U.S. patent application number 11/176156 was filed with the patent office on 2005-11-10 for gyrase inhibitors.
Invention is credited to Appelt, Krzysztof, Chu, Shaosong, Li, Xiaoming, Yager, Kraig.
Application Number | 20050250823 11/176156 |
Document ID | / |
Family ID | 34229431 |
Filed Date | 2005-11-10 |
United States Patent
Application |
20050250823 |
Kind Code |
A1 |
Yager, Kraig ; et
al. |
November 10, 2005 |
Gyrase inhibitors
Abstract
Compounds comprising an indazolyl group and a thiazolyl group,
preferably 7-substituted 3-(thiazol-2-yl)-1H-indazole compounds in
which the indazolyl group and a thiazolyl group are each
independently optionally substituted, are useful for the treatment
or prophylaxis of bacterial infections in mammals. The compounds
are believed to function by inhibiting gyrase B.
Inventors: |
Yager, Kraig; (Oceanside,
CA) ; Chu, Shaosong; (Encinitas, CA) ; Appelt,
Krzysztof; (Rancho Santa Fe, CA) ; Li, Xiaoming;
(San Diego, CA) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Family ID: |
34229431 |
Appl. No.: |
11/176156 |
Filed: |
July 7, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11176156 |
Jul 7, 2005 |
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10848474 |
May 17, 2004 |
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60500416 |
Sep 5, 2003 |
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60523436 |
Nov 19, 2003 |
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60565886 |
Apr 27, 2004 |
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Current U.S.
Class: |
514/365 ;
548/181 |
Current CPC
Class: |
A61P 31/04 20180101;
A61P 43/00 20180101; C07D 417/14 20130101; C07D 487/08
20130101 |
Class at
Publication: |
514/365 ;
548/181 |
International
Class: |
C07D 417/04; A61K
031/427 |
Claims
What is claimed is:
1. A compound comprising an indazolyl group and a thiazolyl group,
the compound being represented by the structure 367wherein R7 is
selected from the group consisting of C.sub.1-C.sub.6 hydrocarbon,
lower alkoxy, lower thioalkoxy, CN, NO.sub.2, halogen, CF.sub.3,
and OCF.sub.3; and wherein the C.sub.1-C.sub.6 hydrocarbon,
indazolyl group, and thiazolyl group are optionally substituted on
carbon; or a pharmaceutically acceptable salt, ester, solvate or
prodrug thereof.
2. The compound of claim 1, wherein R7 is selected from the group
consisting of methyl, ethyl, propyl, allyl, F, Cl, and Br.
3. The compound of claim 2, wherein the propyl is cyclopropyl.
4. The compound of claim 2, wherein R7 is selected from the group
consisting of methyl, ethyl, F, and Cl.
5. The compound of claim 4, wherein R7 is methyl.
6. The compound of claim 1, wherein the indazolyl group bears at
least one substituent selected from the group consisting of
optionally substituted C.sub.1-C.sub.6 hydrocarbon, optionally
substituted heterocycle, lower alkoxy, CN, NO.sub.2, F, Cl, Br,
CF.sub.3, and OCF.sub.3.
7. The compound of claim 6, wherein the indazolyl bears at least
one substituent selected from the group consisting of optionally
substituted C.sub.1-C.sub.6 hydrocarbon, F, and Cl.
8. The compound of claim 7, wherein the indazolyl group bears at
least one substituent selected from the group consisting of methyl,
ethyl, propyl, allyl, methylcyclopropyl, F, and Cl.
9. The compound of claim 8, wherein the indazolyl group bears at
least one substituent selected from the group consisting of methyl,
ethyl, F, and Cl.
10. The compound of claim 1, wherein the thiazolyl group bears at
least one substituent selected from the group consisting of
optionally substituted C.sub.1-C.sub.10 hydrocarbon, optionally
substituted C.sub.1-C.sub.10 heterocycle, optionally substituted
carboxamido, optionally substituted aminocarboxy, optionally
substituted C.sub.1-C.sub.6 alkoxy, optionally substituted
C.sub.1-C.sub.6 alkoxycarbonyl, OH, and COOH.
11. The compound of claim 10, wherein the thiazolyl group bears at
least one substituent selected from the group consisting of methyl,
ethyl, OH, COOH, COOCH.sub.3, and COOCH.sub.2CH.sub.3.
12. The compound of claim 10, wherein the thiazolyl group bears at
least one substituent selected from the group consisting of
optionally substituted C.sub.1-C.sub.10 hydrocarbon, optionally
substituted C.sub.1-C.sub.6 alkoxycarbonyl, COOH, OH, COOR.sup.3,
and CONR.sup.8R.sup.9, wherein R.sup.3 is selected from the group
consisting of optionally substituted heterocycle and
C.sub.1-C.sub.6 alkyl substituted by heterocycle; wherein R.sup.8
and R.sup.9 are independently selected from the group consisting of
H, optionally substituted heterocycle, and optionally substituted
C.sub.1-C.sub.6 hydrocarbon; wherein R.sup.8 and R.sup.9 may
together form a four-, five-, or six-membered optionally
substituted heterocyclic ring including the N atom to which R.sup.8
and R.sup.9 are attached; and wherein for said ring one to three
carbon atoms may optionally each independently be replaced by an
atom selected from the group consisting of N, O, and S.
13. The compound of claim 10, wherein the thiazolyl group bears two
substituents, each of which is independently selected from the
group consisting of optionally substituted C.sub.1-C.sub.10
hydrocarbon, COOH, optionally substituted C.sub.1-C.sub.6
alkoxycarbonyl, OH, COOR.sup.3, and CONR.sup.8R.sup.9, wherein
R.sup.3 is selected from the group consisting of optionally
substituted heterocycle and C.sub.1-C.sub.6 alkyl substituted by
heterocycle; wherein R.sup.8 and R.sup.9 are independently selected
from the group consisting of H, optionally substituted heterocycle,
and optionally substituted C.sub.1-C.sub.6 hydrocarbon, wherein
R.sup.8 and R.sup.9 may together form a four-, five-, or
six-membered optionally substituted heterocyclic ring including the
N atom to which R and R' are attached; and wherein for said ring
one to three carbon atoms may optionally each independently be
replaced by an atom selected from the group consisting of N, O, and
S.
14. The compound of claim 12, wherein the substituent is selected
from the group consisting of methyl, ethyl, OH, phenyl, COOH,
COOCH.sub.3, COOCH.sub.2CH.sub.3, and
N(CH.sub.3)(CH.sub.2CH.sub.3).
15. The compound of claim 12, wherein the thiazolyl group is
attached to a carbonyl carbon of at least one substituent
represented by a structure selected from the group consisting of
368369
16. The compound of claim 10, wherein the substituent is selected
from the group consisting of phenyl and pyridyl, wherein the phenyl
is optionally substituted with at least one second substituent
selected from the group consisting of OH, OCH.sub.3, F, Cl, Br,
optionally substituted piperazin-1-yl, and optionally substituted
morpholin-4-yl; and wherein the pyridyl is optionally substituted
with at least one third substituent selected from the group
consisting of C.sub.1-C.sub.6 alkyl, F, Cl, Br, I, CF.sub.3
3,5-dimethyl-piperazin-1-yl, and morpholin-4-yl.
17. The compound of claim 16, wherein the optionally substituted
phenyl is selected from the group consisting of 3-hydroxyphenyl,
4-hydroxyphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl,
4-fluoro-3-hydroxy-pheny- l, 3,4-difluoro-phenyl,
3,5-difluoro-phenyl, 4-bromo-3-methoxy-phenyl,
4-(4-methyl-piperazin-1-yl)-phenyl, and
4-(morpholin-4-yl)-phenyl.
18. The compound of claim 16, wherein the pyridyl is selected from
the group consisting of pyridin-3-yl, 6-methyl-pyridin-3-yl,
6-chloro-pyridin-3-yl, and 6-trifluoromethyl-pyridin-3-yl.
19. The compound of claim 1, wherein the compound is
(3-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-pyridin-
-3-yl-thiazol-4-yl]-methanone.
20. The compound of claim 1, wherein the compound is
(3-(S)-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-pyr-
idin-3-yl-thiazol-4-yl]-methanone.
21. The compound of claim 1, wherein the compound is
(3-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol-3-yl)--
5-pyridin-3-yl-thiazol-4-yl]-methanone.
22. The compound of claim 1, wherein the compound is
(3-(S)-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol-3--
yl)-5-pyridin-3-yl-thiazol-4-yl]-methanone.
23. The compound of claim 1, wherein the compound is a
(3-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol-3-yl)--
5-pyridin-3-yl-thiazol-4-yl]-methanone in which the pyridyl is
methyl substituted.
24. The compound of claim 1, wherein the compound is
(3-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-(6-meth-
yl-pyridin-3-yl)-thiazol-4-yl]-methanone.
25. The compound of claim 1, wherein the compound is
(3-(S)-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-(6--
methyl-pyridin-3-yl)-thiazol-4-yl]-methanone.
26. The compound of claim 1, wherein the compound is
(3-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol-3-yl)--
5-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-methanone.
27. The compound of claim 1, wherein the compound is
(3-(S)-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol-3--
yl)-5-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-methanone.
28. The compound of claim 1, wherein the compound is
[2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-methyl--
piperazin-1-yl)-methanone.
29. The compound of claim 1, wherein the compound is
1-[2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-2-(1-met-
hyl-piperidin-4-yl)-ethanone.
30. The compound of claim 1, wherein the compound is
[2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-[3-(4-meth-
yl-piperazin-1-yl)-azetidin-1-yl]-methanone.
31. The compound of claim 1, wherein the compound is
[2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-(3-morphol-
in-4-yl-azetidin-1-yl)-methanone.
32. The compound of claim 1, wherein the compound is
[2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-[3-(ethyl--
methyl-amino)-azetidin-1-yl]-methanone.
33. The compound of claim 1 that is synthetically produced.
34. The isolated, purified compound of claim 1.
35. A composition comprising the compound of claim 1 and a
pharmaceutically acceptable carrier.
36. A method of treating or preventing a bacterial infection in a
mammal, comprising administering to the mammal an effective amount
of the composition of claim 35.
37. A method of treating or preventing a bacterial infection in a
mammal, comprising administering to the mammal an effective amount
of the compound of claim 1.
38. The method of claim 37, comprising identifying a mammal
suffering from the bacterial infection.
39. A method for making the compound of claim 1, comprising:
treating an optionally substituted indazole represented by the
formula 370wherein R7 is selected from the group consisting of
C.sub.1-C.sub.6 hydrocarbon, lower alkoxy, lower thioalkoxy, CN,
NO.sub.2, halogen, CF.sub.3, and OCF.sub.3; wherein the
C.sub.1-C.sub.6 hydrocarbon is optionally substituted; and wherein
LG represents a leaving group; with a cyanide salt to form an
optionally substituted indazole nitrile represented by the formula
371
40. The method of claim 39, wherein the leaving group is selected
from the group consisting of chloro, bromo, iodo,
trifluoromethanesulfonate, methanesulfonate, p-toluenesulfonate,
and trifluoroacetate.
41. The method of claim 40, wherein the leaving group is iodo.
Description
RELATED APPLICATION INFORMATION
[0001] This application claims priority to U.S. Provisional
Application No. 60/500,416, filed Sep. 5, 2003, U.S. Provisional
Application No. 60/523,436, filed on Nov. 19, 2003, and U.S.
Provisional Application No. 60/565,886, filed on Apr. 27, 2004,
each of which is hereby incorporated by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to anti-bacterial compounds and
methods of using them to treat bacterial infections.
[0004] 2. Description of the Related Art
[0005] Bacterial resistance to drugs drives a continuing need for
new anti-bacterial agents that to which the bacteria have not yet
developed resistance. DNA gyrase is an enzyme found in many
gram-positive and gram-negative bacteria. It is believed that DNA
gyrase participates in the unfolding of the DNA double helix that
takes before DNA replication by catalyzing ATP-dependent negative
super-coiling of the DNA. DNA gyrase is believed to contain a
complex of dimeric subunits, called gyrases A and B, that form an
A.sub.2B.sub.2 active enzyme complex. It is further believed that
the A.sub.2 subunit carries out DNA binding, cleavage, and
rejoining, while the B.sub.2 subunit mediates ATPase activity.
[0006] Anti-bacterial agents that target the A subunit, such as
quinolones, now face growing resistance among clinically important
bacterial pathogens. Attempts to inhibit the B, subunit of gyrase
instead have not been entirely successful. Agents that inhibit
catalysis of ATP hydrolysis by the B subunit (e.g., coumarins, such
as novobiocin, and the cyclothialidines) were found to have low
antimicrobial activities and unfavorable toxicity profiles (not
related to the mechanism of action). U.S. Pat. Nos. 6,608,087 and
6,632,809, both of which are hereby incorporated by reference,
describe other gyrase inhibitors. U.S. Pat. Nos. 5,140,034;
5,208,248 and 6,555,539, each of which is incorporated by reference
in its entirety, disclose thiazolyl indazoles and their use as
therapeutic agents, but these compounds are not known to be useful
for inhibiting the B subunit of gyrase.
[0007] A need therefore exists for new anti-bacterial compounds,
and particularly those that target the B subunit of bacterial DNA
gyrase while overcoming the drawbacks of the existing
inhibitors.
SUMMARY OF THE INVENTION
[0008] The present invention provides compounds comprising an
indazolyl group and a thiazolyl group, preferably 7-substituted
3-(thiazol-2-yl)-1H-indazole compounds in which the indazolyl group
and the thiazolyl group are each independently optionally
substituted. In preferred embodiments, the compounds are useful for
the treatment or prophylaxis of bacterial infections in
mammals.
[0009] A preferred embodiment provides a compound comprising an
indazolyl group and a thiazolyl group, the compound being
represented by the structure 1
[0010] wherein R7 is selected from the group consisting of
C.sub.1-C.sub.6 hydrocarbon, lower alkoxy, lower thioalkoxy, CN,
NO.sub.2, halogen, CF.sub.3, and OCF.sub.3; and wherein the
C.sub.1-C.sub.6 hydrocarbon, indazolyl group, and thiazolyl group
are optionally substituted on carbon; or a pharmaceutically
acceptable salt, ester, solvate or prodrug thereof. Preferably, the
compound of the formula (I) is synthetically produced. A compound
of the formula (I) in an isolated, purified form is preferred.
[0011] Another embodiment provides a composition comprising the
compound of claim 1 and a pharmaceutically acceptable carrier.
[0012] Another preferred embodiment provides method of treating or
preventing a bacterial infection in a mammal, comprising
administering to the mammal an effective amount of a compound of
the formula (I) or composition thereof.
[0013] Another preferred embodiment provides a method for making a
compound of the formula (I), comprising: treating an optionally
substituted indazole represented by the formula 2
[0014] wherein R7 is selected from the group consisting of
C.sub.1-C.sub.6 hydrocarbon, lower alkoxy, lower thioalkoxy, CN,
NO.sub.2, halogen, CF.sub.3, and OCF.sub.3; wherein the
C.sub.1-C.sub.6 hydrocarbon is optionally substituted; and wherein
LG represents a leaving group; with a cyanide salt to form an
optionally substituted indazole nitrile represented by the formula
3
[0015] These and other embodiments are described in greater detail
below.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] Definitions
[0017] Technical terms used herein have the meanings ascribed to
them in the McGraw-Hill Dictionary of Scientific and Technical
Terms, 6.sup.th ed., McGraw-Hill, New York, 2003, unless otherwise
noted.
[0018] "Hydrocarbon" as used here includes alkyl, cycloalkyl,
alkenyl, alkynyl, aryl, and combinations thereof.
[0019] "Alkoxy" or "alkoxyl" refers to hydrocarbon groups attached
to the parent structure through an oxygen atom. "Lower alkoxy"
refers to groups containing one to four carbon atoms.
[0020] "Aryl" refers to monocyclic 5- or 6-membered, bicyclic 9- or
10-membered, and tricyclic 13- or 14-membered aromatic carbocyclic
rings, optionally bearing one or more substituents. Non-limiting
examples of such rings include benzene, naphthalene, indane,
tetralin, and fluorene, and of suitable substituents include
halogen, --R.sup.1, --OR.sup.1, --OH, --SH, --SR.sup.1, protected
OH (such as acyloxy), optionally substituted phenyl (Ph),
optionally substituted heterocycles, --NO.sub.2, --CN, optionally
substituted amino groups, optionally substituted carboxamido
groups, --NHCONHR.sup.1, --NHCONR.sup.1R.sup.2,
--NR.sup.1COR.sup.2, --NHCO.sub.2R.sup.1, --CO.sub.2R.sup.1,
CO.sub.2H, COR.sup.1, CONHR.sup.1, --CONR.sup.1R.sup.2,
--S(O).sub.2R.sup.1, --SONH.sub.2--S(O)R.sup.1,
--SO.sub.2NHR.sup.1, and --NHSO.sub.2R.sup.1, where R.sup.1 and
R.sup.2 are optionally substituted aliphatic groups.
[0021] "Heteroaryl" refers to aryl groups containing up to three N,
O, and/or S heteroatoms. Non-limiting examples include imidazole,
pyridine, indole, thiophene, benzopyranone, thiazole, thiadiazole,
furan, benzimidazole, quinoline, isoquinoline, quinoxaline,
pyrimidine, pyrazine, tetrazole and pyrazole.
[0022] "Heterocycle" refers to a cycloalkyl or aryl group in which
from one to three carbon atoms is replaced by N, O and/or S
heteroatoms. The nitrogen and sulfur heteroatoms may optionally be
oxidized, and the nitrogen heteroatom may optionally be quaternized
or substituted with substituents such as R.sup.1, COR.sup.1,
SO.sub.2R.sup.1, and CO.sub.2R.sup.1, where R.sup.1 is an
optionally substituted aliphatic group. In addition to the
heteroaryl groups listed above, examples of heterocycles include
piperidine, morpholine, thiomorpholine, piperazine, pyrrolidine,
pyrrole, pyridazine, oxazole, oxadiazole, oxazoline, isoxazole,
dioxane, tetrahydrofuran; and phenothiazine.
[0023] "Substituted" in reference to, e.g., an alkyl or other group
refers to replacement of H atoms in that group with one or more of
the following: lower alkyl; allyl; halogen; haloalkyl; hydroxy,
lower alkoxy; hydroxy lower alkyl; carboxy; carboalkoxy (also
referred to as alkoxycarbonyl); carboxyalkoxy; carboxamido (also
referred to as alkylaminocarbonyl); cyano; formyl; acyl; nitro;
amino; alkylamino; dialkylamino; anilino; mercapto; alkylthio;
sulfoxide; sulfone; acylamino; amidino; phenyl; benzyl; heteroaryl;
heterocycle; phenoxy; benzoyl; benzoyl substituted with amino,
hydroxy, methoxy, methyl or halo; benzyloxy and heteroaryloxy. When
the group that is substituted contains an alkyl segment, two
hydrogen atoms on the same carbon atom may be replaced by oxo
(.dbd.O). A substitutable nitrogen atom on a heterocyclic ring may
be optionally substituted with substituents such as R.sup.1,
COR.sup.1, SO.sub.2R.sup.1, and CO.sub.2R.sup.1, where R.sup.1 is
an aliphatic group or a substituted aliphatic group.
[0024] "Synthetically produced" means produced in a laboratory or
manufacturing process, as opposed to produced in vivo through a
naturally-occurring process.
[0025] "Aliphatic" as used here means straight chained, branched or
cyclic C.sub.1-C.sub.12 hydrocarbons whether saturated or
unsaturated. Non limiting examples of aliphatic groups include
substituted or unsubstituted linear, branched or cyclic alkyl,
alkenyl, alkynyl groups and hybrids thereof such as
(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0026] "Pharmaceutically acceptable salt" as used herein refers to
salts that are, within the scope of sound medical judgement,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge, et al. describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:
1-19. The salts can be prepared in situ during the final isolation
and purification of compounds of the formula (I) as described
below, or separately by reaction of the free base with a suitable
organic acid. Representative, acid addition salts include acetate,
adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, borate, butyrate, camphorate,
camphersulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,
glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,
hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, palmoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate,
toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like, as well as
nontoxic ammonium, quaternary ammonium, and amine cations,
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like.
[0027] "Pharmaceutically acceptable ester" as used herein refers to
esters that hydrolyze in vivo and include those that break down
readily in the human body to leave the parent compound or a salt
thereof. Suitable ester groups include, for example, those derived
from pharmaceutically acceptable aliphatic carboxylic acids,
particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic
acids, in which each alkyl or alkenyl moiety advantageously has not
more than 6 carbon atoms. Examples of particular esters include
formates, acetates, propionates, butyrates, acrylates and
ethylsuccinates.
[0028] "Pharmaceutically acceptable solvate" as used herein refers
to an aggregate that comprises one or more molecules of the solute,
such as a formula (I) compound, with one or more molecules of a
solvent. When the solvent is water, the resulting solvate may be
referred to as a "hydrate."
[0029] "Pharmaceutically acceptable carrier" as used herein refers
to a non-toxic carrier that may be administered to a patient,
together with a compound of this invention, and that does not
adversely affect the pharmacological activity of the compound.
[0030] "Prodrug" as used herein refers compounds that are
transformed in vivo to yield a compound of the formula (1) below,
or a salt or metabolite thereof. The transformation may occur by
various mechanisms, such as through hydrolysis in blood. A
discussion of the use of prodrugs is provided by T. Higuchi and W.
Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the
A.C.S. Symposium Series, and in Bioreversible Carriers in Drug
Design, ed. Edward B. Roche, American Pharmaceutical Association
and Pergamon Press, 1987.
[0031] For example, if a compound of the formula (I) contains a
carboxylic acid functional group, a prodrug can comprise an ester
formed by the replacement of the hydrogen atom of the acid group
with a group such as (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N-C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
b-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0032] Similarly, if a compound of the formula (I) comprises an
alcohol functional group, a prodrug can be formed by the
replacement of the hydrogen atom of the alcohol group with a group
such as (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl- ,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxyc- arbonyloxymethyl,
N-C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each .alpha.-aminoacyl
group is independently selected from the naturally-occurring
L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
[0033] If a compound of the formula (I) comprises an amine
functional group, a prodrug can be formed by the replacement of a
hydrogen atom in the amine group with a group such as R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
((C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7)cycloalkyl, benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl-natural .alpha.-aminoacyl, --C(OH)C(O)OY wherein
(Y is H, (C.sub.1-C.sub.6)alkyl or benzyl), --C(OY.sub.0)Y.sub.1
wherein Y.sub.0 is (C.sub.1-C.sub.4) alkyl and Y.sub.1 is
((C.sub.1-C.sub.6)alkyl- , carboxy(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylaminoalkyl, --C(Y.sub.2)Y.sub.3
wherein Y.sub.2 is H or methyl and Y.sub.3 is mono-N-- or
di-N,N--(C.sub.1-C.sub.- 6)alkylamino, morpholino, piperidin-1-yl
or pyrrolidin-1-yl.
[0034] Compounds and Compositions
[0035] A preferred embodiment provides compounds of the formula (I)
comprising an indazolyl group and a thiazolyl group:
[0036] (I) 4
[0037] In formula (I), R7 is preferably selected from the group
consisting of C.sub.1-C.sub.6 hydrocarbon, lower alkoxy, lower
thioalkoxy, CN, NO.sub.2, halogen, CF.sub.3, and OCF.sub.3. More
preferably, R7 is selected from the group consisting of methyl,
ethyl, propyl, allyl, F, Cl, and Br. The C.sub.1-C.sub.6
hydrocarbon, indazolyl group, and thiazolyl group are optionally
substituted, preferably substituted on carbon. The indazolyl group
preferably bears at least one substituent selected from the group
consisting of optionally substituted C.sub.1-C.sub.6 hydrocarbon
(e.g., methyl, ethyl, propyl, allyl, methylcyclopropyl), lower
alkoxy, optionally substituted heterocycle, CN, NO.sub.2, halogen
(e.g., F, Cl, Br, I), CF.sub.3 and OCF.sub.3. Preferably, the
substituent is attached to a carbon atom of the indazolyl group
rather than a nitrogen atom.
[0038] The thiazolyl group preferably bears at least one
substituent selected from the group consisting of optionally
substituted C.sub.1-C.sub.10 hydrocarbon (e.g., methyl, ethyl),
optionally substituted C.sub.1-C.sub.10 heterocycle, optionally
substituted carboxamido, optionally substituted aminocarboxy,
optionally substituted C.sub.1-C.sub.6 alkoxy, optionally
substituted C.sub.1-C.sub.6 alkoxycarbonyl (e.g., COOCH.sub.3,
COOCH.sub.2CH.sub.3), OH, COOH, COOR.sup.3, and CONR.sup.8R.sup.9;
wherein R.sup.3 is selected from the group consisting of optionally
substituted heterocycle and C.sub.1-C.sub.6 alkyl substituted by
heterocycle; wherein R.sup.8 and R.sup.9 are independently selected
from the group consisting of H, optionally substituted heterocycle,
and optionally substituted C.sub.1-C.sub.6 hydrocarbon, wherein
R.sup.8 and R.sup.9 may together form a four-, five-, or
six-membered optionally substituted heterocyclic ring including the
N atom to which R.sup.8 and R.sup.9 are attached, and wherein for
said ring one to three carbon atoms may optionally each
independently be replaced by an atom selected from the group
consisting of N, O, and S. Examples of substituents thus include
methyl, ethyl, OH, phenyl, COOH, COOCH.sub.3, COOCH.sub.2CH.sub.3,
and N(CH.sub.3)(CH.sub.2CH.sub.3). In preferred embodiments, the
thiazolyl group is attached to a carbonyl carbon of at least one
substituent represented by a structure selected from the group
consisting of 56
[0039] For compounds of the formula (I) in which the thiazolyl
group bears a phenyl substituent, the phenyl is optionally
substituted with at least one substituent selected from the group
consisting of OH, OCH.sub.3, F, Cl, Br, optionally substituted
piperazin-1-yl, and optionally substituted morpholin-4-yl. Examples
of phenyl groups include 3-hydroxyphenyl, 4-hydroxyphenyl,
3-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl,
4-fluoro-3-hydroxyphenyl, 3,4-difluoro-phenyl, 3,5-difluoro-phenyl,
4-bromo-3-methoxy-phenyl, 4-(4-methyl-piperazin-1-yl)-phenyl, and
4-(morpholin-4-yl)-phenyl. For compounds of the formula (1) in
which the thiazolyl group bears a pyridyl substituent, the pyridyl
is optionally substituted with at least one substituent selected
from the group consisting of C.sub.1-C.sub.6 alkyl, F, Cl, Br, I,
CF.sub.3, 3,5-dimethyl-piperazin-1-yl, and morpholin-4-yl. Examples
of pyridyl groups include pyridin-3-yl, 6-methyl-pyridin-3-yl,
6-chloro-pyridin-3-yl, and 6-trifluoromethyl-pyridin-3-yl
[0040] It is apparent from the foregoing that the thiazolyl group
may optionally bear two substituents. Preferably, each of the two
substituents on the thiazolyl group is independently selected from
the group consisting of optionally substituted C.sub.1-C.sub.10
hydrocarbon, COOH, optionally substituted C.sub.1-C.sub.6
alkoxycarbonyl, OH, COOR.sup.3, and CONR.sup.8R.sup.9, wherein
R.sup.3 is selected from the group consisting of optionally
substituted heterocycle and C.sub.1-C.sub.6 alkyl substituted by
heterocycle; wherein R.sup.8 and R.sup.9 are independently selected
from the group consisting of H, optionally substituted heterocycle,
and optionally substituted C.sub.1-C.sub.6 hydrocarbon, wherein
R.sup.8 and R.sup.9 may together form a four-, five-, or
six-membered optionally substituted heterocyclic ring including the
N atom to which R and R' are attached, and wherein for said ring
one to three carbon atoms may optionally each independently be
replaced by an atom selected from the group consisting of N, O, and
S.
[0041] Those skilled in the art will recognize that certain
compounds of the formula (I) may exist in tautomeric forms, all
such forms of the compounds being within the scope of the
invention. Unless otherwise stated, structures depicted herein also
encompass all stereochemical forms of the structure, including the
R and S configurations for each asymmetric center. Therefore,
single stereochemical isomers as well as enantiomeric and
diastereomeric mixtures of the present compounds are within the
scope of the invention. Preferred compounds of the formula (I) are
synthetically produced to provide an isolated, substantially pure
form according to the synthetic methods described below.
[0042] Those skilled in the art will understand that the in vivo
effects resulting from administration of the compounds of the
formula (I) may result not from the compounds themselves, but
instead by one or more products of degradation, such as by a
metabolic process. Thus, those skilled in the art will understand
that reference herein to a compound of the formula (1) includes
pharmacologically acceptable esters, amides, salts (e.g., metal
salts), hydrates, and other derivatives thereof (known in the art
as "pro-drugs") that undergo biotransformation to yield the active
drug. Pro-drugs are described generally in, e.g., Goodman and
Gilman's "Biotransformation of Drugs," in the Pharmacological Basis
of Therapeutics, 8.sup.th Ed., McGraw Hill, Int. Ed. 1992, pages
13-15, which is hereby incorporated by reference in its entirety.
Particularly favored derivatives or prodrugs are those that
increase the bioavailability of the compounds of the formula (I)
when such compounds are administered to a mammal (e.g., by allowing
an orally administered compound to be more readily absorbed into
the blood) or that enhance delivery of the parent compound to a
biological compartment (e.g., the brain or lymphatic system)
relative to the parent species.
[0043] A preferred embodiment provides compositions comprising a
compound of the formula (I) and a pharmaceutically acceptable
carrier. Pharmaceutically acceptable carriers useful in these
compositions include, but are not limited to, ion exchangers,
alumina, aluminum stearate, lecithin, serum proteins, such as human
serum albumin, buffer substances such as phosphates, glycine,
sorbic acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or electrolytes, such
as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropyle- ne-block
polymers, wool fat and self-emulsifying drug delivery systems
(SEDDS) such as a-tocopherol, polyethyleneglycol 1000 succinate, or
other similar polymeric delivery matrices.
[0044] Certain compounds of the formula (I) possess an acidic or
basic group, and may therefore form salts with
pharmaceutically-acceptable cations or anions. All such
pharmaceutically-acceptable salts are contemplated in the present
invention. The identities of pharmaceutically-acceptable cations
and anions are well-known in the art, and appear in such compendia
as the Physicians' Desk Reference, 56.sup.th ed., Medical Economics
Company, Inc., Montvale, N.J., 2002. The compounds may also form
hydrates or exist in a substantially anhydrous form.
[0045] Pharmaceutical compositions for parenteral administration,
such as by injection intravenously, preferably contain a
pharmaceutically acceptable amount of a compound of the formula (I)
as a soluble salt dissolved in a pharmaceutically acceptable liquid
carrier such as, for example, water-for-injection and a buffer to
provide a suitably buffered isotonic solution having, for example,
a pH of about 3.5-6. Suitable buffering agents include, for
example, trisodium orthophosphate, sodium bicarbonate, sodium
citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine. The
compounds of the formula (1) generally will be dissolved in the
carrier in an amount sufficient to provide a pharmaceutically
acceptable injectable concentration in the range of about 1 mg/mL
to about 400 mg/mL of solution. The resulting liquid pharmaceutical
composition will be so administered as to obtain a dosage effective
against bacteria.
[0046] Nonlimiting examples of preferred compounds of the formula
(I) include:
[0047]
1-[2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-2--
(1-methyl-piperidin-4-yl)-ethanone;
[0048]
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-m-
ethyl-piperazin-1-yl)-methanone;
[0049]
(3-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol--
3-yl)-5-pyridin-3-yl-thiazol-4-yl]-methanone;
[0050]
(3-dimethylamino-pyrrolidin-1-yl)-[2-(6-fluoro-7-methyl-1H-indazol--
3-yl)-5-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-methanone;
[0051]
(3-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-p-
yridin-3-yl-thiazol-4-yl]-methanone;
[0052]
(3-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-(-
6-methyl-pyridin-3-yl)-thiazol-4-yl]-methanone;
[0053]
(3,5-dimethyl-piperidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-pyrid-
in-3-yl-thiazol-4-yl]-methanone;
[0054]
(3-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-(-
6-trifluoromethyl-pyridin-3-yl)-thiazol-4-yl]-methanone;
[0055]
(3-dimethylamino-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-p-
yridin-3-yl-thiazol-4-yl]-methanone;
[0056]
(3-dimethylamino-pyrrolidin-1-yl)-[5-(3-methoxy-phenyl)-2-(7-methyl-
-1H-indazol-3-yl)-thiazol-4-yl]-methanone;
[0057]
(3-dimethylamino-pyrrolidin-1-yl)-[5-(4-hydroxy-phenyl)-2-(7-methyl-
-1H-indazol-3-yl)-thiazol-4-yl]-methanone;
[0058]
(3-hydroxy-azetidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-
-yl-thiazol-4-yl]-methanone;
[0059]
(3-hydroxy-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-(6-morp-
holin-4-yl-pyridin-3-yl)-thiazol-4-yl]-methanone;
[0060]
(3-hydroxy-pyrrolidin-1-yl)-[2-(7-methyl-1H-indazol-3-yl)-5-pyridin-
-3-yl-thiazol-4-yl]-methanone;
[0061]
[2-(6-chloro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-
-(4-methyl-piperazin-1-yl)-methanone;
[0062]
[2-(6-chloro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-
-(3-hydroxy-pyrrolidin-1-yl)-methanone;
[0063]
[2-(6-chloro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-
-(3-dimethylamino-pyrrolidin-1-yl)-methanone;
[0064]
[2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl)-(4-methy-
l-piperazin-1-yl)-methanone;
[0065]
[2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-pyrid-
in-4-yl-piperazin-1-yl]-methanone;
[0066]
[2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl)-morpholi-
n-4-yl-methanone;
[0067]
[2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-piperidi-
n-1-yl-methanone;
[0068]
[5-(3,4-difluoro-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazol-4-yl]-
-(3-dimethylamino-pyrrolidin-1-yl)-methanone;
[0069]
[5-(3,4-difluoro-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazol-4-yl]-
-(3-hydroxy-pyrrolidin-1-yl)-methanone;
[0070]
[5-(3,4-difluoro-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazol-4-yl]-
-(4-methyl-piperazin-1-yl)-methanone;
[0071]
[5-(3,5-difluoro-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazol-4-yl]-
-(3-hydroxy-pyrrolidin-1-yl)-methanone;
[0072]
[5-(3,5-difluoro-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazol-4-yl]-
-(4-methyl-piperazin-1-yl)-methanone;
[0073] [5-(3-fluoro-phenyl)-2-(7-methyl-
H-indazol-3-yl)-thiazol-4-yl]-(4--
methyl-piperazin-1-yl)-methanone;
[0074]
[5-(4-fluoro-3-hydroxy-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazol-
-4-yl]-(4-methyl-piperazin-1-yl)-methanone;
[0075]
[5-(4-fluoro-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazol-4-yl]-(3--
hydroxy-pyrrolidin-1-yl)-methanone;
[0076]
[5-(4-fluoro-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazol-4-yl]-(4--
methyl-piperazin-1-yl)-methanone;
[0077]
[5-(6-chloro-pyridin-3-yl)-2-(7-methyl-1H-indazol-3-yl)-thiazol-4-y-
l]-(3-dimethylamino-pyrrolidin-1-yl)-methanone;
[0078]
[5-(6-chloro-pyridin-3-yl)-2-(7-methyl-1H-indazol-3-yl)-thiazol-4-y-
l]-(3-hydroxy-pyrrolidin-1-yl)-methanone;
[0079]
[5-[6-(3,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-2-(7-methyl-1H-in-
dazol-3-yl)-thiazol-4-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone;
[0080]
{4-[2-(1H-indazol-3-yl)-thiazol-4-yl]-phenyl}-(4-methyl-piperazin-1-
-yl)-methanone;
[0081]
{4-[2-(1H-indazol-3-yl)-thiazol-4-yl]-phenyl}-morpholin-4-yl-methan-
one;
[0082]
1-[2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carbonyl]-
-piperidine-4-carboxylic acid;
[0083] 2-(1H-indazol-3-yl)-4-phenyl-thiazole-5-carboxylic acid
ethyl ester;
[0084] 2-(1H-indazol-3-yl)-5-phenyl-thiazol-4-ol;
[0085] 2-(1H-indazol-3-yl)-5-phenyl-thiazole-4-carboxylic acid
(2,3-dihydroxy-propyl)-amide;
[0086] 2-(1H-indazol-3-yl)-5-phenyl-thiazole-4-carboxylic acid
(2-dimethyl-amino-ethyl)-amide;
[0087] 2-(1H-indazol-3-yl)-5-phenyl-thiazole-4-carboxylic acid
(2-methoxy-ethyl)-amide;
[0088] 2-(1H-indazol-3-yl)-5-phenyl-thiazole-4-carboxylic acid
cyclopropylmethyl-amide;
[0089] 2-(1H-indazol-3-yl)-5-phenyl-thiazole-4-carboxylic acid
methyl ester;
[0090]
2-(4-chloro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-car-
boxylic acid methyl ester;
[0091]
2-(6-chloro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-car-
boxylic acid methyl ester;
[0092] 2-(7-ethyl-1H-indazol-3-yl)-5-phenyl-thiazole-4-carboxylic
acid methyl ester;
[0093]
2-(7-methyl-1H-indazol-3-yl)-5-(6-trifluoromethyl-pyridin-3-yl)-thi-
azole-4-carboxylic acid methyl ester;
[0094] 2-(7-methyl-1H-indazol-3-yl)-5-phenyl-thiazole-4-carboxylic
acid 2-morpholin-4-yl-ethyl ester;
[0095] 2-(7-methyl-1H-indazol-3-yl)-5-phenyl-thiazole-4-carboxylic
acid methyl ester;
[0096]
2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
acid ethyl-methyl-amide;
[0097]
2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
acid 1-methyl-piperidin-4-yl ester;
[0098]
2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
acid 1-methyl-pyrrolidin-3-yl ester;
[0099]
2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
acid (2-dimethylamino-ethyl)-methyl-amide;
[0100]
2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
acid (1-methyl-piperidin-4-yl)-amide;
[0101]
2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
acid;
[0102]
2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
acid (2-diethylmino-ethyl)-amide;
[0103]
2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
acid methyl ester;
[0104]
2-(7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
acid ethyl ester;
[0105] 2-[2-(1H-indazol-3-yl)-thiazol-4-yl]-phenol;
[0106]
2-bromo-5-[2-(1H-indazol-3-yl)-4-methyl-thiazol-5-yl]-phenol;
[0107]
2-hydroxy-5-[2-(1H-indazol-3-yl)-5-methyl-thiazol-4-yl]-benzoic
acid;
[0108] 3-(4,5-diphenyl-thiazol-2-yl)-1H-indazole;
[0109] 3-(4-ethyl-5-phenyl-thiazol-2-yl)-1H-indazole;
[0110] 3-(4-ethyl-thiazol-2-yl)-1H-indazole;
[0111] 3-(4-naphthalen-2-yl-thiazol-2-yl)-1H-indazole;
[0112] 3-(4-phenyl-thiazol-2-yl)-1H-indazole;
[0113] 3-(4-p-tolyl-thiazol-2-yl)-1H-indazole;
[0114] 3-(4-pyridin-2-yl-thiazol-2-yl)-1H-indazole;
[0115] 3-(4-pyridin-3-yl-thiazol-2-yl)-1H-indazole;
[0116] 3-(5-methyl-4-phenyl-thiazol-2-yl)-1H-indazole;
[0117] 3-(5-phenyl-thiazol-2-yl)-1H-indazole;
[0118] 3-(5-phenyl-thiazol-2-yl)-1H-indazole;
[0119] 3-[2-(1H-indazol-3-yl)-4-methyl-thiazol-5-yl]-phenol;
[0120] 3-[2-(1H-indazol-3-yl)-4-methyl-thiazol-5-yl]-phenol;
[0121] 3-[2-(1H-indazol-3-yl)-thiazol-4-yl]-benzoic acid;
[0122]
3-[2-(7-chloro-1H-indazol-3-yl)-4-methyl-thiazol-5-yl]-phenol;
[0123] 3-[4-(2,5-dimethyl-phenyl)-thiazol-2-yl]-1H-indazole;
[0124] 3-[4-(2-fluoro-phenyl)-thiazol-2-yl]-1H-indazole;
[0125] 3-[4-(2-methoxy-phenyl)-thiazol-2-yl]-1H-indazole;
[0126] 3-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-1H-indazole;
[0127] 3-[4-(3,4-difluoro-phenyl)-thiazol-2-yl]-1H-indazole;
[0128] 3-[4-(3-bromo-phenyl)-thiazol-2-yl]-1H-indazole;
[0129] 3-[4-(3-fluoro-phenyl)-thiazol-2-yl]-1H-indazole;
[0130] 3-[4-(3-methoxy-phenyl)-thiazol-2-yl]-1H-indazole;
[0131] 3-[4-(4-chloro-phenyl)-thiazol-2-yl]-1H-indazole;
[0132]
3-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-1H-indazole;
[0133] 3-[4-(4-methoxy-phenyl)-thiazol-2-yl]-1H-indazole;
[0134]
3-[4-(4-morpholin-4-yl-phenyl)-thiazol-2-yl]-1H-indazole;
[0135]
3-[4-(4-pyrrolidin-1-yl-phenyl)-thiazol-2-yl]-1H-indazole;
[0136]
3-[4-methyl-5-(4-morpholin-4-yl-phenyl)-thiazol-2-yl]-1H-indazole;
[0137]
3-[5-(3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-1H-indazole;
[0138]
3-[5-(3-methoxy-phenyl)-4-methyl-thiazol-2-yl-1H-indazole;
[0139]
3-[5-(4-bromo-3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-1H-indazole;
[0140]
3-[5-(6-chloro-pyridin-3-yl)-4-methyl-thiazol-2-yl]-1H-indazole;
[0141]
3-{4-methyl-5-[4-(4-methyl-piperazin-1-yl)-phenyl]-thiazol-2-yl}-1H-
-indazole;
[0142] 4-[2-(1H-indazol-3-yl)-thiazol-4-yl]-benzoic acid methyl
ester;
[0143] 4-[2-(1H-indazol-3-yl)-thiazol-4-yl]-benzoic acid;
[0144] 4-[2-(1H-indazol-3-yl)-thiazol-4-yl]-benzonitrile;
[0145]
5-(3-fluoro-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazole-4-carboxy-
lic acid methyl ester;
[0146]
5-(4-fluoro-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazole-4-carboxy-
lic acid ethyl ester;
[0147]
5-(4-hydroxy-phenyl)-2-(7-methyl-1H-indazol-3-yl)-thiazole-4-carbox-
ylic acid methyl ester;
[0148]
5-(6-chloro-pyridin-3-yl)-2-(7-methyl-1H-indazol-3-yl)-thiazole-4-c-
arboxylic acid methyl ester;
[0149]
7-chloro-3-[5-(3-methoxy-benzyl)-thiazol-2-yl]-1H-indazole;
[0150]
7-chloro-3-[5-(3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-1H-indazole-
;
[0151]
diethyl-{4-[2-(1H-indazol-3-yl)-thiazol-4-yl]-phenyl}-amine;
[0152]
N-(2-dimethylamino-ethyl)-3-[2-(1H-indazol-3-yl)-thiazol-4-yl]-benz-
amide.
[0153] Methods of Making Compounds and Compositions
[0154] Compounds of the formula (I) are preferably prepared
according to the following synthetic scheme:
[0155] Acetylation
[0156] Acetylation preferably comprises reacting an aryl amine with
an acetyl halide to form an optionally substituted aryl amide
represented by the formula (II): 7
[0157] R7 is preferably selected from the group consisting of
C.sub.1-C.sub.6 hydrocarbon, lower alkoxy, lower thioalkoxy, CN,
NO.sub.2, halogen, CF.sub.3, and OCF.sub.3; wherein the
C.sub.1-C.sub.6 hydrocarbon and the aryl ring of the aryl amide are
optionally substituted. Acetylation is illustrated by the
following: An aryl amine such as aniline (82.5 mmoles) is dissolved
in 400 mL of dichloromethane and cooled to 0.degree. C. To this
solution is added dropwise acetyl chloride (71 mL, 1 mole) followed
by a 200 mL solution of triethyl amine (140 mL, 1 mole). This
solution is stirred until reaction is complete. The resulting solid
is filtered off and the filtrate poured into brine, extracted twice
with dichloromethane, dry filtered and concentrated to give the
acetylated amine.
[0158] Cyclization
[0159] Cyclization preferably comprises reacting the optionally
substituted aryl amide with an alkyl nitrite in the presence of an
acid to form an optionally substituted indazole represented by the
formula (III): 8
[0160] Cyclization is illustrated by the following: An acetylated
amine such as N-(2,6-dimethylphenyl)-acetamide (1 eq) is dissolved
in dichloroethane. To this solution is added acetic acid (1.1 eq)
followed by the dropwise addition of isoamyl nitrite (1.1 eq). The
reaction is then heated to reflux overnight, poured into water and
extracted two additional times with dichloromethane. The extracts
are combined, washed with saturated bicarbonate, then brine, and
dried with magnesium sulfate filter before being concentrated to a
solid. Yields typically 80%.
[0161] Iodination
[0162] Iodination preferably comprises reacting the optionally
substituted indazole with iodine in the presence of a base to form
an optionally substituted iodinated indazole represented by the
formula (IV): 9
[0163] Iodination is illustrated by the following: The optionally
substituted indazole represented by the formula (I) (1 eq) is
dissolved in DMF (0.5 M) and to this solution is added iodine
crystals (3 eq) and KOH pellets (5 eq). This reaction is allowed to
stir at RT until complete by thin layer chromatography (TLC),
approximately 3 hours. The solution is concentrated to about one
third volume, and then poured into a 5% NaHSO.sub.3 solution and
extracted with ether 3 times. The ether extracts are washed with
water followed by saturated brine solution and dried over magnesium
sulfate. The drying agent is removed by filtration and the ether
solution concentrated to an orange solid to quantitative yields of
the 3-iodo-indazole.
[0164] Those skilled in the art will appreciate that iodine is a
leaving group (LG), and that other leaving groups may be used in
place of the iodine in the compound represented by the formula
(IV), thereby forming a compound represented by the formula (V):
10
[0165] For the compound represented by the formula (V), LG
represents a leaving group. Preferred leaving groups include
chloro, bromo, iodo, trifluoromethanesulfonate, methanesulfonate,
p-toluenesulfonate, and trifluoroacetate. Iodo is a highly
preferred leaving group.
[0166] Nitrile Displacement
[0167] Nitrile displacement preferably comprises reacting the
optionally substituted iodinated indazole with a cyanide salt to
form an optionally substituted indazole nitrile represented by the
formula (VI): 11
[0168] Nitrile displacement is illustrated by the following: The
optionally substituted iodinated indazole is dissolved in anhydrous
N-methylpyrrolidinone (0.5 M). To this solution is added sodium
cyanide (2 equivalents) and copper (I) cyanide (3 equivalents). The
solution is heated to 135.degree. C. for 6 hours or until complete
by TLC or HPLC. The reaction is then concentrated to 1/3 volume and
partitioned between ether and water. The resulting suspension is
filtered through diatomaceous earth. The filtrate is separated and
extracted with two additional portions of ether. The combined
extracts are washed with water and brine, dried over magnesium
sulfate, filtered and concentrated to an off white solid. (50%
yield).
[0169] Those skilled in the art will understand that iodine is an
example of a leaving group, and thus that nitrile displacement may
also be carried out in a similar fashion using compounds of the
formula (V).
[0170] Thioamide Formation
[0171] Thioamide formation preferably comprises reacting the
optionally substituted indazole nitrile with hydrogen sulfide in
the presence of a base to form an optionally substituted indazole
thioamide represented by the formula (VU): 12
[0172] Thioamide formation is illustrated by the following: The
optionally substituted indazole nitrile is dissolved in 20%
triethyl amine in pyridine and cooled to 0.degree. C. The solution
is then saturated for 10 minutes with hydrogen sulfide gas. The
reactor is sealed and allowed to stir while warming to room
temperature. After 3 hours, or when the reaction is complete by
TLC, it is de-gassed with a light vacuum before being concentrated
to a yellow solid. The solid is suspended in hexane and filtered
under vacuum. The solid is then dried under high vacuum with
P.sub.2O.sub.5 until dried to a constant weight.
[0173] Cyclization
[0174] Cyclization preferably comprises reacting the optionally
substituted indazole thioamide with a carbonyl compound to form a
compound of the formula (I). Preferably, the carbonyl compound is
substituted with a leaving group in the position alpha to the
carbonyl. Preferred carbonyl compounds include optionally
substituted .alpha.-LG aldehyde, optionally substituted .alpha.-LG
ketone, and optionally substituted .alpha.-LG ester. Cyclization is
illustrated in Examples 3-4 below.
[0175] It will be understood by those skilled in the art that
additional or alternate chemical reactions or process steps may be
employed in addition to or instead of those set forth in the
synthetic scheme outlined above. Thus, the knowledge of those
skilled in the art may be combined with the teachings provided
herein to prepare a wide variety of compounds of the formula (I).
For example, Table I provides the names and structures of various
preferred compounds of the formula (I) prepared in accordance with
the methods described herein.
1TABLE 1 No. Name Structure 1. 2-(1H-Indazol-3-yl)-5-phenyl-
thiazol-4-ol 13 2. 3-(4-Pyridin-3-yl-thiazol-2-yl)-1H- indazole 14
3. 3-(4-Phenyl-thiazol-2-yl)-1H- indazole 15 4.
3-(5-Phenyl-thiazol-2-yl)-1H- indazole 16 5.
2-(1H-Indazol-3-yl)-4-phenyl- thiazole-5-carboxylic acid ethyl
ester 17 6. 4-[2-(1H-Indazol-3-yl)-thiazol-4- yl]-benzoic acid 18
7. 4-[2-(1H-Indazol-3-yl)-thiazol-4- yl]-benzolc acid methyl ester
19 8. N-(2-Dimethylamino-ethyl)-4-[2-
(1H-indazal-3-yl)-thiazol-4-yl]- benzamide 20 9.
3-[2-(1H-Indazol-3-yl)-thiazol-4- yl]-benzoic acid 21 10.
3-(5-Methyl-4-phenyl-thiazol-2- yl)-1H-indazole 22 11.
N-(2-Dimethylamino-ethyl)-3-[2- (1H-indazol-3-yl)-thiazol-4-yl]-
benzamide 23 12. {4-[2-(1H-Indazol-3-yl)-thiazol-4-
yl]-phenyl}-(4-methyl-piperazin-1- yl)-methanone 24 13.
{4-[2-(1H-Indazol-3-yl)-thiazol-4- yl]-phenyl}-morpholin-4-yl-
methanone 25 14. 3-[5-(3-Methoxy-phenyl)-4-
methyl-thiazol-2-yl]-1H- -indazole 26 15.
3-[4-(4-Bromo-phenyl)-5-methyl- thiazol-2-yl]-1H-indazole 27 16.
3-[5-Methyl-4-(4-morphol- in-4-yl-
phenyl)-thiazol-2-yl]-1H-indazole 28 17.
3-[2-(1H-Indazol-3-yl)-4-methyl- thiazol-5-yl]-phenol 29 18.
3-{5-Methyl-4-[4-(4-methyl- piperazin-1-yl)-phenyl]-thiazol-2-
yl}-1H-indazole 30 19. 2-Hydroxy-5-[2-(1H-indazol-3-yl)-
5-methyl-thiazol-4-yl]-benzoic acid 31 20.
2-(7-Fluoro-1H-indazol-3-yl)-5- phenyl-thiazol-4-ol 32 21.
5-[2-(1H-Indazol-3-yl)-5-methyl- thiazol-4-yl]-2-morpholin-4-yl-
benzoic acid 33 22. 5-[2-(1H-Indazol-3-yl)-5-methyl-
thiazol-4-yl]-2-morpholin-4-yl- benzoic acid methyl ester 34 23.
3-[4-(4-Bromo-phenyl)-5-methyl- thiazol-2-yl]-7-fluoro-1H-indazole
35 24. 7-Fluoro-3-{5-methyl-4-[4-(4-
methyl-piperazin-1-yl)-phenyl]- thiazol-2-yl}-1H-indazole 36 25.
3-[5-(4-Bromo-3-methoxy- phenyl)-4-methyl-thiazol-2-yl]-
1H-indazole 37 26. 7-Chloro-3-[5-(3-methoxy-
phenyl)-4-methyl-thiazol-2-yl]- 1H-indazole 38 27.
7-Chloro-3-(5-(3-methoxy- benzyl)-thiazol-2-yl]-1H-indazole 39 28.
3-[2-(7-ChIoro-1H-indazol-3-yl)- 4-methyl-thiazol-5-yl)-phenol 40
29. [2-(1H-Indazol-3-yl)-4-phenyl- thiazol-5-yl]-methanol 41 30.
3-[5-(4-Bromo-phenyl)-4-met- hyl- thiazol-2-yl]-1H-indazole 42 31.
2-(1H-Indazol-3-yl)-4-phenyl- thiazole-5-carboxylic acid 43 32.
4-[2-(1H-Indazol-3-yl)-5-methyl- thiazol-4-yl]-2-methoxy-phenol 44
33. 3-[4-(6-Bromo-pyridin-3-yl)-5- methyl-thiazol-2-yl]-1H-indazole
45 34. 3-[4-Methyl-5-(4-morpholin-4-yl-
phenyl)-thiazol-2-yl]-1H-indazole 46 35.
3-{4-Methyl-5-[4-(4-methyl- piperazin-1-yl)-phenyl]-thiaz- ol-2-
yl}-1H-indazole 47 36. 3-(5-Methyl-4-(6-morpholin-4-- yl-
pyridin-3-yl)-thiazol-2-yl]-1H- indazole 48 37.
{4-[2-(1H-Indazol-3-yl)-5-methyl-
thiazol-4-yl]-phenyl)-piperazin-1- yl-methanone 49 38.
3-{5-Methyl-4-[6-(2-morpholin-4-
yl-ethoxy)-pyridin-3-yl]-thiazol-2- yl}-1H-indazole 50 39.
3-(5-Methyl-4-pyridin-3-yl-thiazol- 2-yl)-1H-indazole 51 40.
3-{4-[6-(3,5-Dimethyl-piperazin- 1-yl)-pyridin-3-yl]-5-methyl-
thiazol-2-yl}-1H-indazole 52 41. 3-{4-[6-(4-Cyclopentyl-p-
iperazin- 1-yl)-pyridin-3-yl]-5-methyl- thiazol-2-yl}-1H-indazole
53 42. 3-{4-[6-(4-Isopropyl-piperazin-1- yl)-pyridin-3-yl]-5-methy-
l-thiazol- 2-yl)-1H-indazole 54 43. (2-{5-[2-(1H-Indazol-3-yl)-5-
methyl-thiazol-4-yl]-pyridin-2- yloxy}-ethyl)-dimethyl-amine 55 44.
3-[5-Methyl-4-(6-piperazin-1-yl- pyridin-3-yl)-thiazol-2-yl]-1H-
indazole 56 45. 1-(4-{5-[2-(1H-Indazol-3-yl)-5-
methyl-thiazol-4-yl]-pyridin-2-yl}- piperazin-1-yl)-ethanone 57 46.
3-(4-Ethyl-5-phenyl-thiazol-2-yl)- 1H-indazole 58 47.
1-{5-[2-(1H-Indazol-3-yl)-5- methyl-thiazol-4-yl]-pyridin-2-yl}-
pyrrolidin-3-ol 59 48. 3-{5-Methyl-4-[6-(4-methyl-
piperazin-1-yl)-pyridin-3-yl]- thiazol-2-yl}-1H-indazole 60 49.
2-{5-[2-(1H-Indazol-3-yl)-5- methyl-thiazol-4-yl]-pyridin-2-
yloxy}-ethanol 61 50. 3-[5-(6-Chloro-pyridin-3-yl)-4-
methyl-thiazol-2-yl]-1H-indazole 62 51.
3-(4,5-Diphenyl-thiazol-2-yl)-1H- indazole 63 52.
2-(1H-Indazol-3-yl)-5-phenyl- thiazole-4-carboxylic acid methyl
ester 64 53. 3-Diethylamino-1-(4-{5-[2-(1H-
indazol-3-yl)-5-methyl-thiazol-4-
yl]-pyridin-2-yl}-piperazin-1-yl)- propan-1-one 65 54.
3-{4-Methyl-5-[6-(4-methyl- piperazin-1-yl)-pyridin-3-yl]-
thiazol-2-yl)-1H-indazole 66 55. (2-{5-[2-(1H-Indazol-3-yl)-4-
methyl-thiazol-5-yl]-pyridin-2- yloxy}-ethyl)-dimethyl-amine 67 56.
5-(2-Hydroxy-phenyl)-2-(1H- indazol-3-yl)-thiazol-4-ol 68 57.
2-(1H-Indazol-3-yl)-5-phenyl- thiazole-4-carboxylic acid 69 58.
3-[5-Methyl-4-(6-piperazin-1-yl- pyridin-3-yl)-thiazol-2-yl]-7- -
trifluoromethyl-1H-indazole 70 59. 2-(1H-Indazol-3-yl)-5-phenyl-
thiazole-4-carboxylic acid (2- methoxy-ethyl)-amide 71 60.
2-(1H-Indazol-3-yl)-5-phenyl- thiazole-4-carboxylic acid (2-
dimethylamino-ethyl)-amide 72 61. 2-(1H-Indazol-3-yl)-5-phenyl-
thiazole-4-carboxylic acid (2,3- dihydroxy-propyl)-amide 73 62.
2-(1H-Indazol-3-yl)-5-phen- yl- thiazole-4-carboxylic acid
cyclopropylmethyl-amide 74 63. 3-{4-[6-(3,5-Dimethyl-piperazin-
1-yl)-pyridin-3-yl]-5-methyl- thiazol-2-yl}-7-trifiuoromethyl-1H-
indazole 75 64. 2-Dimethylamino-1-(4-{5-(2-(1H-
indazol-3-yl)-5-methyl-thiazol-4-
yl]-pyridin-2-yl}-piperazin-1-yl)- ethanone 76 65.
2-Bromo-5-[2-(1H-indazol-3-yl)- 4-methyl-thiazol-5-yl]-phenol 77
66. 2-(7-Methyl-1H-indazol-3-yl)-5- phenyl-thiazole-4-carboxylic
acid methyl ester 78 67. 2-(7-Chloro-1H-indazol-3-yl)-5-
phenyl-thiazole-4-carboxylic acid methyl ester 79 68.
7-Methyl-3-[5-methyl-4-(6- piperazin-1-yl-pyridin-3-yl)-
thiazol-2-I]-1H-indazole 80 69. 3-{4-[6-(3,5-Dimethyl-pip- erazin-
1-yl)-pyridin-3-yl]-5-methyl- thiazol-2-yl}-7-methyl-1H- indazole
81 70. 2-(7-Ethyl-1H-indazol-3-yl)-5- phenyl-thiazole-4-carboxylic
acid methyl ester 82 71. 2-(7-Methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid ethyl ester 83 72.
2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazole-4-carboxylic
acid methyl ester 84 73. 4-[2-(1H-Indazol-3-yl)-5-methyl-
thiazol-4-yl]-N-pyridin-3-yl- benzamide 85 74.
2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazole-4-carboxylic
acid (2-diethylamino-ethyl)- amide 86 75.
2-(7-Methyl-1H-indazol-3-yl)-5- phenyl-thiazole-4-carboxylic acid
2-morpholin-4-yl-ethyl ester 87 76. 2-(7-Methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carbo- xylic acid 88 77.
2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazole-4-carboxylic
acid (1-methyl-piperidin-4-yl)- amide 89 78.
2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazole-4-carboxylic
acid (2-dimethylamino-ethyl)- methyl-amide 90 79.
[2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-(4-
pyridin-4-yl-piperazin-1-yl)- methanone 91 80.
(3-Dimethylamino-pyrrolidin-1- yl)-[2-(7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazol-4-yl]- methanone 92 81.
(3-Dimethylamino-pyrrolidin-1- yl)-[2-(7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazol-4-yl]- methanone 93 82.
[2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-(4-
methyl-piperazin-1-yl)- methanone 94 83.
5-(6-Chloro-pyridin-3-yl)-2-(7- methyl-1H-indazol-3-yl)-thi- azole-
4-carboxylic acid methyl ester 95 84.
(3-Hydroxy-pyrroiidin-1-yl)-[2-(7- methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]- methanone 96 85.
2-(7-Methyl-1H-indazol-3-yl)-5- (6-trifluoromethyl-pyridin-3-yl)-
thiazole-4-carboxylic acid methyl ester 97 86.
2-(7-Methyl-1H-indazol-3-yl)-5- pyridln-3-yl-thlazole-4-carboxylic
acid 1-methyl-pyrrolidin-3-yl ester 98 87.
2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazole-4-carboxylic
acid 1-methyl-piperidin-4-yl ester 99 88.
(3,5-Dimethyl-piperazin-1-yl)-[2- (7-methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]- methanone 100 89.
[5-(6-Chloro-pyridin-3-yl)-2-(7- methyl-1H-indazol-3-yl)-thiazol-
4-yl]-(3-hydroxy-pyrrolidin-1-yl)- methanone 101 90.
(3-Hydroxy-pyrrolidin-1-yl)-[2-(7- methyl-1H-indazol-3-yl)-5-(6-
morpholin-4-yl-pyridin-3-yl)- thiazol-4-yl]-methanone 102 91.
[5-[6-(3,5-Dimethyl-piperazin-1- yl)-pyridin-3-yl]-2-(7-methyl-1H-
indazol-3-yl)-thiazol-4-yl]-(3- hydroxy-pyrrolidin-1-yl)- methanone
103 92. (3-Dimethylamino-pyrrolidin-1- yl)-[2-(7-methyl-1H-inda-
zol-3-yl)- 5-(6-trifluoromethyl-pyridin-3-yl)-
thiazol-4-yl]-methanane 104 93. [5-(6-Chloro-pyridin-3-yl)-2-(7-
methyl-1H-indazol-3-yl)-thiazol- 4-yl]-(3-dimethylamino-pyrrolidin-
1-yl)-methanone 105 94. [2-(7-Methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-piperidin- 1-yl-methanone 106 95.
(3,5-Dimethyl-piperidin-1-yl)-[2- (7-methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]- methanone 107 96.
[2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-
morpholin-4-yl-methanone 108 97. (3-Dimethylamino-pyrroli- din-1-
yl)-[5-(3-methoxy-phenyl)-2-(7- methyl-1H-indazol-3-yl)-thiazol-
4-yl]-methanone 109 98. 2-(6-Chloro-7-methyl-1H-indazol-
3-yl)-5-pyridin-3-yl-thiazole-4- carboxylic acid methyl ester 110
99. [2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(3-dimethylamino- pyrrolidin-1-yl)-methanone 111 100.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(3-hydroxy- pyrrolidin-1-yl)-methanone 112 101.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-methyl-piperazin- 1-yl)-methanone 113 102.
2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazole-4-carboxylic
acid ethyl-methyl-amide 114 103. 5-(4-Fluoro-phenyl)-2-(7- -methyl-
1H-indazol-3-yl)-thiazole-4- carboxylic acid methyl ester 115 104.
5-(4-Hydroxy-phenyl)-2-(7- methyl-1H-indazol-3-yl)-thiaz- ole-
4-carboxylic acid methyl ester 116 105.
2-(4-Chloro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazole-4-
carboxylic acid methyl ester 117 106.
[5-(4-Fluoro-phenyl)-2-(7-methyl-
1H-indazol-3-yl)-thiazol-4-yl]-(4- methyl-piperazin-1-yl)-
methanone 118 107. [5-(4-Fluoro-phenyl)-2-(7-methyl-
1H-indazol-3-yl)-thiazol-4-yl]-(3- hydroxy-pyrrolidin-1-yl)-
methanone 119 108. 5-(3-Fluoro-phenyl)-2-(7-methyl-
1H-indazol-3-yl)-thiazole-4- carboxylic acid methyl ester 120 109.
[5-(3,5-Difluoro-phenyl)-2-(7- methyl-1H-indazol-3-yl)-thiazol-
4-yl]-(4-methyl-piperazin-1-yl)- methanone 121 110.
[5-(3,5-Difluoro-phenyl)-2-(7- methyl-1H-indazol-3-yl)-thiazol-
4-yl]-(3-hydroxy-pyrrolidin-1-yl)- methanone 122 111.
(3-Hydroxy-azetidin-1-yl)-[2-(7- methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]- methanone 123 112.
[5-(3-Fluoro-phenyl)-2-(7-methyl- 1H-indazol-3-yl)-thiazo-
l-4-yl]-(4- methyl-piperazin-1-yl)- methanone 124 113.
(3-Dimethylamino-pyrrolidin-1- yl)-[5-(4-hydroxy-phenyl)-2-(7-
methyl-1H-indazol-3-yl)-thiazol- 4-yl]-methanone 125 114.
[5-(3,4-Difluoro-phenyl)-2-(7- methyl-1H-indazol-3-yl)-thiazol-
4-yl]-(4-methyl-piperazin-1-yl)- methanone 126 115.
[5-(3,4-Difluoro-phenyl)-2-(7- methyl-1H-indazol-3-yl)-thiazol-
4-yl]-(3-hydroxy-pyrrolidin-1-yl)- methanone 127 116.
[5-(3,4-Difluoro-phenyl)-2-(7- methyl-1H-indazol-3-yl)-thiazol-
4-yl]-(3-dimethylamino-pyrrolidin- 1-yl)-methanone 128 117.
[5-(4-Fluoro-3-hydroxy-phenyl)- 2-(7-methyl-1H-indazol-3-yl)-
thiazol-4-yl]-(4-methyl-piperazin- 1-yl)-methanone 129 118.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(3-hydroxy-azetidin- 1-yl)-methanone 130 119.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-pyridin-4-yl- piperazin-1-yl)-methanone 131 120.
2-(6-Chloro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazole-
carboxylic acid (2-diethylamino- ethyl)-amide 132 121.
[2-(6-Fluoro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-methyl-piperazin- 1-yl)-methanone 133 122.
[5-(6-Methoxy-pyridin-3-yl)-2-(7- methyl-1H-indazol-3-yl)-thiazol-
4-yl]-(4-methyl-piperazin-1-yl)- methanone 134 123.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yq-piperazin-1-yl- methanone 135 124.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(3-hydroxy- pyrrolidin-1-yl)-methanone 136 125.
2-(6-Chloro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazole-4-
carboxylic acid methyl-(1-methyl- pyrrolidin-3-ylmethyl)-amide 137
126. [2-(7-Ethyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]--
(4- methyl-piperazin-1-yl)- methanone 138 127.
(3-Dimethylamino-pyrrolidin-1- yl)-[2-(7-ethyl-1H-[indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]- methanone 139 128.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-pyridin-2-yl- piperazin-1-yl)-methanone 140 129.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-pyridin-2- ylmethyl-piperazin-1-yl)- methanone 141
130. [2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-[4-(2-hydroxy-ethyl)- piperazin-1-yl]-methanone 142
131. 2-(6-Chloro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazo-
le-4- carboxylic acid (1-methyl- piperidin-4-yl)-amide 143 132.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(2,3,5,6-tetrahydro-
[1,2']bipyrazinyl-4-yl)-methanone 144 133.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-- yl-
thiazol-4-yl]-(4-pyrimidin-2-yl- piperazin-1-yl)-methanone 145 134.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-[3-(ethyl-methyl- amino)-azetidin-1-yl]-methanone 146
135. 2-(6-Chloro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thia-
zole-4- carboxylic acid methyl-(2- methylamino-ethyl)-amide 147
136. 2-(6-Chloro-7-methyl-1H-indazol-
3-yl)-5-pyridin-3-yl-thiazole-- 4- carboxylic acid (2-
dimethylamino-1-methyl-ethyl)- amide 148 137.
2-(6-Chloro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazole-- 4-
carboxylic acid (2-pyrrolidin-1-yl- ethyl)-amide 149 138.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-isopropyl- piperazin-1-yl)-methanone 150 139.
2-(6-Chloro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazole-4-
carboxylic acid (2-morpholin-4- yl-ethyl)-amide 151 140.
2-(6-Chloro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazole-4-
carboxylic acid [2-(1-methyl- pyrrolidin-2-yl)-ethyl]-amide 152
141. 2-(6-Chloro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazol-
e-4- carboxylic acid (2- dimethylamino-ethyl)-methyl- amide 153
142. [2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-[4-(2-diethylamino- ethyl)-piperazin-1-yl]-methanone
154 143. 2-(6-Chloro-7-methyl-1H-indazol-
3-yl)-5-pyridin-3-yl-thiazole-4- carboxylic acid [3-(5-oxo-4,5-
dihydro-1H-pyrazot-4-yl)-propyl]- amide 155 144.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(3-methylamino- pyrrolidin-1-yl)-methanone 156 145.
[2-(6-Chloro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-pyridin-4- ylmethyl-piperazin-1-yl)- methanone 157
146. [2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl-
]-(4- pyridin-4-ylmethyl-piperazin-1- yl)-methanone 158 147.
2-(4,7-Dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-4-
carboxylic acid methyl ester 159 148.
2-(4,7-Dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-4-
carboxylic acid ethyl ester 160 149. [2-(4,7-Dimethyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4- methyl-piperazin-1-yl)-
methanone
161 150. 2-(6-Methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid methyl ester 162 151.
2-(4-Fluoro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazole-4-
carboxylic acid methyl ester 163 152.
2-(6-Fluoro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazole-4-
carboxylic acid methyl-(2- methylamino-ethyl)-amide 164 153.
[2-(6-Fluoro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-piperazin-1-yl- methanone 165 154.
(3-Dimethylamino-pyrrolidin-1- yl)-[2-(6-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazol-4-yl]- methanone 166 155.
(3-Dimethylamino-pyrrolidin-1- yl)-[2-(4-fluoro-7-methyl-1H-
indazol-3-yl)-5-pyridin-3-yl- thiazol-4-yl]-methanone 167 156.
[2-(6-Chloro-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-
piperazin-1-yl-methanone 168 157. [2-(6-Chloro-7-methyl-1- H-
indazol-3-yl)-5-pyridin-3-yl- thiazol-4-yl]-[3-(4-methyl-
piperazin-1-yl)-azetidin-1-yl]- methanone 169 158.
[2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-
piperazin-1-yl-methanone 170 159. (3-Dimethylamino-pyrrol- idin-1-
yl)-[2-(6-fluoro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-methanone 171 160. [1,4]Diazepan-1-yl-[2-(7- -methyl-
1H-indazol-3-yl)-5-pyridin-3-yl- thiazol-4-yl]-methanone 172 161.
(2,5-Diaza-bicyclo[2.2.1]hept-2- yl)-[2-(7-methyl-1H-inda-
zol-3-yl}- 5-pyridin-3-yl-thiazol-4-yl]- methanone 173 162.
[2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-(4-
morpholin-4-yl-piperidin-1-yl)- methanone 174 163.
[1,4']Bipiperidinyl-1'-yl-[2-(7- methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]- methanone 175 164.
[2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-(4-
pyrrolidin-1-yl-piperidin-1-yl)- methanone 176 165.
(3-Dimethylamino-pyrrolidin-1- yl)-[2-(4,7-dimethyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]- methanone 177 166.
(3-Dimethylamino-pyrrolidin-1- yl)-[2-(5,7-dimethyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]- methanone 178 167.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
methyl-piperazin-1-yl)- methanone 179 168.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-
piperazin-1-yl-methanone 180 169. (3-Dimethylamino-pyrrol- idin-1-
yl)-[2-(7-methyl-1H-indazol-3-yl)- 5-(6-methyl-pyridin-3-yl)-thiaz-
ol- 4-yl]-methanone 181 170. (3-Dimethylamino-pyrrolidin-1- -
yl)-[2-(5-fluoro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-methanone 182 171. 2-(7-Methyl-1H-indazol-3- -yl)-5-
pyridin-4-yl-thiazole-4-carboxylic acid ethyl ester 183 172.
(4-Dimethylamino-piperidin-1-yl)- [2-(7-methyl-1H-indazol-3-yl)-
-5- pyridin-3-yl-thiazol-4-yl]- methanone 184 173.
(4-Dimethylamino-piperidin-1-yl)-
[2-(5,7-dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazol-4-yl]-
methanone 185 174. 2-(5,7-Dimethyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4- carboxylic acid methyl-(2-
methylamino-ethyl)-amide 186 175. 2-(5,7-Dimethyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4- carboxylic acid (2-
dimethylamino-ethyl)-methyl- amide 187 176.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
pyridin-4-ylmethyl-piperazin-1- yl)-methanone 188 177.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-(2-
pyrrolidin-1-ylmethyl-pyrrolidin-1- yl)-methanone 189 178.
[2-(5-Fluoro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-methyl-piperazin- 1-yl)-methanone 190 179.
[2-(5-Fluoro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-piperazin-1-yl- methanone 191 180.
(3-Methylamino-pyrrolidin-1-yl)- [2-(7-methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]- methanone 192 181.
(3-Diethylamino-pyrrolidin-1-yl)- [2-(7-methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]- methanone 193 182.
(3-Diethylamino-pyrrolidin-1-yl)-
[2-(5,7-dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazol-4-yl]-
methanone 194 183. [2-(5,7-Dimethyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]- (2,3,5,6-tetrahydro-
[1,2']bipyrazinyl-4-yl)-methanone 195 184.
2-(5,7-Dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-4-
carboxylic acid (1-methyl- piperidin-4-yl)-amide 196 185.
(4-Cyclopentyl-piperazin-1-yl)-[2-
(5,7-dimethyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-
methanone 197 186. [2-(5,7-Dimethyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4- pyridin-2-yl-piperazin-1-yl)-
methanone 198 187. [2-(5,7-Dimethyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4- isopropyl-piperazin-1-yl)-
methanone 199 188. [2-(5,7-Dimethyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
pyridin-2-ylmethyl-piperazin-1- yl)-methanone 200 189.
[2-(5-Fluoro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-pyridin-2-yl- piperazin-1-yl)-methanone 201 190.
2-(5-Fluoro-7-methyl-1H-indazol- 3-yl)-5-pyridin-3-yl-thiazole-4-
carboxylic acid (1-methyl- piperidin-4-yl)-amide 202 191.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
pyridin-4-yl-piperazin-1-yl)- methanone 203 192.
[2-(5-Fluoro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-isopropyl- piperazin-1-yl)-methanone 204 193.
[2-(5-Fluoro-7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-(4-pyridin-2- ylmethyl-piperazin-1-yl)- methanone 205
194. [2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol--
4-yl]-[4- (2,2-dimethyl-propyl)-piperazin- 1-yl]-methanone 206 195.
2-(5,7-Dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-4-
carboxylic acid [1-(2,2-dimethyl- propyl)-piperidin-4-yl]-amide 207
196. 2-(5,7-Dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-- 4-
carboxylic acid (1-isopropyl- piperidin-4-yl)-amide 208 197.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-[3-
(4-methyl-piperazin-1-yl)- azetidin-1-yl]-methanone 209 198.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-(3-
morpholin-4-yl-azetidin-1-yl)- methanone 210 199.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-[3-
(ethyl-methyl-amino)-azetidin-1- yl]-methanone 211 200.
(3-Methylamino-pyrrolidin-1-yl)- [2-(7-methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]- methanone 212 201.
2-(5,7-Dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-4-
carboxylic acid (1,2,2,6,6- pentamethyl-piperidin-4-yl)- amide 213
202. 2-(5,7-Dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-4-
carboxylic acid piperidin-4- ylamide 214 203.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-(3-
morpholin-4-yl-pyrrolidin-1-yl)- methanone 215 204.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-(3-
hydroxy-[1,3']bipyrrolidinyl-1'-yl)- methanone 216 205.
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-[3-
(ethyl-methyl-amino)-pyrrolidin- 1-yl]-methanone 217 206
[2-(5,7-Dimethyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-yl]-[3-
(isopropyl-methyl-amino)- pyrrolidin-1-yl]-methanone 218 207.
2-(5,7-Dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-4-
carboxylic acid methyl-(1-methyl- pyrrolidin-3-yl)-amide 219 208.
[1,3']Bipyrrolidinyl-1'-yl-[2-(5,7- dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]- methanone 220 209.
2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazole-4-carboxylic
acid methyl-(1-methyl-pyrrolidin- 3-yl)-amide 221 210.
2-(5,7-Dimethyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-4-
carboxylic acid methyl-(1-methyl- piperidin-4-yl)-amide 222 211.
2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazole-4-carboxylic
acid methyl-(1-methyl-piperidin- 4-yl)-amide 223 212.
2-(7-Methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazole-4-carboxylic
acid (1,2,2,6,6-pentamethyl- piperidin-4-yl)-amide 224 213.
(3-Diethylamino-azetidin-1-yl)-[2-
(5,7-dimethyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-
methanone 225 214. [1,3']Bipyrrolidinyl-1'-yl-[2-(7-
methyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]- methanone
226 215. [3-(Isopropyl-methyl-amino)-
pyrrolidin-1-yl]-[2-(7-methyl-1H- indazol-3-yl)-5-pyridin-3-yl-
thiazol-4-yl]-methanone 227 216. [2-(7-Methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-(3- morpholin-4-yl-azetidin-1-yl)-
methanone 228 217. 2-(7-Methyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid
(1-isopropyl-piperidin-4-yl)- amide 229
[0176] Methods of Using Compounds and Compositions
[0177] Preferred compounds of the formula (I) exhibit antimicrobial
activity against a variety of pathogens. This invention is not
bound by any theory of operation, but it is believed that compounds
of the formula (I) exert their antimicrobial action by inhibiting
gyrase B in the target bacteria in vivo and in vitro.
[0178] A preferred embodiment provides methods of treating or
preventing a bacterial infection in a mammal, comprising
administering to the mammal a therapeutically effective amount of a
compound of the formula (I). Reference herein to the use of a
compound of the formula (I) will be understood as including
reference to pharmaceutical compositions thereof, as well as
pharmaceutically acceptable salts, esters, solvates and/or prodrugs
thereof. The prophylactic or therapeutic dose of the compounds of
the present invention, in treatment of a bacterial infection will
vary with the severity of the infection and the route by which the
drug is administered, such as orally, topically, transdermally,
and/or parenterally. The compounds of this invention are
advantageously administered orally in either solid or liquid dosage
forms, with the dose, and perhaps the dose frequency, varying
according to the age, body weight, and response of the individual
patient. In general, the total daily dose range of the present
compounds for a 70 kg person is from about 1 mg to about 2000 mg,
in single or divided doses, but those skilled in the art can
readily determine the appropriate dose through standard
methods.
[0179] Preferred compounds of the formula (I) have useful activity
against a variety of organisms. The activity of the compounds can
be assessed by standard testing procedures such as the
determination of minimum inhibitory concentration (MIC) by agar
dilution as described in "Approved Standard. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow
Aerobically", 3.sup.rd ed., published 1993 by the National
Committee for Clinical Laboratory Standards, Villanova, Pa., USA. A
number of the compounds of the formula (I) shown in Table 1 exhibit
activity against one or more pathogenic bacteria such as
Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus
pneumoniae, Streptococcus pyogenes, Enterococcus faecalis,
Moraxella catarrhalis and H. influenzae. For example, Table 2
provides the names and structures of compounds of the formula (I)
that were found to have a MIC of about 10 .mu.M or less in the
Methicillin-resistant Staphylococcus aureus assay conducted as
described below in Examples 25-154.
EXAMPLES
[0180] General Chemistry Methods. Proton NMR spectra were run at
300 MHz on a Bruker Avance 300 spectrometer, and chemical shifts
are reported in parts per million (8) downfield from
tetramethylsilane as internal standard. Atmospheric pressure
ionization electrospray mass spectra and LCMS were recorded on an
Agilent 1100 Series LC/MSD-SL 1946 D spectrometer equipped with an
Agilent 100 series HPLC System. Silica gel 60 (230-400 mesh) from
EM Science was used for column chromatography, and analytical or
preparative thin-layer chromatography was conducted using EM
Science Kieselgel 60 F.sub.254 plates. An Agilent 1100 Series HPLC
with an Agilent Zorbax Eclipse XDB-C8 (4.6.times.150 mm) reversed
phase column was used for analytical HPLC analyses. Preparative
RP-HPLC was performed on a Gilson instrument with a MetaSil AQUEOUS
10 m C18 column. The elution buffer was an A/B gradient;
A=H.sub.2O-0.1% trifluoroacetic acid, B=CH.sub.3 CN-0.1%
trifluoroacetic acid. Products were generally characterized by
.sup.1H-NMR, LC, and/or LC-MS.
[0181] For reactions performed under anhydrous conditions,
glassware was either oven- or flame-dried and the reaction was run
under a positive pressure of nitrogen. Anhydrous solvents were used
as purchased from commercial sources. Except where noted, reagents
were purchased from commercial sources and used without further
purification. The reported yields are the actual isolated yields of
purified material and are not optimized. The
[0182] Examples 1-11 below describe the preparations of various
specific compounds and are illustrative of the various materials
and techniques that may be employed in the synthesis of the
compounds of the formula (I). Examples 12-24 describe various steps
in the synthesis of a particular compound of the formula (I). Table
1 provides the names and structures of various preferred compounds
of the formula (I) prepared in accordance with the methods
described herein. Examples 25-154 describe the
Methicillin-resistant Staphylococcus aureus assay used to determine
the activity of the compounds shown in Table 2.
Example 1
[0183] Dimethyl aniline (10 g, 82.5 mmoles; Scheme 1) was dissolved
in 400 mL of dichloromethane and cooled to 0.degree. C. To this
solution was added dropwise acetyl chloride (71 mL, 1 mole)
followed by a 200 mL solution of triethyl amine (140 mL, 1 mole).
This solution was stirred until complete. Filter off the solid and
pour the filtrate into brine, extract twice with dichloromethane,
dry filter and concentrate to give 127.3 g (95% yield) of the
acetylated amine as a tan solid. NMR data (300 MHz, CDCl.sub.3) for
7-methyl indazoles: 7-methyl indazole: 8.14 (s, 1H); 7.62 (d, 1H,
J=8.8 Hz); 7.18 (m, 1H); 7.09 (m, 2H); 2.6 (s, 3H); 3-iodo-7-methyl
indazole: 7.36 (d, 1H, J=8.8 Hz); 7.24 (dd, 1H, J=1 Hz, 6.7 Hz);
2.55 (s, 3H); 3-cyano-7-methyl indazole: 11 (bs, 1H); 7.7 (m, 1H),
7.3 (m, 2H); 2.6 (s, 3H). 230 231
Example 2
[0184] Representative Thioamide Preparation
1H-indazole-3-carboximidothioic Acid (16, R.sup.1=R.sup.2=H; Scheme
2)
[0185] A solution of 1H-indazole-3-carbonitrile (11,
R.sup.1=R.sup.2=H) (0.150 g, 1.05 mmol) in 20% Et.sub.3 N/pyridine
(10 mL) was cooled to -78.degree. C. Through this was then bubbled
H.sub.2 S gas for 20 minutes, and then the vessel was sealed and
allowed to warm to room temperature and stir overnight. Residual
H.sub.2 S was removed in vacuo and the mixture concentrated. The
resultant ivory colored solid was suspended in hexane, collected by
filtration, and dried to provide 0.178 g, (95%) of product 16.
Examples 3-4
[0186] Representative Thiazole Preparations
3-[4-(4-bromophenyl)-5-methyl-thiazol-2-yl]-1H-indazole (17a,
R.sup.1=R.sup.2=H, R.sup.3=CH.sub.3, Ar=3-bromophenyl; Scheme
2)
[0187] A mixture of 1H-indazole-3-carboximidothioic acid (16,
R.sup.1=R.sup.2=H) (354 mg, 2 mmol) and 2,4'-dibromopropiophenone
(584 mg, 2 mmol) in dry MeOH (10 mL) was heated at 50.degree. C.
for 20 h. The reaction mixture was filtered, the solids washed with
MeOH and dried to give 430 mg (58%) of product 17a as a tan
solid.
[0188] 2-(1H-indazol-3-yl)-5-phenyl-thiazol-4-ol (18,
R.sup.1=R.sup.2=H; Scheme 2). Similarly,
1H-indazole-3-carboximidothioic acid (16, R.sup.1=R.sup.2=H) (0.150
g, 0.85 mmol), methyl .alpha.-bromophenyl acetate (0.195 g, 0.85
mmol), and NaHCO.sub.3 (0.142 g, 1.7 mmol) were dissolved in dry
methanol and stirred overnight. The solution was concentrated, and
the residue purified by preparative RP-HPLC providing 12 mg (5%) of
the desired product 18 as an orange solid.
Examples 5-6
[0189] Representative Palladium-Mediated Aryl Amination 232
3-{5-Methyl-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-thiazol-2-yl)-1H-indazo-
le (19a, R.sup.1=R.sup.2=H, R.sup.4=R.sup.5=cyclo-CH.sub.2 CH.sub.2
N(CH.sub.3)CH.sub.2 CH.sub.2; Scheme 3)
[0190] An oven-dried round-bottom flask was charged with
3-[4-(4-bromo-phenyl)-5-methyl-thiazol-2-yl]-1-1H-indazole (17,
R.sup.1=R.sup.2=H, R.sup.3=CH.sub.3) (37 mg, 0.1 mmol),
1-methylpiperazine (67 .mu.L, 0.6 mmol), NaO.sup.tBu (14 mg, 0.14
mmol) and anhydrous dimethyl ether (2 mL). The reaction mixture was
evacuated and backfilled with N.sub.2 several times. The catalyst,
Pd.sub.2(dba).sub.3(9 mg, 0.01 mmol) and the ligand,
2-(dicyclohexylphosphino)biphenyl (14 mg, 0.04 mmol) were added.
The reaction mixture was again evacuated and backfilled with
N.sub.2 and then heated at reflux overnight after which time HPLC
analysis indicated complete consumption of starting material. The
mixture was concentrated in vacuo, dissolved in EtOAc (20 mL) and
washed with H.sub.2 0 (2.times.5 mL), brine (1.times.5 mL) and
dried over anhydrous Na.sub.2 SO.sub.4. Removal of solvent afforded
the crude product that was purified by RP-HPLC to give 10 mg of
product 19a (25%) as a light yellow solid.
[0191]
3-[5-methyl-4-(4-morpholin-4-yl-phenyl)-thiazol-2-yl]-1H-indazole
(19b, R.sup.1=R.sup.2=H, R.sup.4=R.sup.5=cyclo-CH.sub.2 CH.sub.2
OCH.sub.2 CH.sub.2; Scheme 3). An oven-dried round-bottom flask was
charged with (17, R.sup.1=R.sup.2H, R.sup.3=CH.sub.3) (37 mg, 0.1
mmol), morpholine (52 .mu.L, 0.6 mmol), NaOtBu (14 mg, 0.14 mmol)
and anhydrous toluene (2 mL). The reaction mixture was evacuated
and backfilled with N.sub.2 several times. The catalyst, Pd.sub.2
(dba).sub.3(9 mg, 0.01 mmol) and the ligand, BINAP (18 mg, 0.03
mmol) were added. The reaction mixture was again evacuated and
backfilled with N.sub.2 and then heated at reflux overnight after
which time HPLC analysis indicated complete consumption of starting
material. The mixture was concentrated in vacuo, dissolved in EtOAc
(20 mL) and washed with H.sub.2O (2.times.5 mL), brine (1.times.5
mL) and dried over anhydrous Na.sub.2 SO.sub.4. Removal of solvent
affords the crude product 19b that was purified by RP-HPLC. 233
Example 7
2-hydroxy-3-pyridin-3-yl-acrylic Acid Methyl Ester (Scheme 4)
[0192] To a mixture of dry ethanol (0.2 mL) and ether (20 mL) was
added NaH (60% dispersion in oil, 800 mg, 20 mmol) at 0.degree. C.
and allowed it to stand for 10 min. After which,
N,N-dimethylglycine methyl ester (3.5 g, 30 mmol) and 3-pyridine
carboxyaldehyde (944 .mu.L, 10 mmol) were added. The reaction
mixture was stirred at 0.degree. C. first and later at room
temperature overnight. The mixture was diluted to ethyl acetate and
washed with water. The organic layer was mixed with 1 N HCl and
shaken well. Saturated NaHCO.sub.3 solution was added to neutralize
the aqueous layer, and the product was extracted three times with
ethyl acetate. The combined organic layers were concentrated to
give a solid mass, which was then treated with the minimum amount
of ethyl acetate and filtered to give the product
2-hydroxy-3-pyridin-3-yl-acrylic acid methyl ester.
Example 8
3-bromo-2-oxo-3-pyridin-3-yl-propionic Acid Methyl Ester
Hydrobromide (Scheme 4)
[0193] To a solution of 2-hydroxy-3-pyridin-3-yl-acrylic acid
methyl ester (579 mg, 3 mmol, 1 equiv.) in 30 mL of THF was added
bromine (154 .mu.L, 3 mmol, 1 equiv.) in THF dropwise, followed by
addition of methanol to dissolve the precipitate. The reaction
mixture was allowed to stir at room temperature for 0.5 h and
concentrated at room temperature with trituation a few times with
THF and ethyl acetate. The product
3-bromo-2-oxo-3-pyridin-3-yl-propionic acid methyl ester
hydrobromide was then dried under high vacuum and used without
further purification.
Example 9
2-(6-chloro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
Acid Methyl Ester (Scheme 4)
[0194] To a round-bottom flask charged with
3-bromo-2-oxo-3-pyridin-3-yl-p- ropionic acid methyl ester
hydrobromide (obtained above, 353 mg, 1 mmol, 2 equiv.) and 5 mL of
anhydrous methanol was added collidine (158 .mu.L, 1.2 mmol, 2.4
equiv.) at 0.degree. C., followed by the thioamide (112 mg, 0.5
mmol, 1 equiv.). The reaction mixture was then moved to 50.degree.
C., stirred for 2 h. LC-MS showed the complete consumption of the
thioamide and the formation of a cyclized intermediate (before
dehydration). At which point, ethanesulfonic acid (98 .mu.L, 1.2
mmol, 2.4 equiv.) was added and the reaction mixture was stirred at
50.degree. C. overnight. The reaction mixture was concentrated and
the residue was purified by RP-HPLC or used for the next step
(hydrolysis).
Example 10
2-(6-chloro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
Acid (Scheme 4)
[0195] The ester obtained above
(2-(6-chloro-7-methyl-1H-indazol-3-yl)-5-p-
yridin-3-yl-thiazole-4-carboxylic acid methyl ester) was hydrolyzed
in refluxing methanol in the presence of 1 N NaOH. The reaction
mixture was then concentrated and diluted with water. HCl was then
added to acidify the solution. The precipitate was filtered, washed
by water. The solid was dried under high vacuum. The product was
finally purified by RP-HPLC.
Example 11
[2-(6-chloro-7-methyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazol-4-yl]-methan-
one Hydrochloride
[0196] To a mixture of the acid,
2-(6-chloro-7-methyl-1H-indazol-3-yl)-5-p-
yridin-3-yl-thiazole-4-carboxylic acid (1 equiv.), triethyl amine
(3 equiv.), the amine (5-10 equiv.) in DMF, was added
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (1.4 equiv.). The reaction was completed
usually within minutes. The product was purified by RP-HPLC. The
trifluoroacetate salt was transferred to hydrochloride salt.
234235236
Example 12
N-(2,4,6-trimethyl-phenyl)-acetamide (Scheme 5, Step 1)
[0197] A solution of 2,4,6-trimethyl-phenylamine (1) (50 g, 0.370
moles) in CH.sub.2Cl.sub.2 (500 mL) was cooled to 0.degree. C.
(ice-water bath). To this was added acetyl chloride (29.8 g, 27 mL,
380 mmol) during 5 minutes via an addition funnel; this was
followed by portion-wise addition of Et.sub.3N (38.5 g, 53 mL, 380
mmol). The ice-bath was removed and the solution was allowed to
warm to room temperature and stir for 2 h. The resultant ivory
colored solid was collected by filtration and dried in vacuo. To
remove residual Et.sub.3N--HCl, the solid was suspended H.sub.2O
(600 mL) stirred for 0.5 h, collected by filtration and dried to a
constant weight. The original organic filtrate was washed with
H.sub.2O (3.times.100 mL) and brine (1.times.100 mL), dried
(MgSO.sub.4), filtered and concentrated providing additional
product. Combined with material collected from the water afforded
60.2 g (99% yield) of the desired acetamide. RP-HPLC Method: 2-100
B in 2 minutes.
Example 13
5,7-Dimethyl-1H-indazole (2) (Scheme 5, Step 2)
[0198] N-(2,4,6-trimethyl-phenyl)-acetamide (23.8 g, 133 mmol)
(prepared as described in Example 12) was dissolved in a mixture of
toluene (300 mL) and glacial AcOH (10.4 g, 173 mmol, 1.3 eq) and
then treated slowly with isoamyl nitrite (20.3 g, 23.2 mL, 173
mmol, 1.3 eq). The mixture was heated at reflux overnight or until
all the starting material was consumed as judged by TLC (30%
EtOAc-hexanes). The solution was then poured into H.sub.2O (1.3 L)
and extracted with EtOAc (2.times.300 mL). The combined organic
extracts were then washed with saturated aq. NaHCO.sub.3 solution
(2.times.200 mL) and brine (1.times.100 mL). The extracts were
dried (MgSO.sub.4), filtered, and concentrated to provide 19.5 g of
5,7-dimethyl-1H-indazole 2 as a red waxy solid. This material was
carried on without additional purification. RP-HPLC Method: 2-100%
B in 2 minutes.
Example 14
3-Iodo-5,7-dimethyl-1H-indazole (3) (Scheme 5, Step 3)
[0199] Indazole 2 (27.2 g, 186 mmol) in DMF (500 mL) was treated
with iodine crystals (143.9 g, 567 mmol, 3 eq) and KOH (52.9 g, 945
mmol, 5 eq). The mixture was stirred at room temperature for 2 h or
until complete as indicated by TLC (30% EtOAc-hexanes). The
solution was concentrated to half volume, poured into 5% aq.
NHSO.sub.3 (250 mL) and extracted with Et.sub.2O (3.times.250 mL).
The organic extracts were combined, washed with H.sub.2O
(2.times.200 mL) and brine (1.times.200 mL), dried over
(MgSO.sub.4), filtered and concentrated. The resultant dark solid
was suspended in hot EtOAc (300 mL), treated with hexane (600 mL)
and then allowed to cool for 2 h. The solids were collected by
filtration, providing 17.50 g of crop 1. The filtrate was
concentrated and crop 2 was isolated via silica gel plug
filtration. (20% EtOAc-hexanes). Concentration of the appropriate
"filtography" fractions afforded 9.5 g of material that was
combined with crop 1 give a total of 27 g (53% overall yield from
acetanilide) of 3-iodo-5,7-dimethyl-1H-indaz- ole 3. RP-HPLC Method
2-100% B in 2 minutes.
Example 15
5,7-Dimethyl-1H-indazole-3-carbonitrile (4) (Scheme 5, Step 4)
[0200] Iodide 3 (20 g, 74.0 mmol) was dissolved in anhydrous NMP
(300 mL). To this solution were added CuCN (19.9 g, 222 mmol, 3 eq)
and NaCN (7.25 g, 148 mmol, 2 eq) and the mixture was heated at
130.degree. C. for 18 h under an inert atmosphere. This solution
was then poured into 0.25 M KH.sub.2PO.sub.4 (1.5 L) and Et.sub.2O
(750 mL) and Celite (-100 g) were added. The suspension was stirred
vigorously for 0.5 h then filtered through a sintered glass funnel.
The phases were separated and the aqueous layer extracted with
Et.sub.2O (3.times.200 mL). The combined organic extracts were
washed with H.sub.2O (2.times.200 mL), brine (1.times.200 mL),
dried (MgSO.sub.4), filtered and concentrated provide 8.3 g (65%
yield) of 5,7-dimethyl-1H-indazole-3-carbonitrile 4. The nitrile
was used as is for the next reaction. RP-HPLC Method: 2-100% B in 2
minutes.
Example 16
5,7-Dimethyl-1H-indazole-3-carboximidothioic Acid A (5) (Scheme 5,
Step 5)
[0201] A solution of nitrile 4 (3.90 g, 22.0 mmol) in 20%
Et.sub.3N-pyridine (v/v, 50 mL) was cooled to 0.degree. C.
(ice-water bath) and then saturated with H.sub.2S by bubbling
H.sub.2S gas through for 5 minutes. The reaction vessel was sealed
with stoppers and Parafilm, removed from the cooling bath, and
stirred for 1.5 h, or until consumption of starting material was
complete as indicated by TLC (50% EtOAc-hexanes). Upon completion,
the solution was stirred under vacuum to remove excess H.sub.2S and
then concentrated to leave a brown solid. The crude product was
suspended in hexane (250-300 mL), collected by vacuum filtration
and dried over P.sub.2O.sub.5 in vacuo to give 4.2 g, (93% yield)
of A (5) as a yellow solid. RP-HPLC Method: 30-95% B in 4.5
minutes.
Example 17
2-Hydroxy-3-pyridin-3-yl-acrylic Acid Ethyl Ester (8) (Scheme 5,
Step 6)
[0202] A dry 1 L round bottomed flask was charged with anhydrous
Et.sub.2O (500 mL) and cooled to 0.degree. C. (ice-water bath).
After having been rinsed with hexane, NaH (60% w/w suspension in
mineral oil, 16 g, 400 mmol, 2 eq, weight before rinsing) was added
followed by absolute EtOH (23.2 mL, 400 moles, 2 eq). After 10
minutes, a mixture of 3-pyridine carboxaldehyde (18.8 mL, 200 mmol,
1 eq) and N,N-dimethyl glycine ethyl ester (84.8 mL, 3 eq)
(N,N-dimethyl glycine methyl ester also performs satisfactorily in
this preparation) was added during 1 minute. This mixture was as
stirred overnight at room temperature, heated at 30.degree. C. for
1 h, and then transferred to a 2 L separation funnel. The mixture
was diluted with EtOAc (500 mL) and H.sub.2O (500 mL) and the
organic phase was transferred to a beaker and stirred with 1N HCl
(500 mL) at room temperature for 10 minutes. The mixture was
checked to confirm a pH=1 and then the phases were separated. The
aqueous layer was retained and slowly neutralized by the addition
of solid NaHCO.sub.3. This solution was extracted with EtOAc
(3.times.300 mL), the combined extracts dried (Na.sub.2SO.sub.4),
filtered and concentrated to a yellow solid. Crystallization from
EtOAc-Hexanes (4:1) provided 20.0 g (52% yield) of pale yellow 8.
RP-HPLC Method 2-100% B.
Example 18
3-Bromo-2-oxo-3-pyridin-3-yl-propionic Acid Ethyl Ester
Hydrobromide B (9) (Scheme 5, Step 7)
[0203] To a solution of the pyruvate 8 (19.3 g, 100.0 mmol) in dry
THF (400 mL) was added bromine (5.12 mL, 100.0 mmol) dropwise,
followed by the addition of methanol (-10 mL) to maintain
homogeneity. The reaction mixture was stirred for 30 minutes at
room temperature, and then concentrated in vacuo at a bath
temperature at or below 25.degree. C. The resulting solid was
triturated with THF (50 mL) and EtOAc (50 mL) three times. The
resulting bromo pyruvate hydrobromide was isolated as yellow foam
after drying under high vacuum in quantitative yields. The solid
was used without further purification. (Occasionally, the crude
bromo pyruvate product dries to a sticky gum. In this event, the
material was dried as thoroughly as possible, dissolved in MeOH
(0.5 mmol/mL), and used as is in the next step.) RP-HPLC Method
30-95% B in 8 minutes.
Example 19
3-Bromo-2-oxo-3-pyridin-3-yl-propionic Acid Ethyl Ester (10)
(Scheme 5, Step 11)
[0204] Contained in a 2-neck round-bottomed flask a suspension of
thioamide A (5) (4.5 g, 22.0 mmol) in dry MeOH (100 mL) was heated
at 50.degree. C. Separately, a solution of bromo-pyruvate B (9)
(15.5 g, 44.0 mmol) in anhydrous MeOH (88 mL) was treated with
collidine (10.2 mL, 77.0 mmol) at 0.degree. C. The bromo
pyruvate/collidine solution was added dropwise to the thioamide
suspension maintained at 50.degree. C. The mixture, becoming
homogeneous during addition of the bromo-pyruvate solution, is
heated at 50.degree. C. for 2 h, or until consumption of thioamide
is complete as judged by RP-HPLC-MS (the condensed, non-dehydrated
intermediate is observable; expected mass +18). After this time,
EtSO.sub.3H acid (6.3 mL, 77.0 mmol) was added and heating
continued at 50.degree. C. overnight. The mixture was concentrated
and the oily residue treated with saturated aqueous sodium
bicarbonate solution (.about.100 mL). The resultant solid is
collected by vacuum filtration and rinsed with water (2.times.30
mL) and dried under vacuum. The solid is purified by silica
gel-plug filtration: an initial eluent of 100% CH.sub.2Cl.sub.2
removes any nitrile 4 formed (typically 1-3%) and subsequent
elution with 2-5% MeOH--CH.sub.2Cl.sub.2 provides the methyl and
ethyl ester mixture. RP-HPLC Methods: 30-95% B in 8 minutes for the
non-dehydrated intermediate. 10-95% B in 8 minutes for the
dehydrated final product.
Example 20
2-(5,7-dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazole-4-carboxylic
Acid (11) (Scheme 5, Step 12)
[0205] A solution of esters 10 (8 g, .about.22 mmol) in MeOH (100
mL) and 1N NaOH (50 mL) was heated at reflux for 2 hours. The
mixture was concentrated, acidified with 1N HCl (100 mL), and the
resulting solid collected by vacuum filtration. The solid was
rinsed with H.sub.2O (3.times.20 mL) and dried under high vacuum to
give 7.9 g, (51%) overall from thioamide 5. RP-HPLC Method: 10-95%
B in 8 minutes.
Example 21
Methanesulfonic Acid 1-benzhydryl-azetidin-3-yl Ester (12) (Scheme
5, Step 8)
[0206] To a solution of 1-benzhydryl-azetidin-3-ol (15.0 g, 62.7
mmol) in dry CH.sub.2Cl.sub.2 (1 mL) at 0.degree. C. (ice-water
bath) under nitrogen was added dry Et.sub.3N (25 mL, 94.0 mmol). To
this was then added a solution of methanesulfonyl chloride (5.8 mL,
75.2 mmol) in dry CH.sub.2Cl.sub.2 (50 mL) dropwise via pressure
equalizing addition funnel. Upon complete addition, the cooling
bath was removed and the mixture was stirred for 2 h. The
heterogeneous mixture was treated with H.sub.2O (70 mL), the layers
were separated and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.100 mL). The combined organic extracts
were dried (MgSO.sub.4), filtered and concentrated to leave a
clear, colorless oil. Upon addition of hexanes (100 mL) the viscous
oil product solidified and was collected by vacuum filtration.
Drying under high vacuum provided 19.7 g (100% yield) of 12 as a
colorless solid.
Example 22
1-(1-Benzhydryl-azetidin-3-yl)-4-methyl-piperazine (13) (Scheme 5,
Step 9)
[0207] To a suspension of methanesulfonic acid
1-benzhydryl-azetidin-3-yl ester (12) (18 g, 56.7 mmol) in t-BuOH
(150 mL) was added 1-methyl piperazine (17.04 g, 18.8 mL, 170.1
mmol) under an inert atmosphere. After heating at reflux
temperature for 12 h, the mixture was concentrated to dryness,
treated with saturated NaHCO.sub.3 (250 mL) and extracted with
EtOAc (3.times.250 mL). The combined organic layers were washed
with H.sub.2O (1.times.250 mL) and brine (1.times.250 mL) and dried
(Na.sub.2SO.sub.4). Filtration and removal of solvent left oil that
was purified by silica gel (-300 g) filtration (first washed with
EtOAc, then with 100% ammoniacal CH.sub.2Cl.sub.2-5%
MeOH/ammoniacal CH.sub.2Cl.sub.2) to afford 7.6 g (42%) of 13 as a
colorless, waxy solid. Ammoniacal CH.sub.2Cl.sub.2 is prepared as
follows: concentrated NH.sub.4OH (100 mL) is extracted with
CH.sub.2Cl.sub.2 (1.times.500 mL), the layers are separated, and
the CH.sub.2Cl.sub.2 layer is dried and stored over anhydrous
K.sub.2CO.sub.3.
Example 23
1-Azetidin-3-yl-4-methyl-piperazine Dihydrochloride C (14) (Scheme
5, Step 10)
[0208] A mixture of
1-(1-benzhydryl-azetidin-3-yl)-4-methyl-piperazine (13) (1.13 g,
3.5 mmol), wet 20% Pd(OH).sub.2/C (0.6 g) or wet 10% Pd/C degussa
type (0.22 g), MeOH (50 ml) and 4N HCl in MeOH solution (1.8 ml,
7.0 mmol) was shaken under an H.sub.2 gas (50 p.s.i.g.) for 12 h.
The catalyst was removed by filtration over Celite; the filter bed
was rinsed with MeOH (3.times.10 mL) and the filtrate evaporated to
dryness, and the residue rinsed with a mixture of Et.sub.2O (2 mL)
and hexanes (10 ml) to remove diphenylmethane. The product C (14)
crystallized upon standing providing 0.77 g (96% yield) of
colorless, hygroscopic material that was used as is in subsequent
steps.
Example 24
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-pyridin-3-yl-thiazo-4-yl]-[3-(4-methyl-
-piperazin-1-yl)-azetidin-1-yl]-methanone (15) (Scheme 5, Step
13)
[0209] A mixture of acid 11 (1.04 g; 3.07 mmol) and azetidine
dihydrochloride C (14) (0.77 g, 3.37 mmol) in dry DMF (20 mL) was
treated with dry Et.sub.3N (2.14 mL, 15.34 mmol) under an inert
atmosphere. To this was then added HATU (1.46 g, 3.84 mmol) in one
portion. Efficient couplings have also been achieved using PyBop
(1.4 equivalents based on 11) as the coupling agent. After stirring
for 0.25 h, RP-HPLC indicates complete reaction. The mixture was
transferred onto stirring concentrated NH.sub.4OH (400 mL) and the
resulting tan solid collected by vacuum filtration. Rinsing with
H.sub.2O (2.times.10 mL) and vacuum drying provided 0.64 g (44%
yield) of 15 as the free base. Concentrating the filtrate,
re-suspending in concentrated NH.sub.4OH (7 mL) and collecting by
vacuum filtration provided an additional 90 mg of 15.
Examples 25-154
[0210] Biological Assams
[0211] ATPase enzymatic assay: DNA gyrase B activities were
determined by following the gyrase B-dependent release of inorganic
phosphate from ATP hydrolysis and subsequent detection through use
of a 7-methyl-6-thioguanosine/phosphorylase spectrophotometric
assay. Assays were performed in 25 mM Tris-HCl buffer (pH 7.6), 2
mM MgCl.sub.2, and 125 mM NaCl, 0.2 mM 7-methyl-6-thioguanosine,
purine nucleoside phosphorylase (1 unit/mL), 0.4 mM ATP and various
concentrations of the inhibitor compounds prepared in Me.sub.2SO.
The final Me.sub.2SO concentration in each reaction was 2.5%.
[0212] The compounds of the formula (1) shown in Table 1 were
assayed against one or more of Staphylococcus aureus,
Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus
pyogenes, Enterococcus faecalis, Moraxella catarrhalis and H.
influenzae. The concentration of enzyme in the assay ranged from 65
nM for E. faecalis full-length gyrase B to 1 .mu.M for H.
influenzae full-length gyrase B. Reactions were initiated with the
addition of ATP, and monitored at 360 nm at room temperature for 30
min.
[0213] Tight-binding kinetic analysis (Morrison, J. F. Biochim.
Biophys. Acta 1969, 185, 269-286) was used to determine K.sub.i if
the concentration of inhibitor did not exceed that of enzyme.
[0214] Antimicrobial Activity Assay (MIC Determination)
[0215] Bacteria Preparations: Overnight bacterial colonies were
suspended in 0.9% NaCl to a turbidity approximately comparable to
the MacFarland's standard. The spectrometer was blanked (600 nm)
using well-suspended standard. Into a cuvette was placed 0.5 mL of
bacterial suspension and absorbance measured. A 0.9% NaCl solution
was added to the cuvette, mixed and measured until the absorbance
is 0. From this the dilution factor (to achieve an absorbance of 0)
for the stock bacterial solution was calculated. A solution of
bacteria at this dilution is defined as a stock of 1.times.10.sup.8
bacteria/mL. A final concentration of 5.times.10.sup.5 bacteria per
well was used for MIC determinations.
[0216] Compound Preparation: Test compounds of the formula (I) were
assayed over a wide range of concentrations using serial dilutions,
dropping concentration by half at each step. Controls included
wells containing no drug (uninhibited growth control), controls for
no additive (no serum etc.), and controls for contamination
(additives but no drugs or bacteria).
[0217] The compounds of the formula (I) shown in Table 1 were found
to exhibit activity against one or more of Staphylococcus aureus,
Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus
pyogenes, Enterococcus faecalis, Moraxella catarrhalis and H.
influenzae. Table 2 provides the names and structures of compounds
of the formula (I) that were found to have a MIC of about 10 .mu.M
or less in the Methicillin-resistant Staphylococcus aureus
assay.
[0218] It will be appreciated by those skilled in the art that
various omissions, additions and modifications may be made to the
processes described above without departing from the scope of the
invention, and all such modifications and changes are intended to
fall within the scope of the invention, as defined by the appended
claims.
2TABLE 2 NO. STRUCTURE NAME 1. 237
2-(7-Methyl-1H-indazol-3-yl)-5-pyri- din-3-yl-thiazole-4-carboxylic
acid (1,2,2,6,6-pentamethyl-piperidin-4- yl)-amide 2. 238
2-(7-Methyl-1H-indazol-3-yl)-5-pyri- din-3-yl-thiazole-4-carboxylic
acid methyl-(1-methyl-piperidin-4-yl)-amid- e 3. 239
2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid
methyl-(1-methyl-piperidin-4-yl)- amide 4. 240
2-(7-Methyl-1H-indazol-3-yl)-5-pyri- din-3-yl-thiazole-4-carboxylic
acid methyl-(1-methyl-pyrrolidin-3-yl)- amide 5. 241
[1,3']Bipyrrolidinyl-1'-yl-[2-(5,7-
dimethyl-1H-indazol-3-yl)-5-pyridin- 3-yl-thiazol-4-yl]-methanone
6. 242 2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid
methyl-(1-methyl-pyrrolidin-3- yl)-amide 7. 243
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thia.zol-4-yl]-[3-(iso
propyl-methyl-amino)-pyrrolidin-1-yl]- - methanone 8. 244
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-[3-(ethyl-
methyl-amino)-pyrrolidin-1-yl]- methanone 9. 245
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-(3-hydroxy-
[1,3']bipyrrolidinyl-1'-yl)-methan- one 10. 246
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-(3-
morpholin-4-yl-pyrrolidin-1-yl)-methanone 11. 247
2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid piperidin-4-ylamide 12. 248
2-(5,7-Dimethyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazole-4-car-
boxylic acid (1,2,2,6,6-pentamethyl-piperidin- 4-yl)-amide 13. 249
(3-Methylamino-pyrrolidin-1-yl)-[2- (7-methyl-1H-indazol-3-yl)-5--
pyridin- 3-yl-thiazol-4-yl]-methanone 14. 250
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-[3
-(ethyl- methyl-amino)-azetidin-1-yl]- methanone 15. 251
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-(3-morpho- lin-
4-yl-azetidin-1-yl)-methanone 16. 252
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-[3-(4-
methyl-piperazin-1-yl)-azetidin-1-yl]- methanone 17. 253
2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic
acid(1-isopropyl-piperidin-4-yl)-amide 18. 254
2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid [1-(2,2-dimethyl-propyl)-
piperidin-4-yl]-amide 19. 255 [2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-[4-(2- ,2-
dimethyl-propyl)-piperazin-1-yl]- methanone 20. 256
[2-(5-Fluoro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
pyridin-2-ylmethyl-piperazin-1-yl)- methanone 21. 257
[2-(5-Fluoro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
isopropyl-piperazin-1-yl)-methanone 22. 258
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-(4-pyridi- n-
4-yl-piperazin-1-yl)-methanone 23. 259
2-(5-Fluoro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carboxyl- ic acid
(1-methyl-piperidin-4-yl)- amide 24. 260
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-(4-pyridi- n-
2-ylmethyl-piperazin-1-yl)- methanone 25. 261
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-(4-iso- propyl-piperazin-1-yl)-methanone
26. 262 [2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-(4-pyridi- n-
2-yl-piperazin-1-yl)-methanone 27. 263
(4-Cyclopentyl-piperazin-1-yl)-[2-(5,7-
dimethyl-1H-indazol-3-yl)-5- pyridin-3-yl-thiazol-4-yl]-methanone
28. 264 2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid
(1-methyl-piperidin-4-yl)-amide 29. 265
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-(2,3,5,
6-tetrahydro-[1,2']bipyrazinyl-4-yl)- methanone 30. 266
(3-Diethylamino-pyrrolidin-1-yl)-[2-
(5,7-dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-methanone 31. 267
(3-Diethylamino-pyrrolidin-1-yl)-[2-
(7-methyl-1H-indazol-3-yl)-5-pyridin- -
3-yl-thiazol-4-yl]-methanone 32. 268
(3-Methylamino-pyrrolidin-1-yl)-[2-
(7-methyl-1H-indazol-3-yl)-5-pyridin- 3-yl-thiazol-4-yl]-methanone
33. 269 [2-(5-Fluoro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]- piperazin-1-yl-methanone 34. 270
[2-(5-Fluoro-7-methyl-1H- -indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4- methyl-piperazin-1-yl)-me-
thanone 35. 271 [2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-(2-pyrroli-
din-1-ylmethyl-pyrrolidin-1-yl)- methanone 36. 272
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-(4-pyridin- 4-ylmethyl-piperazin-1-yl)-
methanone 37. 273 2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid
(2-dimethylamino-ethyl)-methyl- amide 38. 274
2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid
methyl-(2-methylamino-ethyl)-amid- e 39. 275
(4-Dimethylamino-piperidin-1-yl)-[2-
(5,7-dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl)-methanone 40. 276
(4-Dimethylamino-piperidin-1-yl)-[2- (7-methyl-i
H-indazol-3-yl)-5-pyridin- 3-yl-thiazol-4-yl]-methanone 41. 277
(3-Dimethylamino-pyrrolidin-1-yl)-[2- (5-fluoro-7-methyl-1H-indaz-
ol-3-yl)- 5-pyridin-3-yl-thiazol-4-yl]-methanone 42. 278
(3-Dimethylamino-pyrrolidin-1-yl)-[2-
(7-methyl-1H-indazol-3-yl)-5-(6-
methyl-pyridin-3-yl)-thiazol-4-yl]- methanone 43. 279
[2-(5,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-piperazin- - 1-yl-methanone 44. 280
[2-(5,7-Dimethyl-1H-indazol-3-yl)- -5-
pyridin-3-yl-thiazol-4-yl]-(4-methyl- piperazin-1-yl)-methanone 45.
281 (3-Dimethylamino-pyrrolidin-1-yl)-[2-
2-(5,7-dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-methanone 46. 282
(3-Dimethylamino-pyrrolidin-1-yl)-[2-
(4,7-dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazol-4-yl]-methanone 47. 283
[2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazol-4-yl]-(4-pyrrolidin-
1-yl-piperidin-1-yl)-methanone 48. 284
[1,4']Bipiperidinyl-1'-yl-[2-(7-methyl-
1H-indazol-3-yl)-5-pyridin-3-yl- thiazol-4-yl]-methanone 49. 285
[2-(7-Methyl-1H-indazol-3-yl)-5-pyri- din-3-yl-thiazol-4-yl]-(4-m-
orpholin- 4-yl-piperidin-1-yl)-methanone 50. 286
(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-
[2-(7-methyl-1H-indazol-3-yl)-5-pyri- -
din-3-yl-thiazol-4-yl)-methanone 51. 287
[1,4]Diazepan-1-yl-[2-(7-methyl-1H-
indazol-3-yl)-5-pyndm-3-yl-thiazol- 4-yl]-methanone 52. 288
(3-Dimethylamino-pyrrolidin-1-yl)- -[2-
(6-fluoro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazol-4-yl]-met- hanone 53. 289
[2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazol-4-yl]-piperazin-1- yl-methanone 54. 290
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-[3-
(4-methyl-piperazin-1-yl)-azetidin- 1-yl]-methanone 55. 291
(3-Dimethylamino-pyrrolidin-1-yl)-[2-
2-(4-fluoro-7-methyl-1H-indazol- -3-yl)-
5-pyridin-3-yl-thiazol-4-yl]-methanone 56. 292
[2-(6-Fluoro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]- piperazin-1-yl-methanone 57. 293
2-(6-Fluoro-7-methyl-1H-- indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carboxylic acid
methyl-(2-methylamino-ethyl)- amide 58. 294
2-(4-Fluoro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carboxyl- ic acid methyl ester 59. 295
[2-(4,7-Dimethyl-1H-indazol-3- -yl)-5-
pyridin-3-yl-thiazol-4-yl]-(4-methyl- piperazin-1-yl)-methanone 60.
296 2-(4,7-Dimethyl-1H-indazol-3-yl)-5-
pyridin-3-yl-thiazole-4-carboxylic acid methyl ester 61. 297
[2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazol-4-yl]-(4-pyrid- in-
4-ylmethyl-piperazin-1-yl)-methanone 62. 298
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
pyridin-4-ylmethyl-piperazin-1-yl)- methanone 63. 299
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(3-
methylamino-pyrrolidin-1-yl)-methanone 64. 300
2-(6-Chloro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carboxyl- ic acid
[3-(5-oxo-4,5-dihydro-1H- pyrazol-4-yl)-propyl]-amide 65. 301
[2-(6-Chloro-7-methyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-
-4-yl]-[4- (2-diethylamino-ethyl)-piperazin-1- yl]-methanone 66.
302 2-(6-Chloro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-- 4-carboxylic acid
(2-dimethylamino-ethyl)- methyl-amide 67. 303
2-(6-Chloro-7-methyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-4--
carboxylic acid [2-(1-methyl-pyrrolidin-2- yl)-ethyl]-amide 68. 304
2-(6-Chloro-7-methyl-1H-indazol-3-yl)- 5-pyridin-3-yl-thiazole-4-
-carboxylic acid (2-morpholin-4-yl-ethyl)- amide 69. 305
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl)-(4-
isopropyl-piperazin-1-yl)-methanone 70. 306
2-(6-Chloro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carboxyl- ic acid
(2-pyrrolidin-1-yl-ethyl)-amide 71. 307
2-(6-Chloro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carboxyl- ic acid
(2-dimethylamino-1-methyl- ethyl)-amide 72. 308
2-(6-Chloro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carboxyl- ic acid
methyl-(2-methylamino-ethyl)- amide 73. 309
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-[3-
(ethyl-methyl-amino)-azetidin-1-yl]- methanone 74. 310
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(2,
3,5,6-tetrahydro-[1,2']bipyrazinyl- 4-yl)-methanone 75. 311
2-(6-Chloro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carb- oxylic acid
(1-methyl-piperidin-4-yl)- amide 76. 312
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-[4-
(2-hydroxy-ethyl)-piperazin-1-yl]- methanone 77. 313
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
pyridin-2-ylmethyl-piperazin-1-yl)- methanone 78. 314
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
pyridin-2-yl-piperazin-1-yl)-methanone 79. 315
(3-Dimethylamino-pyrrolidin-1-yl)-[2-
(7-ethyl-1H-indazol-3-yl)-5-pyridin- - 3-yl-thiazol-4-yl]-methanone
80. 316 [2-(7-Ethyl-1H-indazol-3-yl)-5-pyridin-
3-yl-thiazol-4-yl]-(4-methyl-pipe- ri- azin-1-yl)-methanone 81. 317
[2-(6-Chloro-7-methyl-1H-- indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(3- hydroxy-pyrrolidin-1-yl)-m-
ethanone 82. 318 [2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]- piperazin-1-yl-methanone 83. 319
[5-(6-Methoxy-pyridin-3-yl)-2-(7- methyl-1H-indazol-3-yl)-thiazo-
l-4-yl]- (4-methyl-piperazin-1-yl)-methanone 84. 320
[2-(6-Fluoro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
methyl-piperazin-1-yl)-methanone 85. 321
2-(6-Chloro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carboxyl- ic acid
(2-diethylamino-ethyl)-amide 86. 322
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(4-
pyridin-4-yl-piperazin-1-yl)-methanone 87. 323
[2-(6-Chloro-7-methyl-1H-indazol-3- yl)-5-pyridin-3
-yl-thiazol-4-yl]-(3- hydroxy-azetidin-1-yl)-methanone 88. 324
[5-(3,4-Difluoro-phenyl)-2-(7-methyl-
1H-indazol-3-yl)-thiazol-4-yl]-(3- dimethylamino-pyrrolidin-1-yl)-
methanone 89. 325 [5-(3,4-Difluoro-phenyl)-2-(7-methyl-
1H-indazol-3-yl)-thiazol-4-yl]-(3-
hydroxy-pyrrolidin-1-yl)-methanone 90. 326
[5-(3,4-Difluoro-phenyl)-2-(7-methyl-
1H-indazol-3-yl)-thiazol-4-yl]-(4- methyl-piperazin-1-yl)-methanone
91. 327 (3-Dimethylamino-pyrrolidin-1-yl)-[5-
(4-hydroxy-phenyl)-2-(7-methyl-1H-
indazol-3-yl)-thiazol-4-yl]-methanone 92. 328
[5-(3-Fluoro-phenyl)-2-(7-methyl-1H-
indazol-3-yl)-thiazol-4-yl]-(4-methy- l- piperazin-1-yl)-methanone
93. 329 (3-Hydroxy-azetidin-1-yl)-[2-(7-methyl-
1H-indazol-3-yl)-5-pyridin-3-yl- thiazol-4-yl]-methanone 94. 330
[5-(3,5-Difluoro-phenyl)-- 2-(7-methyl-
1H-indazol-3-yl)-thiazol-4-yl]-(3- hydroxy-pyrrolidin-1-yl)-m-
ethanone 95. 331 [5-(3,5-Difluoro-phenyl)-2-(7-methyl-
1H-indazol-3-yl)-thiazol-4-yl]-(4- methyl-piperazin-1-yl)-methanone
96. 332 [5-(4-Fluoro-phenyl)-2-(7-methyl-1H-
indazol-3-yl)-thiazol-4-yl]-(3-hydroxy- pyrrolidin-1-yl)-methanone
97. 333 2-(4-Chloro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carboxylic acid methyl ester 98. 334
5-(4-Hydroxy-phenyl)-2-(7-methyl-1H- indazol-3-yl)-thiazole-4-car-
boxylic acid methyl ester 99. 335 5-(4-Fluoro-phenyl)-2-(7-
-methyl-1H- indazol-3-yl)-thiazole-4-carboxylic acid methyl ester
100. 336 2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazole-4-carboxylic acid ethyl-methyl-amide 101. 337
[2-(6-Chloro-7-methyl-1H-indazol-3- yl)-5-pyridin-3-yl-thiazol-4-
-yl]-(4- methyl-piperazin-1-yl)-methanone 102. 338
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(3-
hydroxy-pyrrolidin-1-yl)-methanone 103. 339
[2-(6-Chloro-7-methyl-1H-indazol-3-
yl)-5-pyridin-3-yl-thiazol-4-yl]-(3-
dimethylamino-pyrrolidin-1-yl)- methanone 104. 340
2-(6-Chloro-7-methyl-1H-indazol-3-yl)-
5-pyridin-3-yl-thiazole-4-carboxyl- ic acid methyl ester 105. 341
[2-(7-Methyl-1H-indazol-3-yl- )-5-pyri-
din-3-yl-thiazol-4-yl]-morpholin-4-yl- methanone 106. 342
(3-Dimethylamino-pyrrolidin-1-yl)-[5- (3-methoxy-phenyl)-2-(7-me-
thyl-1H- indazol-3-yl)-thiazol-4-yl]-methanone 107. 343
(3,5-Dimethyl-piperidin-1-yl)-[2-(7-
methyl-1H-indazol-3-yl)-5-pyridin- 3-yl-thiazol-4-yl]-methanone
108. 344 [2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazol-4-yl]-piperidin-1-- yl- methanone 109. 345
[5-(6-Chloro-pyridin-3-yl)-2-(7-met- hyl-
1H-indazol-3-yl)-thiazol-4-yl]- (3-dimethylamino-pyrrolidin-1-yl)-
methanone 110. 346 (3-Dimethylamino-pyrrolidin-1-yl)-[2-
(7-methyl-1H-indazol-3-yl)-5-(6-tri-
fluoromethyl-pyridin-3-yl)-thiazol- 4-yl]-methanone 111. 347
(3-Hydroxy-pyrrolidin-1-yl)-[2-(- 7-
methyl-1H-indazol-3-yl)-5-pyridin-3- yl-thiazol-4-yl]-methanone
112. 348 (3,5-Dimethyl-piperazin-1-yl)-[2-(7-
methyl-1H-indazol-3-yl)-5-pyridin- 3-yl-thiazol-4-yl]-methanone
113. 349 2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazole-4-carboxylic acid 1-methyl-piperidin-4-yl ester
114. 350 2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazole-4-carboxylic acid 1-methyl-pyrrolidin-3-yl ester
115. 351 [2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazol-4-yl]-(4-methyl- piperazin-1-yl)-methanone 116.
352 (3-Dimethylamino-pyrrolidin-1-yl)-[2- (7-methyl-1H-indazol-3-y-
l)-5-pyri- din-3-yl-thiazol-4-yl]-methanone 117. 353
(3-Dimethylamino-pyrrolidin-1-yl)-[2-
(7-methyl-1H-indazol-3-yl)-5-pyri- din-3-yl-thiazol-4-yl]-methanone
118. 354 [2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazol-4-yl]-(4-pyridin- 4-yl-piperazin-1-yl)-methanone
119. 355 2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazole-4-carboxylic acid
(2-dimethylamino-ethyl)-methyl-amide 120. 356
2-(7-Methyl-1H-indazol-3-yl)-5-pyri- din-3-yl-thiazole-4-carboxylic
acid (1-methyl-piperidin-4-yl)-amide 121. 357
2-(7-Methyl-1H-indazol-3-yl)-5-pyri- din-3-yl-thiazole-4-carboxylic
acid (2-diethylamino-ethyl)-amide 122. 358
2-(7-Methyl-1H-indazol-3-yl)-5-pyri- din-3-yl-thiazole-4-carboxylic
acid ethyl ester 123. 359 2-(7-Methyl-1H-indazol-3-yl)-5-pyri-
din-3-yl-thiazole-4-carboxylic acid methyl ester 124. 360
2-(7-Methyl-1H-mdazol-3-yl)-5-phenyl- thiazole-4-carboxylic acid
methyl ester 125. 361 2-Bromo-5-[2-(1H-indazol-3-yl)-4- methyl
thiazol-5-yl]-phenol 126. 362 2-(1H-Indazol-3-yl)-5-pheny-
l-thiazole- 4-carboxylic acid (2-dimethylamino- ethyl)-amide 127.
363 3-[2-(7-Chloro-1H-indazol-3-yl)-4- methyl-thiazol-5-yl]-phenol
128. 364 2-(1H-Indazol-3-yl)-5-phenyl- thiazol-4-ol 129. 365
3-[2-(1H-Indazol-3-yl)-4-methyl- thiazol-5-yl]-phenol 130. 366
3-[5-(4-Bromo-3-methoxy-phenyl)-4-
methyl-thiazol-2-yl]-1H-indazole
* * * * *