U.S. patent application number 17/573973 was filed with the patent office on 2022-09-08 for novel ptefb inhibiting macrocyclic compounds.
The applicant listed for this patent is Bayer Aktiengesellschaft, Bayer Pharma Aktiengesellschaft. Invention is credited to Clara CHRIST, Daniel HOG, Philip LIENAU, Ulrich LUCKING, Ulrike SACK, Franziska SIEGEL, Nicolas WERBECK.
Application Number | 20220281892 17/573973 |
Document ID | / |
Family ID | 1000006344861 |
Filed Date | 2022-09-08 |
United States Patent
Application |
20220281892 |
Kind Code |
A1 |
LUCKING; Ulrich ; et
al. |
September 8, 2022 |
NOVEL PTEFB INHIBITING MACROCYCLIC COMPOUNDS
Abstract
The present invention relates to novel modified macrocyclic
compounds with improved tolerability of general formula (I) as
described and defined herein, and methods for their preparation,
their use for the treatment and/or prophylaxis of disorders, in
particular of hyper-proliferative disorders and/or virally induced
infectious diseases and/or of cardiovascular diseases. The
invention further relates to intermediate compounds useful in the
preparation of said compounds of general formula (I).
Inventors: |
LUCKING; Ulrich; (Berlin,
DE) ; HOG; Daniel; (Dusseldorf, DE) ; CHRIST;
Clara; (Berlin, DE) ; SACK; Ulrike; (Berlin,
DE) ; SIEGEL; Franziska; (Berlin, DE) ;
LIENAU; Philip; (Berlin, DE) ; WERBECK; Nicolas;
(Berlin, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bayer Aktiengesellschaft
Bayer Pharma Aktiengesellschaft |
Leverkusen
Berlin |
|
DE
DE |
|
|
Family ID: |
1000006344861 |
Appl. No.: |
17/573973 |
Filed: |
January 12, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16498662 |
Sep 27, 2019 |
11254690 |
|
|
PCT/EP2018/057359 |
Mar 22, 2018 |
|
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17573973 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 498/18 20130101;
C07D 498/08 20130101; A61P 35/00 20180101 |
International
Class: |
C07D 498/18 20060101
C07D498/18; A61P 35/00 20060101 A61P035/00; C07D 498/08 20060101
C07D498/08 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 28, 2017 |
EP |
17163377.9 |
Sep 28, 2017 |
EP |
17193837.6 |
Claims
1.-27. (canceled)
28. A compound of general formula (7): ##STR00189## wherein: Z is
hydrogen or fluorine; L is a C.sub.3-C.sub.8-alkylene moiety;
wherein said moiety is optionally substituted with (i) one
substituent selected from hydroxy, --NR.sup.8R.sup.9,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-,
C.sub.3-C.sub.4-cycloalkyl-, hydroxy-C.sub.1-C.sub.3-alkyl, and
--(CH.sub.2)NR.sup.8R.sup.9, and/or (ii) one or two or three or
four substituents, identically or differently, selected from
halogen and C.sub.1-C.sub.3-alkyl-; or wherein one carbon atom of
said C.sub.3-C.sub.8-alkylene moiety forms a three- or
four-membered ring together with a bivalent moiety to which it is
attached, wherein said bivalent moiety is selected from
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2OCH.sub.2--; R.sup.1 is C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-, or
heterocyclyl-; wherein said group is optionally substituted with
one or two or three substituents, identically or differently,
selected from the group consisting of hydroxy, cyano, halogen,
C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.3-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, --OP(.dbd.O)(OH).sub.2, --C(.dbd.O)OH, and
--C(.dbd.O)NH.sub.2; R.sup.2 is hydrogen, fluorine, chlorine,
bromine, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, or C.sub.1-C.sub.3-fluoroalkoxy-;
R.sup.3 and R.sup.4 are independently from each other, a group
selected from hydrogen, fluorine, chlorine, bromine, cyano,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; and
R.sup.8 and R.sup.9 are independently from each other, a group
selected from hydrogen, C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, and
heteroaryl-; wherein said C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- or
heteroaryl-group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-, or
R.sup.8 and R.sup.9, together with the nitrogen atom they are
attached to, form a cyclic amine; or salt thereof.
29. The compound of claim 28, wherein: Z is hydrogen or fluorine; L
is a C.sub.3-C.sub.5-alkylene moiety, wherein said moiety is
optionally substituted with i) one substituent selected from
hydroxy, C.sub.3-C.sub.4-cycloalkyl-, and
hydroxy-C.sub.1-C.sub.3-alkyl-, and --(CH.sub.2)NR.sup.8R.sup.9,
and/or ii) one or two or three substituents, identically or
differently, selected from halogen and C.sub.1-C.sub.3-alkyl-;
R.sup.1 is C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.5-cycloalkyl-;
wherein said group is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group consisting of hydroxy, cyano, halogen,
C.sub.1-C.sub.3-alkyl-, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.3-alkoxy-, C.sub.1-C.sub.2-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, cyclic amines, --OP(.dbd.O)(OH).sub.2,
--C(.dbd.O)OH, and --C(.dbd.O)NH.sub.2; R.sup.2 is hydrogen,
fluorine, chlorine, cyano, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, fluoro-C.sub.1-C.sub.2-alkyl-, or
C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.3 and R.sup.4 are
independently from each other, a group selected from hydrogen,
fluorine, chlorine, cyano, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, fluoro-C.sub.1-C.sub.2-alkyl-, and
C.sub.1-C.sub.2-fluoroalkoxy-; and R.sup.8 and R.sup.9 are
independently from each other, a group selected from hydrogen,
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl-, and
benzyl-; wherein said C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, phenyl- or benzyl- group is optionally
substituted with one, two or three substituents, identically or
differently, selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, cyclic amines,
fluoro-C.sub.1-C.sub.2-alkyl-, and C.sub.1-C.sub.2-fluoroalkoxy-,
or R.sup.8 and R.sup.9, together with the nitrogen atom they are
attached to, form a cyclic amine; or a salt thereof.
30. The compound of claim 28, wherein; Z is hydrogen or fluorine; L
is a C.sub.3-C.sub.5-alkylene moiety, wherein said moiety is
optionally substituted with (i) one substituent selected from
C.sub.3-C.sub.4-cycloalkyl- and hydroxymethyl, and/or (ii) one or
two or three C.sub.1-C.sub.2-alkyl- group substituents, identically
or differently; R.sup.1 is C.sub.1-C.sub.4-alkyl- or
C.sub.3-C.sub.5-cycloalkyl-; wherein said group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group consisting of hydroxy, cyano,
halogen, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-,
--NH.sub.2, and --C(.dbd.O)OH; R.sup.2 is hydrogen, fluorine,
chlorine, cyano, methyl-, methoxy-, trifluoromethyl-, or
trifluoromethoxy-; R.sup.3 is hydrogen, fluorine, chlorine, cyano,
methyl-, methoxy-, trifluoromethyl-, or trifluoromethoxy-; R.sup.4
is hydrogen or fluorine; or a salt thereof.
31. The compound of claim 28, wherein; Z is hydrogen or fluorine; L
is C.sub.3-C.sub.5-alkylene; R.sup.1 is C.sub.1-C.sub.4-alkyl
optionally substituted with one or two substituents, identically or
differently, selected from the group consisting of hydroxy,
C.sub.1-C.sub.2-alkoxy-, --NH.sub.2, and --C(.dbd.O)OH; R.sup.2 is
hydrogen or fluorine; R.sup.3 is hydrogen, fluorine, or methoxy;
and R.sup.4 is hydrogen; or a salt thereof.
32. The compound of claim 28, wherein; L is
C.sub.3-C.sub.5-alkylene; or a salt thereof.
33. The compound of claim 28, wherein; Z is hydrogen or fluorine; L
is C.sub.3-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is
hydrogen; R.sup.3 is hydrogen or fluorine; and R.sup.4 is hydrogen;
or a salt thereof.
34. The compound of claim 28, wherein: Z is hydrogen or fluorine; L
is C.sub.3-C.sub.5-alkylene; R.sup.1 is C.sub.1-C.sub.3-alkyl;
R.sup.2 is hydrogen or fluorine; R.sup.3 is hydrogen, fluorine, or
methoxy; and R.sup.4 is hydrogen; or a salt thereof.
35. The compound of claim 28, wherein: Z is hydrogen or fluorine; L
is C.sub.4-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is
hydrogen; R.sup.3 is hydrogen or fluorine; and R.sup.4 is hydrogen;
or a salt thereof.
36. The compound of claim 28, wherein; Z is hydrogen or fluorine,
R.sup.3 is fluorine; and R.sup.4 is hydrogen; or a salt
thereof.
37. The compound of claim 28, wherein: Z is hydrogen or fluorine, L
is C.sub.3-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is
hydrogen; R.sup.3 is fluorine; and R.sup.4 is hydrogen; or a salt
thereof.
38. A compound of general formula (19): ##STR00190## wherein: Z is
hydrogen or fluorine; L is a C.sub.3-C.sub.8-alkylene moiety;
wherein said moiety is optionally substituted with (i) one
substituent selected from hydroxy, --NR.sup.8R.sup.9,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-,
C.sub.3-C.sub.4-cycloalkyl-, hydroxy-C.sub.1-C.sub.3-alkyl, and
--(CH.sub.2)NR.sup.8R.sup.9, and/or (ii) one or two or three or
four substituents, identically or differently, selected from
halogen and C.sub.1-C.sub.3-alkyl-; or wherein one carbon atom of
said C.sub.3-C.sub.8-alkylene moiety forms a three- or
four-membered ring together with a bivalent moiety to which it is
attached, wherein said bivalent moiety is selected from
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2OCH.sub.2--; R.sup.1 is C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-, or
heterocyclyl-; wherein said group is optionally substituted with
one or two or three substituents, identically or differently,
selected from the group consisting of hydroxy, cyano, halogen,
C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.3-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, --OP(.dbd.O)(OH).sub.2, --C(.dbd.O)OH, and
--C(.dbd.O)NH.sub.2; R.sup.2 is hydrogen, fluorine, chlorine,
bromine, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, or C.sub.1-C.sub.3-fluoroalkoxy-;
R.sup.3 and R.sup.4 are independently from each other, a group
selected from hydrogen, fluorine, chlorine, bromine, cyano,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; and
R.sup.8 and R.sup.9 are independently from each other, a group
selected from hydrogen, C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, and
heteroaryl-; wherein said C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- or
heteroaryl-group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-, or
R.sup.8 and R.sup.9, together with the nitrogen atom they are
attached to, form a cyclic amine; or salt thereof.
39. The compound of claim 38, wherein: Z is hydrogen or fluorine; L
is a C.sub.3-C.sub.5-alkylene moiety, wherein said moiety is
optionally substituted with i) one substituent selected from
hydroxy, C.sub.3-C.sub.4-cycloalkyl-, and
hydroxy-C.sub.1-C.sub.3-alkyl-, and --(CH.sub.2)NR.sup.8R.sup.9,
and/or ii) one or two or three substituents, identically or
differently, selected from halogen and C.sub.1-C.sub.3-alkyl-;
R.sup.1 is C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.5-cycloalkyl-;
wherein said group is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group consisting of hydroxy, cyano, halogen,
C.sub.1-C.sub.3-alkyl-, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.3-alkoxy-, C.sub.1-C.sub.2-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, cyclic amines, --OP(.dbd.O)(OH).sub.2,
--C(.dbd.O)OH, and --C(.dbd.O)NH.sub.2; R.sup.2 is hydrogen,
fluorine, chlorine, cyano, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, fluoro-C.sub.1-C.sub.2-alkyl-, or
C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.3 and R.sup.4 are
independently from each other, a group selected from hydrogen,
fluorine, chlorine, cyano, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, fluoro-C.sub.1-C.sub.2-alkyl-, and
C.sub.1-C.sub.2-fluoroalkoxy-; and R.sup.8 and R.sup.9 are
independently from each other, a group selected from hydrogen,
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl-, and
benzyl-; wherein said C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, phenyl- or benzyl- group is optionally
substituted with one, two or three substituents, identically or
differently, selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, cyclic amines,
fluoro-C.sub.1-C.sub.2-alkyl-, and C.sub.1-C.sub.2-fluoroalkoxy-,
or R.sup.8 and R.sup.9, together with the nitrogen atom they are
attached to, form a cyclic amine; or a salt thereof.
40. The compound of claim 38, wherein: Z is hydrogen or fluorine; L
is a C.sub.3-C.sub.5-alkylene moiety, wherein said moiety is
optionally substituted with (i) one substituent selected from
C.sub.3-C.sub.4-cycloalkyl- and hydroxymethyl, and/or (ii) one or
two or three C.sub.1-C.sub.2-alkyl- group substituents, identically
or differently; R.sup.1 is C.sub.1-C.sub.4-alkyl- or
C.sub.3-C.sub.5-cycloalkyl-; wherein said group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group consisting of hydroxy, cyano,
halogen, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-,
--NH.sub.2, and --C(.dbd.O)OH; R.sup.2 is hydrogen, fluorine,
chlorine, cyano, methyl-, methoxy-, trifluoromethyl-, or
trifluoromethoxy-; R.sup.3 is hydrogen, fluorine, chlorine, cyano,
methyl-, methoxy-, trifluoromethyl-, or trifluoromethoxy-; R.sup.4
is hydrogen or fluorine; or a salt thereof.
41. The compound of claim 38, wherein: Z is hydrogen or fluorine; L
is C.sub.3-C.sub.5-alkylene; R.sup.1 is C.sub.1-C.sub.4-alkyl
optionally substituted with one or two substituents, identically or
differently, selected from the group consisting of hydroxy,
C.sub.1-C.sub.2-alkoxy-, --NH.sub.2, and --C(.dbd.O)OH; R.sup.2 is
hydrogen or fluorine; R.sup.3 is hydrogen, fluorine, or methoxy;
and R.sup.4 is hydrogen; or a salt thereof.
42. The compound of claim 38, wherein: L is
C.sub.3-C.sub.5-alkylene; or a salt thereof.
43. The compound of claim 38, wherein: Z is hydrogen or fluorine; L
is C.sub.3-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is
hydrogen; R.sup.3 is hydrogen or fluorine; and R.sup.4 is hydrogen;
or a salt thereof.
44. The compound of claim 38, wherein: Z is hydrogen or fluorine; L
is C.sub.3-C.sub.5-alkylene; R.sup.1 is C.sub.1-C.sub.3-alkyl;
R.sup.2 is hydrogen or fluorine; R.sup.3 is hydrogen, fluorine, or
methoxy; and R.sup.4 is hydrogen; or a salt thereof.
45. The compound of claim 38, wherein: Z is hydrogen or fluorine; L
is C.sub.4-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is
hydrogen; R.sup.3 is hydrogen or fluorine; and R.sup.4 is hydrogen;
or a salt thereof.
46. The compound of claim 38, wherein: Z is hydrogen or fluorine,
R.sup.3 is fluorine; and R.sup.4 is hydrogen; or a salt
thereof.
47. The compound of claim 38, wherein: Z is hydrogen or fluorine, L
is C.sub.3-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is
hydrogen; R.sup.3 is fluorine; and R.sup.4 is hydrogen; or a salt
thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 16/498,662, filed on Sep. 27, 2019, which is a U.S.
National Stage Application under 35 U.S.C. .sctn. 371 of
International Application No. PCT/EP2018/057359, filed
internationally on Mar. 22, 2018, which claims benefit of priority
to European Application No. 17193837.6, filed Sep. 28, 2017 and
European Application No. 17163377.9, filed Mar. 28, 2017, all of
which are incorporated by reference herein in their entireties.
[0002] The present invention relates to novel modified macrocyclic
compounds of general formula (I) as described and defined herein,
and methods for their preparation, their use for the treatment
and/or prophylaxis of disorders, in particular of
hyper-proliferative disorders and/or virally induced infectious
diseases and/or of cardiovascular diseases. The invention further
relates to intermediate compounds useful in the preparation of said
compounds of general formula (I).
[0003] The family of cyclin-dependent kinase (CDK) proteins
consists of members that are key regulators of the cell division
cycle (cell cycle CDK's), that are involved in regulation of gene
transcription (transcriptional CDK's), and of members with other
functions. CDKs require for activation the association with a
regulatory cyclin subunit. The cell cycle CDKs CDK1/cyclin B,
CDK2/cyclin A, CDK2/cyclinE, CDK4/cyclinD, and CDK6/cyclinD get
activated in a sequential order to drive a cell into and through
the cell division cycle. The transcriptional CDKs CDK9/cyclin T and
CDK7/cyclin H regulate the activity of RNApolymerase II via
phosphorylation of the carboxy-terminal domain (CTD). Positive
transcription factor b (PTEFb) is a heterodimer of CDK9 and one of
the cyclin partners cyclin T1, cyclin T2a or T2b.
[0004] Whereas CDK9 (NCBI GenBank Gene ID 1025) is exclusively
involved in transcriptional regulation, CDK7 in addition
participates in cell cycle regulation as CDK-activating kinase
(CAK). Transcription of genes by RNA polymerase II is initiated by
assembly of the pre-initiation complex at the promoter region and
phosphorylation of Ser 5 and Ser 7 of the CTD by CDK7/cyclin H. For
a major fraction of genes RNA polymerase II stops mRNA
transcription after it moved 20-40 nucleotides along the DNA
template. This promoter-proximal pausing of RNA polymerase II is
mediated by negative elongation factors and is recognized as a
major control mechanism to regulate expression of rapidly induced
genes in response to a variety of stimuli (Cho et al., Cell Cycle
9, 1697, 2010). PTEFb is crucially involved in overcoming
promoter-proximal pausing of RNA polymerase II and transition into
a productive elongation state by phosphorylation of Ser 2 of the
CTD as well as by phosphorylation and inactivation of negative
elongation factors (reviewed in Jonkers and John, Nat. Rev. Mol.
Cell Biol. 16, 167, 2015).
[0005] Activity of PTEFb itself is regulated by several mechanisms.
About half of cellular PTEFb exists in an inactive complex with 7SK
small nuclear RNA (7SK snRNA), La-related protein 7 (LARP7/PIP7S)
and hexamethylene bis-acetamide inducible proteins 1/2 (HEXIM1/2,
He et al., Mol Cell 29, 588, 2008). The remaining half of PTEFb
exists in an active complex containing the bromodomain protein Brd4
(Yang et al., Mol Cell 19, 535, 2005). Brd4 recruits PTEFb through
interaction with acetylated histones to chromatin areas primed for
gene transcription. Through alternately interacting with its
positive and negative regulators, PTEFb is maintained in a
functional equilibrium: PTEFb bound to the 7SK snRNA complex
represents a reservoir from which active PTEFb can be released on
demand of cellular transcription and cell proliferation (Zhou &
Yik, Microbiol Mol Biol Rev 70, 646, 2006). Furthermore, the
activity of PTEFb is regulated by posttranslational modifications
including phosphorylation/de-phosphorylation, ubiquitination, and
acetylation (reviewed in Cho et al., Cell Cycle 9, 1697, 2010).
[0006] Deregulated activity of CDK9 kinase activity of the PTEFb
heterodimer is associated with a variety of human pathological
settings such as hyper-proliferative diseases (e.g. cancer),
virally induced infectious diseases or cardiovascular diseases:
[0007] Cancer is regarded as a hyper-proliferative disorder
mediated by a disbalance of proliferation and cell death
(apoptosis). High levels of anti-apoptotic Bcl-2-family proteins
are found in various human tumors and account for prolonged
survival of tumor cells and therapy resistance. Inhibition of PTEFb
kinase activity was shown to reduce transcriptional activity of RNA
polymerase II leading to a decline of short-lived anti-apoptotic
proteins, especially Mcl-1 and XIAP, reinstalling the ability of
tumor cells to undergo apoptosis. A number of other proteins
associated with the transformed tumor phenotype (such as Myc, NF-kB
responsive gene transcripts, mitotic kinases) are either
short-lived proteins or are encoded by short-lived transcripts
which are sensitive to reduced RNA polymerase II activity mediated
by PTEFb inhibition (reviewed in Wang & Fischer, Trends
Pharmacol Sci 29, 302, 2008).
[0008] Many viruses rely on the transcriptional machinery of the
host cell for the transcription of their own genome. In case of
HIV-1, RNA polymerase II gets recruited to the promoter region
within the viral LTR's. The viral transcription activator (Tat)
protein binds to nascent viral transcripts and overcomes
promoter-proximal RNA polymerase II pausing by recruitment of PTEFb
which in turn promotes transcriptional elongation. Furthermore, the
Tat protein increases the fraction of active PTEFb by replacement
of the PTEFb inhibitory proteins HEXIM1/2 within the 7SK snRNA
complex. Recent data have shown that inhibition of the kinase
activity of PTEFb is sufficient to block HIV-1 replication at
kinase inhibitor concentrations that are not cytotoxic to the host
cells (reviewed in Wang & Fischer, Trends Pharmacol Sci 29,
302, 2008). Similarly, recruitment of PTEFb by viral proteins has
been reported for other viruses such as B-cell cancer-associated
Epstein-Barr virus, where the nuclear antigen EBNA2 protein
interacts with PTEFb (Bark-Jones et al., Oncogene, 25, 1775, 2006),
and the human T-lymphotropic virus type 1 (HTLV-1), where the
transcriptional activator Tax recruits PTEFb (Zhou et al., J Virol.
80, 4781, 2006).
[0009] Cardiac hypertrophy, the heart's adaptive response to
mechanical overload and pressure (hemodynamic stress e.g.
hypertension, myocardial infarction), can lead, on a long term, to
heart failure and death. Cardiac hypertrophy was shown to be
associated with increased transcriptional activity and RNA
polymerase II CTD phosphorylation in cardiac muscle cells. PTEFb
was found to be activated by dissociation from the inactive 7SK
snRNA/HEXIM1/2 complex. These findings suggest pharmacological
inhibition of PTEFb kinase activity as a therapeutic approach to
treat cardiac hypertrophy (reviewed in Dey et al., Cell Cycle 6,
1856, 2007).
[0010] In summary, multiple lines of evidence suggest that
selective inhibition of the CDK9 kinase activity of the PTEFb
heterodimer (=CDK9 and one of the cyclin partners cyclin T1, cyclin
T2a or T2b) represents an innovative approach for the treatment of
diseases such as cancer, viral diseases, and/or diseases of the
heart. CDK9 belongs to a family of at least 13 closely related
kinases of which the subgroup of the cell cycle CDK's fulfills
multiple roles in regulation of cell proliferation. Thus,
co-inhibition of cell cycle CDKs (e.g. CDK1/cyclin B, CDK2/cyclin
A, CDK2/cyclinE, CDK4/cyclinD, CDK6/cyclinD) and of CDK9, is
expected to impact normal proliferating tissues such as intestinal
mucosa, lymphatic and hematopoietic organs, and reproductive
organs. To maximize the therapeutic value of CDK9 kinase
inhibitors, molecules with improved duration of action and/or high
potency and efficacy and/or selectivity towards CDK9 are
required.
[0011] CDK inhibitors in general as well as CDK9 inhibitors are
described in a number of different publications: WO2008129070 and
WO2008129071 both describe 2,4 disubstituted aminopyrimidines as
CDK inhibitors in general. It is also asserted that some of these
compounds may act as selective CDK9 inhibitors (WO2008129070) and
as CDK5 inhibitors (WO2008129071), respectively, but no specific
CDK9 IC.sub.50 (WO2008129070) or CDK5 IC.sub.50 (WO2008129071) data
are presented. These compounds do not contain a fluorine atom in
5-position of the pyrimidine core.
[0012] WO2008129080 discloses 4,6 disubstituted aminopyrimidines
and demonstrates that these compounds show an inhibitory effect on
the protein kinase activity of various protein kinases, such as
CDK1, CDK2, CDK4, CDK5, CDK6 and CDK9, with a preference for CDK9
inhibition (example 80).
[0013] WO2005026129 discloses 4,6 disubstituted aminopyrimidines
and demonstrates that these compounds show an inhibitory effect on
the protein kinase activity of various protein kinases, in
particular CDK2, CDK4, and CDK9.
[0014] WO2009118567 discloses pyrimidine and [1,3,5]triazine
derivatives as protein kinase inhibitors, in particular CDK2, CDK7
and CDK9.
[0015] WO2011116951 discloses substituted triazine derivatives as
selective CDK9 inhibitors.
[0016] WO2012117048 discloses disubstituted triazine derivatives as
selective CDK9 inhibitors.
[0017] WO2012117059 discloses disubstituted pyridine derivatives as
selective CDK9 inhibitors.
[0018] WO2012143399 discloses substituted
4-aryl-N-phenyl-1,3,5-triazin-2-amines as selective CDK9
inhibitors.
[0019] EP1218360 B1, which corresponds to US2004116388A1, U.S. Pat.
No. 7,074,789B2 and WO2001025220A1, describes triazine derivatives
as kinase inhibitors, but does not disclose potent or selective
CDK9 inhibitors.
[0020] WO2008079933 discloses aminopyridine and aminopyrimidine
derivatives and their use as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6,
CDK7, CDK8 or CDK9 inhibitors.
[0021] WO2011012661 describes aminopyridine derivatives useful as
CDK inhibitors.
[0022] WO2011026917 discloses carboxamides derived from substituted
4-phenylpyridine-2-amines as inhibitors of CDK9.
[0023] WO2012066065 discloses phenyl-heteroaryl amines as
inhibitors of CDK9. A selectivity towards CDK9 over other CDK
isoforms is preferred, however disclosure of CDK-inhibition data is
confined to CDK 9. No bicyclic ring systems are disclosed attached
to the C4 position of the pyrimidine core. Within the group
attached to C4 of the pyrimidine core, alkoxy phenyls can be
regarded as encompassed, but there is no suggestion for a specific
substitution pattern characterised by a fluorine atom attached to
C5 of the pyrimidine ring, and an aniline at C2 of the pyrimidine,
featuring a substituted sulfonyl-methylene group in meta position.
Compounds shown in the examples typically feature a substituted
cycloalkyl group as R.sup.1 but no phenyl.
[0024] WO2012066070 discloses 3-(aminoaryl)-pyridine compounds as
inhibitors of CDK9. The biaryl core mandatorily consists of two
heteroaromatic rings.
[0025] WO2012101062 discloses substituted bi-heteroaryl compounds
featuring a 2-aminopyridine core as inhibitors of CDK9. The biaryl
core mandatorily consists of two heteroaromatic rings.
[0026] WO2012101063 discloses carboxamides derived from substituted
4-(heteroaryl)-pyridine-2-amines as inhibitors of CDK9.
[0027] WO2012101064 discloses N-acyl pyrimidine biaryl compounds as
inhibitors of CDK9.
[0028] WO2012101065 discloses pyrimidine biaryl compounds as
inhibitors of CDK9. The biaryl core mandatorily consists of two
heteroaromatic rings.
[0029] WO2012101066 discloses pyrimidine biaryl compounds as
inhibitors of CDK9. Substitution R.sup.1 of the amino group
attached to the heteroaromatic core is confined to non-aromatic
groups but does not cover substituted phenyls. Furthermore, the
biaryl core mandatorily consists of two heteroaromatic rings.
[0030] WO2011077171 discloses 4,6-disubstituted aminopyrimidine
derivatives as inhibitors of CDK9.
[0031] WO2014031937 discloses 4,6-disubstituted aminopyrimidine
derivatives as inhibitors of CDK9.
[0032] WO2013037896 discloses disubstituted 5-fluoropyrimidines as
selective inhibitors of CDK9.
[0033] WO2013037894 discloses disubstituted 5-fluoropyrimidine
derivatives containing a sulfoximine group as selective inhibitors
of CDK9.
[0034] Wang et al. (Chemistry & Biology 17, 1111-1121, 2010)
describe 2-anilino-4-(thiazol-5-yl)pyrimidine transcriptional CDK
inhibitors, which show anticancer activity in animal models.
[0035] WO2014060376 discloses substituted
4-(ortho)-fluorophenyl-5-fluoropyrimidin-2-yl amine derivatives
containing a sulfone group as selective inhibitors of CDK9.
[0036] WO2014060375 discloses substituted
5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a
sulfone group as selective inhibitors of CDK9.
[0037] WO2014060493 discloses substituted
N-(pyridin-2-yl)pyrimidin-4-amine derivatives containing a sulfone
group as selective inhibitors of CDK9.
[0038] WO2014076028 discloses substituted
4-(ortho)-fluorophenyl-5-fluoropyrimidin-2-yl amine derivatives
containing a sulfoximine group as selective inhibitors of CDK9.
[0039] WO2014076091 discloses substituted
5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a
sulfoximine group as selective inhibitors of CDK9.
[0040] WO2014076111 discloses substituted
N-(pyridin-2-yl)pyrimidin-4-amine derivatives containing a
sulfoximine group as selective inhibitors of CDK9.
[0041] WO2015001021 discloses
5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a
sulfoximine group as selective inhibitors of CDK9.
[0042] WO 2015136028 discloses
5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a
sulfone group as selective inhibitors of CDK9.
[0043] WO2004009562 discloses substituted triazine kinase
inhibitors. For selected compounds CDK1 and CDK4 test data, but no
CDK9 data is presented.
[0044] WO2004072063 describes heteroaryl (pyrimidine, triazine)
substituted pyrroles as inhibitors of protein kinases such as ERK2,
GSK3, PKA or CDK2.
[0045] WO2010009155 discloses triazine and pyrimidine derivatives
as inhibitors of histone deacetylase and/or cyclin dependent
kinases (CDKs). For selected compounds CDK2 test data is
described.
[0046] WO2003037346 (corresponding to U.S. Pat. No. 7,618,968B2,
U.S. Pat. No. 7,291,616B2, US2008064700A1, US2003153570A1) relates
to aryl triazines and uses thereof, including to inhibit
lysophosphatidic acid acyltransferase beta (LPAAT-beta) activity
and/or proliferation of cells such as tumor cells.
[0047] WO2005037800 discloses sulfoximine substituted
anilino-pyrimidines as inhibitors of VEGFR and CDK kinases, in
particular VEGFR2, CDK1 and CDK2, having no aromatic ring directly
bonded to the pyrimidine ring and having the sulfoximine group
directly bonded to the aniline group. No CDK9 data are
disclosed.
[0048] WO2008025556 describes carbamoyl sulfoximides having a
pyrimidine core, which are useful as kinase inhibitors. No CDK9
data is presented. No molecules are exemplified, which possess a
fluoropyrimidine core.
[0049] WO2002066481 describes pyrimidine derivatives as cyclin
dependent kinase inhibitors. CDK9 is not mentioned and no CDK9 data
is presented.
[0050] WO2008109943 concerns phenyl aminopyri(mi)dine compounds and
their use as kinase inhibitors, in particular as JAK2 kinase
inhibitors. The specific examples mainly focus on compounds having
a pyrimidine core.
[0051] WO2009032861 describes substituted pyrimidinyl amines as JNK
kinase inhibitors. The specific examples mainly focus on compounds
having a pyrimidine core.
[0052] WO2011046970 concerns amino-pyrimidine compounds as
inhibitors of TBK1 and/or IKK epsilon. The specific examples mainly
focus on compounds having a pyrimidine core.
[0053] WO2012142329 concerns amino-pyrimidine compounds as
inhibitors of TBK1 and/or IKK epsilon.
[0054] WO2012139499 discloses urea substituted anilino-pyrimidines
as inhibitors of various protein kinases.
[0055] WO2014106762 discloses 4-pyrimidinylamino-benzenesulfonamide
derivatives as inhibitors of polo-like kinase-1.
[0056] Macrocyclic compounds have been described as therapeutically
useful substances, in particular of various protein kinases
including cyclin dependent kinases. However, the documents listed
below do not disclose specific compounds as inhibitors of CDK9.
[0057] WO2007147574 discloses sulfonamido-macrocycles as inhibitors
of Tie2 showing selectivity over CDK2 and Aurora kinase C, inter
alia for the treatment of diseases accompanied with dysregulated
vascular growth.
[0058] WO2007147575 discloses further sulfonamido-macrocycles as
inhibitors of Tie2 and KDR showing selectivity over CDK2 and Plk1,
inter alia for the treatment of diseases accompanied with
dysregulated vascular growth.
[0059] WO2006066957/EP1674470 discloses further
sulfonamido-macrocycles as inhibitors of Tie2 showing low
cytotoxicity, inter alia for the treatment of diseases accompanied
with dysregulated vascular growth.
[0060] WO2006066956/EP1674469 discloses further
sulfonamido-macrocycles as inhibitors of Tie2 showing low
cytotoxicity, inter alia for the treatment of diseases accompanied
with dysregulated vascular growth.
[0061] WO2004026881/DE10239042 discloses macrocyclic pyrimidine
derivatives as inhibitors of cyclin dependent kinases, in
particular CDK1 and CDK2, as well as VEGF-R, inter alia for the
treatment of cancer. The compounds of the present invention differ
from those disclosed in WO2004026881 in featuring a mandatory
biaromatic portion within the macrocyclic ring system. Furthermore,
none of the example compounds disclosed in WO2004026881 features a
group --CH.sub.2-A-R.sup.1, in which A and R.sup.1 are as defined
for the compounds of the formula (I) of the present invention,
attached to one of the two aromatic portions of the macrocyclic
ring system.
[0062] WO2007079982/EP1803723 discloses macrocyclic
benzenacyclononaphanes as inhibtors of multiple protein kinases,
e.g. Aurora kinases A and C, CDK1, CDK2 and c-Kit, inter alia for
the treatment of cancer. The compounds of the present invention
differ from those disclosed in WO 2007079982 in featuring a
mandatory biaromatic portion within the macrocyclic ring system.
Furthermore, the compounds of the present invention do not feature
a group --S(.dbd.O)(N.dbd.R.sup.2)R.sup.1 directly attached to the
phenylene portion of the macrocyclic ring system as disclosed in WO
2007079982.
[0063] WO2006106895/EP1710246 discloses sulfoximine-macrocycle
compounds as inhibitors of Tie2 showing low cytotoxicity, inter
alia for the treatment of diseases accompanied with dysregulated
vascular growth.
[0064] WO2012009309 discloses macrocyclic compounds fused to
benzene and pyridine rings for the reduction of beta-amyloid
production.
[0065] WO2009132202 discloses macrocyclic compounds as inhibitors
of JAK 1, 2 and 3, TYK2 and ALK and their use in the treatment of
JAK/ALK-associated diseases, including inflammatory and autoimmune
disease as well as cancer.
[0066] WO2004078682/U.S. Pat. No. 7,151,096 discloses a class of
cyclic compounds for treating or preventing diseases and disorders
associated with cyclin-dependent kinases (CDKs) activity,
particularly diseases associated with the activity of CDK2 and
CDK5.
[0067] WO2015155197 discloses macrocyclic compounds as selective
inhibitors of CDK9 for the treatment and/or prophylaxis of
disorders, in particular of hyper-proliferative disorders and/or
virally induced infectious diseases and/or of cardiovascular
diseases. The compounds of the present invention differ from those
in WO2015155197 by the point of attachment of bridging
alkylenedioxy moiety.
[0068] WO2015150555 and WO2015150557 disclose substituted
macrocylic compounds having EF2K inhibitory activity and optionally
also Vps34 inhibitory activity. The compounds of the present
invention differ from those in WO2015150555 and WO2015150557 i.a.
by the point of attachment of the bridging moiety.
[0069] WO2008140420 discloses macrocylic compounds that may be
useful as agents targeting kinase related disorders. The compounds
of the present invention differ from those in WO2008140420 i.a. by
the structure of the bridging moiety.
[0070] ChemMedChem 2007, 2(1), 63-77 describes macrocyclic
aminopyrimidines as multitarget CDK and VEGF-R inhibitors with
potent antiproliferative activity. The compounds of the present
invention differ from those disclosed in said journal publication
in featuring a mandatory biaromatic portion within the macrocyclic
ring system. Furthermore, none of the compounds disclosed in
ChemMedChem 2007, 2(1), 63-77 features a group --CH.sub.2-A-R.sup.1
in which A and R.sup.1 are as defined for the compounds of the
formula (I) or the present invention, attached to one of the two
aromatic portions of the macrocyclic ring system.
[0071] Despite the fact that various inhibitors of CDKs are known,
there remains a need for selective CDK9 inhibitors, especially CDK9
inhibitors which are selective at high ATP concentrations, to be
used for the treatment of diseases such as hyper-proliferative
diseases, viral diseases, and/or diseases of the heart, which offer
one or more advantages over the compounds known from prior art,
such as: [0072] improved activity and/or efficacy, allowing e.g. a
dose reduction [0073] improved side effect profile, such as fewer
undesired side effects, lower intensity of side effects, or reduced
(cyto)toxicity [0074] improved duration of action, e.g. by improved
pharmacokinetics and/or improved target residence time [0075]
Specifically modified PK profile to reduce unwanted side
effects
[0076] A particular object of the invention is to provide selective
CDK9 kinase inhibitors, which show a high anti-proliferative
activity in tumor cell lines, such as HeLa, HeLa-MaTu-ADR,
NCI-H460, DU145, Caco-2, B16F10, A2780 or MOLM-13, compared to
compounds known from prior art.
[0077] Another particular object of the invention is to provide
selective CDK9 kinase inhibitors which show an increased potency to
inhibit CDK9 activity at high ATP concentrations compared to
compounds known from prior art.
[0078] Another particular object of the invention is to provide
selective CDK9 kinase inhibitors which show an increased target
residence time compared to compounds known from prior art.
[0079] Another particular object of the invention is to provide
selective CDK9 kinase inhibitors which show an improved duration of
action, e.g. by improved pharmacokinetics and/or improved target
residence time.
[0080] Further, it is an object of the present invention to provide
selective CDK9 kinase inhibitors, which, compared to the compounds
known from prior art, show a high anti-proliferative activity in
tumor cell lines, such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145,
Caco-2, B16F10, A2780 or MOLM-13, and/or which show an increased
potency to inhibit CDK9 activity (demonstrated by a lower IC.sub.50
value for CDK9/Cyclin T1), especially an increased potency to
inhibit CDK9 activity at high ATP concentrations, and/or which show
an increased target residence time compared to the compounds known
from prior art.
[0081] Another particular object of the invention is to provide
selective CDK9 kinase inhibitors which show an improved therapeutic
window.
[0082] A further object of the invention is to provide CDK9 kinase
inhibitors simultaneously featuring selectivity for CDK9/Cyclin T1
over CDK2/Cyclin E, especially at high ATP concentrations.
[0083] The present invention relates to compounds of general
formula (I)
##STR00001##
wherein [0084] A represents a bivalent moiety selected from the
group consisting of --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--,
--S(.dbd.O)(.dbd.NR.sup.5)--; --S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--;
[0085] Z represents a hydrogen atom or a fluorine atom; [0086] L
represents a C.sub.3-C.sub.8-alkylene moiety, [0087] wherein said
moiety is optionally substituted with [0088] (i) one substituent
selected from hydroxy, --NR.sup.8R.sup.9, C.sub.2-C.sub.3-alkenyl-,
C.sub.2-C.sub.3-alkynyl-, C.sub.3-C.sub.4-cycloalkyl-,
hydroxy-C.sub.1-C.sub.3-alkyl, --(CH.sub.2)NR.sup.8R.sup.9, and/or
[0089] (ii) one or two or three or four substituents, identically
or differently, selected from halogen and C.sub.1-C.sub.3-alkyl-,
[0090] or wherein [0091] one carbon atom of said
C.sub.3-C.sub.8-alkylene moiety forms a three- or four-membered
ring together with a bivalent moiety to which it is attached,
wherein said bivalent moiety is selected from --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2OCH.sub.2--; [0092] X, Y
represent CH or N with the proviso that one of X and Y represents
CH and one of X and Y represents N; [0093] R.sup.1 represents a
group selected from C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-,
heterocyclyl-, wherein said group is optionally substituted with
one or two or three substituents, identically or differently,
selected from the group consisting of hydroxy, cyano, halogen,
C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.3-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, --OP(.dbd.O)(OH).sub.2, --C(.dbd.O)OH,
--C(.dbd.O)NH.sub.2; [0094] R.sup.2 represents a group selected
from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine
atom, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0095]
R.sup.3, R.sup.4 represent, independently from each other, a group
selected from a hydrogen atom, a fluorine atom, a chlorine atom, a
bromine atom, cyano, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-; [0096] R.sup.5 represents a group
selected from a hydrogen atom, cyano, --C(.dbd.O)R.sup.10,
--C(.dbd.O)OR.sup.10, --S(.dbd.O.sub.2) R.sup.10,
--C(.dbd.O)NR.sup.8R.sup.9, C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, [0097] wherein said
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-
group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0098]
R.sup.6, R.sup.7 represents, independently from each other, a group
selected from a hydrogen atom, cyano, --C(.dbd.O)R.sup.10,
--C(.dbd.O)OR.sup.10, --S(.dbd.O).sub.2R.sup.10,
--C(.dbd.O)NR.sup.8R.sup.9, C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, [0099] wherein said
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-
group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0100]
R.sup.8, R.sup.9 represent, independently from each other, a group
selected from a hydrogen atom, C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- and
heteroaryl-, [0101] wherein said C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- or
heteroaryl- group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-, or
[0102] R.sup.8 and R.sup.9, together with the nitrogen atom they
are attached to, form a cyclic amine; [0103] R.sup.10 represents a
group selected from C.sub.1-C.sub.6-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.3-C.sub.7-cycloalkyl-,
heterocyclyl-, phenyl-, benzyl- and heteroaryl-, [0104] wherein
said group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-, or the
enantiomers, diastereomers, salts, solvates or salts of solvates
thereof.
[0105] Compounds according to the invention are the compounds of
the formula (I) and the salts, solvates and solvates of the salts
thereof, the compounds of the hereinafter recited formula which are
encompassed by formula (I) and the salts, solvates and solvates of
the salts thereof, and the compounds which are encompassed by
formula (I) and are mentioned hereinafter as exemplary embodiments
and the salts, solvates and solvates of the salts thereof, where
the compounds which are encompassed by formula (I) and are
mentioned hereinafter are not already salts, solvates and solvates
of the salts.
[0106] The compounds according to the invention may, depending on
their structure, exist in stereoisomeric forms (enantiomers,
diastereomers). The invention therefore relates to the enantiomers
or diastereomers and respective mixtures thereof. The
stereoisomerically pure constituents can be isolated in a known
manner from such mixtures of enantiomers and/or diastereomers.
[0107] If the compounds according to the invention can be in
tautomeric forms, the present invention encompasses all tautomeric
forms.
[0108] Further, the compounds of the present invention can exist in
free form, e.g. as a free base, or as a free acid, or as a
zwitterion, or can exist in the form of a salt. Said salt may be
any salt, either an organic or inorganic addition salt,
particularly any physiologically acceptable organic or inorganic
addition salt, customarily used in pharmacy.
[0109] Salts which are preferred for the purposes of the present
invention are physiologically acceptable salts of the compounds
according to the invention. However, salts which are not suitable
for pharmaceutical applications per se, but which, for example, can
be used for the isolation or purification of the compounds
according to the invention, are also comprised.
[0110] The term "physiologically acceptable salt" refers to a
relatively non-toxic, inorganic or organic acid addition salt of a
compound of the present invention, for example, see S. M. Berge, et
al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.
[0111] Physiologically acceptable salts of the compounds according
to the invention encompass acid addition salts of mineral acids,
carboxylic acids and sulfonic acids, for example salts of
hydrochloric acid, hydrobromic acid, hydroiodic, sulfuric acid,
bisulfuric acid, phosphoric acid, nitric acid or with an organic
acid, such as formic, acetic, acetoacetic, pyruvic,
trifluoroacetic, propionic, butyric, hexanoic, heptanoic,
undecanoic, lauric, benzoic, salicylic,
2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,
cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic,
nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic,
picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic,
trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic,
benzenesulfonic, para-toluenesulfonic, methansulfonic,
2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid,
citric, tartaric, stearic, lactic, oxalic, malonic, succinic,
malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic,
ascorbic, glucoheptanoic, glycerophosphoric, aspartic,
sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.
[0112] Physiologically acceptable salts of the compounds according
to the invention also comprise salts of conventional bases, such
as, by way of example and by preference, alkali metal salts (for
example sodium and potassium salts), alkaline earth metal salts
(for example calcium and magnesium salts) and ammonium salts
derived from ammonia or organic amines with 1 to 16 C atoms, such
as, by way of example and by preference, ethylamine, diethylamine,
triethylamine, ethyldiisopropylamine, monoethanolamine,
diethanolamine, triethanolamine, dicyclohexylamine,
dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,
arginine, lysine, ethylenediamine, N-methylpiperidine,
N-methylglucamine, dimethylglucamine, ethylglucamine,
1,6-hexadiamine, glucosamine, sarcosine, serinol,
tris(hydroxymethyl)aminomethane, aminopropanediol, Sovak base, and
1-amino-2,3,4-butanetriol. Additionally, the compounds according to
the invention may form salts with a quarternary ammonium ion
obtainable e.g. by quarternisation of a basic nitrogen containing
group with agents such as lower alkylhalides such as methyl-,
ethyl-, propyl-, and butylchlorides, -bromides and -iodides;
dialkylsulfates such as dimethyl-, diethyl-, dibutyl- and
diamylsulfates, long chain halides such as decyl-, lauryl-,
myristyl- and stearylchlorides, -bromides and -iodides,
aralkylhalides such as benzyl- and phenethylbromides and others.
Examples of suitable quarternary ammonium ions are
tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium,
tetra (n-butyl)ammonium, or N-benzyl-N,N,N-trimethylammonium.
[0113] The present invention includes all possible salts of the
compounds of the present invention as single salts, or as any
mixture of said salts, in any ratio.
[0114] Solvates is the term used for the purposes of the invention
for those forms of the compounds according to the invention which
form a complex with solvent molecules by coordination in the solid
or liquid state. Hydrates are a special form of solvates in which
the coordination takes place with water. Hydrates are preferred as
solvates within the scope of the present invention.
[0115] The invention also includes all suitable isotopic variations
of a compound of the invention. An isotopic variation of a compound
of the invention is defined as one in which at least one atom is
replaced by an atom having the same atomic number but an atomic
mass different from the atomic mass usually or predominantly found
in nature. Examples of isotopes that can be incorporated into a
compound of the invention include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine
and iodine, such as .sup.2H (deuterium), .sup.3H (tritium),
.sup.13C, .sup.14C, .sup.15N, .sup.17O, .sup.18O, .sup.32P,
.sup.33P, .sup.33S, .sup.34S, .sup.35S, .sup.36S, .sup.18F,
.sup.36Cl, .sup.82Br, .sup.123I, .sup.124I, .sup.129I and
.sup.131I, respectively. Certain isotopic variations of a compound
of the invention, for example, those in which one or more
radioactive isotopes such as .sup.3H or .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution studies.
Tritiated and carbon-14, i.e., .sup.14C, isotopes are particularly
preferred for their ease of preparation and detectability. Further,
substitution with isotopes such as deuterium may afford certain
therapeutic advantages resulting from greater metabolic stability,
for example, increased in vivo half-life or reduced dosage
requirements and hence may be preferred in some circumstances.
Isotopic variations of a compound of the invention can generally be
prepared by conventional procedures known by a person skilled in
the art such as by the illustrative methods or by the preparations
described in the examples hereafter using appropriate isotopic
variations of suitable reagents.
[0116] In addition, the present invention also encompasses prodrugs
of the compounds according to the invention. The term "prodrugs"
encompasses compounds which themselves may be biologically active
or inactive, but are converted (for example by metabolism or
hydrolysis) to compounds according to the invention during their
residence time in the body.
[0117] Furthermore, the present invention includes all possible
crystalline forms, or polymorphs, of the compounds of the present
invention, either as single polymorphs, or as a mixture of more
than one polymorphs, in any ratio.
[0118] Accordingly, the present invention includes all possible
salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g.:
esters) thereof, and diastereoisomeric forms of the compounds of
the present invention as single salt, polymorph, metabolite,
hydrate, solvate, prodrug (e.g.: esters) thereof, or
diastereoisomeric form, or as mixture of more than one salt,
polymorph, metabolite, hydrate, solvate, prodrug (e.g.: esters)
thereof, or diastereoisomeric form in any ratio.
[0119] For the purposes of the present invention, the substituents
have the following meaning, unless otherwise specified:
[0120] The term "halogen", "halogen atom" or "halo" represents
fluorine, chlorine, bromine and iodine, particularly bromine,
chlorine or fluorine, preferably chlorine or fluorine, more
preferably fluorine.
[0121] The term "alkyl-" represents a linear or branched alkyl-
group having the number of carbon atoms specifically indicated,
e.g. C.sub.1-C.sub.10 one, two, three, four, five, six, seven,
eight, nine or ten carbon atoms, e.g. methyl-, ethyl-, n-propyl-,
isopropyl-, n-butyl-, isobutyl-, sec-butyl-, tert-butyl-, pentyl-,
isopentyl-, hexyl-, heptyl-, octyl-, nonyl-, decyl-,
2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-,
1,2-dimethylpropyl-, neo-pentyl-, 1,1-dimethylpropyl-,
4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-,
2-ethylbutyl-, 1-ethylbutyl-, 3,3-dimethylbutyl-,
2,2-dimethylbutyl-, 1,1-dimethylbutyl-, 2,3-dimethylbutyl-,
1,3-dimethylbutyl-, or 1,2-dimethylbutyl-. If the number of carbon
atoms is not specifically indicated, the term "alkyl-" represents a
linear or branched alkyl- group having, as a rule, 1 to 9,
particularly 1 to 6, preferably 1 to 4 carbon atoms. Particularly,
the alkyl- group has 1, 2, 3, 4, 5 or 6 carbon atoms
("C.sub.1-C.sub.6-alkyl-"), e.g. methyl-, ethyl-, n-propyl-,
isopropyl-, n-butyl-, tert-butyl-, pentyl-, isopentyl-, hexyl-,
2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-,
1,2-dimethylpropyl-, neo-pentyl-, 1,1-dimethylpropyl-,
4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-,
2-ethylbutyl-, 1-ethylbutyl-, 3,3-dimethylbutyl-,
2,2-dimethylbutyl-, 1,1-dimethylbutyl-, 2,3-dimethylbutyl-,
1,3-dimethylbutyl-, or 1,2-dimethylbutyl-. Preferably, the
alkyl-group has 1, 2 or 3 carbon atoms ("C.sub.1-C.sub.3-alkyl"),
methyl-, ethyl-, n-propyl- or isopropyl-.
[0122] The term "C.sub.3-C.sub.8-alkylene" is to be understood as
preferably meaning a linear, bivalent and saturated hydrocarbon
moiety having 3 to 8, particularly 3, 4 or 5 carbon atoms, as in
"C.sub.3-C.sub.5-alkylene", more particularly 4 or 5 carbon atoms,
as in "C.sub.4-C.sub.5-alkylene" e.g. ethylene, n-propylene,
n-butylene, n-pentylene, or n-hexylene, preferably n-propylene or
n-butylene.
[0123] The term "C.sub.2-C.sub.6-alkenyl-" is to be understood as
preferably meaning a linear or branched, monovalent hydrocarbon
group, which contains one double bond, and which has 2, 3, 4, 5 or
6 carbon atoms ("C.sub.2-C.sub.6-alkenyl-"). Particularly, said
alkenyl group is a C.sub.2-C.sub.3-alkenyl-,
C.sub.3-C.sub.6-alkenyl- or C.sub.3-C.sub.4-alkenyl-group. Said
alkenyl- group is, for example, a vinyl-, allyl-,
(E)-2-methylvinyl-, (Z)-2-methylvinyl- or isopropenyl- group.
[0124] The term "C.sub.2-C.sub.6-alkynyl-" is to be understood as
preferably meaning a linear or branched, monovalent hydrocarbon
group which contains one triple bond, and which contains 2, 3, 4, 5
or 6 carbon atoms.
[0125] Particularly, said alkynyl- group is a
C.sub.2-C.sub.3-alkynyl-, C.sub.3-C.sub.6-alkynyl- or
C.sub.3-C.sub.4-alkynyl- group. Said C.sub.2-C.sub.3-alkynyl- group
is, for example, an ethynyl-, prop-1-ynyl- or prop-2-ynyl-
group.
[0126] The term "C.sub.3-C.sub.7-cycloalkyl-" is to be understood
as preferably meaning a saturated or partially unsaturated,
monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6
or 7 carbon atoms. Said C.sub.3-C.sub.7-cycloalkyl- group is for
example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl-,
cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- group. Said
cycloalkyl- ring is non-aromatic but can optionally contain one or
more double bonds e.g. cycloalkenyl-, such as a cyclopropenyl-,
cyclobutenyl-, cyclopentenyl-, cyclohexenyl- or cycloheptenyl-
group, wherein the bond between said ring with the rest of the
molecule may be to any carbon atom of said ring, be it saturated or
unsaturated. Particularly, said cycloalkyl- group is a
C.sub.4-C.sub.6-cycloalkyl-, a C.sub.5-C.sub.6-cycloalkyl- or a
cyclohexyl- group.
[0127] The term "C.sub.3-C.sub.5-cycloalkyl-" is to be understood
as preferably meaning a saturated, monovalent, monocyclic
hydrocarbon ring which contains 3, 4 or 5 carbon atoms. In
particular said C.sub.3-C.sub.5-cycloalkyl-group is a monocyclic
hydrocarbon ring such as a cyclopropyl-, cyclobutyl- or
cyclopentyl- group. Preferably said "C.sub.3-C.sub.5-cycloalkyl-"
group is a cyclopropyl- group.
[0128] The term "C.sub.3-C.sub.4-cycloalkyl-" is to be understood
as preferably meaning a saturated, monovalent, monocyclic
hydrocarbon ring which contains 3 or 4 carbon atoms. In particular,
said C.sub.3-C.sub.4-cycloalkyl- group is a monocyclic hydrocarbon
ring such as a cyclopropyl- or cyclobutyl- group.
[0129] The term "heterocyclyl-" is to be understood as meaning a
saturated or partially unsaturated, monovalent, mono- or bicyclic
hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms
and further containing 1, 2 or 3 heteroatom-containing groups
selected from oxygen, sulfur, nitrogen. Particularly, the term
"heterocyclyl-" is to be understood as meaning a "4- to 10-membered
heterocyclic ring".
[0130] The term "a 4- to 10-membered heterocyclic ring" is to be
understood as meaning a saturated or partially unsaturated,
monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4,
5, 6, 7, 8 or 9 carbon atoms, and further containing 1, 2 or 3
heteroatom-containing groups selected from oxygen, sulfur,
nitrogen.
[0131] A C.sub.3-C.sub.9-heterocyclyl- is to be understood as
meaning a heterocyclyl- which contains at least 3, 4, 5, 6, 7, 8 or
9 carbon atoms and additionally at least one heteroatom as ring
atoms. Accordingly in case of one heteroatom the ring is 4- to
10-membered, in case of two heteroatoms the ring is 5- to
11-membered and in case of three heteroatoms the ring is 6- to
12-membered.
[0132] Said heterocyclic ring is for example, a monocyclic
heterocyclic ring such as an oxetanyl-, azetidinyl-,
tetrahydrofuranyl-, pyrrolidinyl-, 1,3-dioxolanyl-,
imidazolidinyl-, pyrazolidinyl-, oxazolidinyl-, isoxazolidinyl-,
1,4-dioxanyl-, pyrrolinyl-, tetrahydropyranyl-, piperidinyl-,
morpholinyl-, 1,3-dithianyl-, thiomorpholinyl-, piperazinyl-, or
chinuclidinyl- group. Optionally, said heterocyclic ring can
contain one or more double bonds, e.g. 4H-pyranyl-, 2H-pyranyl-,
2,5-dihydro-1H-pyrrolyl-, 1,3-dioxolyl-, 4H-1,3,4-thiadiazinyl-,
2,5-dihydrofuranyl-, 2,3-dihydrofuranyl-, 2,5-dihydrothienyl-,
2,3-dihydrothienyl-, 4,5-dihydrooxazolyl-, 4,5-dihydroisoxazolyl-,
or 4H-1,4-thiazinyl- group, or, it may be benzo fused.
[0133] Particularly, a C.sub.3-C.sub.7-heterocyclyl- is to be
understood as meaning a heterocyclyl- which contains at least 3, 4,
5, 6, or 7 carbon atoms and additionally at least one heteroatom as
ring atoms. Accordingly in case of one heteroatom the ring is 4- to
8-membered, in case of two heteroatoms the ring is 5- to 9-membered
and in case of three heteroatoms the ring is 6- to 10-membered.
[0134] Particularly, a C.sub.3-C.sub.6-heterocyclyl- is to be
understood as meaning a heterocyclyl- which contains at least 3, 4,
5 or 6 carbon atoms and additionally at least one heteroatom as
ring atoms. Accordingly in case of one heteroatom the ring is 4- to
7-membered, in case of two heteroatoms the ring is 5- to 8-membered
and in case of three heteroatoms the ring is 6- to 9-membered.
[0135] Particularly, the term "heterocyclyl-" is to be understood
as being a heterocyclic ring which contains 3, 4 or 5 carbon atoms,
and 1, 2 or 3 of the above-mentioned heteroatom-containing groups
(a "4- to 8-membered heterocyclic ring"), more particularly said
ring can contain 4 or 5 carbon atoms, and 1, 2 or 3 of the
above-mentioned heteroatom-containing groups (a "5- to 8-membered
heterocyclic ring"), more particularly said heterocyclic ring is a
"6-membered heterocyclic ring", which is to be understood as
containing 4 carbon atoms and 2 of the above-mentioned
heteroatom-containing groups or 5 carbon atoms and one of the
above-mentioned heteroatom-containing groups, preferably 4 carbon
atoms and 2 of the above-mentioned heteroatom-containing
groups.
[0136] The term "C.sub.1-C.sub.6-alkoxy-" is to be understood as
preferably meaning a linear or branched, saturated, monovalent,
hydrocarbon group of formula --O-alkyl-, in which the term "alkyl-"
is defined supra, e.g. a methoxy-, ethoxy-, n-propoxy-,
iso-propoxy-, n-butoxy-, iso-butoxy-, tert-butoxy-, sec-butoxy-,
pentyloxy-, iso-pentyloxy-, n-hexyloxy- group, or an isomer
thereof. Particularly, the "C.sub.1-C.sub.6-alkoxy-" group is a
"C.sub.1-C.sub.4-alkoxy-", a "C.sub.1-C.sub.3-alkoxy-", a methoxy-,
ethoxy-, or propoxy- group, preferably a methoxy-, ethoxy- or
propoxy- group. Further preferred is a "C.sub.1-C.sub.2-alkoxy-"
group, particularly a methoxy- or ethoxy- group.
[0137] The term "C.sub.1-C.sub.3-fluoroalkoxy-" is to be understood
as preferably meaning a linear or branched, saturated, monovalent,
C.sub.1-C.sub.3-alkoxy- group, as defined supra, in which one or
more of the hydrogen atoms is replaced, identically or differently,
by one or more fluorine atoms. Said
C.sub.1-C.sub.3-fluoroalkoxy-group is, for example a
1,1-difluoromethoxy-, a 1,1,1-trifluoromethoxy-, a 2-fluoroethoxy-,
a 3-fluoropropoxy-, a 2,2,2-trifluoroethoxy-, a
3,3,3-trifluoropropoxy-, particularly a
"C.sub.1-C.sub.2-fluoroalkoxy-" group.
[0138] The term "alkylamino-" is to be understood as preferably
meaning an alkylamino group with one linear or branched alkyl-
group as defined supra. (C.sub.1-C.sub.3)-alkylamino- for example
means a monoalkylamino- group with 1, 2 oder 3 carbon atoms,
(C.sub.1-C.sub.6)-alkylamino- with 1, 2, 3, 4, 5 or 6 carbon atoms.
The term "alkylamino-" comprises for example methylamino-,
ethylamino-, n-propylamino-, iso-propylamino-, tert-butylamino-,
n-pentylamino- or n-hexylamino-.
[0139] The term ",dialkylamino-" is to be understood as preferably
meaning an alkylamino- group having two linear or branched alkyl-
groups as defined supra, which are independent from each other.
(C.sub.1-C.sub.3)-dialkylamino- for example represents a
dialkylamino- group with two alkyl- groups each of them having 1 to
3 carbon atoms per alkyl- group. The term "dialkylamino-" comprises
for example: N,N-dimethylamino-, N,N-diethylamino-,
N-ethyl-N-methylamino-, N-methyl-N-n-propylamino-,
N-iso-propyl-N-n-propylamino-, N-tert-butyl-N-methylamino-,
N-ethyl-N-n-pentylamino- and N-n-hexyl-N-methylamino-.
[0140] The term "cyclic amine" is to be understood as preferably
meaning a cyclic amine group. Preferably, a cyclic amine means a
saturated, monocyclic group with 4 to 10, preferably 4 to 7 ring
atoms of which at least one ring atom is a nitrogen atom. Suitable
cyclic amines are especially azetidine, pyrrolidine, piperidine,
piperazine, 1-methylpiperazine, morpholine, thiomorpholine, which
could be optionally substituted by one or two methyl groups.
[0141] The term "halo-C.sub.1-C.sub.3-alkyl-", or, used
synonymously, "C.sub.1-C.sub.3-haloalkyl-", is to be understood as
preferably meaning a linear or branched, saturated, monovalent
hydrocarbon group in which the term "C.sub.1-C.sub.3-alkyl-" is
defined supra, and in which one or more hydrogen atoms is replaced
by a halogen atom, identically or differently, i.e. one halogen
atom being independent from another. Preferably, a
halo-C.sub.1-C.sub.3-alkyl- group is a
fluoro-C.sub.1-C.sub.3-alkyl- or a fluoro-C.sub.1-C.sub.2-alkyl-
group, such as for example --CF.sub.3, --CHF.sub.2, --CH.sub.2F,
--CF.sub.2CF.sub.3, or --CH.sub.2CF.sub.3, more preferably it is
--CF.sub.3.
[0142] The term "hydroxy-C.sub.1-C.sub.3-alkyl-", is to be
understood as preferably meaning a linear or branched, saturated,
monovalent hydrocarbon group in which the term
"C.sub.1-C.sub.3-alkyl-" is defined supra, and in which one or more
hydrogen atoms is replaced by hydroxy group, preferably not more
than one hydrogen atom per carbon atom being replaced by a hydroxy
group. Particularly, a hydroxy-C.sub.1-C.sub.3-alkyl- group is, for
example, --CH.sub.2OH, --CH.sub.2--CH.sub.2OH,
--C(H)OH--CH.sub.2OH, --CH.sub.2--CH.sub.2--CH.sub.2OH.
[0143] The term "phenyl-C.sub.1-C.sub.3-alkyl-" is to be understood
as preferably meaning a phenyl group, in which one of the hydrogen
atoms is replaced by a C.sub.1-C.sub.3-alkyl group, as defined
supra, which links the phenyl-C.sub.1-C.sub.3-alkyl- group to the
rest of the molecule. Particularly, the
"phenyl-C.sub.1-C.sub.3-alkyl-" is a phenyl-C.sub.1-C.sub.2-alkyl-,
preferably it is a benzyl- group.
[0144] The term "heteroaryl-" is to be understood as preferably
meaning a monovalent, aromatic ring system having 5, 6, 7, 8, 9,
10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl-"
group), particularly 5 (a "5-membered heteroaryl-") or 6 (a
"6-membered heteroaryl-") or 9 (a"9-membered heteroaryl-") or 10
ring atoms (a "10-membered heteroaryl-"), and which contains at
least one heteroatom which may be identical or different, said
heteroatom being such as oxygen, nitrogen or sulfur, and can be
monocyclic, bicyclic, or tricyclic, and in addition in each case
can be benzo-condensed. Particularly, heteroaryl- is selected from
thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-,
pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-,
thiadiazolyl-, tetrazolyl- etc., and benzo derivatives thereof,
such as, for example, benzofuranyl-, benzothienyl-, benzoxazolyl-,
benzisoxazolyl-, benzimidazolyl-, benzotriazolyl-, indazolyl-,
indolyl-, isoindolyl-, etc.; or pyridyl-, pyridazinyl-,
pyrimidinyl-, pyrazinyl-, triazinyl-, etc., and benzo derivatives
thereof, such as, for example, quinolinyl-, quinazolinyl-,
isoquinolinyl-, etc.; or azocinyl-, indolizinyl-, purinyl-, etc.,
and benzo derivatives thereof; or cinnolinyl-, phthalazinyl-,
quinazolinyl-, quinoxalinyl-, naphthyridinyl-, pteridinyl-,
carbazolyl-, acridinyl-, phenazinyl-, phenothiazinyl-,
phenoxazinyl-, xanthenyl-, or oxepinyl-, etc. Preferably,
heteroaryl- is selected from monocyclic heteroaryl-, 5-membered
heteroaryl- or 6-membered heteroaryl-.
[0145] The term "5-membered heteroaryl-" is understood as
preferably meaning a monovalent, aromatic ring system having 5 ring
atoms and which contains at least one heteroatom which may be
identical or different, said heteroatom being such as oxygen,
nitrogen or sulfur. Particularly, "5-membered heteroaryl-" is
selected from thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-,
imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-,
triazolyl-, thiadiazolyl-, tetrazolyl-.
[0146] The term "6-membered heteroaryl-" is understood as
preferably meaning a monovalent, aromatic ring system having 6 ring
atoms and which contains at least one heteroatom which may be
identical or different, said heteroatom being such as oxygen,
nitrogen or sulfur. Particularly, "6-membered heteroaryl-" is
selected from pyridyl-, pyridazinyl-, pyrimidinyl-, pyrazinyl-,
triazinyl-.
[0147] The term "heteroaryl-C.sub.1-C.sub.3-alkyl-" is to be
understood as preferably meaning a heteroaryl-, a 5-membered
heteroaryl- or a 6-membered heteroaryl- group, each as defined
supra, in which one of the hydrogen atoms is replaced by a
C.sub.1-C.sub.3-alkyl- group, as defined supra, which links the
heteroaryl-C.sub.1-C.sub.3-alkyl- group to the rest of the
molecule. Particularly, the "heteroaryl-C.sub.1-C.sub.3-alkyl-" is
a heteroaryl-C.sub.1-C.sub.r-alkyl-, a
pyridinyl-C.sub.1-C.sub.3-alkyl-, a pyridinylmethyl-, a
pyridinylethyl-, a pyridinylpropyl-, a
pyrimidinyl-C.sub.1-C.sub.3-alkyl-, a pyrimidinylmethyl-, a
pyrimidinylethyl-, a pyrimidinylpropyl-, preferably a
pyridinylmethyl- or a pyridinylethyl- or a pyrimidinylethyl- or a
pyrimidinylpropyl- group.
[0148] As used herein, the term "leaving group" refers to an atom
or a group of atoms that is displaced in a chemical reaction as
stable species taking with it the bonding electrons. Preferably, a
leaving group is selected from the group comprising: halo, in
particular a chlorine atom, a bromine atom or an iodine atom,
methanesulfonyloxy-, p-toluenesulfonyloxy-,
trifluoromethanesulfonyloxy-, nonafluorobutanesulfonyloxy-,
(4-bromo-benzene)sulfonyloxy-, (4-nitro-benzene)sulfonyloxy-,
(2-nitro-benzene)-sulfonyloxy-, (4-isopropyl-benzene)sulfonyloxy-,
(2,4,6-tri-isopropyl-benzene)-sulfonyloxy-,
(2,4,6-trimethyl-benzene)sulfonyloxy-,
(4-tert-butyl-benzene)sulfonyloxy-, benzenesulfonyloxy-, and
(4-methoxy-benzene)sulfonyloxy-.
[0149] As used herein, the term "C.sub.1-C.sub.3-alkylbenzene"
refers to a partially aromatic hydrocarbon consisting of a benzene
ring which is substituted by one or two C.sub.1-C.sub.3-alkyl-
groups, as defined supra. Particularly,
"C.sub.1-C.sub.3-alkylbenzene" is toluene, ethylbenzene, cumene,
n-propylbenzene, ortho-xylene, meta-xylene or para-xylene.
Preferably, "C.sub.1-C.sub.3-alkylbenzene" is toluene.
[0150] As used herein, the term "carboxamide based solvent" refers
to lower aliphatic carboxamides of the formula
C.sub.1-C.sub.2-alkyl-C(.dbd.O)--N(C.sub.1-C.sub.2-alkyl).sub.2, or
lower cyclic aliphatic carboxamides of the formula
##STR00002##
in which G represents --CH.sub.2--, --CH.sub.2--CH.sub.2-- or
--CH.sub.2--CH.sub.2--CH.sub.2--. Particularly, "carboxamide based
solvent" is N,N-dimethylformamide, N,N-dimethylacetamide or
N-methylpyrrolidin-2-one. Preferably, "carboxamide based solvent"
is N,N-dimethylformamide or N-methyl-pyrrolidin-2-one.
[0151] The term "C.sub.1-C.sub.10", as used throughout this text,
e.g. in the context of the definition of "C.sub.1-C.sub.10-alkyl"
is to be understood as meaning an alkyl group having a finite
number of carbon atoms of 1 to 10, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9
or 10 carbon atoms. It is to be understood further that said term
"C.sub.1-C.sub.10" is to be interpreted as any sub-range comprised
therein, e.g. C.sub.1-C.sub.10, C.sub.1-C.sub.9, C.sub.1-C.sub.8,
C.sub.1-C.sub.7, C.sub.1-C.sub.6 C.sub.1-C.sub.5, C.sub.1-C.sub.4,
C.sub.1-C.sub.3, C.sub.1-C.sub.2, C.sub.2-C.sub.10,
C.sub.2-C.sub.9, C.sub.2-C.sub.8, C.sub.2-C.sub.7, C.sub.2-C.sub.6,
C.sub.2-C.sub.5, C.sub.2-C.sub.4, C.sub.2-C.sub.3,
C.sub.3-C.sub.10, C.sub.3-C.sub.9, C.sub.3-C.sub.8,
C.sub.3-C.sub.7, C.sub.3-C.sub.6, C.sub.3-C.sub.5, C.sub.3-C.sub.4,
C.sub.4-C.sub.10, C.sub.4-C.sub.9, C.sub.4-C.sub.8,
C.sub.4-C.sub.7, C.sub.4-C.sub.6, C.sub.4-C.sub.5,
C.sub.5-C.sub.10, C.sub.5-C.sub.9, C.sub.5-C.sub.8,
C.sub.5-C.sub.7, C.sub.5-C.sub.6, C.sub.6-C.sub.10,
C.sub.6-C.sub.9, C.sub.6-C.sub.8, C.sub.6-C.sub.7,
C.sub.7-C.sub.10, C.sub.7-C.sub.9, C.sub.7-C.sub.8,
C.sub.8-C.sub.10, C.sub.8-C.sub.9, C.sub.9-C.sub.10.
[0152] Similarly, as used herein, the term "C.sub.1-C.sub.6", as
used throughout this text, e.g. in the context of the definition of
"C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkoxy" is to be
understood as meaning an alkyl group having a finite number of
carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. It is
to be understood further that said term "C.sub.1-C.sub.6" is to be
interpreted as any sub-range comprised therein, e.g.
C.sub.1-C.sub.6 C.sub.1-C.sub.5, C.sub.1-C.sub.4, C.sub.1-C.sub.3,
C.sub.1-C.sub.2, C.sub.2-C.sub.6, C.sub.2-C.sub.5, C.sub.2-C.sub.4,
C.sub.2-C.sub.3, C.sub.3-C.sub.6, C.sub.3-C.sub.5, C.sub.3-C.sub.4,
C.sub.4-C.sub.6, C.sub.4-C.sub.5, C.sub.5-C.sub.6.
[0153] Similarly, as used herein, the term "C.sub.1-C.sub.4", as
used throughout this text, e.g. in the context of the definition of
"C.sub.1-C.sub.4-alkyl", "C.sub.1-C.sub.4-alkoxy" is to be
understood as meaning an alkyl group having a finite number of
carbon atoms of 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms. It is to be
understood further that said term "C.sub.1-C.sub.4" is to be
interpreted as any sub-range comprised therein, e.g.
C.sub.1-C.sub.4, C.sub.1-C.sub.3, C.sub.1-C.sub.2, C.sub.2-C.sub.4,
C.sub.2-C.sub.3, C.sub.3-C.sub.4.
[0154] Similarly, as used herein, the term "C.sub.1-C.sub.3", as
used throughout this text, e.g. in the context of the definition of
"C.sub.1-C.sub.3-alkyl", "C.sub.1-C.sub.3-alkoxy" or
"C.sub.1-C.sub.3-fluoroalkoxy" is to be understood as meaning an
alkyl group having a finite number of carbon atoms of 1 to 3, i.e.
1, 2 or 3 carbon atoms. It is to be understood further that said
term "C.sub.1-C.sub.3" is to be interpreted as any sub-range
comprised therein, e.g. C.sub.1-C.sub.3, C.sub.1-C.sub.2,
C.sub.2-C.sub.3.
[0155] Further, as used herein, the term "C.sub.3-C.sub.6", as used
throughout this text, e.g. in the context of the definition of
"C.sub.3-C.sub.6-cycloalkyl", is to be understood as meaning a
cycloalkyl group having a finite number of carbon atoms of 3 to 6,
i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that
said term "C.sub.3-C.sub.6" is to be interpreted as any sub-range
comprised therein, e.g. C.sub.3-C.sub.6, C.sub.3-C.sub.5,
C.sub.3-C.sub.4, C.sub.4-C.sub.6, C.sub.4-C.sub.5, C.sub.5-C.sub.6.
Further, as used herein, the term "C.sub.3-C.sub.7", as used
throughout this text, e.g. in the context of the definition of
"C.sub.3-C.sub.7-cycloalkyl", is to be understood as meaning a
cycloalkyl group having a finite number of carbon atoms of 3 to 7,
i.e. 3, 4, 5, 6 or 7 carbon atoms, particularly 3, 4, 5 or 6 carbon
atoms. It is to be understood further that said term
"C.sub.3-C.sub.7" is to be interpreted as any sub-range comprised
therein, e.g. C.sub.3-C.sub.7, C.sub.3-C.sub.6, C.sub.3-C.sub.5,
C.sub.3-C.sub.4, C.sub.4-C.sub.7, C.sub.4-C.sub.6, C.sub.4-C.sub.5,
C.sub.5-C.sub.7, C.sub.5-C.sub.6, C.sub.6-C.sub.7.
[0156] A symbol at a bond denotes the linkage site in the
molecule.
[0157] As used herein, the term "one or more times", e.g. in the
definition of the substituents of the compounds of the general
formulae of the present invention, is understood as meaning one,
two, three, four or five times, particularly one, two, three or
four times, more particularly one, two or three times, even more
particularly one or two times.
[0158] Where the plural form of the word compounds, salts,
hydrates, solvates and the like, is used herein, this is taken to
mean also a single compound, salt, isomer, hydrate, solvate or the
like.
[0159] In another embodiment, the present invention concerns
compounds of general formula (I), wherein [0160] A represents a
bivalent moiety selected from the group consisting of --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --S(.dbd.O)(.dbd.NR.sup.5)--;
--S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--; [0161] Z represents a hydrogen
atom or a fluorine atom; [0162] L represents a
C.sub.3-C.sub.5-alkylene moiety, [0163] wherein said moiety is
optionally substituted with [0164] i) one substituent selected from
hydroxy, C.sub.3-C.sub.4-cycloalkyl-,
hydroxy-C.sub.1-C.sub.3-alkyl-, --(CH.sub.2)NR.sup.8R.sup.9, and/or
[0165] ii) one or two or three substituents, identically or
differently, selected from halogen and C.sub.1-C.sub.3-alkyl-;
[0166] X, Y represent CH or N with the proviso that one of X and Y
represents CH and one of X and Y represents N; [0167] R.sup.1
represents a group selected from C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group consisting of hydroxy, cyano,
halogen, C.sub.1-C.sub.3-alkyl-, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.3-alkoxy-, C.sub.1-C.sub.2-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, cyclic amines, --OP(.dbd.O)(OH).sub.2,
--C(.dbd.O)OH, --C(.dbd.O)NH.sub.2; [0168] R.sup.2 represents a
group selected from a hydrogen atom, a fluorine atom, a chlorine
atom, cyano, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-,
fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-;
[0169] R.sup.3, R.sup.4 represent, independently from each other, a
group selected from a hydrogen atom, a fluorine atom, a chlorine
atom, cyano, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-,
fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-;
[0170] R.sup.5 represents a group selected from a hydrogen atom,
cyano, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, [0171] wherein
said C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.5-cycloalkyl- group is
optionally substituted with one, two or three substituents,
identically or differently, selected from the group consisting of
halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
cyclic amines, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-; [0172] R.sup.6, R.sup.7 represent,
independently from each other, a group selected from a hydrogen
atom, cyano, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, [0173] wherein
said C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.5-cycloalkyl- group is
optionally substituted with one, two or three substituents,
identically or differently, selected from the group consisting of
halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
cyclic amines, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-; [0174] R.sup.8, R.sup.9 represent,
independently from each other, a group selected from a hydrogen
atom, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl-
and benzyl-, [0175] wherein said C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, phenyl- or benzyl- group is optionally
substituted with one, two or three substituents, identically or
differently, selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, cyclic amines,
fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-, or
[0176] R.sup.8 and R.sup.9, together with the nitrogen atom they
are attached to, form a cyclic amine; [0177] R.sup.10 represents a
group selected from C.sub.1-C.sub.6-alkyl-,
fluoro-C.sub.1-C.sub.3-alkyl-, C.sub.3-C.sub.5-cycloalkyl-,
phenyl-, and benzyl-, [0178] wherein said group is optionally
substituted with one, two or three substituents, identically or
differently, selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, cyclic amines,
fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy- or the
enantiomers, diastereomers, salts, solvates or salts of solvates
thereof.
[0179] In another embodiment, the present invention concerns
compounds of general formula (I), wherein [0180] A represents a
bivalent moiety selected from the group consisting of --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --S(.dbd.O)(.dbd.NR.sup.5)--;
--S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--; [0181] Z represents a hydrogen
atom or a fluorine atom; [0182] L represents a
C.sub.3-C.sub.5-alkylene moiety, [0183] wherein said moiety is
optionally substituted with [0184] (i) one substituent selected
from C.sub.3-C.sub.4-cycloalkyl-, hydroxymethyl, and/or [0185] (ii)
one or two or three C.sub.1-C.sub.2-alkyl- group substituents,
identically or differently; [0186] X, Y represent CH or N with the
proviso that one of X and Y represents CH and one of X and Y
represents N; [0187] R.sup.1 represents a group selected from
C.sub.1-C.sub.4-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, wherein said
group is optionally substituted with one or two or three
substituents, identically or differently, selected from the group
consisting of hydroxy, cyano, halogen, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, --NH.sub.2, --C(.dbd.O)OH; [0188] R.sup.2
represents a group selected from a hydrogen atom, a fluorine atom,
a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,
trifluoromethoxy-; [0189] R.sup.3 represents a group selected from
a hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-,
methoxy-, trifluoromethyl-, trifluoromethoxy-; [0190] R.sup.4
represents a hydrogen atom or a fluorine atom; [0191] R.sup.5
represents a group selected from a hydrogen atom, cyano,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.4-alkyl-, [0192] wherein said C.sub.1-C.sub.4-alkyl-
group is optionally substituted with one substituent selected from
the group consisting of a fluorine atom, hydroxy, cyano,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
cyclic amines; [0193] R.sup.6, R.sup.7 represent, independently
from each other, a group selected from a hydrogen atom, cyano,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.4-alkyl-, [0194] wherein said C.sub.1-C.sub.4-alkyl-
group is optionally substituted with one substituent selected from
the group consisting of a fluorine atom, hydroxy, cyano,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
cyclic amines; [0195] R.sup.8, R.sup.9 represent, independently
from each other, a group selected from a hydrogen atom,
C.sub.1-C.sub.4-alkyl- and C.sub.3-C.sub.5-cycloalkyl-; [0196]
wherein said C.sub.1-C.sub.4-alkyl- or C.sub.3-C.sub.5-cycloalkyl-
group is optionally substituted with one or two substituents,
identically or differently, selected from the group consisting of
hydroxy, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, cyclic amines, or [0197]
R.sup.8 and R.sup.9, together with the nitrogen atom they are
attached to, form a cyclic amine; [0198] R.sup.10 represents a
group selected from C.sub.1-C.sub.6-alkyl-,
fluoro-C.sub.1-C.sub.3-alkyl-, C.sub.3-C.sub.5-cycloalkyl- and
benzyl-, [0199] wherein said group is optionally substituted with
one substituent selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-,
--NH.sub.2, or the enantiomers, diastereomers, salts, solvates or
salts of solvates thereof.
[0200] In a preferred embodiment, the present invention concerns
compounds of general formula (I), wherein [0201] A represents a
bivalent moiety selected from the group consisting of --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --S(.dbd.O)(.dbd.NR.sup.5)--,
--S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--; [0202] Z represents a hydrogen
atom or a fluorine atom; [0203] L represents a
C.sub.3-C.sub.5-alkylene moiety; [0204] X, Y represent CH or N with
the proviso that one of X and Y represents CH and one of X and Y
represents N; [0205] R.sup.1 represents a
C.sub.1-C.sub.4-alkyl-group, [0206] wherein said group is
optionally substituted with one or two substituents, identically or
differently, selected from the group consisting of hydroxy,
C.sub.1-C.sub.2-alkoxy-, --NH.sub.2, --C(.dbd.O)OH; [0207] R.sup.2
represents a hydrogen atom or a fluorine atom; [0208] R.sup.3
represents a group selected from a hydrogen atom, a fluorine atom
and a methoxy- group; [0209] R.sup.4 represents a hydrogen atom;
[0210] R.sup.5 represents a group selected from a hydrogen atom,
cyano, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--C(.dbd.O)NR.sup.8R.sup.9, C.sub.1-C.sub.4-alkyl-, [0211] wherein
said C.sub.1-C.sub.4-alkyl- group is optionally substituted with
one substituent selected from the group consisting of hydroxy,
cyano, C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-,
dialkylamino-; [0212] R.sup.6, R.sup.7 represent, independently
from each other, a group selected from a hydrogen atom, cyano,
C.sub.1-C.sub.4-alkyl-, [0213] wherein said C.sub.1-C.sub.4-alkyl-
group is optionally substituted with one hydroxy group; [0214]
R.sup.8, R.sup.9 represent, independently from each other, a group
selected from a hydrogen atom, C.sub.1-C.sub.4-alkyl- and
C.sub.3-C.sub.5-cycloalkyl-, or [0215] R.sup.8 and R.sup.9,
together with the nitrogen atom they are attached to, form a cyclic
amine; [0216] R.sup.10 represents a group selected from
C.sub.1-C.sub.6-alkyl-, fluoro-C.sub.1-C.sub.3-alkyl-,
C.sub.3-C.sub.5-cycloalkyl- and benzyl-, [0217] wherein said group
is optionally substituted with one substituent selected from the
group consisting of halogen, hydroxy, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, --NH.sub.2, or the enantiomers,
diastereomers, salts, solvates or salts of solvates thereof.
[0218] In another preferred embodiment, the present invention
concerns compounds of general formula (I), wherein [0219] A
represents a bivalent moiety selected from the group consisting of
--S(.dbd.O).sub.2--, --S(.dbd.O)(.dbd.NR.sup.5)--,
--S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--; [0220] Z represents a hydrogen
atom or a fluorine atom; [0221] L represents a
C.sub.3-C.sub.5-alkylene moiety, [0222] X, Y represent CH or N with
the proviso that one of X and Y represents CH and one of X and Y
represents N; [0223] R.sup.1 represents a methyl- group; [0224]
R.sup.2 represents a hydrogen atom; [0225] R.sup.3 represents a
group selected from a hydrogen atom or a fluorine atom; [0226]
R.sup.4 represents a hydrogen atom; [0227] R.sup.5 represent a
group selected from a hydrogen atom, cyano, --C(.dbd.O)R.sup.10,
--C(.dbd.O)OR.sup.10, C.sub.1-C.sub.4-alkyl-, [0228] wherein said
C.sub.1-C.sub.4-alkyl- group is optionally substituted with one
substituent selected from the group consisting of hydroxy, cyano,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-;
[0229] R.sup.6, R.sup.7 represents, independently from each other,
a group selected from a hydrogen atom, cyano,
C.sub.1-C.sub.4-alkyl-, [0230] wherein said C.sub.1-C.sub.4-alkyl-
group is optionally substituted with one hydroxy group; [0231]
R.sup.8, R.sup.9 represent, independently from each other, a group
selected from a hydrogen atom, C.sub.1-C.sub.2-alkyl; [0232]
R.sup.10 represents a C.sub.1-C.sub.4-alkyl group, or the
enantiomers, diastereomers, salts, solvates or salts of solvates
thereof.
[0233] In another preferred embodiment, the present invention
concerns compounds of general formula (I), wherein [0234] A
represents a bivalent moiety selected from the group consisting of
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--,
--S(.dbd.O)(.dbd.NR.sup.5)--; [0235] Z represents a hydrogen atom
or a fluorine atom; [0236] L represents a C.sub.3-C.sub.5-alkylene
moiety; [0237] X, Y represent CH or N with the proviso that one of
X and Y represents CH and one of X and Y represents N; [0238]
R.sup.1 represents a C.sub.1-C.sub.3-alkyl- group; [0239] R.sup.2
represents a hydrogen atom or a fluorine atom; [0240] R.sup.3
represents a group selected from a hydrogen atom, a fluorine atom
and a methoxy- group; [0241] R.sup.4 represents a hydrogen atom;
[0242] R.sup.5 represents a group selected from a hydrogen atom,
cyano, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
C.sub.1-C.sub.3-alkyl-; [0243] R.sup.6, R.sup.7 represent,
independently from each other, a group selected from a hydrogen
atom, cyano, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
C.sub.1-C.sub.3-alkyl-; [0244] R.sup.10 represents a group selected
from C.sub.1-C.sub.4-alkyl-, trifluoromethyl- and benzyl-, or the
enantiomers, diastereomers, salts, solvates or salts of solvates
thereof.
[0245] In another preferred embodiment, the present invention
concerns compounds of general formula (I), wherein [0246] A
represents a bivalent moiety selected from the group consisting of
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--,
--S(.dbd.O)(.dbd.NR.sup.5)--, --S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--;
[0247] Z represents a group selected from a hydrogen atom and a
fluorine atom; [0248] L represents a C.sub.4-C.sub.5-alkylene
moiety; [0249] X, Y represent CH or N with the proviso that one of
X and Y represents CH and one of X and Y represents N; [0250]
R.sup.1 represents a methyl- group; [0251] R.sup.2 represents a
hydrogen atom; [0252] R.sup.3 represents a hydrogen atom or a
fluorine atom; [0253] R.sup.4 represents a hydrogen atom; [0254]
R.sup.8 represents a group selected from a hydrogen atom,
--C(.dbd.O)OR.sup.10; [0255] R.sup.6, R.sup.7 represent,
independently from each other, a group selected from a hydrogen
atom, --C(.dbd.O)OR.sup.10; [0256] R.sup.10 represents a group
selected from tert-butyl- and benzyl-, the enantiomers,
diastereomers, salts, solvates or salts of solvates thereof.
[0257] In another preferred embodiment, the present invention
concerns compounds of general formula (I), wherein [0258] Z
represents a group selected from a hydrogen atom and a fluorine
atom, [0259] R.sup.3 represents a fluorine atom, and [0260] R.sup.4
represents a hydrogen atom, or the enantiomers, diastereomers,
salts, solvates or salts of solvates thereof.
[0261] In another preferred embodiment, the present invention
concerns compounds of general formula (I), wherein [0262] A
represents a bivalent moiety --S(.dbd.O)(.dbd.NR.sup.5)--; [0263] Z
represents a group selected from a hydrogen atom and a fluorine
atom, [0264] L represents a C.sub.3-C.sub.5-alkylene moiety; [0265]
X, Y represent CH or N with the proviso that one of X and Y
represents CH and one of X and Y represents N; [0266] R.sup.1
represents a methyl- group; [0267] R.sup.2 represents a hydrogen
atom; [0268] R.sup.3 represents a fluorine atom; [0269] R.sup.4
represents a hydrogen atom; [0270] R.sup.5 represents a hydrogen
atom or a --C(.dbd.O)OR.sup.10-- group; [0271] R.sup.10 represents
a tertbutyl- group; or the enantiomers, diastereomers, salts,
solvates or salts of solvates thereof.
[0272] In particular, a preferred subject of the present invention
is a compound selected from: [0273] (rac)-tert-butyl
[{[3,20-difluoro-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.s-
up.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(me-
thyl)oxido-.lamda..sup.6-sulfanylidene]carbamate [0274]
(rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-
-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(-
24),9,11,19,21-nonaene [0275] (rac)-tert-butyl
[{[3,20-difluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.s-
up.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(me-
thyl)oxido-.lamda..sup.6-sulfanylidene]carbamate [0276]
(rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,25-
-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(-
24),9,11,19,21-nonaene [0277] (rac)-tert-butyl
[{[3,21-difluoro-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1.sup.2,6.1.s-
up.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10-yl]methyl}(met-
hyl)oxido-.lamda..sup.6-sulfanylidene]carbamate [0278]
(rac)-3,21-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,26-
-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(2-
5),9,11,20,22-nonaene [0279] (rac)-tert-butyl
[methyl(oxido){[3,20,23-trifluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.-
3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-
-10-yl]methyl}-1.lamda..sup.6-sulfanylidene]carbamate [0280]
(rac)-3,20,23-trifluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,-
7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,-
5,8(24),9,11,19,21-nonaene [0281] (rac)-tert-butyl
[{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.s-
up.8,12]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(me-
thyl)oxido-.lamda..sup.6-sulfanylidene]carbamate [0282]
(rac)-3,19-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,17-dioxa-5,7,24-
-triazatetracyclo[16.3.1.1.sup.2,6.1.sup.8,12]tetracosa-1(22),2(24),3,5,8(-
23),9,11,18,20-nonaene [0283]
(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7-
,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5-
,8(24),9,11,19,21-nonaene [0284] Enantiomer 1 of
(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7-
,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5-
,8(24),9,11,19,21-nonaene [0285] Enantiomer 2 of
(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7-
,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5-
,8(24),9,11,19,21-nonaene [0286] Diastereoisomer 1 of
3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,-
7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,-
5,8(24),9,11,19,21-nonaene [0287] Diastereoisomer 2 of
3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,-
7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,-
5,8(24),9,11,19,21-nonaene [0288] Diastereoisomer 3 of
3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,-
7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,-
5,8(24),9,11,19,21-nonaene [0289] Diastereoisomer 4 of
3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,-
7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,-
5,8(24),9,11,19,21-nonaene [0290]
(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7-
,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,-
8(25),9,11,20,22-nonaene [0291] Enantiomer 1 of
3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-tr-
iazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),-
9,11,20,22-nonaene [0292] Enantiomer 2 of
3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-tr-
iazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),-
9,11,20,22-nonaene [0293] Mixture of diastereoisomers 1 and 2 of
3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,-
7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5-
,8(25),9,11,20,22-nonaene [0294] Mixture of diastereoisomers 3 and
4 of
3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,-
7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5-
,8(25),9,11,20,22-nonaene [0295]
(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7-
,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5-
,8(26),9,11,21,23-nonaene [0296] Enantiomer 1 of
3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-tr-
iazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26)-
,9,11,21,23-nonaene [0297] Enantiomer 2 of
3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-tr-
iazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26)-
,9,11,21,23-nonaene [0298] Mixture of diastereoisomers 1 and 2 of
3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,-
7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,-
5,8(26),9,11,21,23-nonaene [0299] Mixture of diastereoisomers 3 and
4 of
3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,-
7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,-
5,8(26),9,11,21,23-nonaene [0300] Mixture of enantiomers of
3,20-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,18-dioxa-5,7,24-tr-
iazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24)-
,9,11,19,21-nonaene [0301] Enantiomer 1 of
3,21-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-tr-
iazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),-
9,11,20,22-nonaene [0302] Enantiomer 2 of
3,21-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-tr-
iazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),-
9,11,20,22-nonaene [0303] Enantiomer 1 of
3,22-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-tr-
iazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(25),2(27),3,5,8(26),-
9,11,21,23-nonaene [0304] Enantiomer 2 of
3,22-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-tr-
iazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(25),2(27),3,5,8(26),-
9,11,21,23-nonaene and the enantiomers, diastereomers, salts,
solvates or salts of solvates thereof.
[0305] The invention relates to compounds of formula (I), in which
A represents a bivalent moiety selected from the group consisting
of --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--,
--S(.dbd.O)(.dbd.NR.sup.5)--;
--S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--.
[0306] In another embodiment the invention relates to compounds of
formula (I), in which A represents a bivalent moiety
--S(.dbd.O).sub.2--, --S(.dbd.O)(.dbd.NR.sup.5)--,
--S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--.
[0307] In another embodiment the invention relates to compounds of
formula (I), in which A represents a bivalent moiety selected from
the group consisting of --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--,
--S(.dbd.O)(.dbd.NR)--.
[0308] In a preferred embodiment the invention relates to compounds
of formula (I), in which A represents a bivalent moiety selected
from the group consisting of --S--, --S(.dbd.O)--,
--S(.dbd.O)(.dbd.NR.sup.5)--,
--S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--.
[0309] In another preferred embodiment the invention relates to
compounds of formula (I), in which A represents a bivalent moiety
--S(.dbd.O)(.dbd.NR.sup.5)--,
--S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--.
[0310] In another preferred embodiment the invention relates to
compounds of formula (I), in which A represents a bivalent moiety
--S(.dbd.NR.sup.6)(.dbd.NR.sup.7)--.
[0311] In another preferred embodiment the invention relates to
compounds of formula (I), in which A represents a bivalent moiety
--S(.dbd.NH)(.dbd.NH)--.
[0312] In another preferred embodiment the invention relates to
compounds of formula (I), in which A represents a bivalent moiety
--S(.dbd.O).sub.2--.
[0313] In another preferred embodiment the invention relates to
compounds of formula (I), in which A represents a bivalent moiety
--S(.dbd.O)(.dbd.NR.sup.5)--.
[0314] In another preferred embodiment the invention relates to
compounds of formula (I), in which A represents a bivalent moiety
--S(.dbd.O)(.dbd.N--C(.dbd.O)O--C(CH.sub.3).sub.3)--.
[0315] In another preferred embodiment the invention relates to
compounds of formula (I), in which A represents a bivalent moiety
--S(.dbd.O)(.dbd.NCH.sub.3)--.
[0316] In another preferred embodiment the invention relates to
compounds of formula (I), in which A represents a bivalent moiety
--S(.dbd.O)(.dbd.NH)--.
[0317] In another embodiment the invention relates to compounds of
formula (I), in which Z represents a hydrogen atom or a fluorine
atom.
[0318] In a preferred embodiment the invention relates to compounds
of formula (I), in which Z represents a fluorine atom.
[0319] In another preferred embodiment the invention relates to
compounds of formula (I), in which Z represents a hydrogen
atom.
[0320] The invention relates to compounds of formula (I), in which
L represents a C.sub.3-C.sub.5 alkylene moiety,
wherein said moiety is optionally substituted with [0321] i) one
substituent selected from hydroxy, --NR.sup.8R.sup.9,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-, C.sub.3-C.sub.4
cycloalkyl-, hydroxy-C.sub.1-C.sub.3-alkyl,
--(CH.sub.2)NR.sup.8R.sup.9, and/or [0322] ii) one or two or three
or four substituents, identically or differently, selected from
halogen and C.sub.1-C.sub.3-alkyl-, or wherein one carbon atom of
said C.sub.3-C.sub.5-alkylene moiety forms a three- or
four-membered ring together with a bivalent moiety to which it is
attached, wherein said bivalent moiety is selected from
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2OCH.sub.2--.
[0323] In a another embodiment the invention relates to compounds
of formula (I), in which L represents a C.sub.3-C.sub.5-alkylene
moiety,
wherein said moiety is optionally substituted with [0324] i) one
substituent selected from hydroxy, C.sub.3-C.sub.4-cycloalkyl-,
hydroxy-C.sub.1-C.sub.3-alkyl-, --(CH.sub.2)NR.sup.8R.sup.9, and/or
[0325] ii) one or two or three substituents, identically or
differently, selected from halogen and C.sub.1-C.sub.3-alkyl-.
[0326] In a another embodiment the invention relates to compounds
of formula (I), in which L represents a C.sub.3-C.sub.5-alkylene
moiety,
wherein said moiety is optionally substituted with [0327] (i) one
substituent selected from C.sub.3-C.sub.4-cycloalkyl-,
hydroxymethyl, and/or [0328] (ii) one or two or three substituents,
identically or differently, selected from
C.sub.1-C.sub.2-alkyl-.
[0329] In a preferred embodiment the invention relates to compounds
of formula (I), in which L represents a C.sub.3-C.sub.5-alkylene
moiety.
[0330] In a particularly preferred embodiment the invention relates
to compounds of formula (I), in which L represents a
C.sub.4-C.sub.5-alkylene moiety.
[0331] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which L represents a moiety
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--
or --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--.
[0332] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which L represents a moiety
--CH.sub.2CH.sub.2CH.sub.2--.
[0333] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which L represents a moiety
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--.
[0334] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which L represents a moiety
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--.
[0335] The invention relates to compounds of formula (I, in which
X, Y represent CH or N with the proviso that one of X and Y
represents CH and one of X and Y represents N.
[0336] In another embodiment the invention relates to compounds of
formula (I), in which X represents N, and in which Y represents
CH.
[0337] In another embodiment the invention relates to compounds of
formula (I), in which X represents CH, and in which Y represents
N.
[0338] The invention relates to compounds of formula (I), in which
R.sup.1 represents a group selected from C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-,
heterocyclyl-,
wherein said group is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group consisting of hydroxy, cyano, halogen,
C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.3-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, --OP(.dbd.O)(OH).sub.2, --C(.dbd.O)OH,
--C(.dbd.O)NH.sub.2.
[0339] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.1 represents a group selected from
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-,
wherein said group is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group consisting of hydroxy, cyano, halogen,
C.sub.1-C.sub.3-alkyl-, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.3-alkoxy-, C.sub.1-C.sub.2-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, cyclic amines, --OP(.dbd.O)(OH).sub.2,
--C(.dbd.O)OH, --C(.dbd.O)NH.sub.2.
[0340] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.1 represents a group selected from
C.sub.1-C.sub.4-alkyl-, C.sub.3-C.sub.5-cycloalkyl-,
wherein said group is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group consisting of hydroxy, cyano, halogen,
C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, --NH.sub.2,
--C(.dbd.O)OH.
[0341] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.1 represents a
C.sub.1-C.sub.4-alkyl-group,
wherein said group is optionally substituted with one or two
substituents, identically or differently, selected from the group
consisting of hydroxy, C.sub.1-C.sub.2-alkoxy-, --NH.sub.2,
--C(.dbd.O)OH.
[0342] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.1 represents a
C.sub.1-C.sub.4-alkyl- group.
[0343] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.1 represents a
C.sub.1-C.sub.3-alkyl- group.
[0344] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
C.sub.1-C.sub.2-alkyl- group.
[0345] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
methyl- group.
[0346] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
C.sub.1-C.sub.4-alkyl- group, and R.sup.2 represents a hydrogen
atom or a fluoro atom.
[0347] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
C.sub.1-C.sub.4-alkyl- group, and R.sup.2 represents a hydrogen
atom.
[0348] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
methyl group, and R.sup.2 represents a hydrogen atom.
[0349] R.sup.1 is bound in all compounds according to the present
invention to the sulfur atom of the group A.
[0350] The invention relates to compounds of formula (I), in which
R.sup.2 represents a group selected from a hydrogen atom, a
fluorine atom, a chlorine atom, a bromine atom, cyano,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-.
[0351] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from a
hydrogen atom, a fluorine atom, a chlorine atom, cyano,
C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-,
fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-.
[0352] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.2 represents a group selected from a
hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-,
methoxy-, trifluoromethyl-, trifluoromethoxy-.
[0353] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.2 represents a hydrogen
atom or a fluorine atom.
[0354] In a particularly preferred embodiment the invention relates
to compounds of formula (I), in which R.sup.2 represents a fluorine
atom.
[0355] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.2 represents a
hydrogen atom.
[0356] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.2 represents a
hydrogen atom, R.sup.3 represents a fluorine atom, R.sup.4
represents a hydrogen atom and Z represents a hydrogen atom.
[0357] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
methyl- group, R.sup.2 represents a hydrogen atom, R.sup.3
represents a fluorine atom, R.sup.4 represents a hydrogen atom and
Z represents a hydrogen atom.
[0358] The invention relates to compounds of formula (I), in which
R.sup.3, R.sup.4 represent, independently from each other, a group
selected from a hydrogen atom, a fluorine atom, a chlorine atom, a
bromine atom, cyano, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-.
[0359] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3, R.sup.4 represent, independently
from each other, a group selected from a hydrogen atom, a fluorine
atom, a chlorine atom, cyano, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-.
[0360] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3, R.sup.4 represent, independently
from each other, a group selected from a hydrogen atom, a fluorine
atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,
trifluoromethoxy-.
[0361] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3, R.sup.4 represent, independently
from each other, a group selected from a hydrogen atom or a
fluorine atom.
[0362] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a group selected from a
hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom,
cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy and in
which R.sup.4 represents a hydrogen atom or a fluorine atom.
[0363] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a group selected from a
hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom,
cyano, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-,
halo-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy and in
which R.sup.4 represents a hydrogen atom.
[0364] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a group selected from a
hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-,
methoxy-, trifluoromethyl-, trifluoromethoxy- and in which R.sup.4
represents a hydrogen atom.
[0365] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a group selected from a
hydrogen atom, a fluorine atom and a methoxy- group an in which
R.sup.4 represents a hydrogen atom.
[0366] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a group selected from a
hydrogen atom or a fluorine atom and in which R.sup.4 represents a
hydrogen atom.
[0367] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a fluorine atom and in
which R.sup.4 represents a hydrogen atom.
[0368] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.3 represents a group selected from a
hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-,
methoxy-, trifluoromethyl-, trifluoromethoxy-.
[0369] In a particularly preferred embodiment the invention relates
to compounds of formula (I), in which R.sup.3 represents a hydrogen
atom or a fluorine atom.
[0370] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.3 represents a
fluorine atom.
[0371] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.3 represents a
hydrogen atom.
[0372] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.4 represents a group selected from a
hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-,
methoxy-, trifluoromethyl-, trifluoromethoxy-.
[0373] In a particularly preferred embodiment the invention relates
to compounds of formula (I), in which R.sup.4 represents a hydrogen
atom or a fluorine atom.
[0374] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.4 represents a
fluorine atom.
[0375] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.4 represents a
hydrogen atom.
[0376] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a group selected from a
hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-,
methoxy-, trifluoromethyl-, trifluoromethoxy-, in which R.sup.4
represents a hydrogen atom, and in which Z represents a hydrogen
atom or a fluorine atom,
wherein R.sup.3 is attached in para-position to the ring directly
bonded to the phenyl-ring to which R.sup.3 is attached, which is a
pyridine ring if Y represents CH and a pyrimidine ring if Y
represents N.
[0377] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.3 represents a hydrogen atom or a
fluorine atom, in which R.sup.4 represents a hydrogen atom, and in
which Z represents a hydrogen atom or a fluorine atom,
wherein R.sup.3 is attached in para-position to the ring directly
bonded to the phenyl-ring to which R.sup.3 is attached, which is a
pyridine ring if Y represents CH and a pyrimidine ring if Y
represents N.
[0378] In a particularly preferred embodiment the invention relates
to compounds of formula (I), in which R.sup.3 represents a fluorine
atom, in which R.sup.4 represents a hydrogen atom, and in which Z
represents a hydrogen atom,
wherein R.sup.3 is attached in para-position to the ring directly
bonded to the phenyl-ring to which R.sup.3 is attached, which is a
pyridine ring if Y represents CH and a pyrimidine ring if Y
represents N.
[0379] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.3 represents a fluorine atom, in
which R.sup.4 represents a hydrogen atom, and in which Z represents
a hydrogen atom.
[0380] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.3 represents a
fluorine atom,
wherein R.sup.3 is attached in para-position to the ring directly
bonded to the phenyl-ring to which R.sup.3 is attached, which is a
pyridine ring if Y represents CH and a pyrimidine ring if Y
represents N.
[0381] The invention relates to compounds of formula (I), in which
R.sup.5 represents a group selected from a hydrogen atom, cyano,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O.sub.2)R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-,
heterocyclyl-,
wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-
and heterocyclyl- group is optionally substituted with one, two or
three substituents, identically or differently, selected from the
group consisting of halogen, hydroxy, cyano,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-.
[0382] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a group selected from a
hydrogen atom, cyano, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-,
wherein said C.sub.1-C.sub.6-alkyl- and C.sub.3-C.sub.5-cycloalkyl-
group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
cyclic amines, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-.
[0383] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.5 represents a group selected from a
hydrogen atom, cyano, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.4-alkyl-,
wherein said C.sub.1-C.sub.4-alkyl- group is optionally substituted
with one substituent selected from the group consisting of a
fluorine atom, hydroxy, cyano, C.sub.1-C.sub.3-alkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, cyclic amines.
[0384] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.5 represents a group
selected from a hydrogen atom, cyano, --C(.dbd.O)R.sup.10,
--C(.dbd.O)OR.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.4-alkyl-, wherein said C.sub.1-C.sub.4-alkyl- group
is optionally substituted with one substituent selected from the
group consisting of hydroxy, cyano, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-.
[0385] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.5 represents a group
selected from a hydrogen atom, cyano, --C(.dbd.O)R.sup.10,
--C(.dbd.O)OR.sup.10, C.sub.1-C.sub.4-alkyl-,
wherein said C.sub.1-C.sub.4-alkyl- group is optionally substituted
with one substituent selected from the group consisting of hydroxy,
cyano, C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-,
dialkylamino-.
[0386] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.5 represents a group selected from a
hydrogen atom, cyano, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.4-alkyl-.
[0387] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.5 represents a group selected from a
hydrogen atom, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.4-alkyl-.
[0388] In a particularly preferred embodiment the invention relates
to compounds of formula (I), in which R.sup.5 represents a group
selected from a hydrogen atom, --C(.dbd.O)R.sup.10,
--C(.dbd.O)OR.sup.10, --S(.dbd.O).sub.2R.sup.10,
--C(.dbd.O)NR.sup.8R.sup.9, methyl-.
[0389] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.5 represents a
--C(.dbd.O)OR.sup.10 group.
[0390] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.5 represents a
--C(.dbd.O)R.sup.10 group.
[0391] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.5 represents a
--S(.dbd.O).sub.2R.sup.10 group.
[0392] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.5 represents
C.sub.1-C.sub.4-alkyl- group.
[0393] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.5 represents methyl-
group.
[0394] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.5 represents a cyano
group.
[0395] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.5 represents a
--C(.dbd.O)NR.sup.8R.sup.9 group.
[0396] In a particularly preferred embodiment the invention relates
to compounds of formula (I), in which R represents a
--C(.dbd.O)O--C(CH.sub.3).sub.3) group.
[0397] In a particularly preferred embodiment the invention relates
to compounds of formula (I), in which R.sup.5 represents a hydrogen
atom.
[0398] The invention relates to compounds of formula (I), in which
R.sup.6 and R.sup.7, independently from each other represent a
group selected from a hydrogen atom, cyano, --C(.dbd.O)R.sup.10,
--C(.dbd.O)OR.sup.10, --S(.dbd.O).sub.2R.sup.10,
--C(.dbd.O)NR.sup.8R.sup.9, C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-,
wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-,
heterocyclyl- group is optionally substituted with one, two or
three substituents, identically or differently, selected from the
group consisting of halogen, hydroxy, cyano,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-.
[0399] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.6 and R.sup.7, independently from
each other represent a group selected from a hydrogen atom, cyano,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-,
wherein said C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.5-cycloalkyl-
group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
cyclic amines, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-.
[0400] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.6 and R.sup.7, independently from
each other represent a group selected from a hydrogen atom, cyano,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.4-alkyl-,
wherein said C.sub.1-C.sub.4-alkyl- group is optionally substituted
with one substituent selected from the group consisting of a
fluorine atom, hydroxy, cyano, C.sub.1-C.sub.3-alkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, cyclic amines.
[0401] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.6 and R.sup.7,
independently from each other represent a group selected from a
hydrogen atom, cyano, C.sub.1-C.sub.4-alkyl-,
wherein said C.sub.1-C.sub.4-alkyl- group is optionally substituted
with one hydroxy group.
[0402] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.6 and R.sup.7,
independently from each other represent a group selected from a
hydrogen atom, cyano, C.sub.1-C.sub.4-alkyl-,
wherein said C.sub.1-C.sub.4-alkyl- group is optionally substituted
with one hydroxy group.
[0403] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.6 and R.sup.7,
independently from each other represent a group selected from a
hydrogen atom, cyano, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
C.sub.1-C.sub.3-alkyl-.
[0404] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.6 and R.sup.7,
independently from each other represent a group selected from a
hydrogen atom and --C(.dbd.O)OR.sup.10.
[0405] In particularly preferred embodiment the invention relates
to compounds of formula (I), in which R.sup.6 and R.sup.7,
independently from each other represent a group selected from a
hydrogen atom and C.sub.1-C.sub.3-alkyl-.
[0406] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.6 and R.sup.7,
independently from each other represent a group selected from a
hydrogen atom and a cyano group.
[0407] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.6 and R.sup.7,
independently from each other represent a group selected from a
hydrogen atom and a methyl- group.
[0408] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.6 and R.sup.7
represent a hydrogen atom;
[0409] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.6 represents a hydrogen atom and
R.sup.7 represents a group selected from a hydrogen atom, cyano,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-,
heterocyclyl-,
wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-,
heterocyclyl-group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-.
[0410] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.6 represents a hydrogen atom and
R.sup.7 represents a group selected from a hydrogen atom, cyano,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-,
wherein said C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.5-cycloalkyl-
group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
cyclic amines, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-.
[0411] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.6 represents a hydrogen atom and
R.sup.7 represents a group selected rom a hydrogen atom, cyano,
--C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.4-alkyl-, C.sub.3-C.sub.5-cycloalkyl-,
wherein said C.sub.1-C.sub.4-alkyl- or C.sub.3-C.sub.5-cycloalkyl-
group is optionally substituted with one substituent selected from
the group consisting of fluorine, hydroxy, cyano,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
cyclic amines.
[0412] In another preferred embodiment the invention relates to
compounds of formula (I in which R.sup.6 represents a hydrogen atom
and R.sup.7 represents a group selected from a hydrogen atom,
cyano, --C(.dbd.O)R.sup.10, --C(.dbd.O)OR.sup.10,
--S(.dbd.O).sub.2R.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.4-alkyl-, C.sub.3-C.sub.5-cycloalkyl-,
wherein said C.sub.1-C.sub.4-alkyl- group is optionally substituted
with one hydroxy group.
[0413] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.6 represents a hydrogen
atom and R.sup.7 represents a group selected from a hydrogen atom,
cyano, --C(.dbd.O)OR.sup.10, --C(.dbd.O)NR.sup.8R.sup.9,
C.sub.1-C.sub.4-alkyl-, C.sub.3-C.sub.5-cycloalkyl-,
wherein said C.sub.1-C.sub.4-alkyl- group is optionally substituted
with one hydroxy group.
[0414] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.6 represents a hydrogen
atom and R.sup.7 represents a group selected from a hydrogen atom,
cyano, C.sub.1-C.sub.4-alkyl-, C.sub.3-C.sub.5-cycloalkyl-.
[0415] In another preferred embodiment the invention relates to
compounds of formula (I) in which R.sup.6 represents a hydrogen
atom and R.sup.7 represents a group selected from a hydrogen atom,
cyano, C.sub.1-C.sub.4-alkyl-.
[0416] In a particularly preferred embodiment the invention relates
to compounds of formula (I) in which R.sup.6 represents a hydrogen
atom and R.sup.7 represents a group selected from a hydrogen atom,
cyano, C.sub.1-C.sub.3-alkyl-, cyclopropyl-.
[0417] In a particularly preferred embodiment the invention relates
to compounds of formula (I), in which R.sup.6 represents a hydrogen
atom and R.sup.7 represents a group selected from a hydrogen atom,
cyano, C.sub.1-C.sub.3-alkyl-.
[0418] In another particularly preferred embodiment the invention
relates to compounds of formula (I) in which R.sup.6 represents a
hydrogen atom and R.sup.7 represents a cyano group.
[0419] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.6 represents a
hydrogen atom and R.sup.7 represents a methyl- group.
[0420] The invention relates to compounds of formula (I), in which
R.sup.8, R.sup.9 represent, independently from each other, a group
selected from a hydrogen atom, C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- and
heteroaryl-,
wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-,
heterocyclyl-, phenyl-, benzyl- or heteroaryl- group is optionally
substituted with one, two or three substituents, identically or
differently, selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-, or
R.sup.8 and R.sup.9, together with the nitrogen atom they are
attached to, form a cyclic amine.
[0421] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.8, R.sup.9 represent, independently
from each other, a group selected from a hydrogen atom,
C.sub.1-C.sub.4-alkyl- and C.sub.3-C.sub.5-cycloalkyl-;
wherein said C.sub.1-C.sub.4-alkyl- or
C.sub.3-C.sub.5-cycloalkyl-group is optionally substituted with one
or two substituents, identically or differently, selected from the
group consisting of hydroxy, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
cyclic amines, or R.sup.8 and R.sup.9, together with the nitrogen
atom they are attached to, form a cyclic amine.
[0422] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.8, R.sup.9 represent, independently
from each other, a group selected from a hydrogen atom,
C.sub.1-C.sub.4-alkyl- and C.sub.3-C.sub.5-cycloalkyl-, or
R.sup.8 and R.sup.9, together with the nitrogen atom they are
attached to, form a cyclic amine.
[0423] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.8, R.sup.9 represent, independently
from each other, a group selected from a hydrogen atom,
C.sub.1-C.sub.2-alkyl.
[0424] In a particularly preferred embodiment the invention relates
to compounds of formula (I), in which R.sup.8 and R.sup.9
represent, independently from each other, a group selected from a
hydrogen atom and C.sub.1-C.sub.2-alkyl-.
[0425] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.8 represents a
group selected from a hydrogen atom and C.sub.1-C.sub.2-alkyl-, and
in which R.sup.9 represents a hydrogen atom.
[0426] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.8 represents a
group selected from a hydrogen atom and C.sub.1-C.sub.2-alkyl-.
[0427] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.9 represents a
hydrogen atom.
[0428] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.8 represents a
hydrogen atom, and in which R.sup.9 represents a hydrogen atom.
[0429] The invention relates to compounds of formula (I), in which
R.sup.10 represents a group selected from C.sub.1-C.sub.6-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.3-C.sub.7-cycloalkyl-,
heterocyclyl-, phenyl-, benzyl- and heteroaryl-,
wherein said group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-.
[0430] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.10 represents a group selected from
C.sub.1-C.sub.6-alkyl-, fluoro-C.sub.1-C.sub.3-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, phenyl- and benzyl-,
wherein said group is optionally substituted with one, two or three
substituents, identically or differently, selected from the group
consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, --NH.sub.2, alkylamino-, dialkylamino-,
cyclic amines, fluoro-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-.
[0431] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.10 represents a group selected from
C.sub.1-C.sub.6-alkyl-, fluoro-C.sub.1-C.sub.3-alkyl-,
C.sub.3-C.sub.5-cycloalkyl- and benzyl-,
wherein said group is optionally substituted with one substituent
selected from the group consisting of halogen, hydroxy,
C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, --NH.sub.2.
[0432] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.10 represents a group
selected from C.sub.1-C.sub.4-alkyl-,
fluoro-C.sub.1-C.sub.3-alkyl-.
[0433] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.10 represents a
C.sub.1-C.sub.4-alkyl- group.
[0434] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.10 represents a
tert-butyl- group.
[0435] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.3 represents a
fluorine atom, R.sup.4 represents a hydrogen atom and R.sup.5
represents a hydrogen atom.
[0436] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
methyl- group, R.sup.3 represents a fluorine atom, R.sup.4
represents a hydrogen atom and R.sup.5 represents a hydrogen
atom.
[0437] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
methyl- group, R.sup.2 represents a hydrogen atom, R.sup.3
represents a fluorine atom, R.sup.4 represents a hydrogen atom and
R.sup.5 represents a hydrogen atom.
[0438] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
methyl-group, R.sup.2 represents a hydrogen atom, R.sup.3
represents a fluorine atom, R.sup.4 represents a hydrogen atom,
R.sup.5 represents a hydrogen atom and Z represents a hydrogen
atom.
[0439] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
methyl- group and R.sup.5 represents a hydrogen atom.
[0440] In another particularly preferred embodiment the invention
relates to compounds of formula (I), in which R.sup.1 represents a
methyl- group, R.sup.5 represents a hydrogen atom and Z represents
a hydrogen atom.
[0441] It is to be understood that the present invention relates to
any sub-combination within any embodiment of the present invention
of compounds of formula (I), supra.
[0442] More particularly still, the present invention covers
compounds of formula (I) which are disclosed in the Example section
of this text, infra.
[0443] Very specially preferred are combinations of two or more of
the abovementioned preferred embodiments.
[0444] The above mentioned definitions of groups and radicals which
have been detailed in general terms or in preferred ranges also
apply to the end products of the formula (I) and, analogously, to
the starting materials or intermediates required in each case for
the preparation.
[0445] The present invention further relates to intermediate
compounds of general formula (7)
##STR00003##
wherein Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L are as defined
for the compound of general formula (I) according to the invention,
or the enantiomers, diastereomers, salts, solvates or salts of
solvates thereof.
[0446] The present invention further relates to intermediate
compounds of general formula (19)
##STR00004##
wherein Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L are as defined
for the compound of general formula (I) according to the invention,
or the enantiomers, diastereomers, salts, solvates or salts of
solvates thereof.
[0447] The present invention further relates to the use of
intermediate compounds of general formula (7),
##STR00005##
wherein Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L are as defined
for the compound of general formula (I) according to the invention,
or the enantiomers, diastereomers, salts, solvates or salts of
solvates thereof, for the preparation of a compound of general
formula (I) according to the invention.
[0448] The present invention further relates to the us of
intermediate compounds of general formula (19),
##STR00006##
wherein Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L are as defined
for the compound of general formula (I) according to the invention,
or the enantiomers, diastereomers, salts, solvates or salts of
solvates thereof, for the preparation of a compound of general
formula (I) according to the invention.
[0449] The present invention further relates to a process for the
preparation of a compound of formula (Ta), in which process a
compound of the formula (7) wherein Z, R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and L are as defined for the compound of general formula
(I) according to the invention,
##STR00007##
[0450] is reacted in a C--N cross-coupling reaction to give
compounds of the formula (Ia),
##STR00008##
and in which process the resulting compound is optionally, if
appropriate, converted with the corresponding (i) solvents and/or
(ii) bases or acids to the solvates, salts and/or solvates of the
salts thereof.
[0451] The present invention further relates to a process for the
preparation of a compound of formula (Id), in which process a
compound of the formula (19), wherein Z, R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and L are as defined for the compound of general formula
(I) according to the invention,
##STR00009##
[0452] is reacted in a C--N cross-coupling reaction to give
compounds of the formula (Id),
##STR00010##
and in which process the resulting compound is optionally, if
appropriate, converted with the corresponding (i) solvents and/or
(ii) bases or acids to the solvates, salts and/or solvates of the
salts thereof.
[0453] The present invention further relates to a process for the
preparation of the compounds of formula (Ta), in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, Z and L are as defined for the compound
of formula (I) according to the invention, in which process
compounds of formula (7),
##STR00011##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z and L are as defined
for the compound of formula (I) according to the invention, are
reacted in an intramolecular Palladium-catalyzed C--N
cross-coupling reaction,
##STR00012##
to give compounds of the formula (Ia), and in which process the
resulting compounds are optionally, if appropriate, converted with
the corresponding (i) solvents and/or (ii) bases or acids to the
solvates, salts and/or solvates of the salts thereof.
##STR00013##
to give compounds of the formula (Tb),
[0454] The present invention further relates to a process for the
preparation of the compounds of formula (Id), in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, Z and L are as defined for the compound
of formula (I) according to the invention, in which process
compounds of formula (19)
##STR00014##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z and L are as defined
for the compound of formula (I) according to the invention, are
reacted in an intramolecular Palladium-catalyzed C--N
cross-coupling reaction,
##STR00015##
to give compounds of the formula (Id), and in which process the
resulting compounds are optionally, if appropriate, converted with
the corresponding (i) solvents and/or (ii) bases or acids to the
solvates, salts and/or solvates of the salts thereof.
##STR00016##
to give compounds of the formula (Ie),
[0455] The compounds according to the invention show a valuable
pharmacological spectrum of action which could not have been
predicted.
[0456] They are therefore suitable for use as medicaments for the
treatment and/or prophylaxis of disorders in humans and
animals.
[0457] The pharmaceutical activity of the compounds according to
the invention can be explained by their action as selective
inhibitors of CDK9, and, more significantly, as selective
inhibitors of CDK9 at high ATP concentrations.
[0458] Thus, the compounds according to the general formula (I) as
well as the enantiomers, diastereomers, salts, solvates and salts
of solvates thereof are used as selective inhibitors for CDK9.
[0459] Furthermore, the compounds according to the invention show a
particularly high potency (demonstrated by a low IC.sub.50 value in
the CDK9/CycT1 assay) for selectively inhibiting CDK9 activity, in
particular at high ATP concentrations.
[0460] In context of the present invention, the IC.sub.50 value
with respect to CDK9 can be determined by the methods described in
the method section below.
[0461] As compared to many CDK9 inhibitors described in the prior
art, compounds of the present invention according to general
formula (I) show a surprisingly high potency for inhibiting CDK9
activity, especially at high ATP concentrations, which is
demonstrated by their low IC.sub.50 value in the CDK9/CycT1 high
ATP kinase assay. Thus, these compounds have a lower probability to
be competed out of the ATP-binding pocket of CDK9/CycT1 kinase due
to the high intracellular ATP concentration (R. Copeland et al.,
Nature Reviews Drug Discovery 2006, 5, 730-739). According to this
property the compounds of the present invention are particularly
able to inhibit CDK9/CycT1 within cells for a longer period of time
as compared to classical ATP competitive kinase inhibitors. This
increases the anti-tumor cell efficacy at pharmacokinetic
clearance-mediated declining serum concentrations of the inhibitor
after dosing of a patient or an animal.
[0462] As compared to CDK9 inhibitors in the prior art, compounds
in the present invention show a surprisingly long target residence
time. It has been suggested earlier that the target residence time
is an appropriate predictor for drug efficacy on the basis that
equilibrium-based in vitro assays inadequately reflect in vivo
situations where drug concentrations fluctuate due to adsorption,
distribution and elimination processes and the target protein
concentration may be dynamically regulated (Tummino, P. J. and R.
A. Copeland, Residence time of receptor--ligand complexes and its
effect on biological function. Biochemistry, 2008. 47(20): p.
5481-5492; Copeland, R. A., D. L. Pompliano, and T. D. Meek,
Drug-target residence time and its implications for lead
optimization. Nature Reviews Drug Discovery, 2006. 5(9): p.
730-739).
[0463] Therefore, the equilibrium binding parameter, K.sub.D, or
the functional representative, IC.sub.50, may not fully reflect
requirements for in vivo efficacy. Assuming that a drug molecule
can only act as long as it remains bound to its target, the
"lifetime" (residence time), of the drug-target complex may serve
as a more reliable predictor for drug efficacy in a non-equilibrium
in vivo system. Several publications appreciated and discussed its
implications for in vivo efficacy (Lu, H. and P. J. Tonge,
Drug-target residence time: critical information for lead
optimization. Curr Opin Chem Biol, 2010. 14(4): p. 467-74;
Vauquelin, G. and S. J. Charlton, Long-lasting target binding and
rebinding as mechanisms to prolong in vivo drug action. Br J
Pharmacol, 2010. 161(3): p. 488-508).
[0464] One example for the impact of target residence time is given
by the drug tiotropium that is used in COPD treatment. Tiotropium
binds to the M1, M2 and M3 subtype of the muscarinic receptors with
comparable affinities, but is kinetically selective as it has the
desired long residence times only for the M3 receptor. Its
drug-target residence time is sufficiently long that after washout
from human trachea in vitro, tiotropium maintains inhibition of
cholinergic activity with a half-life of 9 hours. This translates
to protection against bronchospasms for more than 6 hours in vivo
(Price, D., A. Sharma, and F. Cerasoli, Biochemical properties,
pharmacokinetics and pharmacological response of tiotropium in
chronic obstructive pulmonary disease patients. 2009; Dowling, M.
(2006) Br. J. Pharmacol. 148, 927-937).
[0465] Another example is Lapatinib (Tykerb). It was found was that
the long target residence time found for lapatinib in the purified
intracellular domain enzyme reaction correlated with the observed,
prolonged signal inhibition in tumor cells based on receptor
tyrosine phosphorylation measurements. It was subsequently
concluded that the slow binding kinetics may offer increased signal
inhibition in the tumor, thus leading to greater potential to
affect the tumor growth rates or effectiveness of co-dosing with
other chemotherapeutic agents. (Wood et al (2004) Cancer Res. 64:
6652-6659; Lackey (2006) Current Topics in Medicinal Chemistry,
2006, Vol. 6, No. 5)
[0466] In context of the present invention, the IC.sub.50 value
with respect to CDK9 at high ATP concentrations can be determined
by the methods described in the method section below. Preferably,
it is determined according to Method 1b ("CDK9/CycT1 high ATP
kinase assay") as described in the Materials and Method section
below.
[0467] If desired, the IC.sub.50 value with respect to CDK9 at low
ATP concentration can e.g. be determined by the methods described
in the method section below, according to Method 1a. ("CDK9/CycT1
kinase assay") described in the Materials and Method section
below.
[0468] In context of the present invention, the target residence
time of selective CDK9 inhibitors according to the present
invention can be determined by the methods described in the method
section below. Preferably, it is determined according to Method 8
("Surface Plasmon Resonance PTEFb") as described in the Materials
and Method section below.
[0469] Further, compounds of the present invention according to
formula (I) surprisingly show a surprisingly high
anti-proliferative activity in tumor cell lines, such as HeLa,
HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 or MOLM-13,
compared to CDK9 inhibitors described in the prior art.
[0470] In context of the present invention, the anti-proliferative
activity in tumor cell lines such as HeLa, HeLa-MaTu-ADR, NCI-H460,
DU145, Caco-2, B16F10, A2780 or MOLM-13 is preferably determined
according to Method 3. ("Proliferation Assay") as described in the
Materials and Method section below.
[0471] In context of the present invention, the aqueous solubility
is preferably determined according to Method 4. ("Equilibrium Shake
Flask Solubility Assay") described in the Materials and Method
section below.
[0472] In context of the present invention, the metabolic stability
in rat hepatocytes is preferably determined according to Method 6.
("Investigation of in vitro metabolic stability in rat
hepatocytes") described in the Materials and Method section
below.
[0473] In context of the present invention, the half-life in rats
upon administration in vivo is preferably determined according to
Method 7. ("In vivo pharmacokinetics in rats") described in the
Materials and Method section below.
[0474] In context of the present invention, the apparent Caco-2
permeability values from the basal to apical compartment (P.sub.app
A-B) or the efflux ratio (defined as the ratio ((P.sub.app
B-A)/(P.sub.app A-B)) are preferably determined according to Method
5. ("Caco-2 Permeation Assay") described in the Materials and
Method section below.
[0475] A further subject matter of the present invention is the use
of the compounds of general formula (I) according to the invention
for the treatment and/or prophylaxis of disorders, preferably of
disorders relating to or mediated by CDK9 activity, in particular
of hyper-proliferative disorders, virally induced infectious
diseases and/or of cardiovascular diseases, more preferably of
hyper-proliferative disorders.
[0476] The compounds of the present invention may be used to
inhibit selectively the activity or expression of CDK9.
[0477] Therefore, the compounds of formula (I) are expected to be
valuable as therapeutic agents. Accordingly, in another embodiment,
the present invention provides a method of treating disorders
relating to or mediated by CDK9 activity in a patient in need of
such treatment, comprising administering to the patient an
effective amount of a compound of formula (I) as defined above. In
certain embodiments, the disorders relating to CDK9 activity are
hyper-proliferative disorders, virally induced infectious diseases
and/or of cardiovascular diseases, more preferably
hyper-proliferative disorders, particularly cancer.
[0478] The term "treating" or "treatment" as stated throughout this
document is used conventionally, e.g., the management or care of a
subject for the purpose of combating, alleviating, reducing,
relieving, improving the condition of a disease or disorder, such
as a carcinoma.
[0479] The term "subject" or "patient" includes organisms which are
capable of suffering from a cell proliferative disorder or a
disorder associated with reduced or insufficient programmed cell
death (apoptosis) or who could otherwise benefit from the
administration of a compound of the invention, such as human and
non-human animals. Preferred humans include human patients
suffering from or prone to suffering from a cell proliferative
disorder or associated state, as described herein. The term
"non-human animals" includes vertebrates, e.g., mammals, such as
non-human primates, sheep, cow, dog, cat and rodents, e.g., mice,
and non-mammals, such as chickens, amphibians, reptiles, etc.
[0480] The term "disorders relating to or mediated by CDK9" shall
include diseases associated with or implicating CDK9 activity, for
example the hyperactivity of CDK9, and conditions that accompany
with these diseases. Examples of "disorders relating to or mediated
by CDK9" include disorders resulting from increased CDK9 activity
due to mutations in genes regulating CDK9 activity such as LARP7,
HEXIM1/2 or 7sk snRNA, or disorders resulting from increased CDK9
activity due to activation of the CDK9/cyclinT/RNApolymerase II
complex by viral proteins such as HIV-TAT or HTLV-TAX or disorders
resulting from increased CDK9 activity due to activation of
mitogenic signaling pathways.
[0481] The term "hyperactivity of CDK9" refers to increased
enzymatic activity of CDK9 as compared to normal non-diseased
cells, or it refers to increased CDK9 activity leading to unwanted
cell proliferation, or to reduced or insufficient programmed cell
death (apoptosis), or mutations leading to constitutive activation
of CDK9.
[0482] The term "hyper-proliferative disorder" includes disorders
involving the undesired or uncontrolled proliferation of a cell and
it includes disorders involving reduced or insufficient programmed
cell death (apoptosis). The compounds of the present invention can
be utilized to prevent, inhibit, block, reduce, decrease, control,
etc., cell proliferation and/or cell division, and/or produce
apoptosis. This method comprises administering to a subject in need
thereof, including a mammal, including a human, an amount of a
compound of this invention, or a pharmaceutically acceptable salt,
hydrate or solvate thereof which is effective to treat or prevent
the disorder.
[0483] Hyper-proliferative disorders in the context of this
invention include, but are not limited to, e.g., psoriasis, keloids
and other hyperplasias affecting the skin, endometriosis, skeletal
disorders, angiogenic or blood vessel proliferative disorders,
pulmonary hypertension, fibrotic disorders, mesangial cell
proliferative disorders, colonic polyps, polycystic kidney disease,
benign prostate hyperplasia (BPH), and solid tumors, such as
cancers of the breast, respiratory tract, brain, reproductive
organs, digestive tract, urinary tract, eye, liver, skin, head and
neck, thyroid, parathyroid, and their distant metastases. Those
disorders also include lymphomas, sarcomas and leukemias.
[0484] Examples of breast cancer include, but are not limited to
invasive ductal carcinoma, invasive lobular carcinoma, ductal
carcinoma in situ, and lobular carcinoma in situ, and canine or
feline mammary carcinoma.
[0485] Examples of cancers of the respiratory tract include, but
are not limited to small-cell and non-small-cell lung carcinoma, as
well as bronchial adenoma, pleuropulmonary blastoma, and
mesothelioma.
[0486] Examples of brain cancers include, but are not limited to
brain stem and hypothalmic glioma, cerebellar and cerebral
astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as
neuroectodermal and pineal tumor.
[0487] Tumors of the male reproductive organs include, but are not
limited to prostate and testicular cancer.
[0488] Tumors of the female reproductive organs include, but are
not limited to endometrial, cervical, ovarian, vaginal and vulvar
cancer, as well as sarcoma of the uterus.
[0489] Tumors of the digestive tract include, but are not limited
to anal, colon, colorectal, esophageal, gallbladder, gastric,
pancreatic, rectal, small-intestine, salivary gland cancers, anal
gland adenocarcinomas, and mast cell tumors.
[0490] Tumors of the urinary tract include, but are not limited to
bladder, penile, kidney, renal pelvis, ureter, urethral, and
hereditary and sporadic papillary renal cancers.
[0491] Eye cancers include, but are not limited to intraocular
melanoma and retinoblastoma.
[0492] Examples of liver cancers include, but are not limited to
hepatocellular carcinoma (liver cell carcinomas with or without
fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct
carcinoma), and mixed hepatocellular cholangiocarcinoma.
[0493] Skin cancers include, but are not limited to squamous cell
carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin
cancer, non-melanoma skin cancer, and mast cell tumors.
[0494] Head-and-neck cancers include, but are not limited to
laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer,
lip and oral cavity cancer, squamous cell cancer, and oral
melanoma.
[0495] Lymphomas include, but are not limited to AIDS-related
lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma,
Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central
nervous system.
[0496] Sarcomas include, but are not limited to sarcoma of the soft
tissue, osteosarcoma, malignant fibrous histiocytoma,
lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis,
fibrosarcoma, hemangiosarcoma, hemangiopericytoma, and
leiomyosarcoma.
[0497] Leukemias include, but are not limited to acute myeloid
leukemia, acute lymphoblastic leukemia, chronic lymphocytic
leukemia, chronic myelogenous leukemia, and hairy cell
leukemia.
[0498] Fibrotic proliferative disorders, i.e. the abnormal
formation of extracellular matrices, that may be treated with the
compounds and methods of the present invention include lung
fibrosis, atherosclerosis, restenosis, hepatic cirrhosis, and
mesangial cell proliferative disorders, including renal diseases
such as glomerulonephritis, diabetic nephropathy, malignant
nephrosclerosis, thrombotic microangiopathy syn-dromes, transplant
rejection, and glomerulopathies.
[0499] Other conditions in humans or other mammals that may be
treated by administering a compound of the present invention
include tumor growth, retinopathy, including diabetic retinopathy,
ischemic retinal-vein occlusion, retinopathy of prematurity and
age-related macular degeneration, rheumatoid arthritis, psoriasis,
and bullous disorders associated with subepidermal blister
formation, including bullous pemphigoid, erythema multiforme and
dermatitis herpetiformis.
[0500] The compounds of the present invention may also be used to
prevent and treat diseases of the airways and the lung, diseases of
the gastrointestinal tract as well as diseases of the bladder and
bile duct.
[0501] The disorders mentioned above have been well characterized
in humans, but also exist with a similar etiology in other animals,
including mammals, and can be treated by administering
pharmaceutical compositions of the present invention.
[0502] In a further aspect of the present invention, the compounds
according to the invention are used in a method for preventing
and/or treating infectious diseases, in particular virally induced
infectious diseases. The virally induced infectious diseases,
including opportunistic diseases, are caused by retroviruses,
hepadnaviruses, herpesviruses, flaviviridae, and/or adenoviruses.
In a further preferred embodiment of this method, the retroviruses
are selected from lentiviruses or oncoretroviruses, wherein the
lentivirus is selected from the group comprising: HIV-1, HIV-2,
FIV, BIV, SIVs, SHIV, CAEV, VMV or EIAV, preferably HIV-1 or HIV-2
and wherein the oncoretrovirus is selected from the group of:
HTLV-I, HTLV-II or BLV. In a further preferred embodiment of this
method, the hepadnavirus is selected from HBV, GSHV or WHV,
preferably HBV, the herpesvirus is selected from the group
comprising: HSV I, HSV II, EBV, VZV, HCMV or HHV 8, preferably HCMV
and the flaviviridae is selected from HCV, West nile or Yellow
Fever.
[0503] The compounds according to general formula (I) are also
useful for prophylaxis and/or treatment of cardiovascular diseases
such as cardiac hypertrophy, adult congenital heart disease,
aneurysm, stable angina, unstable angina, angina pectoris,
angioneurotic edema, aortic valve stenosis, aortic aneurysm,
arrhythmia, arrhythmogenic right ventricular dysplasia,
arteriosclerosis, arteriovenous malformations, atrial fibrillation,
Behcet syndrome, bradycardia, cardiac tamponade, cardiomegaly,
congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive
cardiomyopathy, cardiovascular disease prevention, carotid
stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes,
Ebstein's Anomaly, Eisenmenger complex, cholesterol embolism,
bacterial endocarditis, fibromuscular dysplasia, congenital heart
defects, heart diseases, congestive heart failure, heart valve
diseases, heart attack, epidural hematoma, hematoma, subdural,
Hippel-Lindau disease, hyperemia, hypertension, pulmonary
hypertension, hypertrophic growth, left ventricular hypertrophy,
right ventricular hypertrophy, hypoplastic left heart syndrome,
hypotension, intermittent claudication, ischemic heart disease,
Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome, long
QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneous
lymph node syndrome, myocardial infarction, myocardial ischemia,
myocarditis, pericarditis, peripheral vascular diseases, phlebitis,
polyarteritis nodosa, pulmonary atresia, Raynaud disease,
restenosis, Sneddon syndrome, stenosis, superior vena cava
syndrome, syndrome X, tachycardia, Takayasu's arteritis, hereditary
hemorrhagic telangiectasia, telangiectasis, temporal arteritis,
tetralogy of fallot, thromboangiitis obliterans, thrombosis,
thromboembolism, tricuspid atresia, varicose veins, vascular
diseases, vasculitis, vasospasm, ventricular fibrillation, Williams
syndrome, peripheral vascular disease, varicose veins and leg
ulcers, deep vein thrombosis, Wolff-Parkinson-White syndrome.
[0504] Preferred are cardiac hypertrophy, adult congenital heart
disease, aneurysms, angina, angina pectoris, arrhythmias,
cardiovascular disease prevention, cardiomyopathies, congestive
heart failure, myocardial infarction, pulmonary hypertension,
hypertrophic growth, restenosis, stenosis, thrombosis and
arteriosclerosis.
[0505] A further subject matter of the present invention is the use
of the compounds of general formula (I) according to the invention
as a medicament.
[0506] A further subject matter of the present invention is the use
of the compounds of general formula (I) according to the invention
for the treatment and/or prophylaxis of disorders, in particular of
the disorders mentioned above.
[0507] A further subject matter of the present invention is the use
of the compounds of general formula (I) according to the invention
for the treatment and/or prophylaxis of hyper-proliferative
disorders, virally induced infectious diseases and/or of
cardiovascular diseases.
[0508] A preferred subject matter of the present invention is the
use of the compounds of general formula (I) according to the
invention for the treatment and/or prophylaxis of lung carcinomas,
especially non-small cell lung carcinomas, prostate carcinomas,
especially hormone-independent human prostate carcinomas, cervical
carcinomas, including multidrug-resistant human cervical
carcinomas, colorectal carcinomas, melanomas, ovarian carcinomas or
leukemias, especially acute myeloid leukemias.
[0509] A further subject matter of the present invention are the
compounds of general formula (I) according to the invention for the
use as a medicament.
[0510] A further subject matter of the present invention are the
compounds of general formula (I) according to the invention for the
use of treating and/or prophylaxis of the disorders mentioned
above.
[0511] A further subject matter of the present invention are the
compounds of general formula (I) according to the invention for the
use of treating and/or prophylaxis of hyper-proliferative
disorders, virally induced infectious diseases and/or of
cardiovascular diseases.
[0512] A preferred subject matter of the present invention are the
compounds of general formula (I) according to the invention for the
use of treating and/or prophylaxis of lung carcinomas, especially
non-small cell lung carcinomas, prostate carcinomas, especially
hormone-independent human prostate carcinomas, cervical carcinomas,
including multidrug-resistant human cervical carcinomas, colorectal
carcinomas, melanomas, ovarian carcinomas or leukemias, especially
acute myeloid leukemias.
[0513] A further subject matter of the present invention are the
compounds of general formula (I) according to the invention for the
use in a method for the treatment and/or prophylaxis of the
disorders mentioned above.
[0514] A further subject matter of the present invention are the
compounds of general formula (I) according to the invention for the
use in a method for the treatment and/or prophylaxis of
hyper-proliferative disorders, virally induced infectious diseases
and/or of cardiovascular diseases.
[0515] A preferred subject matter of the present invention are the
compounds of general formula (I) according to the invention for the
use in a method of treatment and/or prophylaxis of lung carcinomas,
especially non-small cell lung carcinomas, prostate carcinomas,
especially hormone-independent human prostate carcinomas, cervical
carcinomas, including multidrug-resistant human cervical
carcinomas, colorectal carcinomas, melanomas, ovarian carcinomas or
leukemias, especially acute myeloid leukemias.
[0516] A further subject matter of the present invention is the use
of the compounds of general formula (I) according to the invention
in the manufacture of a medicament for the treatment and/or
prophylaxis of disorders, in particular the disorders mentioned
above.
[0517] A further subject matter of the present invention is the use
of the compounds of general formula (I) according to the invention
in the manufacture of a medicament for the treatment and/or
prophylaxis of hyper-proliferative disorders, virally induced
infectious diseases and/or of cardiovascular diseases.
[0518] A preferred subject matter of the present invention is the
use of the compounds of general formula (I) according to the
invention in the manufacture of a medicament for the treatment
and/or prophylaxis of lung carcinomas, especially non-small cell
lung carcinomas, prostate carcinomas, especially
hormone-independent human prostate carcinomas, cervical carcinomas,
including multidrug-resistant human cervical carcinomas, colorectal
carcinomas, melanomas, ovarian carcinomas or leukemias, especially
acute myeloid leukemias.
[0519] A further subject matter of the present invention is a
method for the treatment and/or prophylaxis of disorders, in
particular the disorders mentioned above, using an effective amount
of the compounds of general formula (I) according to the
invention.
[0520] A further subject matter of the present invention is a
method for the treatment and/or prophylaxis of hyper-proliferative
disorders, virally induced infectious diseases and/or of
cardiovascular diseases, using an effective amount of the compounds
of general formula (I) according to the invention.
[0521] A preferred subject matter of the present invention is a
method for the treatment and/or prophylaxis of lung carcinomas,
especially non-small cell lung carcinomas, prostate carcinomas,
especially hormone-independent human prostate carcinomas, cervical
carcinomas, including multidrug-resistant human cervical
carcinomas, colorectal carcinomas, melanomas, ovarian carcinomas or
leukemias, especially acute myeloid leukemias using an effective
amount of the compounds of general formula (I) according to the
invention.
[0522] Another aspect of the present invention relates to
pharmaceutical combinations comprising a compound of general
formula (I) according to the invention in combination with at least
one or more further active ingredients.
[0523] As used herein the term "pharmaceutical combination" refers
to a combination of at least one compound of general formula (I)
according to the invention as active ingredient together with at
least one other active ingredient with or without further
ingredients, carrier, diluents and/or solvents.
[0524] Another aspect of the present invention relates to
pharmaceutical compositions comprising a compound of general
formula (I) according to the invention in combination with an
inert, nontoxic, pharmaceutically suitable adjuvant.
[0525] As used herein the term "pharmaceutical composition" refers
to a galenic formulation of at least one pharmaceutically active
agent together with at least one further ingredient, carrier,
diluent and/or solvent.
[0526] Another aspect of the present invention relates to the use
of the pharmaceutical combinations and/or the pharmaceutical
compositions according to the invention for the treatment and/or
prophylaxis of disorders, in particular of the disorders mentioned
above.
[0527] Another aspect of the present invention relates to the use
of the pharmaceutical combinations and/or the pharmaceutical
compositions according to the invention for the treatment and/or
prophylaxis of lung carcinomas, especially non-small cell lung
carcinomas, prostate carcinomas, especially hormone-independent
human prostate carcinomas, cervical carcinomas, including
multidrug-resistant human cervical carcinomas, colorectal
carcinomas, melanomas, ovarian carcinomas or leukemias, especially
acute myeloid leukemias.
[0528] Another aspect of the present invention relates to
pharmaceutical combinations and/or the pharmaceutical compositions
according to the invention for use of the treatment and/or
prophylaxis of disorders, in particular of the disorders mentioned
above.
[0529] Another aspect of the present invention relates to
pharmaceutical combinations and/or the pharmaceutical compositions
according to the invention for use of the treatment and/or
prophylaxis of lung carcinomas, especially non-small cell lung
carcinomas, prostate carcinomas, especially hormone-independent
human prostate carcinomas, cervical carcinomas, including
multidrug-resistant human cervical carcinomas, colorectal
carcinomas, melanomas, ovarian carcinomas or leukemias, especially
acute myeloid leukemias.
[0530] Compounds of formula (I) may be administered as the sole
pharmaceutical agent or in combination with one or more additional
therapeutic agents where the combination causes no unacceptable
adverse effects.
[0531] This pharmaceutical combination includes administration of a
single pharmaceutical dosage formulation which contains a compound
of formula (I) and one or more additional therapeutic agents, as
well as administration of the compound of formula (I) and each
additional therapeutic agent in its own separate pharmaceutical
dosage formulation. For example, a compound of formula (I) and a
therapeutic agent may be administered to the patient together in a
single oral dosage composition such as a tablet or capsule, or each
agent may be administered in separate dosage formulations.
[0532] Where separate dosage formulations are used, the compound of
formula (I) and one or more additional therapeutic agents may be
administered at essentially the same time (e.g., concurrently) or
at separately staggered times (e.g., sequentially).
[0533] In particular, the compounds of the present invention may be
used in fixed or separate combination with other anti-tumor agents
such as alkylating agents, anti-metabolites, plant-derived
anti-tumor agents, hormonal therapy agents, topoisomerase
inhibitors, camptothecin derivatives, kinase inhibitors, targeted
drugs, antibodies, interferons and/or biological response
modifiers, anti-angiogenic compounds, and other anti-tumor drugs.
In this regard, the following is a non-limiting list of examples of
secondary agents that may be used in combination with the compounds
of the present invention: [0534] Alkylating agents include, but are
not limited to, nitrogen mustard N-oxide, cyclophosphamide,
ifosfamide, thiotepa, ranimustine, nimustine, temozolomide,
altretamine, apaziquone, brostallicin, bendamustine, carmustine,
estramustine, fotemustine, glufosfamide, mafosfamide, bendamustin,
and mitolactol; platinum-coordinated alkylating compounds include,
but are not limited to, cisplatin, carboplatin, eptaplatin,
lobaplatin, nedaplatin, oxaliplatin, and satraplatin; [0535]
Anti-metabolites include, but are not limited to, methotrexate,
6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone or
in combination with leucovorin, tegafur, doxifluridine, carmofur,
cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine,
fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine,
decitabine, eflornithine, ethynylcytidine, cytosine arabinoside,
hydroxyurea, melphalan, nelarabine, nolatrexed, ocfosfite, disodium
premetrexed, pentostatin, pelitrexol, raltitrexed, triapine,
trimetrexate, vidarabine, vincristine, and vinorelbine; [0536]
Hormonal therapy agents include, but are not limited to,
exemestane, Lupron, anastrozole, doxercalciferol, fadrozole,
formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitors,
17-alpha hydroxylase/17,20 lyase inhibitors such as abiraterone
acetate, 5-alpha reductase inhibitors such as finasteride and
epristeride, anti-estrogens such as tamoxifen citrate and
fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene,
letrozole, anti-androgens such as bicalutamide, flutamide,
mifepristone, nilutamide, Casodex, and anti-progesterones and
combinations thereof; [0537] Plant-derived anti-tumor substances
include, e.g., those selected from mitotic inhibitors, for example
epothilones such as sagopilone, ixabepilone and epothilone B,
vinblastine, vinflunine, docetaxel, and paclitaxel; [0538]
Cytotoxic topoisomerase inhibiting agents include, but are not
limited to, aclarubicin, doxorubicin, amonafide, belotecan,
camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,
diflomotecan, irinotecan, topotecan, edotecarin, epimbicin,
etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone,
pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and
combinations thereof; [0539] Immunologicals include interferons
such as interferon alpha, interferon alpha-2a, interferon alpha-2b,
interferon beta, interferon gamma-1a and interferon gamma-ni, and
other immune enhancing agents such as L19-IL2 and other IL2
derivatives, filgrastim, lentinan, sizofilan, TheraCys, ubenimex,
aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab,
denileukin, gemtuzumab, ozogamicin, ibritumomab, imiquimod,
lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,
sargramostim, tasonermin, tecleukin, thymalasin, tositumomab,
Vimlizin, epratuzumab, mitumomab, oregovomab, pemtumomab, and
Provenge; Merial melanoma vaccine [0540] Biological response
modifiers are agents that modify defense mechanisms of living
organisms or biological responses such as survival, growth or
differentiation of tissue cells to direct them to have anti-tumor
activity; such agents include, e.g., krestin, lentinan, sizofiran,
picibanil, ProMune, and ubenimex; [0541] Anti-angiogenic compounds
include, but are not limited to, acitretin, aflibercept,
angiostatin, aplidine, asentar, axitinib, recentin, bevacizumab,
brivanib alaninat, cilengtide, combretastatin, DAST, endostatin,
fenretinide, halofuginone, pazopanib, ranibizumab, rebimastat,
removab, revlimid, sorafenib, vatalanib, squalamine, sunitinib,
telatinib, thalidomide, ukrain, and vitaxin; [0542] Antibodies
include, but are not limited to, trastuzumab, cetuximab,
bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab,
catumaxomab, atacicept, oregovomab, and alemtuzumab; [0543] VEGF
inhibitors such as, e.g., sorafenib, DAST, bevacizumab, sunitinib,
recentin, axitinib, aflibercept, telatinib, brivanib alaninate,
vatalanib, pazopanib, and ranibizumab; Palladia [0544] EGFR (HER1)
inhibitors such as, e.g., cetuximab, panitumumab, vectibix,
gefitinib, erlotinib, and Zactima; [0545] HER2 inhibitors such as,
e.g., lapatinib, trastuzumab, and pertuzumab; [0546] mTOR
inhibitors such as, e.g., temsirolimus, sirolimus/Rapamycin, and
everolimus; [0547] c-Met inhibitors; [0548] PI3K and AKT
inhibitors; [0549] CDK inhibitors such as roscovitine and
flavopiridol; [0550] Spindle assembly checkpoints inhibitors and
targeted anti-mitotic agents such as PLK inhibitors, Aurora
inhibitors (e.g. Hesperadin), checkpoint kinase inhibitors, and KSP
inhibitors; [0551] HDAC inhibitors such as, e.g., panobinostat,
vorinostat, MS275, belinostat, and LBH589; [0552] HSP90 and HSP70
inhibitors; [0553] Proteasome inhibitors such as bortezomib and
carfilzomib; [0554] Serine/threonine kinase inhibitors including
MEK inhibitors (such as e.g. RDEA 119) and Raf inhibitors such as
sorafenib; [0555] Farnesyl transferase inhibitors such as, e.g.,
tipifarnib; [0556] Tyrosine kinase inhibitors including, e.g.,
dasatinib, nilotibib, DAST, bosutinib, sorafenib, bevacizumab,
sunitinib, AZD2171, axitinib, aflibercept, telatinib, imatinib
mesylate, brivanib alaninate, pazopanib, ranibizumab, vatalanib,
cetuximab, panitumumab, vectibix, gefitinib, erlotinib, lapatinib,
tratuzumab, pertuzumab, and c-Kit inhibitors; Palladia, masitinib
[0557] Vitamin D receptor agonists; [0558] Bcl-2 protein inhibitors
such as obatoclax, oblimersen sodium, and gossypol; [0559] Cluster
of differentiation 20 receptor antagonists such as, e.g.,
rituximab; [0560] Ribonucleotide reductase inhibitors such as,
e.g., gemcitabine; [0561] Tumor necrosis apoptosis inducing ligand
receptor 1 agonists such as, e.g., mapatumumab; [0562]
5-Hydroxytryptamine receptor antagonists such as, e.g., rEV598,
xaliprode, palonosetron hydrochloride, granisetron, Zindol, and
AB-1001; [0563] Integrin inhibitors including alpha5-beta1 integrin
inhibitors such as, e.g., E7820, JSM 6425, volociximab, and
endostatin; [0564] Androgen receptor antagonists including, e.g.,
nandrolone decanoate, fluoxymesterone, Android, Prost-aid,
andromustine, bicalutamide, flutamide, apo-cyproterone,
apo-flutamide, chlormadinone acetate, Androcur, Tabi, cyproterone
acetate, and nilutamide; [0565] Aromatase inhibitors such as, e.g.,
anastrozole, letrozole, testolactone, exemestane,
amino-glutethimide, and formestane; [0566] Matrix metalloproteinase
inhibitors; [0567] Other anti-cancer agents including, e.g.,
alitretinoin, ampligen, atrasentan bexarotene, bortezomib,
bosentan, calcitriol, exisulind, fotemustine, ibandronic acid,
miltefosine, mitoxantrone, I-asparaginase, procarbazine,
dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,
tazaroten, velcade, gallium nitrate, canfosfamide, darinaparsin,
and tretinoin.
[0568] The compounds of the present invention may also be employed
in cancer treatment in conjunction with radiation therapy and/or
surgical intervention.
[0569] Generally, the use of cytotoxic and/or cytostatic agents in
combination with a compound or composition of the present invention
will serve to: [0570] (1) yield better efficacy in reducing the
growth of a tumor or even eliminate the tumor as compared to
administration of either agent alone, [0571] (2) provide for the
administration of lesser amounts of the administered
chemotherapeutic agents, [0572] (3) provide for a chemotherapeutic
treatment that is well tolerated in the patient with fewer
deleterious pharmacological complications than observed with single
agent chemotherapies and certain other combined therapies, [0573]
(4) provide for treating a broader spectrum of different cancer
types in mammals, especially humans, [0574] (5) provide for a
higher response rate among treated patients, [0575] (6) provide for
a longer survival time among treated patients compared to standard
chemotherapy treatments, [0576] (7) provide a longer time for tumor
progression, and/or [0577] (8) yield efficacy and tolerability
results at least as good as those of the agents used alone,
compared to known instances where other cancer agent combinations
produce antagonistic effects.
[0578] Furthermore, the compounds of formula (I) may be utilized,
as such or in compositions, in research and diagnostics, or as
analytical reference standards, and the like, which are well known
in the art.
[0579] The compounds according to the invention can act
systemically and/or locally. For this purpose, they can be
administered in a suitable way, such as, for example, by the oral,
parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal,
dermal, transdermal, conjunctival or otic route, or as an implant
or stent.
[0580] For these administration routes, it is possible to
administer the compounds according to the invention in suitable
application forms.
[0581] Suitable for oral administration are administration forms
which work as described in the prior art and deliver the compounds
according to the invention rapidly and/or in modified form, which
comprise the compounds according to the invention in crystalline
and/or amorphous and/or dissolved form, such as, for example,
tablets (coated or uncoated, for example tablets provided with
enteric coatings or coatings whose dissolution is delayed or which
are insoluble and which control the release of the compound
according to the invention), tablets which rapidly decompose in the
oral cavity, or films/wafers, films/lyophilizates, capsules (for
example hard or soft gelatin capsules), sugar-coated tablets,
granules, pellets, powders, emulsions, suspensions, aerosols or
solutions.
[0582] Parenteral administration can take place with avoidance of
an absorption step (for example intravenously, intraarterially,
intracardially, intraspinally or intralumbally) or with inclusion
of absorption (for example intramuscularly, subcutaneously,
intracutaneously, percutaneously or intraperitoneally).
Administration forms suitable for parenteral administration are,
inter alia, preparations for injection and infusion in the form of
solutions, suspensions, emulsions, lyophilizates or sterile
powders.
[0583] Examples suitable for the other administration routes are
pharmaceutical forms for inhalation (inter alia powder inhalers,
nebulizers), nasal drops/solutions/sprays; tablets to be
administered lingually, sublingually or buccally, films/wafers or
capsules, suppositories, preparations for the eyes or ears, vaginal
capsules, aqueous suspensions (lotions, shaking mixtures),
lipophilic suspensions, ointments, creams, transdermal therapeutic
systems (such as plasters, for example), milk, pastes, foams,
dusting powders, implants or stents.
[0584] The compounds according to the invention can be converted
into the stated administration forms. This can take place in a
manner known per se by mixing with inert, nontoxic,
pharmaceutically suitable adjuvants. These adjuvants include, inter
alia, carriers (for example microcrystalline cellulose, lactose,
mannitol), solvents (for example liquid polyethylene glycols),
emulsifiers and dispersants or wetting agents (for example sodium
dodecyl sulphate, polyoxysorbitan oleate), binders (for example
polyvinylpyrrolidone), synthetic and natural polymers (for example
albumin), stabilizers (for example antioxidants, such as, for
example, ascorbic acid), colorants (for example inorganic pigments,
such as, for example, iron oxides) and flavour- and/or
odour-masking agents.
[0585] The present invention furthermore provides medicaments
comprising at least one compound according to the invention,
usually together with one or more inert, nontoxic, pharmaceutically
suitable adjuvants, and their use for the purposes mentioned
above.
[0586] When the compounds of the present invention are administered
as pharmaceuticals, to humans or animals, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1% to
99.5% (more preferably 0.5% to 90%) of active ingredient in
combination with one or more inert, nontoxic, pharmaceutically
suitable adjuvants.
[0587] Regardless of the route of administration selected, the
compounds according to the invention of general formula (I) and/or
the pharmaceutical composition of the present invention are
formulated into pharmaceutically acceptable dosage forms by
conventional methods known to those of skill in the art.
[0588] Actual dosage levels and time course of administration of
the active ingredients in the pharmaceutical compositions of the
invention may be varied so as to obtain an amount of the active
ingredient which is effective to achieve the desired therapeutic
response for a particular patient without being toxic to the
patient.
Materials and Methods:
[0589] The percentage data in the following tests and examples are
percentages by weight unless otherwise indicated; parts are parts
by weight. Solvent ratios, dilution ratios and concentration data
of liquid/liquid solutions are in each case based on volume.
[0590] Examples were tested in selected biological and/or
physicochemical assays one or more times. When tested more than
once, data are reported as either average values or as median
values, wherein [0591] the average value, also referred to as the
arithmetic mean value, represents the sum of the values obtained
divided by the number of times tested, and [0592] the median value
represents the middle number of the group of values when ranked in
ascending or descending order. If the number of values in the data
set is odd, the median is the middle value. If the number of values
in the data set is even, the median is the arithmetic mean of the
two middle values.
[0593] Examples were synthesized one or more times. When
synthesized more than once, data from biological and/or
physicochemical assays represent average values or median values
calculated utilizing data sets obtained from testing of one or more
synthetic batch.
[0594] The in vitro pharmacological, pharmacokinetic and
physicochemical properties of the compounds can be determined
according to the following assays and methods.
[0595] Noteworthily, in the CDK9 assays described below the
resolution power is limited by the enzyme concentrations, the lower
limit for IC.sub.50s is about 1-2 nM in the CDK9 high ATP assay and
2-4 nM in the CDK low ATP assays. For compounds exhibiting
IC.sub.50s in this range the true affinity to CDK9 and thus the
selectivity for CDK9 over CDK2 might be even higher, i.e. for these
compounds the selectivity factors calculated in columns 4 and 7 of
Table 2, infra, are minimal values, they could be also higher.
1a. CDK9/CycT1 Kinase Assay
[0596] CDK9/CycT1-inhibitory activity of compounds of the present
invention was quantified employing the CDK9/CycT1 TR-FRET assay as
described in the following paragraphs.
[0597] Recombinant full-length His-tagged human CDK9 and CycT1,
expressed in insect cells and purified by Ni-NTA affinity
chromatography, were purchase from Invitrogen (Cat. No PV4131). As
substrate for the kinase reaction biotinylated peptide
biotin-Ttds-YISPLKSPYKISEG (C-terminus in amid form) was used which
can be purchased e.g. form the company JERINI peptide technologies
(Berlin, Germany). For the assay 50 nl of a 100fold concentrated
solution of the test compound in DMSO was pipetted into a black low
volume 384well microtiter plate (Greiner Bio-One, Frickenhausen,
Germany), 2 .mu.l of a solution of CDK9/CycT1 in aqueous assay
buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl2, 1.0 mM dithiothreitol,
0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were
added and the mixture was incubated for 15 min at 22.degree. C. to
allow pre-binding of the test compounds to the enzyme before the
start of the kinase reaction. Then the kinase reaction was started
by the addition of 3 .mu.l of a solution of adenosine-tri-phosphate
(ATP, 16.7 .mu.M=>final conc. in the 5 .mu.l assay volume is 10
.mu.M) and substrate (1.25 .mu.M=>final conc. in the 5 .mu.l
assay volume is 0.75 .mu.M) in assay buffer and the resulting
mixture was incubated for a reaction time of 25 min at 22.degree.
C. The concentration of CDK9/CycT1 was adjusted depending of the
activity of the enzyme lot and was chosen appropriate to have the
assay in the linear range, typical concentrations were in the range
of 1 .mu.g/ml. The reaction was stopped by the addition of 5 .mu.l
of a solution of TR-FRET detection reagents (0.2 .mu.M
streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM
anti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and
1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody
[Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution
(100 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES pH
7.5).
[0598] The resulting mixture was incubated 1 h at 22.degree. C. to
allow the formation of complex between the phosphorylated
biotinylated peptide and the detection reagents. Subsequently the
amount of phosphorylated substrate was evaluated by measurement of
the resonance energy transfer from the Eu-chelate to the
streptavidine-XL. Therefore, the fluorescence emissions at 620 nm
and 665 nm after excitation at 350 nm was measured in a TR-FRET
reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany)
or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm
and at 622 nm was taken as the measure for the amount of
phosphorylated substrate. The data were normalised (enzyme reaction
without inhibitor=0% inhibition, all other assay components but no
enzyme=100% inhibition). Usually the test compounds were tested on
the same microtiterplate in 11 different concentrations in the
range of 20 .mu.M to 0.07 nM (20 .mu.M, 5.7 .mu.M, 1.6 .mu.M, 0.47
.mu.M, 0.13 .mu.M, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07
nM, the dilution series prepared separately before the assay on the
level of the 100fold concentrated solutions in DMSO by serial
dilutions, exact concentrations may vary depending pipettors used)
in duplicate values for each concentration and IC50 values were
calculated using Genedata Screener.TM. software.
1b. CDK9/CycT1 High ATP Kinase Assay
[0599] CDK9/CycT1-inhibitory activity of compounds of the present
invention at a high ATP concentration after preincubation of enzyme
and test compounds was quantified employing the CDK9/CycT1 TR-FRET
assay as described in the following paragraphs.
[0600] Recombinant full-length His-tagged human CDK9 and CycT1,
expressed in insect cells and purified by Ni-NTA affinity
chromatography, were purchased from Life Technologies (Cat. No
PV4131). As substrate for the kinase reaction biotinylated peptide
biotin-Ttds-YISPLKSPYKISEG (C-terminus in amide form) was used
which can be purchased e.g. form the company JERINI peptide
technologies (Berlin, Germany).
[0601] For the assay 50 nl of a 100fold concentrated solution of
the test compound in DMSO was pipetted into either a black low
volume 384well microtiter plate or a black 1536well microtiter
plate (both Greiner Bio-One, Frickenhausen, Germany), 2 .mu.l of a
solution of CDK9/CycT1 in aqueous assay buffer [50 mM Tris/HCl pH
8.0, 10 mM MgCl2, 1.0 mM dithiothreitol, 0.1 mM sodium
ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added and the
mixture was incubated for 15 min at 22.degree. C. to allow
pre-binding of the test compounds to the enzyme before the start of
the kinase reaction. Then the kinase reaction was started by the
addition of 3 .mu.l of a solution of adenosine-tri-phosphate (ATP,
3.3 mM=>final conc. in the 5 .mu.l assay volume is 2 mM) and
substrate (1.25 .mu.M=>final conc. in the 5 .mu.l assay volume
is 0.75 .mu.M) in assay buffer and the resulting mixture was
incubated for a reaction time of 25 min at 22.degree. C. The
concentration of CDK9/CycT1 was adjusted depending of the activity
of the enzyme lot and was chosen appropriate to have the assay in
the linear range, typical concentrations were in the range of 0.5
.mu.g/ml. The reaction was stopped by the addition of 3 .mu.l of a
solution of TR-FRET detection reagents (0.33 .mu.M
streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1.67 nM
anti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and
2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer,
product no. AD0077]) in an aqueous EDTA-solution (167 mM EDTA, 0.2%
(w/v) bovine serum albumin in 100 mM HEPES pH 7.5).
[0602] The resulting mixture was incubated 1 h at 22.degree. C. to
allow the formation of complex between the phosphorylated
biotinylated peptide and the detection reagents. Subsequently the
amount of phosphorylated substrate was evaluated by measurement of
the resonance energy transfer from the Eu-chelate to the
streptavidine-XL. Therefore, the fluorescence emissions at 620 nm
and 665 nm after excitation at 350 nm was measured in a TR-FRET
reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany)
or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm
and at 622 nm was taken as the measure for the amount of
phosphorylated substrate. The data were normalised (enzyme reaction
without inhibitor=0% inhibition, all other assay components but no
enzyme=100% inhibition). Usually the test compounds were tested on
the same microtiterplate in 11 different concentrations in the
range of 20 .mu.M to 0.07 nM (20 .mu.M, 5.7 .mu.M, 1.6 .mu.M, 0.47
.mu.M, 0.13 .mu.M, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07
nM, the dilution series prepared separately before the assay on the
level of the 100fold concentrated solutions in DMSO by serial
dilutions, exact concentrations may vary depending pipettors used)
in duplicate values for each concentration and IC50 values were
calculated using Genedata Screener.TM. software.
2a. CDK2/CycE Kinase Assay
[0603] CDK2/CycE-inhibitory activity of compounds of the present
invention was quantified employing the CDK2/CycE TR-FRET assay as
described in the following paragraphs.
[0604] Recombinant fusion proteins of GST and human CDK2 and of GST
and human CycE, expressed in insect cells (Sf9) and purified by
Glutathion-Sepharose affinity chromatography, were purchase from
ProQinase GmbH (Freiburg, Germany). As substrate for the kinase
reaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG
(C-terminus in amid form) was used which can be purchased e.g. form
the company JERINI peptide technologies (Berlin, Germany).
[0605] For the assay 50 nl of a 100fold concentrated solution of
the test compound in DMSO was pipetted into a black low volume
384well microtiter plate (Greiner Bio-One, Frickenhausen, Germany),
2 .mu.l of a solution of CDK2/CycE in aqueous assay buffer [50 mM
Tris/HCl pH 8.0, 10 mM MgCl2, 1.0 mM dithiothreitol, 0.1 mM sodium
ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added and the
mixture was incubated for 15 min at 22.degree. C. to allow
pre-binding of the test compounds to the enzyme before the start of
the kinase reaction. Then the kinase reaction was started by the
addition of 3 .mu.l of a solution of adenosine-tri-phosphate (ATP,
16.7 .mu.M=>final conc. in the 5 .mu.l assay volume is 10 .mu.M)
and substrate (1.25 .mu.M=>final conc. in the 5 .mu.l assay
volume is 0.75 .mu.M) in assay buffer and the resulting mixture was
incubated for a reaction time of 25 min at 22.degree. C. The
concentration of CDK2/CycE was adjusted depending of the activity
of the enzyme lot and was chosen appropriate to have the assay in
the linear range, typical concentrations were in the range of 130
ng/ml. The reaction was stopped by the addition of 5 .mu.l of a
solution of TR-FRET detection reagents (0.2 .mu.M
streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM
anti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and
1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody
[Perkin-Elmer, product no. AD0077, as an alternative a
Terbium-cryptate-labeled anti-mouse IgG antibody from Cisbio
Bioassays can be used]) in an aqueous EDTA-solution (100 mM EDTA,
0.2% (w/v) bovine serum albumin in 100 mM HEPES pH 7.5).
[0606] The resulting mixture was incubated 1 h at 22.degree. C. to
allow the formation of complex between the phosphorylated
biotinylated peptide and the detection reagents. Subsequently the
amount of phosphorylated substrate was evaluated by measurement of
the resonance energy transfer from the Eu-chelate to the
streptavidine-XL. Therefore, the fluorescence emissions at 620 nm
and 665 nm after excitation at 350 nm was measured in a TR-FRET
reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany)
or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm
and at 622 nm was taken as the measure for the amount of
phosphorylated substrate. The data were normalised (enzyme reaction
without inhibitor=0% inhibition, all other assay components but no
enzyme=100% inhibition). Usually the test compounds were tested on
the same microtiterplate in 11 different concentrations in the
range of 20 .mu.M to 0.07 nM (20 .mu.M, 5.7 .mu.M, 1.6 .mu.M, 0.47
.mu.M, 0.13 .mu.M, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07
nM, the dilution series prepared separately before the assay on the
level of the 100fold concentrated solutions in DMSO by serial
dilutions, exact concentrations may vary depending pipettors used)
in duplicate values for each concentration and IC50 values were
calculated using Genedata Screener.TM. software.
2b. CDK2/CycE High ATP Kinase Assay
[0607] CDK2/CycE-inhibitory activity of compounds of the present
invention at 2 mM adenosine-tri-phosphate (ATP) was quantified
employing the CDK2/CycE TR-FRET (TR-FRET=Time Resolved Fluorescence
Energy Transfer) assay as described in the following
paragraphs.
[0608] Recombinant fusion proteins of GST and human CDK2 and of GST
and human CycE, expressed in insect cells (Sf9) and purified by
Glutathion-Sepharose affinity chromatography, were purchase from
ProQinase GmbH (Freiburg, Germany). As substrate for the kinase
reaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG
(C-terminus in amid form) was used which can be purchased e.g. form
the company JERINI peptide technologies (Berlin, Germany).
[0609] For the assay 50 nl of a 100fold concentrated solution of
the test compound in DMSO was pipetted into either a black low
volume 384well microtiter plate or a black 1536well microtiter
plate (both Greiner Bio-One, Frickenhausen, Germany), 2 .mu.l of a
solution of CDK2/CycE in aqueous assay buffer [50 mM Tris/HCl pH
8.0, 10 mM MgCl2, 1.0 mM dithiothreitol, 0.1 mM sodium
ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added and the
mixture was incubated for 15 min at 22.degree. C. to allow
pre-binding of the test compounds to the enzyme before the start of
the kinase reaction. Then the kinase reaction was started by the
addition of 3 .mu.l of a solution ATP (3.33 mM=>final conc. in
the 5 .mu.l assay volume is 2 mM) and substrate (1.25
.mu.M=>final conc. in the 5 .mu.l assay volume is 0.75 .mu.M) in
assay buffer and the resulting mixture was incubated for a reaction
time of 25 min at 22.degree. C. The concentration of CDK2/CycE was
adjusted depending of the activity of the enzyme lot and was chosen
appropriate to have the assay in the linear range, typical
concentrations were about 10 ng/ml. The reaction was stopped by the
addition of 3 .mu.l of a solution of TR-FRET detection reagents
(0.333 .mu.M streptavidine-XL665 [Cisbio Bioassays, Codolet,
France] and 1.67 nM anti-RB(pSer807/pSer811)-antibody from BD
Pharmingen [#558389] and 2 nM LANCE EU-W1024 labeled anti-mouse IgG
antibody [Perkin-Elmer, product no. AD0077, as an alternative a
Terbium-cryptate-labeled anti-mouse IgG antibody from Cisbio
Bioassays can be used]) in an aqueous EDTA-solution (167 mM EDTA,
0.2% (w/v) bovine serum albumin in 100 mM HEPES pH 7.5).
[0610] The resulting mixture was incubated 1 h at 22.degree. C. to
allow the formation of complex between the phosphorylated
biotinylated peptide and the detection reagents. Subsequently the
amount of phosphorylated substrate was evaluated by measurement of
the resonance energy transfer from the Eu-chelate to the
streptavidine-XL. Therefore, the fluorescence emissions at 620 nm
and 665 nm after excitation at 350 nm was measured in a TR-FRET
reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany)
or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm
and at 622 nm was taken as the measure for the amount of
phosphorylated substrate. The data were normalised (enzyme reaction
without inhibitor=0% inhibition, all other assay components but no
enzyme=100% inhibition). Usually the test compounds were tested on
the same microtiterplate in 11 different concentrations in the
range of 20 .mu.M to 0.07 nM (20 .mu.M, 5.7 .mu.M, 1.6 .mu.M, 0.47
.mu.M, 0.13 .mu.M, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07
nM, the dilution series prepared separately before the assay on the
level of the 100fold concentrated solutions in DMSO by serial
dilutions, exact concentrations may vary depending pipettors used)
in duplicate values for each concentration and IC50 values were
calculated using Genedata Screener.TM. software.
3. Proliferation Assay:
[0611] Cultivated tumour cells (HeLa, human cervical tumour cells,
ATCC CCL-2; NCI-H460, human non-small cell lung carcinoma cells,
ATCC HTB-177; DU 145, hormone-independent human prostate carcinoma
cells, ATCC HTB-81; HeLa-MaTu-ADR, multidrug-resistant human
cervical carcinoma cells, EPO-GmbH Berlin; Caco-2, human colorectal
carcinoma cells, ATCC HTB-37; B16F10, mouse melanoma cells, ATCC
CRL-6475) were plated at a density of 5,000 cells/well (DU145,
HeLa-MaTu-ADR), 3,000 cells/well (NCI-H460, HeLa), 1,500 cells/well
(Caco-2), or 1,000 cells/well (B16F10) in a 96-well multititer
plate in 200 .mu.L of their respective growth medium supplemented
10% fetal calf serum. After 24 hours, the cells of one plate
(zero-point plate) were stained with crystal violet (see below),
while the medium of the other plates was supplemented with the test
substances in various concentrations (0 .mu.M, as well as in the
range of 0.0001-10 .mu.M; the final concentration of the solvent
dimethyl sulfoxide was adjusted to 0.1%) using a Hewlett-Packard HP
D300 Digital Dispenser. The cells were incubated for 4 days in the
presence of test substances. Cell proliferation was determined by
staining the cells with crystal violet: the cells were fixed by
adding 20 .mu.l/measuring point of an 11% glutaric aldehyde
solution for 15 minutes at room temperature. After three washing
cycles of the fixed cells with water, the plates were dried at room
temperature. The cells were stained by adding 100 .mu.l/measuring
point of a 0.1% crystal violet solution (pH 3.0). After three
washing cycles of the stained cells with water, the plates were
dried at room temperature. The dye was dissolved by adding 100
.mu.l/measuring point of a 10% acetic acid solution. The extinction
was determined by photometry at a wavelength of 595 n. The change
of cell number, in percent, was calculated by normalization of the
measured values to the extinction values of the zero-point plate
(=0%) and the extinction of the untreated (0 m) cells (=100%). The
IC.sub.50 values (inhibitory concentration at 50% of maximal
effect) were determined by means of a 4 parameter fit.
[0612] A2780 human ovarian carcinoma cells (ECACC #93112519) and
non-adherent MOLM-13 human acute myeloid leukemia cells (DSMZ ACC
554) were seeded at a density of 3,000 cell/well (A2780) or 5,000
cells/well (MOLM-13) in a 96-well multititer plate in 150 .mu.L of
growth medium supplemented 10% fetal calf serum. After 24 hours,
cell viability of one plate (zero-point plate) was determined with
the Cell Titre-Glo Luminescent Cell Viability Assay (Promega),
while the medium of the other plates was supplemented with the test
substances in various concentrations (0 .mu.M, as well as in the
range of 0.0001-10 .mu.M; the final concentration of the solvent
dimethyl sulfoxide was adjusted to 0.1%) using a Hewlett-Packard HP
D300 Digital Dispenser. Cell viability was assessed after 72-hour
exposure with the Cell Titre-Glo Luminescent Cell Viability Assay
(Promega). IC.sub.50 values (inhibitory concentration at 50% of
maximal effect) were determined by means of a 4 parameter fit on
measurement data which were normalized to vehicle (DMSO) treated
cells (=100%) and measurement readings taken immediately before
compound exposure (=0%).
4. Equilibrium Shake Flask Solubility Assay:
[0613] 4a) High Throughput Determination of Aqueous Drug Solubility
(100 mmolar in DMSO)
[0614] The high throughput screening method to determine aqueous
drug solubility is based on: Thomas Onofrey and Greg Kazan,
Performance and correlation of a 96-well high throughput screening
method to determine aqueous drug solubility,
http://www.millipore.com/publications.nsf/a73664f9f981af8c852569b9005b4ee-
e/e565516fb76e743585256da30052db77/$FILE/AN1731EN00.pdf
[0615] The assay was run in a 96-well plate format. Each well was
filled with an individual compound.
[0616] All pipetting steps were performed using a robot
platform.
[0617] 100 .mu.l of a 10 mmolar solution of drug in DMSO were
concentrated by vacuum centrifugation and resolved in 10 .mu.l
DMSO. 990 .mu.l phosphate buffer pH 6.5 were added. The content of
DMSO amounts to 1%. The multititer plate was put on a shaker and
mixed for 24 hrs at room temperature. 150 .mu.l of the suspension
were transferred to a filtration plate. After filtration using a
vacuum manifold the filtrate was diluted 1:400 and 1:8000. A second
microtiter plate with 20 .mu.l of a 10 mM solution of drug in DMSO
served for calibration. Two concentrations (0.005 .mu.M and 0.0025
.mu.M) were prepared by dilution in DMSO/water 1:1 and used for
calibration. Filtrate and calibration plates were quantified by
HPLC-MS/MS.
Chemicals:
Preparation of 0.1 m Phosphate Buffer pH 6.5:
[0618] 61.86 g NaCl and 39.54 mg KH.sub.2PO.sub.4 were solved in
water and filled up to 11. The mixture was diluted 1:10 with water
and the pH adjusted to 6.5 by NaOH.
Materials:
Millipore MultiScreen.sub.HTS-HV Plate 0.45 .mu.m
[0619] Chromatographic conditions were as follows: HPLC column:
Ascentis Express C18 2.7 .mu.m 4.6.times.30 mm Injection volume: 1
.mu.l Flow: 1.5 ml/min Mobile phase: acidic gradient [0620] A:
Water/0.05% HCOOH [0621] B: Acetonitrile/0.05% HCOOH [0622] 0
min.fwdarw.95% A 5% B [0623] 0.75 min.fwdarw.5% A 95% B [0624] 2.75
min.fwdarw.5% A 95% B [0625] 2.76 min.fwdarw.95% A 5% B [0626] 3
min.fwdarw.95% A 5% B
[0627] The areas of sample- and calibration injections were
determined by using mass spectrometry software (AB SCIEX: Discovery
Quant 2.1.3. and Analyst 1.6.1). The calculation of the solubility
value (in mg/l) was executed by an inhouse developed Excel
macro.
4b) Thermodynamic Solubility in Water from Powder
[0628] The thermodynamic solubility of compounds in water was
determined by an equilibrium shake flask method (see for example:
E. H. Kerns, L. Di: Drug-like Properties: Concepts, Structure
Design and Methods, 276-286, Burlington, Mass., Academic Press,
2008). A saturated solution of the drug was prepared and the
solution was mixed for 24 h to ensure that equilibrium was reached.
The solution was centrifuged to remove the insoluble fraction and
the concentration of the compound in solution was determined using
a standard calibration curve. To prepare the sample, 2 mg solid
compound was weighed in a 4 mL glass vial. 1 mL phosphate buffer pH
6.5 was added. The suspension was stirred for 24 hrs at room
temperature. The solution was centrifuged afterwards. To prepare
the sample for the standard calibration, 2 mg solid sample was
dissolved in 30 mL acetonitrile. After sonification the solution
was diluted with water to 50 mL. Sample and standards were
quantified by HPLC with UV-detection. For each sample two injection
volumes (5 and 50 .mu.l) in triplicates were made. Three injection
volumes (5 .mu.l, 10 .mu.l and 20 .mu.l) were made for the
standard.
Chromatographic Conditions:
[0629] HPLC column: Xterra MS C18 2.5 .mu.m 4.6.times.30 mm
Injection volume: Sample: 3.times.5 .mu.l and 3.times.50 .mu.l
[0630] Standard: 5 .mu.l, 10 .mu.l, 20 .mu.l Flow: 1.5 mL/min
Mobile phase: acidic gradient: [0631] A: Water/0.01% TFA [0632] B:
Acetonitrile/0.01% TFA [0633] 0 min.fwdarw.95% A 5% B [0634] 0-3
min.fwdarw.35% A 65% B, linear gradient [0635] 3-5 min.fwdarw.35% A
65% B, isocratic [0636] 5-6 min.fwdarw.95% A 5% B, isocratic UV
detector: wavelength near the absorption maximum (between 200 and
400 nm)
[0637] The areas of sample- and standard injections as well as the
calculation of the solubility value (in mg/1) were determined by
using HPLC software (Waters Empower 2 FR).
4c) Thermodynamic Solubility in Citrate Buffer pH 4
[0638] Thermodynamic solubility was determined by an equilibrium
shake flask method [Literature: Edward H. Kerns and Li Di (2008)
Solubility Methods in: Drug-like Properties: Concepts, Structure
Design and Methods, p 276-286. Burlington, Mass.: Academic
Press].
[0639] A saturated solution of the drug was prepared and the
solution was mixed for 24 h to ensure that equilibrium has been
reached. The solution was centrifuged to remove the insoluble
fraction and the concentration of the compound in solution was
determined using a standard calibration curve.
[0640] To prepare the sample, 1.5 mg solid compound was weighed in
a 4 ml glass vial. 1 ml Citrate buffer pH 4 was added. The
suspension was put on a stirrer and mixed for 24 hrs at room
temperature. The solution was centrifuged afterwards. To prepare
the sample for the standard calibration, 0.6 mg solid sample was
dissolved in 19 ml acetonitrile/water 1:1. After sonification the
solution was filled up with acetonitrile/water 1:1 to 20 ml.
[0641] Sample and standards were quantified by HPLC with
UV-detection. For each sample two injection volumes (5 and 50
.mu.l) in triplicates were made. Three injection volumes (5 .mu.l,
10 .mu.l and 20 .mu.l) were made for the standard.
Chemicals:
[0642] Citrate buffer pH 4 (MERCK Art. 109435; 1 L buffer
consisting of 11,768 g citric acid, 4,480 g sodium hydroxide, 1,604
g hydrogen chloride) Chromatographic conditions were as follows:
HPLC column: Xterra MS C18 2.5 .mu.m 4.6.times.30 mm Injection
volume: Sample: 3.times.5 .mu.l and 3.times.50 .mu.l [0643]
Standard: 5 .mu.l, 10 .mu.l, 20 .mu.l Flow: 1.5 ml/min Mobile
phase: acidic gradient: [0644] A: Water/0.01% TFA [0645] B:
Acetonitrile/0.01% TFA [0646] 0 min: 95% A 5% B [0647] 0-3 min: 35%
A 65% B, linear gradient [0648] 3-5 min: 35% A 65% B, isocratic
[0649] 5-6 min: 95% A 5% B, isocratic UV detector: wavelength near
the absorption maximum (between 200 and 400 nm)
[0650] The areas of sample- and standard injections as well as the
calculation of the solubility value (in mg/1) were determined by
using HPLC software (Waters Empower 2 FR).
[0651] The areas of sample- and standard injections as well as the
calculation of the solubility value (in mg/1) were determined by
using HPLC software (Waters Empower 2 FR).
5. Caco-2 Permeation Assay:
[0652] Caco-2 cells (purchased from DSMZ Braunschweig, Germany)
were seeded at a density of 4.5.times.10.sup.4 cells per well on 24
well insert plates, 0.4 .mu.m pore size, and grown for 15 days in
DMEM medium supplemented with 10% fetal bovine serum, 1% GlutaMAX
(100.times., GIBCO), 100 U/mL penicillin, 100 .mu.g/mL streptomycin
(GIBCO) and 1% non essential amino acids (100.times.). Cells were
maintained at 37.degree. C. in a humified 5% CO.sub.2 atmosphere.
Medium was changed every 2-3 day. Before running the permeation
assay, the culture medium was replaced by a FCS-free
hepes-carbonate transport buffer (pH 7.2). For assessment of
monolayer integrity the transepithelial electrical resistance
(TEER) was measured. Test compounds were predissolved in DMSO and
added either to the apical or basolateral compartment in final
concentration of 2 .mu.M in transport buffer. Before and after 2 h
incubation at 37.degree. C. samples were taken from both
compartments. Analysis of compound content was done after
precipitation with methanol by LC/MS/MS analysis. Permeability
(Papp) was calculated in the apical to basolateral (A.fwdarw.B) and
basolateral to apical (B.fwdarw.A) directions.
[0653] The apparent permeability was calculated using following
equation:
Papp=(Vr/Po)(1/S)(P2/t)
Where Vr is the volume of medium in the receiver chamber, Po is the
measured peak area or height of the test drug in the donor chamber
at t=o, S the surface area of the monolayer, P2 is the measured
peak area of the test drug in the acceptor chamber after 2 h of
incubation, and t is the incubation time. The efflux ratio
basolateral (B) to apical (A) was calculated by dividing the Papp
B-A by the Papp A-B. In addition the compound recovery was
calculated.
6. Investigation of In Vitro Metabolic Stability in Rat
Hepatocytes
[0654] Hepatocytes from Han Wistar rats were isolated via a 2-step
perfusion method. After perfusion, the liver was carefully removed
from the rat: the liver capsule was opened and the hepatocytes were
gently shaken out into a Petri dish with ice-cold Williams medium E
(purchased from Sigma Aldrich Life Science, St Louis, Mo.). The
resulting cell suspension was filtered through sterile gaze in 50
ml falcon tubes and centrifuged at 50.times.g for 3 min at room
temperature. The cell pellet was resuspended in 30 ml WME and
centrifuged through a Percoll.RTM. gradient for 2 times at
100.times.g. The hepatocytes were washed again with Williams'
medium E (WME) and resuspended in medium containing 5% Fetal calf
serum (FCS, purchased from Invitrogen, Auckland, NZ). Cell
viability was determined by trypan blue exclusion.
[0655] For the metabolic stability assay liver cells were
distributed in WME containing 5% FCS to glass vials at a density of
1.0.times.10.sup.6 vital cells/ml. The test compound was added to a
final concentration of 1 .mu.M. During incubation, the hepatocyte
suspensions were continuously shaken and aliquots were taken at 2,
8, 16, 30, 45 and 90 min, to which equal volumes of cold
acetonitrile were immediately added. Samples were frozen at
-20.degree. C. over night, after subsequently centrifuged for 15
minutes at 3000 rpm and the supernatant was analyzed with an
Agilent 1200 HPLC-system with LCMS/MS detection.
[0656] The half-life of a test compound was determined from the
concentration-time plot. From the half-life the intrinsic
clearances were calculated. Together with the additional parameters
liver blood flow, amount of liver cells in vivo and in vitro, the
maximal oral bioavailability (Fmax) was calculated using the
following scaling parameters: Liver blood flow (rat)--4.2 L/h/kg;
specific liver weight--32 g/kg rat body weight; liver cells in
vivo- 1.1.times.10.sup.8 cells/g liver, liver cells in
vitro--0.5.times.10.sup.6/ml.
7. In Vivo Pharmacokinetics in Rats
[0657] For in vivo pharmacokinetic experiments test compounds were
administered to male Wistar rats intravenously at doses of 0.3 to 1
mg/kg formulated as solutions using either rat plasma or
solubilizers such as PEG400 in well-tolerated amounts.
[0658] For pharmacokinetics after intravenous administration test
compounds were given as i.v. bolus and blood samples were taken at
2 min, 8 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and
24 h after dosing. Depending on the expected half-life additional
samples were taken at later time points (e.g. 48 h, 72 h). Blood
was collected into Lithium-Heparin tubes (Monovetten.RTM.,
Sarstedt) and centrifuged for 15 min at 3000 rpm. An aliquot of 100
.mu.L from the supernatant (plasma) was taken and precipitated by
addition of 400 .mu.L ice cold acetonitrile and frozen at
-20.degree. C. over night. Samples were subsequently thawed and
centrifuged at 3000 rpm, 4.degree. C. for 20 minutes. Aliquots of
the supernatants were taken for analytical testing using an Agilent
1200 HPLC-system with LCMS/MS detection. PK parameters were
calculated by non-compartmental analysis using a PK calculation
software.
[0659] PK parameters derived from concentration-time profiles after
i.v.: CLplasma: Total plasma clearance of test compound (in
L/kg/h); CLblood: Total blood clearance of test compound:
CLplasma*Cp/Cb (in L/kg/h) with Cp/Cb being the ratio of
concentrations in plasma and blood, AUCnorm: Area under the
concentration-time curve from t=0 h to infinity (extrapolated)
divided by the administered dose (in kg*h/L); t.sub.1/2: terminal
half-life (in h).
8. Surface Plasmon Resonance PTEFb
DEFINITIONS
[0660] The term "surface plasmon resonance", as used herein, refers
to an optical phenomenon that allows for the analysis of the
reversible associations of biological molecules in real time within
a biosensor matrix, for example using the Biacore.RTM. system (GE
Healthcare Biosciences, Uppsala, Sweden). Biacore.RTM. uses the
optical properties of surface plasmon resonance (SPR) to detect
alterations in the refractive index of a buffer, which changes as
molecules in solution interact with the target immobilized on the
surface. In brief, proteins are covalently bound to the dextran
matrix at a known concentration and a ligand for the protein is
injected through the dextran matrix. Near infrared light, directed
onto the opposite side of the sensor chip surface is reflected and
also induces an evanescent wave in the gold film, which in turn,
causes an intensity dip in the reflected light at a particular
angle known as the resonance angle. If the refractive index of the
sensor chip surface is altered (e.g. by compound binding to the
bound protein) a shift occurs in the resonance angle. This angle
shift can be measured. These changes are displayed with respect to
time along the y-axis of a sensorgram, which depicts the
association and dissociation of any biological reaction.
[0661] The term "K.sub.D", as used herein, is intended to refer to
the equilibrium dissociation constant of a particular
compound/target protein complex.
[0662] The term "k.sub.off", as used herein, is intended to refer
to the off-rate, i.e. the dissociation rate constant of a
particular compound/target protein complex.
[0663] The term "target residence time", as used herein, is
intended to refer to the inverse of the rate of dissociation rate
constant (1/k.sub.off) of a particular compound/target protein
complex.
[0664] For further descriptions see:
JMnsson U et al al., 1993 Ann Biol Clin.; 51(1):19-26.
Johnsson B et al, Anal Biochem. 1991; 198(2):268-77.
Day Y et al, Protein Science, 2002; 11, 1017-1025
Myskza D G, Anal Biochem., 2004; 329, 316-323
Tummino and Copeland, Biochemistry, 2008; 47(20):5481-5492.
Biological Activity
[0665] The biological activity (e.g. as inhibitors of PTEFb) of the
compounds according to the invention can be measured using the SPR
assay described.
[0666] The level of activity exhibited by a given compound in the
SPR assay can be defined in terms of the K.sub.D value, and
preferred compounds of the present invention are compounds having a
K.sub.D value of less than 1 micromolar, more preferably less than
0.1 micromolar. Furthermore, the time in residence at its target of
a given compound can be defined in terms of the target residence
time (TRT), and preferred compounds of the present invention are
compounds having a TRT value of more than 10 minutes, more
preferably more than 1 hour.
[0667] The ability of the compounds according to the invention to
bind human PTEFb may be determined using surface plasmon resonance
(SPR). K.sub.D values and k.sub.off values may be measured using a
Biacore.RTM. T200 instrument (GE Healthcare, Uppsala, Sweden).
[0668] For SPR measurements, recombinant human PTEFb (CDK9/Cyclin
T1 recombinant human active protein kinase purchased from
ProQinase, Freiburg, Germany) is immobilized using standard amine
coupling (Johnsson B et al, Anal Biochem. 1991 Nov. 1;
198(2):268-77). Briefly, carboxymethylated dextran biosensor chips
(CM7, GE Healthcare) are activated with
N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC)
and N-hydroxysuccinimide (NHS) according to the supplier's
instructions. Human PTEFb is diluted in 1.times.HBS-EP+ (GE
Healthcare) and injected on the activated chip surface.
Subsequently, a 1:1 solution of 1 M ethanolamine-HCl (GE
Healthcare) and 1.times.HBS-EP is injected to block unreacted
groups, resulting in approximately 4000 response units (RU) of
immobilized protein. A reference surface is generated by treatment
with NHS-EDC and ethanolamine-HCl. Compounds are dissolved in 100%
dimethylsulfoxide (DMSO, Sigma-Aldrich, Germany) to a concentration
of 10 mM and subsequently diluted in running buffer
(1.times.HBS-EP+ pH 7.4 [generated from HBS-EP+ Buffer 10.times.
(GE Healthcare): 0.1 M HEPES, 1.5 M NaCl, 30 mM EDTA and 0.5% v/v
Surfactant P20], 1% v/v DMSO). For kinetic measurements, serial
dilutions of compound (0.78 nM up to 25 nM) are injected over
immobilized protein. Binding kinetics is measured at 37.degree. C.
with a flow rate of 100 .mu.l/min in running buffer. Compound
concentrations are injected for 70 s followed by a dissociation
time of 1100 s. The resulting sensorgrams are double-referenced
against the reference surface as well as against blank
injections.
[0669] The double-referenced sensorgrams are fit to a simple
reversible Langmuir 1:1 reaction mechanism as implemented in the
Biacore.RTM. T200 evaluation software 2.0 (GE Healthcare). In cases
were full compound dissociation has not occurred at the end of the
dissociation phase, the Rmax parameter (response at saturation) is
fit as local variable. In all other cases, Rmax is fit as global
variable. SPR measurements are summarized in Table 4
Syntheses of Compounds
[0670] The syntheses of the macrocyclic compounds of formula (I)
according to the present invention are preferably carried out
according to the general synthetic sequences as shown in Schemes
1a, 1b, 1c, 2a and 2b.
[0671] In addition to said routes described below, also other
routes may be used to synthesise the target compounds, in
accordance with common general knowledge of a person skilled in the
art of organic synthesis. The order of transformations exemplified
in the following Schemes is therefore not intended to be limiting,
and suitable synthesis steps from various schemes can be combined
to form additional synthesis sequences. In addition, modification
of any of the substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and/or Z can be achieved before and/or after the
exemplified transformations. These modifications can be such as the
introduction of protective groups, cleavage of protective groups,
reduction or oxidation of functional groups, halogenation,
metallation, metal catalysed coupling reactions, substitution or
other reactions known to a person skilled in the art. These
transformations include those which introduce a functionality
allowing for further interconversion of substituents. Appropriate
protective groups and their introduction and cleavage are
well-known to a person skilled in the art (see for example T. W.
Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis,
4.sup.th edition, Wiley 2006). Specific examples are described in
the subsequent paragraphs. Further, it is possible that two or more
successive steps may be performed without work-up being performed
between said steps, e.g. a "one-pot" reaction, as it is well-known
to a person skilled in the art.
[0672] The geometry of the sulfoximine, sulfodiimine and sulfoxide
moiety renders some of the compounds of the general formula (I)
chiral. Separation of racemic sulfoximines, sulfodiimines and
sulfoxides into their enantiomers can be achieved by methods known
to the person skilled in the art, preferably by means of
preparative HPLC on chiral stationary phase.
[0673] The syntheses of the pyridine derivatives of formulae (Ia),
(Ib) and (Ic), all of them constituting subsets of the general
formula (I) according to the present invention, are preferably
carried out according to the general synthetic sequences as shown
in Schemes 1a, 1b and 1c and 1d.
##STR00017##
##STR00018## ##STR00019##
[0674] Schemes 1a, 1b and 1c, wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, Z and L are as defined for the compound of
general formula (I) according to the present invention, outline the
preparation of pyridine-based macrocyclic compounds of formulae
(Ia), (Ib) and (Ic), from 2-chloro-5-fluoro-4-iodopyridine (1; CAS
#884494-49-9).
[0675] Said starting material (1) can be reacted with a boronic
acid derivative of formula (2), in which R.sup.3, R.sup.4 and Z are
as defined for the compound of general formula (I), to give a
compound of formula (3). The boronic acid derivative (2) may be a
boronic acid (R=--H) or an ester of the boronic acid, e.g. its
isopropyl ester (R=--CH(CH.sub.3).sub.2), preferably an ester
derived from pinacol in which the boronic acid intermediate forms a
2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(R--R=--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--).
[0676] Said coupling reaction can be catalyzed by palladium
catalysts, e.g. by Pd(0) catalysts such as
tetrakis(triphenylphosphine)palladium(0) [Pd(PPh.sub.3).sub.4],
tris(dibenzylideneacetone)di-palladium(0) [Pd.sub.2(dba).sub.3], or
by Pd(II) catalysts such as
dichlorobis(triphenylphosphine)-palladium(II)
[Pd(PPh.sub.3).sub.2Cl.sub.2], palladium(II) acetate and
triphenylphosphine or by
[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
[0677] The reaction can preferably be carried out in a mixture of a
solvent such as 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or
isopropanol with water and in the presence of a base such as
potassium carbonate, sodium bicarbonate or potassium phosphate.
[0678] (review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag
GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references
cited therein).
[0679] The reaction can be performed at temperatures ranging from
room temperature (i.e. approx. 20.degree. C.) to the boiling point
of the respective solvent. Further on, the reaction can be
performed at temperatures above the boiling point using pressure
tubes and a microwave oven. The reaction is preferably completed
after 1 to 36 hours of reaction time.
[0680] In the second step, a compound of formula (3) can be
converted to a compound of formula (4). This reaction can be
carried out by a Palladium-catalyzed C--N cross-coupling reaction
(for a review on C--N cross coupling reactions see for example: a)
L. Jiang, S. L. Buchwald in `Metal-Catalyzed Cross-Coupling
Reactions`, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.:
Wiley-VCH: Weinheim, Germany, 2004).
[0681] Preferred is the herein described use of lithium
bis(trimethylsilyl)amide, tris(dibenzylideneacetone)dipalladium(0)
and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl in THF.
The reactions are preferably run under an atmosphere of argon for
3-24 hours at 60.degree. C. in an oil bath.
[0682] In the third step, a compound of formula (4) can be
converted to a compound of formula (5), by means of cleaving the
methyl ether present in compounds of formula (4).
[0683] Preferred is the herein described use of boron tribromide in
DCM. The reactions are preferably run for 1-24 hours at 0.degree.
C. to room temperature.
[0684] In the fourth step, a compound of formula (5) can be coupled
with a compound of formula (6), in which R.sup.1, R.sup.2 and L are
as defined for the compound of general formula (I) and in which LG
represents a leaving group such as a chlorine atom, a bromine atom
or a iodine atom, C.sub.1-C.sub.4-alkyl-S(.dbd.O).sub.2O--,
trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or
para-toluenesulfonyloxy-, to give a compound of formula (7).
Preferred is the herein described use of potassium carbonate and
potassium iodide in DMF. The reactions are preferably run for 1-36
hours at 40 to 80.degree. C.
[0685] Compounds of the formula (6) can be prepared as outlined in
Scheme Ic, infra.
[0686] In the fifth step, a compound of formula (7) is converted to
a macrocycle of formula (Ia). This cyclization reaction can be
carried out by a Palladium-catalyzed C--N cross-coupling reaction
(for a review on C--N cross coupling reactions see for example: a)
L. Jiang, S. L. Buchwald in `Metal-Catalyzed Cross-Coupling
Reactions`, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.:
Wiley-VCH: Weinheim, Germany, 2004).
[0687] Preferred is the herein described use of
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct,
2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl as catalyst
and ligand, an alkali carbonate or an alkali phosphate, preferably
potassium phosphate, as a base, in a mixture of a
C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent,
preferably a mixture of toluene and NMP, as a solvent. The
reactions are preferably run under an atmosphere of argon for 2-24
hours at 100-130.degree. C. in a microwave oven or in an oil
bath.
[0688] In the sixth step, the tert-butoxycarbonyl-group attached to
the sulfoximine nitrogen can be cleaved under acidic conditions to
give an unprotected sulfoximine of formula (Ib) (see for example:
J. A. Bull, J. Org. Chem. 2015, 80, 6391).
[0689] Preferred is the herein described use of an acid, preferably
trifluoroacetic acid in dichloromethane as a solvent.
[0690] Said N-unprotected sulfoximine of formula (Ib)
(R.sup.5.dbd.H) may be further converted into a N-functionalized
derivative of formula (Ic). There are multiple methods for the
preparation of N-functionalized sulfoximines by functionalization
of the nitrogen of the sulfoximine group: [0691] Alkylation: see
for example: a) U. Lucking et al, US 2007/0232632; b) C. R.
Johnson, J. Org. Chem. 1993, 58, 1922; c) C. Bolm et al, Synthesis
2009, 10, 1601. [0692] Acylation: see for example: a) C. Bolm et
al, Chem. Europ. J. 2004, 10, 2942; b) C. Bolm et al, Synthesis
2002, 7, 879; c) C. Bolm et al, Chem. Europ. J. 2001, 7, 1118.
[0693] Arylation: see for example: a) C. Bolm et al, Tet. Lett.
1998, 39, 5731; b) C. Bolm et al., J. Org. Chem. 2000, 65, 169; c)
C. Bolm et al, Synthesis 2000, 7, 911; d) C. Bolm et al, J. Org.
Chem. 2005, 70, 2346; e) U. Lucking et al, WO2007/71455. [0694]
Reaction with isocyanates: see for example: a) V. J. Bauer et al,
J. Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am. Chem.
Soc. 1970, 92, 6594; c) S. Allenmark et al, Acta Chem. Scand. Ser.
B 1983, 325; d) U. Lucking et al, US2007/0191393. [0695] Reaction
with sulfonylchlorides: see for example: a) D. J. Cram et al, J.
Am. Chem. Soc. 1970, 92, 7369; b) C. R. Johnson et al, J. Org.
Chem. 1978, 43, 4136; c) A. C. Barnes, J. Med. Chem. 1979, 22, 418;
d) D. Craig et al, Tet. 1995, 51, 6071; e) U. Lucking et al,
US2007/191393. [0696] Reaction with chloroformiates: see for
example: a) P. B. Kirby et al, DE2129678; b) D. J. Cram et al, J.
Am. Chem. Soc. 1974, 96, 2183; c) P. Stoss et al, Chem. Ber. 1978,
111, 1453; d) U. Lucking et al, WO2005/37800. [0697] Reaction with
bromocyane: see for example: a) D. T. Sauer et al, Inorganic
Chemistry 1972, 11, 238; b) C. Bolm et al, Org. Lett. 2007, 9,
2951; c) U. Lucking et al, WO 2011/29537.
##STR00020##
[0698] Intermediates of the formula (6), in which R.sup.1, R.sup.2
and L are as defined for the compound of general formula (I)
according to the present invention and in which LG represents a
leaving group such as a chlorine atom, a bromine atom or a iodine
atom, C.sub.1-C.sub.4-alkyl-S(.dbd.O).sub.2O--,
trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or
para-toluenesulfonyloxy-, can be prepared according to Scheme 1c,
starting e.g. from a 2,6-dichloroisonicotinic acid derivative of
formula (8), in which R.sup.2 is as defined for the compound of
general formula (I), which can be reduced to the corresponding
pyridinemethanol of formula (9), by means of reduction. Preferred
is the herein described use of sulfanediyldimethane-borane (1:1
complex) in tetrahydrofuran.
[0699] Derivatives of isonicotinic acid of formula (8), and esters
thereof, are well known to the person skilled in the art, and are
often commercially available.
[0700] In a second step, said pyridinemethanol of formula (9) can
be reacted to give a compound of formula (10), in which LG
represents a leaving group such as a chlorine atom, a bromine atom
or a iodine atom, C.sub.1-C.sub.4-alkyl-S(.dbd.O).sub.2O--,
trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or
para-toluenesulfonyloxy-. Such conversions are well known to the
person skilled in the art; preferred is the herein described use of
methanesulfonyl chloride in the presence of triethylamine as a
base, in dichloromethane as a solvent, to give a compound of
formula (10) in which LG represents methanesulfonyloxy-.
[0701] In a third step, a compound of formula (10) can be reacted
with a thiol of the formula R.sup.1--SH, in which R.sup.1 is as
defined for the compound of general formula (I), to give a
thioether derivative of formula (11). Thiols of the formula
R.sup.1SH are well known to the person skilled in the art and are
commercially available in considerable variety.
[0702] In a fourth step, a thioether derivative of formula (11) can
be reacted with an anion formed in situ from a diol of the formula
HO-L-OH, in which L is as defined for the compound of general
formula (I), and an alkali metal, preferably sodium, or sodium
hydride in tetrahydrofuran as a solvent, to give intermediate
compounds of formula (12).
[0703] In a fifth step, oxidation of a thioether of formula (12)
can be used to obtain the corresponding sulfoxide of formula (13).
The oxidation can be performed analogously to known processes (see
for example: (a) M. H. Ali et al, Synthesis 1997, 764; (b) M. C.
Carreno, Chem. Rev. 1995, 95, 1717; (c) I. Patel et al, Org. Proc.
Res. Dev. 2002, 6, 225; (d) N. Khiar et al, Chem. Rev. 2003, 103,
3651).
[0704] Preferred is the herein described use of periodic acid und
iron(III) chloride.
[0705] In a sixth step, Rhodium-catalyzed imination of a sulfoxide
of formula (13) can be used to prepare the N-Boc-protected
sulfoximines of formula (14) (Bull et al, J. Org. Chem. 2015, 80,
6391). Preferred is the herein described use of sulfoxide (13),
tert-butyl carbamate, magnesium oxide, rhodium(II) acetate dimer
and iodobenzene diacetate in DCM at room temperature to 45.degree.
C.
[0706] In a seventh step, the alcohol can be reacted with
methanesulfonyl chloride to form the methanesulfonate (6).
[0707] Preferred is the herein described use of trimethylamine as
the base in DCM as the solvent at room temperature.
##STR00021##
[0708] In alternative approach is outlined in Scheme Id.
[0709] In the first step, a compound of formula (5) can be coupled
with an alcohol LG-L-OH, in which L is as defined for the compound
of general formula (I) and in which LG represents a leaving group
such as a chlorine atom, a bromine atom or a iodine atom,
C.sub.1-C.sub.4-alkyl-S(.dbd.O).sub.2O--,
trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or
para-toluenesulfonyloxy-, to give a compound of formula (28).
Preferred is the herein described use a
CH.sub.3--S(.dbd.O).sub.2O-- leaving group in combination with
potassium carbonate and potassium iodide in DMF. The reactions are
preferably run for 1-36 hours at 40 to 80.degree. C.
[0710] In the second step, a compound of formula (28) can be
coupled with a compound of formula (29) to give a compound of
formula (30).
[0711] This reaction can be carried out by a Mitsunobu reaction
(see for example: a) K. C. K. Swamy et al, Chem. Rev. 2009, 109,
2551).
[0712] In the third step, a compound of formula (30) can be
converted to a macrocycle compound of the invention (Ig), which
constitutes a subset of the general formula (I) according to the
present invention, This cyclization reaction can be carried out by
a Palladium-catalyzed C--N cross-coupling reaction (for a review on
C--N cross coupling reactions see for example: a) L. Jiang, S. L.
Buchwald in `Metal-Catalyzed Cross-Coupling Reactions`, 2.sup.nd
ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim,
Germany, 2004).
[0713] Preferred is the herein described use of
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct,
2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl as catalyst
and ligand, an alkali carbonate or an alkali phosphate, preferably
potassium phosphate, as a base, in a mixture of a
C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent,
preferably a mixture of toluene and NMP, as a solvent. The
reactions are preferably run under an atmosphere of argon for 2-24
hours at 100-130.degree. C. in a microwave oven or in an oil
bath.
[0714] In the last step, oxidation of a thioether of formula (Ig)
can be used to obtain the corresponding sulfone of formula (Ih),
which constitutes a subset of the general formula (I) according to
the present invention. The oxidation can be performed analogously
to known processes.
[0715] Preferred is the herein described use of 3-chloroperbenzoic
acid in DCM.
[0716] Alternatively, In the last step, one-pot oxidation/imination
reaction of a thioether of formula (Ig) can be used to obtain the
corresponding NH sulfoximine of formula (Ib), which constitutes a
subset of the general formula (I) according to the present
invention.
[0717] Preferred is the herein described procedure based on A.
Tota, M. Zenzola, S. J. Chawner, S. St. John-Campell, C. Carlucci,
G. Romanazzi, L. Degennaro, J. A. Bull, R. Luisi; ChemComm 2017,
348
[0718] The syntheses of the pyrimidine derivatives of formulae
(Id), (Ie) and (If), all of them also constituting subsets of the
general formula (I) according to the present invention, are
preferably carried out according to the general synthetic sequences
as shown in Schemes 2a and 2b.
[0719] Schemes 2a and 2b, wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, Z and L are as defined for the compound of
general formula (I) according to the present invention, outline the
preparation of pyrimidine compounds of the general formula (Id),
(Ie) and (If) from 2,4-dichloro-5-fluoropyrimidine (CAS
#2927-71-1), (15). Said starting material (15) can be reacted with
a boronic acid derivative of formula (2) to give a compound of
formula (16). The boronic acid derivative (2) may be a boronic acid
(R=--H) or an ester of the boronic acid, e.g. its isopropyl ester
(R=--CH(CH.sub.3).sub.2), preferably an ester derived from pinacol
in which the boronic acid intermediate forms a
2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(R--R=--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--). Boronic acids and
their esters are commercially available and well-known to the
person skilled in the art; see e.g. D. G. Hall, Boronic Acids, 2005
WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8
and references cited therein.
[0720] The coupling reaction is catalyzed by Pd catalysts, e.g. by
Pd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0)
[Pd(PPh.sub.3).sub.4], tris(dibenzylideneacetone)di-palladium(0)
[Pd.sub.2(dba).sub.3], or by Pd(II) catalysts such as
dichlorobis(triphenylphosphine)-palladium(II)
[Pd(PPh.sub.3).sub.2Cl.sub.2], palladium(II) acetate and
triphenylphosphine or by
[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
[Pd(dppf)Cl.sub.2].
[0721] The reaction can preferably be carried out in a mixture of a
solvent such as 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or
isopropanol with water and in the presence of a base such as
aqueous potassium carbonate, aqueous sodium bicarbonate or
potassium phosphate.
[0722] The reaction can be performed at temperatures ranging from
room temperature (=20.degree. C.) to the boiling point of the
solvent. Further on, the reaction can be performed at temperatures
above the boiling point using pressure tubes and a microwave oven.
(review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH
& Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited
therein).
[0723] The reaction is preferably completed after 1 to 36 hours of
reaction time.
[0724] In the second step, a compound of formula (16) can be
coupled with a compound of formula (17) to give a compound of
formula (18).
[0725] This reaction can be carried out by a Mitsunobu reaction
(see for example: a) K. C. K. Swamy et al, Chem. Rev. 2009, 109,
2551).
[0726] Compounds of the formula (17) can be prepared as outlined in
Scheme 2b, infra.
[0727] Said compounds of formula (18) (Scheme 2a), wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, L and Z are defined for the compound of
general formula (I) according to the present invention, can be
reduced to give an aniline of formula (19). The reduction can be
prepared analogously to known processes (see for example: (a)
Sammond et al; Bioorg. Med. Chem. Lett. 2005, 15, 3519; (b) R. C.
Larock, Comprehensive Organic Transformations, VCH, New York, 1989,
411-415). Preferred is the herein described use of Platinum 1% and
vanadium 2%, on activated carbon in methanol and THF at room
temperature under a hydrogen atmosphere.
[0728] In the fourth step, a compound of formula (19) can be
converted to a macrocycle compound of the invention (Id). This
cyclization reaction can be carried out by a Palladium-catalyzed
C--N cross-coupling reaction (for a review on C--N cross coupling
reactions see for example: a) L. Jiang, S. L. Buchwald in
`Metal-Catalyzed Cross-Coupling Reactions`, 2.sup.nd a ed.: A. de
Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany,
2004).
[0729] Preferred is the herein described use of
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct,
2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl as catalyst
and ligand, an alkali carbonate or an alkali phosphate, preferably
potassium phosphate, as a base, in a mixture of a
C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent,
preferably a mixture of toluene and NMP, as a solvent. The
reactions are preferably run under an atmosphere of argon for 2-24
hours at 100-130.degree. C. in a microwave oven or in an oil
bath.
[0730] In the fifth step, the tert-butoxycarbonyl-group attached to
the sulfoximine nitrogen can be cleaved under acidic conditions to
give an unprotected sulfoximine of formula (Ie) (see for example:
J. A. Bull, J. Org. Chem. 2015, 80, 6391).
[0731] Preferred is the herein described use of an acid, preferably
trifluoroacetic acid in dichloromethane as a solvent.
[0732] Said N-unprotected sulfoximine of formula (Ie) (R.sup.5=H)
may be further converted into a N-functionalized derivative of
formula (If). There are multiple methods for the preparation of
N-functionalized sulfoximines by functionalization of the nitrogen
of the sulfoximine group: [0733] Alkylation: see for example: a) U.
Lucking et al, US 2007/0232632; b) C. R. Johnson, J. Org. Chem.
1993, 58, 1922; c) C. Bolm et al, Synthesis 2009, 10, 1601. [0734]
Acylation: see for example: a) C. Bolm et al, Chem. Europ. J. 2004,
10, 2942; b) C. Bolm et al, Synthesis 2002, 7, 879; c) C. Bolm et
al, Chem. Europ. J. 2001, 7, 1118. [0735] Arylation: see for
example: a) C. Bolm et al, Tet. Lett. 1998, 39, 5731; b) C. Bolm et
al., J. Org. Chem. 2000, 65, 169; c) C. Bolm et al, Synthesis 2000,
7, 911; d) C. Bolm et al, J. Org. Chem. 2005, 70, 2346; e) U.
Lucking et al, WO2007/71455. [0736] Reaction with isocyanates: see
for example: a) V. J. Bauer et al, J. Org. Chem. 1966, 31, 3440; b)
C. R. Johnson et al, J. Am. Chem. Soc. 1970, 92, 6594; c) S.
Allenmark et al, Acta Chem. Scand. Ser. B 1983, 325; d) U. Lucking
et al, US2007/0191393. [0737] Reaction with sulfonylchlorides: see
for example: a) D. J. Cram et al, J. Am. Chem. Soc. 1970, 92, 7369;
b) C. R. Johnson et al, J. Org. Chem. 1978, 43, 4136; c) A. C.
Barnes, J. Med. Chem. 1979, 22, 418; d) D. Craig et al, Tet. 1995,
51, 6071; e) U. Lucking et al, US2007/191393. [0738] Reaction with
chloroformiates: see for example: a) P. B. Kirby et al, DE2129678;
b) D. J. Cram et al, J. Am. Chem. Soc. 1974, 96, 2183; c) P. Stoss
et al, Chem. Ber. 1978, 111, 1453; d) U. Lucking et al,
WO2005/37800. [0739] Reaction with bromocyane: see for example: a)
D. T. Sauer et al, Inorganic Chemistry 1972, 11, 238; b) C. Bolm et
al, Org. Lett. 2007, 9, 2951; c) U. Lucking et al, WO
2011/29537.
##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026##
##STR00027##
[0740] Compounds of the formula (17), in which R.sup.1, R.sup.2 and
L are as defined for the compound of general formula (I) according
to the present invention, can be prepared according to Scheme 2b,
starting e.g. from a benzylic alcohol derivative of formula (20),
in which R.sup.2 is as defined for the compound of general formula
(I), is reacted to give a compound of formula (21), in which LG
represents a leaving group such as a chlorine atom, a bromine atom
or an iodine atom, C.sub.1-C.sub.4-alkyl-S(.dbd.O).sub.2O--,
trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or
para-toluenesulfonyloxy-. Such conversions are well known to the
person skilled in the art; preferred is the herein described use of
thionyl chloride in N,N-dimethylformamide (DMF) as a solvent, to
give a compound of formula (21) in which LG represents a chlorine
atom.
[0741] Benzylic alcohol derivative of formula (20), or the
corresponding carboxylic acids and their esters, are known to the
person skilled in the art, and are commercially available in
certain cases.
[0742] In a second step, a compound of formula (21) can be reacted
with a thiol of the formula R.sup.1--SH, in which R.sup.1 is as
defined for the compound of general formula (I), to give a
thioether derivative of formula (22).
[0743] Thiols of the formula R.sup.1SH are well known to the person
skilled in the art and are commercially available in considerable
variety.
[0744] In a third step, a thioether derivative of formula (22) can
be reacted with a carboxylic ester of formula (23), in which L'
represents a C.sub.2-C.sub.7-alkylene group featuring one carbon
atom less as compared to the corresponding group L in formula (17),
R.sup.E represents a C.sub.1-C.sub.4-alkyl group, and in which LG
represents a leaving group such as a chlorine atom, a bromine atom
or an iodine atom, CH.sub.3--S(.dbd.O).sub.2O--,
trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or
para-toluenesulfonyloxy-, in the presence of a base, such as an
alkali carbonate, preferably potassium carbonate, in
N,N-dimethylformamide (DMF) as a solvent, to give a compound of
formula (24).
[0745] In a fourth step, oxidation of a thioether of formula (24)
can be used to obtain the corresponding sulfoxide of formula (25)
The oxidation can be performed analogously to known processes (see
for example: (a) M. H. Ali et al, Synthesis 1997, 764; (b) M. C.
Carreno, Chem. Rev. 1995, 95, 1717; (c) I. Patel et al, Org. Proc.
Res. Dev. 2002, 6, 225; (d) N. Khiar et al, Chem. Rev. 2003, 103,
3651). Preferred is the herein described use of periodic acid und
iron(III) chloride.
[0746] In a fifth step, a Rhodium-catalyzed imination of a
sulfoxide of formula (25) can be used to prepare the
N-Boc-protected sulfoximines of formula (26) (Bull et al, J. Org.
Chem. 2015, 80, 6391). Preferred is the herein described use of
sulfoxide, tert-butyl carbamate, magnesium oxide, rhodium(II)
acetate dimer and iodobenzene diacetate in DCM at room temperature
to 45.degree. C.
[0747] In a sixth step, an ester of the formula (26) can be reduced
using a reducing agent such as lithium aluminium hydride or
di-iso-butylaluminiumhydride (DIBAL), in an ether, preferably
tetrahydrofuran, as a solvent, to give compound of the formula (17)
which can be further processed as shown in the Scheme 2a.
##STR00028## ##STR00029##
Abbreviations Used in the Description of the Chemistry and in the
Examples that Follow are:
[0748] br. (broad, .sup.1H NMR signal); CDCl.sub.3 (deuterated
chloroform); cHex (cyclohexane); DCE (dichloroethane); d (doublet,
.sup.1H NMR signal); DCM (dichloromethane); DIPEA
(di-iso-propylethylamine); DMAP (4-N,N-dimethylaminopyridine), DME
(1,2-dimethoxyethane), DMF (N,N-dimethylformamide); DMSO (dimethyl
sulfoxide); ES (electrospray); EtOAc (ethyl acetate); EtOH
(ethanol); h (hour(s)); .sup.1H NMR (proton nuclear magnetic
resonance spectroscopy); HPLC (High Performance Liquid
Chromatography), iPrOH (iso-propanol); m (multiplet, .sup.1H NMR
signal); mCPBA (meta-chloroperoxybenzoic acid), MeCN
(acetonitrile), MeOH (methanol); min (minute(s)); MS (mass
spectrometry); MTBE (methyl tert-butyl ether); NMP
(N-Methylpyrrolidin-2-one); NMR (nuclear magnetic resonance);
Pd(dppf)Cl.sub.2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloro
palladium(II) complex with dichloromethane); q (quartet, .sup.1H
NMR signal); quin (quintet, .sup.1H NMR signal); rac (racemic); RT
(room temperature); s (singlet, .sup.1H NMR signal); sat. aq.
(saturated aqueous); SiO.sub.2 (silica gel); t (triplet, .sup.1H
NMR signal); TFA (trifluoroacetic acid); TFAA (trifluoroacetic
anhydride), THF (tetrahydrofuran); UPLC (Ultra-High Performance
Liquid Chromatography), UV (ultraviolet), wt-% (percent by
weight).
.sup.1H-NMR Spectra
[0749] .sup.1H-NMR signals are specified with their
multiplicity/combined multiplicities as apparent from the spectrum;
possible higher-order effects are not considered. Chemical shifts
of the signals (.delta.) are specified as ppm (parts per
million).
Chemical Naming:
[0750] Chemical names were generated using the ACD/Name software
from ACD/Labs. In some cases generally accepted names of
commercially available reagents were used in place of ACD/Name
generated names.
Salt Stoichiometry:
[0751] In the present text, in particular in the Experimental
Section, for the synthesis of intermediates and of examples of the
present invention, when a compound is mentioned as a salt form with
the corresponding base or acid, the exact stoichiometric
composition of said salt form, as obtained by the respective
preparation and/or purification process, is, in most cases,
unknown.
[0752] Unless specified otherwise, suffixes to chemical names or
structural formulae such as "hydrochloride", "trifluoroacetate",
"sodium salt", or "x HCl", "x CF.sub.3COOH", "x Na*", for example,
are to be understood as not a stoichiometric specification, but
solely as a salt form.
[0753] This applies analogously to cases in which synthesis
intermediates or example compounds or salts thereof have been
obtained, by the preparation and/or purification processes
described, as solvates, such as hydrates with (if defined) unknown
stoichiometric composition.
Preparative HPLC Methods:
Autopurifier: Acidic Conditions
TABLE-US-00001 [0754] System: Waters Autopurificationsystem: Pump
2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD Column:
XBrigde C18 5 .mu.m 100 .times. 30 mm Solvent: A = H.sub.2O + 0.1
vol-% HCOOH (99%) B = MeCN Gradient: 0.00-0.50 min 5% B, 25 mL/min
0.51-5.50 min 10-100% B, 70 mL/min 5.51-6.50 min 100% B, 70 mL/min
Temperature: RT Solution: max. 250 mg/max. 2.5 mL DMSO or DMF
Injection: 1 .times. 2.5 ml Detection: DAD scan range 210-400 nm MS
ESI+, ESI-, scan range 160-1000 m/z
Autopurifier: Basic Conditions
TABLE-US-00002 [0755] System: Waters Autopurificationsystem: Pump
2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD Column:
XBrigde C18 5 .mu.m 100 .times. 30 mm Solvent: A = H.sub.2O + 0.2%
vol-% aqueous NH.sub.3 (32%) B = MeCN Gradient: 0.00-0.50 min 5% B,
25 mL/min 0.51-5.50 min 10-100% B, 70 mL/min 5.51-6.50 min 100% B,
70 mL/min Temperature: RT Solution: max. 250 mg/max. 2.5 mL DMSO or
DMF Injection: 1 .times. 2.5 ml Detection: DAD scan range 210-400
nm MS ESI+, ESI-, scan range 160-1000 m/z
General Methods for LC-MS Analysis
Method a:
[0756] Instrument: Waters Acquity UPLCMS SingleQuad; Column:
Acquity UPLC BEH C18 1.7 .mu.m, 50.times.2.1 mm; eluent A:
water+0.1 vol % formic acid (99%), eluent B: acetonitrile;
gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min;
temperature: 60.degree. C.; DAD scan: 210-400 nm.
Method b:
[0757] Instrument: Waters Acquity UPLCMS SingleQuad; Column:
Acquity UPLC BEH C18 1.7 .mu.m, 50.times.2.1 mm; eluent A:
water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile;
gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min;
temperature: 60.degree. C.; DAD scan: 210-400 n.
Example 1
(rac)-tert-butyl
[{[3,20-difluoro-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.s-
up.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(me-
thyl)oxido-.lamda..sup.6-sulfanylidene]carbamate
##STR00030##
[0758] Preparation of Intermediate 1.1:
2-chloro-5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridine
##STR00031##
[0760] A batch with 2-chloro-5-fluoro-4-iodopyridine [CAS-RN:
884494-49-9] (3000 mg; 11.65 mmol),
(4-fluoro-3-methoxyphenyl)boronic acid [CAS-RN: 854778-31-7] (1981
mg; 11.65 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
[CAS-RN: 72287-26-4] (952 mg; 1.17 mmol) in 1,2-dimethoxyethane
(30.0 mL) and 2 M aqueous solution of potassium carbonate (23 mL)
was degassed using argon. The batch was stirred under an atmosphere
of argon for 4 hours at 100.degree. C. After cooling, the batch was
diluted with ethyl acetate and THF and washed with a saturated
aqueous solution of sodium chloride. The organic layer was filtered
using a Whatman filter and concentrated. The residue was purified
by column chromatography (hexane to hexane/ethyl acetate 50%) to
give the title compound (2600 mg; 10.2 mmol).
[0761] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.92 (s,
3H), 7.28 (ddt, 1H), 7.39 (dd, 1H), 7.48 (dd, 1H), 7.86 (d, 1H),
8.55 (d, 1H).
Preparation of Intermediate 1.2:
5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridin-2-amine
##STR00032##
[0763] A solution of lithium bis(trimethylsilyl)amide in THF (1M;
10.2 mL; 10.17 mmol; Aldrich Chemical Company Inc.) [CAS-RN:
4039-32-1] was added to a mixture of
2-chloro-5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridine (1.30 g;
5.09 mmol; see Intermediate 1.1),
tris(dibenzylideneacetone)dipalladium (0) (0.09 g; 0.10 mmol;
Aldrich Chemical Company Inc.) [CAS-RN: 51364-51-3] and
2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (0.10 g;
0.20 mmol; Aldrich Chemical Company Inc.) [CAS-RN: 564483-18-7] in
THF (10.4 mL) under an atmosphere of argon at room temperature. The
mixture was stirred at 60.degree. C. for 5 hours. The mixture was
cooled to -20.degree. C. and the pH was adjusted under cooling to
4-6 by the addition of aqueous hydrogen chloride solution (1N). The
mixture was stirred at room temperature for 15 minutes before the
pH was adjusted to 11 by the addition of aqueous sodium hydroxide
solution (2N). The mixture was three times extracted with ethyl
acetate. The combined organic layers were filtered using a Whatman
filter and concentrated. The residue was purified by column
chromatography on silica gel (hexane to hexane/ethyl acetate 80%)
to give the title compound (0.99 g; 4.2 mmol).
[0764] 1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=2.32-2.45 (m, 1H),
2.67 (s, 1H), 3.50 (s, 1H), 3.88 (s, 3H), 5.92 (s, 2H), 6.55 (d,
1H), 7.10 (ddd, 1H), 7.28-7.37 (m, 2H), 7.94 (d, 1H).
Preparation of Intermediate 1.3:
5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol
##STR00033##
[0766] A solution of boron tribromide in DCM (1M; 11.7 mL; 11.7
mmol; Aldrich Chemical Company Inc.) [CAS-RN: 10294-33-4] was added
dropwise to a stirred solution of
5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridin-2-amine (988 mg; 4.18
mmol) in DCM (19 mL) at 0.degree. C. The mixture was slowly warmed
to room temperature while stirring overnight. The mixture was
cautiously diluted with a saturated, aqueous solution of sodium
bicarbonate under stirring at 0.degree. C. and was stirred at room
temperature for 1 hour. A saturated solution of sodium chloride was
added and the mixture was extracted with ethyl acetate. The
combined organic layers were filtered using a Whatman filter and
concentrated to give the title compound (1240 mg) that was used
without further purification.
[0767] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=5.92 (s,
2H), 6.48 (d, 1H), 6.96 (ddd, 1H), 7.13 (dt, 1H), 7.25 (dd, 1H),
7.92 (d, 1H), 10.19 (br s, 1H).
Preparation of Intermediate 1.4:
(2,6-Dichloropyridin-4-yl)methanol
##STR00034##
[0769] To a stirred solution 2,6-dichloroisonicotinic acid (10.0 g,
52.1 mmol) [CAS-RN: 5398-44-7] in THF (300 mL) at 0.degree. C. was
added a solution of sulfanediyldimethane-borane (1:1) [CAS-RN:
13292-87-0](16.0 g, 210.5 mmol) in THF. The mixture was allowed to
react at room temperature overnight. Then MeOH (22 mL) was
cautiously added to the stirred mixture while cooling with an ice
bath. The reaction mixture was diluted with ethyl acetate (300 mL),
washed with an aqueous sodium hydroxide solution (1N, 100 mL) and
saturated aqueous sodium chloride solution. The organic layer was
concentrated and the residue was purified by column chromatography
on silica gel (hexane/ethyl acetate=7:1 to 3:1) to give the title
compound (8.3 g; 46.6 mmol).
[0770] .sup.1H-NMR (400 MHz, CDCl3, 300K): .delta. [ppm]=2.24 (br
s, 1H), 4.77 (s, 2H), 7.25 (s, 2H),
Preparation of Intermediate 1.5:
(2,6-dichloropyridin-4-yl)methyl methanesulfonate
##STR00035##
[0772] (2,6-Dichloropyridin-4-yl)methanol (1.0 g; 5.62 mmol) was
dissolved in DCM (20 mL) and triethyl amine (1.0 g; 9.88 mmol) was
added. The resulting mixture was cooled to 0.degree. C. and
methanesulfonyl chloride [CAS-RN: 124-63-0] (0.9 g, 7.9 mmol) was
added. The mixture was stirred at room temperature for 1 hour. By
adding an aqueous hydrogen chloride solution (1N), the pH value of
the mixture was adjusted to 3, before it was extracted three times
with ethyl acetate. The combined organic layers were concentrated
to give the crude title compound (1.4 g) that was used without
further purification.
Preparation of Intermediate 1.6:
2,6-Dichloro-4-[(methylsulfanyl)methyl]pyridine
##STR00036##
[0774] (2,6-Dichloropyridin-4-yl)methyl methanesulfonate (1.40 g)
was dissolved in THF (20 mL) and a mixture of sodium thiomethoxide
and sodium hydroxide (wt 1/1, 0.70 g, 5 mmol, supplied by Shanghai
DEMO Medical Tech Co., Ltd) was added. The resulting mixture was
stirred overnight at room temperature. The reaction mixture was
diluted with water (10 mL) and extracted three times with ethyl
acetate. The combined organic layers were concentrated and the
residue was purified by column chromatography on silica gel
(hexane/ethyl acetate=6:1 to 3:1) to give the title compound (0.54
g; 2.60 mmol).
[0775] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.97 (s,
3H), 3.53-3.92 (s, 2H), 7.54 (s, 2H).
Preparation of Intermediate 1.7:
4-({6-Chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)butan-1-ol)
##STR00037##
[0777] Sodium hydride (55-60%; 1.15 g) was added to a stirred
solution of butane-1,4-diol (5.41 g; 60.1 mmol) in THF (165 mL) at
0.degree. C. The ice bath was removed and the reaction mixture was
stirred at room temperature for 30 min.
2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (5.0 g; 24.0 mmol)
was added and the reaction mixture was stirred under reflux
overnight. After cooling the batch was concentrated and ethyl
acetate and water was added. The mixture was three times extracted
with ethyl acetate. The combined organic layers were washed with an
aqueous solution of sodium chloride, filtered using a Whatman
filter and concentrated. The residue was purified by column
chromatography on silica gel (hexane to hexane/ethyl acetate 60%)
to give the title compound (4.3 g; 16.4 mmol).
[0778] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.49-1.61
(m, 2H), 1.64-1.90 (m, 2H), 1.95-2.00 (m, 3H), 3.37-3.47 (m, 2H),
3.58-3.70 (m, 2H), 4.21 (t, 2H), 4.46 (t, 1H), 6.74 (s, 1H), 7.02
(d, 1H).
Preparation of Intermediate 1.8:
(rac)-4-({6-chloro-4-[(methylsulfinyl)methyl]pyridin-2-yl}oxy)butan-1-ol
##STR00038##
[0780] Iron(III)chloride (37 mg; 0.22 mmol) was added to a mixture
of
4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)butan-1-ol
(2000 mg; 7.64 mmol) in acetonitrile (18.5 mL) and the batch was
stirred at room temperature for 10 minutes. The batch was cooled to
0.degree. C. and periodic acid (1.86 g; 8.18 mmol) was added under
stirring in one portion. After 5 hours the ice bath was removed and
the mixture was stirred at room temperature. Additional periodic
acid (0.52 g; 2.29 mmol) was added and the mixture was stirred for
2 hours at room temperature before it was added to a stirred
solution of sodium thiosulfate pentahydrate [CAS-RN: 10102-17-7]
(10.62 g; 42.79 mmol) in ice water (220 mL). The batch was stirred
at room temperature for 1 hour and then extracted twice with ethyl
acetate. The combined organic layers were washed with an aqueous
solution of sodium chloride, filtered using a Whatman filter and
concentrated. The residue was purified by column chromatography on
silica gel (ethyl acetate to ethyl acetate/ethanol 30%) to give the
title compound (1.30 g; 4.68 mmol).
[0781] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.48-1.58
(m, 2H), 1.65-1.81 (m, 2H), 3.35-3.51 (m, 2H), 3.90-4.05 (m, 1H),
4.13-4.26 (m, 3H), 4.45 (t, 1H), 6.75 (d, 1H), 7.02 (d, 1H).
Preparation of Intermediate 1.9:
(rac)-tert-butyl
[{[2-chloro-6-(4-hydroxybutoxy)pyridin-4-yl]methyl}(methyl)oxido-.lamda..-
sup.6-sulfanylidene]carbamate
##STR00039##
[0783] To a suspension of
(rac)-4-({6-chloro-4-[(methylsulfinyl)methyl]pyridin-2-yl}oxy)butan-1-ol
(1.30 g, 4.68 mmol), tert-butyl carbamate (822 mg, 7.02 mmol),
magnesium oxide (754 mg, 18.72 mmol) and rhodium(II) acetate dimer
[CAS-RN: 15956-28-2] (103 mg, 0.23 mmol) in DCM (45 mL) was added
iodobenzene diacetate [CAS-RN: 3240-34-4] (2.26 g, 7.02 mmol) at
room temperature. The batch was stirred for 18 h at room
temperature, filtered over celite and concentrated. The residue was
purified by column chromatography on silica gel (ethyl acetate) to
give the title compound (960 mg, 2.44 mmol).
[0784] 1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=1.29-1.41 (m, 9H),
1.48-1.58 (m, 2H), 1.66-1.81 (m, 2H), 3.15-3.29 (m, 3H), 3.36-3.47
(m, 2H), 4.20-4.29 (m, 2H), 4.46 (t, 1H), 4.91 (d, 2H), 6.86 (s,
1H), 7.08 (d, 1H).
Preparation of Intermediate 1.10:
(rac)-4-[(4-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-6-chlo-
ropyridin-2-yl)oxy]butyl methanesulfonate
##STR00040##
[0786] Methanesulfonyl chloride [CAS-RN: 124-63-0] (133 mg; 1.16
mmol) was added dropwise to a stirred solution of (rac)-tert-butyl
[{[2-chloro-6-(4-hydroxybutoxy)pyridin-4-yl]methyl}(methyl)oxido-.lamda..-
sup.6-sulfanylidene]carbamate (380 mg; 0.97 mmol) and
trimethylamine (196 mg; 1.93 mmol) in DCM (4.2 mL) at 0.degree. C.
The ice bath was removed after 30 minutes and the reaction mixture
was stirred for 2 hours at room temperature. The reaction mixture
was diluted with water and extracted twice with ethyl acetate. The
combined organic layers were filtered using a Whatman filter and
concentrated. The residue was purified by column chromatography on
silica gel (hexane to hexane/ethyl acetate 70%) to give the title
compound (450 mg, 0.96 mmol).
[0787] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.39 (s,
9H), 1.75-1.86 (m, 4H), 3.18 (s, 6H), 4.22-4.31 (m, 4H), 4.91 (d,
2H), 6.88 (d, 1H), 7.10 (d, 1H).
Preparation of Intermediate 1.11:
(rac)-tert-butyl
{[(2-{4-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]butoxy}-6-chlor-
opyridin-4-yl)methyl](methyl)oxido-.lamda..sup.6-sulfanylidene}carbamate
##STR00041##
[0789] A mixture of 5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol
(see Intermediate 1.3; 94 mg, 0.43 mmol),
(rac)-4-[(4-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-6-chl-
oropyridin-2-yl)oxy]butyl methanesulfonate (200 mg; 0.43 mmol)
potassium carbonate (70 mg; 0.51 mmol) and potassium iodide (7 mg;
0.04 mmol) in DMF (3.3 mL) was stirred at 40.degree. C. overnight.
After cooling the mixture was diluted with ethyl acetate and washed
with water. The organic phase was concentrated and the residue was
purified by preparative HPLC (see method Autopurifier: acidic
conditions) to give the title compound (70 mg; 0.12 mmol).
Example 1 Preparation of End Product
[0790] To a solution of (rac)-tert-butyl
{[(2-{4-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]butoxy}-6-chlor-
opyridin-4-yl)methyl](methyl)oxido-.lamda..sup.6-sulfanylidene}carbamate
(70 mg, 0.12 mmol) in toluene (8.4 mL) and NMP (0.6 mL) was
sequentially added potassium phosphate (124 mg, 0.59 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl [CAS-RN:
564483-18-7] (5.6 mg, 0.01 mmol) and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct
[CAS-RN: 1028206-56-5] (9.7 mg, 0.01 mmol). The suspension was
degassed and heated under an atmosphere of argon to 110.degree. C.
for 4 hours. After cooling, the reaction mixture was diluted with
aqueous sodium chloride solution and extracted three times with
ethyl acetate. The combined organic layers were filtered using a
Whatman filter and concentrated. The residue was purified with
preparative HPLC (see method Autopurifier: acidic conditions) to
give the title compound (3 mg) still showing minor impurities.
[0791] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.28-1.43
(m, 9H), 1.65-1.82 (m, 4H), 3.20 (s, 3H), 4.41-4.56 (m, 4H),
4.71-4.82 (m, 2H), 6.32 (d, 1H), 6.66 (s, 1H), 7.30-7.42 (m, 2H),
7.60 (d, 1H), 8.32 (d, 1H), 8.80 (d, 1H), 10.02 (s, 1H).
Example 2
(rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24--
triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(2-
4),9,11,19,21-nonaene
##STR00042##
[0793] To a solution of (rac)-tert-butyl
[{[3,20-difluoro-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.s-
up.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(me-
thyl)oxido-.lamda..sup.6-sulfanylidene]carbamate (5 mg) in
dichloromethane (0.2 mL) was added trifluoroacetic acid (22 .mu.L)
and the mixture was stirred for 2 h. The pH value of the reaction
mixture was adjusted to pH>7 by the addition of saturated
aqueous sodium bicarbonate solution. The mixture was extracted
three times with dichloromethane. The combined organic layers were
filtered using a Whatman filter and concentrated to give the title
compound (3 mg, 6.5 .mu.mol).
[0794] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.62-1.85
(m, 4H), 2.92 (s, 3H), 4.03 (q, 1H), 4.30-4.56 (m, 7H), 6.36 (s,
1H), 6.66 (s, 1H), 7.32-7.41 (m, 2H), 7.62 (d, 1H), 8.33 (d, 1H),
8.83 (d, 1H), 9.97 (s, 1H).
Example 3
(rac)-tert-butyl
[{[3,20-difluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.s-
up.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(me-
thyl)oxido- .lamda..sup.6-sulfanylidene]carbamate
##STR00043##
[0795] Preparation of Intermediate 3.1:
5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol
##STR00044##
[0797] A batch with 2,4-dichloro-5-fluoropyrimidine [CAS-RN:
1293994-86-1] (1000 mg; 5.99 mmol),
(4-fluoro-3-hydroxyphenyl)boronic acid [CAS-RN: 913835-74-2] (1027
mg; 6.59 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
[CAS-RN: 72287-26-4] (489 mg; 0.60 mmol) in 1,2-dimethoxyethane (18
mL) and 2 M aqueous solution of potassium carbonate (9 mL) was
degassed using argon. The batch was stirred under an atmosphere of
argon for 3 hours at 90.degree. C. After cooling, the batch was
diluted with ethyl acetate and washed with an aqueous solution of
sodium chloride. The organic layer was filtered using a Whatman
filter and concentrated. The residue was purified by column
chromatography (hexane to hexane/ethyl acetate 30%) to give the
title compound (307 mg; 1.3 mmol).
[0798] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=7.33-7.41
(m, 1H), 7.53 (dddt, 1H), 7.73 (dd, 1H), 8.93 (d, 1H), 10.42 (br s,
1H).
Preparation of Intermediate 3.2:
3-(Chloromethyl)-5-nitrophenol
##STR00045##
[0800] Thionyl chloride (84.0 g; 712 mmol) was added dropwise to a
stirred solution of 3-(hydroxymethyl)-5-nitrophenol (60.0 g; 355
mmol) [CAS-RN: 180628-74-4] purchased from Struchem in DMF (1200
mL) at 0.degree. C. The mixture was stirred at 10.degree. C. for 3
hours. The mixture was concentrated, diluted with water and
extracted three times with ethyl acetate. The combined organic
layers were washed twice with water and concentrated to afford the
crude title compound (60.0 g) that was used without further
purification.
Preparation of Intermediate 3.3:
3-[(Methylsulfanyl)methyl]-5-nitrophenol
##STR00046##
[0802] To a solution of crude 3-(chloromethyl)-5-nitrophenol (60.0
g) in acetone (600 mL) at room temperature was added an aqueous
solution of sodium thiomethoxide (21%, 180 mL). The mixture was
stirred at room temperature for 3 hours before additional aqueous
solution of sodium thiomethoxide (21%, 180 mL) was added and the
mixture was stirred at room temperature overnight. Finally,
additional aqueous solution of sodium thiomethoxide (21%, 90 mL)
was added and the mixture was stirred at room temperature for 6
hours. The batch was diluted with ethyl acetate and an aqueous
solution of sodium chloride and extracted three times with ethyl
acetate. The combined organic layers were concentrated and the
residue was purified by column chromatography on silica gel
(pentane/ethyl acetate 4:1) to afford the desired product (60.0 g,
302 mmol).
[0803] .sup.1H NMR (300 MHz, CDCl.sub.3, 300K) 6=7.71 (1H), 7.57
(1H), 7.15 (1H), 3.66 (2H), 1.99 (3H).
Preparation of Intermediate 3.4:
ethyl 4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butanoate
##STR00047##
[0805] To a suspension of 3-[(methylsulfanyl)methyl]-5-nitrophenol
(6.00 g) and potassium carbonate (4.99 g) in DMF (58 ml) at
0.degree. C. was added dropwise ethyl 4-bromobutanoate [CAS-RN:
2969-81-5] (4.7 mL). The mixture was allowed to warm to room
temperature and stirred for 24 h. The reaction was diluted with
water (300 mL) and the mixture was extracted three times with ethyl
acetate (200 mL each). The combined organic layers were washed with
saturated aqueous sodium chloride, dried and concentrated to yield
the title compound (11.69 g, 90% purity) that was contaminated by
DMF and excess ethyl 4-bromobutanoate and which was used without
further purification.
[0806] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K)
.delta./ppm=1.15-1.21 (m, 3H), 1.94-2.03 (m, 5H), 3.74-3.81 (m,
2H), 4.02-4.14 (m, 4H), 7.33-7.36 (m, 1H), 7.57-7.61 (m, 1H),
7.75-7.80 (m, 1H) (one methylene group is overlayed by residual
DMSO).
Preparation of Intermediate 3.5:
(rac)-ethyl
4-(3-{[S-methylsulfinyl]methyl}-5-nitrophenoxy)butanoate
##STR00048##
[0808] To a solution of crude ethyl
4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butanoate (11.7 g) in
acetonitrile (410 mL) at 0.degree. C. was added iron trichloride
(605 mg) and the mixture was stirred for 15 min. Then, periodic
acid (25.5 g) was added and the reaction was stirred for 1.5 h at
0.degree. C. The reaction was stopped by the addition of saturated
aqueous sodium thiosulfate solution, and the mixture was extracted
three times with ethyl acetate (300 mL each). The combined organic
layers were washed with saturated aqueous sodium chloride, dried
and concentrated to yield the title compound (10.5 g, 99% purity)
that was used without further purification.
[0809] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K)
.delta./ppm=1.15-1.21 (m, 3H), 1.97-2.06 (m, 2H), 4.04-4.15 (m,
5H), 4.24-4.31 (m, 1H), 7.28-7.36 (m, 1H), 7.65-7.69 (m, 1H),
7.76-7.82 (m, 1H).
Preparation of Intermediate 3.6:
(rac)-ethyl
4-(3-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-5-nitropheno-
xy)butanoate
##STR00049##
[0811] To a suspension of (rac)-ethyl
4-(3-{[S-methylsulfinyl]methyl}-5-nitrophenoxy)butanoate (10.5 g),
tert-butyl carbamate (5.60 g), magnesium oxide (5.14 g), and
rhodium(II)acetate dimer [CAS-RN: 15956-28-2] (352 mg) in
dichloromethane (530 mL) was added iodobenzene diacetate [CAS-RN:
3240-34-4] (15.4 g), and the mixture was stirred for 4.5 h at
45.degree. C. Additional portions of tert-butyl carbamate (1.87 g),
rhodium(II)acetate dimer (117 mg) and iodobenzene diacetate (5.1 g)
were added, and the mixture was stirred for further 12 h at
45.degree. C. The mixture was allowed to cool to room temperature,
filtered over a pad of Celite and concentrated. The crude product
was purified by flash column chromatography (silica gel,
hexanes/ethyl acetate) to yield the title compound (12.8 g, 97%
purity).
[0812] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K)
.delta./ppm=1.15-1.24 (m, 3H), 1.39 (s, 9H), 1.98-2.06 (m, 2H),
2.44-2.44 (m, 1H), 3.09-3.19 (m, 3H), 4.04-4.16 (m, 4H), 4.95-5.10
(m, 2H), 7.41-7.47 (m, 1H), 7.73-7.80 (m, 1H), 7.88-7.94 (m,
1H).
Preparation of Intermediate 3.7:
(rac)-tert-butyl
{[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-P6-sulfanylidene}carbam-
ate
##STR00050##
[0814] To a solution of (rac)-ethyl
4-(3-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-5-nitropheno-
xy)butanoate (12.8 g) in THF (210 mL) at -20.degree. C. was added
dropwise diisobutylaluminum hydride (120 mL, 1.0 M in THF). The
mixture was allowed to warm to room temperature and stirred for 2.5
h. The reaction was stopped by the addition of saturated aqueous
sodium potassium tartrate solution. The mixture was vigorously
stirred for 2 h and subsequently extracted three times with ethyl
acetate (100 mL each). The combined organic layers were washed with
saturated aqueous sodium chloride solution, dried and concentrated.
The crude product was purified by flash column chromatography
(silica gel, hexane/ethyl acetate 40%->ethyl
acetate.fwdarw.ethyl acetate/methanol 20%) to yield the title
compound (8.01 g, 97% purity).
[0815] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) .delta./ppm=1.39
(s, 9H), 1.51-1.65 (m, 2H), 1.73-1.83 (m, 2H), 3.14 (s, 3H),
3.43-3.51 (m, 2H), 4.09-4.16 (m, 2H), 4.46-4.51 (m, 1H), 4.93-5.07
(m, 2H), 7.37-7.50 (m, 1H), 7.73-7.79 (m, 1H), 7.86-7.92 (m,
1H).
Preparation of Intermediate 3.8:
(rac)- tert-butyl
[(3-{4-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]butoxy}-5-nit-
robenzyl)(methyl)oxido- .lamda..sup.6-sulfanylidene]carbamate
##STR00051##
[0817] Under argon, diisopropyl azodicarboxylate [CAS-RN:
2446-83-5] (0.45 mL; 2.27 mmol) was added dropwise to a stirred
mixture of 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol (see
Intermediate 3.1; 300 mg; 1.24 mmol), (rac)-tert-butyl
{[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-.lamda..sup.6-sulfanyli-
dene}carbamate (452 mg; 1.12 mmol) and triphenylphosphine (613 mg;
2.34 mmol) in THF (29 mL) at 0.degree. C. The ice bath was removed
and the mixture was stirred at room temperature overnight. The
mixture was concentrated and the residue was purified by column
chromatography on silica gel (hexane to hexane/ethyl acetate 50%)
to give the desired title compound (285 mg), still containing some
impurities.
Preparation of Intermediate 3.9:
(rac)-tert-butyl
[(3-amino-5-{4-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]butox-
y}benzyl)(methyl)oxido- .lamda..sup.6-sulfanylidene]carbamate
##STR00052##
[0819] Platinum 1% and vanadium 2%, on activated carbon (50-70%
wetted powder, 44 mg) was added to a solution of (rac)-tert-butyl
[(3-{4-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]butoxy}-5-nit-
robenzyl)(methyl)oxido-.lamda..sup.6-sulfanylidene]carbamate (282
mg) in methanol (7 mL) and THF (2 mL) and the mixture was stirred
for 3 h at room temperature at room temperature under a hydrogen
atmosphere. Additional platinum 1% and vanadium 2%, on activated
carbon (50-70% wetted powder, 44 mg) was added and the mixture was
stirred for additional 3 h at room temperature under a hydrogen
atmosphere. The mixture was filtered and the filtrate was
concentrated to give the title compound that was used without
further purification (231 mg).
Example 3--Preparation of the End Product
[0820] To a solution of (rac)-tert-butyl
[(3-amino-5-{4-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]butox-
y}benzyl)(methyl)oxido-.lamda..sup.6-sulfanylidene]carbamate (229
mg) in toluene (29 mL) and NMP (1 mL) was sequentially added
potassium phosphate (407 mg, 1.91 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl [CAS-RN:
564483-18-7] (18 mg, 0.038 mmol) and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct
[CAS-RN: 1028206-56-5] (32 mg, 0.038 mmol). The suspension was
degassed and heated under argon to 110.degree. C. for 3 hours.
After cooling, the reaction mixture was diluted with aqueous sodium
chloride solution and extracted three times with ethyl acetate.
[0821] The combined organic layers were filtered using a Whatman
filter and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate 30% to ethyl
acetate) to give the title compound (53 mg; 0.09 mmol).
[0822] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.38 (s,
9H), 1.66-1.88 (m, 2H), 1.92-2.03 (m, 2H), 3.16 (s, 3H), 4.16 (t,
2H), 4.30 (t, 2H), 4.70-4.85 (m, 2H), 6.78 (s, 1H), 6.87 (s, 1H),
7.39 (dd, 1H), 7.62-7.71 (m, 1H), 8.01 (t, 1H), 8.18 (dd, 1H), 8.66
(d, 1H), 9.93 (s, 1H).
Example 4
(rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,25--
triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(2-
4),9,11,19,21-nonaene
##STR00053##
[0824] To a solution of (rac)-tert-butyl
[{[3,20-difluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.s-
up.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(me-
thyl)oxido-.lamda..sup.6-sulfanylidene]carbamate (see Example 3; 53
mg; 0.09 mmol) in dichloromethane (0.7 mL) was added
trifluoroacetic acid (0.2 mL) and the mixture was stirred for 2 h.
The pH value of the reaction mixture was adjusted to pH>7 by the
addition of saturated aqueous sodium bicarbonate solution. The
mixture was extracted three times with ethyl acetate/THF. The
combined organic layers were filtered using a Whatman filter and
concentrated. The residue was purified by column chromatography on
silica gel (DCM to DCM/ethanol 20%) to give the title compound (20
mg, 0.04 mmol).
[0825] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.70-1.87
(m, 2H), 1.87-2.04 (m, 2H), 2.84 (s, 3H), 3.63 (s, 1H), 4.12-4.21
(m, 2H), 4.25-4.34 (m, 4H), 6.79 (s, 1H), 6.84 (s, 1H), 7.39 (dd,
1H), 7.60-7.72 (m, 1H), 7.95 (t, 1H), 8.19 (dd, 1H), 8.65 (d, 1H),
9.87 (s, 1H).
Example 5
(rac)-tert-butyl
[{[3,21-difluoro-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1.sup.2,6.1.s-
up.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10-yl]methyl}(met-
hyl)oxido-.lamda..sup.6-sulfanylidene]carbamate
##STR00054##
[0826] Preparation of Intermediate 5.1:
methyl 5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentanoate
##STR00055##
[0828] To a suspension of 3-[(methylsulfanyl)methyl]-5-nitrophenol
(see Intermediate 3.3; 2.00 g; 10.0 mmol) and potassium carbonate
(2.08 g; 15.1 mmol) in DMF (20 ml) at 0.degree. C. was added methyl
5-bromopentanoate [CAS-RN: 5454-83-1] (1.7 mL; 12.0 mmol). The
mixture was allowed to warm to room temperature and stirred
overnight. The reaction was diluted with aqueous sodium chloride
solution and was three times extracted with ethyl acetate. The
combined organic layers were filtered using a Whatman filter and
concentrated to give the title compound (2.90 g) which was used
without further purification.
[0829] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.56-1.84
(m, 4H), 1.96 (s, 3H), 2.40 (tr, 3H), 3.33 (s, 3H), 3.79 (s, 2H),
4.10 (t, 2H), 7.35 (s, 1H), 7.59 (t, 1H), 7.78 (s, 1H).
Preparation of Intermediate 5.2:
5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentan-1-ol
##STR00056##
[0831] To a solution of methyl
5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentanoate (2.90 g) in
THF (45 mL) at -78.degree. C. was added dropwise a solution of
diisobutylaluminum hydride in THF (1.0 M; 32.9 mL, 32.9 mmol). The
mixture was allowed to warm to 0.degree. C. and stirred for 2 h at
this temperature. Water was cautiously added and the pH was
adjusted to pH 4 by the addition of an aqueous solution of hydrogen
chloride (1N). The mixture was three times extracted with ethyl
acetate. The combined organic layers were washed with saturated
aqueous sodium chloride solution, filtered using a Whatman filter
and concentrated. The residue was purified by flash column
chromatography on silica gel (hexane to hexane/ethyl acetate 70%)
to give the title compound (2.40 g, 8.4 mmol).
[0832] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35-1.52
(m, 4H), 1.69-1.80 (m, 2H), 1.96 (s, 3H), 3.32-3.43 (m, 2H), 3.76
(s, 3H), 3.97-4.11 (m, 2H), 4.39 (t, 1H), 7.35 (s, 1H), 7.58 (t,
1H), 7.77 (t, 1H).
Preparation of Intermediate 5.3:
(rac)-5-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}pentan-1-ol
##STR00057##
[0834] To a solution of
5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentan-1-ol (2.30 g;
8.06 mmol) in acetonitrile (215 mL) at 0.degree. C. was added iron
trichloride (38 mg; 0.23 mmol) and the mixture was stirred for 15
min at room temperature. Periodic acid (1.97 g; 8.62 mmol) was
added and the reaction was stirred for 4 h at 0.degree. C. The ice
bath was removed and the reaction was warmed to room temperature
under stirring before it was added to a stirred solution of sodium
thiosulfate pentahydrate (11.20 g; 45.14 mmol) in ice water (250
mL). The batch was saturated with solid sodium chloride and
extracted twice with THF and extracted twice with ethyl acetate.
The combined organic layers were filtered using a Whatman filter
and concentrated. The residue was purified by flash column
chromatography on silica gel (hexane to hexane/ethyl acetate 70%)
to give the title compound (1.43 g, 4.75 mmol).
[0835] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.40-1.52 (m, 4H),
1.75 (quin, 2H), 3.38-3.44 (m, 2H), 4.03-4.12 (m, 3H), 4.28 (d,
1H), 4.39 (t, 1H), 7.35 (s, 1H), 7.68 (t, 1H), 7.79 (s, 1H).
Preparation of Intermediate 5.4:
(rac)-tert-butyl
[{3-[(5-hydroxypentyl)oxy]-5-nitrobenzyl}(methyl)oxido-.lamda..sup.6-sulf-
anylidene]carbamate
##STR00058##
[0837] To a suspension of
(rac)-5-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}pentan-1-ol
(1430 mg; 4.75 mmol), tert-butyl carbamate (833 mg; 7.11 mmol),
magnesium oxide (765 mg; 18.98 mmol), and rhodium(II)acetate dimer
[CAS-RN: 15956-28-2] (105 mg; 0.24 mmol) in dichloromethane (46 mL)
was added iodobenzene diacetate [CAS-RN: 3240-34-4] (2293 mg; 7.12
mmol), and the mixture was stirred at room temperature overnight.
Additional portions of tert-butyl carbamate (416 mg; 3.56 mmol),
magnesium oxide (382 mg; 9.49 mmol), rhodium(II)acetate dimer (52
mg; 0.12 mmol) and iodobenzene diacetate (1146 mg; 3.56 mmol) were
added, and the mixture was stirred for further 12 h at room
temperature. The mixture was filtered over a pad of Celite and
concentrated. The residue was purified by flash column
chromatography on silica gel, (hexane to hexane/ethyl acetate 30%)
to give the title compound (920 mg; 2.20 mmol).
[0838] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.32-1.55
(m, 13H), 1.70-1.83 (m, 2H), 3.14 (s, 3H), 3.35-3.44 (m, 2H),
4.06-4.13 (m, 2H), 4.39 (t, 1H), 4.95-5.05 (m, 2H), 7.44 (s, 1H),
7.72-7.77 (m, 1H), 7.90 (s, 1H).
Preparation of Intermediate 5.5:
(rac)-tert-butyl
{[3-({5-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]pentyl}oxy)--
5-nitrobenzyl](methyl)oxido-
.lamda..sup.6-sulfanylidene}carbamate
##STR00059##
[0840] Under an atmosphere of argon, diisopropyl azodicarboxylate
[CAS-RN: 2446-83-5] (0.88 mL; 4.46 mmol) was added dropwise to a
stirred mixture of
5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol (see
Intermediate 3.1; 589 mg; 2.43 mmol), (rac)-tert-butyl
[{3-[(5-hydroxypentyl)oxy]-5-nitrobenzyl}(methyl)oxido-.lamda..sup.6-sulf-
anylidene]carbamate (920 mg; 2.21 mmol) and triphenylphosphine
(1205 mg; 4.60 mmol) in THF (10 mL) at 0.degree. C. The ice bath
was removed and the mixture was stirred at room temperature
overnight. Additional portions of triphenylphosphine (1205 mg; 4.60
mmol) and diisopropyl azodicarboxylate (0.88 mL; 4.46 mmol) were
added and the mixture was stirred for 5 h at room temperature. The
mixture was concentrated and the residue was purified by column
chromatography on silica gel (hexane to hexane/ethyl acetate 50%)
to give the desired title compound (456 mg), still containing some
impurities.
Preparation of Intermediate 5.6:
(rac)- tert-butyl
{[3-amino-5-({5-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]pent-
yl}oxy)benzyl](methyl)oxido-
.lamda..sup.6-sulfanylidene}carbamate
##STR00060##
[0842] Platinum 1% and vanadium 2%, on activated carbon (50-70%
wetted powder, 117 mg) was added to a solution of (rac)-tert-butyl
{[3-({5-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]pentyl}oxy)--
5-nitrobenzyl](methyl)oxido- .lamda..sup.6-sulfanylidene}carbamate
(456 mg; 0.71 mmol) in methanol (115 mL) and the mixture was
stirred for 2 h at room temperature under a hydrogen atmosphere.
The mixture was filtered and the filtrate was concentrated to give
the title compound that was used without further purification (385
mg).
Example 5--Preparation of the End Product
[0843] To a solution of (rac)- tert-butyl
{[3-amino-5-({5-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]pent-
yl}oxy)benzyl](methyl)oxido-.lamda..sup.6-sulfanylidene}carbamate
(385 mg) in toluene (47 mL) and NMP (6 mL) was sequentially added
potassium phosphate (668 mg, 3.15 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl [CAS-RN:
564483-18-7] (30 mg, 0.063 mmol) and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct
[CAS-RN: 1028206-56-5] (52 mg, 0.063 mmol). The suspension was
degassed and heated under argon to 110.degree. C. for 5 hours.
After cooling, the reaction mixture was diluted with aqueous sodium
chloride solution and extracted twice with DCM and extracted twice
with ethyl acetate. The combined organic layers were filtered using
a Whatman filter and concentrated. The residue was purified with
preparative HPLC see method: Autopurifier: acidic conditions) to
give the title compound (60 mg; 0.10 mmol).
[0844] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=1.39 (s, 9H),
1.61-1.70 (m, 2H), 1.81-1.87 (m, 2H), 1.88-1.97 (m, 2H), 3.16 (s,
3H), 3.97 (t, 2H), 4.26-4.32 (m, 2H), 4.72-4.80 (m, 2H), 6.62 (s,
1H), 6.88 (s, 1H), 7.41 (dd, 1H), 7.59-7.75 (m, 1H), 8.16 (dd, 1H),
8.47 (t, 1H), 8.68 (d, 1H), 10.01 (s, 1H).
Example 6
(rac)-3,21-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,26--
triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25-
),9,11,20,22-nonaene
##STR00061##
[0846] To a solution of (rac)-tert-butyl
[{[3,21-difluoro-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1.sup.2,6.1.s-
up.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10-yl]methyl}(met-
hyl)oxido-.lamda..sup.6-sulfanylidene]carbamate (58 mg; 0.10 mmol)
in dichloromethane (0.90 mL) was added trifluoroacetic acid (0.25
mL) and the mixture was stirred for 2 h. The pH value of the
reaction mixture was adjusted to pH>7 by the addition of
saturated aqueous sodium bicarbonate solution. The mixture was
extracted three times with ethyl acetate. The combined organic
layers filtered using a Whatman filter and concentrated. The
residue was purified by preparative HPLC (see method: Autopurifier:
basic conditions) to give the title compound (5 mg, 0.01 mmol).
[0847] .sup.1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.60-1.70 (m,
2H), 1.80-1.99 (m, 4H), 2.85 (s, 3H), 3.62 (s, 1H), 3.97 (t, 2H),
4.23-4.34 (m, 4H), 6.63 (s, 1H), 6.84 (s, 1H), 7.41 (dd, 1H),
7.56-7.75 (m, 1H), 8.16 (dd, 1H), 8.42 (t, 1H), 8.67 (d, 1H), 9.95
(s, 1H).
Example 7
(rac)-tert-butyl
[methyl(oxido){[3,20,23-trifluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.-
3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-
-10-yl]methyl}-1.lamda..sup.6-sulfanylidene]carbamate
##STR00062##
[0848] Preparation of Intermediate 7.1:
2-chloro-4-(2,4-difluoro-3-methoxyphenyl)-5-fluoropyrimidine
##STR00063##
[0850] A batch with 2,4-dichloro-5-fluoropyrimidine [CAS-RN:
2927-71-1] (3978 mg; 23.82 mmol),
(2,4-difluoro-3-methoxyphenyl)boronic acid [CAS-RN: 406482-18-6)
(4925 mg; 26.21 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
[CAS-RN: 72287-26-4] (1945 mg; 2.38 mmol) in 1,2-dimethoxyethane
(70 mL) and 2 M aqueous solution of potassium carbonate (36 mL) was
degassed using argon. The batch was stirred under an atmosphere of
argon for 3 hours at 100.degree. C. After cooling, the batch was
diluted with ethyl acetate and washed with a saturated aqueous
solution of sodium chloride. The organic layer was filtered using a
Whatman filter and concentrated. The residue was purified by column
chromatography (hexane to hexane/ethyl acetate 33%) to give the
title compound (4030 mg; 14.7 mmol).
[0851] 1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=3.99 (s, 3H),
7.39-7.43 (m, 1H), 7.45 (d, 1H), 9.06 (d, 1H).
Preparation of Intermediate 7.2:
3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenol
##STR00064##
[0853] A solution of boron tribromide [CAS-RN: 10294-33-4] in DCM
(1M; 74.9 mL; 74.9 mmol) was added dropwise to a stirred solution
of 2-chloro-4-(2,4-difluoro-3-methoxyphenyl)-5-fluoropyrimidine
(3700 mg; 13.5 mmol) in DCM (325 mL) at 0.degree. C. The mixture
was slowly warmed to room temperature while stirring overnight. The
mixture was cautiously diluted with a saturated, aqueous solution
of sodium bicarbonate under stirring at 0.degree. C. and then solid
sodium bicarbonate was added. The mixture was stirred at room
temperature for 1 hour before being filtered using a Whatman
filter. The filtrate was concentrated to give the crude product
(2160 mg) that was used without further purification.
[0854] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=7.15 (ddd,
1H), 7.25-7.31 (m, 1H), 9.03 (d, 1H), 10.73 (br s, 1H).
Preparation of Intermediate 7.3:
(rac)-tert-butyl
[(3-{4-[3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenoxy]butoxy}-5-
-nitrobenzyl)(methyl)oxido-.lamda..sup.6-sulfanylidene]carbamate
##STR00065##
[0856] Under an atmosphere of argon, diisopropyl azodicarboxylate
[CAS-RN: 2446-83-5] (0.21 mL; 1.06 mmol) was added dropwise to a
stirred mixture of crude
3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenol (150 mg),
(rac)-tert-butyl
{[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-.lamda..sup.6-sulfanyli-
dene}carbamate (see Intermediate 3.7; 211 mg; 0.52 mmol) and
triphenylphosphine (285 mg; 1.09 mmol) in THF (2.5 mL) at 0.degree.
C. The ice bath was removed and the mixture was stirred at room
temperature for 3 days. The mixture was concentrated and the
residue was purified by column chromatography on silica gel (hexane
to hexane/ethyl acetate 50%) to give the desired title compound
(309 mg), still containing some impurities.
Preparation of Intermediate 7.4:
(rac)- tert-butyl
[(3-amino-5-{4-[3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenoxy]b-
utoxy}benzyl)(methyl)oxido-
.lamda..sup.6-sulfanylidene]carbamate
##STR00066##
[0858] Platinum 1% and vanadium 2%, on activated carbon (50-70%
wetted powder, 46 mg) was added to a solution of (rac)-tert-butyl
[(3-{4-[3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenoxy]butoxy}-5-
-nitrobenzyl)(methyl)oxido-.lamda..sup.6-sulfanylidene]carbamate
(307 mg) in methanol (7 mL) and THF (2 mL) and the mixture was
stirred for 3 h at room temperature under a hydrogen atmosphere.
The mixture was filtered and the filtrate was concentrated to give
the title compound that was used without further purification (310
mg).
Example 7--Preparation of the End Product
[0859] To a solution of (rac)-tert-butyl
[(3-amino-5-{4-[3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenoxy]b-
utoxy}benzyl)(methyl)oxido- .lamda..sup.6-sulfanylidene]carbamate
(100 mg) in toluene (12 mL) and NMP (1.5 mL) was sequentially added
potassium phosphate (172 mg, 0.81 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl [CAS-RN:
564483-18-7] (8 mg, 0.016 mmol) and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct
[CAS-RN: 1028206-56-5] (13 mg, 0.016 mmol). The suspension was
degassed and heated under an atmosphere of argon to 110.degree. C.
for 3 hours. After cooling, the reaction mixture was diluted with
aqueous sodium chloride solution and extracted three times with
ethyl acetate. The combined organic layers were filtered using a
Whatman filter and concentrated. The residue was purified with
preparative HPLC (see method: Autopurifier: acidic conditions) to
give the title compound (3 mg; 0.01 mmol).
[0860] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.38 (s, 9H),
1.63-1.79 (m, 2H), 1.80-1.95 (m, 2H), 3.13 (s, 3H), 3.90-4.01 (m,
2H), 4.37 (br t, 2H), 4.64-4.78 (m, 2H), 6.57 (s, 1H), 6.84 (s,
1H), 7.32 (t, 1H), 7.47 (q, 1H), 8.36 (s, 1H), 8.77 (d, 1H), 10.06
(s, 1H).
Example 8
(rac)-3,20,23-trifluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7-
,25-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5-
,8(24),9,11,19,21-nonaene
##STR00067##
[0862] To a solution of (rac)-tert-butyl
[methyl(oxido){[3,20,23-trifluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.-
3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-
-10-yl]methyl}-.lamda..sup.6-sulfanylidene]carbamate (3.0 mg; 0.005
mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid
(0.012 mL) and the mixture was stirred for 2 h. The pH value of the
reaction mixture was adjusted to pH>7 by the addition of
saturated aqueous sodium bicarbonate solution. The mixture was
extracted with three times with ethyl acetate. The combined organic
layers were filtered using a Whatman filter and concentrated to
give the title compound (2.6 mg, 0.005 mmol).
[0863] .sup.1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.62-1.78 (m,
2H), 1.80-1.99 (m, 2H), 2.99 (s, 3H), 3.87-4.05 (m, 2H), 4.33-4.49
(m, 4H), 6.59 (s, 1H), 6.83 (s, 1H), 7.32 (t, 1H), 7.41-7.65 (m,
1H), 8.35 (t, 1H), 8.77 (d, 1H), 10.05 (s, 1H).
Example 9
(rac)-tert-butyl
[{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1.sup.2,61.su-
p.8,12]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(met-
hyl)oxido-.lamda..sup.6-sulfanylidene]carbamate
##STR00068##
[0864] Preparation of Intermediate 9.1:
3-{3-[(Methylsulfanyl)methyl]-5-nitrophenoxy}propan-1-ol
##STR00069##
[0866] 3-Bromopropan-1-ol (1.13 g; 8.1 mmol) was added dropwise to
a stirred mixture of 3-[(methylsulfanyl)methyl]-5-nitrophenol (see
Intermediate 3.3; 1.5 g; 7.5 mmol) and potassium carbonate (1.25 g;
9.0 mmol) in DMF (15 mL) at 0.degree. C. The ice bath was removed
and the reaction mixture was stirred overnight at room temperature.
The reaction mixture was diluted with an aqueous solution of sodium
chloride and extracted three times with ethyl acetate. The combined
organic layers were filtered using a Whatman filter and
concentrated. The residue was purified by column chromatography on
silica gel (hexane to hexane/ethyl acetate 60%) to give the title
compound (1.6 g; 6.2 mmol).
[0867] .sup.1H NMR (400 MHz, DMSO, 300K) .delta.=1.85-1.97 (m, 5H),
3.56 (q, 2H), 3.80 (s, 2H), 4.15 (t, 2H), 4.60 (t, 1H), 7.36 (s,
1H), 7.58 (t, 1H), 7.78 (s, 1H).
Preparation of Intermediate 9.2:
(rac)-3-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}propan-1-ol
##STR00070##
[0869]
(rac)-3-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}propan-1-ol
(1.30 g; 4.8 mmol) was prepared from
3-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}propan-1-ol (1.30 g;
5.1 mmol) under similar conditions as described in the preparation
protocol for Intermediate 5.3.
[0870] .sup.1H NMR (400 MHz, DMSO, 300K) .delta.=1.89 (quin, 2H),
3.36-3.59 (m, 2H), 4.00-4.10 (m, 1H), 4.12-4.19 (m, 2H), 4.28 (d,
1H), 4.61 (t, 1H), 7.35 (dd, 1H), 7.69 (t, 1H), 7.79 (s, 1H).
Preparation of Intermediate 9.3:
(rac)-tert-butyl
{[3-(3-hydroxypropoxy)-5-nitrobenzyl](methyl)oxido-.lamda..sup.6-sulfanyl-
idene}carbamate
##STR00071##
[0872] (rac)-tert-butyl
{[3-(3-hydroxypropoxy)-5-nitrobenzyl](methyl)oxido-.lamda..sup.6-sulfanyl-
idene}carbamate (1.10 g; 2.8 mmol) was prepared from
(rac)-3-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}propan-1-ol
(1.30 g; 4.8 mmol) under similar conditions as described in the
preparation protocol for Intermediate 5.4.
[0873] .sup.1H NMR (400 MHz, DMSO, 300K) .delta.=1.39 (s, 9H), 1.89
(quin, 2H), 3.14 (s, 3H), 3.54-3.59 (m, 2H), 4.17 (t, 2H), 4.61 (t,
1H), 4.96-5.05 (m, 2H), 7.45 (dd, 1H), 7.76 (t, 1H), 7.90 (t,
1H).
Preparation of Intermediate 9.4:
(rac)-tert-butyl
[(3-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}-5-ni-
trobenzyl)(methyl)oxido-.lamda..sup.6-sulfanylidene]carbamate
##STR00072##
[0875] (rac)-tert-butyl
[(3-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}-5-ni-
trobenzyl)(methyl)oxido-.lamda..sup.6-sulfanylidene]carbamate (293
mg; 0.48 mmol) was prepared from
5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol (206 mg; 0.85
mmol) and (rac)-tert-butyl
{[3-(3-hydroxypropoxy)-5-nitrobenzyl](methyl)oxido-.lamda..sup.6-sulfanyl-
idene}carbamate (300 mg; 0.77 mmol) under similar conditions as
described in the preparation protocol for Intermediate 5.5.
[0876] .sup.1H NMR (400 MHz, DMSO, 300K) .delta.=1.36 (s, 9H),
2.26-2.32 (m, 2H), 3.14 (s, 3H), 4.28-4.36 (m, 4H), 4.95-5.05 (m,
2H), 7.44-7.50 (m, 2H), 7.61-7.68 (m, 1H), 7.76-7.81 (m, 2H), 7.91
(t, 1H), 8.98 (d, 1H).
Preparation of Intermediate 9.5:
(rac)-tert-butyl
[(3-amino-5-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propo-
xy}benzyl)(methyl)oxido-.lamda..sup.6-sulfanylidene]carbamate
##STR00073##
[0878] (rac)-tert-butyl
[(3-amino-5-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propo-
xy}benzyl)(methyl)oxido-.lamda..sup.6-sulfanylidene]carbamate (148
mg) was prepared as a crude product from (rac)-tert-butyl
[(3-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}-5-ni-
trobenzyl)(methyl)oxido-.lamda.6-sulfanylidene]carbamate (293 mg;
0.48 mmol) under similar conditions as described in the preparation
protocol for Intermediate 5.6.
Example 9--Preparation of the End Product
[0879] (rac)-tert-butyl
[{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.s-
up.8,12]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(me-
thyl)oxido-.lamda..sup.6-sulfanylidene]carbamate (31 mg; 0.06 mmol)
was prepared from crude (rac)-tert-butyl
[(3-amino-5-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propo-
xy}benzyl)(methyl)oxido-.lamda..sup.6-sulfanylidene]carbamate (148
mg; 0.25 mmol) under similar conditions as described in the
preparation protocol for Example 5. The product was purified by
preparative HPLC (see method: Autopurifier: basic conditions).
[0880] .sup.1H-NMR (400 MHz, DMSO-d6)=1.37 (s, 9H), 2.14-2.31 (m,
2H), 3.13 (s, 3H), 4.32 (br t, 2H), 4.47 (br t, 2H), 4.74 (s, 2H),
6.70 (s, 1H), 6.84 (s, 1H), 7.36 (dd, 1H), 7.46-7.58 (m, 1H),
8.09-8.16 (m, 2H), 8.67 (d, 1H), 9.91 (s, 1H).
Example 10
[0881]
(rac)-3,19-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,17-dioxa--
5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.sup.8,12]tetracosa-1(22),2(24),-
3,5,8(23),9,11,18,20-nonaene
##STR00074##
[0882]
(rac)-3,19-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,17-dioxa--
5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.sup.8,12]tetracosa-1(22),2(24),-
3,5,8(23),9,11,18,20-nonaene (9 mg; 0.02 mmol) was prepared from
(rac)-tert-butyl
[{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.s-
up.8,12]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(me-
thyl)oxido-.lamda..sup.6-sulfanylidene]carbamate (28 mg; 0.05 mmol)
under similar conditions as described in the preparation protocol
for Example 6.
[0883] .sup.1H-NMR (400 MHz, DMSO-d6)=2.16-2.31 (m, 2H), 2.81 (s,
3H), 4.15-4.34 (m, 4H), 4.43-4.62 (m, 2H), 6.71 (s, 1H), 6.82 (s,
1H), 7.32-7.41 (m, 1H), 7.47-7.62 (m, 1H), 8.05-8.15 (m, 2H), 8.66
(d, 1H), 9.85 (s, 1H).
Example 11
[0884]
(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dio-
xa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(2-
5),3,5,8(24),9,11,19,21-nonaene
##STR00075##
Preparation of Intermediate 11.1:
5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-one
##STR00076##
[0886] A mixture of 5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol
(Intermediate 1.3; 1.00 g; 4.50 mmol), 5-chloropentan-2-one (1.63
g; 13.5 mmol), potassium carbonate (1.86 g; 13.5 mmol) and
potassium iodide (0.07 g; 0.45 mmol) in DMF (20 mL) was stirred for
4 h at 80.degree. C. Additional chloropentan-2-one (0.81 g; 6.75
mmol) and potassium carbonate (0.62 g; 4.50 mmol) was added and the
mixture was stirred at 80.degree. C. overnight. After cooling the
mixture was diluted with water and the mixture was three times
extracted with ethyl acetate. The combined organic layers were
filtered using a Whatman filter and concentrated. The residue was
purified by column chromatography on silica gel (DCM to DCM/EtOH
20%) to give the title compound (1.20 g; 3.91 mmol).
[0887] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.77-1.99
(m, 2H), 2.11 (s, 3H), 2.61 (t, 2H), 4.07 (t, 2H), 5.92 (s, 2H),
6.53 (d, 1H), 7.10 (ddd, 1H), 7.28 (d, 1H), 7.33 (t, 1H), 7.94 (d,
1H).
Preparation of Intermediate 11.2:
(rac)-5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-ol
##STR00077##
[0889] Sodium borohydride (0.30 g; 7.84 mmol) was added portionwise
to a stirred solution of
5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-one
(1.20 g; 3.91 mmol) in methanol (18 mL) at 0.degree. C. After the
addition the ice bath was removed and the mixture was stirred at
room temperature for 1 h. The mixture was concentrated using a
rotovab. The residue was taken up with ethyl acetate and was washed
two times with a saturated aqueous solution of sodium bicarbonate.
The organic phase was filtered using a Whatman filter and
concentrated. The residue was purified by column chromatography on
silica gel (hexane to hexane/ethylacetate 100%) to give the title
compound (0.70 g; 2.27 mmol).
[0890] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.07 (d,
3H), 1.40-1.53 (m, 2H), 1.62-1.89 (m, 2H), 3.60-3.69 (m, 1H), 4.09
(t, 2H), 4.45 (d, 1H), 5.92 (s, 2H), 6.54 (d, 1H), 7.09 (ddt, 1H),
7.28 (d, 1H), 7.30-7.36 (m, 1H), 7.94 (d, 1H).
Preparation of Intermediate 11.3:
6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol
##STR00078##
[0892] Potassium hydroxide (2.0 g; 36.0 mmol) was added to a
solution of 2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine
(Intermediate 1.6; 5.0 g; 24.0 mmol) in tert-butanol (150 mL) and
the mixture was stirred at 100.degree. C. overnight. After cooling
the mixture was diluted with a saturated aqueous solution of sodium
chloride and extracted three times with ethyl acetate. The combined
organic layers were filtered using a Whatman filter and
concentrated. The residue was taken up in ethyl acetate and washed
with aqueous hydrogen chloride solution. The organic layer was
filtered using a Whatman filter and concentrated. The residue was
stirred in hexane for 1 h before it was filtered and dried in vacuo
to give the title compound (2.3 g; 12.1 mmol).
[0893] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.96 (s,
3H), 3.62 (s, 2H), 6.54 (s, 1H), 6.88 (s, 1H), 11.48 (br s,
1H).
Preparation of Intermediate 11.4:
(rac)-4-(3-{[4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)penty-
l]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine
##STR00079##
[0895] Under argon, diisopropyl azodicarboxylate [CAS-RN:
2446-83-5] (0.98 mL; 5.00 mmol) was added dropwise to a stirred
mixture of (rac)
5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-ol
(Intermediate 11.2; 1.40 g; 4.54 mmol),
6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol (Intermediate 11.3;
861 mg; 4.54 mmol) and triphenylphosphine (1.31 g; 5.00 mmol) in
DCM (28 mL) and the mixture was stirred at room temperature
overnight. The mixture was concentrated and the residue was
purified by column chromatography on silica gel (hexane to
hexane/ethyl acetate 80%) to give the desired title compound (1.50
g; 3.13 mmol).
[0896] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.29 (d,
3H), 1.73-1.90 (m, 4H), 1.95 (s, 3H), 3.62 (s, 2H), 4.09-4.16 (m,
2H), 5.09-5.17 (m, 1H), 5.92 (s, 2H), 6.53 (d, 1H), 6.68 (s, 1H),
6.99 (d, 1H), 7.09 (ddd, 1H), 7.25-7.35 (m, 2H), 7.93 (d, 1H).
Example 11: Preparation of End Product
[0897] To a solution of
(rac)-4-(3-{[4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)pent-
yl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine (1.50 g, 3.13 mmol)
in toluene (225 mL) and NMP (15 mL) was sequentially added
potassium phosphate (3.32 g, 15.63 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl [CAS-RN:
564483-18-7] (149 mg, 0.31 mmol) and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct
[CAS-RN: 1028206-56-5] (258 mg, 0.31 mmol). The suspension was
degassed and stirred under an atmosphere of argon at 110.degree. C.
overnight. After cooling, the reaction mixture was diluted with an
aqueous, saturated sodium chloride solution and extracted three
times with ethyl acetate. The combined organic layers were filtered
using a Whatman filter and concentrated. The residue was purified
by column chromatography on silica gel (hexane to hexane/ethyl
acetate 40%) to give the desired title compound (1.30 g; 2.93
mmol).
[0898] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.11 (d,
3H), 1.37-1.60 (m, 2H), 1.81-2.04 (m, 5H), 3.50-3.62 (m, 2H),
4.36-4.48 (m, 2H), 5.19-5.27 (m, 1H), 6.20 (s, 1H), 6.60 (s, 1H),
7.37 (d, 2H), 7.58 (d, 1H), 8.30 (d, 1H), 8.68 (d, 1H), 9.83 (s,
1H).
Example 12 and 13
Enantiomers of
3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-tr-
iazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24)-
,9,11,19,21-nonaene
##STR00080##
[0900]
(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dio-
xa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(2-
5),3,5,8(24),9,11,19,21-nonaene (1.30 g; Example 11) was separated
into the single enantiomers by preparative chiral HPLC.
TABLE-US-00003 System: Labomatic HD5000, Labocord-5000; Gilson
GX-241, Labcol Vario 4000 Column: YMC Amylose SA, 5 .mu.m 250
.times. 30 mm Solvent: Hexane/EtOH 1:1 Flow: 40 mL/min Temperature:
25.degree. C. Solution: 1.30 g in 6 ml DCM/MeOH 1:1 Injection: 6
.times. 1 mL Detection: UV 280 nm Retention time in min purity in %
yield Example 12 5.9-8.1 98.1% 150 mg Enantiomer 1 Example 13
10.1-12.4 94.2% 126 mg Enantiomer 2
Examples 14 and 15
Diastereoisomers 1 and 2 of
3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,-
7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,-
5,8(24),9,11,19,21-nonaene
##STR00081##
[0902] Ammonium carbamate (38 mg; 0.49 mmol) and
(diacetoxyiodo)benzene (221 mg; 0.69 mmol) were added to a solution
of
3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-tr-
iazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24)-
,9,11,19,21-nonaene (Enantiomer 1, example 12; 145 mg; 0.33 mmol)
in methanol (2.2 mL). The mixture was stirred in an open flask for
2 hours at room temperature before it was concentrated. The residue
was purified with preparative HPLC (see method: Autopurifier:
acidic conditions) to give the mixture of two diastereoisomers (32
mg; 0.06 mmol). The mixture of two diastereoisomers was then
separated into the single diastereoisomers by preparative chiral
HPLC.
TABLE-US-00004 System: Labomatic HD5000, Labocord-5000; Gilson
GX-241, Labcol Vario 4000 Column: YMC Amylose SA, 5 .mu.m 250
.times. 30 mm Solvent: tert-Butyl methyl ether/MeOH 1:1 Flow: 40
mL/min Temperature: 25.degree. C. Solution: 20 mg in 1 mL DCM/MeOH
1:1 Injection: 1 .times. 1 mL Detection: UV 280 nm Retention time
in min purity in % yield Example 14 5.4-6.1 99.2% 4.5 mg
Diasteroisomer 1 Example 15 6.9-8.1 99.5% 3.6 mg Diasteroisomer
2
[0903] Example 14: 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.09-1.17
(m, 3H), 1.43 (br dd, 1H), 1.57 (td, 1H), 1.82-2.04 (m, 2H), 2.86
(s, 3H), 3.72-3.79 (m, 1H), 4.24-4.48 (m, 4H), 5.21-5.29 (m, 1H),
6.33 (s, 1H), 6.67 (s, 1H), 7.34-7.40 (m, 2H), 7.59 (d, 1H), 8.31
(d, 1H), 8.67 (d, 1H), 9.92 (s, 1H).
[0904] Example 15: 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.08-1.17
(m, 3H), 1.35-1.48 (m, 1H), 1.48-1.66 (m, 1H), 1.86 (ddt, 1H),
1.94-2.03 (m, 1H), 2.87 (s, 3H), 3.71-3.79 (m, 1H), 4.25-4.34 (m,
2H), 4.36-4.49 (m, 2H), 5.21-5.29 (m, 1H), 6.32 (s, 1H), 6.67 (s,
1H), 7.34-7.40 (m, 2H), 7.59 (br d, 1H), 8.31 (d, 1H), 8.67 (d,
1H), 9.91 (s, 1H).
Examples 16 and 17
Diastereoisomers 3 and 4 of
3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,-
7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,-
5,8(24),9,11,19,21-nonaene
##STR00082##
[0906] Ammonium carbamate (32 mg; 0.41 mmol) and
(diacetoxyiodo)benzene (186 mg; 0.58 mmol) were added to a solution
of
3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-tr-
iazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24)-
,9,11,19,21-nonaene (Enantiomer 2, example 12; 122 mg; 0.28 mmol)
in methanol (1.9 mL). The mixture was stirred in an open flask for
2 hours at room temperature before it was concentrated. The residue
was purified with preparative HPLC (see method: Autopurifier:
acidic conditions) to give the mixture of two diastereoisomers (32
mg; 0.06 mmol). The mixture of two diastereoisomers was separated
into the single diastereoisomers by preparative chiral HPLC.
TABLE-US-00005 System: Labomatic HD5000, Labocord-5000; Gilson
GX-241, Labcol Vario 4000 Column: YMC Amylose SA, 5 .mu.m 250
.times. 30 mm Solvent: tert-Butyl methyl ether/MeOH 1:1 Flow: 40
mL/min Temperature: 25.degree. C. Solution: 20 mg in 1 mL DCM/MeOH
1:1 Injection: 1 .times. 1 mL Detection: UV 280 nm Retention time
in min purity in % yield Example 16 14.1-16.2 99.7% 9.0 mg
Diasteroisomer 3 Example 17 16.9-18.9 97.0% 8.3 mg Diasteroisomer
4
[0907] Example 16: 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.09-1.17
(m, 3H), 1.43 (br s, 1H), 1.57 (br d, 1H), 1.87 (br d, 1H),
1.94-2.03 (m, 1H), 2.87 (s, 3H), 3.75 (s, 1H), 4.29 (d, 2H),
4.38-4.48 (m, 2H), 5.25 (br d, 1H), 6.32 (s, 1H), 6.67 (s, 1H),
7.38 (d, 2H), 7.60 (d, 1H), 8.32 (d, 1H), 8.67 (d, 1H), 9.92 (s,
1H).
[0908] Example 17: 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.06-1.18
(m, 3H), 1.44 (br d, 1H), 1.57 (br d, 1H), 1.82-1.93 (m, 1H), 1.99
(br s, 1H), 2.86 (s, 3H), 3.75 (s, 1H), 4.24-4.35 (m, 2H),
4.38-4.48 (m, 2H), 5.21-5.31 (m, 1H), 6.33 (s, 1H), 6.67 (s, 1H),
7.38 (d, 2H), 7.60 (d, 1H), 8.32 (d, 1H), 8.68 (d, 1H), 9.92 (s,
1H).
Example 18
(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,-
25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8-
(25),9,11,20,22-nonaene
##STR00083##
[0909] Preparation of Intermediate 18.1:
(rac)-5-hydroxyhexyl methanesulfonate
##STR00084##
[0911] Methanesulfonyl chloride (2.6 mL; 33.8 mmol) was added
dropwise to a stirred solution of hexane-1,5-diol (5.1 mL; 42.3
mmol) and triethylamine (5.9 mL; 42.3 mmol) in DCM (182 mL) at
0.degree. C. The mixture was stirred at 0.degree. C. for 30 min
before the ice bath was removed and the mixture was stirred for 3
hours at room temperature. The mixture was diluted with an aqueous
solution of sodium chloride and extracted two times with DCM. The
combined organic layers were filtered using a Whatman filter and
concentrated. The residue was taken up in ethyl acetate and the
solution was washed with water and two times with aqueous sodium
chloride solution. The organic layer was filtered using a Whatman
filter and concentrated to give the crude product (5.6 g), that was
used without further purification.
Preparation of Intermediate 18.2: 6365-2
6-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]hexan-2-ol
##STR00085##
[0913] (rac)-5-Hydroxyhexyl methanesulfonate (697 mg; 3.56 mmol)
was slowly added to a mixture of
5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol (Intermediate 1.3;
790 mg; 3.56 mmol), potassium carbonate (589 mg; 4.27 mmol) and
potassium iodide (59 mg; 0.36 mmol) in DMF (28 mL) at 0.degree. C.
The mixture was stirred at 60.degree. C. overnight. After cooling,
the mixture was diluted with ethyl acetate and washed with aqueous
sodium chloride solution. The organic layer was filtered using a
Whatman filter and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate 50% to ethyl
acetate 100%) to give the desired title compound (688 mg, 2.13
mmol).
[0914] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.00-1.06 (m, 3H),
1.26-1.54 (m, 4H), 1.68-1.79 (m, 2H), 3.53-3.63 (m, 1H), 4.00-4.11
(m, 2H), 4.36 (d, 1H), 5.92 (s, 2H), 6.54 (d, 1H), 7.09 (ddt, 1H),
7.26-7.35 (m, 2H), 7.92-7.96 (m, 1H).
Preparation of Intermediate 18.3:
(rac)-4-(3-{[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)hexyl-
]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine
##STR00086##
[0916]
(rac)-4-(3-{[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}ox-
y)hexyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine (530 mg; 1.07
mmol) was prepared from
6-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]hexan-2-ol (685
mg; 2.13 mmol) and 6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol
(Intermediate 11.3; 403 mg; 2.13 mmol) under similar conditions as
described in the preparation protocol for Intermediate 11.4.
[0917] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.15-1.29 (m, 3H),
1.41-1.81 (m, 6H), 1.95 (s, 3H), 3.63 (s, 2H), 4.00-4.14 (m, 2H),
5.08 (sxt, 1H), 5.91 (s, 2H), 6.53 (d, 1H), 6.68 (d, 1H), 6.98 (d,
1H), 7.08 (ddt, 1H), 7.25-7.34 (m, 2H), 7.93 (d, 1H).
Example 18: Preparation of End Product
[0918]
(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dio-
xa-5,7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26-
),3,5,8(25),9,11,20,22-nonaene (215 mg; 0.47 mmol) was prepared
from
(rac)-4-(3-{[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)hexy-
l]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine (528 mg; 1.07 mmol)
under similar conditions as described in the preparation protocol
for Example 11.
[0919] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.11 (d, 3H),
1.39-1.54 (m, 1H), 1.57-1.82 (m, 4H), 1.90-2.00 (m, 4H), 3.52-3.60
(m, 2H), 4.36 (br t, 2H), 5.11-5.19 (m, 1H), 6.19 (s, 1H), 6.55 (s,
1H), 7.24-7.45 (m, 3H), 8.25 (d, 1H), 8.31 (d, 1H), 9.77 (s,
1H).
Example 19 and 20
Enantiomers of
3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-tr-
iazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),-
9,11,20,22-nonaene
##STR00087##
[0921]
(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dio-
xa-5,7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26-
),3,5,8(25),9,11,20,22-nonaene (1.32 g) was separated into the
single enantiomers by preparative chiral HPLC.
TABLE-US-00006 System: Sepiatec: Prep SFC100 Column: Chiralpak IG,
5 .mu.m 250 .times. 30 mm Solvent: CO.sub.2/EtOH; 40% EtOH Flow:
100 mL/min Temperature: 40.degree. C. Solution: 1.32 g in 17.5 ml
DCM/MeOH/DMSO 1:1:1.5 Injection: 20 .times. 0.9 mL Detection: UV
254 nm Retention time in min purity in % yield Example 19 6.5-8.5
97.1% 560 mg Enantiomer 1 Example 20 9.8-12.8 98.8% 385 mg
Enantiomer 2
Example 21
Mixture of Two Diastereoisomers 1 and 2 of
3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,-
7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5-
,8(25),9,11,20,22-nonaene
##STR00088##
[0923] The mixture of diastereoisomers 1 and 2 of
3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,-
7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5-
,8(25),9,11,20,22-nonaene (12 mg; 0.02 mmol) was prepared from
enantiomer 1 of
3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,-
25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8-
(25),9,11,20,22-nonaene (Example 19; 505 mg; 1.10 mmol) under
similar conditions as described in the preparation protocol for
Examples 14 and 15.
[0924] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.09-1.16 (m, 3H),
1.36-1.55 (m, 1H), 1.58-1.82 (m, 4H), 1.86-2.06 (m, 1H), 2.86 (d,
3H), 3.71-3.88 (m, 1H), 4.20-4.40 (m, 4H), 4.99-5.31 (m, 1H),
6.12-6.45 (m, 1H), 6.50-6.71 (m, 1H), 7.18-7.49 (m, 3H), 8.14-8.28
(m, 1H), 8.28-8.44 (m, 1H), 9.76-9.99 (m, 1H).
Example 22
Mixture of Two Diastereoisomers 3 and 4 of
3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,-
7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5-
,8(25),9,11,20,22-nonaene
##STR00089##
[0926] The mixture of diastereoisomers 3 and 4 of
3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,-
7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5-
,8(25),9,11,20,22-nonaene (27 mg; 0.06 mmol) was prepared from
enantiomer 2 of
3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,-
25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8-
(25),9,11,20,22-nonaene (Example 20; 330 mg; 0.72 mmol) under
similar conditions as described in the preparation protocol for
Examples 14 and 15.
[0927] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.10-1.14 (m, 3H),
1.49 (br d, 1H), 1.59-1.82 (m, 4H), 1.89-2.00 (m, 1H), 2.87 (d,
3H), 3.76 (s, 1H), 4.23-4.39 (m, 4H), 5.12-5.20 (m, 1H), 6.32 (dd,
1H), 6.61 (d, 1H), 7.28 (br s, 1H), 7.33-7.45 (m, 2H), 8.24 (dd,
1H), 8.32 (d, 1H), 9.84 (d, 1H).
Example 23
(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,-
26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,-
8(26),9,11,21,23-nonaene
##STR00090##
[0928] Preparation of Intermediate 23.1:
(rac)-6-hydroxyheptyl methanesulfonate
##STR00091##
[0930] Crude (rac)-6-hydroxyheptyl methanesulfonate (4.0 g) was
prepared from heptane-1,6-diol (3.5 g; 26.5 mmol) under similar
conditions as described in the preparation protocol for
Intermediate 18.1.
Preparation of Intermediate 23.2:
(rac)-7-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]heptan-2-ol
##STR00092##
[0932]
(rac)-7-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]heptan-2--
ol (528 mg; 1.57 mmol) was prepared from crude
(rac)-6-hydroxyheptyl methanesulfonate (748 mg) and
5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol (Intermediate 1.3;
790 mg; 3.56 mmol) under similar conditions as described in the
preparation protocol for Intermediate 18.2.
[0933] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.03 (d, 3H),
1.23-1.45 (m, 6H), 1.69-1.79 (m, 2H), 3.57 (dt, 1H), 4.09 (t, 2H),
4.32 (d, 1H), 5.92 (s, 2H), 6.54 (d, 1H), 7.06-7.12 (m, 1H),
7.26-7.36 (m, 2H), 7.92-7.96 (m, 1H).
Preparation of Intermediate 23.3:
(rac)-4-(3-{[6-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)hepty-
l]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine
##STR00093##
[0935]
(rac)-4-(3-{[6-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}ox-
y)heptyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine (573 mg; 1.13
mmol) was prepared from
(rac)-7-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]heptan-2-ol
(476 mg; 1.42 mmol)) and
6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol (Intermediate 11.3;
268 mg; 1.42 mmol) under similar conditions as described in the
preparation protocol for Intermediate 18.3.
Example 23: Preparation of End Product
[0936]
(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dio-
xa-5,7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(2-
7),3,5,8(26),9,11,21,23-nonaene (224 mg; 0.48 mmol) was prepared
from
(rac)-4-(3-{[6-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)hept-
yl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine (571 mg; 1.12 mmol)
under similar conditions as described in the preparation protocol
for Example 18.
[0937] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.05 (d, 3H),
1.29-1.55 (m, 5H), 1.62-1.75 (m, 3H), 1.99-2.02 (m, 3H), 3.53-3.60
(m, 2H), 4.28 (dt, 1H), 4.36-4.45 (m, 1H), 4.82-4.90 (m, 1H),
6.16-6.19 (m, 1H), 6.57 (s, 1H), 7.25-7.39 (m, 2H), 7.50 (dd, 1H),
8.29 (d, 1H), 8.53 (d, 1H), 9.81 (s, 1H).
Example 24 and 25
Enantiomers of
3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-tr-
iazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26)-
,9,11,21,23-nonaene
##STR00094##
[0939]
(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dio-
xa-5,7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(2-
7),3,5,8(26),9,11,21,23-nonaene (150 mg) was separated into the
single enantiomers by preparative chiral HPLC.
TABLE-US-00007 System: Sepiatec: Prep SFC100 Column: Chiralpak IA,
5 .mu.m 250 .times. 30 mm Solvent: CO.sub.2/EtOH; 35% EtOH Flow:
100 mL/min Temperature: 40.degree. C. Solution: 150 mg in 2 mL DMSO
Injection: 5 .times. 0.4 mL Detection: UV 254 nm Retention time in
min purity in % yield Example 24 5.5-7.0 99.7% 65 mg Enantiomer 1
Example 25 7.4-10.0 97.6% 75 mg Enantiomer 2
Example 26
Mixture of Two Diastereoisomers 1 and 2 of
3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,-
7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,-
5,8(26),9,11,21,23-nonaene
##STR00095##
[0941] The mixture of diastereoisomers 1 and 2 of
3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,-
7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,-
5,8(26),9,11,21,23-nonaene (14 mg; 0.03 mmol) was prepared from
Enantiomer 1 of
3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,-
26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,-
8(26),9,11,21,23-nonaene (Example 24; 60 mg; 0.13 mmol) under
similar conditions as described in the preparation protocol for
Examples 14 and 15.
[0942] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.02-1.10 (m, 3H),
1.30-1.60 (m, 5H), 1.61-1.78 (m, 3H), 2.88 (s, 3H), 3.76 (s, 1H),
4.25-4.33 (m, 3H), 4.40 (s, 1H), 4.79-4.95 (m, 1H), 6.30 (s, 1H),
6.64 (s, 1H), 7.29 (br s, 1H), 7.34-7.40 (m, 1H), 7.50 (d, 1H),
8.30 (d, 1H), 8.53 (dd, 1H), 9.89 (d, 1H).
Example 27
Mixture of Two Diastereoisomers 3 and 4 of
3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,-
7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,-
5,8(26),9,11,21,23-nonaene
##STR00096##
[0944] The mixture of diastereoisomers 3 and 4 of
3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,-
7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,-
5,8(26),9,11,21,23-nonaene (6 mg; 0.01 mmol) was prepared from
Enantiomer 2 of
3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,-
26-triazatetracyclo
[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-n-
onaene (Example 25; 70 mg; 0.15 mmol) under similar conditions as
described in the preparation protocol for Examples 14 and 15.
[0945] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.04-1.14 (m, 3H),
1.30-1.56 (m, 5H), 1.58-1.79 (m, 3H), 2.88 (s, 3H), 3.76 (s, 1H),
4.24-4.44 (m, 4H), 4.86 (br s, 1H), 6.30 (s, 1H), 6.64 (s, 1H),
7.25-7.43 (m, 2H), 7.50 (dd, 1H), 8.24-8.32 (m, 1H), 8.53 (dd, 1H),
9.83-9.91 (m, 1H).
Example 28
Mixture of enantiomers of
3,20-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,18-dioxa-5,7,24-tr-
iazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24)-
,9,11,19,21-nonaene
##STR00097##
[0947] 3-Chloroperbenzoic acid (23 mg; 0.14 mmol) was added to a
solution of
(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa--
5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),-
3,5,8(24),9,11,19,21-nonaene (30 mg; 0.07 mmol) in DCM (0.7 mL) at
0.degree. C. The ice bath was removed and the mixture was stirred
at room temperature for 1 hour. The mixture was diluted with an
aqueous solution of sodium bicarbonate and extracted two times with
DCM. The combined organic layers were filtered using a Whatman
filter and concentrated. The residue was purified with preparative
HPLC (see method: Autopurifier: acidic conditions) to give the
title compound (7 mg; 0.01 mmol).
[0948] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.11 (d, 3H), 1.40
(br dd, 1H), 1.53-1.62 (m, 1H), 1.81-1.94 (m, 1H), 1.97-2.01 (m,
1H), 2.94-3.00 (m, 3H), 4.30-4.46 (m, 4H), 5.19-5.27 (m, 1H), 6.28
(s, 1H), 6.65 (s, 1H), 7.33-7.40 (m, 2H), 7.56 (br d, 1H), 8.30 (d,
1H), 8.65 (d, 1H), 9.90 (s, 1H).
Examples 29 and 30
Enantiomer 1 and 2 of
3,21-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-tr-
iazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),-
9,11,20,22-nonaene
##STR00098##
[0950] 3-Chloroperbenzoic acid (75 mg; 0.43 mmol) was added to a
solution of
(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa--
5,7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3-
,5,8(25),9,11,20,22-nonaene (Example 18; 100 mg; 0.22 mmol) in DCM
(2.1 mL) at 0.degree. C. The ice bath was removed and the mixture
was stirred at room temperature for 1 hour. The mixture was diluted
with an aqueous solution of sodium bicarbonate and extracted two
times with DCM. The combined organic layers were filtered using a
Whatman filter and concentrated. The residue was purified with
preparative HPLC (see method: Autopurifier: acidic conditions) to
give the racemate (32 mg; 0.07 mmol).
[0951] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.12 (d, 3H), 1.49
(br d, 1H), 1.58-1.83 (m, 4H), 1.87-2.01 (m, 1H), 2.99 (s, 3H),
4.32-4.47 (m, 4H), 5.12-5.21 (m, 1H), 6.28 (s, 1H), 6.62 (s, 1H),
7.27 (br dd, 1H), 7.36 (t, 1H), 7.43 (d, 1H), 8.24 (d, 1H), 8.33
(d, 1H), 9.90 (s, 1H).
[0952] The racemate was separated into the single enantiomers by
preparative chiral HPLC.
TABLE-US-00008 System: Sepiatec: Prep SFC100 Column: Chiralpak IA,
5 .mu.m 250 .times. 30 mm Solvent: CO.sub.2/EtOH + 0.2 vol %
aqueous ammonia (32%); 50% EtOH Flow: 100 mL/min Temperature:
40.degree. C. Solution: 150 mg in 2 mL DMSO Injection: 5 .times.
0.4 mL Detection: UV 220 nm Retention time in min purity in % yield
Example 29 7.1-9.1 99.7% 5 mg Enantiomer 1 Example 30 10.1-13.1
97.9% 5 mg Enantiomer 2
Example 31 and 32
Enantiomer 1 and 2 of
3,22-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-tr-
iazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(25),2(27),3,5,8(26),-
9,11,21,23-nonaene
##STR00099##
[0954] 3-Chloroperbenzoic acid (71 mg; 0.31 mmol) was added to a
solution of
(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa--
5,7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]
heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene (Example 23; 68
mg; 0.14 mmol) in DCM (3.5 mL) at 0.degree. C. The ice bath was
removed and the mixture was stirred at room temperature for 3
hours. The mixture was diluted with an aqueous solution of sodium
bicarbonate and extracted two times with DCM. The combined organic
layers were filtered using a Whatman filter and concentrated. The
residue was purified with preparative HPLC (see method:
Autopurifier: acidic conditions) to give the racemate (35 mg; 0.07
mmol).
[0955] 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.06 (d, 3H),
1.32-1.56 (m, 5H), 1.64-1.74 (m, 3H), 3.00 (s, 3H), 4.27 (dt, 1H),
4.39-4.46 (m, 3H), 4.83-4.91 (m, 1H), 6.26 (d, 1H), 6.64 (d, 1H),
7.26-7.31 (m, 1H), 7.34-7.39 (m, 1H), 7.51 (dd, 1H), 8.31 (d, 1H),
8.52 (d, 1H), 9.95 (s, 1H).
[0956] The racemate was separated into the single enantiomers by
preparative chiral HPLC.
TABLE-US-00009 System: Labomatic HD5000, Labocord-5000; Gilson
GX-241, Labcol Vario 4000 Column: YMC Amylose SA, 5 .mu.m 250
.times. 30 mm Solvent: Hexane/EtOH 60:40 Flow: 40 mL/min
Temperature: 25.degree. C. Solution: 31 mg in 1 mL DCM/MeOH 1:1
Injection: 1 .times. 1 mL Detection: UV 254 nm Retention time in
min purity in % yield Example 31 14.2-16.0 98.1% 15 mg Enantiomer 1
Example 32 20.0-22.0 96.6% 15 mg Enantiomer 2
[0957] The following Table 1 provides an overview on the compounds
described in the example section:
TABLE-US-00010 TABLE 1 Example No. Structure Name of compound 1
##STR00100## (rac)-tert-butyl [{[3,20-difluoro-13,18-dioxa-
5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-
yl]methyl}(methyl)oxido-.lamda..sup.6- sulfanylidene]carbamate 2
##STR00101## (rac)-3,20-difluoro-10-[(S-
methylsulfonimidoyl)methyl]-13,18-dioxa-
5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaene 3 ##STR00102##
(rac)-tert-butyl [{[3,20-difluoro-13,18-dioxa-
5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-
yl]methyl}(methyl)oxido-.lamda..sup.6- sulfanylidene]carbamate 4
##STR00103## (rac)-3,20-difluoro-10-[(S-
methylsulfonimidoyl)methyl]-13,18-dioxa-
5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11.19,21-nonaene 5 ##STR00104##
(rac)-tert-butyl [{[3,21-difluoro-13,19-dioxa-
5,7,26-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10-
yl]methyl}(methyl)oxido-.lamda..sup.6- sulfanylidene]carbamate 6
##STR00105## (rac)-3,21-difluoro-10-[(S-
methylsulfonimidoyl)methyl]-13,19-dioxa-
5,7,26-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(24),2(26),3,5,8(25),9,11,20,22-nonaene 7 ##STR00106##
(rac)-tert-butyl [methyl(oxido){[3,20,23-
trifluoro-13,18-dioxa-5,7,25-
triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(24),2(25),3,5,8(24),9,11,19,21-nonaen-10-
yl]methyl}-1.lamda..sup.6-sulfanylidene]carbamate 8 ##STR00107##
(rac)-3,20,23-trifluoro-10-[(S-
methylsulfonimidoyl)methyl]-13,18-dioxa-
5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaene 9 ##STR00108##
(rac)-tert-butyl [{[3,19-difluoro-13,17-dioxa-
5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.sup.8,12]tetracosa-
1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-
yl]methyl}(methyl)oxido-.lamda..sup.6- sulfanylidene]carbamate 10
##STR00109## (rac)-3,19-difluoro-10-[(S-
methylsulfonimidoyl)methyl]-13,17-dioxa-
5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.sup.8,12]tetracosa-
1(22),2(24),3,5,8(23),9,11,18,20-nonaene 11 ##STR00110##
(rac)-3,20-difluoro-14-methyl-10-
[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-
triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaene 12 ##STR00111## Enantiomer
1 of (rac)-3,20-difluoro-14-methyl-
10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-
triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaene 13 ##STR00112## Enantiomer
2 of (rac)-3,20-difluoro-14-methyl-
10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-
triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaene 14 ##STR00113##
Diastereoisomer 1 of 3,20-difluoro-14-methyl-10-
[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-
5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaene 15 ##STR00114##
Diastereoisomer 2 of 3,20-difluoro-14-methyl-10-
[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-
5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaene 16 ##STR00115##
Diastereoisomer 3 of 3,20-difluoro-14-methyl-10-
[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-
5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaene 17 ##STR00116##
Diastereoisomer 4 of 3,20-difluoro-14-methyl-10-
[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-
5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaene 18 ##STR00117##
(rac)-3,21-difluoro-14-methyl-10-
[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-
triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(24),2(26),3,5,8(25),9,11,20,22-nonaene 19 ##STR00118## Enantiomer
1 of 3,21-difluoro-14-methyl-10-
[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-
triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(24),2(26),3,5,8(25),9,11,20,22-nonaene 20 ##STR00119## Enantiomer
2 of 3,21-difluoro-14-methyl-10-
[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-
triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(24),2(26),3,5,8(25),9,11,20,22-nonaene 21 ##STR00120## Mixture of
diastereoisomers 1 and 2 of 3,21-difluoro-
14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,19-dioxa-5,7,25-
triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(24),2(26),3,5,8(25),9,11,20,22-nonaene 22 ##STR00121## Mixture of
diastereoisomers 3 and 4 of 3,21-difluoro-
14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,19-dioxa-5,7,25-
triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(24),2(26),3,5,8(25),9,11,20,22-nonaene 23 ##STR00122##
(rac)-3,22-difluoro-14-methyl-10-
[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-
triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-
1(25),2(27),3,5,8(26),9,11,21,23-nonaene 24 ##STR00123## Enantiomer
1 of 3,22-difluoro-14-methyl-10-
[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-
triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-
1(25),2(27),3,5,8(26),9,11,21,23-nonaene 25 ##STR00124## Enantiomer
2 of 3,22-difluoro-14-methyl-10-
[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-
triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-
1(25),2(27),3,5,8(26),9,11,21,23-nonaene 26 ##STR00125## Mixture of
diastereoisomers 1 and 2 of 3,22-difluoro-
14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,20-dioxa-5,7,26-
triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-
1(25),2(27),3,5,8(26),9,11,21,23-nonaene 27 ##STR00126## Mixture of
diastereoisomers 3 and 4 of 3,22-difluoro-
14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,20-dioxa-5,7,26-
triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-
1(25),2(27),3,5,8(26),9,11,21,23-nonaene 28 ##STR00127## Mixture of
enantiomers of 3,20-difluoro-14-methyl-
10-[(methylsulfonyl)methyl]-13,18-dioxa-5,7,24-
triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-
1(23),2(25),3,5,8(24),9,11,19,21-nonaene 29 ##STR00128## Enantiomer
1 of 3,21-difluoro-14-methyl-10-
[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-
triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(24),2(26),3,5,8(25),9,11,20,22-nonaene 30 ##STR00129## Enantiomer
2 of 3,21-difluoro-14-methyl-10-
[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-
triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(24),2(26),3,5,8(25),9,11,20,22-nonaene 31 ##STR00130## Enantiomer
1 of 3,22-difluoro-14-methyl-10-
[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-
triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(25),2(27),3,5,8(26),9,11,21,23-nonaene 32 ##STR00131## Enantiomer
2 of 3,22-difluoro-14-methyl-10-
[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-
triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]hexacosa-
1(25),2(27),3,5,8(26),9,11,21,23-nonaene
Results:
[0958] Table 2: Inhibition for CDK9 and CDK2 of compounds according
to the present invention
[0959] The IC.sub.50 (inhibitory concentration at 50% of maximal
effect) values are indicated in nM, "n.t." means that the compounds
have not been tested in the respective assay. [0960] {circle around
(1)}: Example Number [0961] {circle around (2)}: high ATP CDK9:
CDK9/CycT1 kinase assay as described under Method 1b. of Materials
and Methods [0962] {circle around (3)}: high ATP CDK2: CDK2/CycE
kinase assay as described under Method 2b. of Materials and Methods
[0963] {circle around (4)}: Selectivity high ATP CDK9 over high ATP
CDK2: IC.sub.50 (high ATP CDK2)/IC.sub.50 (high ATP CDK9) according
to Methods 1b. and 2b. of Materials and Methods
[0964] Noteworthily, in the CDK9 assays, as described supra in the
Methods 1a. and 1b. of Materials and Methods, resolution power is
limited by the enzyme concentrations, the lower limit for
IC.sub.50s is about 1-2 nM in the CDK9 high ATP assay and 2-4 nM in
the CDK low ATP assays. For compounds exhibiting IC.sub.50s in this
range the true affinity to CDK9 and thus the selectivity for CDK9
over CDK2 might be even higher, i.e. for these compounds the
selectivity factors calculated in columns 4 and 7 of Table 2,
infra, are minimal values, they could be also higher.
TABLE-US-00011 TABLE 2 {circle around (1)} Structure {circle around
(2)} {circle around (3)} {circle around (4)} 2 ##STR00132## 7 737
105 3 ##STR00133## 5 >20000 >4000 4 ##STR00134## 3 1540 513 5
##STR00135## 24 >20000 >833 6 ##STR00136## 5 16200 3240 8
##STR00137## 17 6520 385 10 ##STR00138## 25 4750 190 11
##STR00139## 7 4670 667 12 ##STR00140## 4 6450 1613 13 ##STR00141##
4 711 178 14 ##STR00142## 3 1510 503 15 ##STR00143## 3 1620 540 16
##STR00144## 2 144 72 17 ##STR00145## 1 132 132 18 ##STR00146## 32
>20000 >625 19 ##STR00147## 138 >20000 >145 20
##STR00148## 23 12600 548 21 ##STR00149## 2 2450 1225 22
##STR00150## 2 501 251 23 ##STR00151## 67 >20000 >298 24
##STR00152## 68 >20000 >294 25 ##STR00153## 93 >20000
>215 26 ##STR00154## 4 13000 3250 27 ##STR00155## 5 2720 544 28
##STR00156## 2 360 189 29 ##STR00157## 4 691 173 30 ##STR00158## 3
3590 1196 31 ##STR00159## 16 >20000 1250 32 ##STR00160## 18 4980
277
[0965] Tables 3a and 3b: Inhibition of proliferation of HeLa,
HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 and MOLM-13
cells by compounds according to the present invention, determined
as described under Method 3. of Materials and Methods. All
IC.sub.50 (inhibitory concentration at 50% of maximal effect)
values are indicated in nM, "n.t." means that the compounds have
not been tested in the respective assay.
{circle around (1)}: Example Number
[0966] {circle around (2)}: Inhibition of HeLa cell proliferation
{circle around (3)}: Inhibition of HeLa-MaTu-ADR cell proliferation
{circle around (4)}: Inhibition of NCI-H460 cell proliferation
{circle around (5)}: Inhibition of DU145 cell proliferation {circle
around (6)}: Inhibition of Caco-2 cell proliferation {circle around
(7)}: Inhibition of B16F10 cell proliferation {circle around (8)}:
Inhibition of A2780 cell proliferation {circle around (9)}:
Inhibition of MOLM-13 cell proliferation
TABLE-US-00012 TABLE 3a Indications represented by cell lines Cell
line Source Indication HeLa ATCC Human cervical tumour
HeLa-MaTu-ADR EPO-GmbH Multidrug-resistant human Berlin cervical
carcinoma NCI-H460 ATCC Human non-small cell lung carcinoma DU 145
ATCC Hormone-independent human prostate carcinoma Caco-2 ATCC Human
colorectal carcinoma B16F10 ATCC Mouse melanoma A2780 ECACC Human
ovarian carcinoma MOLM-13 DSMZ Human acute myeloid leukemia
TABLE-US-00013 TABLE 3b Inhibition of proliferation {circle around
(1)} Structure {circle around (2)} {circle around (3)} {circle
around (4)} {circle around (5)} {circle around (6)} {circle around
(7)} {circle around (8)} {circle around (9)} 2 ##STR00161## 90 78
157 85 96 110 9 27 3 ##STR00162## 244 218 267 206 163 270 56 108 4
##STR00163## 150 140 331 138 177 176 41 20 5 ##STR00164## 964 1000
479 585 658 993 >100 228 6 ##STR00165## 199 169 277 121 144 171
39 140 8 ##STR00166## 177 179 217 196 181 224 68 45 10 ##STR00167##
128 155 238 180 159 209 48 33 11 ##STR00168## n.t. n.t. n.t. n.t.
n.t. n.t. 346 n.t. 14 ##STR00169## n.t. n.t. n.t. n.t. n.t. n.t. 23
n.t. 15 ##STR00170## n.t. n.t. n.t. n.t. n.t. n.t. 16 n.t. 16
##STR00171## n.t. n.t. n.t. n.t. n.t. n.t. 6 n.t. 17 ##STR00172##
n.t. n.t. n.t. n.t. n.t. n.t. 6 n.t. 21 ##STR00173## n.t. n.t. n.t.
n.t. n.t. n.t. 27 n.t. 22 ##STR00174## n.t. n.t. n.t. n.t. n.t.
n.t. 0.7 n.t. 26 ##STR00175## n.t. n.t. n.t. n.t. n.t. n.t. 53 n.t.
27 ##STR00176## n.t. n.t. n.t. n.t. n.t. n.t. 102 n.t. 28
##STR00177## n.t. n.t. n.t. n.t. n.t. n.t. 16. n.t. 29 ##STR00178##
n.t. n.t. n.t. n.t. n.t. n.t. 25 n.t. 30 ##STR00179## n.t. n.t.
n.t. n.t. n.t. n.t. 55 n.t. 31 ##STR00180## n.t. n.t. n.t. n.t.
n.t. n.t. 121 n.t. 32 ##STR00181## n.t. n.t. n.t. n.t. n.t. n.t.
146 n.t.
[0967] Table 4: Equilibrium dissociation constants K.sub.D [M],
dissociation rate constants k.sub.off [l/s], and target residence
times [min] as determined by Method 8.
[0968] Dissociation rate constants below of what is resolvable with
the respective assay are reported using the "<"-symbol (e.g.
<8.0 E-5 s.sup.-1).
[0969] Values labeled with "*" represent arithmetic means of more
than one value.
{circle around (1)}: Example Number
[0970] {circle around (2)}: Equilibrium dissociation constant
K.sub.D [M] {circle around (3)}: Dissociation rate constant
k.sub.off [l/s] {circle around (4)}: Target residence time
[min]
TABLE-US-00014 TABLE 4 {circle around (1)} Structure {circle around
(2)} {circle around (3)} {circle around (4)} 2 ##STR00182## 1.2
E-9* 2.2 E-4* 75* 4 ##STR00183## 1.2 E-9* 6.7 E-4* 25* 16
##STR00184## 2.8 E-10 6.6 E-11 2.4 E-11 2.9 E-11 <8.0 E-5
<8.0 E-5 1.3 E-4 <8.0 E-5 >208 >208 131 >208 17
##STR00185## 7.7 E-11* <8.0 E-5* >208* 21 ##STR00186## 1.0
E-9* 1.6 E-3* 10* 22 ##STR00187## 1.9 E-10* 3.9 E-4* 43* 28
##STR00188## 9.2 E-11 9.1 E-11 1.2 E-10 1.5 E-13 3.5 E-4 <8.0
E-5 3.1 E-4 <8.0 E-5 48 >208 54 >208
[0971] It is expected that that the prolonged residence time of
macrocyclic CDK9 inhibitors according to the invention will result
in a sustained inhibitory effect on CDK9 signaling, ultimately
contributing to sustained target engagement and anti-tumor
efficacy.
* * * * *
References