U.S. patent application number 12/921588 was filed with the patent office on 2011-05-19 for thiazolyl-dihydro-indazoles.
This patent application is currently assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH. Invention is credited to Maria Impagnatiello, Dirk Kessler, Oliver Kraemer, Darryl Mcconnell, Siegfried Schneider, Lars Van Der Veen, Ulrike Weyer-Czernilofsky, Tobias Wunberg.
Application Number | 20110118208 12/921588 |
Document ID | / |
Family ID | 39591172 |
Filed Date | 2011-05-19 |
United States Patent
Application |
20110118208 |
Kind Code |
A1 |
Mcconnell; Darryl ; et
al. |
May 19, 2011 |
Thiazolyl-Dihydro-Indazoles
Abstract
The present invention encompasses compounds of general formula
(1) ##STR00001## wherein R.sup.1 to R.sup.3 are defined as in claim
1, which are suitable for the treatment of diseases characterised
by excessive or abnormal cell proliferation, and the use thereof
for preparing a medicament having the above-mentioned
properties.
Inventors: |
Mcconnell; Darryl; (Vienna,
AU) ; Impagnatiello; Maria; (Vienna, AU) ;
Kessler; Dirk; (Vienna, AU) ; Kraemer; Oliver;
(Vienna, AU) ; Schneider; Siegfried; (Vienna,
AU) ; Van Der Veen; Lars; (Vienna, AU) ;
Weyer-Czernilofsky; Ulrike; (Ingelheim am Rhein, DE)
; Wunberg; Tobias; (Hinterbruehl, AU) |
Assignee: |
BOEHRINGER INGELHEIM INTERNATIONAL
GMBH
Ingelheim am Rhein
DE
|
Family ID: |
39591172 |
Appl. No.: |
12/921588 |
Filed: |
March 13, 2009 |
PCT Filed: |
March 13, 2009 |
PCT NO: |
PCT/EP2009/052959 |
371 Date: |
December 22, 2010 |
Current U.S.
Class: |
514/64 ;
514/210.18; 514/232.8; 514/253.1; 514/314; 514/318; 514/333;
514/338; 544/131; 544/364; 546/13; 546/167; 546/194; 546/256;
546/270.1 |
Current CPC
Class: |
A61P 17/00 20180101;
A61P 31/00 20180101; A61P 37/06 20180101; A61P 35/02 20180101; A61P
9/10 20180101; A61P 1/04 20180101; A61P 9/04 20180101; A61P 17/02
20180101; A61P 37/00 20180101; C07D 513/04 20130101; A61P 13/12
20180101; A61P 43/00 20180101; A61P 19/02 20180101; A61P 29/00
20180101; A61P 17/06 20180101; A61P 19/00 20180101; A61P 35/00
20180101; A61P 31/12 20180101; A61P 25/28 20180101; A61P 33/00
20180101 |
Class at
Publication: |
514/64 ; 544/131;
546/270.1; 546/194; 546/167; 546/256; 546/13; 544/364; 514/232.8;
514/338; 514/318; 514/314; 514/333; 514/210.18; 514/253.1 |
International
Class: |
A61K 31/69 20060101
A61K031/69; C07D 513/04 20060101 C07D513/04; C07F 5/02 20060101
C07F005/02; A61K 31/5377 20060101 A61K031/5377; A61K 31/4439
20060101 A61K031/4439; A61K 31/4545 20060101 A61K031/4545; A61K
31/4709 20060101 A61K031/4709; A61K 31/444 20060101 A61K031/444;
A61K 31/496 20060101 A61K031/496; A61P 35/00 20060101 A61P035/00;
A61P 31/00 20060101 A61P031/00; A61P 29/00 20060101 A61P029/00;
A61P 37/06 20060101 A61P037/06 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 13, 2008 |
EP |
08152721.0 |
Claims
1. A compound of the formula (1), ##STR00412## wherein R.sup.1 is
selected from among --NHR.sup.c, --NHC(O)R.sup.c, --NHC(O)OR.sup.c,
--NHC(O)NR.sup.cR.sup.c, --NHC(O)N(R.sup.g)OR.sup.e and
--NHC(O)SR.sup.c, and R.sup.2 denotes hydrogen or a group selected
from among C.sub.1-6alkyl, C.sub.3-8cycloalkyl, 3-8 membered
heterocycloalkyl, C.sub.6-10aryl, C.sub.7-16arylalkyl and 5-10
membered heteroaryl, optionally substituted by one or more
identical or different R.sup.4 and R.sup.3 denotes a 6 membered
heteroaryl, substituted by one or more identical or different
R.sup.a and/or R.sup.b, or R.sup.3 denotes a 8-10 membered
heteroaryl, optionally substituted by one or more identical or
different R.sup.e and/or R.sup.f, and each R.sup.4 denotes a group
selected from among R.sup.a, R.sup.b and R.sup.a substituted by one
or more identical or different R.sup.b and/or R.sup.c; and each
R.sup.a independently of one another denotes a group optionally
substituted by one or more identical or different R.sup.b and/or
R.sup.c, selected from among C.sub.1-6alkyl, 2-6 membered
heteroalkyl, C.sub.1-6haloalkyl, C.sub.3-10cycloalkyl,
C.sub.4-16cycloalkylalkyl, C.sub.6-10aryl, C.sub.7-16arylalkyl,
5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14
membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl,
each R.sup.b denotes a suitable group and is selected independently
of one another from among .dbd.O, --OR.sup.c,
C.sub.1-3haloalkyloxy, --OCF.sub.3, .dbd.S, --SR.sup.c,
.dbd.NR.sup.c, .dbd.NOR.sup.c, .dbd.NNR.sup.cR.sup.c,
.dbd.NN(R.sup.g)C(O)NR.sup.cR.sup.c, --NR.sup.cR.sup.c,
--ONR.sup.cR.sup.c, --N(OR.sup.c)R.sup.c,
--N(R.sup.g)NR.sup.cR.sup.c, halogen, --CF.sub.3, --CN, --NC,
--OCN, --SCN, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3,
--S(O)R.sup.c, --S(O)OR.sup.c, --S(O).sub.2R.sup.c,
--S(O).sub.2OR.sup.c, --S(O)NR.sup.cR.sup.c,
--S(O).sub.2NR.sup.cR.sup.c, --OS(O)R.sup.c, --OS(O).sub.2R.sup.c,
--OS(O).sub.2OR.sup.c, --OS(O)NR.sup.cR.sup.c,
--OS(O).sub.2NR.sup.cR.sup.c, --C(O)R.sup.c, --C(O)OR.sup.c,
--C(O)SR.sup.c, --C(O)NR.sup.cR.sup.c,
--C(O)N(R.sup.g)NR.sup.cR.sup.c, --C(O)N(R.sup.g)OR.sup.c,
--C(NR.sup.g)NR.sup.cR.sup.c, --C(NOH)R.sup.c,
--C(NOH)NR.sup.cR.sup.c, --OC(O)R.sup.c, --OC(O)OR.sup.c,
--OC(O)SR.sup.c, --OC(O)NR.sup.cR.sup.c,
--OC(NR.sup.g)NR.sup.cR.sup.c, --SC(O)R.sup.c, --SC(O)OR.sup.c,
--SC(O)NR.sup.cR.sup.c, --SC(NR.sup.g)NR.sup.cR.sup.c,
--N(R.sup.g)C(O)R.sup.c, --N[C(O)R.sup.c].sub.2,
--N(OR.sup.g)C(O)R.sup.c, --N(R.sup.g)C(NR.sup.g)R.sup.c,
--N(R.sup.g)N(R.sup.g)C(O)R.sup.c, --N[C(O)R.sup.c]NR.sup.cR.sup.c,
--N(R.sup.g)C(S)R.sup.c, --N(R.sup.g)S(O)R.sup.c,
--N(R.sup.g)S(O)OR.sup.c, --N(R.sup.g)S(O).sub.2R.sup.c,
--N[S(O).sub.2R.sup.c].sub.2, --N(R.sup.g)S(O).sub.2OR.sup.c,
--N(R.sup.g)S(O).sub.2NR.sup.cR.sup.c,
--N(R.sup.g)[S(O).sub.2].sub.2R.sup.c, --N(R.sup.g)C(O)OR.sup.c,
--N(R.sup.g)C(O)SR.sup.c, --N(R.sup.g)C(O)NR.sup.cR.sup.c,
--N(R.sup.g)C(O)NR.sup.gNR.sup.cR.sup.c,
--N(R.sup.g)N(R.sup.g)C(O)NR.sup.cR.sup.c,
--N(R.sup.g)C(S)NR.sup.cR.sup.c, --[N(R.sup.g)C(O)].sub.2R.sup.c,
--N(R.sup.g)[C(O)].sub.2R.sup.c, --N{[C(O)].sub.2R.sup.c}.sub.2,
--N(R.sup.g)[C(O)].sub.2OR.sup.c,
--N(R.sup.g)[C(O)].sub.2NR.sup.cR.sup.c,
--N{[C(O)].sub.2OR.sup.c}.sub.2,
--N{[C(O)].sub.2NR.sup.cR.sup.c].sub.2,
--[N(R.sup.g)C(O)].sub.2OR.sup.c, --N(R.sup.g)C(NR.sup.g)OR.sup.c,
--N(R.sup.g)C(NOH)R.sup.c, --N(R.sup.g)C(NR.sup.g)SR.sup.c,
--N(R.sup.g)C(NR.sup.g)NR.sup.cR.sup.c, --N.dbd.R.sup.cR.sup.c and
--N.dbd.C(R.sup.g)NR.sup.cR.sup.c and each R.sup.c independently of
one another denotes hydrogen or a group optionally substituted by
one or more identical or different R.sup.d and/or R.sup.e, selected
from among C.sub.1-6alkyl, 2-6 membered heteroalkyl,
C.sub.1-6haloalkyl, C.sub.3 -10cycloalkyl,
C.sub.4-16cycloalkylalkyl, C.sub.6-10aryl C.sub.7-16arylalkyl, 5-12
membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 membered
heterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and each
R.sup.d denotes a suitable group and is selected independently of
one another from among .dbd.O, --OR.sup.e, C.sub.1-3haloalkyloxy,
--OCF.sub.3, .dbd.S, --SR.sup.e, .dbd.NR.sup.e, .dbd.NOR.sup.e,
.dbd.NNR.sup.eR.sup.e, .dbd.NN(R.sup.g)C(O)NR.sup.eR.sup.e,
--NR.sup.eR.sup.e, --ONR.sup.eR.sup.e, --N(R.sup.g)NR.sup.eR.sup.e,
halogen, --CF.sub.3, --CN, --NC, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --S(O)R.sup.e, --S(O)OR.sup.e,
--S(O).sub.2R.sup.e, --S(O).sub.2OR.sup.e, --S(O)NR.sup.eR.sup.e,
--S(O).sub.2NR.sup.eR.sup.e, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O).sub.2OR.sup.e, --OS(O)NR.sub.eR.sup.e,
--OS(O).sub.2NR.sup.eR.sup.e, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)SR.sup.e, --C(O)NR.sup.eR.sup.e,
--C(O)N(R.sup.g)NR.sup.eR.sup.e, --C(O)N(R.sup.g)OR.sup.e,
--C(NR.sup.g)NR.sup.eR.sup.e, --C(NOH)R.sup.e,
--C(NOH)NR.sup.eR.sup.e, --OC(O)R.sup.e, --OC(O)OR.sup.e,
--OC(O)SR.sup.e, --OC(O)NR.sup.eR.sup.e,
--OC(NR.sup.g)NR.sup.eR.sup.e, --SC(O)R.sup.e, --SC(O)OR.sup.e,
--SC(O)NR.sup.eR.sup.e, --SC(NR.sup.g)NR.sup.eR.sup.e,
--N(R.sup.g)C(O)R.sup.e, --N[C(O)R.sup.e].sub.2,
--N(OR.sup.g)C(O)R.sup.e, --N(R.sup.g)C(NR.sup.g)R.sup.e,
--N(R.sup.g)N(R.sup.g)C(O)R.sup.e, --N[C(O)R.sup.e]NR.sup.eR.sup.e,
--N(R.sup.g)C(S)R.sup.e, --N(R.sup.g)S(O)R.sup.e,
--N(R.sup.g)S(O)OR.sup.e--N(R.sup.g)S(O).sub.2R.sup.e,
--N[S(O).sub.2R.sup.e].sub.2, --N(R.sup.g)S(O).sub.2OR.sup.e,
--N(R.sup.g)S(O).sub.2NR.sup.eR.sup.e,
--N(R.sup.g)[S(O).sub.2].sub.2R.sup.e, --N(R.sup.g)C(O)OR.sup.e,
--N(R.sup.g)C(O)SR.sup.e, --N(R.sup.g)C(O)NR.sup.eR.sup.e,
--N(R.sup.g)C(O)NR.sup.gNR.sup.eR.sup.e,
--N(R.sup.g)N(R.sup.g)C(O)NR.sup.eR.sup.e,
--N(R.sup.g)C(S)NR.sup.eR.sup.e, --[N(R.sup.g)C(O)].sub.2R.sup.e,
--N(R.sup.g)[C(O)].sub.2R.sup.e, --N{[C(O)].sub.2R.sup.e}.sub.2,
--N(R.sup.g)[C(O)].sub.2OR.sup.e,
--N(R.sup.g)[C(O)].sub.2NR.sup.eR.sup.e,
--N{[C(O)].sub.2OR.sup.e}.sub.2,
--N{[C(O)].sub.2NR.sup.eR.sup.e}.sub.2,
--[N(R.sup.g)C(O)].sub.2OR.sup.e, --N(R.sup.g)C(NR.sup.g)OR.sup.e,
--N(R.sup.g)C(NOH)R.sup.e, --N(R.sup.g)C(NR.sup.g)SR.sup.e,
--N(R.sup.g)C(NR.sup.g)NR.sup.eR.sup.e, --N.dbd.R.sup.eR.sup.e and
--N.dbd.C(R.sup.g)NR.sup.eR.sup.e each R.sup.e independently of one
another denotes hydrogen or a group optionally substituted by one
or more identical or different R.sup.f and/or R.sup.g, selected
from among C.sub.1-6alkyl, 2-6 membered heteroalkyl,
C.sub.1-6haloalkyl, C.sub.3 -10cycloalkyl,
C.sub.4-16cycloalkylalkyl, C.sub.6-10aryl C.sub.7-16arylalkyl, 5-12
membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 membered
heterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and each
R.sup.f denotes a suitable group and in each case is selected
independently of one another from among .dbd.O, --OR.sup.g,
C.sub.1-3haloalkyloxy, --OCF.sub.3, .dbd.S, --SR.sup.g,
.dbd.NR.sup.g, .dbd.NOR.sup.g, .dbd.NNR.sup.gR.sup.g,
.dbd.NN(R.sup.h)C(O)NR.sup.gR.sup.g, --NR.sup.gR.sup.g,
--ONR.sup.gR.sup.g, --N(R.sup.h)NR.sup.gR.sup.g, halogen,
--CF.sub.3, --CN, --NC, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --S(O)R.sup.g, --S(O)OR.sup.g,
--S(O).sub.2R.sup.g, --S(O).sub.2OR.sup.g, --S(O)NR.sup.gR.sup.g,
--S(O).sub.2NR.sup.gR.sup.g, --OS(O)R.sup.g, --OS(O).sub.2R.sup.g,
--OS(O).sub.2OR.sup.g, --OS(O)NR.sup.gR.sup.g,
--OS(O).sub.2NR.sup.gR.sup.g, --C(O)R.sup.g, --C(O)OR.sup.g,
--C(O)SR.sup.g, --C(O)NR.sup.gR.sup.g,
--C(O)N(R.sup.h)NR.sup.gR.sup.g, --C(O)N(R.sup.h)OR.sup.g,
--C(NR.sup.h)NR.sup.gR.sup.g, --C(NOH)R.sup.g,
--C(NOH)NR.sup.gR.sup.g, --OC(O)R.sup.g, --OC(O)OR.sup.g,
--OC(O)SR.sup.g, --OC(O)NR.sup.gR.sup.g,
--OC(NR.sup.h)NR.sup.gR.sup.g, --SC(O)R.sup.g, --SC(O)OR.sup.g,
--SC(O)NR.sup.gR.sup.g, --SC(NR.sup.h)NR.sup.gR.sup.g,
--N(R.sup.h)C(O)R.sup.g, --N[C(O)R.sup.g9.sub.2,
--N(OR.sup.h)C(O)R.sup.g, --N(R.sup.h)C(NR.sup.h)R.sup.g,
--N(R.sup.h)N(R.sup.h)C(O)R.sup.g, --N[C(O)R.sup.g]NR.sup.gR.sup.g,
--N(R.sup.h)C(S)R.sup.g, --N(R.sup.h)S(O)R.sup.g,
--N(R.sup.h)S(O)OR.sup.g, --N(R.sup.h)S(O).sub.2R.sup.g,
--N[S(O).sub.2R.sup.g].sub.2, --N(R.sup.h)S(O).sub.2OR.sup.g,
--N(R.sup.h)S(O).sub.2NR.sup.gR.sup.g,
--N(R.sup.h)[S(O).sub.2].sub.2R.sup.g, --N(R.sup.h)C(O)OR.sup.g,
--N(R.sup.h)C(O)SR.sup.g, --N(R.sup.h)C(O)NR.sup.gR.sup.g,
--N(R.sup.h)C(O)NR.sup.hNR.sup.gR.sup.g,
--N(R.sup.h)N(R.sup.h)C(O)NR.sup.gR.sup.g,
--N(R.sup.h)C(S)NR.sup.gR.sup.g, --[N(R.sup.h)C(O)].sub.2R.sup.g,
--N(R.sup.h)[C(O)].sub.2R.sup.g, --N{[C(O)].sub.2R.sup.g}.sub.2,
--N(R.sup.h)[C(O)].sub.2OR.sup.g,
--N(R.sup.h)[C(O)].sub.2NR.sup.gR.sup.g,
--N{[C(O)].sub.2OR.sup.g}.sub.2,
--N{[C(O)].sub.2NR.sup.gR.sup.g}.sub.2,
--[N(R.sup.h)C(O)].sub.2OR.sup.g, --N(R.sup.h)C(NR.sup.h)OR.sup.g,
--N(R.sup.h)C(NOH)R.sup.g, --N(R.sup.h)C(NR.sup.h)SR.sup.g,
--N(R.sup.h)C(NR.sup.h)NR.sup.gR.sup.g, --N.dbd.R.sup.hR.sup.h and
--N.dbd.C(R.sup.h)NR.sup.hR.sup.h; and each R.sup.g independently
of one another denotes hydrogen or a group optionally substituted
by one or more identical or different R.sup.h, selected from among
C.sub.1-6alkyl, 2-6 membered heteroalkyl, C.sub.1-6haloalkyl,
C.sub.3-10cycloalkyl, C.sub.4-16cycloalkylalkyl, C.sub.6-10aryl,
C.sub.7-16arylalkyl, 5-12 membered hetero aryl, 6-18 membered
heteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 membered
heterocycloalkylalkyl; and each R.sup.h is selected independently
of one another from among hydrogen, C.sub.1-6alkyl, 2-6 membered
heteroalkyl, C.sub.1-6haloalkyl, C.sub.3-10cycloalkyl,
C.sub.4-16cycloalkylalkyl, C.sub.6-10aryl, C.sub.7-16arylalkyl,
5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14
membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl,
or a tautomer or pharmacologically acceptable salt thereof.
2. A compound according to claim 1, wherein R.sup.3 is a radical
selected from the group consisting of pyridyl, pyrazinyl,
pyrimidinyl and pyridazinyl, optionally substituted by one or more
R.sup.4.
3. A compound according to claim 2, wherein R.sup.3 is pyridyl.
4. A compound according to claim 3, wherein R.sup.3 is substituted
by a residue selected from the group consisting of halogen, --CN,
--NR.sup.cR.sup.c and C.sub.1-6alkyl optionally substituted by
R.sup.b.
5. A compound according to claim 1, wherein R.sup.1 is
--NHC(O)R.sup.c.
6. A compound according to claim 5, wherein R.sup.1 is
--NHC(O)CH.sub.3.
7-8. (canceled)
9. A pharmaceutical preparation comprising a compound of formula
(1) according to one of claims 1 to 6 or a pharmacologically
effective salts thereof, in combination with conventional
excipients and/or carriers.
10. A method for treating cancer, infections, inflammatory and
autoimmune diseases, which comprises administering to a host
suffering one of said conditions a therapeutically effective amount
of a compound of the formula (1) according to one of claims 1 to 6
or a pharmacologically acceptable salt thereof.
11. (canceled)
Description
[0001] The present invention relates to new
thiazolyl-dihydro-indazoles of general formula (1)
##STR00002##
wherein the groups R' to R.sup.3 have the meanings given in the
claims and specification, the isomers thereof, processes for
preparing these thiazolyl-dihydro-indazoles and their use as
medicaments.
BACKGROUND TO THE INVENTION
[0002] A number of protein kinases have already proved to be
suitable target molecules for therapeutic intervention in a variety
of indications, e.g. cancer and inflammatory and autoimmune
diseases. Since a high percentage of the genes involved in the
development of cancer which have been identified thus far encode
kinases, these enzymes are attractive target molecules for the
therapy of cancer in particular.
[0003] Phosphatidylinositol-3-kinases (PI3-kinases) are a subfamily
of the lipid kinases which catalyse the transfer of a phosphate
group to the 3'-position of the inositol ring of
phosphoinositides.
[0004] They play an important role in numerous cell processes such
as e.g. cell growth and differentiation processes, the control of
cytoskeletal changes and the regulation of intracellular transport
processes. On the basis of their in vitro specificity for certain
phosphoinositide substrates the PI3-kinases can be divided into
different categories.
DETAILED DESCRIPTION OF THE INVENTION
[0005] It has now surprisingly been found that compounds of general
formula (1), wherein the groups R.sup.1 to R.sup.3 have the
meanings given below, act as inhibitors of specific cell cycle
kinases. Thus, the compounds according to the invention may be used
for example for the treatment of diseases connected with the
activity of specific cell cycle kinases and characterised by
excessive or abnormal cell proliferation.
[0006] The present invention relates to compounds of general
formula (1)
##STR00003##
wherein
[0007] R.sup.1 is selected from among --NHR.sup.c, --NHC(O)R.sup.c,
--NHC(O)OR.sup.c, --NHC(O)NR.sup.cR.sup.c,
--NHC(O)N(R.sup.g)OR.sup.c and --NHC(O)SR.sup.c, and
[0008] R.sup.2 denotes hydrogen or a group selected from among
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, 3-8 membered heterocycloalkyl,
C.sub.6-10aryl, C.sub.7-16arylalkyl and 5-10 membered heteroaryl,
optionally substituted by one or more identical or different
R.sup.4 and
[0009] R.sup.3 denotes a 6 membered heteroaryl, substituted by one
or more identical or different R.sup.a and/or R.sup.b, or
[0010] R.sup.3 denotes a 8-10 membered heteroaryl, optionally
substituted by one or more identical or different R.sup.e and/or
R.sup.f, and
[0011] each R.sup.4 denotes a group selected from among R.sup.a,
R.sup.b and R.sup.a substituted by one or more identical or
different R.sup.b and/or R.sup.c; and
[0012] each R.sup.a independently of one another denotes a group
optionally substituted by one or more identical or different
R.sup.b and/or R.sup.c, selected from among C.sub.1-6alkyl, 2-6
membered heteroalkyl, C.sub.1-6haloalkyl, C.sub.3-10cycloalkyl,
C.sub.4-16cycloalkylalkyl, C.sub.6-10aryl, C.sub.7-16arylalkyl,
5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14
membered heterocycloalkyl and 4-14 membered
heterocycloalkylalkyl,
[0013] each R.sup.b denotes a suitable group and is selected
independently of one another from among .dbd.O, --OR',
C.sub.1-3haloalkyloxy, --OCF.sub.3, .dbd.S, --SR.sup.c,
.dbd.NR.sup.c, .dbd.NOR.sup.c, .dbd.NNR.sup.cR.sup.c,
.dbd.NN(R.sup.g)C(O)NR.sup.cR.sup.c, --NR.sup.cR.sup.c,
--ONR.sup.cR.sup.c, --N(OR.sup.c)R.sup.c,
--N(R.sup.g)NR.sup.cR.sup.c, halogen, --CF.sub.3, --CN, --NC,
--OCN, --SCN, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3,
--S(O)R.sup.c, --S(O)OR.sup.c, --S(O).sub.2R.sup.c,
--S(O).sub.2OR.sup.c, --S(O)NR.sup.cR.sup.c,
--S(O).sub.2NR.sup.cR.sup.c, --OS(O)R.sup.c, --OS(O).sub.2R.sup.c,
--OS(O).sub.2OR.sup.c, --OS(O)NR.sup.cR.sup.c,
--OS(O).sub.2NR.sup.cR.sup.c, --C(O)R.sup.c, --C(O)OR.sup.c,
--C(O)SR.sup.c, --C(O)NR.sup.cR.sup.c,
--C(O)N(R.sup.c)NR.sup.cR.sup.c, --C(O)N(R.sup.g)OR.sup.c,
--C(NR.sup.g)NR.sup.cR.sup.c, --C(NOH)R.sup.c,
--C(NOH)NR.sup.cR.sup.c, --OC(O)R.sup.c, --OC(O)OR.sup.c,
--OC(O)SR.sup.c, --OC(O)NR.sup.cR.sup.c,
--OC(NR.sup.g)NR.sup.cR.sup.c, --SC(O)R.sup.c, --SC(O)OR.sup.c,
--SC(O)NR.sup.cR.sup.c, --SC(NR.sup.g)NR.sup.cR.sup.c,
--N(R.sup.g)C(O)R.sup.c, --N[C(O)R.sup.c].sub.2,
--N(OR.sup.g)C(O)R.sup.c, --N(R.sup.g)C(NR.sup.g)R.sup.c,
--N(R.sup.g)N(R.sup.g)C(O)R.sup.c, --N[C(O)R.sup.c]NR.sup.cR.sup.c,
--N(R.sup.g)C(S)R.sup.c, --N(R.sup.g)S(O)R.sup.c,
--N(R.sup.g)S(O)OR.sup.c, --N(R.sup.g)S(O).sub.2R.sup.c,
--N[S(O).sub.2R.sup.c].sub.2, --N(R.sup.g)S(O).sub.2OR.sup.c,
--N(R.sup.g)S(O).sub.2NR.sup.cR.sup.c,
--N(R.sup.g)[S(O).sub.2].sub.2R.sup.c, --N(R.sup.g)C(O)OR.sup.c,
--N(R.sup.g)C(O)SR.sup.c, --N(R.sup.g)C(O)NR.sup.cR.sup.c,
--N(R.sup.g)C(O)NR.sup.gNR.sup.cR.sup.c,
--N(R.sup.g)N(R.sup.g)C(O)NR.sup.cR.sup.c,
--N(R.sup.g)C(S)NR.sup.cR.sup.c, --[N(R.sup.g)C(O)].sub.2R.sup.c,
--N(R.sup.g)[C(O)].sub.2R.sup.c, --N{[C(O)].sub.2R.sup.c}.sub.2,
--N(R.sup.g)[C(O)].sub.2OR.sup.c,
--N(R.sup.g)[C(O)].sub.2NR.sup.cR.sup.c,
--N{[C(O)].sub.2OR.sup.c}.sub.2,
--N{[C(O)].sub.2NR.sup.cR.sup.c}.sub.2,
--[N(R.sup.g)C(O)].sub.2OR.sup.c, --N(R.sup.g)C(NR.sup.g)OR.sup.c,
--N(R.sup.g)C(NOH)R.sup.c, --N(R.sup.g)C(NR.sup.g)SR.sup.c,
--N(R.sup.g)C(NR.sup.g)NR.sup.cR.sup.c, --N.dbd.R.sup.cR.sup.c and
--N.dbd.C(R.sup.g)NR.sup.cR.sup.c and [0014] each R.sup.c
independently of one another denotes hydrogen or a group optionally
substituted by one or more identical or different R.sup.d and/or
R.sup.e, selected from among C.sub.1-6alkyl, 2-6 membered
heteroalkyl, C.sub.1-6halo alkyl, C.sub.3-10cycloalkyl,
C.sub.4-16cycloalkylalkyl, C.sub.6-10aryl, C.sub.7-16arylalkyl,
5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14
membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl,
and [0015] each R.sup.d denotes a suitable group and is selected
independently of one another from among .dbd.O, --OR.sup.e,
C.sub.1-3haloalkyloxy, --OCF.sub.3, .dbd.S, --SR.sup.e,
.dbd.NR.sup.e, .dbd.NOR.sup.e, .dbd.NNR.sup.eR.sup.e,
.dbd.NN(R.sup.g)C(O)NR.sup.eR.sup.e, --NR.sup.eR.sup.e,
--ONR.sup.eR.sup.e, --N(R.sup.g)NR.sup.eR.sup.e, halogen,
--CF.sub.3, --CN, --NC, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --S(O)R.sup.e, --S(O)OR.sup.e,
--S(O).sub.2R.sup.e, --S(O).sub.2OR.sup.e, --S(O)NR.sup.eR.sup.e,
--S(O).sub.2NR.sup.eR.sup.e, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O).sub.2OR.sup.e, --OS(O)NR.sup.eR.sup.e,
--OS(O).sub.2NR.sup.eR.sup.e, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)SR.sup.e, --C(O)NR.sup.eR.sup.e,
--C(O)N(R.sup.g)NR.sup.eR.sup.e, --C(O)N(R.sup.g)OR.sup.e,
--C(NR.sup.g)NR.sup.eR.sup.e, --C(NOH)R.sup.e,
--C(NOH)NR.sup.eR.sup.e, --OC(O)R.sup.e, --OC(O)OR.sup.e,
--OC(O)SR.sup.e, --OC(O)NR.sup.eR.sup.e,
--OC(NR.sup.g)NR.sup.eR.sup.e, --SC(O)R.sup.e, --SC(O)OR.sup.e,
--SC(O)NR.sup.eR.sup.e, --SC(NR.sup.g)NR.sup.eR.sup.e,
--N(R.sup.g)C(O)R.sup.e, --N[C(O)R.sup.e].sub.2,
--N(OR.sup.g)C(O)R.sup.e, --N(R.sup.g)C(NR.sup.g)R.sup.e,
--N(R.sup.g)N(R.sup.g)C(O)R.sup.e, --N[C(O)R.sup.e]NR.sup.eR.sup.e,
--N(R.sup.g)C(S)R.sup.e, --N(R.sup.g)S(O)R.sup.e,
--N(R.sup.g)S(O)OR.sup.e, --N(R.sup.g)S(O).sub.2R.sup.e,
--N[S(O).sub.2R.sup.e].sub.2, --N(R.sup.g)S(O).sub.2OR.sup.e,
--N(R.sup.g)S(O).sub.2NR.sup.eR.sup.e,
--N(R.sup.g)[S(O).sub.2].sub.2R.sup.e, --N(R.sup.g)C(O)OR.sup.e,
--N(R.sup.g)C(O)SR.sup.e, --N(R.sup.g)C(O)NR.sup.eR.sup.e,
--N(R.sup.g)C(O)NR.sup.gNR.sup.eR.sup.e,
--N(R.sup.g)N(R.sup.g)C(O)NR.sup.eR.sup.e,
--N(R.sup.g)C(S)NR.sup.eR.sup.e, --[N(R.sup.g)C(O)].sub.2R.sup.e,
--N(R.sup.g)[C(O)].sub.2R.sup.e, --N{[C(O)].sub.2R.sup.e}.sub.2,
--N(R.sup.g)[C(O)].sub.2OR.sup.e,
--N(R.sup.g)[C(O)].sub.2NR.sup.eR.sup.e,
--N{[C(O)].sub.2OR.sup.e}.sub.2,
--N{[C(O)].sub.2NR.sup.eR.sup.e}.sub.2,
--[N(R.sup.g)C(O)].sub.2OR.sup.e, --N(R.sup.g)C(NR.sup.g)OR.sup.e,
--N(R.sup.g)C(NOH)R.sup.e, --N(R.sup.g)C(NR.sup.g)SR.sup.e,
--N(R.sup.g)C(NR.sup.g)NR.sup.eR.sup.e, --N.dbd.R.sup.eR.sup.e and
--N.dbd.C(R.sup.g)NR.sup.eR.sup.e [0016] each R.sup.e independently
of one another denotes hydrogen or a group optionally substituted
by one or more identical or different R.sup.f and/or R.sup.g,
selected from among C.sub.1-6alkyl, 2-6 membered heteroalkyl,
C.sub.1-6halo alkyl, C.sub.3-10cycloalkyl,
C.sub.4-16cycloalkylalkyl, C.sub.6-10aryl, C.sub.7-16arylalkyl,
5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14
membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl,
and [0017] each R.sup.f denotes a suitable group and in each case
is selected independently of one another from among .dbd.O,
--OR.sup.g, C.sub.1-3haloalkyloxy, --OCF.sub.3, .dbd.S, --SR.sup.g,
.dbd.NR.sup.g, .dbd.NOR.sup.g, .dbd.NNR.sup.gR.sup.g,
.dbd.NN(R.sup.h)C(O)NR.sup.gR.sup.g, --NR.sup.gR.sup.g,
--ONR.sup.gR.sup.g, --N(R.sup.h)NR.sup.gR.sup.g, halogen,
--CF.sub.3, --CN, --NC, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --S(O)R.sup.g, --S(O)OR.sup.g,
--S(O).sub.2R.sup.g, --S(O).sub.2OR.sup.g, --S(O)NR.sup.gR.sup.g,
--S(O).sub.2NR.sup.gR.sup.g, --OS(O)R.sup.g, --OS(O).sub.2R.sup.g,
--OS(O).sub.2OR.sup.g, --OS(O)NR.sup.gR.sup.g,
--OS(O).sub.2NR.sup.gR.sup.g, --C(O)R.sup.g, --C(O)OR.sup.g,
--C(O)SR.sup.g, --C(O)NR.sup.gR.sup.g,
--C(O)N(R.sup.h)NR.sup.gR.sup.g, --C(O)N(R.sup.h)OR.sup.g,
--C(NR.sup.h)NR.sup.gR.sup.g, --C(NOH)R.sup.g,
--C(NOH)NR.sup.gR.sup.g, --OC(O)R.sup.g, --OC(O)OR.sup.g,
--OC(O)SR.sup.g, --OC(O)NR.sup.gR.sup.g,
--OC(NR.sup.h)NR.sup.gR.sup.g, --SC(O)R.sup.g, --SC(O)OR.sup.g,
--SC(O)NR.sup.gR.sup.g, --SC(NR.sup.h)NR.sup.gR.sup.g,
--N(R.sup.h)C(O)R.sup.g, --N[C(O)R.sup.g].sub.2,
--N(OR.sup.h)C(O)R.sup.g, --N(R.sup.h)C(NR.sup.h)R.sup.g,
--N(R.sup.h)N(R.sup.h)C(O)R.sup.g, --N[C(O)R.sup.g]NR.sup.gR.sup.g,
--N(R.sup.h)C(S)R.sup.g, --N(R.sup.h)S(O)R.sup.g,
--N(R.sup.h)S(O)OR.sup.g, --N(R.sup.h)S(O).sub.2R.sup.g,
--N[S(O).sub.2R.sup.g].sub.2, --N(R.sup.h)S(O).sub.2OR.sup.g,
--N(R.sup.h)S(O).sub.2NR.sup.gR.sup.g,
--N(R.sup.h)[S(O).sub.2].sub.2R.sup.g, --N(R.sup.h)C(O)OR.sup.g,
--N(R.sup.h)C(O)SR.sup.g, --N(R.sup.h)C(O)NR.sup.gR.sup.g,
--N(R.sup.h)C(O)NR.sup.hNR.sup.gR.sup.g,
--N(R.sup.h)N(R.sup.h)C(O)NR.sup.gR.sup.g,
--N(R.sup.h)C(S)NR.sup.gR.sup.g, --[N(R.sup.h)C(O)].sub.2R.sup.g,
--N(R.sup.h)[C(O)].sub.2R.sup.g, --N{[C(O)].sub.2R.sup.gh,
--N(R.sup.h)[C(O)].sub.2OR.sup.g,
--N(R.sup.h)[C(O)].sub.2NR.sup.gR.sup.g,
--N{[C(O)].sub.2OR.sup.g}.sub.2,
--N{[C(O)].sub.2NR.sup.gR.sup.g}.sub.2,
--[N(R.sup.h)C(O)].sub.2OR.sup.g, --N(R.sup.h)C(NR.sup.h)OR.sup.g,
--N(R.sup.h)C(NOH)R.sup.g, --N(R.sup.h)C(NR.sup.h)SR.sup.g,
--N(R.sup.h)C(NR.sup.h)NR.sup.gR.sup.g, --N.dbd.R.sup.hR.sup.h and
--N.dbd.C(R.sup.h)NR.sup.hR.sup.h; and [0018] each R.sup.g
independently of one another denotes hydrogen or a group optionally
substituted by one or more identical or different R.sup.h, selected
from among C.sub.1-6alkyl, 2-6 membered heteroalkyl,
C.sub.1-6haloalkyl, C.sub.3-10cycloalkyl,
C.sub.4-16cycloalkylalkyl, C.sub.6-10aryl, C.sub.7-16arylalkyl,
5-12 membered hetero aryl, 6-18 membered heteroarylalkyl, 3-14
membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl;
and [0019] each R.sup.h is selected independently of one another
from among hydrogen, C.sub.1-6alkyl, 2-6 membered heteroalkyl,
C.sub.1-6haloalkyl, C.sub.3-10cycloalkyl,
C.sub.4-16cycloalkylalkyl, C.sub.6-10aryl, C.sub.7-16arylalkyl,
5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14
membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl,
optionally in the form of the prodrugs, the tautomers, the
racemates, the enantiomers, the diastereomers, the prodrugs and the
mixtures thereof, and optionally the pharmacologically acceptable
salts thereof.
[0020] One aspect of the invention are compounds of general
formular (1), wherein R.sup.3 is a radical selected from the group
consisting of pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl,
optionally substituted by one or more R.sup.4.
[0021] A further aspect of the invention are compounds of general
formular (1), wherein R.sup.3 is pyridyl.
[0022] A further aspect of the invention are compounds of general
formular (1), wherein R.sup.3 is substituted by a residue selected
from the group consisting of halogen, --CN, --OR',
--NR.sup.cR.sup.c and C.sub.1-6alkyl optionally substituted by
R.sup.b.
[0023] A further aspect of the invention are compounds of general
formular (1), wherein R.sup.1 is --NHC(O)R.sup.c.
[0024] A further aspect of the invention are compounds of general
formular (1), wherein R.sup.1 is --NHC(O)CH.sub.3.
[0025] A further aspect of the invention are compounds of general
formular (1)--or the pharmaceutically active salts thereof--for use
as a medicament.
[0026] A further aspect of the invention are compounds of general
formular (1)--or the pharmacologically effective salts thereof, for
preparing a medicament with an antiproliferative activity.
[0027] A further aspect of the invention is a pharmaceutical
preparation, containing as active substance one or more compounds
of general formula (1) or the physiologically acceptable salts
thereof optionally in conjunction with conventional excipients
and/or carriers.
[0028] A further aspect of the invention is the use of a compound
of general formula (1) for preparing a pharmaceutical composition
for the treatment and/or prevention of cancer, infections,
inflammatory and autoimmune diseases.
[0029] A further aspect of the invention is a pharmaceutical
preparation comprising a compound of general formula (1) and at
least one other cytostatic or cytotoxic active substance, different
from formula (1), optionally in the form of the tautomers, the
racemates, the enantiomers, the diastereomers and the mixtures
thereof, and optionally the pharmacologically acceptable acid
addition salts thereof.
Definitions
[0030] As used herein the following definitions apply, unless
stated otherwise.
[0031] By alkyl substituents are meant in each case saturated,
unsaturated, straight-chain or branched aliphatic hydrocarbon
groups (alkyl group) and this includes both saturated alkyl groups
and unsaturated alkenyl and alkynyl groups. Alkenyl substituents
are in each case straight-chain or branched, unsaturated alkyl
groups, which have at least one double bond. By alkynyl
substituents are meant in each case straight-chain or branched,
unsaturated alkyl groups, which have at least one triple bond.
[0032] The term heteroalkyl refers to groups which can be derived
from alkyl as defined above in its broadest sense by replacing one
or more of the groups --CH.sub.3 in the hydrocarbon chains
independently of one another by the groups --OH, --SH or
--NH.sub.2, one or more of the groups --CH.sub.2-- independently of
one another by the groups --O--, --S-- or --NH--, one or more of
the groups
##STR00004##
are replaced by the group
##STR00005##
one or more of the groups .dbd.CH-- by the group .dbd.N--, one or
more of the groups .dbd.CH.sub.2 by the group .dbd.NH or one or
more of the groups .ident.CH by the group .ident.N, while in all
only a maximum of three heteroatoms may be present in a
heteroalkyl, there must be at least one carbon atom between two
oxygen and between two sulphur atoms or between one oxygen and one
sulphur atom and the group as a whole must have chemical
stability.
[0033] It flows from the indirect definition/derivation from alkyl
that heteroalkyl is made up of the sub-groups of saturated
hydrocarbon chains with hetero-atom(s), heteroalkenyl and
hetero-alkynyl, while further subdivision into straight-chain
(unbranched) and branched may be carried out. If a heteroalkyl is
supposed to be substituted, the substitution may take place
independently of one another, in each case mono- or
polysubstituted, at all the hydrogen-carrying oxygen, sulphur,
nitrogen and/or carbon atoms. Heteroalkyl itself may be linked to
the molecule as substituent both through a carbon atom and through
a heteroatom.
[0034] By way of example, the following representative compounds
are listed: dimethylaminomethyl; dimethylaminoethyl
(1-dimethylaminoethyl; 2-dimethyl-aminoethyl); dimethylaminopropyl
(1-dimethylaminopropyl, 2-dimethylaminopropyl,
3-dimethylaminopropyl); diethylaminomethyl; diethylaminoethyl
(1-diethylaminoethyl, 2-diethylaminoethyl); diethylaminopropyl
(1-diethylaminopropyl, 2-diethylamino-propyl,
3-diethylaminopropyl); diisopropylaminoethyl
(1-diisopropylaminoethyl, 2-di-isopropylaminoethyl);
bis-2-methoxyethylamino;
[2-(dimethylamino-ethyl)-ethyl-amino]-methyl;
3-[2-(dimethylamino-ethyl)-ethyl-amino]-propyl; hydroxymethyl;
2-hydroxy-ethyl; 3-hydroxypropyl; methoxy; ethoxy; propoxy;
methoxymethyl; 2-methoxyethyl etc.
[0035] Haloalkyl relates to alkyl groups, wherein one or more
hydrogen atoms are replaced by halogen atoms. Haloalkyl includes
both saturated alkyl groups and unsaturated alkenyl and alkynyl
groups, such as for example --CF.sub.3, --CHF.sub.2, --CH.sub.2F,
--CF.sub.2CF.sub.3,--CHFCF.sub.3, --CH.sub.2CF.sub.3,
--CF.sub.2CH.sub.3, --CHFCH.sub.3, --CF.sub.2CF.sub.2CF.sub.3,
--CF.sub.2CH.sub.2CH.sub.3, --CF.dbd.CF.sub.2, --CCl.dbd.CH.sub.2,
--CBr.dbd.CH.sub.2, --Cl.dbd.CH.sub.2, --C.ident.C--CF.sub.3,
--CHFCH.sub.2CH.sub.3 and --CHFCH.sub.2CF.sub.3.
[0036] Halogen refers to fluorine, chlorine, bromine and/or iodine
atoms.
[0037] By cycloalkyl is meant a mono or bicyclic ring, while the
ring system may be a saturated ring or, however, an unsaturated,
non-aromatic ring, which may optionally also contain double bonds,
such as for example cyclopropyl, cyclopropenyl, cyclobutyl,
cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,
norbornyl and norbornenyl.
[0038] Cycloalkylalkyl includes a non-cyclic alkyl group wherein a
hydrogen atom bound to a carbon atom, usually to a terminal C atom,
is replaced by a cycloalkyl group.
[0039] Aryl relates to monocyclic or bicyclic aromatic rings with
6-10 carbon atoms such as phenyl and naphthyl, for example.
[0040] Arylalkyl includes a non-cyclic alkyl group wherein a
hydrogen atom bound to a carbon atom, usually to a terminal C atom,
is replaced by an aryl group.
[0041] By heteroaryl are meant mono- or bicyclic aromatic rings,
which instead of one or more carbon atoms contain one or more,
identical or different hetero atoms, such as e.g. nitrogen, sulphur
or oxygen atoms. Examples include furyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl,
imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,
pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples
of bicyclic heteroaryl groups are indolyl, isoindolyl, benzofuryl,
benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl,
quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl
and benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl,
naphthyridinyl, indolinyl, isochromanyl, chromanyl,
tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuryl,
isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,
pyridopyridyl, benzotetrahydrofuryl, benzotetrahydrothienyl,
purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl,
pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridyl-N-oxide
tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,
dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,
isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide,
pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide,
quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide,
isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide,
phthalazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide,
oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide,
indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide,
pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide,
triazolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide and
benzothiopyranyl-S,S-dioxide.
[0042] Heteroarylalkyl encompasses a non-cyclic alkyl group wherein
a hydrogen atom bound to a carbon atom, usually to a terminal C
atom, is replaced by a heteroaryl group.
[0043] Heterocycloalkyl relates to saturated or unsaturated,
non-aromatic mono-, bicyclic or bridged bicyclic rings comprising
3-12 carbon atoms, which instead of one or more carbon atoms carry
heteroatoms, such as nitrogen, oxygen or sulphur. Examples of such
heterocyloalkyl groups are tetrahydrofuryl, pyrrolidinyl,
pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,
pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl,
morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl,
homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide,
thiomorpholinyl-S,S-dioxide, tetrahydropyranyl, tetrahydrothienyl,
homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,
dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl,
dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, dioxaborolanyl,
tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide,
homothiomorpholinyl-S-oxide, 2-oxa-5-azabicyclo[2,2,1]heptane,
8-oxa-3-aza-bicyclo[3.2.1]octane, 3.8-diaza-bicyclo[3.2.1]-octane,
2,5-diaza-bicyclo[2,2,1]heptane, 3.8-diaza-bicyclo[3.2.1]octane,
3.9-diaza-bicyclo[4.2.1]nonane and
2.6-diaza-bicyclo[3.2.2]nonane.
[0044] Heterocycloalkylalkyl relates to a non-cyclic alkyl group
wherein a hydrogen atom bound to a carbon atom, usually to a
terminal C atom, is replaced by a heterocycloalkyl group.
[0045] The following Examples illustrate the present invention
without restricting its scope.
[0046] Intermediates A:
[0047] The syntheses of substituted
5,6-dihydro-4H-benzothiazol-7-ones used herein as starting
materials are described in earlier applications (see WO2006/040281,
WO2007/113245, and WO2007/113246). Additional starting materials
may be prepared by the procedures described therein.
[0048] General Procedure A1: Formation of Diketones from Acid
Chlorides.
[0049] The monoketone is added to dry THF (e.g. 10 mmol in 90 mL
solvent) and the suspension is cooled to -78.degree. C. under inert
atmosphere. LiHMDS (3.4 eq.) is slowly added to the reaction
mixture so that the reaction temperature is kept below -60.degree.
C. After completion of the addition, a solution of the acid
chloride (1.2 eq.) in dry THF (about 2-2.5 M) is added slowly. The
reaction mixture is stirred overnight allowing it to warm to RT.
For the work-up the mixture is cooled to -20.degree. C. and the
reaction is quenched with diluted hydrochloric acid and phosphate
buffer (22 g NaH.sub.2PO.sub.4, 87 g Na.sub.2HPO.sub.4, 530 mL
H.sub.2O) resulting in a final pH about 6. Ethyl acetate is added
and the organic layer is separated. The aqueous phase is extracted
three times with ethyl acetate, the combined organic phases are
dried over MgSO.sub.4, filtered and the solvent is removed under
reduced pressure. The remaining solid is treated with TBME and the
solvent is filtered off. The product may be used without further
purification.
[0050] General Procedure A2: Formation of Diketones from Esters
[0051] The monoketone (1.0 eq.) is dissolved in DMSO (1 M solution)
and NaOtBu or sodium tert.-pentoxide (3.0 eq.) is slowly added. The
reaction mixture is stirred for 30 min at room temperature before
the ester (1.1 eq.) is added slowly. After completion of the
addition the mixture is stirred for 4 h at RT, poured on ice and
neutralized with saturated ammonium chloride solution. The
precipitate is filtered off, washed with water dried under vacuum
at 40.degree. C. overnight. Alternatively, the solvent is
evaporated after completion of the reaction and the crude product
may be used for the next step without further purification.
[0052] General Procedure A3: Formation of Diketones from Active
Esters.
[0053] a) Formation of the Active Ester
[0054] Carboxylic acid (1.0 eq.) is dissolved in CH.sub.2Cl.sub.2,
CDI (1.0 eq.) is added and the reaction mixture is stirred at RT
over night. The solvent is removed in vacuo and the crude product
is used without further purification.
[0055] b) Formation of the Diketone
[0056] A 1 M solution of LiHMDS (3 eq.) in THF is diluted with THF
and the resulting solution is cooled to -10.degree. C. under inert
atmosphere. The monoketone (1.0 eq.) is added in small portions so
that the reaction temperature is kept below -10.degree. C. After
stirring one additional hour at -10.degree. C. a solution of the
active ester (2.0 eq.) in THF is added slowly. The reaction mixture
is stirred over night allowing it to warm to RT. The reaction is
quenched with a saturated solution of NH.sub.4Cl in water and the
aqueous phase is extracted twice with CH.sub.2Cl.sub.2. The
combined organic layers are dried over MgSO.sub.4, filtered and the
solvent is removed under reduced pressure. The product is purified
by RP-chromatography.
[0057] General Procedure A4: Nucleophilic Aromatic Substitution of
o-fluoropyridines.
[0058] The o-fluoropyridine and an excess of the amine are
dissolved in EtOH or iPrOH/THF (0.1-0.2 M) and the mixture is
heated in the microwave at 100.degree. C. for 30-60 min or
alternatively at RT without heating (the reaction is typically
monitored by LC-MS until all starting material has reacted). After
completion of the reaction the solvent is removed in vacuo and the
product is either purified by chromatography (NP with MeOH/DCM or
RP with ACN/H.sub.2O) or used without further purification.
A-01)
N-[6-(6-Fluoro-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzothiaz-
ol-2-yl]-acetamide
##STR00006##
[0060] The title compound is synthesized according to general
procedure A1 starting form 21.0 g (100 mmol),
N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 20.2 g
(120 mmol, 95% pure) 6-fluoro nicotinic acid chloride. Yield: 27.0
g.
A-02)
N-[6-(6-Dimethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-ben-
zothiazol-2-yl]-acetamide
##STR00007##
[0062] The title compound is obtained from 500 mg (1.5 mmol) A-01
and 5.0 mL of a 2 M solution of dimethylamine in THF (10 mmol). The
reaction is performed in EtOH according to the general procedure
A4. The product is purified by NP-chromatography. Yield 205 mg.
A-03)
N-[6-(6-tert-Butylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-b-
enzothiazol-2-yl]acetamide
##STR00008##
[0064] The title compound is obtained from 160 mg (0.39 mmol, -81%
purity) A-01 and 410 .mu.L (3.90 mmol) tert-butylamine. The
reaction is performed in EtOH according to the general procedure
A4. The crude product is used without further purification. Yield:
157 mg.
A-04)
N-[6-(6-Cyclopropylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro--
benzothiazol-2-yl]-acetamide
##STR00009##
[0066] The title compound is obtained from 160 mg (0.39 mmol, about
81% purity) A-01 and 270 .mu.L (3.90 mmol) cyclopropylamine. The
reaction is performed in EtOH according to the general procedure
A4. The crude product is used without further purification. Yield:
168 mg.
A-05)
N-[6-(6-Allylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzot-
hiazol-2-yl]-acetamide
##STR00010##
[0068] The title compound is obtained from 160 mg (0.39 mmol, about
81% purity) A-01 and 290 .mu.L (3.87 mmol) allylamine according to
the general procedure A4. The reaction is performed in EtOH. The
crude product is used without further purification. Yield: 177
mg.
A-06)
N-[7-Hydroxy-6-(6-isopropylamino-pyridine-3-carbonyl)-4,5-dihydro-be-
nzothiazol-2-yl]-acetamide
##STR00011##
[0070] The title compound is obtained from 160 mg (0.39 mmol, about
81% purity) A-01 and 335 .mu.L (3.89 mmol) isopropylamine. The
reaction is performed in EtOH according to the general procedure
A4. The crude product is used without further purification. Yield:
179 mg.
A-07)
N-[7-Hydroxy-6-(6-methylamino-pyridine-3-carbonyl)-4,5-dihydro-benzo-
thiazol-2-yl]-acetamide
##STR00012##
[0072] The title compound is obtained from 27.0 g (72.90 mmol,
about 90% purity) A-01 and 27 mL (319.7 mmol) of a solution of
methylamine in water. The reaction is performed in a 1:1 mixture of
THF and iPrOH according to the general procedure A4. For the
work-up a large portion of the solvent is removed under reduced
pressure, the formed precipitate is filtered off and washed with a
small amount of iPrOH as well as water. Yield: 17.8 g.
A-08)
N-{6-[6-(2-Dimethylamino-ethylamino)-pyridine-3-carbonyl]-7-hydroxy--
4,5-dihydro-benzothiazol-2-yl}-acetamide (A-08)
##STR00013##
[0074] The title compound is obtained from 1.0 g (3.00 mmol) A-01
and 1.56 mL (14.1 mmol) N,N-dimethylethylendiamine. The reaction is
performed in a 1:1 mixture of THF and iPrOH according to the
general procedure A4. For the work-up the solvent is removed under
reduced pressure, the residue taken up with water, extracted with
CH.sub.2Cl.sub.2, the organic phase dried over MgSO.sub.4, filtered
and the solvent removed in vacuo. Yield: 1.49 g.
A-09)
N-{7-Hydroxy-6-[6-(2-methoxy-ethylamino)-pyridine-3-carbonyl]-4,5-di-
hydro-benzothiazol-2-yl}-acetamide
##STR00014##
[0076] The title compound is obtained from 1.0 g (3.0 mmol) A-01
and 1.22 mL (14.1 mmol) 2-methoxyethylamine. The reaction is
performed in a 1:1 mixture of THF and iPrOH according to the
general procedure A4. For the work-up the solvent is removed under
reduced pressure, the residue treated with water. The precipitate
is filtered off, washed twice with water and dried. Yield: 1.03
g.
A-10)
N-[6-(6-Ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzot-
hiazol-2-yl]-acetamide
##STR00015##
[0078] The title compound is obtained from 25.0 g (67.50 mmol,
about 90% purity) A-01 and 25 mL (314 mmol) of a solution of
ethylamine in water. The reaction is performed in a 1:1 mixture of
THF and iPrOH according to the general procedure A4. For the
work-up a large portion of the solvent is removed under reduced
pressure, water is added and the formed precipitate is filtered
off. The product is washed twice with both iPrOH and water. Yield:
20.2 g.
A-11)
N-[6-(6-Ethylamino-5-methyl-pyridine-3-carbonyl)-7-hydroxy-4,5-dihyd-
ro-benzothiazol-2-yl]acetamide
##STR00016##
[0080] The title compound is obtained from 3.46 g (9.96 mmol)
N-[6-(6-fluoro-5-methyl-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzot-
hiazol-2-yl]-acetamide (made in analogy to A-01) and 3.46 mL (43.5
mmol) of a solution of ethylamine in water. The reaction is
performed in a 1:1 mixture of THF and iPrOH according to the
general procedure A4. The crude product is used without further
purification. Yield: 2.1 g.
A-12)
N-[6-(6-Chloro-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzothiaz-
ol-2-yl]-acetamide
##STR00017##
[0082] The title compound is obtained by reacting 3.34 g (15.9
mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and
6.60 g (31.8 mmol) (6-chloro-pyridin-3-yl)-imidazol-1-yl-methanone
according to the general procedure A3. The product is purified by
RP-HPLC (gradient 5-70% ACN, 25 min, 60 mL/min). Yield: 570 mg.
A-13)
N-[6-(5-Fluoro-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzothiaz-
ol-2-yl]-acetamide
##STR00018##
[0084] The title compound is obtained by reacting 500 mg (2.38
mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and
909 mg (4.76 mmol) (5-fluoro-pyridin-3-yl)-imidazol-1-yl-methanone
according to the general procedure A3. The reaction is quenched
with 4 N HCl in dioxane prior to the addition of phosphate buffer
(pH 6-7). The crude product obtained after extraction is used
without further purification. Yield: 800 mg.
A-14)
N-[7-Hydroxy-6-(5-methyl-pyridine-3-carbonyl)-4,5-dihydro-benzothiaz-
ol-2-yl]-acetamide
##STR00019##
[0086] The title compound is obtained by reacting 786 mg (3.74
mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and
1.40 g (7.48 mmol) of
(5-methyl-pyridin-3-yl)-imidazol-1-yl-methanone according to the
general procedure A3 (-60.degree. C.). The reaction is quenched
with HCl in ether (pH 3) before CH.sub.2Cl.sub.2 and phosphate
buffer (28.1 g NaH.sub.2PO.sub.4.times.2 H.sub.2O, 106.8 g
NaHPO.sub.4.times.2 H.sub.2O, 500 mL H.sub.2O) are added. The
product is purified by RP-HPLC (gradient 5-80% ACN, 40 min). Yield:
439 mg.
A-15)
N-[6-(6-Ethyl-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzothiazo-
l-2-yl]-acetamide
##STR00020##
[0088] The title compound is obtained by reacting 21.0 g (210 mmol)
N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 19.0 g
(115 mmol) of 6-ethyl-nicotinic acid ethyl ester according to the
general procedure A2. Yield: 26.4 g.
A-16)
N-[7-Hydroxy-6-(6-isopropyl-pyridine-3-carbonyl)-4,5-dihydro-benzoth-
iazol-2-yl]-acetamide
##STR00021##
[0090] The title compound is obtained by reacting 1.67 g (7.92
mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and
2.13 g (11.9 mmol) of 6-isopropyl-nicotinic acid ethyl ester
according to the general procedure A2. Yield: 3.82 g.
A-17)
N-[7-Hydroxy-6-(6-methoxy-pyridine-3-carbonyl)-4,5-dihydro-benzothia-
zol-2-yl]-acetamide
##STR00022##
[0092] The title compound is obtained by reacting 3.36 g (16.0
mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and
6.50 g (32.0 mmol) of the
(6-methoxy-pyridin-3-yl)-imidazol-1-yl-methanone according to the
general procedure A3. The reaction is quenched with saturated
NH.sub.4Cl solution prior to extraction. The product is purified by
RP-chromatography (gradient: 5-70% ACN, 25 min, 60 mL/min). Yield:
860 mg.
A-18)
N-[6-(5,6-Dimethyl-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzot-
hiazol-2-yl]-acetamide
##STR00023##
[0094] The title compound is obtained by reacting 5.00 g (23.8
mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and
4.71 g (28.5 mmol) of 5,6-dimethylnicotinic acid methylester
according to the general procedure A2. The product is purified by
NP-HPLC (gradient DCM/MeOH 99:1-80:20, 20 min, 60 mL/min). Yield:
917 mg.
A-19)
N-[7-Hydroxy-6-(quinoline-3-carbonyl)-4,5-dihydro-benzothiazol-2-yl]-
-acetamide
##STR00024##
[0096] The title compound is obtained by reacting 1.67 g (7.95
mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and
2.66 g (23.9 mmol) imidazol-1-yl-quinolin-3-yl-methanone according
to the general procedure A3. A precipitate is formed during the
reaction and is filtered off without quenching, washed with THF,
dissolved in a mixture of saturated NaHCO.sub.3-solution and
CH.sub.2Cl.sub.2. The water phase is extracted with
CH.sub.2Cl.sub.2, the combined organic phases are dried over
MgSO.sub.4, filtered, and the solvent is removed under reduced
pressure. The remaining solid is treated with diethylether,
filtered off and dried. Yield: 1.12 g.
A-20)
N-[6-(6-Cyano-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzothiazo-
l-2-yl]-acetamide
##STR00025##
[0098] The title compound is obtained by reacting 1.91 g (9.08
mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and
2.70 g (13.6 mmol) (6-cyano-pyridin-3-yl)-imidazol-1-yl-methanone
according to the general procedure A3. The reaction is quenched by
adding saturated NaHCO.sub.3-solution. The water phase is extracted
with CH.sub.2Cl.sub.2, the combined organic phases are dried over
MgSO.sub.4, filtered, and the solvent is removed under reduced
pressure. The product is purified by RP-HPLC (gradient 5-80% ACN,
30 min, 60 mL/min). Yield: 149 mg.
A-23)
N-[7-Hydroxy-6-(6-methyl-pyridine-3-carbonyl)-4,5-dihydro-benzothiaz-
ol-2-yl]-acetamide
##STR00026##
[0100] The title compound is obtained by reacting 3.82 g (18.2
mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and
6.80 g (36.3 mmol) (6-methyl-pyrid-3-yl)-imidazol-1-yl-methanone
according to the general procedure A3. The reaction is quenched by
adding saturated NH.sub.4Cl-solution. The water phase is extracted
with CH.sub.2Cl.sub.2, the combined organic phases are dried over
MgSO.sub.4, filtered, and the solvent is removed under reduced
pressure. The product is purified by RP-HPLC (gradient 5-70% ACN,
25 min, 60 mL/min). Yield: 4.68 g.
A-24)
[7-Hydroxy-6-(6-methyl-pyridine-3-carbonyl)-4,5-dihydro-benzothiazol-
-2-yl]-carbamic acid methyl ester
##STR00027##
[0102] The title compound is obtained by reacting 12.7 g (56.3
mmol) (7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid
methyl ester and 13.7 g (73.2 mmol)
(6-methyl-pyrid-3-yl)-imidazol-1-yl-methanone according to the
general procedure A3. The product precipitates during the reaction,
is filtered off and distributed between saturated NaHCO.sub.3
solution and ethyl acetate. The organic phase is dried over
MgSO.sub.4, filtered and the solvent removed under reduced
pressure. The crude product is treated with diethylether, filtered
and dried. Yield: 13.3 g.
A-25)
N-[7-Hydroxy-6-(6-methyl-pyridine-3-carbonyl)-4,5-dihydro-benzothiaz-
ol-2-yl]-propionamide
##STR00028##
[0104] The title compound is obtained by reacting 4.10 g (18.3
mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-propionamide
and 6.79 g (36.0 mmol)
(6-methyl-pyrid-3-yl)-imidazol-1-yl-methanone according to the
general procedure A3. After the complete addition a dark, sticky
gum has formed. The THF is decanted of and the gum is dissolved in
a saturated solution of NaHCO.sub.3 in water. The mixture is
extracted with CH.sub.2Cl.sub.2, the organic phases are washed with
water and brine, dried on MgSO.sub.4 and concentrated in vacuo. The
residue is triturated with diethylether and ACN. Yield: 1.50 g.
A-26)
(2-Chloro-7-hydroxy-4,5-dihydro-benzothiazol-6-yl)-(6-fluoro-pyridin-
-3-yl)-methanone
##STR00029##
[0106] The title compound is obtained from 2.10 g (11.2 mmol)
2-chloro-5,6-dihydro-4H-benzothiazol-7-one and 1.83 g (11.4 mmol)
6-fluoronicotinic acid chloride according to general procedure A1.
The crude product is taken up in DMSO, water and ACN are added. A
precipitate is formed, filtered off and washed with water. Yield:
1.20 g.
A-27)
(2-Amino-7-hydroxy-4,5-dihydro-benzothiazol-6-yl)-(6-methyl-pyridin--
3-yl)-methanone
##STR00030##
[0108] To a solution of 2.50 g A-23 in 20 mL dioxane are added 15
mL of 4 M solution of HCl in dioxane. The mixture is stirred for
2.5 h at 80.degree. C. The solvent is removed under reduced
pressure, the crude product is used without further
purification.
A-28)
[7-Hydroxy-6-(6-methylamino-pyridine-3-carbonyl)-4,5-dihydro-benzoth-
iazol-2-yl]-carbamic acid methyl ester
##STR00031##
[0110] The title compound is obtained from 2.70 g (7.73 mmol)
[7-hydroxy-6-(6-fluoro-pyridine-3-carbonyl)-4,5-dihydro-benzothiazol-2-yl-
]-carbamic acid methyl ester (which was made in analogy to A-01)
and 2.7 mL (32.0 mmol) of a solution of methylamine in water. The
reaction is performed in a 1:1 mixture of THF and iPrOH according
to the general procedure A4. For the work-up the solvent is removed
under reduced pressure, the precipitate is filtered and washed with
iPrOH. Yield: 2.31 g.
A-29)
(2-Cyclopropylamino-7-hydroxy-4,5-dihydro-benzothiazol-6-yl)-(6-meth-
ylamino-pyridin-3-yl)-methanone
##STR00032##
[0112] A solution of 200 mg (0.64 mmol) A-26 in THF is cooled to
0.degree. C. A solution of methylamine in THF (1.6 mL, 2 M) is
added and the mixture is stirred at 0.degree. C. for 2 h and at RT
for 2 h. Subsequently, 50 .mu.L (0.72 mmol) cyclopropylamine are
added and the mixture is stirred at RT for 18 h. The solvent is
removed under reduced pressure. The crude product is used for the
next step without further purification.
A-30)
(7-Hydroxy-2-methylamino-4,5-dihydro-benzothiazol-6-yl)-(6-methylami-
no-pyridin-3-yl)-methanone
##STR00033##
[0114] The title compound is obtained from 100 mg (0.32 mmol) A-26,
160 .mu.L of a 2 M solution of methylamine in THF and 800 .mu.L
(1.60 mmol) of a 2 M solution of ethylamine in THF as outline for
A-29. The product is purified by RP-HPLC. Yield: 33 mg.
A-31) Azetidine-1-carboxylic acid
[7-hydroxy-6-(6-methyl-pyridine-3-carbonyl)-4,5-dihydro-benzothiazol-2-yl-
]-amide
##STR00034##
[0116] To a suspension of 2.0 g (5.33 mmol)
(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-thiocarbamic acid
S-ethyl ester (which was made in analogy to A-32) in 20 mL iPrOH
are added DIPEA (2.74 mL, 16.0 mmol) and azetidin (540 .mu.L, 8.0
mmol). The mixture is heated in the microwave for 30 min at
90.degree. C. and for 30 min at 110.degree. C. After removal of the
solvent in vacuo the product is purified by RP-HPLC. Yield: 831
mg.
A-32)
[6-(6-Fluoro-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzothiazol-
-2-yl]-thiocarbamic acid S-ethyl ester
##STR00035##
[0118] The title compound is obtained from 12.0 g (46.8 mmol)
(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-thiocarbamic acid
S-ethyl ester and 8.22 g (51.1 mmol) 6-fluoro-nicotinic acid
chloride according to general procedure A1. The reaction is
quenched with 25 mL 2 M hydrochloric acid and 100 mL phosphate
buffer (pH 6). The crude product obtained after the extraction is
treated with TBME. Yield: 18.5 g.
A-33)
[7-Hydroxy-6-(6-methylamino-pyridine-3-carbonyl)-4,5-dihydro-benzoth-
iazol-2-yl]-thiocarbarnic acid S-ethyl ester
##STR00036##
[0120] The title compound is obtained from 1.50 g (3.95 mmol) A-32
and 1.50 mL (19.8 mmol) of a solution of methylamine in water
according to the general procedure A4. The reaction is performed in
THF/iPrOH. After removal of the solvent in vacuo the remaining
solid is treated with TBME. Yield 1.47 g.
A-34)
[7-Hydroxy-6-(6-ethylamino-pyridine-3-carbonyl)-4,5-dihydro-benzothi-
azol-2-yl]-thiocarbarnic acid S-ethyl ester
##STR00037##
[0122] The title compound is obtained from 18.5 g (48.8 mmol) A-32
and 20.0 mL (247 mmol) of a solution of ethylamine in water
according to the general procedure A4. The reaction is performed in
THF/iPrOH at RT. Yield: 19.8 g.
A-35)
[7-Hydroxy-6-(6-methyl-pyridine-3-carbonyl)-4,5-dihydro-benzothiazol-
-2-yl]-carbamic acid ethyl ester
##STR00038##
[0124] To a mixture of LiHMDS (1 M in THF, 48 mL) in 75 mL dry THF
3.90 g (16.2 mmol)
(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid ethyl
ester are added under argon atmosphere in small portions at
-15.degree. C. The mixture is stirred for 0.5 h and then the
previously prepared solution of
imidazol-1-yl-(6-methyl-pyridin-3-yl)-methanone is added dropwise.
After the complete addition a dark, sticky gum has formed. The THF
is decanted off and the gum is dissolved in a saturated solution of
NaHCO.sub.3 in water. The mixture is extracted with
CH.sub.2Cl.sub.2, the organic phases are washed with water and
brine, dried over MgSO.sub.4 and concentrated in vacuo. The residue
is triturated with ACN and dried in vacuo at 40.degree. C. Yield:
4.45 g.
A-36)
Ethyl-{5-[7-hydroxy-2-(3-methoxy-propionylamino)-4,5-dihydro-benzoth-
iazole-6-carbonyl]pyridin-2-yl}-carbamic acid tent-butyl ester
##STR00039##
[0125] A-36a) 6-(tert-Butoxycarbonyl-ethyl-amino)-nicotinic
acid
##STR00040##
[0127] 6-Chloro-nicotinic acid methyl ester (60 g, 0.35 mol) is
taken up in 500 mL 2 M ethyl-amine in THF and stirred at
100.degree. C. in a sealed tube for 16 h. The reaction mixture is
cooled to RT and the solvents are removed under reduced pressure.
The residue is poured on ice and stirred for 15 min. The
precipitate is filtered off, washed with water and dried in vacuo.
The dried 6-ethylamino-nicotinic acid methyl ester (30 g, 0.17 mol)
is dissolved in 150 mL DCM and triethylamine (29 mL, 0.20 mol),
DMAP (4.0 g, 33 mmol) and BOC anhydride (100 mL, 0.42 mol) are
added successively at 0.degree. C. The reaction mixture is allowed
to warm up to RT and stirred for 16 h. To the reaction mixture 100
mL of 10% citric acid in water is added and the reaction mixture is
stirred for 10 min. The organic phase is separated, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Yield: 60
g.
[0128] The crude 6-(tert-butoxycarbonyl-ethyl-amino)-nicotinic acid
methyl ester is taken up in 100 mL dioxane and a solution of
lithium hydroxide monohydrate (13.5 g, 0.32 mol) in 100 mL water is
added and the reaction mixture is stirred at RT for 4 h. The
dioxane is removed from the reaction mixture under reduced
pressure, water is added and the reaction mixture is acidified to
pH 6 with a solution of 10% citric acid in water. The formed
precipitate is filtered off and dried in vacuo. Yield: 36 g.
.sup.1H NMR (DMSO-d6): .delta. 13.2 (s, 1H), 8.8 (s, 1H), 8.2 (d,
1H), 7.8 (d, 1H), 4.0 (quart, 2H), 1.5 (s, 9H), 1.2 (t, 3H).
A-36b) (5-Chlorocarbonyl-pyridin-2-yl)-ethyl-carbamic acid
tent-butyl ester
##STR00041##
[0130] A-36a (6.40 g, 24.0 mmol) is taken up in 150 mL DCE,
1-chloro-N,N-2-trimethylpropenyl-amine (6.42 mL, 48.1 mmol) is
added and the reaction mixture is stirred overnight at RT.
[0131] The reaction mixture is concentrated under reduced pressure
and the crude product is used in the next step without
purification.
A-36c)
3-Methoxy-N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-propionami-
de
##STR00042##
[0133] To a mixture of 2-amino-5,6-dihydro-4H-benzothiazol-7--ONe
(3.0 g, 18 mmol) and DBU (5.3 mL, 36 mmol) in 100 mL acetonitrile
is added a solution of 1-imidazol-1-yl-3-methoxy-propan-1-one (6.9
g, 45 mmol) in acetonitrile. The reaction mixture is stirred for 15
min at RT and then concentrated under reduced pressure. The residue
is poured in water, acidified to pH 5 with 6 M aqueous HCl and the
product is extracted with ethyl acetate. The combined organic
phases are dried over MgSO.sub.4 and concentrated under reduced
pressure. Yield: 3.8 g. The product is used in the next step
without purification. A-36 is synthesized according to general
procedure A1 starting from 3.8 g (15 mmol) A-36c and 6.8 g (24
mmol) A-36b. Yield: 1.23 g.
A-37)
4-Dimethylamino-N-[6-(6-ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,-
5-dihydro-benzothiazol-2-yl]-butyramide
##STR00043##
[0134] A-37a)
(2-Amino-7-hydroxy-4,5-dihydro-benzothiazol-6-yl)-(6-ethylamino-pyridin-3-
-yl)-methanone
##STR00044##
[0136] To a mixture of 4.0 g (11 mmol) A-10 in 12 mL dioxane is
added 8.8 mL conc. HCl and the reaction mixture is stirred for 2 h
at 95.degree. C. The reaction mixture is concentrated under reduced
pressure and the residue is triturated with methanol and dried in
vacuo at 40.degree. C. Yield: 3.7 g.
[0137] To a mixture of 3.7 g (11 mmol) A-37a in 45 mL acetonitrile
is added 3.5 mL (23 mmol) DBU and the reaction mixture is stirred
for 10 min. at RT. Then a solution of 5.3 g (29 mmol)
4-dimethylamino-1-imidazol-1-yl-butan-1-one in acetonitrile is
added and the reaction mixture is stirred for 2 h at 100.degree. C.
and overnight at 60.degree. C. The reaction mixture is concentrated
under reduced pressure and the product is purified by HPLC (C-18,
2-70% acetonitrile in water). Yield: 2.9 g.
A-38)
N-tert-Butoxycarbonyl-[5-(2-acetylamino-7-hydroxy-4,5-dihydro-benzot-
hiazole-6-carbonyl)-pyridin-2-yl]-carbamic acid tent-butyl
ester
##STR00045##
[0138] A-38a) 6-[N,N-Di-(tert-butoxycarbonyl)-amino]-nicotinic
acid
##STR00046##
[0140] 6-Amino-nicotinic acid methyl ester (13.7 g, 90.0 mmol),
triethyl amine (12.5 mL, 90.0 mmol) and DMAP (3.30 g, 27.0 mmol)
are taken up in 200 mL DCM and a solution of di-tert-butyl
dicarbonate (41.3 g, 189 mmol) in 40 mL DCM is added drop wise. The
reaction mixture is stirred overnight at RT. An aqueous 5%
KHSO.sub.4 solution is added and the reaction mixture is extracted
with DCM. The combined organic phases are washed with an aqueous
50% saturated KHCO.sub.3 solution, dried over MgSO.sub.4 and
concentrated under reduced pressure. Yield: 34.9 g.
[0141] Of this residue 17.3 g is taken up in a mixture of 150 mL
MeOH and 300 mL water, lithium hydroxide (2.33 g, 97.3 mmol) is
added and the reaction mixture is stirred for 3 h at RT. The
reaction mixture is acidified to pH 4 with acetic acid and the
formed precipitate is filtered off, washed with water and dried in
vacuo. Yield: 11.8 g. .sup.1H NMR (DMSO-d6): .delta. 9.0 (s, 1H),
8.2 (d, 1H), 7.2 (d, 2H), 1.4 (s, 18H).
A-38b)
N-tert-Butoxycarbonyl-(5-chlorocarbonyl-pyridin-2-yl)-carbamic acid
tert-butyl ester
##STR00047##
[0143] A-38a (5.00 g, 14.8 mmol) is dried by azeotropic
distillation with toluene and then taken up in 20 mL dry THF and
cooled to 0.degree. C. 1-Chloro-N,N-2-trimethylpropenyl-amine (3.95
g, 30.0 mmol) is added drop wise and the reaction mixture is
stirred at RT for 3 h. The reaction mixture is concentrated under
reduced pressure and the crude product is used in the next step
without purification.
[0144] A-38 is synthesized according to general procedure A1
starting from 8.0 g (38 mmol)
N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 21.7 g
(61 mmol) A-38b. Yield: 10.9 g.
A-39)
N-[6-(6-Ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzot-
hiazol-2-yl]-3-(1-methyl-1H-imidazol-2-yl)-propionamide
##STR00048##
[0146] Example A-39 is prepared analogously to example A-37
starting from 0.30 g (0.95 mmol) A-37a, 0.21 mL (1.4 mmol) DBU and
0.48 g (2.4 mmol)
1-imidazol-1-yl-3-(1-methyl-1H-imidazol-2-yl)-propan-1-one. Yield:
66 mg.
A-40)
{[6-(6-Ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzoth-
iazol-2-ylcarbamoyl]-methyl}-methyl-carbamic acid tert-butyl
ester
##STR00049##
[0148] Example A-40 is prepared analogously to example A-37
starting from 0.30 g (0.95 mmol) A-37a, 0.21 mL (1.4 mmol) DBU and
0.57 g (2.4 mmol) (2-imidazol-1-yl-2-oxo-ethyl)-methyl-carbamic
acid tert-butyl ester. Yield: 0.16 g.
A-41)
{[6-(6-Ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzoth-
iazol-2-ylcarbamoyl]-methyl}-carbamic acid tert-butyl ester
##STR00050##
[0150] Example A-41 is prepared analogously to example A-37
starting from 0.30 g (0.95 mmol) A-37a, 0.21 mL (1.4 mmol) DBU and
0.53 g (2.4 mmol) (2-imidazol-1-yl-2-oxo-ethyl)-carbamic acid
tert-butyl ester. Yield: 0.19 g.
A-42)
2-Dimethylamino-N-[6-(6-ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,-
5-dihydro-benzothiazol-2-yl-]-acetamide
##STR00051##
[0152] Example A-42 is prepared analogously to example A-37
starting from 0.30 g (0.95 mmol) A-37a, 0.21 mL (1.4 mmol) DBU and
0.36 g (2.4 mmol) 2-dimethylamino-1-imidazol-1-yl-ethanone. Yield:
0.20 g.
A-43)
[7-Hydroxy-6-(6-methyl-pyridine-3-carbonyl)-4,5-dihydro-benzothiazol-
-2-yl]-carbamic acid 3-methoxy-propyl ester
##STR00052##
[0154] A mixture of 0.30 g (1.0 mmol) A-27, 0.42 g (2.6 mmol) CDI
and 0.31 mL (2.1 mmol) DBU is stirred at 100.degree. C. for 8 h.
Then 0.50 mL (5.2 mmol) 3-methoxy-1-propanol is added and the
reaction mixture is stirred at 100.degree. C. overnight. The
reaction mixture is concentrated under reduced pressure and the
product is purified by HPLC (C-18, 5-80% acetonitrile in water).
Yield: 87 mg.
A-44)
[7-Hydroxy-6-(6-methyl-pyridine-3-carbonyl)-4,5-dihydro-benzothiazol-
-2-yl]-carbamic acid tetrahydro-furan-2-ylmethyl ester
##STR00053##
[0156] Example A-44 is prepared analogously to example A-43
starting from 0.30 g (1.0 mmol) A-27, 0.42 g (2.6 mmol) CDI, 0.31
mL (2.1 mmol) DBU and 0.50 mL (5.2 mmol) tetrahydrofurfuryl
alcohol. Yield: 0.14 g.
A-45)
[7-Hydroxy-6-(6-methyl-pyridine-3-carbonyl)-4,5-dihydro-benzothiazol-
-2-yl]-carbamic acid tetrahydro-furan-3-ylmethyl ester
##STR00054##
[0158] Example A-45 is prepared analogously to example A-43
starting from 0.30 g (1.0 mmol) A-27, 0.42 g (2.6 mmol) CDI, 0.31
mL (2.1 mmol) DBU and 0.50 mL (5.2 mmol)
(tetrahydro-furan-3-yl)-methanol. Yield: 83 mg.
A-46)
N-tert-Butoxycarbonyl-{5-[2-(3,3-dimethyl-ureido)-7-hydroxy-4,5-dihy-
dro-benzothiazole-6-carbonyl]-pyridin-2-yl}-carbamic acid
tert-butyl ester
##STR00055##
[0159] A-46a)
1,1-Dimethyl-3-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-urea
##STR00056##
[0161] A mixture of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (10
g, 59 mmol), DBU (18 mL, 0.12 mol) and CDI (24 g, 0.15 mol) in 400
mL acetonitrile is stirred for 5 h at 100.degree. C. Then
dimethylamine (150 mL, 2M in THF) is added and the reaction mixture
is stirred overnight at 100.degree. C. The reaction mixture is
concentrated under reduced pressure and the residue is poured in
water. The mixture is acidified to pH 5 with 6 M HCl in water and
extracted with ethyl acetate. The combined organic phases are dried
over MgSO.sub.4 and concentrated under reduced pressure. The
residue is triturated with diethyl ether. Yield: 9.1 g.
[0162] Example A-46 is synthesized according to general procedure
A1 starting from 0.20 g (2.5 g, 10 mmol) A-46a and 6.0 g (17 mmol)
A-38b. Yield: 2.5 g.
A-47)
N-[6-(6-Amino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzothiazo-
l-2-yl]-4-dimethylamino-butyramide
##STR00057##
[0163] A-47a)
(2-Amino-7-hydroxy-4,5-dihydro-benzothiazol-6-yl)-(6-amino-pyridin-3-yl)--
methanone
##STR00058##
[0165] A-47a is prepared analogously to example A-37a starting from
4.0 g (7.6 mmol) A-38. Yield: 2.7 g.
[0166] Example A-47 is prepared analogously to example A-37
starting from 2.0 g (6.9 mmol) A-47a, 2.1 mL (14 mmol) DBU and 3.1
g (17 mmol) 4-dimethylamino-1-imidazol-1-yl-butan-1-one. Yield: 1.9
g.
A-48)
1-[6-(6-Ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzot-
hiazol-2-yl]-3-methyl-urea
##STR00059##
[0168] A solution of 5.00 g (12.4 mmol) A-34 in 30 mL of a 2 M
solution of methylamine in methanol is heated at 100.degree. C. for
20 min. The solvent is removed under reduced pressure and the crude
reaction product is used without further purification in the next
step.
A-49)
1-[6-(6-Ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzot-
hiazol-2-yl]-urea
##STR00060##
[0170] A solution of 0.90 g (2.2 mmol) A-34 in 5.5 mL of a 2 M
solution of ammonia in methanol is heated at 100.degree. C. for 30
min. The solvent is removed under reduced pressure and the crude
reaction product is used without further purification in the next
step.
A-50)
1-[6-(6-Ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzot-
hiazol-2-yl]-3-ethyl-urea
##STR00061##
[0172] A solution of 450 mg (1.1 mmol) A-34 in 2.8 mL of a 2 M
solution of ethylamine in THF is heated at 120.degree. C. for 20
min. The solvent is removed under reduced pressure and the crude
reaction product is used without further purification in the next
step.
A-51)
1-(2-Dimethylamino-ethyl)-3-[6-(6-ethylamino-pyridine-3-carbonyl)-7--
hydroxy-4,5-dihydro-benzothiazol-2-yl]-urea
##STR00062##
[0174] A solution of 400 mg (0.99 mmol) A-34 and 545 .mu.L (4.94
mmol) N,N-dimethyl-ethylene-diamine in 2 mL THF is heated at
120.degree. C. for 20 min. The solvent is removed under reduced
pressure and the crude reaction product is used without further
purification in the next step.
A-52)
1-[6-(6-Ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzot-
hiazol-2-yl]-3-(2-methoxy-ethyl)-urea
##STR00063##
[0176] A solution of 300 mg (0.74 mmol) A-34 and 322 .mu.l (3.71
mmol) 2-methoxy-ethylamine in 3 mL THF is heated at 120.degree. C.
for 20 min. The solvent is removed under reduced pressure and the
crude reaction product is used without further purification in the
next step.
A-53)
1-(3-Dimethylamino-propyl)-3-[6-(6-ethylamino-pyridine-3-carbonyl)-7-
-hydroxy-4,5-dihydro-benzothiazol-2-yl]-urea
##STR00064##
[0178] A solution of 300 mg (0.74 mmol) A-34 and 467 .mu.L (3.71
mmol) N,N-dimethyl-1,3-propenediamine in 3 mL THF is heated at
120.degree. C. for 20 min. The solvent is removed under reduced
pressure and the crude reaction product is used without further
purification in the next step.
A-54)
1-[6-(6-Ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzot-
hiazol-2-yl]-3-(3-methoxy-propyl)-urea
##STR00065##
[0180] A solution of 300 mg (0.74 mmol) A-34 and 378 .mu.L (3.71
mmol) 3-methoxy-propylamine in 3 mL THF is heated at 120.degree. C.
for 20 min. The solvent is removed under reduced pressure and the
crude reaction product is used without further purification in the
next step.
A-55)
1-(3-Dimethylamino-propyl)-3-[7-hydroxy-6-(6-methyl-pyridine-3-carbo-
nyl)-4,5-dihydro-benzothiazol-2-yl]-urea
##STR00066##
[0182] To a suspension of 2.0 g (6.96 mmol) A-27 and 2.26 g (13.9
mmol) CDI in 7 mL acetonitrile is added 1.0 mL (6.52 mmol) DBU. The
reaction mixture is heated for 10 min at 90.degree. C. in the
microwave. 1.56 g (15.3 mmol) N,N-dimethyl-1,3-propanediamine is
added and the reaction mixture is heated for 10 min at 120.degree.
C. in the microwave. DCM and water are added and the mixture is
adjusted to pH 1 with concentrated HCl solution. After phase
separation the aqueous phase is washed five times with DCM. The
aqueous phase is evaporated and the residue is taken up in DMSO.
Purification is performed via preparative RP-HPLC. After removal of
the solvent 350 mg (0.84 mmol) of the desired compound are
obtained.
[0183] Intermediates B (Hydrazines)
B-01) 3-Chloro-4-hydrazino-N,N-dimethyl-benzamide hydrochloride
##STR00067##
[0184] B-01a) 3-Chloro-4-fluoro-N,N-dimethyl-benzamide
##STR00068##
[0186] To a mixture of 3-chloro-4-fluorobenzoic acid (20.0 g, 115
mmol) in 100 mL THF is added carbonyldiimidazole (20.0 g, 126 mmol)
and the reaction mixture is stirred at RT for 0.5 h. Then
dimethylamine (1 M in THF, 171 mL) is added and the reaction
mixture is stirred for another h. The reaction mixture is
concentrated in vacuo, re-dissolved in DCM, washed with saturated
aqueous sodium carbonate and brine and concentrated in vacuo.
Yield: 20.0 g.
[0187] Hydrazine hydrate (150 mL, 4.96 mol) is added to a mixture
of B-01a (20.0 g, 99.3 mmol) in 100 mL dioxane and the reaction
mixture is stirred at reflux temperature for 16 h. The reaction
mixture is concentrated in vacuo, DCM is added and the reaction
mixture washed with water and brine, dried over sodium sulfate and
concentrated in vacuo. The residue is dissolved in dioxane, cooled
to 0.degree. C. and hydrochloric acid (4 M in dioxane, 25 mL) is
added. The reaction mixture is stirred for 1 h and then
concentrated in vacuo. The residue is triturated with diethyl
ether. Yield: 21 g.
B-02) 4-Hydrazino-N,N-dimethyl-benzamide
##STR00069##
[0188] B-02a) 4-Nitro-N,N-dimethyl-benzamide
##STR00070##
[0190] To a mixture of 4-nitrobenzoyl chloride (7.20 g, 38.8 mmol)
and dimethylamine hydrochloride (3.20 g, 39.2 mmol) in 100 mL DCM
is added triethyl amine (14.0 mL, 99.6 mmol) at 0.degree. C. The
cooling bath is removed and the reaction mixture is stirred
overnight at RT. Then 300 mL DCM is added and the reaction mixture
is washed with 50% saturated aqueous ammonium chloride, water, 50%
saturated aqueous sodium hydrogen carbonate and 0.1 M aqueous NaOH.
The organic phase is dried over MgSO.sub.4 and concentrated in
vacuo. Yield: 5.37 g.
B-02b) 4-Amino-N,N-dimethyl-benzamide
##STR00071##
[0192] B-02a (2.0 g, 10.3 mmol) is dissolved in 120 mL MeOH and 10%
palladium on coal (200 mg) is added. The reaction mixture is
stirred for 2 h under an atmosphere of 4 bar hydrogen. The reaction
mixture is filtered and concentrated in vacuo. Yield: 1.69 g. To a
mixture of B-02b (1.68 g, 10.2 mmol) in 30 mL concentrated
hydrochloric acid at -10.degree. C. is added a solution of sodium
nitrite (755 mg, 10.9 mmol) in 7 mL water. The reaction mixture is
stirred for 1 h at 0.degree. C. and then at -5.degree. C. a
solution of tin(II) chloride dehydrate (4.81 g, 21.4 mmol) in 10 mL
concentrated HCl is added. The cooling bath is removed and the
reaction mixture is stirred for 1 h at RT. The reaction mixture is
basified with 8 M aqueous sodium hydroxide and extracted with ethyl
acetate. The combined organic phases are dried over MgSO.sub.4 and
concentrated in vacuo. The residue is taken up in diethyl ether and
2 M HCl in diethyl ether is added until no more precipitate is
formed. The precipitate is filtered of and dried in vacuo at
40.degree. C. Yield: 213 mg.
B-03) [3-Fluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]hydrazine
hydrochloride
##STR00072##
[0193] B-03a) 4-[2-(4-Bromo-2-fluoro-phenoxy)-ethyl]-morpholine
##STR00073##
[0195] 4-Bromo-2-fluorophenol (16.7 g, 87.4 mmol) is dissolved in
100 mL DMF. N-(2-Chloro-ethyl)morpholine hydrochloride (18.5 g,
99.4 mmol), potassium carbonate (28.0 g, 203 mmol) and potassium
iodide (100 mg, 0.602 mmol) are added and the reaction mixture is
stirred for 3 h at 65.degree. C. The reaction mixture is poured in
water and extracted with ethyl acetate. The combined organic phases
are washed with water and brine, dried over magnesium sulfate and
concentrated in vacuo. Yield: 27.7 g.
B-03b)
N-Benzhydrylidene-N'-[3-fluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]--
hydrazine
##STR00074##
[0197] B-03a (27.7 g, 91.1 mmol) is dissolved in 300 mL toluene,
degassed and added under argon atmosphere dropwise to a mixture of
benzophenone hydrazone (18.8 g, 95.8 mmol), sodium tert-butoxide
(13.1 g, 136 mmol), BINAP (2.0 g, 3.21 mmol) and palladium(II)
acetate (400 mg, 1.78 mmol). The reaction mixture is warmed to
100.degree. C. and stirred for 2 h. Active charcoal is added and
reaction mixture is filtered over Celite. The filtrate is
concentrated in vacuo and the residue is purified by flash
chromatography (silica gel, 0-10% MeOH in DCM) followed by
trituration with MeOH. Yield: 27.6 g.
[0198] B-03b (27.6 g, 65.7 mmol) is dissolved in 50 mL n-propanol
and 50 mL concentrated hydrochloric acid is added. The reaction
mixture is stirred at 120.degree. C. for 3 h and then concentrated
in vacuo. The residue is taken up in fresh n-propanol, concentrated
in vacuo again, triturated with DCM and dried in vacuo. Yield: 17.3
g.
B-04) [1-(4-Hydrazino-phenyl)-cyclopropyl]-dimethyl-amine
##STR00075##
[0200] The compound is prepared according to WO 2007/113246.
B-05) 2-Fluoro-4-hydrazino-N,N-dimethyl-benzamide
##STR00076##
[0201] B-05a) 2-Fluoro-4-nitro-benzoyl chloride
##STR00077##
[0203] To a solution of 2-fluoro-4-nitrobenzoic acid (5.0 g, 27.0
mmol) in 70 mL DCM is added thionyl chloride (12.1 mL, 162 mmol).
The reaction mixture is stirred at 50.degree. C. for 1.5 h and
overnight at RT. The reaction mixture is concentrated in vacuo, the
residue is taken up in fresh DCM and concentrated in vacuo again.
Yield: 5.12 g.
B-05b) 2-Fluoro-N,N-dimethyl-4-nitro-benzamide
##STR00078##
[0205] B-05a (5.12 g, 25.2 mmol) is dissolved in 60 mL THF and
cooled to 0.degree. C. DIPEA (5.17 ml, 30.2 mmol) is added followed
by a 2 M solution of methyl amine in THF (12.6 mL, 25.2 mmol) and
the reaction mixture is stirred overnight at RT. Then 20 mL of a
saturated aqueous sodium bicarbonate solution is added and the
reaction mixture is extracted with ethyl acetate. The combined
organic phases are washed with saturated aqueous sodium hydrogen
carbonate solution, dried over magnesium sulfate and concentrated
in vacuo. Yield: 1.94 g.
B-05c) 4-Amino-2-fluoro-N,N-dimethyl-benzamide
##STR00079##
[0207] A mixture of B-05b (1.94 g, 9.13 mmol) and 10% Pd on coal
(194 mg) in 50 mL MeOH is stirred overnight at RT under an
atmosphere of 5 bar hydrogen. The reaction mixture is filtered and
concentrated in vacuo. Yield: 1.40 g.
[0208] B-05c (1.40 g, 7.68 mmol) is dissolved in 20 mL concentrated
HCl and cooled to -10.degree. C. Slowly a solution of sodium
nitrite (1.36 g, 11.5 mmol) in 10 mL water is added and the
reaction mixture is stirred for 4 h. A solution of tin(II)chloride
dihydrate (6.94 g, 30.7 mmol) in 10 mL concentrated HCl is added
and the reaction mixture is stirred overnight at RT. The reaction
mixture is cooled to 0.degree. C., basified with 10 M aqueous NaOH
and extracted with chloroform. The combined organic phases are
washed with water, dried over MgSO.sub.4 and concentrated in vacuo.
Yield: 1.0 g.
B-06) (2-Methyl-2,3-dihydro-1H-isoindol-5-yl)-hydrazine
hydrochloride
##STR00080##
[0209] B-06a) 5-Bromo-2-methyl-isoindole-1,3-dione
##STR00081##
[0211] A mixture of 3-bromophthalimide (10.0 g, 44.2 mmol),
potassium carbonate (12.2 g, 88.5 mmol) and potassium iodide (50
mg, 0.30 mmol) are stirred in 80 mL DMF for 15 min. The reaction
mixture is cooled to 0.degree. C., methyl iodide (3.04 mL, 48.7
mmol) is added and the reaction mixture is stirred overnight at RT.
The reaction mixture is filtered, the solids are washed with DMF
and the filtrate is poured in water. The mixture is extracted with
ethyl acetate and the combined organic phases are washed several
times with water, dried over MgSO.sub.4 and concentrated in vacuo.
Yield: 7.10 g.
B-06b) 5-Bromo-2-methyl-2,3-dihydro-1H-isoindole
##STR00082##
[0213] B-06a (5.8 g, 24.2 mmol) is dissolved in 60 mL THF and
cooled to 0.degree. C. Borane dimethylsulfide complex (9.18 mL, 121
mmol) is added and the reaction mixture is warmed to RT. The
reaction mixture is stirred overnight at reflux temperature.
Additional borane dimethyl sulfide complex (9.18 mL, 121 mmol) is
added and the reaction mixture is stirred for another 20 h at
reflux temperature. The reaction mixture is cooled to RT, 40 mL
MeOH and 12 mL conc. HCl are added and the reaction mixture is
stirred overnight at 80.degree. C. The reaction mixture is
concentrated in vacuo, the residue is taken up in ethyl acetate and
washed with saturated aqueous sodium hydrogen carbonate solution.
The water phase is extracted with ethyl acetate, the combined
organic phases are dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. Yield: 4.56 g.
B-06c)
N-Benzhydrylidene-N'-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-hydraz-
ine
##STR00083##
[0215] B-06c is prepared analogously to B-03b starting from B-06b
(3.5 g, 16.5 mmol), benzophenone hydrazone (3.24 g, 16.5 mmol),
sodium tert-butoxide (2.38 g, 24.8 mmol),
(2-biphenyl)-di-tert-butylphosphine (246 mg, 0.825 mmol) and
palladium(II) acetate (111 mg, 0.495 mmol). Yield: 1.25 g.
[0216] B-06 is prepared analogously to B-03 starting from B-06c
(1.55 g, 4.73 mmol). Yield: 620 mg.
B-07) (4-Hydrazino-benzyl)-dimethyl-amine hydrochloride
##STR00084##
[0217] B-07a) (4-Bromo-benzyl)-dimethyl-amine
##STR00085##
[0219] At 5.degree. C. 4-bromobenzylbromide (100 g, 402 mmol) in
100 mL DMF is added to a mixture of dimethylamine (40% in water,
150 mL, 1.33 mol). After 0.5 h stirring at RT, 6 M aqueous HCl is
added and the reaction mixture is extracted with diethyl ether. The
combined organic phases are washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue is purified
by vacuum distillation (bp 58.degree. C. at 2 mbar). Yield: 77.6 g.
B-07b) [4-(N'-Benzhydrylidene-hydrazino)-benzyl]-dimethyl-amine
##STR00086##
[0220] B-07b is prepared analogously to B-03b starting from B-07a
(77.6 g, 362 mmol), benzophenone hydrazone (71.0 g, 362 mmol),
sodium tert-pentoxide (59.8 g, 543 mmol), BINAP (5.12 mg, 8.20
mmol) and palladium(II)acetate (1.38 g, 6.16 mmol). Yield: 122 g.
The product is purified by treatment with active coal in
n-propanol.
[0221] B-07 is prepared analogously to B-03 starting from B-07b
(122 g, 362 mmol). Yield: 57.6 g.
B-08) 2-(4-Hydrazino-phenyl)-ethanol
##STR00087##
[0223] B-08 is prepared analogously to B-05 starting from
4-aminophenethyl alcohol (7.3 g, 53.2 mmol), sodium nitrite (3.7 g,
53.6 mmol) and tin(II) chloride dihydrate (50.0 g, 222 mmol).
Yield: 3.70 g.
B-09) (4-Fluoro-3-morpholin-4-ylmethyl-phenyl)-hydrazine
hydrochloride
##STR00088##
[0224] B-09a) 4-(5-Bromo-2-fluoro-benzyl)-morpholine
##STR00089##
[0226] 5-Bromo-2-fluorobenzaldehyde (2.5 g, 12.3 mmol) and
morpholine (1.62 g, 18.5 mmol) are dissolved in 50 mL DCE and
stirred for 0.5 h. Acetic acid (0.42 mL, 7.4 mmol) and sodium
trisacetoxyboronhydride (3.92 g, 18.5 mmol) are added and the
reaction mixture is stirred for 2 h. Then 50 mL of a saturated
aqueous solution of sodium hydrogencarbonate is added and the
reaction mixture is stirred for another 0.5 h. The reaction mixture
is extracted with DCM and the combined organic phases are dried
over MgSO.sub.4 and concentrated in vacuo. Yield: 3.02 g.
B-09b)
N-Benzhydrylidene-N'-(4-fluoro-3-morpholin-4-ylmethyl-phenyl)-hydra-
zine
##STR00090##
[0228] B-09b is prepared analogously to B-03b starting from B-09a
(3.0 g, 10.9 mmol), benzophenone hydrazone (2.15 g, 10.9 mmol),
sodium tert-butoxide (1.58 g, 16.4 mmol),
(2-biphenyl)-di-tert-butylphosphine (135 mg, 0.438 mmol) and
palladium(II)acetate (49 mg, 0.22 mmol). Yield: 2.40 g.
[0229] B-09 is prepared analogously to B-03 starting from B-09b
(2.40 g, 6.16 mmol). Yield: 1.64 g.
B-10) [4-(1-Methyl-pyrrolidin-2-yl)-phenyl]hydrazine
hydrochloride
##STR00091##
[0230] B-10a) 5-(4-Bromo-phenyl)-3,4-dihydro-2H-pyrrole
##STR00092##
[0232] A mixture of 4`-bromo-4-chlororbutyrophenone (20.0 g, 76.5
mmol), sodium azide (7.46 g, 115 mmol) and sodium iodide (344 mg,
2.29 mmol) is stirred overnight at 55.degree. C. The reaction
mixture is poured on water and extracted with DCM. The organic
phases are dried over MgSO.sub.4 and concentrated in vacuo. The
residue is dissolved in 150 mL cyclohexane, triphenylphosphine
(20.1 g, 76.5 mmol) is added and the reaction mixture is stirred
overnight at RT. The reaction mixture is filtered and the solids
are washed with cold diethyl ether. The filtrate is concentrated in
vacuo, water is added and the mixture is extracted with DCM. The
combined organic phases are washed with water and brine, dried over
MgSO.sub.4 and concentrated in vacuo. The residue is treated with a
mixture diethyl ether/cyclohexane (1/1, v/v), filtered and the
filtrate is concentrated in vacuo. Yield: 15.6 g.
B-10b) 2-(4-Bromo-phenyl)-pyrrolidine
##STR00093##
[0234] To a mixture of B-10a (5.50 g, 24.5 mmol) in 20% acetic acid
in MeOH at 0.degree. C. is added sodium boronhydride (1.93 g, 36.8
mmol). The reaction mixture is stirred at 0.degree. C. for 1 h and
then 4 h at RT. Then 20 mL 1M HCl is added and the reaction mixture
is extracted with diethyl ether. The aqueous phase is basified with
10 M aqueous NaOH and extracted with DCM. The combined organic
extracts are washed with brine, dried over MgSO.sub.4 and
concentrated in vacuo. Yield: 3.92 g.
B-10c) 2-(4-Bromo-phenyl)-1-methyl-pyrrolidine
##STR00094##
[0236] To a mixture of B-10b (2.5 g, 11.1 mmol) and potassium
carbonate (3.06 g, 22.1 mmol) in ACN is added methyl iodide (0.76
mL, 12 mmol) at 0.degree. C. The reaction mixture is stirred 0.5 h
at RT and then filtered. The solids are washed with ACN and the
filtrate is concentrated in vacuo. The residue is dissolved in
ethyl acetate, washed with 0.01 M aqueous NaOH and brine, dried
over MgSO.sub.4 and concentrated in vacuo. The residue is purified
by flash chromatography (silica gel, 0-10% MeOH in DCM containing
0.5% ammonia). Yield: 1.35 g.
B-10d)
N-Benzhydrylidene-N-[4-(1-methyl-pyrrolidin-2-yl)-phenyl]-hydrazine
##STR00095##
[0238] B-10d is prepared analogously to B-03b starting from B-10c
(1.35 g, 5.62 mmol) benzophenone hydrazone (1.10 g, 5.62 g), sodium
tert-butoxide (0.81 g, 8.4 mmol), (2-biphenyl)di-tert-butyl
phosphine (84 mg, 0.28 mmol) and paldium(II) acetate (38 mg, 0.17
mmol). Yield: 1.20 g.
[0239] B-10 is prepared analogously to B-03 starting from B-10d
(1.20 g, 3.38 mmol). Yield: 0.42 g.
[0240] B-11) (4-Hydrazino-phenyl)-methanol is commercially
available.
##STR00096##
B-12) (3-Methanesulfonyl-phenyl)-hydrazine
##STR00097##
[0242] B-012 is prepared analogously to B-05 starting from
3-methylsulfonylaniline hydrochloride (2.50 g, 11.4 mmol), sodium
nitrite (1.18 g, 17.1 mmol) and tin(II)chloride dihydrate (14.9 g,
66.0 mmol). The product is purified by precipitation from ethyl
acetate with cyclohexane. Yield: 1.08 g.
B-13) N-(3-Chloro-4-hydrazino-phenyl)-N-methyl-acetamide
##STR00098##
[0243] B-13a) N-(4-Bromo-3-chloro-phenyl)-N-methyl-acetamide
##STR00099##
[0245] To a solution of 4-bromo-3-chloroacetanilide (10.0 g, 40.2
mmol) in 50 mL THF is added 60% sodium hydride in mineral oil (2.40
g, 60.0 mmol) and the reaction mixture is stirred for 1 h at RT.
The reaction mixture is cooled to 0.degree. C., methyliodide (2.49
mL, 40.0 mmol) is added. After 2 h additional methyl iodide (0.25
mL, 4.0 mmol) is added and the reaction mixture is stirred at RT
for 10 min. The reaction mixture is quenched with saturated aqueous
ammonium chloride, filtered and extracted with diethyl ether. The
organic phases are washed with brine, dried over Na.sub.2SO.sub.4
and evaporated to dryness. Yield: 10.3 g.
[0246] B-13b)
N-[4-(Acetyl-methyl-amino)-2-chloro-phenyl]-hydrazinedicarboxylic
acid di-tert-butyl ester
##STR00100##
[0247] To lithium chloride (906 mg, 21.0 mmol) in 20 mL THF is
added a 2 M solution of isopropylmagnesium chloride in diethyl
ether (11.0 mL, 22.0 mmol) and the reaction mixture is stirred at
RT for 0.5 h. The reaction mixture is cooled to -78.degree. C. and
a solution of B-13a (5.0 g, 19.0 mmol) in 10 mL THF is added. The
reaction mixture is warmed to -15.degree. C. and after 2 h
di-tert-butylazodicarboxylate (4.39 g, 19.0 mmol) is added. After
20 min saturated aqueous ammonium chloride is added and the
reaction mixture is extracted with diethyl ether. The organic
phases are washed with water and brine, dried over Na.sub.2SO.sub.4
and concentrated in vacuo. The residue is purified by
chromatography (silica gel, 50 to 70% ethyl acetate in
cyclohexane). Yield: 3.91 g.
[0248] B-13b (1.96 g, 4.74 mmol) is dissolved in 20 mL DCM, cooled
to 0.degree. C. and 20 mL trifluoroacetic acid is added. The
reaction mixture is warmed to RT and stirred for 2 h. The reaction
mixture is concentrated in vacuo, neutralized with 5 M aqueous NaOH
and extracted with DCM. The organic phases are washed with water
and brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
Yield: 960 mg.
B-14) (4-Hydrazino-phenyl)-ethanone O-methyl-oxime
hydrochloride
##STR00101##
[0249] B-14a) N-(4-Acetyl-phenyl)-hydrazinedicarboxylic acid
di-tert-butyl ester
##STR00102##
[0251] A mixture of 4-methoxycarbonylphenylboronic acid (2.0 g,
12.2 mmol), di-tert-butylazo-dicarboxylate (2.88 g, 12.5 mmol) and
copper(II) acetate (220 mg, 1.21 mmol) in 35 mL MeOH is stirred for
4 h at 45.degree. C. The reaction mixture is concentrated in vacuo,
DCM is added and the mixture is washed with water. The organic
phase is washed with brine, dried over MgSO.sub.4 and concentrated
in vacuo. The residue is triturated with hot n-hexane. Yield: 2.46
g.
B-14b)
N-(4-{1-[(E)-Methoxyimino]-ethyl}-phenyl)-hydrazinedicarboxylic
acid di-tert-butyl ester
##STR00103##
[0253] B-14a (2.10 g, 5.99 mmol) and O-methylhydroxylamine
hydrochloride (500 mg, 5.99 mmol) are stirred in MeOH for 4 h. The
reaction mixture is diluted with DCM and washed with water and
brine. The water phases are neutralized with saturated aqueous
sodium hydrogencarbonate and extracted with DCM. The combined
organic phases are dried over MgSO.sub.4 and concentrated in vacuo.
Yield: 1.92 g.
[0254] B-14b (1.92 g, 5.09 mmol) is dissolved in 20 mL dioxane and
12.8 mL 4 M HCl in dioxane are added. The reaction mixture is
stirred for 2 h at 50.degree. C. and overnight at RT. The reaction
mixture is filtered and the solids are dried in vacuo. Yield: 1.10
g.
B-15) 4-Hydrazino-benzaldehyde O-(2-methoxy-ethyl)-oxime
hydrochloride
##STR00104##
[0255] B-15a) 2-(2-Methoxy-ethoxy)-isoindole-1,3-dione
##STR00105##
[0257] A mixture of N-hydroxyphthalimide (30.0 g, 184 mmol) and
potassium carbonate (25.4 g, 138 mmol) in 300 mL NMP is heated to
50.degree. C. Potassium iodide (0.15 g, 0.90 mmol) and 2-bromoethyl
methyl ether (19.0 ml, 202 mmol) are added and the reaction mixture
is stirred at 80.degree. C. for 2 h. The reaction mixture is poured
on 1 M aqueous HCl and extracted with ethyl acetate. The combined
organic phases are dried over MgSO.sub.4 and concentrated in vacuo.
The residue is triturated with water and subsequently crystallized
from EtOH. Yield: 17.1 g.
B-15b) O-(2-Methoxy-ethyl)-hydroxylamine hydrochloride
##STR00106##
[0259] B-15a (17.1 g, 77.3 mmol) is dissolved in ethyl acetate,
ethanolamine (5.13 mL, 85.0 mmol) is added and the reaction mixture
is stirred for 2 h at 80.degree. C. The reaction mixture is
concentrated in vacuo, triturated with diethyl ether and filtered.
To the filtrate 1 M HCl in diethyl ether (77.3 mL, 77.3 mmol) is
added and the formed precipitate is filtered off and dried in
vacuo. Yield: 4.76 g.
B-15c) N-(4-Formyl-phenyl)-hydrazinedicarboxylic acid di-tert-butyl
ester
##STR00107##
[0261] B-15c is prepared analogously to B-14a starting from
4-formylphenylboronic acid (3.52 g, 23.5 mmol),
di-tert-butylazodicarboxylate (5.95 g, 25.8 mmol) and copper(II)
acetate (230 mg, 1.27 mmol). The product is purified by flash
chromatography (silica gel, 0-60% ethyl acetate in
cyclohexane).Yield: 7.50 g.
[0262] B-15d)
N-{4-[(2-Methoxy-ethoxyimino)-methyl]-phenyl}-hydrazinedicarboxylic
acid di-tert-butyl ester
##STR00108##
[0263] B-15d is prepared analogously to B-14b starting from B-15c
(3.96 g, 11.8 mmol) and B-15b (1.50 g, 11.8 mmol). The product is
purified by preparative RP-HPLC (5-98% ACN in water). Yield: 4.25
g.
[0264] B-15 is prepared analogously to B-14 starting from B-15d
(4.25 g, 10.4 mmol) and 4 M HCl in dioxane (25.9 mL, 104 mmol).
Yield: 2.90 g.
B-16) 4-Hydrazino-benzaldehyde O-(2-morpholin-4-yl-ethyl)-oxime
hydrochloride
##STR00109##
[0265] B-16a) 2-(2-Morpholin-4-yl-ethoxy)-isoindole-1,3-dione
hydrochloride
##STR00110##
[0267] B-16a is prepared analogously to B-15a starting from
N-hydroxyphthalimide (5.0 g, 30.7 mmol), potassium carbonate (4.24
g, 30.7 mmol) and N-(2-chloroethyl)morpholine hydrochloride (6.27
g, 33.7 mmol). The product is isolated as the hydrochloride.
[0268] Yield: 4.22 g.
B-16b) O-(2-Morpholin-4-yl-ethyl)-hydroxylamine hydrochloride
##STR00111##
[0270] B-16b is prepared analogously to B-15b starting from B-16a
(4.22 g, 15.3 mmol) and ethanolamine (1.01 mL, 16.8 mmol). Yield:
1.31 g.
B-16c)
N-{4-[(2-Morpholin-4-yl-ethoxyimino)-methyl]-phenyl}-hydrazinedicar-
boxylic acid di-tert-butyl ester
##STR00112##
[0272] B-16c is prepared analogously to B-14a starting from B-16b
(1.31 g, 7.17 mmol) and B-15c (2.41 g, 7.17 mmol). The product is
purified by preparative RP-HPLC (5-98% ACN in water) Yield: 1.48
g.
[0273] B-16c is taken up in 5 mL dioxane and 8.0 mL of a 4 M
solution of HCl in dioxane is added. The reaction mixture is
stirred overnight at RT and then concentrated in vacuo. The residue
is triturated in DCM. Yield: 0.52 g.
B-17) 2,6-Difluoro-4-hydrazino-benzaldehyde
O-(2-methoxy-ethyl)-oxime hydrochloride
##STR00113##
[0275] B-17a)
N,N-(3,5-Difluoro-4-formyl-phenyl)-hydrazinedicarboxylic acid
di-tert-butyl ester
##STR00114##
[0276] B-17a is prepared analogously to B-14a starting from
3,5-difluoro-4-formylboronic acid (5.0 g, 26.9 mmol),
di-tert-butylazocarboxylate (6.81 g, 29.6 mmol) and copper(II)
acetate (488 mg, 2.69 mmol). Yield: 9.93 g.
B-17b)
N,N-{3,5-Difluoro-4-[(2-methoxy-ethoxyimino)-methyl]-phenyl}-hydraz-
ine-dicarboxylic acid di-tert-butyl ester
##STR00115##
[0278] B-17b is prepared analogously to B-14b starting from B-17a
(1.46 g, 3.92 mmol) and B-15b (500 mg, 3.92 mmol). The product is
purified by preparative RP-HPLC (5-98% ACN in water). Yield: 700
mg.
[0279] B-17 is prepared analogously to B-14 starting from B-17b
(700 mg, 1.57 mmol) and 4 M HCl in dioxane (3.93 mL, 15.7 mmol).
Yield: 263 mg.
B-18) 2,3-Difluoro-4-hydrazino-benzaldehyde
O-(2-methoxy-ethyl)-oxime hydrochloride
##STR00116##
[0280] B-18a)
N,N-(2,3-Difluoro-4-formyl-phenyl)-hydrazinedicarboxylic acid
di-tert-butyl ester
##STR00117##
[0282] B-18a is prepared analogously to B-14a starting from
2,3-difluoro-4-formylboronic acid (5.0 g, 26.9 mmol),
di-tert-butylazodicarboxylate (6.81 g, 29.6 mmol) and copper(II)
acetate (488 mg, 2.69 mmol). Yield: 9.70 g.
[0283] B-18b)
N,N-{2,3-Difluoro-4-[(2-methoxy-ethoxyimino)-methyl]-phenyl}-hydrazine-di-
carboxylic acid di-tert-butyl ester
##STR00118##
[0284] B-18b is prepared analogously to B-14b starting from B-18a
(1.46 g, 3.92 mmol) and B-15b (500 mg, 3.92 mmol). The product is
purified by preparative RP-HPLC (5-98% ACN in water). Yield: 840
mg.
[0285] B-18 is prepared analogously to B-14 starting from B-18b
(840 mg, 1.89 mmol) and 4 M HCl in dioxane (4.72 ml, 18.9 mmol).
Yield: 276 mg.
B-19) Cyclopropylmethyl-hydrazine hydrochloride
##STR00119##
[0286] B-19a) N-[1-Cyclopropyl-methylidene]-hydrazinecarboxylic
acid tert-butyl ester
##STR00120##
[0288] Cyclopropylcarboxaldehyde (4.07 mL, 14.3 mmol) is dissolved
in 3 mL MeOH and tert-butylcarbazate (1.89 g, 14.3 mmol) is added.
The reaction mixture is stirred overnight at RT and subsequently
concentrated in vacuo. Yield: 2.57 g.
B-19b) N-Cyclopropylmethyl-hydrazinecarboxylic acid tert-butyl
ester
##STR00121##
[0290] To a mixture of B-19a (2.57 g, 13.9 mmol) in 13 mL 50%
aqueous acetic acid is added sodium cyanoborohydride (877 mg, 13.9
mmol) and the reaction mixture is stirred overnight RT. The
reaction mixture is basified with 10 M aqueous NaOH and extracted
with DCM. The combined organic extracts are washed with saturated
aqueous sodium hydrogen carbonate, dried over MgSO.sub.4 and
concentrated in vacuo. Yield: 2.05 g.
[0291] B-19b (2.05 g, 11.0 mmol) is dissolved in 3 mL dioxane and 4
M HCl in dioxane (13.8 mL, 55.0 mmol) is added. The reaction
mixture is stirred at RT and then concentrated in vacuo. Yield:
1.30 g.
B-20 (1-Ethyl-propyl)-hydrazine hydrochloride
##STR00122##
[0292] B-20a) N-(1-Ethyl-propylidene)-hydrazinecarboxylic acid
tert-butyl ester
##STR00123##
[0294] B-20a is prepared analogously to B-19a starting from
3-pentanone (1.23 mL, 11.6 mmol) and tert-butylcarbazate (1.53 g,
11.6 mmol). Yield: 2.26 g.
B-20b) N-(1-Ethyl-propyl)-hydrazinecarboxylic acid tert-butyl
ester
##STR00124##
[0296] B-20b was prepared analogously to B-19b starting from B-20a
(2.26 g, 11.3 mmol) and sodium cyanoborohydride (709 mg, 11.3
mmol). Yield: 1.68 g.
[0297] B-20 is prepared analogously to B-19 starting from B-20b
(1.68 g, 8.31 mmol) and 4 M hydrochloric acid in dioxane (10.4 ml,
41.5 mmol). Yield: 1.20 g.
B-21) Isobutyl-hydrazine hydrochloride
##STR00125##
[0298] B-21a) N-[2-Methyl-propylidene]-hydrazinecarboxylic acid
tert-butyl ester
##STR00126##
[0300] B-21a is prepared analogously to B-19a starting from
isobutyraldehyde (1.26 mL, 13.9 mmol) and tert-butylcarbazate (1.83
g, 13.9 mmol). Yield: 2.56 g.
B-21b) N-Isobutyl-hydrazinecarboxylic acid tert-butyl ester
##STR00127##
[0302] B-21b is prepared analogously to B-19b starting from B-21a
(2.56 g, 13.7 mmol) and sodium cyanoborohydride (864 mg, 13.7
mmol). Yield: 1.97 g.
[0303] B-21 is prepared analogously to B-19 starting from B-21b
(1.97 g, 10.5 mmol) and 4 M HCl in dioxane (13.1 mL, 52.3 mmol).
Yield: 1.30 g.
B-22) (Tetrahydro-pyran-4-yl)-hydrazine
##STR00128##
[0304] B-22a) N-(Tetrahydro-pyran-4-ylidene)-hydrazinecarboxylic
acid tert-butyl ester
##STR00129##
[0306] B-22a was prepared analogously to B-19a starting from
tetrahydro-4H-pyran-4-one (923 .mu.L, 9.99 mmol) and
tert-butylcarbazate (1.32 g, 9.99 mmol). Yield: 2.15 g.
B-22b) N-(Tetrahydro-pyran-4-yl)-hydrazinecarboxylic acid
tert-butyl ester
##STR00130##
[0308] B-22b is prepared analogously to B-19b starting from B-22a
(2.15 g, 10.0 mmol) and sodium cyanoborohydride (631 mg, 10.0
mmol). Yield: 1.57 g.
[0309] B-22 is prepared analogously to B-19 starting from B-22b
(1.57 g, 7.26 mmol) and 4 M HCl in dioxane (9.07 ml, 36.3 mmol).
Yield: 1.10 g.
B-23) (2-Methyl-allyl)-hydrazine hydrochloride
##STR00131##
[0310] B-23a)
N-[2-Methyl-prop-2-en-(E)-ylidene]-hydrazinecarboxylic acid
tert-butyl ester
##STR00132##
[0312] B-23a is prepared analogously to B-19a starting from
methacroleine (1.18 ml, 14.3 mmol) and tert-butylcarbazate (1.89 g,
14.3 mmol). Yield: 2.61 g.
B-23b) N-(2-Methyl-allyl)-hydrazinecarboxylic acid tert-butyl
ester
##STR00133##
[0314] B-23b is prepared analogously to B-19b starting from B-23a
(2.61 g, 14.2 mmol) and sodium cyanoborohydride (890 mg, 14.2
mmol). Yield: 1.88 g.
[0315] B-23 is prepared analogously to B-19 starting from B-23b
(1.88 g, 10.1 mmol) and 4 M HCl in dioxane (12.6 mL, 50.5 mmol).
Yield: 1.14 g.
B-24) (2-Methoxy-ethyl)-hydrazine hydrochloride
##STR00134##
[0316] B-24a) N'-Isopropylidene-hydrazinecarboxylic acid tert-butyl
ester
##STR00135##
[0318] To a solution of tert-butylcarbazate (50.0 g, 378 mmol) in
40 mL acetone is added 10 g MgSO.sub.4 and 5 mL acetic acid and the
reaction mixture is stirred at reflux temperature for 1 h. The
reaction mixture is filtered and concentrated in vacuo. The residue
is crystallized from diethyl ether/cyclohexane. Yield: 49.4 g.
B-24b) N-Isopropylidene-N-(2-methoxy-ethyl)-hydrazinecarboxylic
acid tert-butyl ester
##STR00136##
[0320] B-24a (5.0 g, 29.0 mmol) is dissolved in 70 mL toluene and
potassium hydroxide (2.12 g, 37.7 mmol) and tetrabutylammonium
hydrogensulfate (986 mg, 2.90 mmol) are added. The reaction mixture
is heated to 50.degree. C. and 2-bromoethyl methyl ether (3.23 mL,
34.8 mmol) is added. Next the reaction mixture is heated to
80.degree. C. and stirred for 2 h. The reaction mixture is washed
with water, the organic phase is dried on MgSO.sub.4 and
concentrated in vacuo. Yield: 4.35 g.
[0321] To a solution of B-24b (4.25 g, 18.9 mmol) in 80 mL THF is
added 2 M aqueous HCl (18.9 mL, 37.8 mmol) and the reaction mixture
is stirred at reflux temperature for 3 h. The reaction mixture is
concentrated in vacuo and co-evaporated several times with toluene.
Yield: 2.93 g.
B-25) Prop-2-ynyl-hydrazine hydrochloride
##STR00137##
[0322] B-25a) N'-Isopropylidene-N-prop-2-ynyl-hydrazinecarboxylic
acid tert-butyl ester hydrochloride
##STR00138##
[0324] B-25a is prepared analogously to B-24b starting from B-24a
(2.34 g, 13.6 mmol), potassium hydroxide (991 mg, 17.7 mmol),
tetrabutylammonium hydrogensulfate (461 mg, 1.36 mmol) and
propargyl chloride (70% in toluene, 1.8 mL, 16.3 mmol). Yield: 1.99
g.
[0325] B-25 is prepared analogously to B-24 starting from B-25a
(1.99 g, 9.64 mmol) and 2 M aqueous HCl (9.46 mL, 18.9 mmol).
Yield: 1.03 g.
B-26) Piperidin-4-yl-hydrazine is commercially available.
##STR00139##
[0326] B-27) [1-(2-Methoxy-ethyl)-piperidin-4-yl]hydrazine
hydrochloride
##STR00140##
[0327] B-27a) N-Piperidin-4-ylidene-hydrazinecarboxylic acid
tert-butyl ester hydrochloride
##STR00141##
[0329] A mixture of 4-piperidone hydrochloride monohydrate (31.2 g,
203 mmol) and tert-butylcarbazate (26.8 g, 203 mmol) in 100 mL MeOH
is stirred over weekend at RT and then concentrated in vacuo. The
residue is crystallized from ethyl acetate. Yield: 47.5 g.
[0330] B-27b) N'-Piperidin-4-yl-hydrazinecarboxylic acid tert-butyl
ester
##STR00142##
[0331] B-27a (40.2 g, 161 mmol) is dissolved in 50% aqueous acetic
acid (240 mL) and sodium cyanoborohydride (12.1 g, 193 mmol) is
added under cooling with an ice bath and the reaction mixture is
stirred for 1 h. The reaction mixture is basified and extracted
with DCM. The organic phases are washed with saturated aqueous
sodium hydrogencarbonate, dried over sodium sulfate and
concentrated in vacuo. Yield: 21.1 g.
B-27c) N-E1-(2-Methoxy-ethyl)-piperidin-4-yl]-hydrazinecarboxylic
acid tert-butyl ester
##STR00143##
[0333] To a mixture of B-27b (2.50 g, 11.6 mmol), potassium
carbonate (2.76 g, 20.0 mmol) and potassium iodide (50 mg, 0.30
mmol) in 25 mL DMF is added 2-bromoethyl methyl ether (1.23 mL,
12.8 mmol) and the reaction mixture is stirred overnight at RT. The
reaction mixture is poured on water and extracted with ethyl
acetate. The combined organic extracts are washed with water and
brine, dried over MgSO.sub.4 and concentrated in vacuo. Yield: 2.65
g.
[0334] B-27c is taken up in dioxane, treated with 4 M hydrochloric
acid in dioxane (10.0 mL, 40.0 mmol) and stirred overnight at RT.
The formed precipitate is filtered off and dried in vacuo. Yield:
1.2 g.
B-28) (1-Prop-2-ynyl-piperidin-4-yl)-hydrazine hydrochloride
##STR00144##
[0335] B-28a) N'-(1-Prop-2-ynyl-piperidin-4-yl)-hydrazinecarboxylic
acid tert-butyl ester
##STR00145##
[0337] B-28a is prepared analogously to B-27c starting from B-27b
(10.0 g, 46.4 mmol), potassium carbonate (4.0 g, 29.0 mmol) and
propargyl bromide (80% in toluene, 5.26 mL, 48.8 mmol). Yield: 12.4
g.
[0338] B-28 is prepared analogously to B27 starting from B-28 a
(12.4 g, approximately 46.4 mmol) and 4 M hydrochloric acid in
dioxane (61.3 ml, 245 mmol). Yield: 9.30 g.
B-29) (1-Cyclopropyl-piperidin-4-yl)-hydrazine hydrochloride
##STR00146##
[0339] B-29a)
N'-(1-Cyclopropyl-piperidin-4-ylidene)-hydrazinecarboxylic acid
tert-butyl ester
##STR00147##
[0341] A mixture of 1-cyclopropyl-4-piperidon (10.0 g. 71.8 mmol)
and tert-butylcarbazate (9.50 g, 71.8 mmol) in 25 mL THF is stirred
for 3 h at RT and then concentrated in vacuo. Yield: 19.2 g.
B-29b) N'-(1-Cyclopropyl-piperidin-4-yl)-hydrazinecarboxylic acid
tert-butyl ester
##STR00148##
[0343] B-29b is prepared analogously to B-27b starting from B-29a
(18.0 g, 71.1 mmol) and sodium cyanoborohydride (4.47 g, 71.1
mmol). Yield: 17.2 g.
[0344] Under cooling with an ice bath acetyl chloride (14.3 mL, 201
mmol) is added to 40 mL EtOH. Then B-29b (17.2 g, 67.3 mmol) is
added and the reaction mixture is stirred for 1 h at RT. The
reaction mixture is filtered and the solids are dried in vacuo at
40.degree. C. Yield: 12.3 g.
B-30) (1-Methyl-piperidin-4-yl)-hydrazine is commercially
available
##STR00149##
[0345] B-31) 4-Hydrazino-benzaldehyde O-methyl-oxime
hydrochloride
##STR00150##
[0347] A mixture of B-15c (7.50 g, 22.3 mmol) and methoxyamine
hydrochloride (1.95 g, 23.4 mmol) in 50 mL MeOH is stirred under
reflux at 75.degree. C. for 2 h. Then 1 mL of concentrated
hydrochloric acid is added and the reaction mixture is stirred for
another h at 75.degree. C. and then concentrated in vacuo. The
residue is dried in vacuo at 40.degree. C. overnight and then
triturated with DCM. Yield: 3.2 g.
B-32 [1-(3-Fluoro-4-hydrazino-phenyl)-cyclopropyl]-dimethyl-amine
hydrochloric acid
##STR00151##
[0348] B-32a) [1-(4-Bromo-3-fluoro-phenyl)-cyclopropyl]-carbamic
acid tert-butyl ester
##STR00152##
[0350] A mixture of
1-(4-bromo-3-fluorophenyl)cyclopropanecarboxylic acid (7.4 g, 28.6
mmol, prepared from 1-bromo-4-bromomethyl-2-fluorobenzene according
to Peretto et al. J Med. Chem. 2005, 48, 5705-20), DIPEA (6.36 mL,
37.1 mmol), tert-butanol (67.0 mL, 714 mmol),
diphenylphosphorylazide (7.37 mL, 34.3 mmol) and molsieve (4 .ANG.)
in 100 mL toluene is stirred under reflux overnight. The reaction
mixture is filtered and concentrated in vacuo. The residue is taken
up in ethylacetate and washed with 5% aqueous citric acid,
saturated aqueous sodium hydrogencarbonate and brine. The organic
phase is dried over MgSO.sub.4 and concentrated in vacuo. Yield:
9.37 g.
B-32b) [1-(4-Bromo-3-fluoro-phenyl)-cyclopropyl]-methyl-carbamic
acid tert-butyl ester
##STR00153##
[0352] To a solution of B-32a (9.37 g, 28.4 mmol) in 120 mL DMF is
added sodium hydride (60% in mineral oil, 1.7 g, 42.6 mmol) and the
reaction mixture is stirred at RT for 0.5 h. The reaction mixture
is warmed to 40.degree. C. and methyl iodide (3.89 mL, 62.4 mmol)
is added. After 1 h the reaction mixture is poured on ice water and
extracted with ethyl acetate. The combined organic phases are
washed with water and brine, dried over MgSO.sub.4 and concentrated
in vacuo. Yield: 8.54 g.
B-32c) [1-(4-Bromo-3-fluoro-phenyl)-cyclopropyl]-methyl-amine
hydrochloride
##STR00154##
[0354] A mixture of B-32b (8.54 g, 24.8 mmol) in 4 M hydrochloric
acid in dioxane (31.0 mL, 124 mmol) is stirred for 1 h at RT and
then concentrated in vacuo. Yield: 7.28 g.
B-32d) [1-(4-Bromo-3-fluoro-phenyl)-cyclopropyl]-dimethyl-amine
##STR00155##
[0356] A mixture of B-32c (7.28 g, 25.9 mmol) and formaldehyde (30%
in water, 3.90 mL, 38.9 mmol) in 150 mL 1,2-dichloroethane is
stirred vigorously for 0.5 h at RT. Acetic acid (2.23 mL, 38.9
mmol) and sodium trisacetoxyborohydride (8.25 g, 38.9 mmol) are
added under cooling with ice water and the reaction mixture is
stirred for 2 h at RT. Saturated aqeous sodium hydrogencarbonate is
added and the reaction mixture is extracted with DCM. The combined
organic phases are dried over MgSO.sub.4 and concentrated in vacuo.
Yield: 7.07 g.
B-32e)
{1-[4-(N-Benzhydrylidene-hydrazino)-3-fluoro-phenyl]-cyclopropyl}-d-
imethyl-amine
##STR00156##
[0358] A mixture of B-32d (7.07 g, approximately 25.9 mmol),
benzophenone hydrazone (5.38 g, 27.4 mmol), sodium tert-butoxide
(3.95 g, 41.1 mmol) and (2-biphenyl)-di-tert-butylphosphine (422
mg, 1.37 mmol) in 200 mL dioxane is degassed and put under an argon
atmosphere. Palladium(II) acetate (122 mg, 548 .mu.mol) is added
and the reaction mixture is stirred for 2 h at 80.degree. C. The
reaction mixture is filtered and concentrated in vacuo. The residue
purified by flash chromatography (silica gel, 1-5% MeOH in DCM).
Yield: 4.84 g.
[0359] B-32e (4.8 g, 12.9 mmol) is dissolved in 10 mL n-propanol
and 10 mL concentrated HCl is added. The reaction mixture is
stirred for 1 h at 100.degree. C. and then concentrated in vacuo.
The residue is taken up in fresh n-propanol, concentrated in vacuo
again, triturated with DCM and dried in vacuo at 40.degree. C.
Yield: 1.93 g.
[0360] B-33) 4-Hydrazino-3-methoxy-benzoic acid methyl ester is
prepared according to WO2007113245.
##STR00157##
B-34) 3-Ethoxy-4-hydrazino-benzoic acid methyl ester
##STR00158##
[0361] B-34a) 3-Ethoxy-4-nitro-benzoic acid methyl ester
##STR00159##
[0363] A mixture of methyl 3-hydroxyl-4-nitrobenzoate (25.1 g, 125
mmol) and bromoethane (20 mL, 263 mmol) in 200 mL ACN is cooled to
15.degree. C. Potassium carbonate (54.4 g, 390 mmol) is added and
the reaction mixture is stirred overnight at 60.degree. C.
Additional bromoethane (10 mL, 131 mmol) is added and the reaction
mixture is stirred overnight at 95.degree. C. The reaction mixture
is filtered and the filtrate is concentrated in vacuo. The residue
is triturated with ACN and dried in vacuo. Yield: 26.5 g.
B-34b) 4-Amino-3-ethoxy-benzoic acid methyl ester
##STR00160##
[0365] A mixture of B-34a (26.5 g, 118 mmol) and Raney nickel (1.5
g, 5.43 mmol) in 150 mL THF is stirred for 5 d at RT under an
atmosphere of 10 bar dihydrogen. The reaction mixture is filtered
and the filtrate is concentrated in vacuo. The residue is
lyophilized from dioxane. Yield: 21.7 g.
[0366] B-34 is prepared analogously to B-05 starting from B-34b
(21.5 g, 108 mmol), sodium nitrite (7.75 g, 110 mmol) and tin(II)
chloride dihydrate (104 g, 453 mmol). The product is lyophilized
from dioxane. Yield: 19.3 g.
B-35) 3-Hydrazino-N,N-dimethyl-benzenesulfonamide hydrochloride
##STR00161##
[0367] B-35a) N-(3-Dimethylsulfamoyl-phenyl)-hydrazinedicarboxylic
acid di-tert-butyl ester
##STR00162##
[0369] B-35a is prepared analogously to B-14a starting from
3-(N,N-dimethylsulphonamido)-benzeneboronic acid (1.0 g, 4.37
mmol), di-tert-butylazodicarboxylate (1.11 g, 4.83 mmol) and
copper(II) acetate (79 mg, 0.44 mmol). The product is purified by
preparative RP-HPLC (5-98% ACN in water). Yield: 1.15 g.
[0370] B-35 is prepared analogously to B-14 starting from B-35a
(1.15 g, 2.77 mmol) and 4 M HCl in dioxane (6.92 ml, 27.8 mmol).
Yield: 527 mg.
B-36) (3-Trifluoromethoxy-phenyl)-hydrazine hydrochloride
##STR00163##
[0371] B-36a) N-(3-Trifluoromethoxy-phenyl)-hydrazinedicarboxylic
acid di-tert-butyl ester
##STR00164##
[0373] B-36a is prepared analogously to B-14a starting from
3-(trifluoromethoxy)benzeneboronic acid (1.0 g, 4.86 mmol),
di-tert-butylazodicarboxylate (1.23 g, 5.34 mmol) and copper(II)
acetate (88 mg, 0.49 mmol). The product is purified by preparative
RP-HPLC (5-98% ACN in water). Yield: 1.26 g.
[0374] B-36 is prepared analogously to B-14 starting from B-36a
(1.26 g, 3.21 mmol) and 4 M HCl in dioxane (8.03 ml, 32.1 mmol).
Yield: 557 mg.
B-37) (3-Pyrazol-1-yl-phenyl)-hydrazine hydrochloride
##STR00165##
[0375] B-37a) N-(3-Pyrazol-1-yl-phenyl)-hydrazinedicarboxylic acid
di-tert-butyl ester
##STR00166##
[0377] B-37a is prepared analogously to B-14a starting from
3-(1H-pyrazol-1-yl)phenylboronic acid (800 mg, 4.26 mmol),
di-tert-butylazodicarboxylate (1.08 g, 4.68 mmol) and copper(II)
acetate (77 mg, 0.43 mmol). Yield: 1.17 g.
[0378] B-37 is prepared analogously to B-14 starting from B-37a
(1.17 g, 3.13 mmol) and 4 M HCl in dioxane (7.81 mL, 31.3 mmol).
Yield: 518 mg.
EXAMPLES C
[0379] Examples C-01 to C-118 can be synthesized according to one
of the following general procedures. The appropriate hydrazine and
diketone required for synthesis can be deduced from the table of
examples.
[0380] General Procedure C1:
[0381] The appropriate diketone (1 eq.) and the appropriate
hydrazine or hydrazine hydrochloride (1 eq.) are added to acetic
acid and allowed to stir at RT for 24 h. The acetic acid is removed
under reduced pressure, the resulting crude material is dissolved
in NMP and purified using RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen
carbonate pH 9.3). The resulting product fractions are collected
and the solvent removed via freeze-drying to yield the desired
product.
[0382] General Procedure C2:
[0383] The appropriate diketone (1 eq.) and the appropriate
hydrazine or hydrazine hydrochloride (5-10 eq.) are added to acetic
acid and heated to 85.degree. C.-160.degree. C. for 1-6 h in the
microwave. The acetic acid is removed under reduced pressure, the
resulting crude material dissolved in NMP and purified using
RP-LC/MS (ACN:H.sub.2O-TFA pH 1). The resulting product fractions
recollected and the solvent removed via freeze-drying to yield the
desired product.
[0384] General Procedure C3
[0385] The appropriate diketone (1 eq.) and the appropriate
hydrazine hydrochloride (1 eq.) are added to EtOH and heated to
100.degree. C.-140.degree. C. for 15-60 min in the microwave. The
EtOH is removed under reduced pressure, the resulting crude
material dissolved in NMP and purified using RP-LC/MS
(ACN:H.sub.2O-TFA pH 1). The resulting product fractions are
collected and the solvent removed via freeze-drying to yield the
desired product.
[0386] General Procedure C4:
[0387] The appropriate diketone (1 eq.) and the appropriate
hydrazine or hydrazine hydrochloride (1.3 eq.) are added to acetic
acid and allowed to stir at 70.degree. C. for 2 d. The acetic acid
is removed under reduced pressure, the resulting crude material is
dissolved in DMSO/TFA and purified using RP-LC/MS. The resulting
product fractions are collected and the solvent is removed via
freeze-drying to yield the desired product.
TABLE-US-00001 TABLE 1 Examples C-01-C-117 No. MOLSTRUCTURE
Diketone Hydrazine [M + H].sup.+ rt C-01 ##STR00167## A-01 B-03 553
1.51 C-02 ##STR00168## A-02 B-01 536 1.09 C-03 ##STR00169## A-02
B-31 488 1.25 C-04 ##STR00170## A-03 B-01 564 1.18 C-05
##STR00171## A-04 B-01 548 1.06 C-06 ##STR00172## A-04 B-31 500
1.19 C-07 ##STR00173## A-05 B-01 548 1.06 C-08 ##STR00174## A-05
B-31 500 1.19 C-09 ##STR00175## A-06 B-01 550 1.1 C-10 ##STR00176##
A-06 B-31 502 1.24 C-11 ##STR00177## A-07 B-19 395 1.01 C-12
##STR00178## A-07 B-20 411 1.13 C-13 ##STR00179## A-07 B-21 397
1.05 C-14 ##STR00180## A-07 B-28 462 1.02 C-15 ##STR00181## A-07
B-29 464 1.12 C-16 ##STR00182## A-07 cyclopentyl- hydrazine 409
1.18 C-17 ##STR00183## A-07 ethylhydrazine 369 0.99 C-18
##STR00184## A-07 hydrazine 341 0.95 C-19 ##STR00185## A-07
isopropyl- hydrazine 383 1.03 C-20 ##STR00186## A-07 o,o-dimethyl-
phenylhydrazine 445 1.09 C-21 ##STR00187## A-07 o-methylphenyl-
hydrazine 431 1.11 C-22 ##STR00188## A-07 t-butylhydrazine 397 1.14
C-23 ##STR00189## A-08 o-chlorophenyl hydrazine 508 1.15 C-24
##STR00190## A-09 cyclohexyl- hydrazine 467 1.22 C-25 ##STR00191##
A-10 B-22 439 1.04 C-26 ##STR00192## A-10 B-23 409 1.06 C-27
##STR00193## A-10 B-24 413 1.01 C-28 ##STR00194## A-10 B-25 393
1.02 C-29 ##STR00195## A-10 B-28 476 1.09 C-30 ##STR00196## A-10
B-30 452 1.06 C-31 ##STR00197## A-10 ethylhydrazine 383 1.03 C-32
##STR00198## A-10 isopropyl- hydrazine 397 1.1 C-33 ##STR00199##
A-10 methyl- hydrazine 369 1.01 C-34 ##STR00200## A-10
o-methylphenyl- hydrazine 445 1.95 C-35 ##STR00201## A-10 t-butyl-
hydrazine 411 1.21 C-36 ##STR00202## A-11 B-27 510 1.09 C-37
##STR00203## A-11 isopropyl- hydrazine 411 1.14 C-38 ##STR00204##
analogous to A-11 isopropyl- hydrazine 397 1.06 C-39 ##STR00205##
A-12 B-04 505 1.6 C-40 ##STR00206## A-13 phenyl- hydrazine 406 1.97
C-41 ##STR00207## A-14 B-02 473 1.48 C-42 ##STR00208## A-15
isopropyl- hydrazine 382 1.12 C-43 ##STR00209## A-16 B-01 535 1.16
C-44 ##STR00210## A-17 B-05 507 1.04 C-45 ##STR00211## A-17 B-06
473 1.13 C-46 ##STR00212## A-17 ethyl- hydrazine 370 1.04 C-47
##STR00213## A-18 isopropyl- hydrazine 382 1.1 C-48 ##STR00214##
A-19 B-28 483 1.19 C-49 ##STR00215## A-20 B-07 470 1.47 C-52
##STR00216## A-23 (2,2,2-trifluoro- ethyl)- hydrazine 408 1.1 C-53
##STR00217## A-23 (2-bromo- phenyl)- hydrazine 480 1.15 C-54
##STR00218## A-23 (2-fluoro- phenyl)- hydrazine 420 1.12 C-55
##STR00219## A-23 B-37 468 1.16 C-56 ##STR00220## A-23 B-36 486
1.26 C-57 ##STR00221## A-23 (6-chloro- pyridin-3-yl)- hydrazine 437
1.14 C-58 ##STR00222## A-23 2-hydrazino- benzonitrile 427 1.16 C-59
##STR00223## A-23 2-hydrazino- ethanol 370 0.95 C-60 ##STR00224##
A-23 B-35 509 1.15 C-61 ##STR00225## A-23 3-hydrazino-
propionitrile 379 1.01 C-62 ##STR00226## A-23 B-08 446 1.45 C-63
##STR00227## A-23 B-12 480 1.01 C-64 ##STR00228## A-23 B-13 507
1.78 C-65 ##STR00229## A-23 B-14 473 1.18 C-66 ##STR00230## A-23
B-15 503 1.2 C-67 ##STR00231## A-23 B-16 558 1.15 C-68 ##STR00232##
A-23 B-17 539 1.21 C-69 ##STR00233## A-23 B-18 539 1.2 C-70
##STR00234## A-23 B-26 409 1.01 C-71 ##STR00235## A-23 B-31 459
2.01 C-72 ##STR00236## A-23 benzyl- hydrazine 416 1.14 C-73
##STR00237## A-23 isopropyl- hydrazine 368 1.13 C-74 ##STR00238##
A-23 N-(3-hydrazino- phenyl)- acetamide HCl 459 1.02 C-75
##STR00239## A-23 pyridin-2-yl- hydrazine 403 1.15 C-76
##STR00240## A-24 B-09 535 C-77 ##STR00241## A-24 B-10 501 C-78
##STR00242## A-24 B-11 448 0.93 C-79 ##STR00243## A-24 cyclobutyl-
hydrazine 396 1.01 C-80 ##STR00244## A-24 isopropyl- hydrazine 384
0.99 C-81 ##STR00245## A-27 isopropyl- hydrazine 326 1.09 C-82
##STR00246## A-28 o-methylphenyl- hydrazine 447 1.01 C-83
##STR00247## A-29 B-31 472 1.25 C-84 ##STR00248## A-30 B-31 446
1.19 C-85 ##STR00249## A-31 isopropyl- hydrazine 409 1.08 C-86
##STR00250## A-35 B-32 533 C-87 ##STR00251## A-23 (2-hydrazino-
ethyl)- dimethyl- amine 397 1.27 C-88 ##STR00252## A-23
(2-morpholin- 4-yl-ethyl)- hydrazine 439 1.25 C-89 ##STR00253##
A-23 (2-trifluoro- methyl- phenyl)- hydrazine 470 1.58 C-90
##STR00254## A-23 (2-methoxy- phenyl)- hydrazine 432 1.47 C-91
##STR00255## A-23 (2-trifluoro- methoxy- phenyl)- hydrazine 486
1.70 C-92 ##STR00256## A-23 o-methyl- phenyl- hydrazine 416 1.89
C-93 ##STR00257## A-23 isobutyl- hydrazine 382 1.86 C-94
##STR00258## A-36 isopropyl- hydrazine 441 1.53 C-95 ##STR00259##
A-37 isopropyl- hydrazine 468 1.63 C-96 ##STR00260## A-47
isopropyl- hydrazine 440 1.49 C-97 ##STR00261## A-39 o-methyl-
phenyl- hydrazine 539 1.62 C-98 ##STR00262## A-46 o-methyl- phenyl-
hydrazine 446 1.43 C-99 ##STR00263## A-38 o-methyl- phenyl-
hydrazine 417 1.59 C-100 ##STR00264## A-37 o-methyl- phenyl-
hydrazine 516 1.76 C-101 ##STR00265## A-36 o-methyl- phenyl-
hydrazine 489 1.75 C-102 ##STR00266## A-41 o-methyl- phenyl-
hydrazine 460 1.39 C-103 ##STR00267## A-40 o-methyl- phenyl-
hydrazine 474 1.49 C-104 ##STR00268## A-42 o-methyl- phenyl-
hydrazine 488 1.71 C-105 ##STR00269## A-43 isopropyl- hydrazine 442
1.46 C-106 ##STR00270## A-44 isopropyl- hydrazine 454 1.43 C-107
##STR00271## A-45 isopropyl- hydrazine 454 1.44 C-108 ##STR00272##
A-49 o-tolylhydrazine hydrochloride 446 1.53 C-109 ##STR00273##
A-48 o-tolylhydrazine hydrochloride 460 1.59 C-110 ##STR00274##
A-50 o-tolylhydrazine hydrochloride 474 C-111 ##STR00275## A-51
o-tolylhydrazine hydrochloride 517 1.61 C-112 ##STR00276## A-52
o-tolylhydrazine hydrochloride 504 1.76 C-113 ##STR00277## A-54
o-tolylhydrazine hydrochloride 518 1.83 C-114 ##STR00278## A-53
o-tolylhydrazine hydrochloride 531 1.84 C-115 ##STR00279## A-55
isopropyl- hydrazine hydrochloride 454 1.6 C-116 ##STR00280## A-23
2-chloro- pyridin-3-yl- hydrazine 437/439 1.55 C-117 ##STR00281##
A-07 2-chloro- pyridin-3-yl- hydrazine 452 1.38
EXAMPLES D
D-01)
N-[1-(4-Amino-2-chloro-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-
-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
##STR00282##
[0388] D-01a)
N-[1-(2-Chloro-4-nitro-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-p-
yrazolo[4,3-g]benzothiazol-7-yl]-acetamide
##STR00283##
[0390] A suspension of 5.0 g (15.2 mmol)
N-[6-(6-methyl-pyridine-3-carbonyl)-7-oxo-4,5,6,7-tetrahydro-benzothiazol-
-2-yl]-acetamide (A-23) and 3.74 g (16.7 mmol)
(2-chloro-4-nitro-phenyl)-hydrazine hydrochloride in 100 mL glacial
acetic acid is stirred at 60.degree. C. After stirring for 24 h at
60.degree. C. the solvent is evaporated, the residue taken up in
200 mL of ACN and stirred for 20 min. The solid is filtered off and
dried at 40.degree. C. yielding 5.33 g of the desired product.
[0391] A reaction mixture of 5.30 g (11.0 mmol) D-01a, 596 mg (2.20
mmol) vanadyl acetyl-acetonate and 530 mg Pt/C (5%) in 180 mL DMF
and 270 mL THF is hydrogenated with a hydrogen pressure of 3 bar at
RT over night. The reaction mixture is filtered over celite and the
solvent is evaporated under reduced pressure. The residue is taken
up in ACN. The solid material is filtered off and dried at
60.degree. C. yielding 3.94 g D-01.
D-02)
N-[1-(4-Amino-2-fluoro-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-
-1H-pyrazolo[4,3-g]benzothiazol-7-yl]-acetamide
##STR00284##
[0392] D-02a)
N-[1-(2-Fluoro-4-nitro-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-p-
yrazolo[4,3-dbenzothiazol-7-yl]-acetamide
##STR00285##
[0394] A suspension of 2.30 g (6.98 mmol) A-23 and 1.45 g (6.98
mmol) (2-fluoro-4-nitro-phenyl)-hydrazine hydrochloride in 40 mL
glacial acetic acid is stirred at 40.degree. C. over night. The
solvent is evaporated, water is added and the mixture is stirred
for 30 min. The formed precipitate is filtered off and dried in a
vacuum drying chamber at 40.degree. C. yielding 2.70 g D-02a.
[0395] A reaction mixture of 6.3 g (13.6 mmol) D-02a, 734 mg (2.71
mmol) vanadyl acetyl-acetonate and 700 mg Pt/C (5%) in 100 mL DMF
and 150 mL THF is hydrogenated with a hydrogen pressure of 4 bar at
RT over night. The reaction mixture is filtered over silica and the
solvent is evaporated under reduced pressure. The residue is taken
up in ACN and the solid material is filtered off and dried at
60.degree. C. yielding 5.34 g D-02.
D-03)
N-[1-(4-Bromo-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyraz-
olo[4,3-g]benzothiazol-7-yl]-acetamide
##STR00286##
[0397] To a suspension of 10.0 g (30.4 mmol) A-23 in 40 mL glacial
acetic acid is added 7.46 g (33.4 mmol) (4-Bromo-phenyl)-hydrazine
hydrochloride. After stirring at RT over night the precipitation is
filtered off and washed three times with EtOH. The solid is dried
and yields 11 g D-03.
D-04)
N-{3-(6-Methyl-pyridin-3-yl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)-phenyl]-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl}-aceta-
mide
##STR00287##
[0399] A solution of 5.50 g (11.4 mmol) D-03, 3.20 g (12.6 mmol)
bis(pinacolato)diboron, 3.38 g (34.4 mmol) potassium acetate and
468 mg (0.572 mmol) palladium 1,1'-bis(diphenyl-phosphino)ferrocene
dichloride DCM complex in 40 mL dry DMF is heated under an argon
atmosphere at 105.degree. C. over night. The suspension is reduced
to the half volume and the precipitation is filtered off, washed
twice with 5 mL water and 5 mL EtOH and dried under reduced
pressure yielding 5.6 g D-04. The product is used in the next step
without further purification.
D-05)
N-[1-(4-Bromo-phenyl)-3-(6-ethylamino-pyridin-3-yl)-4,5-dihydro-1H-p-
yrazolo[4,3-g]benzothiazol-7-yl]-acetamide
##STR00288##
[0401] To a suspension of 4.12 g (11.5 mmol) A-10 in 30 mL glacial
acetic acid is added 3.11 g (13.9 mmol) (4-bromo-phenyl)-hydrazine
hydrochloride. After stirring at RT over night and 1 h at
50.degree. C. the solvent is evaporated, the residue suspended in
25 mL MeOH and sonicated for 25 min. The solid material is filtered
off and dried yielding 1.66 g D-05.
D-06)
N-[1-(4-Bromo-phenyl)-3-(6-methylamino-pyridin-3-yl)-4,5-dihydro-1H--
pyrazolo[4,3-g]benzothiazol-7-yl]-acetamide
##STR00289##
[0403] To a suspension of 4.0 g (11.6 mmol) A-07 in 30 mL glacial
acetic acid is added 3.11 g (13.9 mmol) (4-bromo-phenyl)-hydrazine
hydrochloride. After stirring at RT over night and 1 h at
50.degree. C. the solvent is evaporated, the residue is suspended
in 20 mL EtOH and sonicated for 25 min. The solid material is
filtered off and dried yielding 2.66 g D-06, which is used without
further purification.
D-07)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzo-thiazol-1-yl]-cis-cyclohexanecarboxylic acid
##STR00290##
[0404] D-07a)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo
[4,3-g]benzothiazol-1-yl]-cis-cyclohexanecarboxylic acid ethyl
ester
##STR00291##
[0406] A solution of 1.30 g (3.95 mmol) A-23 and 1.01 g (4.74 mmol)
4-hydrazino-cyclohexane-carboxylic acid ethyl ester hydrochloride
in 30 mL glacial acetic acid is stirred at 65.degree. C. for 50 h.
The solvent is evaporated and the residue is taken up in DMF.
Purification is performed via RP-prep. HPLC chromatography
(gradient 2-60% ACN). After freeze-drying 510 mg of D-07a are
obtained
[0407] To a solution of 737 mg (1.54 mmol) D-07a in 35 mL THF is
added a solution of 294 mg (12.3 mmol) LiOH in 14 mL water. The
reaction mixture is stirred at 30.degree. C. for 3 d. Glacial
acetic acid is added until pH 4-5 is reached and the solvent is
evaporated under reduced pressure. The residue is taken up in DCM
and water is added. The formed precipitate is filtered off. More
water is added to the filtrate to drive the precipitation to
completion. The combined solid fractions are dried yielding 372 mg
D-07.
D-08)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzo-thiazol-1-yl]-cis-cyclohexanecarboxylic acid
##STR00292##
[0408] D-08a)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3-g]ben-
zo-thiazol-1-yl]-trans-cyclohexanecarboxylic acid ethyl ester
##STR00293##
[0410] A solution of 1.30 g (3.95 mmol) A-23 and 0.967 g (4.34
mmol) 4-hydrazino-cyclohexane-carboxylic acid ethyl ester
hydrochloride in 30 mL glacial acetic acid is stirred at 60.degree.
C. for 50 h. The solvent is evaporated and the residue is taken up
in DMF. Purification is performed via RP-prep. HPLC chromatography
(gradient 2-60% ACN). After freeze-drying 298 mg of D-08a are
obtained.
[0411] To a solution of 371 mg (0.774 mmol) D-08a in 17 mL THF is
added a solution of 148 mg (6.19 mmol) LiOH in 7.0 mL water. The
reaction mixture is stirred at RT for 24 h. Glacial acetic acid is
added until pH 4-5 is reached and the solvent is evaporated under
reduced pressure. The residue is taken up in DCM and water is
added. The formed precipitate is filtered off. More water is added
to the filtrate to drive the precipitation to completion. The
combined solid fractions are dried at 40.degree. C. over night
yielding 284 mg D-08.
D-09)
N-[1-(4-Cyano-2-methyl-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-
-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
##STR00294##
[0413] A solution of 2.50 g (8 mmol) A-23 and 1.68 g (11 mmol)
4-hydrazino-3-methyl-benzonitrile in 10 mL glacial acetic acid is
stirred at 45.degree. C. over night. The solvent is evaporated and
the residue is taken up in 10 mL EtOH. After stirring over night
the formed precipitate is filtered off and dried yielding 1.4 g
D-09.
D-10)
N-[1-(4-Formyl-2-methyl-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydr-
o-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
##STR00295##
[0415] To a reaction mixture of 600 mg (1.36 mmol) D-09 in 2.0 mL
glacial acetic acid, 2.0 mL pyridine and 2.0 mL water is added 1.0
g (21.7 mmol) formic acid and 300 mg Raney-Nickel nickel and
stirred at 90.degree. C. for 30 min. The reaction mixture is
filtered off without cooling and washed with 5 mL glacial acetic
acid. The filtrate is evaporated under reduced pressure and 10 mL
of water are added to the residue. The formed precipitation is
filtered off, washed with water and dried in vacuum yielding 450 mg
D-10, which is used in the next step without further
purification.
D-11)
N-[1-(2-Bromo-4-cyano-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro--
1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
##STR00296##
[0417] A solution of 5.0 g (15.2 mmol) A-23) and 5.20 g (22.1 mmol)
3-bromo-4-hydrazino-benzonitrile in 20 ml glacial acetic acid is
stirred at 60.degree. C. for 3 h. The solvent is evaporated and the
residue is taken up in 10 mL EtOH. After stirring over night the
formed precipitation is filtered off and dried, yielding 4.30 g of
the desired product D-11.
D-12)
N-[1-(2-Bromo-4-formyl-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-
-1H- pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
##STR00297##
[0419] To a reaction mixture of 600 mg (1.19 mmol) D-11 in 2 mL
glacial acetic acid, 2 mL pyridine and 2 mL water is added 1.0 g
(21.7 mmol) formic acid and 300 mg Raney--Nickel and stirred at
90.degree. C. for 30 min. The reaction mixture is filtered off
without cooling and washed twice with 20 mL MeOH/DCM. The filtrate
is evaporated under reduced pressure and 10 mL of water are added
to the residue. The formed precipitate is filtered off, washed
twice with 3 mL water and dried in vacuum yielding 588 mg D-12,
which is used in the next step without further purification.
D-13)
N-[1-[2-Bromo-4-(methoxyimino-methyl)-phenyl]-3-(6-methyl-pyridin-3--
yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
##STR00298##
[0421] A reaction mixture of 170 mg (0.301 mmol) D-12 and 50.3 mg
(0.602 mmol) O-methyl-hydroxylamine hydrochloride in 2 mL MeOH is
stirred at 40.degree. C. over night. The reaction mixture is
evaporated under reduced pressure and the residue is taken up in 2
mL MeOH/DCM with 5% triethyl amine. Purification is perfomed via
prep. HPLC yielding 150 mg of D-13.
D-14)
N-[3-(6-Methyl-pyridin-3-yl)-1-piperidin-4-yl-4,5-dihydro-1H-pyrazol-
o[4,3-g]benzothiazol-7-yl]acetamide
##STR00299##
[0423] A mixture of 5.20 g (15.8 mmol) A-23 and 3.6 g (19.1 mmol)
B-26 in 200 mL glacial acetic acid is stirred at 80.degree. C. for
72 h. The solvent is evaporated and the residue is taken up in
water and aqueous 5% potassium carbonate solution. The formed
precipitate is filtered off and washed with water. Purification of
the crude product is performed via MPLC (DCM/MeOH 93:7 as eluent)
yielding 4.0 g of D-14.
D-15)
[1-[4-(Methoxyimino-methyl)-phenyl]-3-(6-methyl-pyridin-3-yl)-4,5-di-
hydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]thiocarbamic acid S-ethyl
ester
##STR00300##
[0425] To a solution of 150 mg (0.306 mmol) D-16 in 2 mL NMP is
added 153 .mu.L (0.895 mmol) diisopropylethylamine and 122 mg
(0.981 mmol) ethyl-chloro-thioformate. The reaction mixture is
stirred at RT over night. Water is added to the reaction and the
resultant mixture is extracted twice with 15 mL DCM. The combined
organic layers are dried over Na.sub.2SO.sub.4 and evaporated under
reduced pressure yielding 150 mg D-15 which is used in the next
step without further purification.
D-16)
4-[7-Amino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3-g]benz-
othiazol-1-yl]-benzaldehyde O-methyl-oxime
##STR00301##
[0427] To a solution of 500 mg (1.09 mmol) D-29 in 10 mL MeOH and 3
mL DCM is added 5 mL of 4 M HCl dioxane solution. The reaction
mixture is stirred at 60.degree. C. for 6 h. The solvent is
evaporated under reduced pressure and the residue is taken up in
water and DCM. Potassium carbonate is added until the aqueous phase
becomes basic. After phase separation the aqueous phase is
extracted twice with 50 mL DCM. The combined organic layers are
washed with 1 M aqueous HCl solution. Some MeOH is added to the
organic layer, dried over Na.sub.2SO.sub.4 and the solvent is
evaporated under reduced pressure yielding 113 mg D-16, which is
used in the next step without further purification.
D-17)
1-Isopropyl-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]-
benzothiazol-7-ylamine
##STR00302##
[0429] To a suspension of 4.7 g (13 mmol) C-73 in 5 mL dioxane is
added dropwise 2.14 mL conc. aqueous HCl solution. After complete
addition the reaction mixture is heated at 95.degree. C. for 2 h.
Saturated NaHCO.sub.3 solution is added to the cooled reaction
mixture until pH 8 is reached. The formed precipitate is filtered
off, washed twice with 5 mL water and dried in vacuo yielding 3.70
g D-17, which is used for the next step without further
purification.
D-18)
[1-(4-Bromo-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyrazol-
o[4,3-g]benzothiazol-7-yl]-carbamic acid methyl ester
##STR00303##
[0431] A mixture of 400 mg (1.27 mmol) A-24 and 284 mg (1.27 mmol)
(4-bromo-phenyl)-hydrazine hydrochloride in 10 mL glacial acetic
acid is stirred at 50.degree. C. for 48 h. The solvent is
evaporated, the residue is taken up in MeOH and sonicated for 15
min. The solid material is filtered off and dried yielding 780 mg
D-18.
D-19)
4-[7-Acetylamino-3-(6-chloro-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]-3-chloro--N,N-dimethyl-benzamide
##STR00304##
[0433] A mixture of 1.50 g (4.29 mmol) A-12 and 1.39 g (5.58 mmol)
B-01 in 35 mL glacial acetic acid is stirred at 40.degree. C. over
night. The solvent is evaporated, the residue is taken up in DCM
and saturated Na.sub.2CO.sub.3 solution. The aqueous layer is
extracted twice with DCM, the combined organic layers are dried
over MgSO.sub.4 and evaporated under reduced pressure yielding 1.05
g D-19.
D-20)
[3-(6-Ethylamino-pyridin-3-yl)-1-o-tolyl-4,5-dihydro-1H-pyrazolo[4,3-
-g]benzothiazol-7-yl]thiocarbamic acid S-ethyl ester
##STR00305##
[0435] A solution of 2.50 g (4.94 mmol) A-34 and 0.941 g (1.11
mmol) 2-methyl-phenylhydrazine hydrochloride in 10 mL glacial
acetic acid is stirred at 80.degree. C. over night. The solvent is
evaporated under reduced pressure and the residue is taken up in
DMSO/MeOH. Solid material is filtered off and the filtrate is
purified via prep. HPLC yielding 0.680 g D-20, which is used
without further purification for the next step.
D-21)
[1-(2-Chloro-phenyl)-3-(6-methylamino-pyridin-3-yl)-4,5-dihydro-1H-p-
yrazolo[4,3-g]benzothiazol-7-yl]thiocarbamic acid S-ethyl ester
##STR00306##
[0437] To a suspension of 200 mg (0.512 mmol) A-33 in 15 mL
isopropanol is added 275 mg (1.54 mmol) 2-chlorophenylhydrazine
hydrochloride. After stirring at 80.degree. C. over night the
solvent is evaporated under reduced pressure yielding 150 mg D-21,
which is used without further purification for the next step.
D-22)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]-3-methoxy-benzoic acid methyl ester
##STR00307##
[0439] A reaction mixture of 3 g (8.93 mmol) A-23 and 2.5 g (13
mmol) B-33 in 20 mL glacial acetic acid is stirred at 60.degree. C.
over night. The solvent is evaporated and the residue is taken up
in 10 mL EtOH. The precipitation is filtered off, washed twice with
4 mL of EtOH and dried yielding 3.30 g D-22.
D-23)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]-3-methoxy-benzoic acid
##STR00308##
[0441] D-23 is made in analoguously to D-25
D-24)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]-3-ethoxy-benzoic acid methyl ester
##STR00309##
[0443] A reaction mixture of 6.72 g (22 mmol) A-23 and 4.29 g (20
mmol) B-34 in 50 mL glacial acetic acid is stirred at RT over
night. The solvent is evaporated and the residue is taken up in
dioxane. After freeze-drying the residue is suspended in 40 mL of
EtOH and sonicated for a few minutes. The solid material is
filtered off and dried yielding 4.80 g of the desired product
D-24.
D-25)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]-3-ethoxy-benzoic acid
##STR00310##
[0445] A solution of 4.80 g (9.44 mmol) D-24 and 1.61 g (37.8 mmol)
LiOH in 60 mL dioxane and 12 mL water is stirred at RT for 2 h. 100
mL water and 1 M aqueous HCl solution are added to the reaction
until pH 4 is reached. More water (150 mL) is added and the formed
precipitation is filtered off, washed five times with 20 mL water
suspended in water and dried in the freeze dryer yielding 4.30 g
D-25.
D-26)
N-[1-(3-Cyano-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyraz-
olo[4,3-g]benzothiazol-7-yl]acetamide
##STR00311##
[0447] A reaction mixture of 5.04 g (15 mmol) A-23 and 2.40 g (16.2
mmol) 3-hydrazino-benzonitrile in 50 mL glacial acetic acid is
stirred at RT over night. The formed precipitation is filtered off,
washed twice with 75 mL glacial acetic acid and dried yielding 4.04
g D-26.
D-27)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]-3-chloro-benzoic acid methyl ester
##STR00312##
[0449] A reaction mixture of 4.16 g (12 mmol) A-23 and 2.79 g (13.2
mmol) 3-chloro-4-hydrazino-benzoic acid methyl ester in 30 mL
glacial acetic acid is stirred at RT over night. The solvent is
evaporated and the residue is taken up in dioxane/water. After
freeze-drying the residue is suspended in 50 mL of EtOH and
sonicated for a few minutes. The solid material is filtered off
washed with 50 mL EtOH and dried yielding 2.61 g D-27.
D-28)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]-3-chloro-benzoic acid
##STR00313##
[0451] A solution of 2.60 g (5.16 mmol) D-27 and 879 mg (20.6 mmol)
LiOH in 30 mL dioxane and 8 mL water is stirred at RT for 2 h. 150
mL water and 1 M aqueous HCl solution are added to the reaction
until pH 4 is reached. More water (150 mL) is added and the formed
precipitate is filtered off, washed five times with 20 mL water
suspended in water and dried in the freeze dryer yielding 1.72 g
D-28.
D-29)
N-[1-[4-(Methoxyimino-methyl)-phenyl]-3-(6-methyl-pyridin-3-yl)-4,5--
dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
##STR00314##
[0453] A reaction mixture of 2.00 g (6.07 mmol) A-23 and 1.74 g
(7.29 mmol) B-31 in 20 mL glacial acetic acid is stirred at RT over
night. The solvent is evaporated under reduced pressure. Water is
added to the residue and it is extracted seven times with DCM. The
combined organic layers are washed with saturated NaCl solution,
dried over Na.sub.2SO.sub.4 and the solvent is evaporated under
reduced pressure yielding 2.68 g D-29.
D-30)
N-[3-(6-Ethyl-pyridin-3-yl)-1-piperidin-4-yl-4,5-dihydro-1H-pyrazolo-
[4,3-g]benzothiazol-7-yl]acetamide
##STR00315##
[0455] D-30 can be synthesized in analoguously to D-14.
EXAMPLES E
E-01)
N-[1-(2-Chloro-4-{[1-cyclobutyl-1-pyrrolidin-1-yl-meth-(E)-ylidene]--
amino}-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]ben-
zothiazol-7-yl]-acetamide
[0456] To a solution of 597 mg (3 mmol)
cyclobutyl-pyrrolidin-1-yl-methanone in 2 mL dry CH.sub.2Cl.sub.2 a
solution of 330 .mu.L (3.9 mmol) oxalyl chloride in 1 mL
CH.sub.2Cl.sub.2 is added and the reaction mixture is stirred at RT
for 1 h. To a solution of 100 mg (0.23 mmol) D01 in 1 mL NMP the
freshly prepared solution of
1-(chloro-cyclobutyl-methylene)-pyrrolidinium chloride in 3 mL
CH.sub.2Cl.sub.2 is added in one portion. The reaction mixture is
stirred for 10 min at RT. The CH.sub.2Cl.sub.2 is evaporated and
the product isolated from the NMP solution by both RP-HPLC and
NP-HPLC. Yield: 81 mg.
[0457] E-02 to E-04 are prepared in a procedure analogous to
example E-01
E-05)
N-[1-[4-(6-Chloro-pyridin-3-yl)-phenyl]-3-(6-methyl-pyridin-3-yl)-4,-
5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0458] Intermediate D-04 (70 mg), 2-chloro-5-bromopyridine (38 mg)
and potassium carbonate (73 mg) are added to DMF (1 mL). The
reaction flask is purged with argon and
tetrakis-(triphenylphosphine)palladium(0) (8 mg) is added. The
reaction is heated to 110.degree. C. for 24 h. The mixture is
cooled to RT, filtered and washed with MeOH (300 .mu.L). The
resulting filtrate is purified using RP-LC/MS (ACN:H.sub.2O-TFA pH
1). Yield: 3 mg.
E-06)
N-[3-(6-Methyl-pyridin-3-yl)-1-(4-thiophen-3-yl-phenyl)-4,5-dihydro--
1H-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]-acetamide
[0459] Intermediate D-04 (70 mg), 3-bromothiophene (33 mg) and
potassium carbonate (73 mg) are added to DMF (1 mL). The reaction
flask is purged with argon and
tetrakis(triphenyl-phosphine)palladium(0) (8 mg) is added. The
reaction is heated to 110.degree. C. for 24 h. The mixture is
cooled to RT, filtered and washed with MeOH (300 .mu.L). The
resulting filtrate is purified using RP-LC/MS (ACN:H.sub.2O-TFA pH
1). Yield: 2 mg.
E-07)
N-[1-(2'-Methoxy-biphenyl-4-yl)-3-(6-methyl-pyridin-3-yl)-4,5-dihydr-
o-1H-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-7-yl]-acetamide
[0460] Intermediate D-04 (70 mg), 2-bromoanisol (37 mg) and
potassium carbonate (73 mg) are added to DMF (1 mL). The reaction
flask was purged with argon and
tetrakis(triphenyl-phosphine)palladium(0) (8 mg) is added. The
reaction is heated to 110.degree. C. for 24 h. The mixture is
cooled to RT, filtered and washed with MeOH (300 .mu.L). The
resulting filtrate is purified using RP-LC/MS (ACN:H.sub.2O-TFA pH
1). Yield: 20 mg, 30.
E-08)
N-{3-(6-Methyl-pyridin-3-yl)-1-[4-(4-methyl-pyridin-3-yl)-phenyl]-4,-
5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl}-acetamide
[0461] Intermediate D-04 (150 mg), 3-bromo-4-methylpyridine (50
.mu.L) and potassium carbonate (390 mg) are added to DMF (5 mL).
The reaction flask is purged with argon and
tetrakis-(triphenylphosphine)palladium(0) (8 mg) is added. The
reaction is heated to 100.degree. C. for 3.5 h. The mixture is
cooled to RT and added to DCM (15 mL). The resulting mixture is
filtered and washed with DCM (15 mL). The DCM is removed under
reduced pressure and the resulting DMF solution is purified using
RP-LC/MS (ACN:H.sub.2O-TFA pH 1). Yield: 16 mg.
E-09)
N-[3-(6-Ethylamino-pyridin-3-yl)-1-(4-pyridin-3-yl-phenyl)-4,5-dihyd-
ro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]-acetamide
[0462] Intermediate D-05 (156 mg), pyridine-3-boronic acid (80 mg)
and potassium carbonate (275 mg) are added to DMF (4 mL). The
reaction flask is purged with argon and
tetrakis-(triphenylphosphine)palladium(0) (35 mg) is added. The
reaction is heated to 100.degree. C. for 24 h. The mixture is
cooled to RT and added to DCM (15 mL). The resulting mixture is
filtered and washed with DCM (15 mL). The DCM was removed under
reduced pressure and the resulting DMF solution is purified using
RP-LC/MS (ACN:H.sub.2O-TFA pH 1). Yield: 49 mg.
E-10)
N-{3-(6-Ethylamino-pyridin-3-yl)-1-[4-(2-methyl-pyridin-4-yl)-phenyl-
]-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl}-acetamide
[0463] Intermediate D-05 (515 mg), 4-methylpyridine-4-boronic acid
pinacol ester (480 mg) and potassium carbonate (990 mg) were added
to DMF (15 mL). The reaction flask was purged with argon and
tetrakis(triphenylphosphine)palladium(0) (120 mg) was added. The
reaction was heated to 100.degree. C. for 24 h. The mixture was
cooled to RT and added to DCM (15 mL). The resulting mixture was
filtered and washed with DCM (15 mL). The DCM was removed under
reduced pressure and the resulting DMF solution was purified using
RP-LC/MS (ACN:H.sub.2O-TFA pH 1). Yield: 120 mg.
E-11)
N-{3-(6-Methylamino-pyridin-3-yl)-1-[4-(2-methyl-pyridin-4-yl)-pheny-
l]-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl}-acetamide
[0464] Intermediate D-06 (500 mg), 2-methylpyridine-4-boronic acid
pinacol ester (480 mg) and potassium carbonate (990 mg) were added
to DMF (15 mL). The reaction flask was purged with argon and
tetrakis(triphenylphosphine)palladium(0) (120 mg) was added. The
reaction was heated to 110.degree. C. for 2 h in the microwave. The
mixture was cooled to RT and added to DCM (15 mL). The resulting
mixture was filtered and washed with DCM (15 mL). The DCM was
removed under reduced pressure and the resulting DMF solution was
purified using RP-LC/MS (ACN:H.sub.2O-TFA pH 1). Yield: 226 mg.
E-12)
4-[(S)-7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[-
4,3-g]benzo-thiazol-1-yl]-cyclohexanecarboxylic acid
methyl-(1-methyl-piperidin-4-yl)-amide
[0465] To a suspension of 40 mg (0.09 mmol) D07 in DMF 45 .mu.L
(0.27 mmol) DIPEA 40 mg (0.11 mmol) HATU are added. The mixture is
stirred at RT for 15 min before 14 .mu.L (0.10 mmol)
1-methyl-4-(methylamino)piperidine are added. The mixture is
stirred overnight. The precipitated product is collected and washed
with a saturated solution of NaHCO.sub.3 and water. Finally, the
product is dried in vacuo. Yield: 30 mg.
[0466] E-13 and E-14 are prepared in a procedure analogous to
example E-12. If the compounds did not precipitate in sufficient
purity they are purified by prep. HPLC-MS.
E-15)
N-[1-[4-(Methoxyimino-methyl)-2-methyl-phenyl]-3-(6-methyl-pyridin-3-
-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0467] Intermediate D-10 (3.3 g) and methoxyamine hydrochloride
(1.3 g) are added to MeOH (20 mL) and allowed to stir at 40.degree.
C. for 30 min. The solvent is then removed under reduced pressure,
5 mL NMP are added and the resulting solution is purified using
RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen carbonate pH 9.3). Yield:
1.78 g.
E-16)
N-[1-[4-(Isopropoxyimino-methyl)-2-methyl-phenyl]-3-(6-methyl-pyridi-
n-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0468] Intermediate D-10 (70 mg) and isopropoxyamine hydrochloride
(42 mg) are added to MeOH (2 mL) and allowed to stir at 40.degree.
C. overnight. The solvent is then removed under reduced pressure,
dissolved in a mixture of MeOH/DCM, and purified using RP-LC/MS
(ACN:H.sub.2O-ammonium hydrogen carbonate pH 9.3). Yield: 48
mg.
E-17)
N-[1-[2-Ethynyl-4-(methoxyimino-methyl)-phenyl]-3-(6-methyl-pyridin--
3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0469] Intermediate D-13 (70 mg), trimethylsilylacetylene (15 mg),
copper(I)iodide (1 mg), bis-(triphenylphosphine)palladium(II)
chloride (5 mg), triphenylphosphine (7 mg), and diethylamine (500
.mu.L) are added to DMSO (500 .mu.L). The reaction is then heated
to 115.degree. C. for 100 seconds in the microwave. The reaction
mixture is filtered and purified using RP-LC/MS
(ACN:H.sub.2O-ammonium hydrogen carbonate pH 9.3). This material is
then dissolved in THF (1 mL) and TBAF (100 .mu.L of a 1 M solution
in THF) is added. The reaction mixture is heated at 40.degree. C.
for 1 h. The reaction mixture is filtered and purified using
RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen carbonate pH 9.3). Yield:
7 mg.
E-18)
N-[1-[4-(Methoxyimino-methyl)-2-prop-1-ynyl-phenyl]-3-(6-methyl-pyri-
din-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0470] Intermediate D-13 (140 mg), lithium chloride (33 mg),
bis-(triphenylphosphine)-palladium(II)chloride (18 mg) and
triphenylphosphie (27 mg) are added to DMSO and allowed to stir at
RT for 5 min. Tributyl(1-propynyl)-tin (171 mg) is then added
portion-wise and the reaction mixture is then heated at 105.degree.
C. for 25 min. The reaction mixture is filtered and purified using
RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen carbonate pH 9.3). Yield:
35 mg.
E-19)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]piperidine-1-carboxylic acid dimethylamide
[0471] To a mixture of D-14 (15 mg, 367 .mu.mol) and triethylamine
(76.3 .mu.L, 551 .mu.mol) in 2 mL THF is added at 0.degree. C.
dimethylcarbamoylchloride (33.7 .mu.L, 367 .mu.mol). The reaction
mixture is stirred overnight at RT. The reaction mixture is
filtered and the solids are dried in vacuo at 40.degree. C. Yield:
15 mg
[0472] E-20 to E-26 are prepared with a procedure analogous to
example E-19.
E-27)
N-{3-(6-Methyl-pyridin-3-yl)-1-[1-(3-pyridin-3-yl-prop-2-ynyl)-piper-
idin-4-yl]-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl}-acetamide
[0473] A mixture of D-14 (10 mg, 245 .mu.mol), formaldehyde (37% in
water, 92 .mu.L, 1.22 mmol), copper(I) bromide (70.2 mg, 490
.mu.mol), 3-ethynylpyridine (50.5 mg, 490 .mu.mol) and molsieves (4
.ANG.) in 5 mL dry dioxane under an argon atmosphare is stirred at
80.degree. C. for 1 h. The reaction mixture is filtered, DCM added
and the reaction mixture is washed with water and brine. The
organic phase is dried over MgSO.sub.4 and concentrated in vacuo.
The residue is purified by preparative RP-HPLC (5-98% ACN in
water). Yield: 8.2 mg.
[0474] Example E-28 is prepared analogous to example E-27.
E-30)
N-[3-(6-Methyl-pyridin-3-yl)-1-(1-pyridin-2-ylmethyl-piperidin-4-yl)-
-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0475] A mixture of D-14 (8.00 g, 19.6 mmol),
2-pyridinecarboxaldehyde (3.15 g, 29.4 mmol) and acetic acid (3.7
mL, 43.1 mmol) in 60 mL MeOH/DCM (1/1, v/v) is stirred for 2 h at
RT. Then sodium trisacetoxyborohydride (12.5 g, 58.5 mmol) is added
and the reaction mixture is stirred overnight at RT and then 2 h at
40.degree. C. The reaction mixture is poured on saturated aqueous
sodium hydrogencarbonate and extracted with DCM containing 10%
MeOH. The combined organic phases are dried over Na.sub.2SO.sub.4
and concentrated in vacuo. The residue is purified by triturating
with ethyl acetate, flash chromatography (silica gel, 0-10% MeOH in
DCM containing 0.5% ammonia) and finally by triturating with EtOH
and dioxane. Yield: 3.61 g.
[0476] E-29 and E-31 are prepared with a procedure analogous to
example E-30.
E-32)
[1-[4-(Methoxyimino-methyl)-phenyl]-3-(6-methyl-pyridin-3-yl)-4,5-di-
hydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]urea
[0477] A solution of 50 mg (010 mmol) D-15 and ammonia in 1 mL NMP
is stirred at 90.degree. C. over night. The reaction mixture is
purified using RP-LC/MS (ACN:H.sub.2O-TFA pH 1-2). Yield: 1.13
mg.
E-33)
N-[1-[4-(Methoxyimino-methyl)-phenyl]-3-(6-methyl-pyridin-3-yl)-4,5--
dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]-propionamide
[0478] To a solution of 50 mg (0.12 mmol) D-16 in 1 mL NMP is added
60 .mu.L (0.351 mmol) diisopropylethylamine and 32 .mu.L (0.367
mmol) propionyl chloride and stirred at RT for 6 h. The reaction
mixture is purified using RP-LC/MS (ACN:H.sub.2O-formic acid pH
2-3). Yield: 20 mg.
E-34)
2-Methoxy--N-[1-[4-(methoxyimino-methyl)-phenyl]-3-(6-methyl-pyridin-
-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0479] To a solution of 100 mg (0.204 mmol) D-16 in 1 mL NMP is
added 102 .mu.L (0.597 mmol) diisopropylethylamine and 60 .mu.L
(0.658 mmol) methoxy-acetyl chloride and stirred at RT over night.
The reaction mixture is purified using RP-LC/MS
(ACN:H.sub.2O-formic acid pH 2-3). Yield: 46.9 mg.
E-35)
2-Hydroxy--N-[1-[4-(methoxyimino-methyl)-phenyl]-3-(6-methyl-pyridin-
-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0480] To a solution of 453 mg (0.331 mmol) D-16 in 1 mL NMP is
added 165 .mu.L (0.964 mmol) diisopropylethylamine and 226 L (1.99
mmol) acetoxy-acetyl chloride and stirred at RT for 30 min. 20 mL
Water are added to the reaction and the resultant mixture is
extracted three times with 25 mL DCM. The combined organic layers
are dried over Na.sub.2SO.sub.4 and the solvent is evaporated under
reduced pressure. The isolated crude product is dissolved in 5 mL
MeOH and 2 mL (33.1 mmol, 32%) ammonia solution is added. After
stirring at RT for 2 h the solvent is evaporated under reduced
pressure and the residue is taken up in NMP. The reaction mixture
is purified using RP-LC/MS (ACN:H.sub.2O-formic acid pH 2-3).
Yield: 22.7 mg.
E-36) Cyclobutanecarboxylic acid
[1-isopropyl-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benz-
othiazol-7-yl]amide
[0481] Intermediate D-17 (150 mg) and di-isopropylethyl amine (0.18
g) are dissolved in NMP (1 mL). Cyclobutanecarbonyl chloride (0.16
g) is then added and the reaction mixture is allowed to stir at RT
for 2 h. MeOH (1 mL) and 1 drop of HCL (conc.) is added and allowed
to stir for 10 min at RT. The reaction mixture is filtered and
purified using RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen carbonate
pH 9.3). Yield: 52 mg.
E-37)
N-[1-Isopropyl-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-
-g]benzothiazol-7-yl]isobutyramide
[0482] Intermediate D-17 (150 mg) and di-isopropylethyl amine (0.18
g) are dissolved in NMP (1 mL). isobuteric acid chloride (0.15 g)
is then added and the reaction mixture is stirred at RT for 2 h.
MeOH (1 mL) and 1 drop of HCL (conc.) is then added and the mixture
stirred for 10 min at RT. The reaction mixture is filtered and
purified using RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen carbonate
pH 9.3). Yield: 57 mg.
E-38) Cyclopropanecarboxylic acid
[1-isopropyl-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benz-
othiazol-7-yl]-amide
[0483] Cyclopropylcarboxylic acid (0.12 g), diisopropylethyl amine
(0.12 g) and TBTU (0.44 g) are dissolved in DCM (1 mL) and allowed
to react at 30.degree. C. for 30 min. A solution of intermediate
D-17 (150 mg) in NMP (1 mL) is then added dropwise to reaction
mixture which is then heated at 90.degree. C. for 4 h. MeOH (1 mL)
and 1 drop of HCL (conc.) is then added and the mixture stirred for
10 min at RT. The reaction mixture is filtered and purified using
RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen carbonate pH 9.3). Yield:
70 mg.
E-39)
N-[1-Isopropyl-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-
-g]benzothiazol-7-yl]formamide
[0484] Formic acid (0.53 mL) and acetic acid anhydride (0.65 mL)
are added together and stirred at 30.degree. C. for 30 min. The
solution is cooled to 0.degree. C. and intermediate D-17 (150 mg)
is added. The reaction is allowed to react overnight at 30.degree.
C. The reaction mixture is then added to isopropanol (10 mL) and
the resulting solid is removed via filtration and dried in vacuo.
Yield: 119 mg.
E-40)
[1-[4-(4-Methyl-piperazin-1-yl)-phenyl]-3-(6-methyl-pyridin-3-yl)-4,-
5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]-carbamic acid methyl
ester
[0485] To a solution of 200 mg (0.302 mmol) D-18 in 2 mL DMSO is
added under nitrogen 105 mg (0.936 mmol) potassium
2-methyl-propan-2-olate, 70 mg (0.103 mmol) PEPPSI and 70 .mu.L
(0.630 mmol) 1-methyl-piperazine. The reaction mixture is heated
under microwave irradiation at 130.degree. C. for 45 min. The
reaction mixture is purified using RP-LC/MS (ACN:H.sub.2O-ammonium
hydrogen carbonate pH 9.3). Yield: 10.9 mg.
E-41)
[1-{4-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-3-(6-meth-
yl-pyridin-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]-carbamic
acid methyl
[0486] To a solution of 200 mg (0.302 mmol) D-18 in 2 mL DMSO is
added under nitrogen 105 mg (0.936 mmol) potassium
2-methyl-propan-2-olate, 70 mg (0.103 mmol) PEPPSI and 110 mg
(0.600 mmol) 1-methyl-4-piperidin-4-yl-piperazine. The reaction
mixture is heated under microwave irradiation (Biotage) at
130.degree. C. for 45 min. The reaction mixture is purified using
RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen carbonate pH 9.3). Yield:
4.6 mg.
E-42)
4-{7-Acetylamino-3-[6-(3-dimethylamino-prop-1-ynyl)-pyridin-3-yl]-4,-
5-dihydro-pyrazolo[4,3-g]benzothiazol-1-yl}-3-chloro--N,N-dimethyl-benzami-
de
[0487] A reaction mixture of 70 mg (0.133 mmol) D-19, 13.2 g (0.159
mmol) dimethyl-prop-2-ynyl-amine, 2.52 mg (0.013 mmol) CuI, 9.32 mg
(0.013 mmol) bis-(triphenyl-phosphane)-palladium(II) dichloride and
6.96 mg (0.027 mmol) triphenyl-phosphane in 500 .mu.L diethylamine
and 500 .mu.L DMSO under argon is heated under microwave
irradiation (Biotage) at 90.degree. C. for 90 min. The reaction
mixture is purified using RP-LC/MS (ACN:H.sub.2O-formic acid pH
2-3). Yield: 20 mg.
E-43)
4-{7-Acetylamino-3-[6-(3-methoxy-prop-1-ynyl)-pyridin-3-yl]-4,5-dihy-
dro-pyrazolo[4,3-g]benzothiazol-1-yl}-3-chloro--N,N-dimethyl-benzamide
[0488] A reaction mixture of 100 mg (0.190 mmol) D-19, 29 .mu.L
(0.341 mmol) 3-methoxy-propyne, 3.6 mg (0.019 mmol) CuI, 26.6 mg
(0.038 mmol) bis-(triphenyl-phosphane)-palladium(II) dichloride and
9.94 mg (0.038 mmol) triphenyl-phosphane in 500 .mu.L diethylamine
and 500 .mu.L DMSO under argon is heated under microwave
irradiation (Biotage) at 100.degree. C. for 120 min. The reaction
mixture is purified using RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen
carbonate pH 9.3). Yield: 30 mg.
E-44)
4-[7-Acetylamino-3-(6-cyclopropylethynyl-pyridin-3-yl)-4,5-dihydro-p-
yrazolo[4,3-g]benzothiazol-1-yl]-3-chloro--N,N-dimethyl-benzamide
[0489] A reaction mixture of 70 mg (0.133 mmol) D-19, 15.8 mg
(0.239 mmol) ethynyl-cyclopropane, 2.52 mg (0.013 mmol) CuI, 9.32
mg (0.013 mmol) bis-(triphenyl-phosphane)-palladium(II) dichloride
and 6.96 mg (0.027 mmol) triphenyl-phosphane in 500 .mu.L
diethylamine and 500 .mu.L DMSO under argon is heated under
microwave irradiation at 100.degree. C. for 150 min. The reaction
mixture is purified using RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen
carbonate pH 9.3). Yield: 26 mg.
E-45)
4-{17-Acetylamino-3-[6-(3-hydroxy-prop-1-ynyl)-pyridin-3-yl]-4,5-dih-
ydro-pyrazolo[4,3-g]benzothiazol-1-yl}-3-chloro--N,N-dimethyl-benzamide
[0490] A reaction mixture of 70 mg (0.133 mmol D-19, 8.93 mg (0.159
mmol) prop-2-yn-1-ol, 2.52 mg (0.013 mmol) CuI, 9.32 mg (0.013
mmol) bis-(triphenyl-phosphane)-palladium(II) dichloride and 6.96
mg (0.027 mmol) triphenyl-phosphane in 500 .mu.L diethylamine and
500 .mu.L DMSO under argon is heated under microwave irradiation at
100.degree. C. for 30 min. The reaction mixture is purified using
RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen carbonate pH 9.3). Yield:
23 mg.
E-46)
4-[7-Acetylamino-3-(6-phenylethynyl-pyridin-3-yl)-4,5-dihydro-pyrazo-
lo[4,3-g]benzothiazol-1-yl]-3-chloro--N,N-dimethyl-benzamide
[0491] A reaction mixture of 150 mg (0.284 mmol) D-19, 34.9 mg
(0.341 mmol) ethynylbenzene, 5.4 mg (0.028 mmol) CuI, 20.0 mg
(0.028 mmol) bis-(triphenyl-phosphane)-palladium(II) dichloride and
14.9 mg (0.057 mmol) triphenyl-phosphane in 500 .mu.L diethylamine
and 500 .mu.L DMSO under argon is heated under microwave
irradiation (Biotage) at 100.degree. C. for 60 min. The reaction
mixture is purified using RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen
carbonate pH 9.3). Yield: 8 mg.
E-47)
3-[3-(6-Ethylamino-pyridin-3-yl)-1-o-tolyl-4,5-dihydro-1H-pyrazolo[4-
,3-g]benzothiazol-7-yl]-1,1-dimethyl-urea
[0492] To 700 .mu.L of a 1 M solution of dimethylamine in THF is
added 170 mg (0.346 mmol) D-20. The reaction mixture is heated at
85.degree. C. for 2 h, TFA is added to the reaction mixture and
purification is performed using RP-LC/MS (ACN:H.sub.2O-TFA pH 1-2).
Yield: 109 mg.
E-48)
1-Ethyl-3-[3-(6-ethylamino-pyridin-3-yl)-1-o-tolyl-4,5-dihydro-1H-py-
razolo[4,3-g]benzothiazol-7-yl]-1-methyl-urea
[0493] A solution of 170 mg (0.346 mmol) D-20 and 60 .mu.L (0.698
mmol) ethylmethylamine in 200 .mu.L THF is heated at 85.degree. C.
for 2 h. The solid material is filtered off and the filtrate is
purified performed using RP-LC/MS (ACN:H.sub.2O-TFA pH 1-2). Yield:
54.3 mg.
E-49) Azetidine-1-carboxylic acid
[1-(2-chloro-phenyl)-3-(6-methylamino-pyridin-3-yl)-4,5-dihydro-1H-pyrazo-
lo[4,3-g]benzothiazol-7-yl]amide
[0494] A solution of 200 mg (0.42 mmol) D-21, 240 .mu.L (4.2 mmol)
azetidine and 271 .mu.L (2.1 mmol) diisopropylethylamine in 10 mL
isopropanol is heated under microwave irradiation at 100.degree. C.
for 40 min. The solvent is evaporated under reduced pressure, the
residue is taken up in NMP and 3 drops of TFA are added. The
solution is purified with RP-LC/MS (ACN:H.sub.2O-TFA pH 1-2).
Yield: 65 mg.
E-50)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]-3,N-dimethoxy--N-methyl-benzamide
[0495] Intermediate D-23 (500 mg), diisopropylethylamine (0.5 g)
and HATU (0.6 g) are dissolved in DCM (10 mL). The reaction mixture
is stirred at RT for 10 min, then 1,2-dimethylhydroxylamine (0.12
g) is added and stirred for 1 h at RT. Then the solvent is removed
under reduced pressure and isopropanol (5 mL) is added followed by
water (5 mL). The resulting precipitate is collected via
filtration, washed with water (5 mL) and the solid is dried under
reduced pressure. Yield: 460 mg.
E-51)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]-3-ethoxy--N,N-dimethyl-benzamide
[0496] Intermediate D-25 (500 mg), 1,1'-carbonyldiimidazole (96 mg)
are added to ethylacetate (2.4 mL) and NMP (0.6 mL). The reaction
mixture is then stirred at RT for 30 min. Dimethylamine (250 .mu.L,
2 M solution in THF) is then added and allowed to react at RT
overnight. The solvent is then removed under reduced pressure,
dissolved in NMP, filtered and purified using RP-LC/MS
(ACN:H.sub.2O-ammonium hydrogen carbonate pH 9.3). Yield: 124
mg.
E-52)
N-[1-[3-(Methoxyimino-methyl)-phenyl]-3-(6-methyl-pyridin-3-yl)-4,5--
dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0497] Intermediate D-26 (106 mg) and methoxylamine hydrochloride
(128 mg) is dissolved in DCM/MeOH (50:50, 20 mL). Raney nickel (220
mg) and sodium hypophosphite hydrate (220 mg) are then added at RT
and the reaction mixture is stirred for 2 h. The resulting mixture
is filtered and the filtrate is reduced under reduced pressure. The
resulting oil is filtered and the filtrate dissolved in NMP and
purified using RP-LC/MS (ACN:H.sub.2O-formic acid pH 2-3). Yield:
10 mg.
E-53)
4-[7-Acetylamino-3-(6-methyl-pyridin-3-yl)-4,5-dihydro-pyrazolo[4,3--
g]benzothiazol-1-yl]-3-chloro-benzoic acid ethyl ester
[0498] Intermediate D-28 (73 mg) and HATU (0.67 g) are dissolved in
NMP (1 mL) and stirred for 20 min at RT. Diisopropylethylamine (30
.mu.L) and EtOH (63 .mu.L) are then added and stirred at RT for 4
h. The reaction mixture is then filtered and purified using
RP-LC/MS (ACN:H.sub.2O-ammonium hydrogen carbonate pH 9.3). Yield:
34 mg.
E-54)
N-[1-[2-Chloro-4-(4-fluoro-piperidine-1-carbonyl)-phenyl]-3-(6-methy-
l-pyridin-3-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0499] Intermediate D-28 (100 mg), TBTU (100 mg), diisopropylethyl
amine (106 .mu.l) are dissolved in DMF (1 mL) and stirred at
35.degree. C. overnight. The reaction mixture is then filtered and
purified using RP-LC/MS (ACN:H.sub.2O-TFA pH 1). Yield: 15 mg.
E-55)
N-[1-(4-Acetyl-2-methoxy-phenyl)-3-(6-methyl-pyridin-3-yl)-4,5-dihyd-
ro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]acetamide
[0500] E-50 (250 mg) is dissolved in THF (15 mL) and placed under
an atmosphere of argon. A methyllithium solution (1.5 M, 2.6 mL) is
then added over 1 min and the reaction mixture stirred at RT for a
further 1 h. Saturated ammonium chloride solution (1 mL) is added
and the THF is removed under reduced pressure. The resulting
material is dissolved in DMSO (1.8 mL) and water (0.2 mL) and
purified using RP-LC/MS (ACN:H.sub.2O-TFA pH 1). Yield: 12 mg.
TABLE-US-00002 TABLE 2 Examples E-01-E-55 No. MOLSTRUCTURE
Intermediate [M + H].sup.+ rt E-01 ##STR00316## D-01 586 1.29 E-02
##STR00317## D-01 576 1.15 E-03 ##STR00318## D-01 546 1.16 E-04
##STR00319## D-02 516 1.09 E-05 ##STR00320## D-04 513 1.17 E-06
##STR00321## D-04 484 2.14 E-07 ##STR00322## D-04 508 1.27 E-08
##STR00323## D-04 493 1.14 E-09 ##STR00324## D-05 508 1.1 E-10
##STR00325## D-05 522 1.16 E-11 ##STR00326## D-06 508 1.1 E-12
##STR00327## D-07 562 1.05 E-13 ##STR00328## D-08 562 1.11 E-14
##STR00329## D-08 507 1.22 E-15 ##STR00330## D-10 473 1.16 E-16
##STR00331## D-10 501 1.28 E-17 ##STR00332## D-13 483 1.15 E-18
##STR00333## D-13 497 1.19 E-19 ##STR00334## D-14 480 t0 E-20
##STR00335## D-14 516 1.51 E-21 ##STR00336## D-14 490 1.03 E-22
##STR00337## D-14 491 2.05 E-23 ##STR00338## D-14 500 1.05 E-24
##STR00339## D-30 501 1.09 E-25 ##STR00340## D-14 494 0.99 E-26
##STR00341## D-14 491 1.06 E-27 ##STR00342## D-14 524 1.07 E-28
##STR00343## D-14 505 1.09 E-29 ##STR00344## D-14 506 1.83 E-30
##STR00345## D-14 514 1.87 E-31 ##STR00346## D-14 503 2.01 E-32
##STR00347## D-15 460 1.11 E-33 ##STR00348## D-16 473 1.21 E-34
##STR00349## D-16 489 1.06 E-35 ##STR00350## D-16 475 1.01 E-36
##STR00351## D-17 408 2.13 E-37 ##STR00352## D-17 396 2.1 E-38
##STR00353## D-17 394 2.01 E-39 ##STR00354## D-17 354 1.77 E-40
##STR00355## D-18 516 t0 E-41 ##STR00356## D-18 599 t0 E-42
##STR00357## D-19 574 1.08 E-43 ##STR00358## D-19 561 1.05 E-44
##STR00359## D-19 557 1.13 E-45 ##STR00360## D-19 547 0.99 E-46
##STR00361## D-19 593 1.24 E-47 ##STR00362## D-20 474 1.15 E-48
##STR00363## D-20 488 1.25 E-49 ##STR00364## D-21 E-50 ##STR00365##
D-23 519 1.03 E-51 ##STR00366## D-25 517 1.03 E-52 ##STR00367##
D-26 459 1.44 E-53 ##STR00368## D-28 508 1.17 E-54 ##STR00369##
D-28 565 1.1 E-55 ##STR00370## E-50 474 1.05
EXAMPLES F
[0501] Examples F-01 to F-20 can be synthesized according to one of
the following general procedures. The appropriate acid or acid
chloride required for synthesis can be deduced from the table of
examples. Boc-groups are removed with HCl (5-10 eq.) by stirring
overnight in dioxane at 40.degree. C.
[0502] General Procedure F1:
[0503] Example D-17 (1 eq.) is taken up in NMP and sonicated until
all material is dissolved. DMAP (0.1 eq.), DIPEA (5 eq.) and acid
chloride (5 eq.) are added and the reaction mixture is stirred for
1 h at RT. The reaction mixture is poured in water and extracted
with DCM. The organic phases are concentrated under reduced
pressure and the product is purified by flash column chromatography
(silica gel, 0-20% MeOH in DCM).
[0504] General Procedure F2:
[0505] The acid (1 eq.) is taken up in DCE, CDI (1 eq.) is added
and the reaction mixture is stirred for 2 h at RT. Then 50%
saturated brine is added and the reaction mixture is stirred
vigorously for 1 min. The organic phase is separated, concentrated
under reduced pressure, taken up in acetonitrile and added to a
mixture of example D-17 (0.25 eq.) and DBU (0.5 eq.). The resulting
reaction mixture is then stirred at 100.degree. C. for 2 h. The
reaction mixture is concentrated under reduced pressure, poured in
water, brought to pH 8 by the addition of an aqueous saturated
ammonium chloride solution and extracted with ethyl acetate
containing 5% MeOH. The combined organic phase are washed with an
aqueous 1% citric acid solution and brine, dried on magnesium
sulfate and concentrated under reduced pressure. The product is
purified by flash column chromatography (silica gel, 0-20% MeOH in
DCM).
[0506] General Procedure F3:
[0507] The acid (2 eq.) and 2,4,6-trichloro-1,3,5-triazine (1 eq.)
are taken up in NMP and stirred for 15 min at RT. Example D-17 (1
eq.), DBU (4 eq.) and DMAP (0.1 eq.) are taken up in NMP and
stirred at RT for 10 min. Both reaction mixtures are combined and
stirred overnight at 70.degree. C. The reaction mixture is poured
in water and extracted with DCM. The organic phases are
concentrated under reduced pressure and the product is purified by
flash column chromatography (silica gel, 0-20% MeOH in DCM).
TABLE-US-00003 TABLE 3 Examples F-01-F-20 No. MOLSTRUCTURE Acid or
acid chloride [M + H].sup.+ rt F-01 ##STR00371## propionyl chloride
382 3.36 F-02 ##STR00372## butyryl chloride 396 1.62 F-03
##STR00373## methoxy-acetyl chloride 398 1.18 F-04 ##STR00374##
3-methyl-butyryl chloride 410 1.73 F-05 ##STR00375##
3-methyl-but-2-enoyl chloride 408 1.73 F-06 ##STR00376##
pyridin-3-yl-acetic acid 445 1.28 F-07 ##STR00377##
4-1,2,4-triazol-1-yl-butyric acid 463 1.27 F-08 ##STR00378##
3-pyridin-2-yl-propionic acid 459 1.53 F-09 ##STR00379##
imidazol-1-yl-acetic acid 434 0.95 F-10 ##STR00380##
1,2,4-triazol-1-yl-acetic acid 435 2.45 F-11 ##STR00381##
3-methoxy-propionic acid 412 1.66 F-12 ##STR00382##
N,N-dimethyl-succinamic acid 453 1.58 F-13 ##STR00383##
(S)-pyrrolidine-1,2- dicarboxylic acid 1-tert-butyl ester 423 1.41
F-14 ##STR00384## (R)-pyrrolidine-1,2- dicarboxylic acid
1-tert-butyl ester 423 1.33 F-15 ##STR00385##
(tert-butoxycarbonyl-methyl- amino)-acetic acid 397 1.24 F-16
##STR00386## 4-dimethylamino-butyric acid 439 1.76 F-17
##STR00387## (1,4-dimethyl-piperazin-2- y1)-acetic acid 480 1.52
F-18 ##STR00388## 3-(3H-imidazol-4-y1)- propionic acid 448 1.53
F-19 ##STR00389## 3-(1-methyl-1H-imidazol-2- yl)-propionic acid 462
1.56 F-20 ##STR00390## chloro-acetyl chloride 402/404
EXAMPLES G
[0508] Examples G-01 to G-05 can be synthesized according to the
following general procedure. The appropriate amine required for
synthesis can be deduced from the table of examples.
[0509] General Procedure G:
[0510] Example F-20 (1 eq.) is taken up in NMP, DIPEA (2 eq.) and
amine (3 eq.) are added and the reaction mixture is stirred
overnight at RT. The reaction mixture is poured in water, extracted
with DCM and the organic phase is loaded on a SCX column. The
column is washed with DCM and methanol and the product is eluted
with a mixture of DCM and 7N ammonia in methanol. The product is
further purified by flash column chromatography (silica gel, 0-20%
methanol in DCM).
TABLE-US-00004 TABLE 4 Examples G-01 - G-05 No MOLSTRUCTURE Amine
[M + H].sup.+ rt G-01 ##STR00391## morpholine 453 1.33 G-02
##STR00392## dimethyl-amine 411 1.38 G-03 ##STR00393## piperidine
451 1.77 G-04 ##STR00394## pyrrolidine 437 1.51 G-05 ##STR00395##
1-methyl-piperazine 466 1.34
EXAMPLES H
[0511] Examples H-01 to H-14 can be synthesized according to the
following general procedure. The appropriate amine or alcohol
required for synthesis can be deduced from the table of
examples.
[0512] General Procedure H:
[0513] Example D-17 (1 eq.), DBU (2 eq.) and CDI (2.5 eq.) are
taken up in acetonitrile and stirred at 100.degree. C. overnight.
Amine or alcohol (5 eq.) is added and the reaction mixture is
stirred again overnight at 100.degree. C. The reaction mixture is
concentrated under reduced pressure and the product is purified by
HPLC (C-18, 2-98% acetonitrile in water).
TABLE-US-00005 TABLE 5 Examples H-01-H-14 No. MOLSTRUCTURE Amine [M
+ H].sup.+ rt H-01 ##STR00396## O-methyl-hydroxylamine 400 1.37
H-02 ##STR00397## methylamine 383 1.72 H-03 ##STR00398##
pyrrolidine 423 1.90 H-04 ##STR00399## morpholine 439 1.15 H-05
##STR00400## 1-methylpiperazine 452 1.59 H-06 ##STR00401##
ethylamine 397 1.60 H-07 ##STR00402## ammonium chloride 369 1.26
H-08 ##STR00403## dimethylamine 397 1.58 H-09 ##STR00404##
2-dimethylamino-ethanol 441 1.47 H-10 ##STR00405##
N,N-dimethyl-ethylane-1,2- diamine 440 1.63 H-11 ##STR00406##
2-morpholin-4-yl-ethylamine 482 1.59 H-12 ##STR00407##
2-methoxy-ethanol 428 1.50 H-13 ##STR00408##
2-morpholin-4-yl-ethanol 483 1.49 H-14 ##STR00409##
3-dimethylamino-propan-1-ol 455 1.63
EXAMPLES J
[0514] Examples J-01 to J-02 can be synthesized according to the
following general procedure. The appropriate example C can be
deduced from the table of examples.
[0515] General Procedure J:
[0516] To a mixture of 400 mg (0.92 mmol)
N-[1-(2-chloro-pyridin-3-yl)-3-(6-methylamino-pyridin-3-yl)-4,5-dihydro-1-
H-pyrazolo[4,3-g]benzothiazol-7-yl]-acetamide, 2.5 mL (18.3 mmol)
Trimethylboroxide and 16 mg (0.022 mmol)
bis(triphenylphosphine)palladium(II)-dichloride is added 10 mL DME,
2 mL ethanol and 1.37 mL of an aqueous 2 M Cs.sub.2CO.sub.3
solution. The reaction mixture is heated in the microwave for 2 h
at 130.degree. C. DCM (25 mL) and water (25 mL) are added and the
phases are separated. The aqueous phase is washed twice with DCM
(2.times.25 mL each). The combined organic layers are dried over
sodium sulfate and the solvent is removed under reduced pressure.
The crude material is dissolved in DMSO/TFA and purified using
RP-LC/MS. The resulting product fractions are collected and the
solvent is removed via freeze-drying to yield the desired
product.
TABLE-US-00006 TABLE 6 Examples J-01-J-02 No. MOLSTRUCTURE
Heteroaryl chloride [M + H].sup.+ rt J-01 ##STR00410## C-117 417
1.29 J-02 ##STR00411## C-118 432 1.21
[0517] Analytical Method
[0518] HPLC: Agilent 1100 Series
[0519] MS: Agilent LC/MSD SL
[0520] column: Phenomenex, Mercury Gemini C18, 3 .mu.m,
2.0.times.20 mm, [0521] Part.No. 00M-4439-B0-CE
[0522] solvent A: 5 mM NH.sub.4HCO.sub.3/20 mM NH.sub.3 [0523] B:
acetonitrile HPLC grade
[0524] detection: MS: Positive and negative [0525] mass range:
120-700 m/z [0526] fragmentor: 70 [0527] gain EMV: 1 [0528]
threshold: 150 [0529] stepsize: 0.25 [0530] UV: 315 nm [0531]
bandwidth: 170 nm [0532] reference: off [0533] range: 210-400 nm
[0534] range step: 2.00 nm [0535] peakwidth: <0.01 min [0536]
slit: 2 nm
[0537] injection: 5 .mu.L
[0538] flow: 1.00 mL/min
[0539] column temperature: 40.degree. C.
[0540] gradient: 0.00 min 5% B [0541] 0.00-2.50 min 5%.fwdarw.95% B
[0542] 2.50-2.80 min 95% B [0543] 2.81-3.10 min 95%.fwdarw.5% B
[0544] Instrument: Agilent 1100--SL: incl. DAD/MSD
[0545] Chromatography: [0546] Column: Waters X-Bridge.TM. C18,
50.times.2.1 mm, 3.5.mu.
[0547] Method "Acid" [0548] Eluent A: 0.1% formic acid in
acetonitrile [0549] Eluent B: 0.1% formic acid in water [0550]
Linear Gradient program: t.sub.0=2% A, t.sub.4 min=98% A,
t.sub.6min=98% A [0551] Flow: 0.8 mL/min [0552] Column oven
temperature: 35.degree. C.
[0553] Method "Base" [0554] Eluent A: 10 mM ammonia in acetonitrile
[0555] Eluent B: 10 mM ammonia in water [0556] Linear Gradient
program: t.sub.0=2% A, t.sub.4 min=98% A, t.sub.6min=98% A [0557]
Flow: 0.8 mL/min [0558] Column oven temperature: 25.degree. C.
[0559] Diode Array Detector (DAD): [0560] Instrument: Agilent
G1316A [0561] Sample wavelength: 220-320 nm [0562] Reference
wavelength: Off
[0563] Mass Spectroscopy (MSD): [0564] Instrument: Agilent
LC/MSD--SL [0565] Ionisation: ESI (Positive & Negative) [0566]
Mass range: 100-800
TABLE-US-00007 [0566] Abbreviations used bu butyl tert tertiary d
day(s) THF tetrahydrofuran DC thin layer chromatography LiHMDS
Lithium hexamethyl disilazide DCM dichloromethan iPr isopropyl DMF
N,N-dimethylformamide TBME tertiary butylmethylether DMSO
dimethylsulphoxide NP normal phase et ethyl CDI carbonyl
diimidazole h hour(s) ACN acetonitrile HPLC high performance liquid
BINAP 2R,3S,2,2'-bis-(diphenyl-phosphino)- chromatography
1,1'-binapthyl M molar DIPEA diisopropylethyl amine min minute(s)
DCE 1,2-dichloroethane mL millilitre NMP N-methylpyrrolindinone MS
mass spectrometry prep preparative N normal conc. concentrated NMR
nuclear resonance TFA trifluoroacetic acid spectroscopy ppm part
per million HATU N-[(dimethylamino)-(1H-1,2,3-
triazolo[4,5-b]pyridin-1-yl)- methylene]-N-methylmethan-aminium
hexafluorophosphate N-oxide Rf retention factor TBAF
Tetrabutylammonium fluoride RP reversed phase TBTU
O-(Benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium
tetrafluoro-borate RT room temperature PEPPSI
[1,3-Bis(2,6-Diisopropylphenyl)- imidazol-2-ylidene](3-chloro-
pyridyl)palladium(II) dichloride Rt retention time m.p melting
point DMAP dimethyl-pyridin-4-yl- DBU
1,8-diazabicyclo[5.4.0]undec-7-ene amine
[0567] The Examples that follow describe the biological activity of
the compounds according to the invention without restricting the
invention to these Examples.
[0568] PC3 Proliferation Test
[0569] The test is based on measurement of cellular DNA content via
fluorescent dye binding. Because cellular DNA content is highly
regulated, it is closely proportional to cell number. The extent of
proliferation is determined by comparing cell counts for samples
treated with drugs with untreated controls.
[0570] PC3 (human prostate carcinoma cell line) cells are sown in
microtitre plates and incubated overnight in culture medium at
37.degree. C. and 5% CO.sub.2. The test substances are diluted
stepwise and added to the cells such that the total volume is 200
.mu.L/well. Cells to which diluent, but not substance, is added
serve as controls. After an incubation time of 3 days, the medium
is replaced by 100 .mu.L/well dye-binding solution and the cells
are incubated at 37.degree. C. in the dark for a further 60 min.
For measuring the fluorescence, excitation takes place at a
wavelength of 485 nm and the emission is measured at 530 nm.
[0571] EC.sub.50 values are calculated using the GraphPad Prism
program.
[0572] Most compounds of the Examples cited have an EC.sub.50
(Proliferation PC3) of less than 0.5 .mu.M.
[0573] P-AKT Measurement in PC3 Cells
[0574] P-AKT levels in PC3 cells are detected by cell-based ELISA.
Cells are cultured in 96-well plates and treated with serial
dilutions of test substances for 2 h. Cells to which diluent, but
not substance, is added serve as controls. Subsequently, the cells
are fixed rapidly to preserve protein modifications. Each well is
then incubated with a primary antibody specific for
Ser473-phosphorylated AKT. Subsequent incubation with secondary
HRP-conjugated antibody and developing solution provides a
colorimetric readout at 450 nm. EC.sub.50 values are calculated
using the GraphPad Prism program.
[0575] Most compounds of the Examples cited have an EC.sub.50
(P-AKT PC3) of less than 0.5 .mu.M.
[0576] The substances of the present invention are PI3 kinase
inhibitors. On account of their biological properties, the novel
compounds of the general formula (1) and their isomers and their
physiologically tolerated salts are suitable for treating diseases
which are characterized by excessive or anomalous cell
proliferation.
[0577] These diseases include, for example: viral infections (e.g.
HIV and Kaposi's sarcoma); inflammation and autoimmune diseases
(e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis
and wound healing); bacterial, fungal and/or parasitic infections;
leukaemias, lymphomas and solid tumours; skin diseases (e.g.
psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis
and hypertrophy). In addition, the compounds are useful for
protecting proliferating cells (e.g. hair cells, intestinal cells,
blood cells and progenitor cells) from DNA damage due to
irradiation, UV treatment and/or cytostatic treatment (Davis et
al., 2001).
[0578] For example, the following cancers may be treated with
compounds according to the invention, without being restricted
thereto:
brain tumours such as for example acoustic neurinoma, astrocytomas
such as fibrillary, protoplasmic, gemistocytary, anaplastic,
pilocytic astrocytomas, glioblastoma, gliosarcoma, pleomorphic
xanthoastrocytoma, subependymal large-cell giant cell astrocytoma
and desmoplastic infantile astrocytoma; brain lymphomas, brain
metastases, hypophyseal tumour such as prolactinoma, hypophyseal
incidentaloma, HGH (human growth hormone) producing adenoma and
corticotrophic adenoma, craniopharyngiomas, medulloblastoma,
meningeoma and oligodendroglioma; nerve tumours such as for example
tumours of the vegetative nervous system such as neuroblastoma,
ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and
glomus-caroticum tumour, tumours on the peripheral nervous system
such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma,
Schwannoma) and malignant Schwannoma, as well as tumours of the
central nervous system such as brain and bone marrow tumours;
intestinal cancer such as for example carcinoma of the rectum,
colon, anus and duodenum; eyelid tumours (basalioma or
adenocarcinoma of the eyelid apparatus); retinoblastoma; carcinoma
of the pancreas; carcinoma of the bladder; lung tumours (bronchial
carcinoma--small-cell lung cancer (SCLC), non--Small-cell lung
cancer (NSCLC) such as for example spindle-cell plate epithelial
carcinomas, adenocarcinomas (acinary, paillary,
bronchiolo-alveolar) and large-cell bronchial carcinoma (giant cell
carcinoma, clear-cell carcinoma)); breast cancer such as ductal,
lobular, mucinous or tubular carcinoma, Paget's carcinoma;
non-Hodgkin's lymphomas (B-lymphatic or T-lymphatic NHL) such as
for example hair cell leukaemia, Burkitt's lymphoma or mucosis
fungoides; Hodgkin's disease; uterine cancer (corpus carcinoma or
endometrial carcinoma); CUP syndrome (Cancer of Unknown Primary);
ovarian cancer (ovarian carcinoma--mucinous or serous cystoma,
endometriodal tumours, clear cell tumour, Brenner's tumour); gall
bladder cancer; bile duct cancer such as for example Klatskin
tumour; testicular cancer (germinal or non-germinal germ cell
tumours); laryngeal cancer such as for example supra-glottal,
glottal and subglottal tumours of the vocal cords; bone cancer such
as for example osteochondroma, chondroma, chondroblastoma,
chondromyxoid fibroma, chondrosarcoma, osteoma, osteoid osteoma,
osteoblastoma, osteosarcoma, non--OSsifying bone fibroma,
osteofibroma, desmoplastic bone fibroma, bone fibrosarcoma,
malignant fibrous histiocyoma, osteoclastoma or giant cell tumour,
Ewing's sarcoma, and plasmocytoma, head and neck tumours (HNO
tumours) such as for example tumours of the lips, and oral cavity
(carcinoma of the lips, tongue, oral cavity), nasopharyngeal
carcinoma (tumours of the nose, lymphoepithelioma), pharyngeal
carcinoma, oropharyngeal carcinomas, carcinomas of the tonsils
(tonsil malignoma) and (base of the) tongue, hypopharyngeal
carcinoma, laryngeal carcinoma (cancer of the larynx), tumours of
the paranasal sinuses and nasal cavity, tumours of the salivary
glands and ears; liver cell carcinoma (hepatocellular carcinoma
(HCC); leukaemias, such as for example acute leukaemias such as
acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid
leukaemia (AML); chronic lymphatic leukaemia (CLL), chronic myeloid
leukaemia (CML); stomach cancer (papillary, tubular or mucinous
adenocarcinoma, adenosquamous, squamous or undifferentiated
carcinoma; malignant melanomas such as for example superficially
spreading (SSM), nodular (NMM), lentigo-maligna (LMM),
acral-lentiginous (ALM) or amelanotic melanoma (AMM); renal cancer
such as for example kidney cell carcinoma (hypernephroma or
Grawitz's tumour); oesophageal cancer; penile cancer; prostate
cancer; vaginal cancer or vaginal carcinoma; thyroid carcinomas
such as for example papillary, follicular, medullary or anaplastic
thyroid carcinoma; thymus carcinoma (thymoma); cancer of the
urethra (carcinoma of the urethra, urothelial carcinoma) and cancer
of the vulva.
[0579] The novel compounds can be used for the prevention or
short-term or long-term treatment of the abovementioned diseases
including, where appropriate, in combination with other
state-of-the-art compounds such as other anti-tumour substances,
cytotoxic substances, cell proliferation inhibitors, antiangiogenic
substances, steroids or antibodies.
[0580] The compounds of the general formula (1) can be used on
their own or in combination with other active compounds according
to the invention and, where appropriate, in combination with other
pharmacologically active compounds as well. Chemotherapeutic agents
which can be administered in combination with the compounds
according to the invention include, without being restricted
thereto, hormones, hormone analogs and antihormones (e.g.
tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate,
flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone
acetate, finasteride, buserelin acetate, fludrocortisone,
fluoxymesterone, medroxyprogesterone and octreotide), aromatase
inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole,
exemestane and atamestane), LHRH agonists and antagonists (e.g.
goserelin acetate and luprolide), inhibitors of growth factors
(growth factors such as platelet-derived growth factor and
hepatocyte growth factor, examples of inhibitors are growth factor
antibodies, growth factor receptor antibodies and tyrosine kinase
inhibitors, such as gefitinib, imatinib, lapatinib, Erbitux.RTM.
and trastuzumab); antimetabolites (e.g. antifolates such as
methotrexate and raltitrexed, pyrimidine analogs such as
5-fluorouracil, capecitabine and gemcitabine, purine and adenosine
analogs such as mercaptopurine, thioguanine, cladribine and
pentostatin, cytarabine and fludarabine); antitumour antibiotics
(e.g. anthracyclines, such as doxorubicin, daunorubicin, epirubicin
and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin
and streptozocin); platinum derivatives (e.g. cisplatin,
oxaliplatin and carboplatin); alkylating agents (e.g. estramustine,
meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine,
cyclophosphamide, ifosfamide and temozolomide, nitrosoureas such as
carmustine and lomustine and thiotepa); antimitotic agents (e.g.
vinca alkaloids such as vinblastine, vindesine, vinorelbine and
vincristine; and taxans such as paclitaxel and docetaxel);
topoisomerase inhibitors (e.g. epipodophyllo-toxins such as
etoposide and etopophos, teniposide, amsacrine, topotecan,
irinotecan and mitoxantrone) and various chemotherapeutic agents
such as amifostin, anagrelide, clodronate, filgrastin, interferon
alpha, leucovorin, rituximab, procarbazine, levamisole, mesna,
mitotan, pamidronate and porfimer.
[0581] Examples of suitable forms for use are tablets, capsules,
suppositories, solutions, in particular solutions for injection
(s.c., i.v., i.m.) and infusion, syrups, emulsions or dispersible
powders. In this connection, the proportion of the pharmaceutically
active compound(s) should in each case be in the range of 0.1-90%
by weight, preferably 0.5-50% by weight, of the total composition,
that is in quantities which are sufficient to achieve the dosage
range which is specified below. If necessary, the doses mentioned
can be given several times a day.
[0582] Appropriate tablets can be obtained, for example, by mixing
the active compound(s) with known auxiliary substances, for example
inert diluents, such as calcium carbonate, calcium phosphate or
lactose, disintegrants, such as maize starch or alginic acid,
binders, such as starch or gelatine, lubricants, such as magnesium
stearate or talc, and/or agents for achieving a depot effect, such
as carboxymethyl cellulose, cellulose acetate phthalate or
polyvinyl acetate. The tablets can also comprise several
layers.
[0583] Correspondingly, sugar-coated tablets can be produced by
coating cores, which have been prepared in analogy with tablets,
with agents which are customarily used in sugar coatings, for
example collidone or shellac, gum arabic, talc, titanium dioxide or
sugar. The core can also comprise several layers in order to
achieve a depot effect or to avoid incompatibilities.
[0584] In the same way, the sugar coating can also comprise several
layers in order to achieve a depot effect, with it being possible
to use the auxiliary substances which are mentioned above in the
case of the tablets.
[0585] Syrups of the active compounds or active compound
combinations according to the invention can additionally comprise a
sweetening agent, such as saccharine, cyclamate, glycerol or sugar
as well as a taste-improving agent, e.g. flavouring agents such as
vanillin or orange extract. They can also comprise suspension aids
or thickeners, such as sodium carboxymethyl cellulose, wetting
agents, for example condensation products of fatty alcohols and
ethylene oxide, or protectants such as p-hydroxybenzoates.
[0586] Injection and infusion solutions are produced in a customary
manner, e.g. while adding isotonizing agents, preservatives, such
as p-hydroxybenzoates, or stabilizers, such as alkali metal salts
of ethylenediaminetetraacetic acid, where appropriate using
emulsifiers and/or dispersants, with it being possible, for
example, to employ, where appropriate, organic solvents as
solubilizing agents or auxiliary solvents when using water as
diluent, and aliquoted into injection bottles or ampoules or
infusion bottles.
[0587] The capsules, which comprise one or more active compounds or
active compound combinations, can, for example, be produced by
mixing the active compounds with inert carriers, such as lactose or
sorbitol, and encapsulating the mixture in gelatine capsules.
Suitable suppositories can be produced, for example, by mixing with
excipients which are envisaged for this purpose, such as neutral
fats or polyethylene glycol, or their derivatives.
[0588] Auxiliary substances which may be mentioned by way of
example are water, pharmaceutically unobjectionable organic
solvents, such as paraffins (e.g. petroleum fractions), oils of
vegetable origin (e.g. groundnut oil or sesame oil), monofunctional
or poly-functional alcohols (e.g. EtOH or glycerol), carrier
substances such as natural mineral powders (e.g. kaolins,
argillaceous earths, talc and chalk), synthetic mineral powders
(e.g. highly disperse silicic acid and silicates), sugars (e.g.
cane sugar, lactose and grape sugar), emulsifiers (e.g. lignin,
sulphite waste liquors, methyl cellulose, starch and
polyvinyl-pyrrolidone) and glidants (e.g. magnesium stearate, talc,
stearic acid and sodium lauryl sulphate).
[0589] Administration is effected in a customary manner, preferably
orally or transdermally, in particular and preferably orally. In
the case of oral use, the tablets can naturally also comprise, in
addition to the abovementioned carrier substances, additives such
as sodium citrate, calcium carbonate and dicalcium phosphate
together with a variety of further substances such as starch,
preferably potato starch, gelatine and the like. It is furthermore
also possible to use glidants, such as magnesium stearate, sodium
lauryl sulphate and talc, for the tableting. In the case of aqueous
suspensions, a variety of taste improvers or dyes can also be added
to the active compounds in addition to the abovementioned auxiliary
substances.
[0590] For parenteral administration, it is possible to employ
solutions of the active compounds while using suitable liquid
carrier materials. The dosage for intravenous administration is
1-1000 mg per hour, preferably between 5 and 500 mg per hour.
[0591] Despite this, it may be necessary, where appropriate, to
diverge from the abovementioned quantities, depending on the body
weight or the nature of the route of administration, on the
individual response to the medicament, on the nature of its
formulation and on the time or interval at which the administration
is effected. Thus, it may, in some cases, be sufficient to make do
with less than the previously mentioned lowest quantity whereas, in
other cases, the abovementioned upper limit has to be exceeded.
When relatively large quantities are being administered, it may be
advisable to divide these into several single doses which are given
over the course of the day.
[0592] The following formulation examples illustrate the present
invention without, however, restricting its scope:
[0593] Pharmaceutical Formulation Examples
TABLE-US-00008 A) Tablets per tablet Active compound in accordance
with formula (1) 100 mg Lactose 140 mg Maize starch 240 mg
Polyvinylpyrrolidone 15 mg Magnesium stearate 5 mg 500 mg
[0594] The finely ground active compound, lactose and a part of the
maize starch are mixed with each other. The mixture is sieved,
after which it is moistened with a solution of polyvinylpyrrolidone
in water, kneaded, wet-granulated and dried. The granular material,
the remainder of the maize starch and the magnesium stearate are
sieved and mixed with each other. The mixture is pressed into
tablets of suitable shape and size.
TABLE-US-00009 B) Tablets per tablet Active compound in accordance
with formula (1) 80 mg Lactose 55 mg Maize starch 190 mg
Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 15 mg Sodium
carboxymethyl starch 23 mg Magnesium stearate 2 mg 400 mg
[0595] The finely ground active compound, a part of the maize
starch, the lactose, micro-crystalline cellulose and
polyvinylpyrrolidone are mixed with each other, after which the
mixture is sieved and worked, together with the remainder of the
maize starch and water, into a granular material, which is dried
and sieved. The sodium carboxymethyl starch and the magnesium
stearate are then added to the granular material and mixed with it,
and the mixture is pressed into tablets of suitable size.
TABLE-US-00010 C) Ampoule solution Active compound in accordance
with formula (1) 50 mg Sodium chloride 50 mg Water for injection 5
ml
[0596] The active compound is dissolved, either at its intrinsic pH
or, where appropriate, at pH 5.5-6.5, in water after which sodium
chloride is added as isotonizing agent. The resulting solution is
rendered pyrogen-free by filtration and the filtrate is aliquoted,
under aseptic conditions, into ampoules, which are then sterilized
and sealed by melting. The ampoules contain 5 mg, 25 mg and 50 mg
of active compound.
* * * * *