination of
polymerase inhibitors with alpha glucosidase inhibitors [0153]
Influenza virus polymerase inhibitors are novel drugs targeting the
transcription activity of the polymerase. Selective inhibitors
against the cap-binding and endonuclease active sites of the viral
polymerase severely attenuate virus infection by stopping the viral
reproductive cycle. The combination of a polymerase inhibitor
specifically addressing a viral intracellular target, with an
inhibitor of a different extracellular target, especially alpha
glucosidase, is expected to act highly synergistically. This is
based on the fact that these different types of antiviral drugs
exhibit completely different mechanisms of action and
pharmacokinetic properties which act advantageously and
synergistically on the antiviral efficacy of the combination. This
highly efficient drug combination would result in lower substance
concentrations and hence improved dose-response-relationships and
better side effect profiles. Moreover, advantages described under
(i) for polymerase inhibitors would prevail for combinations of
inhibitors of different antiviral targets with polymerase
inhibitors. [0154] Typically, at least one compound selected from
the above-mentioned first group of polymerase inhibitors is
combined with at least one alpha glucosidase inhibitor. [0155] The
alpha glucosidase inhibitor (particularly influenza alpha
glucosidase inhibitor) is not specifically limited. Examples
include the compounds described in Chang et al., Antiviral Research
2011, 89, 26-34. [0156] (vi) The combination of polymerase
inhibitors with ligands of other influenza targets [0157] Influenza
virus polymerase inhibitors are novel drugs targeting the
transcription activity of the polymerase. Selective inhibitors
against the cap-binding and endonuclease active sites of the viral
polymerase severely attenuate virus infection by stopping the viral
reproductive cycle. The combination of a polymerase inhibitor
specifically addressing a viral intracellular target with an
inhibitor of different extracellular, cytoplasmic or nucleic
antiviral targets is expected to act highly synergistically. This
is based on the fact that these different types of antiviral drugs
exhibit completely different mechanisms of action and
pharmacokinetic properties which act advantageously and
synergistically on the antiviral efficacy of the combination.
[0158] This highly efficient drug combination would result in lower
substance concentrations and hence improved
dose-response-relationships and better side effect profiles.
Moreover, advantages described under (i) for polymerase inhibitors
would prevail for combinations of inhibitors of different antiviral
targets with polymerase inhibitors.
[0159] Typically at least one compound selected from the above
mentioned first group of polymerase inhibitors is combined with at
least one ligand of another influenza target. [0160] The ligand of
another influenza target is not specifically limited. Examples
include compounds acting on the sialidase fusion protein, e.g.
Fludase (DAS181), siRNAs and phosphorothioate oligonucleotides,
signal transduction inhibitors (ErbB tyrosine kinase, Abl kinase
family, MAP kinases, PKCa-mediated activation of ERK signaling as
well as interferon (inducers). [0161] (vii) The combination of
(preferably influenza) polymerase inhibitors with a compound used
as an adjuvance to minimize the symptoms of the disease
(antibiotics, anti-inflammatory agents like COX inhibitors (e.g.,
COX-1/COX-2 inhibitors, selective COX-2 inhibitors), lipoxygenase
inhibitors, EP ligands (particularly EP4 ligands), bradykinin
ligands, and/or cannabinoid ligands (e.g., CB2 agonists). Influenza
virus polymerase inhibitors are novel drugs targeting the
transcription activity of the polymerase. Selective inhibitors
against the cap-binding and endonuclease active sites of the viral
polymerase severely attenuate virus infection by stopping the viral
reproductive cycle. The combination of a polymerase inhibitor
specifically addressing a viral intracellular target with an
compound used as an adjuvance to minimize the symptoms of the
disease address the causative and symptomatic pathological
consequences of viral infection. This combination is expected to
act synergistically because these different types of drugs exhibit
completely different mechanisms of action and pharmacokinetic
properties which act advantageously and synergistically on the
antiviral efficacy of the combination. [0162] This highly efficient
drug combination would result in lower substance concentrations and
hence improved dose-response-relationships and better side effect
profiles. Moreover, advantages described under (i) for polymerase
inhibitors would prevail for combinations of inhibitors of
different antiviral targets with polymerase inhibitors.
Compounds Having the General Formula (C)
[0163] The compounds having the general formula (C) are identified
in the following.
##STR00010##
[0164] It is understood that throughout the present specification
the term "a compound having the general formula (C)" encompasses
pharmaceutically acceptable salts, solvates, polymorphs, prodrugs,
tautomers, racemates, enantiomers, or diastereomers or mixtures
thereof unless mentioned otherwise.
[0165] In the present invention the following definitions apply
with respect to the compounds having the general formula (C).
[0166] V is N, or CR.sup.6. [0167] X.sup.1 is O, S, or NR.sup.8,
preferably X.sup.1 is O. [0168] X.sup.2 is NR.sup.5,
N(R.sup.5)C(O), C(O)NR.sup.5, O, C(O), C(O)O, OC(O); S, SO,
SO.sub.2, SO.sub.2N(R.sup.5) or N(R.sup.5)SO.sub.2. Preferably,
X.sup.2 is NR.sup.5 or N(R.sup.5)SO.sub.2. [0169] R* is --H, -Hal,
-(optionally substituted C.sub.1-6 alkyl), -(optionally substituted
mono- or polycyclic group containing 3 to 20 carbon atoms and
optionally 1 to 4 heteroatoms selected from O, N and S),
--C.sub.1-4 alkyl-(optionally substituted mono- or polycyclic group
containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms
selected from O, N and S), or --X.sup.2--R.sup.1. Preferably R* is
H, -(optionally substituted C.sub.1-6 alkyl), -(optionally
substituted C.sub.3-7 cycloalkyl) or --X.sup.2--R.sup.1. [0170]
R.sup.1 is --H, -(optionally substituted C.sub.1-6 alkyl),
-(optionally substituted mono- or polycyclic group containing 3 to
20 carbon atoms and optionally 1 to 4 heteroatoms selected from O,
N and S), --C.sub.1-4 alkyl-(optionally substituted mono- or
polycyclic group containing 3 to 20 carbon atoms and optionally 1
to 4 heteroatoms selected from O, N and S). Preferably R.sup.1 is
--C.sub.1-4 alkyl-(optionally substituted mono- or polycyclic group
containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms
selected from O, N and S). [0171] R.sup.2 is --H, -(optionally
substituted C.sub.1-6 alkyl), -(optionally substituted C.sub.3-7
cycloalkyl), -(optionally substituted aryl), --C.sub.1-4
alkyl-(optionally substituted C.sub.3-7 cycloalkyl), or --C.sub.1-4
alkyl-(optionally substituted aryl) or if X.sup.1 is NR' then
R.sup.2 can also be --OH. Preferably, R.sup.2 is --H or --C.sub.1-6
alkyl. [0172] R.sup.3 is --H, --R.sup.7, or --X.sup.2--R.sup.7.
Preferably R.sup.3 is --H, --C.sub.1-4 alkyl-(optionally
substituted aryl) or --SO.sub.2--R.sup.5. Preferably R.sup.3 is
--H. [0173] R.sup.4 is --H, -(optionally substituted C.sub.1-6
alkyl), -(optionally substituted C.sub.3-7 cycloalkyl),
-(optionally substituted aryl), --C.sub.1-4 alkyl-(optionally
substituted C.sub.3-7 cycloalkyl), or --C.sub.1-4 alkyl-(optionally
substituted aryl). Preferably, R.sup.4 is --H, or -(optionally
substituted C.sub.1-6 alkyl). [0174] R.sup.5 is --H, -(optionally
substituted C.sub.1-6 alkyl), -(optionally substituted C.sub.3-7
cycloalkyl), -(optionally substituted aryl), --C.sub.1-4
alkyl-(optionally substituted C.sub.3-7 cycloalkyl), or --C.sub.1-4
alkyl-(optionally substituted aryl). Preferably R.sup.5 is
--C.sub.1-4 alkyl-(optionally substituted aryl) or -(optionally
substituted C.sub.3-7 cycloalkyl). [0175] R.sup.6 H, --C.sub.1-6
alkyl, -aryl, halogen or CN. Preferably, R.sup.6 is H or -aryl.
[0176] R.sup.7 is -(optionally substituted hydrocarbon group which
contains from 5 to 20 carbon atoms and optionally 1 to 4
heteroatoms selected from O, N and S and which contains at least
one ring). Preferably, R.sup.7 is --C.sub.1-4 alkyl-(optionally
substituted aryl). [0177] R.sup.8 is --H, --C.sub.1-6 alkyl or
--C.sub.1-4 alkyl-(optionally substituted aryl). Preferably,
R.sup.8 is --C.sub.1-6 alkyl or --C.sub.1-4 alkyl-(optionally
substituted aryl). [0178] n is 0 to 4, preferably 0 or 1. [0179]
The optional substituent of the alkyl group can be selected from
the group consisting of halogen, --CN, --NR.sup.5R.sup.5, --OH, and
--O--C.sub.1-6 alkyl. [0180] The optional substituent of the
cycloalkyl group, the aryl group, the mono- or polycyclic group or
the hydrocarbon group can be selected from the group consisting of
--C.sub.1-6 alkyl, halogen, --CF.sub.3, --CN, --X.sup.2--C.sub.1-6
alkyl and --C.sub.1-6 alkyl-aryl.
[0181] Various modifications and variations of the invention will
be apparent to those skilled in the art without departing from the
scope of the invention. Although the invention has been described
in connection with specific preferred embodiments, it should be
understood that the invention as claimed should not be unduly
limited to such specific embodiments. Indeed, various modifications
of the described modes for carrying out the invention which are
obvious to those skilled in the relevant fields are intended to be
covered by the present invention.
[0182] The following examples are merely illustrative of the
present invention and should not be construed to limit the scope of
the invention as indicated by the appended claims in any way.
EXAMPLES
FRET Endonuclease Activity Assay
[0183] The influenza A virus (IAV) PA-Nter fragment (amino acids
1-209) harbouring the influenza endonuclease activity was generated
and purified as described in Dias et al., Nature 2009; April 16;
458(7240), 914-918. The protein was dissolved in buffer containing
20 mM Tris pH 8.0, 100 mM NaCl and 10 mM .beta.-mercaptoethanol and
aliquots were stored at -20.degree. C.
[0184] A 20 bases dual-labelled RNA oligo with 5'-FAM fluorophore
and 3'-BHQ1 quencher was used as a substrate to be cleaved by the
endonuclease activity of the PA-Nter. Cleavage of the RNA substrate
frees the fluorophore from the quencher resulting in an increase of
the fluorescent signal.
[0185] All assay components were diluted in assay buffer containing
20 mM Tris-HCl pH 8.0, 100 mM NaCl, 1 mM MnCl.sub.2, 10 mM
MgCl.sub.2 and 10 mM .beta.-mercaptoethanol. The final
concentration of PA-Nter was 0.5 .mu.M and 1.6 .mu.M RNA substrate.
The test compounds were dissolved in DMSO and generally tested at
two concentrations or a concentration series resulting in a final
plate well DMSO concentration of 0.5%. In those cases where the
compounds were not soluble at that concentration, they were tested
at the highest soluble concentration. SAV-6004 was used as a
reference in the assay at a concentration of 0.1 .mu.M.
[0186] 5 .mu.l of each compound dilution was provided in the wells
of white 384-well microtiter plates (PerkinElmer) in eight
replicates. After addition of PA-Nter dilution, the plates were
sealed and incubated for 30 min at room temperature prior to the
addition of 1.6 .mu.M RNA substrate diluted in assay buffer.
Subsequently, the increasing fluorescence signal of cleaved RNA was
measured in a microplate reader (Synergy HT, Biotek) at 485 nm
excitation and 535 nm emission wavelength. The kinetic read
interval was 35 sec at a sensitivity of 35. Fluorescence signal
data over a period of 20 min were used to calculate the initial
velocity (v0) of substrate cleavage. Final readout was the %
reduction of v0 of compound-treated samples compared to untreated.
The half maximal inhibitory concentration (IC.sub.50) is a measure
of the effectiveness of a compound in inhibiting biological or
biochemical function and was calculated from the initial reaction
velocities (v0) in a given concentration series ranging from
maximum 100 .mu.M to at least 2 nM.
Cytopathic Effect (CPE) Assay
[0187] The influenza A virus (IAV) was obtained from American
Tissue Culture Collection (A/Aichi/2/68 (H3N2); VR-547). Virus
stocks were prepared by propagation of virus on Mardin-Darby canine
kidney (MDCK; ATCC CCL-34) cells and infectious titres of virus
stocks were determined by the 50% tissue culture infective dose
(TCID.sub.50) analysis as described in Reed, L. J., and H. Muench.
1938, Am. J. Hyg. 27:493-497.
[0188] MDCK cells were seeded in 96-well plates at 2.times.10.sup.4
cells/well using DMEM/Ham's F-12 (1:1) medium containing 10% foetal
bovine serum (FBS), 2 mM L-glutamine and 1% antibiotics (all from
PAA). Until infection the cells were incubated for 5 hrs at
37.degree. C., 5.0% CO.sub.2 to form a .about.80% confluent
monolayer on the bottom of the well. Each test compound was
dissolved in DMSO and generally tested at 25 .mu.M and 250 .mu.M.
In those cases where the compounds were not soluble at that
concentration they were tested at the highest soluble
concentration. The compounds were diluted in infection medium
(DMEM/Ham's F-12 (1:1) containing 5 .mu.g/ml trypsin, and 1%
antibiotics) for a final plate well DMSO concentration of 1%. The
virus stock was diluted in infection medium (DMEM/Ham's F-12 (1:1)
containing 5 .mu.g/ml Trypsin, 1% DMSO, and 1% antibiotics) to a
theoretical multiplicity of infection (MOI) of 0.05.
[0189] After removal of the culture medium and one washing step
with PBS, virus and compound were added together to the cells. In
the wells used for cytotoxicity determination (i.e. in the absence
of viral infection), no virus suspension was added. Instead,
infection medium was added. Each treatment was conducted in two
replicates. After incubation at 37.degree. C., 5% CO.sub.2 for 48
hrs, each well was observed microscopically for apparent
cytotoxicity, precipitate formation, or other notable
abnormalities. Then, cell viability was determined using
CellTiter-Glo luminescent cell viability assay (Promega). The
supernatant was removed carefully and 65 .mu.l of the reconstituted
reagent were added to each well and incubated with gentle shaking
for 15 min at room temperature. Then, 60 .mu.l of the solution was
transferred to an opaque plate and luminescence (RLU) was measured
using Synergy HT plate reader (Biotek).
[0190] Relative cell viability values of uninfected-treated versus
uninfected-untreated cells were used to evaluate cytotoxicity of
the compounds. Substances with a relative viability below 80% at
the tested concentration were regarded as cytotoxic and retested at
lower concentrations.
[0191] Reduction in the virus-mediated cytopathic effect (CPE) upon
treatment with the compounds was calculated as follows: The
response (RLU) of infected-untreated samples was subtracted from
the response (RLU) of the infected-treated samples and then
normalized to the viability of the corresponding uninfected sample
resulting in % CPE reduction. The half maximal inhibitory
concentration (IC.sub.50) is a measure of the effectiveness of a
compound in inhibiting biological or biochemical function and was
calculated from the RLU response in a given concentration series
ranging from maximum 100 .mu.M to at least 100 nM.
Compounds Having the General Formula (A)
##STR00011##
[0192] General Procedure
Synthesis of 2-Aminoacetonitrile (I-1) and 5-Aminothiazole-2-Thiol
(I-2)
[0193] A solution of sodium methoxide, prepared from sodium (23 g,
1.0 mol) in dry methanol (500 mL), was added dropwise under
ice-cooling to a stirred suspension of aminoacetonitrile
hydrochloride (100 g, 1.08 mol) in dry methanol (100 mL). This
reaction mixture was stirred for 2 hours at room temperature
(r.t.), then the mixture was concentrated in vacuo, the residue was
dissolved in dry ethyl acetate (500 mL), the mixture was filtered
and the filtrate was dropwise added to the solution of carbon
disulfide (136 g, 1.79 mol) in dry ethyl acetate (100 mL). The
reaction mixture was stirred for overnight while the temperature
rose from 0.degree. C. to room temperature. The precipitate was
filtered to afford the crude product I-2 as yellow solid 107.4 g,
yield 75.6%.
Synthesis of 2-aminoacetonitrile (I-3)
[0194] A solution of sodium methoxide, prepared from sodium (18.7
g, 0.814 mol) in dry methanol (600 ml), was cooled to -78.degree.
C., compound I-2 was added at -78.degree. C. To this red-brown
solution, methyl iodide (115 g, 0.814 mmol) was dropwise added at
-78.degree. C. This reaction mixture was stirred for 3h at
-78.degree. C. The methanol was removed in vacuo and the residue
was extracted with ethyl acetate (EA) and water, the organic phase
was dried and concentrated in vacuo to afford the crude product I-3
as brown oil 117 g, yield 98%.
Synthesis of 2-aminoacetonitrile (I-4)
[0195] The compound I-3 (117 g, 0.801 mmol) was dissolved in
ethanol (400 ml) and diethyl ethoxymethylenemalonate was added.
This reaction mixture was stirred for 3 h at reflux. Then the
mixture was cooled to r.t. The precipitate was filtered to afford
the product I-4 as brown solid 163 g, yield 64%.
Synthesis of 2-aminoacetonitrile (I-5)
[0196] The compound I-4 (20 g, 63.6 mmol) was added to diphenyl
ether (150 mL). The mixture was heated to 250.degree. C. for 40
min. Then the mixture was cooled to r.t. and was added to
petrolether (PE). The precipitate was filtered to afford the
product I-5 as brown solid 16 g, yield 94%.
Synthesis of 2-aminoacetonitrile (I-6)
[0197] The compound I-5 (6.5 g, 24.07 mmol),
2-(bromomethyl)biphenyl (6.5 g, 26.48 mmol) and potassium carbonate
(6.6 g, 48.14 mmol) were added to methylsulfinylmethane (60 mL).
This reaction mixture was stirred for overnight at r.t. The mixture
was extracted with EA and water, the organic phase was concentrated
in vacuo to afford the crude product which was purified by column
chromatography on silica gel with EA to afford the product I-6 as
brown solid 7.4 g, yield 70.5%.
Synthesis of 2-aminoacetonitrile (I-7)
[0198] The compound I-6 (3.1 g, 0.711 mmol) and m-CPBA (3.0 g,
17.775 mmol) were added to dichloromethane (DCM) (20 mL). This
reaction mixture was stirred for 5 h at r.t. The mixture was
extracted with DCM and a saturated NaHCO.sub.3 solution. The
organic phase was concentrated in vacuo to afford the crude product
I-7 as yellow solid 3.2 g, yield 97%.
Representative synthetic method of 2-aminoacetonitrile
(I.sub.4-8)
[0199] The compound I-7 (200 mg, 0.427 mmol), phenylmethanamine
(183 mg, 1.709 mmol) and potassium carbonate (118 mg, 0.854 mmol)
were added to dimethylsulfoxide (DMSO) (3 mL). This reaction
mixture was stirred overnight at r.t. This mixture was extracted
with DCM and water, the organic phase was concentrated in vacuo to
afford the crude product I-8 as brown oil 180 mg, yield 85%.
Representative synthetic method of 2-aminoacetonitrile
(I.sub.4)
[0200] The compound I.sub.4-8 (62 mg, 0.125 mmol) was dissolved in
EtOH (6 mL), then lithium hydroxide hydrate (21 mg, 0.501 mmol) was
added. This reaction mixture was stirred for 4 h at r.t. The
mixture was adjusted to pH=5 with HCl, the precipitate was filtered
to afford the product I.sub.4 as pale white solid 32 mg, yield
55%.
Example 1
4-(Biphenyl-2-ylmethyl)-7-oxo-2-(phenylsulfonamido)-4,7-dihydrothiazolo[5,-
4-b]pyridine-6-carboxylic acid (F4)
##STR00012##
[0202] I-7 (I-7') was treated with phenylsulfonamide according to
the representative method to obtain compound F4 as a pale white
solid.
[0203] Yield: 5%
[0204] MS (ESI): 518(M+H).sup.+, 105
[0205] .sup.1H NMR (d.sub.6-DMSO, 300 Hz):
[0206] .delta. 8.46 (br, s, 1H), 7.34-7.73 (m, 14H), 5.35 (s,
2H)
Example 2
4-(Biphenyl-2-ylmethyl)-2-(methylamino)-7-oxo-4,7-dihydrothiazolo[5,4-b]py-
ridine-6-carboxylic acid (I1)
##STR00013##
[0208] I-7 (I-7') was treated with methanamine according to the
representative method to obtain compound I1 as a pale white
solid.
[0209] Yield: 5%
[0210] MS (ESI): 392 (M+H).sup.+, 157
[0211] .sup.1H NMR (d.sub.6-DMSO, 300 Hz):
[0212] .delta. 8.39 (s, 1H), 8.06-8.07 (br, s, 1H), 7.23-7.51 (m,
9H), 5.58 (s, 2H), 2.84 (d, J=4.8 Hz, 3H)
Example 3
4-(Biphenyl-2-ylmethyl)-2-(cyclopropylamino)-7-oxo-4,7-dihydrothiazolo[5,4-
-b]pyridine-6-carboxylic acid (I2)
##STR00014##
[0214] I-7 (I-7') was treated with aminocyclopropane according to
the representative method to obtain compound I2 as a pale white
solid.
[0215] Yield: 5%
[0216] MS (ESI): 418 (M+H).sup.+
[0217] 1HNMR (d6-DMSO, 300 MHz):
[0218] .delta. 8.59 (s, 1H), 8.48 (s, 1H), 7.49-7.25 (m, 9H), 5.59
(s, 2H), 2.57 (d, J=1.8 Hz, 1H), 0.72 (m, 2H), 0.47 (m, 2H).
Example 4
4-(Biphenyl-2-ylmethyl)-2-(cyclopentylamino)-7-oxo-4,7-dihydrothiazolo[5,4-
-b]pyridine-6-carboxylic acid (I3)
##STR00015##
[0220] I-7 (I-7') was treated with aminocyclopentane according to
the representative method to obtain compound I3 as a yellow
solid.
[0221] Yield: 5%
[0222] MS (ESI): 446 (M+H).sup.+, 407
[0223] .sup.1HNMR (d.sub.5-DMSO, 300 MHz):
[0224] .delta. 8.42 (s, 1H), 8.16 (d, J=6.0 Hz, 1H), 7.48-7.24 (m,
10H), 5.57 (s, 2H), 4.03 (d, J=6.0 Hz, 2H), 1.89-1.85 (m, 2H),
1.63-1.41 (m, 7H)
Example 5
2-(Benzylamino)-4-(biphenyl-2-ylmethyl)-7-oxo-4,7-dihydrothiazolo[5,4-b]py-
ridine-6-carboxylic acid (I4)
##STR00016##
[0226] I-7 (I-7') was treated with benzylamine according to the
representative method to obtain compound I4 as a pale white
solid.
[0227] Yield: 5%
[0228] MS (ESI): 468 (M+H).sup.+
[0229] .sup.1HNMR (d.sub.5-DMSO, 300 MHz):
[0230] .delta. 8.60 (s, 1H), 8.43 (s, 1H), 7.48-7.25 (m, 14H), 5.57
(s, 2H), 4.49 (d, J=4.5 Hz, 2H)
Example 6
4-(Biphenyl-2-ylmethyl)-7-oxo-2-(pyrrolidin-1-yl)-4,7-dihydrothiazolo[5,4--
b]pyridine-6-carboxylic acid (I5)
##STR00017##
[0232] I-7 (I-7') was treated with pyrrolidine according to the
representative method to obtain compound I5 as a pale white
solid.
[0233] Yield: 5%
[0234] MS (ESI): 433 (M+H).sup.+
[0235] .sup.1HNMR (d.sub.5-DMSO, 300 MHz):
[0236] .delta. 8.43 (s, 1H), 7.50-7.269 (m, 9H), 5.54 (d, J=8.4 Hz,
2H), 3.32 (s, 5H), 1.95 (s, 4H)
Example 7
4-(Biphenyl-2-ylmethyl)-2-(4-hydroxypiperidin-1-yl)-7-oxo-4,7-dihydrothiaz-
olo[5,4-b]pyridine-6-carboxylic acid (I6)
##STR00018##
[0238] I-7 (I-7') was treated with piperidin-4-ol according to the
representative method to obtain compound I6 as a yellow solid.
[0239] Yield: 3%
[0240] MS (ESI): 462 (M+H).sup.+
[0241] .sup.1HNMR (d.sub.5-DMSO, 300 MHz):
[0242] .delta. 16.20 (br, s, 1H), 8.45 (s, 1H,), 7.51-7.23 (m,
10H), 5.55 (d, J=7.8 Hz, 2H), 3.76-3.21 (m, 7H), 1.70-1.78 (m, 2H),
1.39-1.48 (m, 2H)
Example 8
4-(Biphenyl-2-ylmethyl)-7-oxo-2-(piperazin-1-yl)-4,7-dihydrothiazolo[5,4-b-
]pyridine-6-carboxylic acid (I7)
##STR00019##
[0244] I-7 (I-7') was treated with piperazine according to the
representative method to obtain compound I7 as a yellow solid.
[0245] Yield: 3%
[0246] MS (ESI): 447 (M+H).sup.+
[0247] .sup.1HNMR (d.sub.5-DMSO, 300 MHz):
[0248] .delta. 9.07 (s, 2H), 8.52 (s, 1H), 7.49-7.23 (m, 10H), 5.61
(s, 2H), 3.63 (s, 4H), 3.22 (s, 4H)
Example 9
2-(4-Benzylpiperazin-1-yl)-4-(biphenyl-2-ylmethyl)-7-oxo-4,7-dihydrothiazo-
lo[5,4-b]pyridine-6-carboxylic acid (I8)
##STR00020##
[0250] I-7 (I-7') was treated with 1-benzylpiperazine according to
the representative method to obtain compound I8 as a yellow
solid.
[0251] Yield: 5%
[0252] MS (ESI): 537 (M+H).sup.+
[0253] .sup.1HNMR (d.sub.6-DMSO, 300 MHz):
[0254] .delta. 8.55 (s, 1H), 7.49-7.22 (m, 14H), 5.61 (s, 2H), 4.30
(s, 2H), 3.16-3.39 (m, 8H)
Example 10
4-(Biphenyl-2-ylmethyl)-7-oxo-2-(piperidin-1-yl)-4,7-dihydrothiazolo[5,4-b-
]pyridine-6-carboxylic acid (I9)
##STR00021##
[0256] I-7 (I-7') was treated with piperidine according to the
representative method to obtain compound I9 as a pale white
solid.
[0257] Yield: 5%
[0258] MS (ESI): 446 (M+H).sup.+
[0259] .sup.1HNMR (d.sub.6-DMSO, 300 MHz):
[0260] .delta. 16.22 (s, 1H), 8.45 (s, 1H), 7.49-7.24 (m, 9H), 5.58
(s, 2H), 3.41-3.42 (m, 4H), 1.57 (s, 6H)
Example 11
4-(Biphenyl-2-ylmethyl)-2-(4-methylpiperidin-1-yl)-7-oxo-4,7-dihydrothiazo-
lo[5,4-b]pyridine-6-carboxylic acid (I10)
##STR00022##
[0262] I-7 (I-7') was treated with 4-methylpiperidine according to
the representative method to obtain compound I10 as a pale white
solid.
[0263] Yield: 5%
[0264] MS (ESI): 460 (M+H).sup.+
[0265] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0266] .delta. 8.44 (s, 1H), 7.25-7.51 (m, 9H), 5.58 (s, 2H),
3.67-3.71 (m, 2H), 3.02-3.10 (t, J=12 Hz, 2H), 1.57-1.70 (m, 3H)
1.11-1.17 (m, 2H), 0.90 (d, J=6.9 Hz, 3H)
Example 12
4-(Biphenyl-2-ylmethyl)-2-(isopropylamino)-7-oxo-4,7-dihydrothiazolo[5,4-b-
]pyridine-6-carboxylic acid (I11)
##STR00023##
[0268] I-7 (I-7') was treated with 2-aminopropane according to the
representative method to obtain compound I11 as a yellow solid.
[0269] Yield: 5%
[0270] MS (ESI): 420 (M+H).sup.+, 105
[0271] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0272] .delta. 8.42 (s, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.23-7.51 (m,
9H), 5.56 (s, 2H), 3.85-3.91 (m, 1H), 1.13 (d, J=6.6 Hz, 6H)
Example 13
4-(Biphenyl-2-ylmethyl)-2-(2-methoxyethylamino)-7-oxo-4,7-dihydrothiazolo[-
5,4-b]pyridine-6-carboxylic acid (I12)
##STR00024##
[0274] I-7 (I-7') was treated with 2-methoxyethanamine according to
the representative method to obtain compound I12 as a pale white
solid.
[0275] Yield: 5%
[0276] MS (ESI): 436 (M+H).sup.+
[0277] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0278] .delta. 8.43 (s, 1H), 8.25 (s, 1H), 7.23-7.51 (m, 9H), 5.57
(s, 2H), 3.45-3.50 (m, 4H), 3.25 (s, 3H)
Example 14
4-(Biphenyl-2-ylmethyl)-2-(4-methyl
piperazin-1-yl)-7-oxo-4,7-dihydrothiazolo[5,4-b]pyridine-6-carboxylic
acid (I14)
##STR00025##
[0280] I-7 (I-7') was treated with 1-methylpiperazine according to
the representative method to obtain compound I14 as a yellow
solid.
[0281] Yield: 2%
[0282] MS (ESI): 461 (M+H).sup.+, 157, 231
[0283] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0284] .delta. 9.89 (s, 1H), 8.54 (s, 1H), 7.21-7.49 (m, 9H), 5.62
(s, 2H), 3.94-3.97 (br, 2H), 3.33-3.48 (m, 4H), 3.12-3.17 (m, 2H),
2.84 (s, 3H).
Example 15
4-(Biphenyl-2-ylmethyl)-2-morpholino-7-oxo-4,7-dihydrothiazolo[5,4-b]pyrid-
ine-6-carboxylic acid (I15)
##STR00026##
[0286] I-7 (I-7') was treated with morpholine according to the
representative method to obtain compound I15 as a yellow solid.
[0287] Yield: 2%
[0288] MS (ESI): 448 (M+H).sup.+, 157
[0289] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0290] .delta. 8.41 (s, 1H), 7.24-7.48 (m, 9H), 5.59 (s, 2H),
3.66-3.68 (m, 4H), 3.40-3.41 (m, 4H)
Example 16
4-(Biphenyl-2-ylmethyl)-N-methyl-2-(methylamino)-7-oxo-4,7-dihydrothiazolo-
[5,4-b]pyridine-6-carboxamide (I16)
##STR00027##
[0292] I-7 (I-7') was treated with methanamine according to the
representative method to obtain compound I16 as a yellow solid.
[0293] Yield: 5%
[0294] MS (ESI): 405 (M+H).sup.+
[0295] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0296] .delta. 10.16 (br, s, 1H), 8.39 (s, 1H), 7.84 (br, s, 1H),
7.29-7.48 (m, 8H), 7.08-7.10 (d, J=6.9 Hz, 1H), 5.43 (s, 2H), 2.83
(s, 3H), 2.81 (s, 3H)
Example 17
2-(Benzylamino)-4-(biphenyl-2-ylmethyl)-N-methyl-7-oxo-4,7-dihydrothiazolo-
[5,4-b]pyridine-6-carboxamide (I17)
##STR00028##
[0298] The ethyl ester precursor of 14 was treated with methanamine
according to the representative method to obtain compound I17 as a
pale white solid.
[0299] Yield: 5%
[0300] MS (ESI): 481 (M+H).sup.+
[0301] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0302] .delta. 10.15 (s, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 7.68-7.72
(m, 1H), 7.28-7.48 (m, 13H), 7.09 (d, J=7.5 Hz, 1H), 5.42 (s, 2H),
4.45 (d, J=5.1 Hz, 2H), 2.82 (d, J=4.2 Hz, 3H)
Example 18
4-(Biphenyl-2-ylmethyl)-N-methyl-7-oxo-2-(pyrrolidin-1-yl)-4,7-dihydrothia-
zolo[5,4-b]pyridine-6-carboxamide (I18)
##STR00029##
[0304] The ethyl ester precursor of 15 was treated with methanamine
according to the representative method to obtain compound I18 as a
pale white solid.
[0305] Yield: 5%
[0306] MS (ESI): 445 (M+H).sup.+, 157
[0307] .sup.1H NMR (CDCl.sub.3, 300 MHz):
[0308] .delta. 10.28 (s, 1H), 8.32 (s, 1H), 7.22-7.46 (m, 8H), 7.08
(d, J=7.8 Hz, 1H), 5.15 (s, 2H), 3.67 (s, 4H), 2.97 (d, J=4.5 Hz,
3H), 2.02 (s, 4H)
Example 19
N-Benzyl-2-(benzylamino)-4-(biphenyl-2-ylmethyl)-7-oxo-4,7-dihydrothiazolo-
[5,4-b]pyridine-6-carboxamide (I19)
##STR00030##
[0310] I4 was treated with benzylamine according to the
representative method to obtain compound I19 as a brown solid.
[0311] Yield: 2%
[0312] MS (ESI): 557 (M+H).sup.+, 105.
[0313] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0314] .delta. 10.75 (s, 1H ), 8.42 (s, 1H), 8.39 (s, 1H),
7.25-7.46 (m, 18H), 7.14 (d, J=7.2 Hz, 1H), 5.44 (s, 2H), 4.52 (d,
J=5.4 Hz, 2H), 4.44 (d, J=5.7 Hz, 2H)
Example 20
4-(Biphenyl-2-ylmethyl)-7-oxo-2-(phenyl
methylsulfonamido)-4,7-dihydrothiazolo[5,4-b]pyridine-6-carboxylic
acid (I20)
##STR00031##
[0316] I-7 (I-7') was treated with benzylsulfonamide according to
the representative method to obtain compound I20 as a pale white
solid.
[0317] Yield: 5%
[0318] MS (ESI): 532 (M+H).sup.+
[0319] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0320] .delta. 8.51 (s, 1H), 7.20-7.54 (m, 14H), 5.53 (s, 2H), 4.36
(s, 2H)
Example 21
4-(Biphenyl-2-ylmethyl)-2-(3-fluorophenylsulfonamido)-7-oxo-4,7-dihydrothi-
azolo[5,4-b]pyridine-6-carboxylic acid (I21)
##STR00032##
[0322] I-7 (I-7') was treated with 3-fluorobenzylsulfonamide
according to the representative method to obtain compound I21 as a
pale white solid.
[0323] Yield: 5%
[0324] MS (ESI): 286 (M+H).sup.+, 157, 105.
[0325] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0326] .delta. 8.53 (s, 1H), 7.24-7.57 (m, 13H), 5.63 (s, 2H)
Example 22
4-(Biphenyl-2-ylmethyl)-2-(methylsulfonamido)-7-oxo-4,7-dihydrothiazolo[5,-
4-b]pyridine-6-carboxylic acid (I22)
##STR00033##
[0328] I-7 (I-7') was treated with methylsulfonamide according to
the representative method to obtain compound I22 as a pale white
solid.
[0329] Yield: 5%
[0330] MS (ESI): 456(M+H).sup.+
[0331] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0332] .delta. 8.55 (s, 1H), 7.26-7.50 (m, 9H), 5.60 (s, 2H), 2.96
(s, 3H)
Example 23
4-(Biphenyl-2-ylmethyl)-2-(2-chlorobenzylamino)-7-oxo-4,7-dihydrothiazolo[-
5,4-b]pyridine-6-carboxylic acid (I.sub.1A)
##STR00034##
[0334] I-7 (I-7') was treated with 2-chlorobenzylamine according to
the representative method to obtain compound I.sub.1A as a pale
white solid.
[0335] Yield: 4%
[0336] MS (ESI): 502 (M+H).sup.+
[0337] .sup.1H NMR (d.sub.6-DMSO, 300 Hz):
[0338] .delta. 8.62 (br, s, 1H), 8.44 (s, 1H), 7.24-7.49 (m, 13H),
5.59 (s, 2H), 4.57 (d, J=3.9 Hz, 2H)
Example 24
Ethyl-4-(biphenyl-2-ylmethyl)-2-(2-chlorobenzylamino)-7-oxo-4,7-dihydrothi-
azolo[5,4-b]pyridine-6-carboxylate (I.sub.1A-h)
##STR00035##
[0340] I-7 (I-7') was treated with 2-chlorobenzylamine according to
the representative method to obtain compound I.sub.1A-h as a pale
white solid.
[0341] Yield: 4%
[0342] MS (ESI): 531(M+H).sup.+, 169
[0343] .sup.1H NMR (d.sub.5-DMSO, 400 Hz):
[0344] .delta. 8.31 (br, s, 1H), 8.07 (s, 1H), 7.20-7.46 (m, 13H),
5.36 (s, 2H), 4.51 (d, J=3.9 Hz, 2H), 4.16 (q, J=6.8 Hz, 2H), 1.26
(t, J=7.2 Hz, 3H)
Example 25
4-(Biphenyl-2-ylmethyl)-2-(3-chlorobenzylamino)-7-oxo-4,7-dihydrothiazolo[-
5,4-b]pyridine-6-carboxylic acid (I.sub.2A)
##STR00036##
[0346] I-7 (I-7') was treated with 3-chlorobenzylamine according to
the representative method to obtain compound I.sub.2A as a pale
white solid.
[0347] Yield: 3%
[0348] MS (ESI): 502 (M+H).sup.+, 405
[0349] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0350] .delta. 8.64 (s, 1H), 8.44 (s, 1H), 7.50-7.23 (m, 13H), 5.59
(s, 2H), 4.51 (d, J=9.2 Hz, 2H).
Example 26
Ethyl
4-(biphenyl-2-ylmethyl)-2-(3-chlorobenzylamino)-7-oxo-4,7-dihydrothi-
azolo[5,4-b]pyridine-6-carboxylate (I.sub.2A-h)
##STR00037##
[0352] I-7 (I-7') was treated with 3-chlorobenzylamine according to
the representative method to obtain compound I.sub.2A-h as a pale
white solid.
[0353] Yield: 4%
[0354] MS (ESI): 530 (M+H).sup.+
[0355] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0356] .delta. 8.39 (s, 1H), 8.10 (s, 1H), 7.48-7.21 (m, 13H), 5.39
(s, 2H), 4.47 (d, J=4.4 Hz, 2H), 4.19 (q, J=7.2 Hz, 2H), 1.27 (t,
J=7.2 Hz, 2H)
Example 27
4-(Biphenyl-2-ylmethyl)-2-(4-chlorobenzylamino)-7-oxo-4,7-dihydrothiazolo[-
5,4-b]pyridine-6-carboxylic acid (I.sub.3A)
##STR00038##
[0358] I-7 (I-7') was treated with 4-chlorobenzylamine according to
the representative method to obtain compound I.sub.3A as a pale
white solid.
[0359] Yield: 3%
[0360] MS (ESI): 502 (M+H).sup.+
[0361] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0362] .delta. 8.63 (s, 1H), 8.44 (s, 1H), 7.48-7.23 (m, 13H), 5.58
(s, 2H), 4.48 (d, J=5.2 Hz, 2H)
Example 28
Ethyl
4-(biphenyl-2-ylmethyl)-2-(4-chlorobenzylamino)-7-oxo-4,7-dihydrothi-
azolo[5,4-b]pyridine-6-carboxylate (I.sub.3A-h)
##STR00039##
[0364] I-7 (I-7') was treated with 4-chlorobenzylamine according to
the representative method to obtain compound I.sub.3A-h as a yellow
solid.
[0365] Yield: 3%
[0366] MS (ESI): 531 (M+H).sup.+
[0367] .sup.1HNMR (d.sub.6-DMSO, 400 MHz), .delta.8.31 (s, 1H),
8.06 (s, 1H), 7.48-7.16 (m, 13H), 5.35 (s, 2H), 4.43 (d, J=5.2 Hz,
2H), 4.16 (q, J=6.8 Hz, 2H), 1.26 (t, J=6.8 Hz, 3H)
Example 29
4-(Biphenyl-2-ylmethyl)-2-(4-methoxybenzylamino)-7-oxo-4,7-dihydrothiazolo-
[5,4-b]pyridine-6-carboxylic acid (I.sub.4A)
##STR00040##
[0369] I-7 (I-7') was treated with 4-methoxybenzylamine according
to the representative method to obtain compound I.sub.4A as a pale
white solid.
[0370] Yield: 11%
[0371] MS (ESI): 498 (M+H).sup.+, 405
[0372] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0373] .delta. 16.38 (s, 1H), 8.44 (s, 1H), 7.42-7.23 (m, 11H),
6.89 (d, J=8.0 Hz, 2H), 5.57 (s, 2H), 4.40 (d, J=5.6 Hz, 2H), 3.73
(s, 3H)
Example 30
Ethyl
4-(biphenyl-2-ylmethyl)-2-(4-methoxybenzylamino)-7-oxo-4,7-dihydroth-
iazolo[5,4-b]pyridine-6-carboxylate (I.sub.4A-h)
##STR00041##
[0375] I-7 (I-7') was treated with 4-methoxybenzylamine according
to the representative method to obtain compound I.sub.4A-h as a
pale white solid.
[0376] Yield: 5%
[0377] MS (ESI): 526 (M+H).sup.+, 405
[0378] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0379] .delta. 8.26 (s, 1H), 8.09 (s, 1H), 7.47-7.18 (m, 11H), 6.87
(d, J=8.4 Hz, 2H), 5.37 (s, 2H), 4.35 (d, J=4.8 Hz, 2H), 4.17 (q,
J=6.8 Hz, 2H), 1.27 (t, J=6.8 Hz, 3H)
Example 31
4-Benzhydryl-2-(4-methoxybenzylamino)-7-oxo-4,7-dihydrothiazolo[5,4-b]pyri-
dine-6-carboxylic acid (I.sub.4D)
##STR00042##
[0381] The analogue of I-7 (I-7') with diphenylmethyl substitution
was treated with 4-methoxybenzylamine according to the
representative method to obtain compound I.sub.4D as a pale white
solid.
[0382] Yield: 5%
[0383] MS (ESI): 498 (M+H).sup.+
[0384] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0385] .delta. 8.63 (s, 1H), 8.03 (s, 1H), 7.47-7.49 (m, 6H),
7.25-7.29 (m, 6H), 7.11 (s, 1H), 6.88 (d, J=8.0 Hz, 2H), 4.45 (d,
J=5.2 Hz, 2H), 3.73 (s, 3H)
Example 32
4-(Biphenyl-2-ylmethyl)-2-(2,6-dichlorobenzylamino)-7-oxo-4,7-dihydrothiaz-
olo[5,4-b]pyridine-6-carboxylic acid (I.sub.5A)
##STR00043##
[0387] I-7 (I-7') was treated with 2,5-dichlorobenzylamine
according to the representative method to obtain compound I.sub.5A
as a pink solid.
[0388] Yield: 2%
[0389] MS (ESI): 536 (M+H).sup.+, 405
[0390] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0391] .delta. 8.48 (s, 1H), 8.34 (s, 1H), 7.21-7.53 (m, 12H), 5.58
(s, 2H), 4.70 (d, J=4.0 Hz, 2H)
Example 33
Ethyl 4-(biphenyl-2-yl
methyl)-2-(2,6-dichlorobenzylamino)-7-oxo-4,7-dihydrothiazolo[5,4-b]pyrid-
ine-6-carboxylate (I.sub.5A-h)
##STR00044##
[0393] I-7 (I-7') was treated with 2,5-dichlorobenzylamine
according to the representative method to obtain compound
I.sub.5A-h as a yellow solid.
[0394] Yield: 2%
[0395] MS (ESI): 564 (M+H).sup.+
[0396] .sup.1HNMR d.sub.6-DMSO, 400 MHz):
[0397] .delta.8.15 (s, 1H), 8.08 (s, 1H), 7.21-7.53 (m, 12H), 5.40
(s, 2H), 4.66 (s, 2H), 4.20 (q, J=6.8 Hz, 2H), 1.29 (t, J=6.8 Hz,
3H)
Example 34
4-(Biphenyl-2-ylmethyl)-2-(4-carbamoyl benzylamino)-7-oxo-4,7-di
hydrothiazolo[5,4-b]pyridine-6-carboxamide (I.sub.6A-h')
##STR00045##
[0399] I-7 (I-7') was treated with ethyl 4-(aminomethyl)benzoate
according to the representative method and then ammonia to obtain
compound I.sub.6A-h' as a pale white solid.
[0400] Yield: 1%
[0401] MS (ESI): 510 (M+H).sup.+
[0402] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0403] .delta. 12.99 (s, 1H), 9.59 (s, 1H), 8.39-8.44 (m, 2H),
7.83-7.88 (m, 2H), 7.48-7.56 (m, 12H), 7.12 (d, J=6.8 Hz, 1H), 5.42
(s, 2H), 4.54 (s, 2H)
Example 35
4-(Biphenyl-2-ylmethyl)-7-oxo-2-(1-phenylethylamino)-4,7-dihydrothiazolo[5-
,4-b]pyridine-6-carboxylic acid (I.sub.7A)
##STR00046##
[0405] I-7 (I-7') was treated with 1-phenylethanamine according to
the representative method to obtain compound I.sub.7A as a pale
white solid.
[0406] Yield: 3%
[0407] MS (ESI): 482 (M+H).sup.+
[0408] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0409] .delta. 8.68 (d, J=7.2 Hz, 1H), 8.43 (s, 1H), 7.23-7.50 (m,
14H), 5.56 (s, 2H), 4.89-4.92 (m, 1H), 1.41 (d, J=6.8 Hz, 3H)
Example 36
Ethyl 4-(biphenyl-2-yl
methyl)-7-oxo-2-(1-phenylethylamino)-4,7-dihydrothiazolo[5,4-b]pyridine-6-
-carboxylate (I.sub.7A-h)
##STR00047##
[0411] I-7 (I-7') was treated with 1-phenylethanamine according to
the representative method to obtain compound I.sub.7A-h as a pink
solid.
[0412] Yield: 1%
[0413] MS (ESI): 510 (M+H).sup.+
[0414] .sup.1HNMR d.sub.6-DMSO, 400 MHz):
[0415] .delta. 8.38 (d, J=6.8 Hz, 1H), 8.07 (s, 1H), 7.16-7.46 (m,
14H), 5.38 (s, 2H), 4.83-4.84 (m, 1H), 4.12-4.17 (m, 2H), 1.39 (d,
J=6.0 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H)
Example 37
4-(Biphenyl-2-ylmethyl)-2-(4-chloro-2-fluorophenylsulfonamido)-7-oxo-4,7-d-
ihydrothiazolo[5,4-b]pyridine-6-carboxylic acid (I.sub.9A)
##STR00048##
[0417] I-7 (I-7') was treated with
2-fluoro-4-chlorophenylsulfonamide according to the representative
method to obtain compound I.sub.9A as a pale white solid.
[0418] Yield: 2%
[0419] MS (ESI): 571 (M+H).sup.+
[0420] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0421] .delta. 8.57 (s, 1H), 7.69-7.77 (m, 2H), 7.25-7.55 (m, 10H),
5.65 (s, 2H)
Example 38
Ethyl
4-(biphenyl-2-ylmethyl)-2-(4-chloro-2-fluorophenylsulfonamido)-7-oxo-
-4,7-dihydrothiazolo[5,4-b]pyridine-6-carboxylate (I.sub.9A-h)
##STR00049##
[0423] I-7 (I-7') was treated with
2-fluoro-4-chlorophenylsulfonamide according to the representative
method to obtain compound I.sub.9A-h as a pale white solid.
[0424] Yield: 7%
[0425] MS (ESI): 599 (M+H).sup.+
[0426] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0427] .delta. 8.21 (s, 1H), 7.68-7.77 (m, 2H), 7.26-7.54 (m, 10H),
5.48 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H)
Example 39
4-Benzhydryl-2-(4-chloro-2-fluorophenylsulfonamido)-7-oxo-4,7-dihydrothiaz-
olo[5,4-b]pyridine-6-carboxylic acid (I.sub.9D)
##STR00050##
[0429] The analogue of I-7 (I-7') with diphenylmethyl substitution
was treated with 2-fluoro-4-chlorophenylsulfonamide according to
the representative method to obtain compound I.sub.9D as a pale
white solid.
[0430] Yield: 1%
[0431] MS (ESI): 570 (M+H).sup.+
[0432] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0433] .delta. 8.14 (s, 1H), 7.67-7.74 (m, 2H), 7.40-7.50 (m, 7H),
7.27-7.30 (m, 5H)
Example 40
Ethyl
4-benzhydryl-2-(4-chloro-2-fluorophenylsulfonamido)-7-oxo-4,7-dihydr-
othiazolo[5,4-b]pyridine-6-carboxylate (I.sub.9D-h)
##STR00051##
[0435] The analogue of I-7 (I-7') with diphenylmethyl substitution
was treated with 2-fluoro-4-chlorophenylsulfonamide according to
the representative method to obtain compound I.sub.9D-h as a yellow
solid.
[0436] Yield: 5%
[0437] MS (ESI): 598 (M+H).sup.+
[0438] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0439] .delta. 8.01 (s, 1H), 7.68-7.73 (m, 2H), 7.40-7.49 (m, 7H),
7.29 (s, 4H), 7.12 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 1.14 (t, J=6.8
Hz, 3H)
Example 41
4-(Biphenyl-2-ylmethyl)-2-(4-cyanophenylsulfonamido)-7-oxo-4,7-dihydrothia-
zzol[5,4-b]pyridine-6-carboxylic acid (I.sub.10A)
##STR00052##
[0441] I-7 (I-7') was treated with 4-cyanophenylsulfonamide
according to the representative method to obtain compound I.sub.10A
as a pale white solid.
[0442] Yield: 9%
[0443] MS (ESI): 543 (M+H).sup.+
[0444] .sup.1H NMR (d.sub.6-DMSO, 400 MHz):
[0445] .delta. 8.54 (s, 1H), 8.02 (d, J=8.0 Hz, 2H), 7.83 (d, J=8.0
Hz, 2H), 7.57 (t, J=7.2 Hz, 1H), 7.46-7.49 (t, J=7.6 Hz, 1H),
7.32-7.41 (m, 5H), 7.24 (d, J=7.2 Hz, 2H), 5.64 (s, 2H),
Example 42
Ethyl
4-(biphenyl-2-ylmethyl)-2-(4-cyanophenylsulfonamido)-7-oxo-4,7-dihyd-
rothiazolo[5,4-b]pyridine-6-carboxylate (I.sub.10A-h)
##STR00053##
[0447] I-7 (I-7') was treated with 4-cyanophenylsulfonamide
according to the representative method to obtain compound
I.sub.10A-h as a pale white solid.
[0448] Yield: 2%
[0449] MS (ESI): 571 (M+H).sup.+
[0450] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0451] .delta. 8.20 (s, 1H), 8.03 (d, J=7.6 Hz, 2H), 7.82 (d, J=8.0
Hz, 2H), 7.26-7.55 (m, 9H), 5.49 (s, 2H), 4.18 (q, J=7.2 Hz, 2H),
1.27 (t, J=7.2 Hz, 3H)
Example 43
Ethyl
4-(biphenyl-2-ylmethyl)-2-(4-(ethoxycarbonyl)phenylsulfonamido)-7-ox-
o-4,7-dihydrothiazolo[5,4-b]pyridine-6-carboxylate
(I.sub.10A-h')
##STR00054##
[0453] I-7 (I-7') was treated with ethyl 4-sulfamoylbenzoate
according to the representative method to obtain compound
I.sub.10A-h' as a pale white solid.
[0454] Yield: 2%
[0455] MS (ESI): 618 (M+H).sup.+
[0456] .sup.1HNMR (d.sub.6-DMSO, 400 MHz):
[0457] .delta. 8.19 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.82 (d, J=7.6
Hz, 2H), 7.53-7.27 (m, 9H), 5.47 (s, 2H), 4.34 (q, J=6.8 Hz, 2H),
4.18 (q, J=6.8 Hz, 2H), 4.20 (q, J=6.8 Hz, 2H), 1.33 (t, J=7.2 Hz,
3H), 1.26 (t, J=7.2 Hz, 3H)
Example 44
4-(Biphenyl-2-ylmethyl)-2-(4-methoxyphenylsulfonamido)-7-oxo-4,7-dihydroth-
iazolo[5,4-b]pyridine-6-carboxylic acid (I.sub.11A)
##STR00055##
[0459] I-7 (I-7') was treated with 4-methoxyphenylsulfonamide
according to the representative method to obtain compound I.sub.11A
as a pale white solid.
[0460] Yield: 7%
[0461] MS (ESI): 548 (M+H).sup.+
[0462] .sup.1H NMR (d.sub.6-DMSO, 400 MHz):
[0463] .delta. 8.56 (s, 1H), 7.59-7.65 (m, 3H), 7.55 (t, J=7.2 Hz,
1H), 7.44 (d, J=7.2 Hz, 1H), 7.29-7.49 (m, 4H), 7.20 (d, J=6.8 Hz,
2H), 7.07 (d, J=7.6 Hz, 2H), 5.63 (s, 2H), 3.83 (s, 3H)
Example 45
Ethyl
4-(biphenyl-2-ylmethyl)-2-(4-methoxyphenylsulfonamido)-7-oxo-4,7-dih-
ydrothiazolo[5,4-b]pyridine-6-carboxylate (I.sub.11A-h)
##STR00056##
[0465] I-7 (I-7') was treated with 4-methoxyphenylsulfonamide
according to the representative method to obtain compound
I.sub.11A-h as a pale white solid.
[0466] Yield: 3%
[0467] MS (ESI): 576(M+H).sup.+, 169
[0468] .sup.1H NMR (d.sub.5-DMSO, 400 MHz):
[0469] .delta. 8.19 (s, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.55 (t, J=7.2
Hz, 1H), 7.48 (t, J=7.2 Hz, 1H), 7.33-7.43 (m, 5H), 7.27 (d, J=6.8
Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 5.48 (s, 2H), 4.18 (q, J=7.2 Hz,
2H), .delta. 3.82 (s, 3H), 1.26 (t, J=7.2 Hz, 3H)
Example 46
4-Benzhydryl-2-(4-methoxyphenylsulfonamido)-7-oxo-4,7-dihydrothiazolo[5,4--
b]pyridine-6-carboxylic acid (I.sub.11D)
##STR00057##
[0471] The analogue of I-7 (I-7') with diphenylmethyl substitution
was treated with 4-methoxyphenylsulfonamide according to the
representative method to obtain compound I.sub.11D as a pale white
solid.
[0472] Yield: 1%
[0473] MS (ESI): 548(M+H).sup.+, 169
[0474] .sup.1H NMR (d.sub.6-DMSO, 400 MHz):
[0475] .delta. 8.12 (s, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.52 (br, s,
6H), 7.32 (br, s, 4H), 7.26 (s, 1H), 7.02 (d, J=8.4 Hz, 2H), 3.83
(s, 3H)
Example 47
Ethyl 4-benzhydryl-2-(4-methoxyphenylsulfonamido)-7-oxo-4,7-dihydro
thiazolo[5,4-b]pyridine-6-carboxylate (I.sub.11D-h)
##STR00058##
[0477] The analogue of I-7 (I-7') with diphenylmethyl substitution
was treated with 4-methoxyphenylsulfonamide according to the
representative method to obtain compound I.sub.11D-h as a pale
white solid.
[0478] Yield: 2%
[0479] MS (ESI): 576(M+H).sup.+, 169
[0480] .sup.1H NMR (d.sub.5-DMSO, 400 MHz):
[0481] .delta. 7.98 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.51 (br, s,
6H), 7.30 (br, s, 4H), 7.11 (s, 1H), 7.02 (d, J=8.4 Hz, 2H), 4.10
(q, J=7.2 Hz, 2H), 3.83 (s, 3H), 1.13 (t, J=7.2 Hz, 3H)
Example 48
4-(Biphenyl-2-ylmethyl)-2-((4-chlorophenyl)methylsulfonamido)-7-oxo-4,7-di-
hydrothiazolo[5,4-b]pyridine-6-carboxylic acid (I.sub.12A)
##STR00059##
[0483] I-7 (I-7') was treated with 4-chlorophenylsulfonamide
according to the representative method to obtain compound I.sub.12A
as a pale white solid.
[0484] Yield: 1%
[0485] MS (ESI): 566 (M+H).sup.+, 157
[0486] .sup.1H NMR (d.sub.6-DMSO, 400 MHz):
[0487] .delta. 8.51 (s, 1H), 7.19-7.54 (m, 13H), 5.57 (s, 2H), 4.39
(s, 2H)
Example 49
Ethyl
4-(biphenyl-2-ylmethyl)-2-((4-chlorophenyl)methylsulfonamido)-7-oxo--
4,7-dihydrothiazolo[5,4-b]pyridine-6-carboxylate(I.sub.12A-h)
##STR00060##
[0489] I-7 (I-7') was treated with 4-chlorophenylsulfonamide
according to the representative method to obtain compound
I.sub.12A-h as a pale white solid.
[0490] Yield: 2%
[0491] MS (ESI): 594 (M+H).sup.+
[0492] .sup.1H NMR (d.sub.6-DMSO, 400 MHz):
[0493] .delta. 8.24 (s, 1H), 8.17 (s, 1H), 7.25-7.50 (m, 13H), 5.36
(s, 2H), 4.30 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz,
3H)
Example 50
Ethyl
4-(biphenyl-2-ylmethyl)-2-((2,4-dichlorophenyl)methylsulfonamido)-7--
oxo-4,7-dihydrothiazolo[5,4-b]pyridine-6-carboxylate
(I.sub.13A-h)
##STR00061##
[0495] I-7 (I-7') was treated with 2,4-dichlorophenylsulfonamide
according to the representative method to obtain compound
I.sub.13A-h as a pale white solid.
[0496] Yield: 1%
[0497] MS (ESI): 628 (M+H).sup.+, 169
[0498] .sup.1H NMR (d.sub.6-DMSO, 400 MHz):
[0499] .delta. 8.16 (s, 1H), 7.23-7.57 (m, 12H), 5.41 (s, 2H), 4.45
(s, 2H), 4.19 (q, J=6.8 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H)
Example 51
Ethyl
7-(benzhydryloxy)-2-(methylthio)thiazolo[5,4-b]pyridine-6-carboxylat-
e (I.sub.d-f')
##STR00062##
[0501] I-5 was treated with (bromomethylene)dibenzene according to
the general procedure to obtain compound I.sub.d-f' as a pale white
solid.
[0502] Yield: 1%
[0503] MS (ESI): 437 (M+H).sup.+, 105
[0504] .sup.1H NMR (d.sub.6-DMSO, 400 MHz):
[0505] .delta. 8.66 (s, 1H), 7.98 (s, 1H), 7.57-7.59 (m, 4H),
7.32-7.36 (m, 4H), 7.23-7.26 (m, 2H), 4.42 (q, J=6.8 Hz, 2H), 2.90
(s, 3H), 1.35-1.38 (t, J=7.2 Hz, 3H)
Example 52
Ethyl 4-(biphenyl-2-yl
methyl)-7-oxo-4,7-dihydrothiazolo[5,4-b]pyridine-6-carboxylate
(I-f-a)
##STR00063##
[0507] I-6 was treated with zinc in acetic acid to obtain compound
I-f-a as a yellow solid.
[0508] Yield: 5%
[0509] MS (ESI): 391(M+H).sup.+, 130, 105
[0510] .sup.1H NMR (CDCl.sub.3, 400 MHz):
[0511] .delta. 8.57 (s, 1H), 8.00 (s, 1H), 7.32-7.50 (m, 7H), 7.12
(d, J=6.4 Hz, 2H), 5.28 (s, 2H), 4.35 (q, J=6.8 Hz, 2H), 1.38 (t,
J=7.2 Hz, 3H)
Example 53
7-Hydroxy-2-(methylthio)thiazolo[5,4-b]pyridine-6-carboxylic acid
(I-e-1)
##STR00064##
[0513] I-5 was treated with LiOH in ethanol and water to obtain
compound I-e-1 as a pale white solid.
[0514] Yield: 5%
[0515] MS (ESI): 243 (M+H).sup.+, 157
[0516] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0517] .delta. 8.77 (s, 1H), 2.79 (s, 3H)
Example 54
7-(Biphenyl-2-ylmethoxy)-2-(methylthio)thiazolo[5,4-b]pyridine-6-carboxyli-
c acid (I-f'-1)
##STR00065##
[0519] I-5 was treated with 2-(bromomethyl)biphenyl and then LiOH
to obtain compound I-f'-1 as a pale white solid.
[0520] Yield: 5%
[0521] MS (ESI): 409 (M+H).sup.+, 157
[0522] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0523] .delta. 13.24 (br,s, 1H), 8.62 (s, 1H), 7.87-7.90 (m, 1H),
7.28-7.46 (m, 8H), 5.92 (s, 2H), 2.54 (s, 3H)
Example 55
4-(Biphenyl-2-ylmethyl)-2-(methylthio)-7-oxo-4,7-dihydrothiazolo[5,4-b]pyr-
idine-6-carboxylic acid (I-f-2)
##STR00066##
[0525] I-5 was treated with 2-(bromomethyl)biphenyl and then LiOH
to obtain compound I-f-2 as a pale white solid.
[0526] Yield: 5%
[0527] MS (ESI): 409(M+H).sup.+, 157
[0528] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0529] .delta. 15.46 (s, 1H), 8.57 (s, 1H), 7.21-7.50 (m, 9H), 5.67
(s, 2H), 2.69 (s, 3H)
Example 56
4-(Biphenyl-2-ylmethyl)-2-hydroxy-7-oxo-4,7-dihydrothiazolo[5,4-b]pyridine-
-6-carboxylic acid(I-h')
##STR00067##
[0531] I-6 was treated with sodium hydroxide to obtain compound
I-h' as a pale white solid.
[0532] Yield: 2%
[0533] MS (ESI): 379(M+H).sup.+
[0534] .sup.1H NMR (d.sub.6-DMSO, 400 MHz):
[0535] .delta. 15.23 (s, 1H), 12.71 (s, 1H), 8.53 (s, 1H),
7.26-7.51 (m, 9H), 5.55 (s, 2H)
[0536] All of the compounds listed in the following table have been
prepared as set out above or by analogous methods.
Activity Data for Compounds Having the General Formula (A)
Structure FRET CPE Structure FRET CPE
TABLE-US-00002 [0537] Structure FRET CPE ##STR00068## IC.sub.50 =
12 .mu.M inactive; Toxic at 50 .mu.M ##STR00069## IC.sub.50 = 6.5
.mu.M IC.sub.50 = 17 .mu.M ##STR00070## IC.sub.50 = 3.2 .mu.M
IC.sub.50 = 19 .mu.M ##STR00071## inactive 70% reduction @ 50 .mu.M
##STR00072## inactive 68% reduction @ 50 .mu.M ##STR00073##
IC.sub.50 = 2.8 .mu.M inactive ##STR00074## IC.sub.50 = 5.5 .mu.M
inactive; toxic at 50 .mu.M ##STR00075## IC.sub.50 = 2.5 .mu.M
IC.sub.50 = 31 .mu.M ##STR00076## inactive 83% reduction @ 50 .mu.M
##STR00077## IC.sub.50 = 14 .mu.M inactive ##STR00078## IC.sub.50 =
9 .mu.M inactive ##STR00079## IC.sub.50 = 0.78 .mu.M inactive
##STR00080## inactive 41% @ 50 .mu.M ##STR00081## IC.sub.50 = 7.3
.mu.M n.d. ##STR00082## IC.sub.50 = 6.7 .mu.M IC.sub.50 = 19 .mu.M
##STR00083## IC.sub.50 = 8.1 .mu.M inactive ##STR00084## IC.sub.50
= 2.3 .mu.M IC.sub.50 = 9.3 .mu.M ##STR00085## IC.sub.50 = 2.9
.mu.M IC.sub.50 = 11 .mu.M ##STR00086## IC.sub.50 = 5.2 .mu.M
IC.sub.50 = 12 .mu.M ##STR00087## IC.sub.50 = 5.8 .mu.M IC.sub.50 =
24 .mu.M ##STR00088## IC.sub.50 = 2.2 .mu.M IC.sub.50 = 18 .mu.M
##STR00089## IC.sub.50 = 0.16 .mu.M IC.sub.50 = 33 .mu.M
##STR00090## IC.sub.50 = 2.7 .mu.M IC.sub.50 = 15 .mu.M
##STR00091## inactive IC.sub.50 = 39 .mu.M ##STR00092## IC.sub.50 =
5.7 .mu.M IC.sub.50 = 11 .mu.M ##STR00093## 6.2% @ 1 .mu.M
IC.sub.50 = 23 .mu.M ##STR00094## IC.sub.50 = 6.3 .mu.M n.d.
##STR00095## 8.1% @ 1 .mu.M n.d. ##STR00096## 21.5% @ 10 .mu.M n.d.
##STR00097## 5.6% @ 1 .mu.M n.d. ##STR00098## 2% @ 1 .mu.M
IC.sub.50 = 26 .mu.M ##STR00099## 7.8% @ 1 .mu.M IC.sub.50 = 31
.mu.M ##STR00100## 25% @ 1 .mu.M IC.sub.50 = 36 .mu.M ##STR00101##
n.d. IC.sub.50 = 27 .mu.M ##STR00102## n.d. IC.sub.50 = 45 .mu.M
##STR00103## IC.sub.50 = 0.78 .mu.M IC.sub.50 = 47 .mu.M
##STR00104## IC.sub.50 = 3.8 .mu.M IC.sub.50 = 22 .mu.M
##STR00105## IC.sub.50 = 0.87 .mu.M IC.sub.50 = 18 .mu.M
##STR00106## n.d. IC.sub.50 = 32 .mu.M ##STR00107## n.d. n.d.
##STR00108## n.d. n.d. ##STR00109## n.d. IC.sub.50 = 14 .mu.M
##STR00110## n.d. n.d. ##STR00111## n.d. 63% @ 50 .mu.M
##STR00112## n.d. 67% @ 50 .mu.M ##STR00113## 64% @ 10 .mu.M
inactive ##STR00114## IC.sub.50 = 7 .mu.M IC.sub.50 = 20 .mu.M
##STR00115## IC.sub.50 = 2.5 .mu.M IC.sub.50 = 14 .mu.M
##STR00116## IC.sub.50 = 7.5 .mu.M IC.sub.50 = 8.9 .mu.M
##STR00117## IC.sub.50 = 4.7 .mu.M inactive ##STR00118## IC.sub.50
= 2.1 .mu.M n.d. ##STR00119## IC.sub.50 = 0.94 .mu.M inactive
##STR00120## IC.sub.50 = 0.25 .mu.M n.d. ##STR00121## inactive 35%
@ 50 .mu.M
Compounds Having the General Formula (C)
Key Intermediate I
2-Formyl-succinic acid diethyl ester
##STR00122##
[0539] To a suspension of sodium (333 mg, 14 mmol, 1.2 eq) in
diethyl ether (7 mL) were added succinic acid diethyl ester (2.1 g,
12 mmol, 1 eq) and formic acid ethyl ester (1.7 mL, 20 mmol, 1.7
eq). The mixture was stirred at 40.degree. C. for 5 h. Water (10
mL) was added and the aqueous layer was washed with diethyl ether
(2.times.10 mL). The aqueous layer was then acidified with a 6N
solution of hydrochloric acid and extracted with diethyl ether
(3.times.10 mL). The organic layers were dried over magnesium
sulfate, filtered and evaporated in vacuo to afford the expected
compound as orange oil (2.6 g, quant. yield).
Key Intermediate II
2-Cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic
acid ethyl ester
##STR00123##
[0541] To a solution of 5-cyclopropyl-2H-pyrazol-3-ylamine (280 mg,
2.3 mmol, 1 eq) in acetic acid (3 mL) was added
2-ethoxymethylene-malonic acid diethyl ester (500 .mu.L, 2.5 mmol,
1.1 eq). The mixture was heated at 120.degree. C. for 2 h in a
sealed tube. After cooling, the precipitate was filtered and washed
with ethanol to afford the expected compound as white powder (420
mg, 75% yield).
Key Intermediate III
2-Isopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic
acid ethyl ester
##STR00124##
[0543] To a solution of 5-isopropyl-2H-pyrazol-3-ylamine (2.5 g, 20
mmol, 1 eq) in acetic acid (20 mL) was added
2-ethoxymethylene-malonic acid diethyl ester (4.4 mL, 22 mmol, 1.1
eq). The mixture was heated at 120.degree. C. for 3 h in a sealed
tube. After cooling, the precipitate was filtered and washed with
ethanol to afford the expected compound as beige powder (3.2 g, 65%
yield).
Key Intermediate IV
2-Cyclopentyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic
acid ethyl ester
##STR00125##
[0544] Step 1:
[0545] To a suspension of sodium hydride (350 mg, 8.8 mmol, 1.2 eq)
in 1,4-dioxane (10 mL) was added acetonitrile (450 .mu.L, 8.8 mmol,
1.2 eq). The mixture was stirred at room temperature for 30 min.
Then cyclopentanecarboxylic acid ethyl ester (660 .mu.L, 7.3 mmol,
1 eq) was added. After stirring for 30 min at room temperature, the
mixture was heated at 105.degree. C. during 16 h. After cooling,
the solvent was evaporated to dryness and water was added (30 mL).
The mixture was extracted with dichloromethane (3.times.30 mL) to
get rid of the starting material and the aqueous phase was
acidified with a 1N solution of hydrochloric acid and extracted
with dichloromethane (3.times.30 mL). The combined organic phases
were dried over magnesium sulfate, filtered and dried in vacuo to
afford 3-cyclopentyl-3-oxo-propionitrile as very volatile yellow
oil (1.0 g, quant. yield)
Step 2:
[0546] To a solution of 3-cyclopentyl-3-oxo-propionitrile (1.0 g,
7.3 mmol, 1 eq) in ethanol (10 mL) was added a 64 wt.-% solution of
hydrazine hydrate (1.1 mL, 14.6 mmol, 2 eq). The mixture was heated
at 80.degree. C. for 16 h and was evaporated to dryness. The
residue was purified by flash chromatography using dichloromethane
and methanol (100/0 to 90/10) to afford
5-cyclopentyl-2H-pyrazol-3-ylamine as yellow oil (510 mg, 46%
yield).
Step 3:
[0547] To a solution of 5-cyclopentyl-2H-pyrazol-3-ylamine (510 mg,
3.4 mmol, 1 eq) in acetic acid (4.8 mL) was added
2-ethoxymethylene-malonic acid diethyl ester (750 .mu.L, 3.7 mmol,
1.1 eq). The mixture was heated at 120.degree. C. for 3 h in a
sealed tube. After cooling, the precipitate was filtered and washed
with ethanol and diethyl ether and recrystallised from methanol to
afford the expected compound as white powder (657 mg, 71%
yield).
[0548] MS: 276.1
[0549] Mp: decomposes at 300.degree. C.
Key Intermediate V
7-Oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2,6-dicarboxylic acid
6-ethyl ester
##STR00126##
[0551] To a solution of 5-amino-1H-pyrazole-3-carboxylic acid (600
mg, 4.7 mmol, 1 eq) in acetic acid (30 mL) was added
2-ethoxymethylene-malonic acid diethyl ester (1.1 g, 5.2 mmol, 1.1
eq). The mixture was heated at 120.degree. C. for 4 h in a sealed
tube. After cooling, the precipitate was filtered and washed with
ethanol to afford the expected compound as grey powder (353 mg, 30%
yield).
General Procedure A
##STR00127##
[0552] Step 1:
[0553] To a solution of the appropriate amine (4.3 mmol, 1 eq) in
ethanol (10 mL) was added dimethyl N-cyanodithioiminocarbonate (1.0
g, 6.8 mmol, 1.6 eq). The mixture was stirred at 80.degree. C. for
20 h. After cooling, the precipitate was filtered and rinsed with
ethanol to afford the expected compound (from 25% to 70%
yield).
Step 2:
[0554] To a solution of the compound from step 1 (1.1 mmol, 1 eq)
in ethanol (10 mL) was added a 1M solution of hydrazine in
tetrahydrofuran (2.3 mL, 2.3 mmol, 2 eq). The mixture was heated at
80.degree. C. for 20 h and was evaporated to dryness. The product
was then triturated with diethyl ether, filtered and washed with
diethyl ether to afford the expected compound (from 75% to 85%
yield).
Step 3:
[0555] To a solution of the compound from step 2 (0.86 mmol, 1 eq)
in acetic acid (4 mL) was added 2-ethoxymethylene-malonic acid
diethyl ester (190 .mu.L, 0.94 mmol, 1.1 eq). The mixture was
heated at 120.degree. C. for 20 h in a sealed tube. After cooling,
the precipitate was filtered and washed with ethanol to afford the
expected compound (from 25% to 65% yield).
Example 58
2-Benzylamino-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxy-
lic acid ethyl ester
##STR00128##
[0557] The expected compound was obtained according to general
procedure A using benzylamine.
[0558] The expected compound was isolated as white powder.
[0559] MS: 314.1
[0560] Mp: 275.degree. C.-278.degree. C.
Example 59
2-(4-Bromobenzylamino)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine--
6-carboxylic acid ethyl ester
##STR00129##
[0562] The expected compound was obtained according to general
procedure A using 4-bromo-benzylamine. The expected compound was
isolated as white powder.
[0563] MS: 392.2
[0564] Mp: 286.degree. C.-287.degree. C.
Example 60
2-[(Naphthalen-1-ylmethyl)-amino]-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5a]p-
yrimidine-6-carboxylic acid ethyl ester
##STR00130##
[0566] The expected compound was obtained according to general
procedure A using C-(2,3-dihydro-naphthalen-1-yl)-methylamine. The
expected compound was isolated as white powder.
[0567] MS: 364.2
[0568] Mp: 273.degree. C.-275.degree. C.
Example 61
2-(4-Isopropoxy-phenylamino)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrim-
idine-6-carboxylic acid ethyl ester
##STR00131##
[0570] The expected compound was obtained according to general
procedure A using 4-isopropoxy-phenylamine. The expected compound
was isolated as pale yellow powder.
[0571] MS: 358.2
[0572] Mp: decomposes at 325.degree. C.-330.degree. C.
Example 62
2-(4-Acetylamino-phenylamino)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyri-
midine-6-carboxylic acid ethyl ester
##STR00132##
[0574] The expected compound was obtained according to general
procedure A using N-(4-amino-phenyl)-acetamide. The expected
compound was isolated as off-white powder.
[0575] MS: 357.2
[0576] Mp>330.degree. C.
Example 63
2-(3-Chloro-4-methyl-phenylamino)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]-
pyrimidine-6-carboxylic acid ethyl ester
##STR00133##
[0578] The expected compound was obtained according to general
procedure A using 3-chloro-4-methyl-phenylamine. The expected
compound was isolated as white powder.
[0579] MS: 348.1
[0580] Mp>340.degree. C.
General Procedure B
##STR00134##
[0581] Step 1:
[0582] To a solution of the appropriate amine (4.3 mmol, 1 eq) in
ethanol (10 mL) was added dimethyl N-cyanodithioiminocarbonate (1.0
g, 6.8 mmol, 1.6 eq). The mixture was stirred at 80.degree. C. for
20 h. After cooling, the precipitate was filtered and rinsed with
ethanol to afford the expected compound (from 25% to 70%
yield).
Step 2:
[0583] To a solution of the compound from step 1 (1.1 mmol, 1 eq)
in ethanol (10 mL) was added a 1M solution of hydrazine in
tetrahydrofuran (2.3 mL, 2.3 mmol, 2 eq). The mixture was heated at
80.degree. C. for 20 h and was evaporated to dryness. The product
was then triturated with diethyl ether, filtered and washed with
diethyl ether to afford the expected compound (from 75% to 85%
yield).
Step 3:
[0584] To a solution of the compound from step 2 (1.2 mmol, 1 eq)
in acetic acid (6 mL) was added 2-formyl-succinic acid diethyl
ester (Key Intermediate I) (277 mg, 1.37 mmol, 1.1 eq). The mixture
was heated in a sealed tube at 120.degree. C. for 20 h. After
cooling, the mixture was evaporated to dryness. The residue was
diluted in ethyl acetate (10 mL) and washed with a saturated
solution of sodium bicarbonate (2.times.10 mL). The organic layers
were dried over magnesium sulfate, filtered and evaporated in
vacuo. If necessary, the crude compound was purified by flash
chromatography using dichloromethane and methanol to afford the
expected compound (from 35% to 45% yield).
Example 64
(7-Oxo-2-phenylamino-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-ace-
tic acid ethyl ester
##STR00135##
[0586] The expected compound was obtained according to general
procedure B using aniline. The expected compound was isolated as
white powder.
[0587] MS: 314.2
[0588] Mp: 255.degree. C.-257.degree. C.
Example 65
[2-(4-Isopropoxy-phenylamino)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyri-
midin-6-yl]-acetic acid ethyl ester
##STR00136##
[0590] The expected compound was obtained according to general
procedure B using 4-isopropoxy-phenylamine. The expected compound
was isolated as pale yellow powder.
[0591] MS: 372.2
[0592] Mp: 235.degree. C.-240.degree. C.
General Procedure C
##STR00137##
[0593] Step 1:
[0594] To a solution of 2H-pyrazol-3-ylamine (2.3 mmol, 1 eq) in
acetic acid (3 mL) was added 2-ethoxymethylene-malonic acid diethyl
ester (500 .mu.L, 2.5 mmol, 1.1 eq). The mixture was heated at
120.degree. C. for 20 h in a sealed tube. After cooling, the
precipitate was filtered and washed with ethanol to afford the
expected compound (from 30% to 80% yield).
Step 2:
[0595] To a solution of the compound from step 1 (1.7 mmol, 1 eq)
in ethanol (2 mL) were added sodium hydroxide (170 mg, 4.24 mmol,
2.5 eq) and water (2 mL). The mixture was heated in a sealed tube
at 100.degree. C. for 4 h. After cooling, the mixture was
evaporated to dryness and water (30 mL) and citric acid (980 mg,
5.1 mmol, 3 eq) were added. The precipitate obtained was filtered,
washed with water and dried under vacuum to afford the expected
compound (50% to quant. yield).
Example 66
3-Bromo-2-methyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic
acid ethyl ester
##STR00138##
[0597] The expected compound was obtained according to general
procedure C step 1 using 4-bromo-5-methyl-2H-pyrazol-3-ylamine. The
expected compound was isolated as pale yellow powder.
[0598] MS: 300.0
[0599] Mp: decomposes at 270.degree. C.-275.degree. C.
Example 67
3-Cyano-2-(3-methylamino-propyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidi-
ne-6-carboxylic acid ethyl ester
##STR00139##
[0601] The expected compound was obtained according to general
procedure C step 1 using
5-imino-3-(3-methylamino-propyl)-4,5-dihydro-1H-pyrazole-4-carbonitrile.
The expected compound was isolated as white powder.
[0602] MS: 304.2
[0603] Mp: 285.degree. C.-287.degree. C.
Example 68
7-Oxo-2-phenyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic
acid
##STR00140##
[0605] The expected compound was obtained according to general
procedure C using 5-phenyl-2H-pyrazol-3-ylamine. The expected
compound was isolated as white powder.
[0606] MS: 256.0
[0607] Mp: decomposes at 325.degree. C.-330.degree. C.
Example 69
2-(4-Ethoxy-phenyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxyl-
ic acid
##STR00141##
[0609] The expected compound was obtained according to general
procedure C using 5-(4-ethoxy-phenyl)-2H-pyrazol-3-ylamine. The
expected compound was isolated as white powder.
[0610] MS: 300.1
[0611] Mp: decomposes at 310.degree. C.-315.degree. C.
Example 70
2-Cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic
acid
##STR00142##
[0613] The expected compound was obtained according to general
procedure C using 5-cyclopropyl-2H-pyrazol-3-ylamine. The expected
compound was isolated as white powder.
[0614] MS: 220.0
[0615] Mp: 275.degree. C.-278.degree. C.
Example 71
2-Isopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic
acid
##STR00143##
[0617] The expected compound was obtained according to general
procedure C using 5-isopropyl-2H-pyrazol-3-ylamine. The expected
compound was isolated as white powder.
[0618] MS: 222.0
[0619] Mp: decomposes at 280.degree. C.-285.degree. C.
Example 72
2-Cyclopentyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic
acid
##STR00144##
[0621] The expected compound was obtained according to general
procedure C using 5-cyclopentyl-2H-pyrazol-3-ylamine. The expected
compound was isolated as white powder.
[0622] MS: 248.1
[0623] Mp: decomposes at 300.degree. C.
Example 73
7-Oxo-2-trifluoromethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic
acid
##STR00145##
[0625] The expected compound was obtained according to general
procedure C using 5-trifluoromethyl-2H-pyrazol-3-ylamine. The
expected compound was isolated as white powder.
[0626] MS: 248.0
[0627] Mp>340.degree. C.
General Procedure D
##STR00146##
[0629] To a solution of
7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl
ester (0.81 mmol, 1 eq) in dimethylformamide (5 mL) were added
potassium carbonate (560 mg, 4 mmol, 5 eq) and the appropriate
bromide (3.2 mmol, 4 eq). The mixture was heated at 50.degree. C.
for 4 h. After cooling, the mixture was poured on brine (15 mL) and
extracted with ethyl acetate (3.times.20 mL). The organic layers
were dried over magnesium sulfate, filtered and evaporated in
vacuo. The crude residue was purified by flash chromatography using
dichloromethane and methanol (100/0 to 95/5) to afford the expected
compound (13% to 97% yield).
Example 74
4-Benzyl-2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carbo-
xylic acid ethyl ester
##STR00147##
[0631] The expected compound was obtained according to general
procedure D using Key Intermediate II and benzyl bromide. The
expected compound was isolated as white powder.
[0632] MS: 338.2
[0633] Mp: 160.degree. C.-165.degree. C.
Example 75
2-Cyclopropyl-7-oxo-4-phenethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-ca-
rboxylic acid ethyl ester
##STR00148##
[0635] The expected compound was obtained according to general
procedure D using Key Intermediate II and phenethyl bromide. The
expected compound was isolated as white powder.
[0636] MS: 352.2
[0637] Mp: 155.degree. C.-160.degree. C.
Example 76
2-Cyclopropyl-4-[2-(4-hydroxy-phenyl)-ethyl]-7-oxo-4,7-dihydro-pyrazolo[1,-
5-a]pyrimidine-6-carboxylic acid ethyl ester
##STR00149##
[0639] The expected compound was obtained according to general
procedure D using Key Intermediate II and 4-(2-bromo-ethyl)-phenol.
The expected compound was isolated as white powder.
[0640] MS: 368.2
[0641] Mp: 95.degree. C.-100.degree. C.
Example 77
4-[2-(4-Chloro-phenyl)-ethyl]-2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-
-a]pyrimidine-6-carboxylic acid ethyl ester
##STR00150##
[0643] The expected compound was obtained according to general
procedure D using Key Intermediate II and
1-(2-bromo-ethyl)-4-chloro-benzene. The expected compound was
isolated as white powder.
[0644] MS: 386.2
[0645] Mp: 190.degree. C.-195.degree. C.
Example 78
2-Cyclopropyl-4-[2-(4-methoxy-phenyl)-ethyl]-7-oxo-4,7-dihydro-pyrazolo[1,-
5-a]pyrimidine-6-carboxylic acid ethyl ester
##STR00151##
[0647] The expected compound was obtained according to general
procedure D using Key Intermediate II and
1-(2-bromo-ethyl)-4-methoxy-benzene. The expected compound was
isolated as white powder.
[0648] MS: 382.2
[0649] Mp: 160.degree. C.-165.degree. C.
Example 79
4-[2-(3-Chloro-phenyl)-ethyl]-2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-
-a]pyrimidine-6-carboxylic acid ethyl ester
##STR00152##
[0651] The expected compound was obtained according to general
procedure D using Key Intermediate II and
1-(2-bromo-ethyl)-3-chloro-benzene. The expected compound was
isolated as white powder.
[0652] MS: 386.2
[0653] Mp: 160.degree. C.-165.degree. C.
Example 80
2-Cyclopropyl-4-[2-(3-fluoro-phenyl)-ethyl]-7-oxo-4,7-dihydro-pyrazolo[1,5-
-a]pyrimidine-6-carboxylic acid ethyl ester
##STR00153##
[0655] The expected compound was obtained according to general
procedure D using Key Intermediate II and
1-(2-bromo-ethyl)-3-fluoro-benzene. The expected compound was
isolated as white powder.
[0656] MS: 370.2
[0657] Mp: 160.degree. C.-165.degree. C.
Example 81
2-Cyclopropyl-7-oxo-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-4,7-dihydro-pyr-
azolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester
##STR00154##
[0659] The expected compound was obtained according to general
procedure D using Key Intermediate II and
1-(2-bromo-ethyl)-3-trifluoromethyl-benzene. The expected compound
was isolated as white powder.
[0660] MS: 420.2
[0661] Mp: 140.degree. C.-145.degree. C.
Example 82
2-Cyclopropyl-7-oxo-4-(3-phenyl-propyl)-4,7-dihydro-pyrazolo[1,5-a]pyrimid-
ine-6-carboxylic acid ethyl ester
##STR00155##
[0663] The expected compound was obtained according to general
procedure E using Key Intermediate II and (3-bromo-propyl)-benzene.
The expected compound was isolated as white powder.
[0664] MS: 366.2
[0665] Mp: 150.degree. C.-155.degree. C.
Example 83
4-Benzyl-2-isopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxy-
lic acid ethyl ester
##STR00156##
[0667] The expected compound was obtained according to general
procedure D using Key Intermediate III and benzyl bromide. The
expected compound was isolated as white powder.
[0668] MS: 340.2
[0669] Mp: 135.degree. C.-140.degree. C.
Example 84
2-Isopropyl-7-oxo-4-phenethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carb-
oxylic acid ethyl ester
##STR00157##
[0671] The expected compound was obtained according to general
procedure D using Key Intermediate III and phenethyl bromide. The
expected compound was isolated as white powder.
[0672] MS: 354.2
[0673] Mp: 130.degree. C.-135.degree. C.
Example 85
2-Isopropyl-7-oxo-4-(3-phenyl-propyl)-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-
e-6-carboxylic acid ethyl ester
##STR00158##
[0675] The expected compound was obtained according to general
procedure D using Key Intermediate III and
(3-bromo-propyl)-benzene. The expected compound was isolated as
colorless oil.
[0676] MS: 368.3
Example 86
4-Benzyl-2-cyclopentyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carbo-
xylic acid ethyl ester
##STR00159##
[0678] The expected compound was obtained according to general
procedure D using Key Intermediate IV and benzyl bromide. The
expected compound was isolated as white powder.
[0679] MS: 366.2
[0680] Mp: 148.degree. C.-150.degree. C.
Example 87
2-Cyclopentyl-7-oxo-4-phenethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-ca-
rboxylic acid ethyl ester
##STR00160##
[0682] The expected compound was obtained according to general
procedure D using Key Intermediate IV and phenethyl bromide. The
expected compound was isolated as white powder.
[0683] MS: 380.3
[0684] Mp: 162.degree. C.-164.degree. C.
General Procedure E
##STR00161##
[0686] To a solution of 2H-pyrazol-3-ylamine (1.3 mmol, 1 eq) in
acetic acid (8 mL) was added 2-formyl-succinic acid diethyl ester
(Key Intermediate I) (286 mg, 1.4 mmol, 1.1 eq). The mixture was
heated in a sealed tube at 120.degree. C. for 20 h. After cooling,
the precipitate was filtered, rinsed with ethanol and dried under
vacuum to afford the expected compound (from 18% to 86% yield).
Example 88
(7-Oxo-2-phenyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-acetic
acid ethyl ester
##STR00162##
[0688] The expected compound was obtained according to general
procedure E using 5-phenyl-2H-pyrazol-3-ylamine. The expected
compound was isolated as white powder.
[0689] MS: 298.1
[0690] Mp: 245.degree. C.-250.degree. C.
Example 89
(7-Oxo-2-trifluoromethyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)-acetic
acid ethyl ester
##STR00163##
[0692] The expected compound was obtained according to general
procedure E using 5-trifluoromethyl-2H-pyrazol-3-ylamine. The
expected compound was isolated as white powder.
[0693] MS: 290.0
[0694] Mp: 290.degree. C.-293.degree. C.
Example 90
(2-Cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-acetic
acid ethyl ester
##STR00164##
[0696] The expected compound was obtained according to general
procedure E using 5-cyclopropyl-2H-pyrazol-3-ylamine. The expected
compound was isolated as white powder.
[0697] MS: 262.1
[0698] Mp: 280.degree. C.-283.degree. C.
Example 91
(2-Cyclopropyl-4-methyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-a-
cetic acid ethyl ester
##STR00165##
[0700] To a suspension of
(2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-acetic
acid ethyl ester (80 mg, 0.3 mmol, 1 eq) described in example 90 in
tetrahydrofuran (2 mL) was added sodium hydride (16 mg, 3.9 mmol,
1.3 eq). The mixture was stirred during 30 min at room temperature
and methyl iodide (30 .mu.L, 0.5 mmol, 1.5 eq) was added. The
mixture was stirred at room temperature for 5 h. The mixture was
then diluted with ethyl acetate (5 mL) and water (5 mL) was added.
The aqueous layer was extracted with ethyl acetate (2.times.10 mL)
and the aqueous phases were dried over magnesium sulfate, filtered
and evaporated in vacuo. The crude residue was purified by flash
chromatography using cyclohexane and ethyl acetate (100/0 to 0/100)
to afford the expected compound as white powder (16 mg, 59%
yield).
[0701] MS: 276.1
[0702] Mp: 147.degree. C.-150.degree. C.
Example 92
(3-Bromo-2-methyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-acetic
acid ethyl ester
##STR00166##
[0704] The expected compound was obtained according to general
procedure E using 4-bromo-5-methyl-2H-pyrazol-3-ylamine. The
expected compound was isolated as pale pink powder.
[0705] MS: 316.0
[0706] Mp: decomposes at 245.degree. C.-250.degree. C.
Example 93
2-[2-(4-Chloro-phenyl)-ethylcarbamoyl]-7-oxo-4,7-dihydro-pyrazolo[1,5-a]py-
rimidine-6-carboxylic acid ethyl ester
##STR00167##
[0707] Step 1:
[0708] To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (200
mg, 1.3 mmol, 1 eq) in tetrahydrofuran (5 mL) were added
triethylamine (350 .mu.L, 1.9 mmol, 1.5 eq), hydroxybenzotriazole
(HOBT) (257 mg, 1.27 mmol, 1 eq), 2-(4-chloro-phenyl)-ethylamine
(180 .mu.L, 1.27 mmol, 1 eq) and EDCI (364 mg, 1.9 mmol, 1.5 eq).
The mixture was stirred at room temperature during 20 h. Water (10
mL) was then added and the aqueous phase was extracted with ethyl
acetate (2.times.15 mL). The organic layers were dried over
magnesium sulfate, filtered and evaporated in vacuo. The crude
residue was purified by flash chromatography using cyclohexane and
ethyl acetate (100/0) to (50/50) to afford
5-nitro-1H-pyrazole-3-carboxylic acid
[2-(4-chloro-phenyl)-ethyl]-amide as white solid (160 mg, 43%
yield).
Step 2:
[0709] To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid
[2-(4-chloro-phenyl)-ethyl]amide (160 mg, 5.42 mmol, 1 eq) in
tetrahydrofuran and ethanol (1 mL/3 mL) was added a saturated
solution of ammonium chloride (1 mL) and iron (97 mg, 1.73 mmol,
3.2 eq). The mixture was stirred at 105.degree. C. for 16 h. After
cooling, the mixture was filtrated on a short pad of celite and
washed with ethanol (10 mL), tetrahydrofuran (10 mL) and water (10
mL). The filtrate was evaporated, water (10 mL) was added and the
aqueous phase was extracted with dichloromethane (2.times.15 mL).
The organic layers were dried over magnesium sulfate, filtered and
evaporated in vacuo to afford 5-amino-1H-pyrazole-3-carboxylic acid
[2-(4-chloro-phenyl)-ethyl]-amide as beige powder (100 mg, 70%
yield).
Step 3:
[0710] To a solution of 5-amino-1H-pyrazole-3-carboxylic acid
[2-(4-chloro-phenyl)-ethyl]-amide (100 mg, 0.4 mmol, 1 eq) in
acetic acid (2 mL) was added 2-ethoxymethylene-malonic acid diethyl
ester (80 .mu.L, 0.44 mmol, 1.1 eq). The mixture was heated at
120.degree. C. for 16 h in a sealed tube. After cooling, the
precipitate was filtered and washed with ethanol (2.times.10 mL) to
afford the expected compound as white powder (55 mg, 38%
yield).
[0711] MS: 389.2
[0712] Mp>300.degree. C.
General Procedure F
##STR00168##
[0714] To a solution of
7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2,6-dicarboxylic acid
6-ethyl ester (Key intermediate V) (176 mg, 0.7 mmol, 1 eq) in
dichloromethane (5 mL) were added triethylamine (195 .mu.L, 1.4
mmol, 2 eq), HOBT (142 mg, 1.05 mmol, 1.5 eq), the appropriate
amine (0.8 mmol, 1.1 eq) and EDCI (201 mg, 1.05 mmol, 1.5 eq). The
mixture was stirred at room temperature during 20 h. Water (10 mL)
was then added and the aqueous phase was extracted with
dichloromethane (2.times.15 mL). The organic layers were dried over
magnesium sulfate, filtered and evaporated in vacuo. The crude
residue was purified by flash chromatography using dichloromethane
and methanol (100/0) to (80/20). The compound obtained was taken up
in methanol and filtered to afford the expected compound as white
powder (145 mg, 49% yield).
Example 94
2-(1-Benzylpiperidin-4-ylcarbamoyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimi-
dine-6-carboxylic acid ethyl ester
##STR00169##
[0716] The expected compound was obtained according to general
procedure F using Key Intermediate V and
1-benzyl-piperidin-4-ylamine. The expected compound was isolated as
white powder.
[0717] MS: 424.3
[0718] Mp: 264.degree. C.-266.degree. C.
Example 95
2-Benzylcarbamoyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic
acid ethyl ester
##STR00170##
[0720] The expected compound was obtained according to general
procedure F using Key Intermediate V and benzylamine. The expected
compound was isolated as pale grey powder.
[0721] MS: 341.2
[0722] Mp: 290.degree. C.-292.degree. C.
General Procedure G
##STR00171##
[0724] To a solution of the ester (0.32 mmol, 1 eq) in ethanol (6
mL) was added a 5N solution of sodium hydroxide (0.5 mL). The
mixture was heated in a sealed tube at 80.degree. C. for 20 h to 48
h. After cooling, the mixture was evaporated to dryness. Then water
(5 mL) and citric acid (3 mL) were added. The precipitate obtained
was filtered and washed with water to afford the expected compound
(65% to quant. yield).
Example 96
2-(4-Isopropoxy-phenylamino)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrim-
idine-6-carboxylic acid
##STR00172##
[0726] The expected compound was obtained according to general
procedure G using
2-(4-isopropoxy-phenylamino)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5--
a]pyrimidine-6-carboxylic acid ethyl ester described in example 61.
The expected compound was isolated as yellow powder.
[0727] MS: 330.1
[0728] Mp: decomposes at 260.degree. C.-265.degree. C.
Example 97
2-Benzylamino-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxy-
lic acid
##STR00173##
[0730] The expected compound was obtained according to general
procedure G using
2-benzylamino-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6--
carboxylic acid ethyl ester described in example 58. The expected
compound was isolated as pale yellow powder.
[0731] MS: 286.1
[0732] Mp: 240.degree. C.-245.degree. C.
Example 98
2-[(Naphthalen-1-ylmethyl)-amino]-7-oxo-4,7-dihydro-[1,2,4]triazolo[1
,5a]pyrimidine-6-carboxylic acid
##STR00174##
[0734] The expected compound was obtained according to general
procedure G using
2-[(naphthalen-1-ylmethyl)-amino]-7-oxo-4,7-dihydro[1,2,4]triazolo[-
1,5a]pyrimidine-6-carboxylic acid ethyl ester described in example
60. The expected compound was isolated as pale orange powder.
[0735] MS: 336.1
[0736] Mp: 245.degree. C.-250.degree. C.
Example 99
2-[(Benzo[1,3]dioxol-5-yl
methyl)-amino]-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbo-
xylic acid sodium salt
##STR00175##
[0738] The expected compound was obtained according to general
procedure G using
2-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-7-oxo-4,7-dihydro-[1,2,4]tr-
iazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester. This
starting material was obtained according to general procedure A
using C-benzo[1,3]dioxol-5-yl-methylamine. The expected acid was
isolated without treatment as sodium salt and as yellow powder.
[0739] MS: 330.1
[0740] Mp decomposes at 300.degree. C.
Example 100
(7-Oxo-2-phenylamino-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-ace-
tic acid
##STR00176##
[0742] The expected compound was obtained according to general
procedure G using
(7-oxo-2-phenylamino-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-6--
yl)-acetic acid ethyl ester described in example 64. The expected
compound was isolated as white powder.
[0743] MS: 286.1
[0744] Mp: 279.degree. C.-281.degree. C.
Example 101
[2-(4-Isopropoxy-phenylamino)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyri-
midin-6-yl]-acetic acid
##STR00177##
[0746] The expected compound was obtained according to general
procedure G using
[2-(4-isopropoxy-phenylamino)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-
-a]pyrimidin-6-yl]-acetic acid ethyl ester described in example
65.
Example 102
4-Benzyl-2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carbo-
xylic acid
##STR00178##
[0748] The expected compound was obtained according to general
procedure G using
4-benzyl-2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine--
6-carboxylic acid ethyl ester described in example 74. The expected
compound was isolated as beige powder.
[0749] MS: 310.1
[0750] Mp: 210.degree. C.-215.degree. C.
Example 103
2-Cyclopropyl-7-oxo-4-phenethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-ca-
rboxylic acid
##STR00179##
[0752] The expected compound was obtained according to general
procedure G using
2-cyclopropyl-7-oxo-4-phenethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidi-
ne-6-carboxylic acid ethyl ester described in example 75. The
expected compound was isolated as beige powder.
[0753] MS: 324.1
[0754] Mp: 185.degree. C.-190.degree. C.
Example 104
2-Cyclopropyl-4-[2-(4-hydroxy-phenyl)-ethyl]-7-oxo-4,7-dihydro-pyrazolo[1,-
5-a]-pyrimidine-6-carboxylic acid
##STR00180##
[0756] The expected compound was obtained according to general
procedure G using
2-cyclopropyl-4-[2-(4-hydroxy-phenyl)-ethyl]-7-oxo-4,
7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester
described in example 76. The expected compound was isolated as
white powder.
[0757] MS: 340.1
[0758] Mp: 265.degree. C.-270.degree. C.
Example 105
4-[2-(4-Chloro-phenyl)-ethyl]-2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-
-a]pyrimidine-6-carboxylic acid
##STR00181##
[0760] The expected compound was obtained according to general
procedure G using
4-[2-(4-chloro-phenyl)-ethyl]-2-cyclopropyl-7-oxo-4,7-dihydro-pyraz-
olo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester described in
example 77. The expected compound was isolated as white powder.
[0761] MS: 358.1
[0762] Mp: 220.degree. C.-225.degree. C.
Example 106
2-Cyclopropyl-4-[2-(4-methoxy-phenyl)-ethyl]-7-oxo-4,7-dihydro-pyrazolo[1,-
5-a]-pyrimidine-6-carboxylic acid
##STR00182##
[0764] The expected compound was obtained according to general
procedure G using
2-cyclopropyl-4-[2-(4-methoxy-phenyl)-ethyl]-7-oxo-4,
7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester
described in example 78. The expected compound was isolated as
white powder.
[0765] MS: 354.2
[0766] Mp: 145.degree. C.-150.degree. C.
Example 107
2-Cyclopropyl-7-oxo-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,7-dihydro-pyr-
azolo[1,5-a]-pyrimidine-6-carboxylic acid
##STR00183##
[0768] The expected compound was obtained according to general
procedure G using
2-cyclopropyl-7-oxo-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,7-dihy-
dro-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester. The
starting material was obtained according to general procedure D
using Key Intermediate II and
1-(2-bromo-ethyl)-4-trifluoromethyl-benzene. The expected compound
was isolated as white powder.
[0769] MS: 392.2
[0770] Mp: 225.degree. C.-230.degree. C.
Example 108
4-[2-(3-Chloro-phenyl)-ethyl]-2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-
-a]-pyrimidine-6-carboxylic acid
##STR00184##
[0772] The expected compound was obtained according to general
procedure G using
4-[2-(3-chloro-phenyl)-ethyl]-2-cyclopropyl-7-oxo-4,7-dihydro-pyraz-
olo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester described in
example 79. The expected compound was isolated as white powder.
[0773] MS: 358.1
[0774] Mp: 230.degree. C.-235.degree. C.
Example 109
2-Cyclopropyl-4-[2-(3-fluoro-phenyl)-ethyl]-7-oxo-4,7-dihydro-pyrazolo[1,5-
-a]pyrimidine-6-carboxylic acid
##STR00185##
[0776] The expected compound was obtained according to general
procedure G using
2-cyclopropyl-4-[2-(3-fluoro-phenyl)-ethyl]-7-oxo-4,7-dihydro-pyraz-
olo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester described in
example 80. The expected compound was isolated as white powder.
[0777] MS: 342.1
[0778] Mp: 220.degree. C.-225.degree. C.
Example 110
2-Cyclopropyl-7-oxo-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-4,7-dihydro-pyr-
azolo[1,5-a]-pyrimidine-6-carboxylic acid
##STR00186##
[0780] The expected compound was obtained according to general
procedure G using
2-cyclopropyl-7-oxo-4-[2-(3-trifluoromethyl-phenyl)-ethyl]-4,7-dihy-
dro-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester
described in example 81. The expected compound was isolated as
white powder.
[0781] MS: 392.2
[0782] Mp: 200.degree. C.-205.degree. C.
Example 111
2-Cyclopropyl-7-oxo-4-(3-phenyl-propyl)-4,7-dihydro-pyrazolo[1,5-a]pyrimid-
ine-6-carboxylic acid
##STR00187##
[0784] The expected compound was obtained according to general
procedure G using
2-cyclopropyl-7-oxo-4-(3-phenyl-propyl)-4,7-dihydro-pyrazolo[1,5-a]-
pyrimidine-6-carboxylic acid ethyl ester described in example 82.
The expected compound was isolated as beige powder.
[0785] MS: 338.2
[0786] Mp: 95.degree. C.-100.degree. C.
Example 112
4-Benzyl-2-isopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxy-
lic acid
##STR00188##
[0788] The expected compound was obtained according to general
procedure G using
4-benzyl-2-isopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6--
carboxylic acid ethyl ester described in example 83. The expected
compound was isolated as beige powder.
[0789] MS: 312.1
[0790] Mp: 180.degree. C.-185.degree. C.
Example 113
2-Isopropyl-7-oxo-4-phenethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carb-
oxylic acid
##STR00189##
[0792] The expected compound was obtained according to general
procedure G using
2-isopropyl-7-oxo-4-phenethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-
-6-carboxylic acid ethyl ester described in example 84. The
expected compound was isolated as white powder.
[0793] MS: 326.2
[0794] Mp: 220.degree. C.-225.degree. C.
Example 114
2-Isopropyl-7-oxo-4-(3-phenyl-propyl)-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-
e-6-carboxylic acid
##STR00190##
[0796] The expected compound was obtained according to general
procedure G using
2-isopropyl-7-oxo-4-(3-phenyl-propyl)-4,7-dihydro-pyrazolo[1,5-a]py-
rimidine-6-carboxylic acid ethyl ester described in example 85. The
expected compound was isolated as orange oil.
[0797] MS: 340.2
Example 115
4-Benzyl-2-cyclopentyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carbo-
xylic acid
##STR00191##
[0799] The expected compound was obtained according to general
procedure G using
4-benzyl-2-cyclopentyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine--
6-carboxylic acid ethyl ester described in example 86. The expected
compound was isolated as white powder.
[0800] MS: 338.2
[0801] Mp: 213.degree. C.-215.degree. C.
Example 116
2-Cyclopentyl-7-oxo-4-phenethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-ca-
rboxylic acid
##STR00192##
[0803] The expected compound was obtained according to general
procedure G using
2-cyclopentyl-7-oxo-4-phenethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidi-
ne-6-carboxylic acid ethyl ester described in example 87. The
expected compound was isolated as white powder.
[0804] MS: 352.2
[0805] Mp: 1980.degree. C.-200.degree. C.
Example 117
(7-Oxo-2-phenyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-acetic
acid
##STR00193##
[0807] The expected compound was obtained according to general
procedure G using
(2-phenyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-acetic
acid ethyl ester described in example 88. The expected compound was
isolated as beige powder.
[0808] MS: 270.1
[0809] Mp decomposes at 285.degree. C.-290.degree. C.
Example 118
[2-(4-Ethoxy-phenyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl]-acet-
ic acid
##STR00194##
[0811] The expected compound was obtained according to general
procedure G using
[2-(4-ethoxy-phenyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-y-
l]-acetic acid ethyl ester. The starting material was obtained
according to general procedure E using
5-(4-ethoxy-phenyl)-2H-pyrazol-3-ylamine. The expected compound was
isolated as white powder.
[0812] MS: 314.1
[0813] Mp: decomposes at 295.degree. C.-300.degree. C.
Example 119
(7-Oxo-2-trifluoromethyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-acetic
acid
##STR00195##
[0815] The expected compound was obtained according to general
procedure G using
(7-oxo-2-trifluoromethyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)--
acetic acid ethyl ester described in example 89. The expected
compound was isolated as pale salmon colored powder.
[0816] MS: 262.0
[0817] Mp: 320.degree. C.-324.degree. C.
Example 120
(2-Cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-acetic
acid
##STR00196##
[0819] The expected compound was obtained according to general
procedure G using
(2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-ace-
tic acid ethyl ester described in example 90. The expected compound
was isolated as white powder.
[0820] MS: 234.1
[0821] Mp>300.degree. C.
Example 121
2-[2-(4-Chloro-phenyl)-ethylcarbamoyl]-7-oxo-4,7-dihydro-pyrazolo[1,5-a]py-
rimidine-6-carboxylic acid
##STR00197##
[0823] The expected compound was obtained according to general
procedure G using
[2-[2-(4-chloro-phenyl)-ethylcarbamoyl]-7-oxo-4,7-dihydro-pyrazolo[-
1,5-a]pyrimidine-6-carboxylic acid ethyl ester described in example
93. The expected compound was isolated as white powder.
[0824] MS: 361.1
[0825] Mp>300.degree. C.
Example 122
Sodium
2-(1-benzyl-piperidin-4-ylcarbamoyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-
-a]-pyrimidine-6-carboxylate
##STR00198##
[0827] The expected compound was obtained according to general
procedure G using
2-(1-benzylpiperidin-4-ylcarbamoyl)-7-oxo-4,7-dihydropyrazolo[1,5-a-
]pyrimidine-6-carboxylic acid ethyl ester described in example 94.
Instead of the described treatment, the precipitate obtained was
filtered to isolate the expected compound as the sodium salt and as
white powder.
[0828] MS: 396.2
[0829] Mp: decomposes at 300.degree. C.
General Procedure H
##STR00199##
[0831] Step 1:
[0832] 1H-1,2,4-Triazole-3,5-diamine (12.4 g, 0.125 mol) was
dissolved in AcOH (50 ml), and diethyl 2-(ethoxymethylene) malonate
(32.5 g, 0.15 mol) was added. The solution was refluxed overnight,
then cooled, filtered, and dried to give Key Intermediate VI (22 g,
79%) as a white solid.
Step 2:
[0833] To a mixture of VI (500 mg, 2.2 mmol) in N-methylpyrrolidone
(20 ml), K.sub.2CO.sub.3 (619 mg, 4.5 mmol) and RBr (3.4 mmol) were
added. The solution was stirred at 50.degree. C. overnight. The
solution was cooled, filtered, and concentrated. The solid was
washed with MeOH (20 ml), and dried to give Key Intermediate VII as
a white solid.
[0834] A mixture of VII and NaOH (2.0 eq. (mmol)) in
CH.sub.3OH/THF/H.sub.2O (5/5/1) was stirred at r.t. for 2 h. The
solvent was removed in vacuum. The residue was dissolved in water
(20 ml), the pH value was adjusted to 6, then filtered, and dried
to give desired compounds as a white solid.
Example 123
2-Amino-4-benzyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carb-
oxylic acid
##STR00200##
[0836] VI was treated with benzylbromide according to the general
procedure H to obtain compound 66 as a white solid.
[0837] Yield: 10%
[0838] MS (ESI): 286 (M+H).sup.+
[0839] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0840] .delta. 12.87 (br, s, 1H), 8.86 (s, 1H), 7.34-7.41 (m, 5H),
6.42 (s, 2H), 5.43 (s, 2H)
Example 124
2-Amino-7-oxo-4-phenethyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-c-
arboxylic
##STR00201##
[0842] VI was treated with phenethylbromide according to the
general procedure H to obtain compound 67 as a white solid.
[0843] Yield: 11%
[0844] MS (ESI): 300 (M+H).sup.+
[0845] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0846] .delta. 12.84 (s, 1H), 8.69 (s, 1H), 7.30-7.40 (m, 5H), 6.54
(s, 2H), 4.49 (t, J=7.2 Hz, 2H), 3.19 (t, J=7.2 Hz, 2H)
[0847] .sup.13C NMR (d.sub.6-DMSO, 300 MHz):
Example 125
2-Amino-4-(cyclohexylmethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrim-
idine-6-carboxylic acid
##STR00202##
[0849] VI was treated with (bromomethyl)cyclohexane according to
the general procedure H to obtain compound 68 as a white solid.
[0850] Yield: 10%
[0851] MS (ESI): 292 (M+H).sup.+
[0852] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0853] .delta. 12.86 (s, 1H), 8.69 (s, 1H), 6.44 (s, 2H), 4.05 (d,
J=7.2 Hz, 2H), 1.89-1.95 (m, 1H), 1.56-1.67 (m, 5H), 0.90-1.15 (m,
5H)
Example 126
2-Amino-4-isopropyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-c-
arboxylic acid
##STR00203##
[0855] VI was treated with 2-bromopropane according to the general
procedure H to obtain compound 69 as a white solid.
[0856] Yield: 11%
[0857] MS (ESI): 238 (M+H).sup.+
[0858] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0859] .delta. 12.97 (s, 1H), 8.71 (s, 1H), 6.50 (s, 2H), 4.86-4.95
(m, 1H), 1.58 (d, J=6.6 Hz, 6H)
Example 127
2-Amino-4-(biphenyl-2-ylmethyl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]py-
rimidine-6-carboxylic acid
##STR00204##
[0861] VI was treated with 2-(bromomethyl)biphenyl according to the
general procedure H to obtain compound 70 as a white solid.
[0862] Yield: 13%
[0863] MS (ESI): 362 (M+H).sup.+
[0864] .sup.1H NMR (d.sub.6-DMSO, 300 MHz):
[0865] .delta. 12.76 (br, s, 1H), 8.47 (s, 1H), 7.34-7.47 (m, 7H),
7.20-7.29 (m, 2H), 6.32 (s, 2H), 5.39 (s, 2H)
Examples 128 and 129
2-Amino-4-[1-adamantyl]-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-
-6-carboxylic acid and
2-amino-4-[1-adamantyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one
##STR00205##
[0867] VI was treated with 1-bromoadamantane according to the
general procedure to obtain compounds 128 and 129 as a brown
solid.
[0868] Yield: 5%
[0869] MS (ESI): 330 (M+H).sup.+, 286
[0870] A19, .sup.1H NMR (CDCl.sub.3, 300 MHz):
[0871] .delta. 8.46 (s, 1H), 2.00-2.22 (m, 9H), 1.58-1.70 (m,
3H)
[0872] A19-0, .sup.1H NMR (CDCl.sub.3, 300 MHz):
[0873] .delta. 7.69 (d, J=6.6 Hz, 1H), 5.73 (d, J=6.6 Hz, 1H)
2.00-2.22 (m, 9H), 1.58-1.70 (m, 3H)
Activity Data for Compounds Having General Formula (C)
TABLE-US-00003 [0874] Structure FRET CPE ##STR00206## IC.sub.50 =
58 .mu.M inactive ##STR00207## inactive 28% @ 50 .mu.M ##STR00208##
26% @ 5 .mu.M inactive ##STR00209## 23% @ 5 .mu.M inactive
##STR00210## IC.sub.50 = 50 .mu.M inactive ##STR00211## IC.sub.50 =
35 .mu.M inactive ##STR00212## 41% @ 25 .mu.M inactive ##STR00213##
42% @ 25 .mu.M inactive ##STR00214## 20% @ 25 .mu.M inactive
##STR00215## 26% @ 25 .mu.M inactive ##STR00216## 22% @ 25 .mu.M
inactive ##STR00217## 22% @ 25 .mu.M inactive ##STR00218## 30% @ 25
.mu.M inactive ##STR00219## 32% @ 25 .mu.M inactive ##STR00220##
IC.sub.50 = 62 .mu.M inactive ##STR00221## 27% @ 25 .mu.M inactive
##STR00222## IC.sub.50 = 69 .mu.M inactive ##STR00223## 29% @ 50
.mu.M inactive ##STR00224## IC.sub.50 = 34 .mu.M n.d. ##STR00225##
IC.sub.50 = 10 .mu.M n.d. ##STR00226## 35% @ 50 .mu.M n.d.
##STR00227## IC.sub.50 = 71 .mu.M inactive ##STR00228## 31% @ 25
.mu.M inactive ##STR00229## 50% @ 25 .mu.M inactive ##STR00230##
38% @ 10 .mu.M inactive ##STR00231## inactive 18% @ 50 .mu.M
* * * * *
References