SG172738A1 - Novel heterocyclic nf-kb inhibitors - Google Patents

Novel heterocyclic nf-kb inhibitors Download PDF

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SG172738A1
SG172738A1 SG2011047610A SG2011047610A SG172738A1 SG 172738 A1 SG172738 A1 SG 172738A1 SG 2011047610 A SG2011047610 A SG 2011047610A SG 2011047610 A SG2011047610 A SG 2011047610A SG 172738 A1 SG172738 A1 SG 172738A1
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Singapore
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alkyl
group
haloalkyl
aryl
heteroaryl
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SG2011047610A
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Johann Leban
Harald Schmitt
Kristina Wolf
Stefano Pegoraro
Andreas Wuzik
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4Sc Ag
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Priority claimed from PCT/EP2005/008261 external-priority patent/WO2006032322A1/en
Application filed by 4Sc Ag filed Critical 4Sc Ag
Publication of SG172738A1 publication Critical patent/SG172738A1/en

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Abstract

5The present invention relates to compounds of the general formula (Ill) orpharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, Formula (Ill) wherein R3 is H, -C(0)NRaRb, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH,10 NR4' OR5' , NH2, amine, alkylamine, alkoxy, cycloalkyl, heterocyclo alkyl,hydroxyalkyl, or haloalkyloxy; R4 is H, halogen, alkyl, -C(NR7)NR7R5, - (CH2)paryl, -(CH2)pNR7R5, -C(0)NR7R5, -N=CR7R5, -NR7C(0)R5, cycloalkyl, heterocycioalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R5 is halogen, alkyl, -C(NR7)NR7R5, -(CH2)paryl, -15 (CH2)pNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl. 20 (No Suitable Figure)

Description

Novel heterocyclic NFB Inhibitors
Field of the invention
The present invention relates to compounds of the general formula (Ia), (Ib), (Ic), (IL), or (OD) or a stereoisomer thereof or possible pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs of these compounds, for use as a medicament. The compounds of the invention are exceptionally useful for the treatment of diseases associated with abnormal and hyperproliferation of cells in mammals, especially in humans. In particular, they are useful for the treatment of diseases characterized by a hyperproliferation of T-cells.
The present invention relates to compounds which are suitable for the therapy of diseases that can be treated by modulating cellular pathways in eukaryotes, e.g. cancer, immunological or inflammatory disorders, and viral infections, to further processes for the preparation of these compounds, and to their use.
T-cell homeostasis is critical for the maintenance of immune tolerance. Defects in T-cell homeostasis can lead to autoimmune pathology, Autoimmune diseases include a large © spectrum of clinically distinct entities that share 2 common aetiology, a misguided, self- directed immune response.
This immune response can also be the consequence of an organ transplant.
Evidence suggests a prime role of T-cell reactivity in autoimmune diseases. Measuring proliferative responses in T-lymphocytes is a widely used assay to measure immune competence (Killestein, J. ef al. J. Newroimmunol. 133,217-24, 2002).
We used a nonradioactive technique for the measurement of in vitro T-cell proliferation (Messele, T. et al. Clinical and Diagnostic Laboratory Immunology 687-692, 2000).
Peripheral blood mononuclear cells (PBMCs) were isolated from human blood obtained from volunteer donators, PBMCs were isolated by centrifugation in ACCUSPIN tubes using HISTOPAQUE.
PBMCs were stimulated with PHA and cell proliferation wes measured with a Roche colorimetric BromUridin incorporation ELISA kit.
Regulation of the immune response is controlled by a variety of signalling pathways such as T-cell or TNF receptor signalling (Chen, G. er al. Science 296, 1634-1635, 2002). To further characterize targets of compounds which we found active in the T-cell proliferation assay, we tested the compounds on their ability to inhibit the human proteasome. ’ The major neutral proteolytic activity in the cytosol and nucleus is the proteasome, a 205 (700 kDa) particle with multiple peptidase activities. The continual turnover of cellular proteins by the ubiquitin-proteasome pathway is used by the immune system to screen for the presence of abnormal intracellular proteins (Dantuma, N.P. et al. Nat. Biotechnol. 2600, 78(5), 538-43; Goldberg, AL. et al. Nature 357, 375, 1993).
The ubiquitin-proteasome pathway plays an essential role in the regulation of NF-kB activity, being responsible for the degradation of the inhibitor IxB-o. In order to be targeted for degradation by the proteasome, IKB-o must first undergo selective phosphorylation at serine residues 32 and 36, followed by ubiquitinylation (Chen, ZJ. er al. Cell 84, 853-862, 1996; Brown, K. ef al. Science 267, 1485, 1995).
NF-xB, a transcription factor, regulates the transcription of an important set of genes, involved in inflammatory responses (Baeuerle, PA. ef al. Cell 87, 1, 13-20, 1996).
Proteasome inhibitors block IkB-a degradation and NF-kB activation (Traeckner et al.
EMBO J. 13, 5433, 1994).
Patents describing proteasome inhibitors have been described in reviews (Adams, J. et al.
Ann. Rev. Med. Chem. 31, 279-288, 1996) and in patents US 6117887, US 5834487, WO 00/004954, WO 00/04954, WO 00/170204, WO 00/33654, WO 00/64863, WO 00/114324,
WO 99/15183, WO 99/37666.
Here we describe novel chemical entities with proteasome inhibitory activity.
NF-kB (Nuclear Factor-kB) is an eucariotic transcription factor of the rel family, which is : located in the oyctoplasm in an inactive comylex, as a homo- or heterodimer.
Predominantly it exists as a heterodimer composed of p50 and p65 subunits, bound to inhibitory proteins of the IxB family, usually IxB-o (D. Thanos ef al, Cell 80, 529, 1995). NF-«B is activaied in response to different stimuli, among which inflammatory cytokines,
UV radiation, phorbol esters, bacterial and viral infections. Stimulation triggers the release of NF-1B from JxB in consequence of the phosphorylation and the following degradation of the IxB-a protein (P.A. Bacuerle ef al, Annu. Rev. Immunol. 12, 141, 1993) by the proteasome. Once it is set free, NF-xB translocates in the nucleus where it binds to the
DNA at specific x¥B-sites and induces the transcription of a variety of genes encoding proteins involved in controlling the immune and inflammatory responses, amongst others - interleuking, TNF-a, the NO-synthase and the cyclooxigenase 2 (S. Grimm ef af, J 5 . Biochem. 250, 297, 1993). Accordingly, NF-xB is considered an early mediator of the immune and inflammatory responses and it is involved in the control of cell proliferation and in the pathogenesis of various human diseases, such as rheumatoid arthritis (f. Beker etal, Clin Exp. Immunol. 99, 325, 1995), ischemia (A. Salminen ef al., Biochem. Biophys.
Res. Comm. 212, 939, 1995), arteriosclerosis (A.S. Baldwin, Annals Rev. Immunol. 212, 649, 1996), as well as in the pathogenesis of AIDS.
Inhibition of NF-«xB mediated gene transcription can be accomplished through inhibition of phosphorylation of the inhibitory protein IxB, inhibition of IxB degradation, inhibition of NF-kB (p50/p65) nuclear translocation, the inhibition of NF-«B-DNA binding or NF- kB-mediated DNA transcription (J.C. Epinat ef al., Oncogene 18, 6896, 1999).
The present invention relates to compounds of the general formula (Ja) or a pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a sterecisomer thereof,
N ~~ R2 ny 1 | z R® (mw) wherein
R is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R! is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; x is CO, C8 or 504;
Y is CO, C8 or SO;
Z isNR*, 8, 0r0;
R” is H, alkyl, -C(O)NR", -C(O)RS, cycloalkyl, haloalkyl, hydroxyalkyl, : hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 5 .
R® is independently H, OH, SH, NROR', NH,, alkylamino, hydroxyalkylamino, halogen, CONR'R, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
RY is H, halogen, alkyl, -CONR'NRR®, -(CHp)yaryl, -(CHy),NRRS, -C(O)NR'RS,
N=CR'R?, NR'C(O)R?, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkytamino, alkylamino, heteroaryl or aryl; : R’, R” independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalicylamino, alkylamino, heteroaryl or aryl; -
Rr? is H, NH,, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;
R® independently represents H, -CN, -OH, SH, -CO,R*, -C(O)RY, -SO,NRY,
NRYRY, -C(O)NR'R?, -SOq-alkyl, -SO,R*, SOR, -N=CR*R®, -NRYC(O)RY", -NR*-CO-haloalkyl, -NO,, -NR*-80,-haloalkyl, -NR*-SOp-alkyl, -NR*-CO-alkyl, -NR*(CHy) heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylemino, aryl hydroxyalkylamino, alkoxy, alkylthio, -O(CH,),[O(CH,),]0CHs, -CNR* INR -benzimidazolyl, -CNR*)NR*benzthiazolyl, -C(NR*NR*benz-oxazolyl, or heteroaryl; :
RY, RY,RY independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamine, alkylamino, -CONRYNR RZ, ~(CHy)paryl, -CH,),NRRE, -
C(O)NR'R®, -N=CR'RS, -NR’C(O)R?, halogen, heteroaryl, or aryl p isl to 6; a is 110 6; .
R? is independently
4 $n N—R5 'R® is independently H, COR®, COR’, SOR, SO:R®, SOR? alkyl, cycloalkyl, alkoxy, “NH,, alkylamine, -NR'COR®, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
RS is independently H, alkyl, cycloalkyl, amino, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, aryl or heteroaryl; an alkyl group, if not stated otherwise, denotes a linear or branched C-Cg-alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C—Cealkenyl or a linear or branched Co—Cg-alkinyl group, which can optionally be substituted by one or more substituents R'; : the C;—Ce—alkyl, Co—Cgalkenyl and C-Cg—alkinyl residue may be selected from the group comprising —CH;, ~C,Hs, ~-CH=CH,;, -C=CH, -C3H;, -CH(CHz);, —CH-CH=CH, ~C(CH3)=CH,, —CH=CH-CH;, -C=C-CHs;, -CH;-C=CH, -CjHy, -CHx~CH(CHz), -CH(CHzs)-CoHs, ~C(CHy)a, —CsHit, ~CeHig, ~CR Ys, Cas, ~CHz—CR a, ~Ca(R D7, —CH~CR 3, —CoH CH=CH, ~CH=CH~-C;Hjs, ~CH=C(CHs)z, --CHz~CH=CH-CHj, ~CH=CH-CH=CH,, —C;H;~C=CH, —C=C-CyHs, ~CH,~C=C—CH;, -C=C-CH=CH,, —CH=CH~C=CH, -C=C-C=CH, -CHsCH(CH;),, —-CH(CH3)-CsH,, ~CHx-CH{CHz)~
Cs, —-CH(CH3)-CH(CHaz),, ~C(CHz)—CaHs, ~CH—C(CHp)s, ~C3Hg~-CH=CEH, ~CH=CH-C3Hy, ~CoH~CH=CH-CH3, -CH,—CH=CH~CyHs, -CH-CH=CH-CH=CH>, ~CH=CH-CH=CH-CHj, -CH=CH-CHy-CH=CH,, —C(CH:)=CH-CH=CH,, ~CH=C(CH:)-CH=CH,, ~CH=CH-C(CHs)}=CH,, ~CH,-CH=C(CHas),, C(CHz)=C(CHs), ~C3HeC=CH, —C=C—C3Hy, ~CoHe-C=C—CH;, —CHp-C=C-CoHs, -CH-C=C-CH=CH,, ~CH—CH=CH-C=CH, ~CH,~C=C-C=CH, -C=C-CH=CH-CH;, ~-CH=CH-C=C-CH3, —C=C-C=C-CH,, —C=C-CH,-CH=CH,, ~CH=CH-CH,~C=CH, ~(=C~CH,~C=CH, ~C(CH3)=CH-CH=CH,, —~CH=C(CHs)-CH=CH,, -CH=CH-C(CH3)=CH,, ~C(CH;)=CH-
C=CH, ~CH=C(CH;)}-C=CH, ~C=C-C(CHa)=CH,, -C3HsCH(CHz), ~CoHsCH(CH;)- : CyHs, —CH(CH3)-CyHy, —~CHp~CH(CHs)-CsHy, ~CH(CH;)-CHo~CH(CHa), ~CH(CHz)~
CH(CH;)~CoHs, ~CHp~CH(CH;)-CH(CHz);, —CHp-C(CHa)—CoHs, ~C(CHs),~-C3H7, —
C(CH:)—CH(CHs)y, —CoHe~C(CHa)s, —CH(CH3)-C(CHa)s, —CiHs-CH=CH,, ~-CH=CH-~
CyHs, —C3He—CH=CH-CH;, —CH-CH=CH-C:Hj; ~CoHy-CH=CH-C,H;, ~CHp-
C(CHz)=C(CHz)y, ~CoHs~CH=C(CHz);, ~C4Hg-C=CH, ~C=C-CyHy, —CsHe-C=C-CHa, ~CHyp~C=C-CsHy, CoH C=C-CaHs;
R® is independently H, -CO,R™, -CONHR™, -CR"O, -SC,NR™, -NR"-CO-haloalkyl,
NQO,, -NR-850s-haloalkyl, “NR -8Cp-alkyl, -SO;-allyl, -NR“-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, OF, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl; :
R™ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; : a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon : ators, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group E, E being 0, S, 80, SO2, N, or NR", BR" being as defined above; the Cs—Cg—ocycloalkyl residue may be selected from the group comprising ~cyclo-C3Hs, —cyclo—CiHy, ~cyclo—CsHs, -cyclo-CeHiy, —cyclo-C7His, —cyclo—CgHys, morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, i-butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; an haloalkyl group denotes an alkyl group which is substituted by one to five halogen "atoms, the alkyl group being as defined above; the haloalkyl group is preferably a ~-C(R'%),
CROR®Y,, —CRERIRY, —CoR)s, —CHrCR™, CH: _CRRY,, CH,
CRYORHRI”, ~C3R'Yy, or —CoHL—CR');, wherein RY, RY, R!"” represent F, Cl, Br or
I, preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a
OCR). -OCRP®RYY, -OCRUPERRY, —0C,R%s, -OCHCR'); -OCH-
CRORY),, —OCH,~CRUR™IRY”, OCR); or ~OCH~CRY®);, wherein RY, RI?
RY represent F, Cl, Br or I, preferably F; a hydroxyalkylamino group denotes an (HO-alkyl),-N- group or HO-alkyl-NH- group, the alkyl group being as defined above;
an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above; a halogen group 1s chlotine, bromine, fluorine or iodine; an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can optionally be substituted by one or more substituents R°, where R’ is as defined above; the aryl group is preferably a benzyl group, a phenyl group, —0—-CeHs~ R', mC R”, —p—
CeHy—-R’, 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl; a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and 8. This heterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-vl, oxazol-5-vl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yi, benzooxazol-2-yl, benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-vl, : 1,2, 5~0xadiazol-4-y1, 1,2 4-thiadiazol-3-vi, 1,2,A-thiadiazol-5-yl, isothiazol-3-vi, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-vl, benzoisothiazol-4-vl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-tmidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4- : yl, 4-imidazolyl, benzoimidazol-4-yl, I-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3- furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4- pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-dimethoxy-6- pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4- pyrazolyl, 1,2.3-tsiazol-4-yl, 1,2,3-triazol-5-vl, 1,2,4-triazol-3-y1, 1,2,4-triazol-3-y1, 1,3,5- triazol-6-yl, 2, 4-dimethoxy-1,3,5-triazol-6-yl, 1 H-tetrazol-2-yl, 1 H-tetrazol-3-yl, tetrazolyl, acridyl, furazene, indazoly!, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3- indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, I-isoindolyl, 3-isoindolyl, 4-isoindolyl,
S-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6- indolinyl, 7-indolinyl, benzo[bjfuranyl, benzofurazane, benzothiofurazane, benzotriazol-1- vl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl. benzotriazol-7-yl, benzotriazine, benzo[bjthiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro- isoquinolinylpurine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazitie, pyrazolopyrimidine, tetra- hydrothieno[3,4-djimidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine, 2.3-dihydrobenzo[1,4]-
dioxin-2-yl, 2,3-dibydrobenzoll,4}-dioxin-3-yl, 2,3-dihydrobenzo[l,4]-dioxin-5-y1, 2,3- dihydrobenzo[1,4]-dioxin-6-y1, 2,6-dimethoxypyrimidin-3-yl, 2,6~dimethoxypyrimidin-4- yl, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, friazolopyridine, triazolopyrazine, triazolopyrimidine, or 4- [1,2,4riazolo[4,3-a]pyridin-3-yl, 1-furo[2,3-clpyridin-4-yl, 1-furo[2,3-clpyridin-5-yl, 1- furo[2,3-clpyridin-3-y], and triazolopyridazine group. This heterocyclic group can be substituted by one or more substituents R', wherein R" is as defined above.
The present invention relates to compounds of the general formula (Ib) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, ry R°
RZ . \ a
X
= — | ~.
R® (Ib) wherein
R! is-C(OJR, -C(O)CHRR?, -C(O)NR'R®, -C(O)OR’, -R'C(OIR?, or -C(S)R”;
R® independently represents H, -CN, -OH, -SH, -COR*, -C(O)R*, -SONR”,
NRYRY, -C(O)NRRS, -80,-alkyl, -SO.R*, SOR”, N=CR¥R”, -NR'C(O)RY",
NR*-CO-haloalkyl, -NO,, -NR*¥-80,-haloalkyl, -NR*-30,-alkyl, -NR*-CO-alkyl, -NR¥(CHp) heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl hydroxyalkylamino, alkoxy, alkylthio, -O(CHy)[O(CHz),]{O0CH;, -CQNR*HINRY- benzimidazolyl, ~~ -CONR*)NR*benzthiazolyl, -CQNR")NR*benzoxazolyl, -(CH2),NR'COR?, or heteroaryl;
RY isH, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, aryl, or R! and R* to gether with the X to which they are attached form a 3 to 8 membered saturated or at least partially unsaturated monocyclic or polycyclic ring system,
wherein at least one ring atom isa heteroatom selected from O, N, and 8, and the ring optionally has one or more substituents R;
X isN,or CRY
Y isCO, CS or SOs
Z isNRY,S,orQ;
RY is H, alkyl, -C(O)NR’, -C(O)R’, cycloalkyl, haloalkyl, hydroxyallyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
RY isH, alkyl, -C(O)N R¥, -C(O) R¥, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxy- alkylamino, alkylamino, heteroaryl, or aryl;
RY, RY RY independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -CNR'YNR” RE, -(CHy),aryl, -CH,),NR'R®, - ~ -C(ONR'R®, -N=CR'R®, -NR'C(O)R®, halogen, heteroaryl, or aryl p is lio 6; a islioé6;
Rr? is independently H, OH, SH, NH,, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl;
RP is independently H, OH, SH, NH, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamine, hydroxyaikylamino, halogen, aryl, or heteroaryl;
R® is independently H, OH, SH, NR¥OR®, NH,, alkylamino, hydroxyalkylamino, halogen, CONR'R®, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R® is H, halogen, alkyl, -C(NR')NR"R®, -(CHy),aryl, ~(CHy),NR'R?, -C(O)NR'R?, -N=CR'R®, -NR'C(O)R?, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, ’ alkylamino, heteroaryl or aryl;
RR” independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, allcylamine, heteroaryl or aryl;
R® is H, NH, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or arvi;
R® independently represents H, -CN, -OH, -SH, -CORY, -C(ORY, -SO,NR?,
NR*R”, -C(O)NR'R, -80,-alkyl, -SO,R¥, SOsR¥, N=CR*R”, -NR*C(O)R"", -NR¥-CO-haloalkyl, -NOy, -NR*-80,-haloalkyl, -NR*-S0,-alkyl, -NR*-CO-alkyl,
NRY(CHy) heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxy- alkylamino, alkoxy, alkylthio, -O(CHz),[O(CHy),]0CHs, -CONRY)NR*benz- imidazolyl, -C(NR*)NR*benzthiazolyl, -CONR*INR*benzoxazolyl, aryl or heteroaryl;
R* is independently $n A—RS of
A isN, 0, or CR;
R’ is independently H, SOR”, SOR’, SO;R’, -C(O)R’, -C(O)CHR'R?, -C(O)NRRS, -
CO)OR?, RIC(ORE, -C(SR’, -CONRIINRTR?, -(CHp)paryl, (CH), NR'RE, -
CONR'RE, N=CR'RE, -NR'C(OR", alkyl, cycloalkyl, alkoxy, -NH,, alkylamino, hydroxyalkylamino, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; n is 0to2; wherein an alkyl group, if not stated otherwise, denotes a linear or branched C,-Cg-alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched Co—Cg—alkenyl or a linear or branched Co~Cg—alkinyl group, which can optionally be substituted by one or more substituents R; the C;—Cg-alkyl, Co—Csalkenyl and Co-Cgsalkinyl residue may be selected from the group comprising ~CH;, —C;Hs, ~CH=CH,, —C=CH, —CsH;, —CH(CH;);, ~CHy-CH=CH,, ~C(CHs)=CH,, —CH~=CH-CH;, ~C=C-CHj;, ~CHy-C=CH, -C4Hs, —-CH;~CH(CHi), ~CH(CHz)~C;Hs, ~C(CHs)s, —CsHyy, ~CsHiz, “CR 3, ~CaR)s, ~CHz-CR 3, ~C3(R Ys, ~CoHC(RY, CoH CH=CH,, -CH=CH-C,Hs, ~CH=C(CHz);, ~CHp~CH=CH-CHa, ~CH=CH-CH=CH,, ~CoH~C=CH, -C=C-C,H;, ~-CHp~C=C-CHa, -C=C--CH=CH,, -CH=CH-C=CH, —C=C-C=CH, -CH,~CH(CHz);, ~CH(CH3)~CsH;, —CH,~CH(CHz)—
C,Hs, ~CH(CH3)~CH(CHj),, ~C(CHz)p~CyHs, ~CHa~C(CH3)s, ~CaHg-CH=CH,, —CH=CH-C;Hy, ~CoHy~CH=CH-CHj, -CH,~CH=CH-C, Hs, ~CHo~CH=CH-CH=CH,,
~CH=CH~CH=CH-CH;, ~CH=CH-CH-CH=CH,, ~C(CHy)=CH-CH=CH,, ~CH=C(CH;-CH=CH,, —-CH=CH-C(CH3)=CH,, ~CHy~CH=C(CHz),, C(CH3)=C(CHs),, —CsHg-C=CH, -C=C-C5Hy, ~CHy-C=C-CH;, ~CHy-C=C-CH;5, ~CH-C=C-CH=CH,, «CH CH=CH-C=CH, —CH—C=C-C=CH, ~C=C-CH=CH~CHj, ~CH=CH~-C=C-CHs, ~C=C-C=C-CHs, ~C=C-CH, CH=CH, —-CH=CH-CH,-C=CH, -C=C~CH,-C=CH, —C(CH3)=CH-CH=CH,, -CH=C(CH,;)-CH=CH,, -CH=CH-C(CH;)=CH;, —-C(CH;)=CH~
C=CH, -CH=C(CH;)-C=CH, —C=C-C(CH;)=CH,, -CsHgCH(CHs),, —CoH—CH(CH3)~
Cols, —CH(CH;3}-CyHy, —~CHy~CH(CH;)-C3Hy, -CH{CH3)-CH,—CH{CHjs),, ~CH(CHz)~
CH(CH:)-CoHs, —CHy-CH(CH;)-CH(CHz)y, —CH;—C({CHy)p—CoHs, —C(CH3)—CsHy, —
C(CH3)—CH(CHs)y, —CoHi—C(CHs)s, —CH(CH3)}-C(CHs)s, ~C4Hg~CH=CH,, ~CH=CH--
CiHy, —CsHe-CH=CH-CH;, -CHy-CH=CH-GHy, -CHiCH=CH-CHs, CH; . C(CH3)=C(CHjz)a, ~Col4—~CH=C(CHz)a, CH CCH, —C=C-CyHo, As He~-C=0-CH;, ~CHy-C=C-C3Hy, ~CoHy~C=C-Co Hs;
R'is independently H, -CO,R™, -CONHR", -CR"0, -SO,NR™, -NR"-CO-haloalkyl, © -NOj, -NR-805-haloalkyl, -NR'*-8Oz-alkyl, -SOs-alkyl, -NR"-CG-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R™ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group E, B being 0, S, SO, S0,, N, or NR, R*" being as defined above; the C3—Cg-cycloalkyl residue may be selected from the group comprising -cyclo~CsHs, —cyclo—~CgHy, —cyclo-CsHg, -cyelo-CeHp, —cyelo—CsHis, —cyclo—CgHis, morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl; : an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, ~butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; an haloalkyl group denotes an alkyl group which is substituted by one to five halogen © 35 atoms, the alkyl group being as defined above; the haloalkyl group is preferably a-CRY;
CRYRY,, —CRORVIRY, CHR), —CH-CR™)s, CH CRPR™), —CH,-
CROERINRY”, CRM), ox —~CoH—C(R' wherein RY, RY, RY” represent F, C1, Br or
I, preferably F; : ) a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a
OCR), —OCRNY®R®),, —OCRMERMRYY, —0C,RY)s, —OCHCR™), -OCH-
CRIO®!YY,, —~OCH,~CRURIMRY”, —0C;RYY, or ~OCH~CRY),, wherein R'?, RY,
RY represent F, Cl, Br or I, preferably F; a hydroxyalkylamino group denotes an (HO-alkyl);-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as : defined above; a halogen group Is chlorine, bromine, fluorine or iodine; an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can optionally be substituted by one or more substituents R°, where R’ is as defined above; the aryl group is preferably a benzyl group, a phenyl group, —0~Cely— KR, —-m~Celle— R7, —p—
Ces R, 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl; a heteroaryl group denotes a 5- or 6~membered heterocyclic group which contains at least one heteroatom selected from O, N, and S. This heterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-v], thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-3-v], isooxazol-3-v1, isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisocoxazol-4-yl, benzoisooxazal-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, . 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-vl, isothiazol-4-vl, isothiazol-5-vl, benzoisothiazol-3 “yl, benzoisothiazol-4-vl, benzoisothiazol-5-vl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2~-imidazolyl, 1,2,5-thiadiazol-4- yl, 4-imidazolyl, benzoimidazol-4-yl, 1l-pyrrolyl, 2-pyrrolyl, 3-pymolyl, 2-furanyl, 3- furanyl, 2-thienyl, 3-thienyl, Z-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4- pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, S-pyrimidinyl, 6-pyrimidinyl, 2.4-dimethoxy-6-
ro 13 pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, Z-pyrazinyl, l-pyrazolyl, 3-pyrazolyl, 4- pyrazolyvl, 1,2 3-triazol-4-vl, 1,2,3-friazol-5-yl, 1,2 4-tdazol-3-v1, 1,2,4-triazol-5-vl, 1,3,5- triazol-6-yl, 2,4-dimethoxy-1,3,5-triazel-6-v1, 1 H-tetrazol-2-yl, 1 H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3- indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, I-isvindolyl, 3-isoindolyl, 4-isoindolyl,
S-isoindolyl, 6-isoindolyl, 7-izsoindolyl, 2~indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6- indolinyl, 7-indolinyl, benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-1- yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-vl, benzotriazol-7-yl, benzoiriazine, benzo[blthiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benz- imidazol-5-yl, bepzimidazol-6-vl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, clomoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro- " isoquinolinyl,purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, iso- thiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, tetrahydro- thieno[3,4-d}imidazol-2-one, pyrazolo[5,1-c][1,2,4}triazine, imidazopyridazine, imidazo- } 15 pyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, 2,3-dihydrobenzofl.4]- dioxin-2-yl, 2,3-dikydrobenzo[l,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4}-dioxin-5-yl, 2,3- dihydrobenzof1,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4- yl, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4-[1,2,4]triazolo[4,3~a]pyridin-3- yi, 1-furo{Z,3-cipyridin-4-yl, 1-furo|[2,3-clpyridin-3-yl, 1-furo|2,3-clpyridin-3-yl, and triazolopyridazine group. This heterocyclic group can be substituted by one or more substituents R, wherein R’ is as defined above.
The present invention relates to compounds of the general formula (Ic) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stercoisomer thereof, x
N vn | AF
J | Re
R3 ] " rito dd " 27 TR t S (Ic) wherein rR} independently represents H, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, . haloalkyloxy, aryl, or heteroaryl;
X is CO, CS or 80;
Y is CO, CS or S04; ' z isNR2", 8, or O;
RY" is H, alkyl, ~C(OYNR?, -C(O)RS, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxy- alkylamino, alkylamino, heteroaryl, or aryl;
RY, RY, RY independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, : hydroxyalkylamino, alkylamino, -CONR'NR" RE, -(CHz)paryl, -(CH2),NR'R®, ~C(O)NR'RE, N=CR'R®, -NR'C{O)R?, halogen, heteroaryl, or aryl p islto 6; gq islto6; m is Oto 4;
T is 0, or 1; t is 0, or I; 8 is 0, or 1;
R® is independently H, OH, SH, NR*OR®, NH,, alkylamino, hydroxyalkylamino, © halogen, CONRR®, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R® is independently H, OH, SH, NRYOR®, NH, alkylamino, hydroxyalkylamino, halogen, CONRR®, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
RY is H, halogen, alkyl, -<CONRINR"R, «(CHp)paryl, -(CHz),NR'R, -C(O)NR'R?, -N=CR'R?, -NR'C(O)R?, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; } | -
R7,R” independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;
RE is H, NH, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, allcylamino, heteroaryl or aryl;
R° independently represents H, -CN, -OH, -SH, -CORY, -C(ORY, -SO,NRY,
NRRY, -C(OWNRR?, -S0-alkyl, -SO.RY, SO5R?, N=CR*R®, -NRYC(ORY, -NR*-CO-haloalkyl, -NOj, -NR*-S0,-haloalkyl, -NR*-SO,-alkyl, -NR¥-CO-alkyl,
NR¥(CHy)sheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkyl- amino, alkoxy, alkylthio, ~O(CHL)[O(CH),J,0CH;, -CONR?)NR*benz- imidazolyl, -C(NR'NR*benzthiazolyl, -C(NR*NR*benz-oxazolyl, arvi or heteroaryl; rR? is independently H, OH, SH, NR¥ORY, NH,, hydroxyalkylamino, alkylamino, 16 halogen, CONRR®, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; an alkyl group, if not stated otherwise, denotes a linear or branched C;-Ce-alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched Co—Cealkenyl or alinear or branched C;—Cgalkinyl group, which can optionally be substituted by one or more substituents R'; the Ci—Ce-alkyl, C-Ce-alkenyl and Cp-Ce-alkinyl residue may be selected from the group comprising —CHs, —CoHs, —~CH=CH,, -C=CH, -C;H;, —CH(CHy);, ~CH,-CH=CH.,, ~C(CH3)=CHz, —CH=CH-CH3;, —C=C-CH;, —CHp-C=CH, -C/Hy, —CH-CH(CH)s, ~CH(CHz)-CoHs, -C(CHa)s, —CsHiy, —CeHis, ~C(R 3, —Ca(R)s, -CHz-C(R)s, ~C5(R)7, ~CoHy~C(R Ys, —CoHy—CH=CH,, —CH=CH-C, Hs, -CH=C(CH3),, —-CH,~CH=CH-CHs, ~CH=CH-CH=CH,, ~C,H;~C=CH, -C=C-CyH;, —-CH,~C=C~-CHj, ~C=C—~CH=CF,, ~CH=CH-C=CH, ~C=C-C=CH, -CH;~CH(CHa),, ~CH(CH3)}~C3Hs, —CH,~CH(CH3)—
CoH, —CH(CH3)-CH(CHa),, ~C(CH3 CoH, “CH—C(CH3)s, ~CsHg—CH=CH,, —CH=CH-C3Hy, —CoH-CH=CH-CHj, -CH,~CH=CH-C,H;, ~CH,~CH=CH-CH=CH., —CH=CH-CH=CH-CH;, ~CH=CH-CH,~CH=CH,, —C{CH3)=CH-CH=CHa, ~CH=C(CH3)-CH=CH,, —~CH=CH-C(CH;)=CHa, ~CHo~CH=C(CHs),, C(CH3)=C(CHz),, + CGH C=CH, —C=C-C3Hy, ~CoH-C=C-CHs, -CH;—C=C-C,Hs, —CH,~C=C~CH=CH,, ~CHy~CH=CH-C=CH, —CH,-C=C-C=CH, -C=C-CH=CH--CH;, ~-CH=CH-C=C-CH,
C=C-C=C-CH;, —-C=C-CH~CH=CH,, -CH=CH-CH,—C=CH, -C=C-CH,—(=CH, —C(CH;)=CH~CH=CH,, ~CH=C(CHz)~CH=CH,, -CH=CH-C(CHz)=CH,, ~C(CH;)~CH-
C=CH, ~CH=C(CHg)-C=CH, -C=C-C(CH3y=CH,, -C3Hs—CH(CHz)y, ~CoH,~CH(CH;)- - Cols, —CH(CHz)-C4Hs, —~CHx—CH(CH3)-CsHy, -CH(CHz)-CHo—~CH(CHa)s, —CH(CHz)—
CH(CH3)-CoHs, ~-CHy-CH(CHz)-CH(CHs)y, —CH—C(CH3)p~CoHs, ~C(CHz)~CaHy, —
C(CHy)—CH(CHz)s, —CoFLi—C(CHa)s, ~CH(CH3)-C(CHy)s, ~C4Hsg-CH=CH,, —CH=CH-
CyHy, ~CalleCH=CH-CH;, -CH-CH=CH-CH;, -CH~CH=CH-CH;, -CH,-
C{CH)=C(CHz)p, —CoHy~CH=C(CHz)p, ~C4Hg~C=CH, ~C=C-CsHp, ~CsHg~C=C-CHs, ~CHy—C=C-CaHy, CH C=C-CoHs;
R'is independently H, -CO,R™, ~CONHR", CRO, ~-80,NR™, -NR"-CO-haloalkyl, “NO, -NR"-802-haloalkyl, -NR'-8Oz-alkyl, -8O;-alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
Ris independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group E, E being 0, 8, 80, S02, N, or NR, R*" being as defined above; the CsCyg-cycloalkyl residue may be selected from the group comprising -cyclo—CyHs, —cyelo—CyHy, —oyclo-CsHy, -cyelo-CgHlyy, —cyclo—CrHs, —cyclo—CeHys, morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, £-butoxXy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R'%)s, -CRYM®RTY,, ~CRIGRINRY CHR; ~CH- CRY), —CH-CRY®RIY,, —CH,—
CRPO®RRY, ~CsR™,, or ~CoH~ CRM, wherein RY, RY, R¥” represent F, Cl, Br or
I, preferably F; : ahydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen - atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a “OCR, —OCRMR™,, —OCRMRIHRM, ~OC Rs, —OCH-CR!;, OCH,
CRYER™Y,, —0CHCRPRIMRYY, -0CR%Y), or —OCHCR!%); wherein RY, RY,
RY” represent F, Cl, Br or I, preferably ¥;
a hydroxyalkylamino group denotes an (HO-alkyl);-N- group or HO-allcyl-NH- group, the allyl group being as defined above; an alkylamino group denotes an FN-alkyl or N-dialkyl group, the alkyl group being as 53 defined above: a halogen group is chlorine, bromine, fluorine or iodine; an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can optionally be substituted by one or more substituents R’, where R' is as defined above; the aryl group is preferably a benzyl group, a phenyl group, —0-CsHy— R’, —m—CeHy- RC, ~p—
Ceily~R’, I-naphthyl, 2-naphthyl, 1-anthracenyl or Z-anthracenyl; a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S. This heterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-v1, thiazol-4-yl, thiazol-5-y1, isothiazol-3-yl, isothiazol-4-vi, isothiazol-5-y1, oxazol-2-v1, oxazoi-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-y1, benzooxazol-4-vl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, benzoisooxazol-5-y], 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-y, isothiazol-3-yl, - isothiazol-4-yl, isothiazol-5-vi, benzoisothiazol-3-y1, benzoisothiazol-4-y1, benzoisothiazol-5-y1, 1,2, 5-thiadiazol-3-y1, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4- yl, 4-imidazolyl, benzoimidazol-4-yl, I-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3- furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4- pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, S-pyrimidinyl, 6-pyrimidinyl, 2,4-dimethoxy-G- pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, I-pyrazolyl, 3-pyrazolyl, 4- pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-y1, 1,2. 4-triazol-3-y1, 1,2 4-iriazol-5-y1, 1,3,5- triazol-6-v], 2,4-dimethoxy-1,3,5-triazol-6-v1, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridyl, firrazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3- indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-iscindolyl, 3-isoindolyl, 4-isoindolyl,
S-isoindolyl, 6-isoindolyl, 7-isoindoly], 2-indolinyl, 3-indolinyl, 4-indolinyl, 5 -indolinyl, 6- indolinyl, 7-indolinyl, benzo[b}furanyl, benzofurazane, benzothiofurazane, benzotriazol-1- vl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-y1, benzotriazine, benzo[blthiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-y1, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoguinolinyl, tetrahydro-
: thieno[?,4-dimidazol-2-one, pyrazolo[5,1-c][1,2,4Triazine, tetrahydroisoguinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazo- pyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolo- pyrazine, triazolopyrimidine, 2,3-diliydrobenzo[l,4]-dioxin-2-y1, 2,3-dihydrobenzo[1,4]- dioxin-3-yl, 2,3-dihydrobenzo[l,4]-dioxin-5-yl, 2,3-dihydrobenzo[1,4]-dioxin-6-vl, 2,6- dimethoxypyrimidin-3-yl, 2,6~dimethoxypyrimidin-4-yl, 4-[1,2,4ltriazolo[4,3-alpyridin-3- yl, 1-furo[2,3-cipyridin-4-yl, 1-furof23-clpyridin-5-yl, 1-fure[2,3-clpyridin-3-yl, and triazolopyridazine group. This heterocyclic group can be substituted by one or more substituents R”, wherein R’ is as defined above,
The present invention also relates to compounds of the gemeral formula (IID) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a sterecisomer thereof, : R4
Am ve -
NT Ne pa {
R1 ~~ X lL (I) wherein
R' is-C(OIR™, -C(O)CHR'RS, -C(ONR'R®, -C(O)OR, -R'C(O)R?, or -C(S)R™;
R? is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamine, alkylamino, heteroaryl, or Rand R* together with the N-atom or the C-atom fo which they are attached form a 3 to 8 membered saturated or at least partially unsaturated monocyclic or polycylic ring system, wherein at least one or more of the carbon atoms in the ring is a heteroatom selected from O, N, and S, and the ring can be substituted by one or more R”
R*® is H, Ci-Ce-alkyl, CoCsalkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -CENR)NR'R?, -(CH)aryl, -(CHy),NR'R, -C(OMNR'R®, -N=CR'R®, -NR'C(O)R?, halogen, heteroaryl, or aryl;
Ris H, -C{C)NRR®, halogen, alkyl, haloalkyl, aryi, heteroaryl, OH, SH, NRY ORY,
NH, bydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, . hydroxyalkyl, or haloalkyloxy;
R* is H, OH, SH, NH, alkoxy, haloalkyloxy, halogen, alkyl, -CONR"NR"RS, - (CHp)paryl, (CHa), NR'R®, -C(O)NR'RY, -N=CR'R’, -NR'C(O)R?, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
B® is halogen, alkyl, -CONR)NR" RY, (CHy)paryl, ~(CHz),NR'R?, -C(O)NRRS, “N=CR'R’, -NR'C(O)R®, cycloalkyl, heterocycloalkyl, haloalicyi, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
R* is H, halogen, alkyl, -CONR'NR"R®, -(CH,),aryl, (CH), NR'R®, -C{O)NR'R®, -N=CR'R’, -NR'C(O)R?, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
R® independently represents H, -CN, -OH, -SH, -CO;RY, -C(O)RY, -SO,NRY, -NR¥R®, -C(O)NR'R?, -S0,-alkyl, -SO,R*, SOR, -N=CR*R”, -NR¥C(O)R*",
NR*-CO-haloalkyl, -NO,, -NR*-80, haloalkyl, NR¥.S0,-alleyl, NEY -CO-allyl, -NR*(CH,) heteroaryl, allyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O(CHy),[O(CH), J OCHS, -CINR*)NR* benzimidazolyl, -CONR*NR* benzthiazolyl, -CNR*YNR* benzoxazolyl, hydroxyalkyl, hydroxy- cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;
R¥, RY, R¥ independently are H, halogen, alkyl, ~CNR))NRTR®, -(CH,) aryl, haloalkyl, ~CHp)NR'R®, -C(O)NR'R®, -N=CR'R®, -NR'C(O)R®, cycloalkyl, heterocycloalkyl, : hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
R’,R” RS independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamine heteroaryl, or aryl;
R™ is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl;
R™ is H, halo gen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl;
A is CO or SO,
X isNR%Y, 0,0;
Zz Is N or CR? ;
RY is A, alkyl, -C(ONR’, -C(O)RP, cycloalkyl, heterocyeloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; p is 1t06; q is 1 to 6;
R? independently represents H, -CN, -OH, -SH, alkoxy, alkylthio, CORY, -C(O)R™,
CONR'R?, -SO,NRY, -NE'R®, -SO,-alkyl, -SO,RY, SORY, -N=CRYRS, . ~ NRYCO)RY, NR¥-CO-haloalkyl, -NO,, -NR*-80,-haloalkyl, -NR¥-SO,-aikyl,
NRY-CO-alkyl, “NR¥(CH;), heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O(CHa)[O(CHy)}(OCH:, -CONRYYNR* benzimidazolyl, ~C(NR*"YNR* benzthiazolyl, CNR INR benzoxazolyl, hydroxyeycloalkyl, hydroxyalkylamino, haloalkyloxy, heterocycloalkyl, (CH)NR'COR?, aryl, or heteroaryl; wherein an Cy-Ce-alkyl group, if not stated otherwise, denotes a linear or branched C;-Cg-alkyl, preferably a linear or branched chain of one to five carbon atoms, which can optionally be substituted by one or more substituents R; an Cp-Cgallenyl group, if not stated otherwise, denotes a linear or branched C,—Cg~ alkenyl, preferably a linear or branched chain of two to six carbon atoms, which can optionally be substituted by one or more substituents R; an alkyl group, if not stated otherwise, denotes a linear or branched C;-Cg-alkyl, preferably a linear or branched chain of one to six carbon atoms, a linear or branched C,-Cy-alkenyl or a linear or branched Co-Cg-alkynyl group, which can be substituted by one or more substituents R"; i
R' is independently H, -CO,R™, -CONHR™, -CR™0, -SO;NR", “NR "-CO-haloalkyl, 30- -NOj, -NR"-80-haloalkyl, -NR-S50;-alkyl, -80,-alkyl, -NR-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R™ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl;
a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group R" being as defined above; the Cs-Cy-cycloallyl residue may be selected from the group comprising ~cyclo-CsHs, ~cyclo-C4Hy, ~cyclo-CsH, ~eyclo-CeHiy, -cyclo-CyHys, ~cyclo-CgHjs: a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atorns and at least one heteroatom selected from 0, N, and S, wherein one or more of the carbon atoms in the ring can be substituted by R* being as defined above; preferred - heterocycloalkyl groups are morpholine-4-yl, piperazinyl, I-alkylpiperazine-4-y1, piperidinyl, pyrrolidinyl, azepane-1 -vl; an. alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, £-butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a CRM, -CRYRY,, -CRUORIRI” -Co(R;, -CH, CRY, -CH,CRYR®,, -CHaCRPRIRY, -C3R1),, or ~CHICR 3, wherein R™, R'”, R'” represent F, C1, Br or I, preferably F; ahydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halo gen atoms, the alkyl group being as defined above; the haloallcyloxy group is preferably a
OCR, -OCRP®R!?Y,, -OCRMRINRIY" -OCR';s, -OCH,CRY,, -OCH.CRMR'),, -OCH,CRORW)RY”, OCR"), or -OCH,CRY), wherein RI,
RY RI” represent F, CL, Bror I, preferably F;
a hydroxyalkylamino group denotes an (HO-alkyl),-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above; | } a halogen group is fluorine, chlorine, bromine, or iodine; : an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R°, where R’ is as defined above; the aryl group is preferably a benzyl group, a phenyl group, -0-CgHy- R', -m-Celly- R', -p-CeHe- R', 1- naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl, R" being as defined above; an arylamino group denotes an HIN-aryl or N-diaryl group, the aryl group being as defined above;
a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S.
This heterocyclic group can be fused to another aromatic ring.
For example, this group can be selected from a thiadiazole, thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, ozazol-2-yl, oxazol-4-vl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yi, benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-vl, 1,2, 4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-¥l,
isothiazol-4-vl, isothiazol-5-y1, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-y1, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4- yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3- furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4- pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-dimethoxy-6-
pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, l-pyrazolyl, 3-pyrazolyl, 4- pyrazelyl, 1,2,3-triazol-4-y1, 1,2.3-triazol-5-y], 1,2,4-triazol-3-v1, 1,2 4-triazol-5-yl, 13,5 triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-y1, 1 H-tetrazol-2-yl, 1H-etrazol-3-yl, tetrazolyl,
acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-
indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindelyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, S-indelinyl, 6- - Indolinyl, 7-indolinyl, benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-1- yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzofriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-1, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro- thieno[3,4-djimidazol-2-one, pyrazolo[5,1-01[1,2,4)triazine, 2,3-dihydrobenzol1,4]-dioxin- 2-yi, 2,3-diliydrobenzof1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl, 2,3 dihydrobenzo[1,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-
Cov, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazo-pyrimidine, ~~ imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4-{1,2,4}triazolo[4,3-a]pyridin-3-v1, 1-furo[2,3-c]pyridin-4-yl, 1-furof2,3-cipyridin-5-v1, 1- furof2,3-clpyridin-3-yl, and triazolopyridazine group. This heterocyclic group can be substituted by one or more substituents R’, wherein R" is as defined above; with the proviso that the following compounds are excluded:
GO
A N R2 atoll { < 8
S M wherein ) rR! independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, hajoalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl;
RR? independently represents NRRY, . $n R® $n N-~—RS rR independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl,
R* independenily represents alkyl, oycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R° independently represents H, CORY, COR, SORS, SORE, SO3RS, alkyl, cycloalkyl, alkoxy, -NHy, alkylamine, -NR'COR®, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
RS independently represents H, alkyl, cycloalkyl, -NH,, alkylamine, aryl or heteroaryl;
R’ independently represents H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio, 16 hydroxyalkyl, aryl, or heteroaryl; p isQ,orl; q is0,or 1; xX is CO or SOs.
The present invention, relates also to compounds of the general formula (Ih) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a sterecisomer thereof, 0 SE "\ N 7 \ yy : —d | N 2” X O
R® I (Ih) wherein
A isNR*,Sor0; t is Oto 4; r . isQ,orl;
R® is independently H, OH, SH, NH,, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl;
R™ is independently H, OH, SH, NIL, -CONRANRR?, (CHa)paryl, (CHa), NR'RE, -
COYNR'RE, -N=CR'R?, -NRTC(O)R?, allyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl;
R' is H, halogen, alkyl, -CONR'NR” RY, (CHy)yaryl, (CEL)NRRS, -C(OINR'R, -N=CR'R’, -NR'C(O)R®, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; Co
RY is-C(O)R™, -C(O)CHR'R®, -C(ONR'R?, -C(OYOR”, -R'C(O)R®, or CSR;
R® is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or R!' and R? to gether with the N-atom or the C-atom to which they are attached form a 3 to 8 membered saturated or af least partially unsaturated monocyclic or polyeylic ring system, wherein at least one or more of the carbon atoms in the ring is a heteroatom selected from O, N, and S, and the ring can be substituted by one or more R*
R®™ is H, Cr-Cealkyl, CrCsalkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -CONR'NR'R?, -(CHparyl, (CH) NR'RS, -C(O)NR'R®, -N=CR'R®, -NR'C(O)R?, halogen, heteroaryl, or aryl;
R® isH, -C(O)NR®R®, halogen, alkyl, haloalkyl, aryl, heteroaryl, OF, SEL NRYOR?,
NH,, hydroxyalkylamino, alkylamine, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, or haloalkyloxy;
R® is H, halogen, alkyl, -CONR")NR"R®, -(CHy),aryl, -(CHo),NR'R®, -C(OYNR'R?, -N=CR'R’, -NR'C(O)R?, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
R' independently represents H, -CN, -OH, -SH, -COR¥, -C(O)RY, -SO,NRY,
NR'RY, -C(OINR'RE, -50,-alkyl, -SO,RY, SO:RY, N=CR'R®, -NR“C(O)R*", -NR*-CO-haloalkyl, -NO,, -NR*-80,-haloalkyl, -NR*-S0,-alkyl, -NR*-CO-alkyl,
NR (CHp)heteroaryl, alkyl, eycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O(CHz),{O(CH,),];OCHs, ~C(NRY)NR* benzimidazolyl, -CQR*")NR* benzthiazolyl, -CNR* JNR* benzoxazolyl, hydroxyalkyl, hydroxy- cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;
RY, RY, R” independently are H, halogen, alkyl, -CORINRT RY, «(CHy)aryl, haloalkyl, -CH)NR'R?, -C(O)NR'R?, -N=CR'R®, -NR'C(O)R?, cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamine, alkylamino, heteroaryl, or aryl;
R" R" R® independently are H, halogen, alkyl, cycloalkyl, beterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino heteroaryl, or aryl;
R™ is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl;
R | is F1, halogen, alkyl, cycloalkyl, heterocycioalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl;
X isNR¥,0,0rS;
Z isNorCRY;
R” is H, alkyl, -C(O)NR’, -C(O)RY, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; p is 1 to 6; g¢g is 110 6;
R’ independently represents H, -CN, -OH, -SH, alkoxy, alkylthio, -CO,RY, -C(O)R™, ~ -C(ONR'R®, -SO,NR¥, -NR*R”, -SOp-alkyl, -SO:RY, SORY, -N=CRYRY,
NRFC(O)R*", -NR*¥-CO-haloalkyl, -NO,, NR*-80,-haloalkyl, -NR*-SO-alkyl, “NR®-CO-alkyl, -NR*(CHp)pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O(CHa),[O(CH,),]OCHs, CNR )NR* benzimidazolyl, -CINR*"YNR* benzthiazolyl, -CONR*INR* benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy, heterooycloatiyl, ~(CH2),NR'COR®, aryl, or heteroaryl; . wherein an C;-Cgalkyl group, if not stated otherwise, denotes a linear or branched C-Ce-alkyl, preferably a linear or branched chain of one to five carbon atoms, which can optionally be “0 substituted by one or more substituents R'; i an Cp-Ce-alkenyl group, if not stated otherwise, denotes a linear or branched CoC alkenyl, preferably a linear or branched chain of two to six carbon atoms, which can optionally be substituted by one or more substituents R*:
an alkyl group, if not stated otherwise, denotes a linear or branched C;-Cs-alkyl, preferably a linear or branched chain of one to six carbon atoms, a linear or branched Cp-Cy-alkenyl or a linear or branched Co-Co-alkynyl group, which can be substituted by one or more substituents R';
Ris independently H, -CO,R™, -CONHR", CRO, ~SO,NR™, -NR-CO-haloalkyl, -NOa, “NR"-80s-haloalkyl, -NR-8Oz-alkyl, -SOp-alkyl, -NR“-CO-alkyl, -CN, allyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R'is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group R* being as defined above; the Cy3-Cg-oycloalkyl residue may be selected from the group comprising ~eyelo-CsHs, ~cyelo-CyHy, ~cyclo-CsHa, ~cyclo-CgHiy, ~cyclo-CqHls, -cvelo-CeHs: a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon . atoms and at least one heteroatom selected from O, N, and 8, wherein one or more of the carbon atoms in the ring can be substituted by R® being as defined above; preferred heterocycloalkyl groups are morpholine-4-yl, piperazinyl, I-alkylpiperazine-4-yl, piperidinyl, pyrrolidinyl, azepane-1-y1; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, z-butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; 30 . an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -CR%;,
CRIOERIY), CRIOERIYRI” CHR); CH,CRY),, -CH,CROR,,
-CERCRRIIR'Y, CRY, or ~CrHaCR®)s, wherein RY, RY, RY” represent F, CI, Br or I, preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OCRY;, ~OCRIRY,, SOCRIRIRI”, “OCH(R)s, -OCH,CR%,, + OCH CRY®), -OCHCRY®'™IR'Y, -OC:®R!Y,, or -OCHLCRY), wherein RY,
RY, RY represent F, Cl, Brorl, preferably F; a hydroxyalkylamino group denotes an (HO-alkyl),-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above; a halogen group is fluorine, chlorine, bromine, or iodine; an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R", where R" is as defined above; the aryl group is preferably a benzyl group, a phenyl group, -0-CéHs~ R', -m-CsHy- R’, -p-Clly- R°, 1- naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl, R* being as defined above; an arylamino group denotes an HN-aryl or N-diaryl group, the aryl group being as defined above; a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least - one heteroatom selected from O, N, and 8, This heterocyclic group can be fiised to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl, benzooxazol-5-yl, benzoiscoxazol-3-yl, benzoisooxazol-4-yl,
benzoisooxazol-3-vl, 1,2,4-oxadiazol-3-yl, 1,2. 4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-vl, 1,2,5-oxadiazol-4-v1, 1,2, 4-thiadiazol-3-yl, 1,2, 4-thmadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-y1, benzoisothiazol-3-vi, benzoisothiazol-4-yl, benzoisothiazol-5-y1, 1,2,5-thiadiazel-3-yi, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4- yl, 4-imidazolyl, benzoimidazol-4-yl, l-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3- furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4- pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, S-pyrimidinyl, 6-pyrimidinyl, 2.4-dimethoxy-6- pyrioidinyl, 3-pyridazinyl, 4-pyridezinyl, 2-pyrazinyl, l-pyrazolyl, 3-pyrazolyl, 4- pyrazolyl, 1,2,3-trazol-4-y1, 1,2,3-triazol-5-v1, 1,2,4-triazol-3-yl, 1,2, 4-triazol-5-yl, 1,3,5- triazol-6-vl, 2. 4-dimethoxy-1,3,5-triazol-6-v1, 1 H-tetrazol-2-yl, 1 H-tetrazol-3-vl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3- indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl,
S-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6- indolinyl, 7-indolinyl, benzo[blfuranyl, benzofurazane, benzothiofurazane, benzotriazol-1- vl, benzotriazol-4-yl, benzotriazol-5-vi, benzotriazol-6-yl, benzotriazol-7-y1, benzotriazine, benzo{blthiophenyl, benzimidazol-2-vl, tH-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-y!, benzothiazolyl, quinazolimyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro- thieno[3,4-d}imidazo!l-2-one, pyrazolo[5,1-cl[1,2,4]triazine, 2,3-dihydrobenzo[l,4]-dioxin- 2-yl, 2,3-dihydrobenzo[l4]-dioxin-3-yl, 2,3-dihydrobenzo[l,4]-dioxin-5-yl, 2,3- dihydrobenzo[1,4]-dioxin-6-yl, 2,6~dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4- yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazo-pyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, iriazolopyridine, triazolopyrazine, friazolopyrimidine, 4-11,2 4Tirlazolof4,3-alpyridin-3-yl, 1-furo[2,3-c]pyridin-4-y1, 1-furo[2,3-clpyridin-5-yi, 1- furo[2,3-c]pyridin-3-yl, and triazolopyridazine group. This heterocyclic group can be substituted by one or more substituents R’, wherein R' is as defined above; : with the proviso that the following compounds are excluded:
a
ST Nowy 7 Spo helt 4
Nd S 0 wherein rR! independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl;
RZ independently represents -NR*R*, Co
Fo 5 N—RS
R® independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, 16 alkylthio, hydroxyalkyl, haloalicyl, haloalkyloxy, aryl or heteroaryl, rR? independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R? independently represents H, CORS, CO,R, SOR, SO,R®, SO3R®, alkyl, cycloalkyl, alkoxy, -NH,, alkylamine, -NR'CORS, halogen, -OH, -8H, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; : independently represents H, alkyl, cycloalkyl, -NH,, alkylamine, aryl or heteroaryl;
R’? independently represénts H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, aryl, or heteroaryl;
P is 0,orl; gq is0,o0r i;
X is CO or 80;.
The- present invention relates also to compounds of the general formula (I) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs, or a sterecisomer thereof,
IN
/ \
AN Yee RB 4
R1
CN, X l (0 wherein
Rl is COR, -C(OYCHRRS, -C(ONR'RE, -C(Q)OR”, -R'C(O)R?, -C(B)R’; rR? is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkylamino, hydroxyalkylamino, heteroaryl, or R! and R? together with the N-atom or the C-atom to which they are attached form a 3 to 8 membered saturated or at least partially unsaturated monocyclic or polycyelic ring system, wherein at least one or more of the carbon atoms intheringisa heteroatom selected from QO, N, and S, and the ring can be substituted by one or more BR’;
R® is H,-C(O)NR'RY, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR* OR”,
NH,, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, or haloalkyloxy;
R® is H, halogen, alkyl, -CONRINR” RS, -(CHa)garyl, -(CHz),NR'RY, -C(O)NR'R’,
N=CR'R?, NR'C(O)R?, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalicyl, hydroxyallkylamino, alkylamino, heteroaryl, or aryl;
R® independently represents H, -CN, -OH, -SH, -COR¥, -C(O)RY, -SONR”,
NRYRY, -C(ONR'R?, -SO-alkyl, -SORY, SO:RY, -N=CR'R’, NRYCORY, © NR*-CO-haloalkyl, -NO, -NR¥-SO,-haloalkyl, -NR*-S0p-aikyl, -NR¥-CO-alkyl,
NR*(CH,)pheterocyele, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O(CHa)e[O(CH2)plqOCHs, -CINR* NR" benzimidazolyl, -C(NR¥NR* benzthiazolyl, -CNR* NR benzoxazolyl, hydroxyalkyl, hydroxy- alkylamino, aryl, heterocycloalkyl, or heteroaryl;
RS is halogen, -C(O)R7, -C(O)CHRRE, -C(O)NR'R?, -C(O)OR’, -R'C(OIRY, -C(SIR’,
CORHNRTR, -(CHoaryl, -(CH),NR'R’, -CONR'R®, -N=CR'R’, -
NR'C(O)R”, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
Rr’ RT R® independently are H, halogen, alkyl, cycloalkyl, heterocyeloalkyl, haloatleyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, ~-NHaryl, heteroaryl, or aryl;
A is CO or SO,
X #sNRY,0,0rS;
Y isN, CR* orif Y is O then RC is absent; 7. isNor CR”; if Z is CH then X is O or NR”
RY isH, alkyl, -C(O)NR?, -C(O)R®, cycloalkyl, heteroeycloalky!, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 1 is Oto 2; p is 1 to 6; q is 1 to 6;
R’ independently represents H, -CN, -OH, -SH, -CORY, -C(O)R*, -C(O)NR'RS, -
SONRY, -NR'RY, -80z-alkyl, -SORY, SOsRY, -N=CRYRY, :NRTCORY", - : NR¥-CO-haloalkyl, -NO,, -NR*-S0,-haloalkyl, -NR*-SO,-alkyl, -NR¥-CO-aikyl,
NR*(CHy)pheteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, hydroxyalkylamino, hydroxyalkyl, hydroxycycloalkyl, aryl, ~O(CHz),[O(CH,),1,O0CH;, ~CONR* NR * benzimidazolyl, -CONR*" INR" benzthiazolyl, -C(NR*")NR*benzoxazolyl, -(CHp),NR'COR®, or heteroaryl;
RY, RY" RY independently are H, halogen, alkyl, -CONR" NR" RE, ~(CHj)paryl, -(CHo),NR'R?, -C(OINRR?, -N=CRR?, -NR'C(O)R?, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
R® is H, Ci-Cealkyl, C;Cealkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR)NR'R®, -(CHy)paryl, -CHo),NR'RS, -C(O)NR'R’, -N=CR'R®, NR'C(O)R®, halogen, heteroaryl, or aryl wherein oo 33 an Ci-Ce-alkyl group, if not stated otherwise, denotes a linear or branched C;-Ce-alkyl, preferably a linear or branched chain of one fo five carbon atoms, which can optionally be substituted by one or more substituents R'; } : an CyCs-alkenyl group, if not stated otherwise, denotes a linear or branched Cyp—Cg— alkenyl, preferably a linear or branched chain of two to six carbon atoms, which can optionally be substituted by one or more substituents rR; an alkyl group, if not stated otherwise, denotes a linear or branched C,-Ce-alkyl, preferably alinear or branched chain of one to six carbon atoms, a linear or branched Co-Cy-atkenyl or a linear or branched C;-Cs-alkynyl group, which can be substituted by one or more substituents Ry
R" is independently H, -CO,R™, ~CONHR™, -CR"O, -SO;NR™, -NR-CO-haloalkyl, “NOs, -NR-80;-haloalkyl, -NR -80;-alkyl, -SO;-alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R'* is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; aheterocycle denotes a heterocycloalkyl group or a heteroaryl group; a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group R® being as defined above; the C3-Cg-cycloalkyl residue may be selected from the group comprising -cyclo-CaHs, -cyclo-Cly, -cyclo-CsH, -cyclo-CeHiy, ~cyelo-CyHis, -cyclo-CgHjys; a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atoms and at least one heteroatom selected from O, N, and S, wherein one or more of the carbon atoms in the ring can be substituted by R* being as defined above; preferred heterocycloalkyl groups dre morpholine-4-yl, piperazinyl, I-alkylpiperazine-4-yl; piperidinyl, pyzrolidinyl, azocane-1-yl; :
an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the . alkoxy group is preferably a methoxy, ethoxy, isopropoxy, &-butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R %,, -CRYE®RIY, -CRIRIRY -Co®R10)s, CH, CR), -CH,CRY®IMY,, .
CHCRERIVRY”, -C3R")y, or -CoHCR Ys, wherein RY, RY”, RY” represent F, C1, Br erl preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloatkyloxy group is preferably a
OCR"), -OCRU®R™Y,, OCRERORY, OCR, -OCHCR', -OCHCRMR'™), -OCH,CRUERIVIRY, -OC, RY), or -OCHCR®): wherein RY,
RIO, R10” represent F, Cl, Br or I, preferably F; a hydroxyalkylamino group denotes an (HO-alkyl),-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above; a halogen group is fluorine, chlorine, bromine, or iodine; an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R", where R' is as defined above; the aryl group is preferably a benzyl group, a phenyl group, ~0-CsHy- R', -m-CeHy R, -p-CeHl- rR, 1- naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl, R' being as defined above; - {
2 heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least: one heteroatom selected from O, N, and S.
This heterocyclic group can be fused to another aromatic ring.
For example, this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-d-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-o0xadiazol-5-yl, 1,2,5-oxadiazol-3-y1, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-vi, isothiazel-5-vl, benzoisothiazol-3-y1, benzoisothiazol-4-yi, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4- yl, 4-imidazolyl, benzoimidazol-4-yl, I-pyrrolyl, 2Z-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3- furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4- pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, S-pyrimidinyl, 6-pyrinudinyl, 2, 4-dimethoxy-6- pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrezinyl, I-pyrazolyl, 3-pyrazolyl, 4- pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-trlazol-5-yl, 1,2,4-triazol-3-yl, 1.2, d-triazol-5-vl, 1,3,5~ trinzol-6-yl, 2 4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-y1, 1 H-tetrazol-3-y1, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, Z-indolyl, 3- indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2~indolinyl, 3-indolinyl, 4-indokinyl, 5 ~indolinyl, 6- indolinyl, 7-indolinyl, benzo[blfuranyl, benzofurazane, benzothiofurazane, benzotriazol-1- yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-vl, benzotriazine, benzo[bjthiophenyl, benzimidazol-2-v1, 1H-benzimidazolyl, benzimidazol-4-yl, benzirnidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro- thieno[3,4-d]imidazol-2-one, pyrazolo[3,1-c][1,2,4 triazine, 2,3-dihydrobenzo{1,4]-dioxin- © 29l, 2,3-dihydrobenzof1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl, 2,3- dihydrobenzo[1,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2.6-dimethoxypyrimidin-4- yl, ietrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindens, isothiazolopyrazine, isothiazolopyrimidine, _ pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, | imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4-[1,2,4Ttdazolo[4,3-a]pyridin-3-y], 1-furo[2,3-¢]pyridin-4-yl, 1-furo[2,3-¢jpyridin-5-yl, 1-
fiaro[2,3-clpyridin-3-yl, and triazolopyridazine group. This heterocyclic group can be substituted by one or more substituents R°, wherein R” is as defined above.
In a preferred embodiment of the invention, in the compounds of formula (Iz), Z is §, Y is
CO, X is CO, R is H, R® is H, and R! is aryl, benzyl, or heteroaryl, R* is
Sn NR n__/ , and R is optionally substituted aryl, benzyl or heteroaryl.
In a preferred embodiment of the invention, in the compounds of formula (Ia), Zis O, Y is
CO, X is CO, R is H, R® is H, and R' is aryl, benzyl, or heteroaryl, R® is 5-1 N——-R5 __/ ,and R’ is optionally substituted aryl, benzyl or heteroaryl.
In a preferred embodiment of the invention, in the compounds of formula (Ib), Zis 8, Y is
C0, X forms a piperidine ring together with BR! and RY, B® and R” is H, R® is F or methyl, 5» N~——-R5
Ris _/ , and R’ is optionally substituted aryl, benzyl or heteroaryl.
In a preferred embodiment of the invention, in the compomds of formula (Ib), Zis 0, Y is
CO, X forms a piperidine ring together with R! and R*, R? and R® is H, R® is H or methyl, $n N-——R?
RYis _/ , and R® is optionally substitated aryl, benzyl or heteroaryl.
In another preferred embodiment, in the compounds of formula (Ic), ris 1,Y is CO, Z is O, tis 0, sis 1, X is CO, R° is H, methyl, ethyl, methoxy, alkylamino, morpholino, N- - 5 . N—R® methylpiperazine, CF3, or OCF, R? is NN , and R® is optionally substituted aryl, benzyl or heteroaryl.
In another preferred embodiment, in the compounds of formula (Ie), ris ,Yis CO, Z is §,
tig 0, sis 0, R® is H, methyl, ethyl, methoxy, alkylamino, morpholino, N-methylpiperazine,
CFs, or OCF, R%is __/ , and R is optionally substituted aryl, benzyl or heteroaryl.
In another preferred embodiment, in the compounds of formula (Jc), ris 1,Y is CO, Z is 5, tis0,sis 1, Xis CO, R®is H, methyl, ethyl, methoxy, alkylamino, morpholino, N- 5x N-—R5 methylpiperazine, CFs, or OCF, R? is __/ , and R’® is optionally substituted aryl, benzyl or heteroaryl.
In another preferred embodiment, in the compounds of formula (Ic), ris 1,Y is CO, Zis 0, tis 0, s is 0, R® is H, methyl, ethyl, methoxy, alkylamino, morpholino, N-methylpiperazine,
Sn N—R5
CF, or OCF Ris NA , and RY is optionally substituted aryl, benzyl or heteroaryl.
A preferred embodiment of the invention, in the compounds of formula (IIT), are compounds of the formula (Ilia),
O 5
L
RA
O N \
IID
R7e P R
H (IIIa) wherein
R? is H, methyl, methoxy, CFs, or OCF3; - © RR’, R™ are defined as above; Xs NR?, OQ or S; and Z is as defined as above.
Another preferred embodiment of the invention, in the compounds of formula (III),
are compounds of the formula (Ia), with R"™ = -NH-aryl.
Another preferred embodiment of the invention, in the compounds of formula (111), are compounds of the fornmla (Ib),
QO
: NHRS y A
J > 7 x : [J 3 (Lib) wherein
R? is H, methyl, methoxy, CFs, or OCFs; R® is defined as above; Xis NR”, O or §; if Zis Nthen X is NR”, Oor 8, or if Z is CR?, X is O;
VY’ is Oor NR®, R%isas defined above;
Another preferred embodiment of the invention, in the compounds of formula (1), are compounds of the formula (IIc),
RN 5 0 pe \ =i oo 0 \ RE yn R12 / N X R? !
H | .
AF
R12 Ri (ic) wherein
RI! R¥ independently represent H, -CN, -OH, -SH, -CO,RY, -C(O)RY -SO;NRY,
NR¥RY, -80,-alkyl, -SO;RY, SOsRY, -N=CR*R”, -NR*C(O)R*", -NR"-CO-haloalky], -NO,, -NR¥-80,-haloalkyl, -NR*-80,-alkyl, -NR*-CO-alkyl, -NR* (CHy) heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -O(CHy)p[O(CHa)p](OCHS, -
CNR NR benzimidazolyl, -CONR INR? benzthiazolyl, -CQNR' INR" benzoxazolyl - hydroxyalkyl, hydroxyoycloalkyl, hydroxyalkylamino, halogen, haloalkyl, baloalkyloxy, aryl, arylalkyl or a heterocycle; and RY, RY", R”" are defined as above; | :
Ris H, methyl, methoxy, CFs, or OCF3; X is NR%, O ors, R* is defined as above,
Rand R” are defined as above,
RY RY? independently represents H, -CN, -OH, -8H, -COR", -C(O)R*, -SO.NRY,
NRYR, -805-alkyl, -SO,RY, SORY, N=CR*RY, -NR*C(O)R*", -NR¥-CO-haloalkyl,
NO, -NR*-80,-haloalkyl, -NR*-SOs-alkyl, -NR*-CO-alkyl, -NR¥ (CHy)pheteroaryl, allyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -O(CHy),[O{CHy),l{OCHS, -CNR*)NR*benzimidazolyl, -C(NR')NR”benzthiazolyl, -CINR*)NR*benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkyl-amino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle; and RY RY, RY are defined as above;
A more preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (111d),
RN R”
O =
N = \. Ce
I
Pa. A
N X R
8 N ol Cd) wherein
Ris H, methyl, methoxy, CFs, or OCF3; Xis NR%,OorS, R'is defined as above,
R? and R” are defined as above, Y’* and RY, R™ are defined as above under formula (lc), Y’isOor NR” and R” is as defined above.
Another more preferred embodiment of the invention, in the compounds of formula 1m, are compounds of the formula (I1le),
J” \. 12 \
R R11 3 —R3
Za z X
N J (111 g) wherein
R3 Rand R® are defined as above, XisOorS,
RM and RY are defined as above under formula (ITlc), and fZisN,XisNR*, OorS,ifZis CH, Xis O.
Another more preferred embodiment of the invention, in the compounds of formula (II), are compounds of the formula (1111),
RN 5 "\ = : N 3 4 ¥ Ri? \ = . J a 3 me z X R i
EN
N
4 @ x \ ri 1 . wherein 7isN or CH, and R® is H, methyl, methoxy, CFs, or OCFs; Xis NR*, O or S,
R* is defined as above, R and R” are defined ag above, R? is as defined above;
Y** and RY, RY, R2, RY are defined as above under formula (Tc).
A preferred embodiment of the invention, are compounds of the formula (Tha),
O ~ Rd
A t "\ MN Se \ Va 4 _R2 ag | NTT 7
R? X 3 | ©
R L I (Tha) wherein
R'is COR™; R%and R** are H; A is NH; R” is as defined above; Z is N;
XisNR¥,00rs; RPisH, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N- methylpiperazine, CFs, or OCF; tis 0; ris 1; and R® is optionally substituted aryl, benzyl or heteroaryl.
Another preferred embodiment of the invention, in the compounds of formula (Th), are compounds of the formula {Iha), with R"™ is optionally substituted aryl, benzyl or heteroaryl.
Another preferred embodiment of the invention, in the compounds of formula (Th), are compounds of the formula (Thb), 0 [Re
N wee \ J Ra > 7 < | N
O
A x R® r (Thb) wherein
R™isH; AisNH;XisNR*,OorS; Y isOorNR?;
RY is as defined above; R® is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino,
N-methylpiperazine, CF3, or OCF; tis 0; r is {; and R?% is optionally substituted aryl, ) benzyl or heteroaryl.
Another more preferred embodiment of the invention, in the compounds of formula (Ih),
are compounds of the formula (The), 0 Re = 14 N 3 4 \ 2
R NR RZ
Lp o . X 3
R r x P (The) wherein
R¥isH; Ais NH;XisNR”,0or§;
R* and R* independently represent H, -CN, -OH, -SH, -CO;RY, -C(O)RY, -SONR*,
NRYRY, -80,-alkyl, -SO,RY, SORY, -N=CR*R’, -NR"C(O)RY", -NR*¥-CO-haloalkyl,
NOy, -NR¥-50,-haloalkyl, -NR*-80,-alkyl, -NR*-CO-alkyl, -NR* (CHp) heteroaryl, alleyl, cycloalkyl, allkylamino, alkoxy, alkylthio, -O(CHy)p[O(CH2)p]OCHa, - :
CER*INR"benzimidazolyl, -CONR" INR" benzthiazolyl, -CNR® INR * benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle; and Rr, RY, RY are defined as above;
R¥ is as defined above; Ris H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, - N-methylpiperazine, CFs, or OCF3; t is 0: r is 1; and R® is optionally substituted aryl, benzyl or heteroaryl.
A preferred embodiment of the invention, in the compounds of formula (II), are compounds of the formula (IIa), oO yy r1 1 / \ P
N N / \ / \ Ke R12 mA
ML © pt ~~, x mw
RZ wherein
R! and R? are defined as above, Z is defined as above; Xis OQ or 5;
R? is H, methyl, methoxy, CFs, or OCFs;
R* and BR" are defined as above under formula (Ie).
A more preferred embodiment of the invention, in the compounds of formula (IL), are compounds of the formula (IIb),
CFs 0 JN
N Y a ot _— of
R 1 Ne (IIb) k wherein
R! and R? are defined as above, Z is defined as above; XisOorS,
R? is H, methyl, methoxy, CFs, or OCF.
Another more preferred embodiment of the invention, in the compounds of formula (II), are compounds of the formula (Hc),
CF,
Q /\ = \ \ / —
Pa > © x
Y wherein
XisOor$; R®isH, methyl, methoxy, CFs, or OCFs, Y' is NR,
Another more preferred embodiment of the invention, in the compounds of formula (IT),
are compounds of the formula (11d),
NSN /
N
__/ \ 7 © rt
N
Is . 7 x
Lo d) rv ’ wherein 7 is defined as above; 'R° is H, methyl, methoxy, CFs, or OCFs,
RIL RY and RY¥ R'™ are defined as above.
In addition, the present invention provides methods for preparing the compounds of the invention such as compounds of formula (Ia), (Ib), (Ic), (II), or (HD.
The compounds of formula (Ia), (Ib), (Ic), (I), or (III) may be obtained via various methods.
Piperidin-4yl-thiazole-4-carboxamide can be prepared by various methodes described in the literature. One such example is the oxidation of the appropriate 2,5-dihydrothiazoles as described in Houben-Weyl, 2002, 730. The dihydrothiazoles can also synthesised by methodes described in the same reference or described in You, S., Razavi, H., Kelly, JW, © Angew. Chem. 2063, 115, 87 or Kawitzky, AR., Cai, C., Suzuki, K., Singh, SK. J. Org.
Chem. 2004, 69, 811-814 and references in both papers. Alternative methods were decribed by Yasuchika, S. et. al. Heterocycles, Vol. 57, No. 5, 2002.
The compounds of formula (II), (Ic), and (III) carrying a further substituent on the heterocycle can be obtained via various methods described in Organic Syntheses, Coll
Vol.9, p.155; and Vol.74,p.229; J Org. Chem., 1975, Vol40, No.10, page 1521, J
Am, Chem. Soc.96:19/September 18,1974; J. Org. Chem., 1990, 55, 4484-4487; Chemische
Berichte 1968, 101 (1), 302-307; Agricultural Chemistry and Biotechnology, 2602, 45 (1), page 37-42.
One possibility for the synthesis of substituted benzimindazole-substituent of formula (IIT) is described in Synthesis, 2006, 4, 597-602.
One possibility for the synthesis of compounds of formula (IIIa, ¢ and Ia, b) (see scheme 1) comprises a step of reacting a compound of formula (V) with a compound of formula (VI) under classical amide coupling conditions, like e.g. HBTU, iPro.NEt, DMF, 0°C to r.t. to obtain intermediate (VII). Another alternative for this step might be the reaction of (V) with the corresponding acid chloride of (VI) to yield (VII). In a second step, compound (VII) is saponified with a 1 M NaOH solution, obtaining the expected acid (VII) in almost quantitative yield. This step could be realized under acidic conditions as well. Finally, another amide coupling step (with primary or secundary amines), which works similarly to step 1 described above, completes the synthesis for compounds of type ([ila, ¢ and Ia, and b). )
c
Ot 0
OEE 0 0 N
R11 Ri Pe \
Ml : X RN OH — X a N x ay cl [J i " es . R R
V) VD (VID rd 0 / 9
N oH
J Nes
Q WN Oo N rY i \ Ri i A ) AN re ( EN oo 7 A FF
R12 g12 (Ilia, c, Ifa, b) (VII)
Scheme 1 Syathesis of derivatives of type (lla, ¢) and (Ila, b)
Compounds dealing with structure (IIIb, d, e, f) and (IIc, d) can be synthesized according to the procedure displayed in scheme 2. Herein, a heterocycle (IX) is reacted with a bromocompound (X), by means of a nucleophilic substitution reaction, to gain a bicyclic ester (XI), which is then saponified under standard and well-known conditions to acid (X10), completing the synthesis with another coupling step as described in scheme 1 above.
0
OEt 0
OEt ) \ 7 . N \ a ML
J : 7 J
Br X 3% Xx) (XD)
R23
Q / Q
N
R
) BB
AS ~~
A
(Ih, 4, &, £, To, d) (0)
Scheme 2 Synthesis of derivatives of type (IIIb, d, e, f) and (Ic, d), with Z=N
In case of Z = CH, structire (IIb, d, e, f) and (IIc, d) type compounds can easily be synthesized following a protocol outlined in scheme 3, wherein a heterocycle (XIII) is converted to compound (XV) by a cyclokondensation step. After saponification, (XVI) is coupled with an amine to yield the desired product (ITTb, 4, ¢, £} or (Ile, d).
0
XN OE
X N \
PY Q 0 Pe > NHp XM _ 7 X 1 Br OE A (XII) FIV) XV)
RI
0 / Q
N oH { J
R
B: i» 7 py Fy pe
A A
(ih, d, e, £, Ic, d) VD
Scheme 3 Synthesis of derivatives of type (IIIb, d, e, f) and (Ile, d), with Z = CH
For the compounds of the formula (Ja), (Ib), (Jc), (II), or (II) above, the term “stereoisomer” means cis/trans or E/Z isomerism. More particularly, the possible double bond(s) present in the various substituent of the compounds of the present invention can be
E or Z configuration. These pure or impure geometrical isomers, alone or as a mixture, form an integral part of the compounds of the formula (Ia), (Ib), (Ic), (II), or (IID.
The term “sterecisomer” includes also all the isomeric forms, alone or as mixture, resulting from the presence of one or more axes and/ or centres of symmetry in the molecules, and resuliing in the rotation of a beam of polarized light. More particularly, it includes enatiomers and diastereomers, in pure form or as a mixture.
The compounds of the formula (fz), (Ib), (Ic), (IN), or (UI) to be used according to the invention can form salts with inorganic or organic acids or bases. Examples of pharmaceutically acceptable salts comprise without limitation non-foxic inorganic or organic salts such as acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enantate derived from heptanoic acid, formiate derived from formic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, chloride derived from hydrochloric acid, bromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methanesulfonic acid, naphtaline-2-sulfonate derived from naphtaline-Z-sulfonic acid, nitrate derived from nitric acid, perchlorate derived from ~ perchloric acid, phosphate derived from phosphoric acid, phthalate derived from phthalic acid, salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, sulphate derived from sulphuric acid, tartrate derived from tartaric acid, toluene-p-sulfate derived from p-toluene- sulfonic acid and others. Such salts can be produced by methods known to someone of skill in the art and described in the prior art.
Other salts like oxalate derived from oxalic acid, which is not considered as pharmaceutically acceptable can be appropriate as intermediates for the production of compounds of the formula (Ia), (Ib), (Ic), (II), or (III) or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable prodrugs, or a stereoisomer thereof.
The invention covers the pharmaceutically acceptable salts, as indicated above, but also salts allowing a suitable seperation or crystallization of the compounds of the formula (Ta),
Ib), (Ic), (ID), or (XID), such as the salts obtained with chiral amines.
The compounds of the formula (Ia), (Ib), (Ic), (ID, or (JI) above also comprise the prodrugs of these compounds.
The term “prodrug” as used lLerein refers to compounds which once administered to the patient are not pharmaceutically active themselves (“prodrugs”) but which are chemically and/ or biologically transformed into their pharmaceutical active form (compounds of formula (Ia), (Ib), (Io), (I), or (IID) in vivo, i.e. in the subject to which the compound is administered.
The compounds according to the invention and medicaments. prepared therewith are generally useful for the treatment of cell proliferation disorders, for the treatment. or prophylaxis of immunological diseases and conditions (as for instance inflammatory diseases, neuroimmunological diseases, autoimmune diseases or other).
The compounds of the present invention are useful for the treatment of discases which are caused by malignant cell proliferation, such as all forms of solid tumors, leukemias and lymphomas. Therefore the compounds according to the invention and medicaments prepared therewith are generally useful for regulating cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death. or to induce systemic changes in metabolism such as changes in sugar, lipid or protein metabolism. They can also be used to support cell generation poiesis, including blood cell growth and generation (prohematopoietic effect) after depletion or destruction of cells, as caused by, for example, toxic agents, radiation, immunotherapy, growth defects, malnutrition, malabsorption, © immune dysregulation, anemia and the like or to provide a therapeutic control of tissue generation and degradation, and therapeutic modification of cell and tissue maintenance and blood cell homeostasis.
These diseases and conditions include but are not limited to cancer as hematological (e.g. leukemia, lymphoma, myeloma) or solid tumors (for example breast, prostate, liver, bladder, lung, esophageal, stomach, colorectal, genitourinary, gastrointestinal, skin, pancreatic, brain, uterine, colon, head and neck, cervical, and ovarian, melanoma, astrocytorna, small cell lung cancer, glioma, basal and squameous cell carcinoma, sarcomas as Kaposi’s sarcoma and osteosarcoma) or for the treatment of diseases which are cured or relieved by the inhibition of one or several kinases and/or phosphatases. “Treatment” according to the present invention is intended to mean complete or partial healing of a disease, or alleviation of a disease or stop of progression of a given disease.
Thus, in one embodiment, the invention relates to the use of the compounds of the formula (fa), (Ib), (ec), (AD), or (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs, or a stereoisomer thereof if desired with appropriate adjuvants and additives for the production of a medicament for the treatment or prevention of a disease characterized by hyperproliferation of keratinocytes and/or T cells, especially inflammatory disorders and immune disorders, preferably selected from the group consisting of Addison's disease, alopecia areata, Ankylosing spondylitis, haemolytic anemia (anemia haemolytica), pernicious anemia (anemia perniciosa), aphthae, aphthous stomatitis, arthritis, arteriosclerotic disorders, osteoarthritis, rheumatoid arthritis, aspermiogenese, asthma bronchiale, auto-immune asthma, auto-immune hemolysis, - : Bechet's disease, Boeck's disease, inflammatory bowel disease, Burkitt's lymphoma,
Crohn's disease, chorioiditis, colitis ulcerosa, Coeliac disease, cryoglobulinemia, dermatitis herpetiformis, dermatomyositis, insulin-dependent type I diabetes, juvenile diabetes, idiopathic diabetes insipidus, insulin-dependent diabetes mellisis, autoimmune demyelinating diseases, Dupuytren's contracture, encephalomyelitis, encephalomyelitis allergica, endoplithalmia phacoanaphylactica, enteritis allergica, autoimmune enteropathy syndrome, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, glomernlo nephritis, Goodpasture's syndrome, Graves’ disease, Harnman-Rich's disease, Hashimoto's disease, Hashimoto's thyroiditis, sudden i5 hearing loss, sensoneural hearing loss, hepatitis chronica, Hodgkin's disease, haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, iritis, leucopenia, leucemia, lupus erythematosus disseminatus, systemic lupus erythematosus, cutaneous fapus erythematosus, lymphogranuloma malignum, mononucleosis infectiosa, myasthenia gravis, traverse myelitis, primary idiopathic myxedema, nephrosis, ophthalmia symphatica, orchitis granulomatosa, pancreatitis, pemphigus, pemphigus vulgaris, polyarteritis nodosa, polyarthritis chronica primaria, polymyositis, polyradiculitis acuta, psoriasis, purpura, pyoderma gangrenosum, Quervain's thyreciditis, Reiter's syndrome, sarcoidosis, ataxic sclerosis, progressive systemic sclerosis, scleritis, sclerodermia, multiple sclerosis, sclerosis disseminata, acquired spenic atrophy, infertility due to antispermatozoan antibodies, thrombocytopenia, idiopathic thrombocytopenia purpura, thymoma, acute anterior uveitis, vitiligo, AIDS, HIV, SCID and Epstein Barr virus associated diseases such as Sjorgren's syndrome, virus (AIDS or EBV) associated B cell lymphoma, parasitic diseases such as Leishmania, and immunesuppressed disease states such as viral infections following allograft transplantations, AIDS, cancer, chronic active hepatitis diabetes, toxic © 30 chock syndrome and food poisoning. )
Furthermore, the invention relates to a method of treatment or prevention of diseases which comprises the administration of an effective amount of compounds of the (a), (Ib), (Ic),
D, or (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs,or a stereoisomer thereof. : The invention also provides a pharmaceutical composition comprising a compound of formula (Ia), (Ib), (Ic), (ID), or (IIL), in free-form or in the form of pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs, together with a pharmaceutically acceptable diluent or carrier therefore.
Ina preferred embodiment, the invention relates to the use of compounds of the formula (Ia), (Ib), (Ic), (ID, or (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs or a steteoisomer thereof if desired with appropriate adjuvants and additives for the production of a medicament for the treatment or prevention of skin diseases in which T cells play a role; especially preferably the skin diseases are selected from the group consisting of psoriasis, atopic dermatitis, alopecia areata, alopecia totals, alopecia subiotalis, alopecia universalis, alopecia diffusa, lupus erythematodes of the skin, - lichen planus, dermatomyostis of the skin, atopic eczema, morphea, sklerodermia, psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa, alopecia areata ophiasis-type, androgenetic alopecia, allergic contact eczema, irritative contact eczema, contact eczema, pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, scarring mucosal pemphigoid, bullous pemphgoid, mucous pemphigoid, dermatitis, dermatitis herpetiformis duhring, urticaria, necrobiosis lipoidica, erythema nodosum, lichen vidal, prurige simplex, prurigo nodularis, prurigo acuta, linear IgA. dermatosis, polymorphic light dermatoses, erythema solaris, lichen sclerosus et atrophicans, exanthema of the skin, drug exanthema, purpura chronica progressiva, dihidrotic eczema, Eczema, fixed drug exanthema, photoallergic skin reaction, lichen simplex eriorale, dermatitis and "Graft versus Host-
Disease", acne, rosacea, scarring, keloids and vitiligo.
Moreover, the compounds of the present invention can be used for the treatment of diseases resulting from ischemia and/or reperfusion injury of organs and/or of parts of the body selected from the group comprising heart, brain, peripheral limb, kidney, liver, spleen and tung, and/or wherein the endothelial dysfunction is associated with diseases selected from a group comprising infarctions such as myocardial infarction and critical Hmb ischemia,and/or wherein the endothelial dysfunction is associated with diseases selected from the group comprising ischemic diseases such as peripheral arterial occlusive disease, e. g. critical leg ischemia, myocardial infarction and ischemic diseases of organs, e. g. of the kidney, spleen, brain and lung.
The compounds of this invention also can be applied for the prevention and the treatment of neurological diseases or disorders (diseases or disorders associated with the brain and nervous system), including but not limited to, Alzheimer's disease, Parkinson's disease,
Creutzfeld-Jacob Disease, Lewy Body Dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, Huntington's Disease, Down's Syndrome, nerve deafness, and Meniere's diseass.). Other neurological diseases and disorders will be apparent to those of skill in the art and are encompassed by the definition as used in this favention.
The compounds of the present invention can further be used for diseases that are caused by protozoal infestations in humans and animals. Such veterinary and human pathogenic . protozoas are preferably intracellular active parasites of the phylum Apicomplexa or
Sarcomastigophora, especially Trypanosoma, Plasmodia, Leishmania, Babesia and
Theileria, Cryptosporidia, Sacrocystida, Amoebia, Coccidia and Trichomonadia. These active substances or corresponding drugs are especially suitable for the treatment of :
Malaria tropica, caused by Plasmodium falciparum, Malaria tertiana, caused by
Plasmodium vivax or Plasmodium ovale and for the treatment of Malaria quartana, caused by: Plasmodium malariae. They are also suitable for the treatment of Toxoplasmosis, caused by Toxoplasma gondii, Coccidiosis, caused for instance by Isospora belli, intestinal
Sarcosporidiosis, caused by Sarcocystis suihominis, dysentery caused by Entamoeba histolytica, Cryptosporidiosis, caused by Cryptosporidium parvum, Chargas’ disease, caused by Trypanosoma cruzi, sleeping sickness, caused by Trypanosoma bruce rhodesiense or gambiense, the cutaneous and visceral as well as other forms of
Leishmaniosis. They are also suitable for the ireatment of animals infected by veterinary pathogenic protozoa, like Theileria parva, the pathogen causing bovine East coast fever,
Trypanosoma congolense congolense or Trypanosoma vivax vivax, Trypanosoma brucei brucei, pathogens causing Nagana cattle disease in Africa, Trypanosoma brucei evansi causing Surra, Babesia bigemina, the pathogen causing Texas fever in cattle and buffalo,
Babesia bovis, the pathogen causing European bovine Babesiosis as well as Babesiosis in dogs, cats and sheep, Sarcocysiis ovicanis and ovifelis pathogens causing Sarcocystiosis in sheep, cattle and pigs, Cryptosporidia, pathogens causing Cryptosporidioses in cattle and ’ birds, Eimeria and Isospora species, pathogens causing Coccidiosis in rabbits, cattle, sheep, goats, pigs and birds, especially in chickens and turkeys. The use of the compounds of the present invention is preferred in particular for the treatment of Coccidiosis or Malaria infections, or for the preparation of a drug or feed stuff for the treatment of these diseases.
This treatment can be prophylactic or curative. In the treatment of malaria, the compounds of the present invention may be combined with other anti-malaria agents. - 10 The compounds of the present invention can further be used for the prophylaxis and/or treatment of infectious diseases caused among others by bacteria and viruses, including opportunistic infections in a mammal, including a human. Said method comprises administering to the mammal an amount of at least one compound of the general formula (Ia), (Ib), (Ie), (AD), or (III) and/or pharmaceutically acceptable salts thereof, effective fo prevent and/or treat said infectious disease and/or opportunistic infection. :
The infectious disease can be selected from the group comprising AIDS, Alveolar Hydatid
Disease (AHD, Echinococcosis), Amebiasis (Entamoeba histolytica Infection), -
Angiostrongylus Infection, Anisakiasis, Anthrax, Babesiosis (Babesia Infection), Balantidium Infection (Balantidiasis), Baylisascaris Infection (Raccoon Roundworm),
Bilharzia (Schistosomiasis), Blastocystis hominisi Infection (Blastomycosis), Boreliosis,
Botulism, Brainerd Diarrhea, Brucellosis, BSE (Bovine Spongiform Encephalopathy),
Candidiasis, Capillariasis (Capillaria Infection), CFS (Chronic Fatigue Syndrome), Chagas
Disease (American Trypanosomiasis), Chickenpox (Varicella-Zoster virus), Chlamydia : pneumoniae Infection, Cholera, Chronic Fatigue Syndrome, CID (Creutzfeldt-Jakob
Disease), Clonorchiasis (Clonorchis Infection), CLM (Cutaneous Larva Migrans,
Hookworm Infection), Coccidioidomycosis, Conjunctivitis, Coxsackievirus Al6 (Hand,
Foot and Mouth Disease), Cryptococcosis, Cryptosporidium Infection (Cryptosporidiosis),
Culex mosquito (Vector of West Nile Virus), Cutaneous Larva Migrans (CLM), Cyclosporiasis (Cyclospora Infection), Cysticercosis (Neurocysticercosis),
Cytomegalovirus Infection (CMV), Dengue / Dengue Fever, Dipylidiom Infection (Dog and Cat Flea Tapeworm), Ebola Virus Hemorrhagic Fever, Echinococcosis (Alveolar
Hydatid Disease), Encephalitis, Entomoeba coli Infection, Entomoeba dispar Infection,
Entomoeba hartmanni Infection, Enfomoeba histolytica Infection (Amebiasis), Entomoeba polecki Infection, Enterobiasis (Pinworm Infection), Enterovirus Infection (Non-Polio),
Epstein-Barr Virus Infection, Escherichia coli Infection, Foodborne Infection, Foot and "mouth Disease, Fungal Dermatitis, Gastroenteritis, Group A. streptococcal Disease, Group
B streptococcal Disease, diseases caused by staphylococcal infections (Staphylococcus aureus and other staphylococcus species), diseases caused by infections with psendomonas aeruginosa and other pseudomonas species, Burkholderia cepacia infections, Hansen's "Disease (Leprosy), Hantavirus Pulmonary Syndrome, Head Lice Infestation (Pediculosis),
Helicobacter pylori Infection, Hematologic Disease, Hendra Virus Infection, Hepatitis,
Herpes Zoster (Shingles), HIV Infection, Human Ehrlichiosis, Human Parainfluenza Virus
Infection, Influenza, Isosporiasis (Isospora Infection), Lassa Fever, Leishmaniasis, Kala- azar (Kala-azar, Leishmania Infection), Leprosy, Lice (Body lice, Head lice, Pubic lice),
Lyme Disease, Marburg Hemorrhagic Fever, Measles, Meningitis, Mosquito-borne
Diseases, Mycobacterium avium Complex (MAC) Infection, Naegleria Infection,
Nosocomial Infections, Nonpathogenic Intestinal Amebae Infection, Onchocerciasis (River
Blindness), Opisthorciasis (Opisthorcis Infection), Parvovirus Infection, Plague, PCP (Pneumocystis carinii Pneumonia), Polio, Q Fever, Rabies, Respiratory Syncytial Virus (RSV) Infection, Rheumatic Fever, Rift Valley Fever, River Blindness (Onchocerciasis),
Rotavirus Infection, Roundworms Infection, Salmonellosis, Salmonella Enteritidis,
Scabies, Shigellosis, Shingles, Sleeping Sickness, Smallpox, Streptococcal Infection,
Tapeworm Infection (Taenia Infection), Tetanus, Toxic Shock Syndrome, Tuberculosis,
Ulcers (Peptic Ulcer Disease), Valley Fever, Vibrio parahaemolyticus Infection, Vibrio vulnificus Infection, Viral Hemorrhagic Fever, Warts, Waterborne infectious Diseases,
West Nile Virus Infection (West Nile Encephalitis), Whooping Cough, Yellow Fever.
The compounds of formula (Ia), (Ib), (Ie), (i), or (I) and their pharmacologically acceptable salts can be administered to aniinals, preferably to mammals, and in particular to humans, dogs and chickens as therapeutics per se, as mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which as active constituent contain an effective dose of at least one compound of the foromla (1a), (Ib), (ec), (I), or (I) or a salt thereof, in addition to customary pharmaceutically innocuous excipients and additives. The compounds of formula (Ia), (Ib), (Io), (I), or dm can also be administered in form of their salts, which are obtainable by reacting the respective compounds with physiologically acceptable acids and bases.
The production of medicaments containing the compounds of formula (1a), (Ib), (Ic), (ID), or (III) according to the invention and their application can be performed according to well-known pharmaceutical methods.
While the compounds of formula (Is), (Ib), (Ic), (AI), or (III) according to the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt in a pharmaceutical composition together with one or anus adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
Such salts of the compounds may be anhydrous or solvated.
In a preferred embodiment, the invention provides medicaments comprising compounds of formula (Ia), Ib), (Ic), (AD, or (II) according to the invention, or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs or a stercoisomer thereof, together with one or more pharmaceutically acceptable carriers thereof, and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful fo the recipient thereof.
A medicament of the invention may be those suitable for oral, rectal, bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.
The compounds according to the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of medicament and unit dosages thereof. Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liguids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such Medicament and unit dosage forms -~ thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
The compound useable according to the invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of formula (Ia), (Ib), (Je), (II), or (III) according to the invention or a pharmaceutically acceptable salt or stersosomer thereof,
For preparing a medicament from a compounds of formula (Ia), (Ib), (Ic), (II), or (IIT) pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material,
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, fragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended fo include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is swrounded by a carrier, which is thus in association with it.
Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured info convenient sized moulds, allowed to cool, and thereby to solidify. Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection
Yiquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
E The compounds of formula (1a), (Ib), (Ie), (ID), or (III) according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre- filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, ‘before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylceliulose, or other well known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
In one embodiment of the present invention, the medicament is applied topically or systemically or viaa combination of the two routes.
In an especially preferred embodiment of the present invention the medicament is applied topically. This reduces possible side effects and limits the necessary treatment to those areas affected.
Preferably the medicament is prepared in form of an ointment, a gel, a plaster, an emulsion, a lotion, a foam, a cream of a mixed phase or amphiphilic emulsion system (oil/water-water/oil mixed phase), a liposome, a transfersome, a paste or a powder.
Otntments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
Compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacantly pastilles - comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacie; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.
In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorvofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
The aerosol may conveniently also contain a surfactant such as lecithin, The dose of drug may be controlled by provision of a metered valve.
Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinyipyrrolidone (PVP).
Conveniently the powder carrier will form a gel in the nasal cavity The powder composition may be presented in unit dose form for example in capsules or cartridges of, £.2., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
When desired, compositions adapted to give sustained release of the active ingredient may be employed.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co. Easton, Pa.).
Pharmaceutical compositions can also contain two or more compounds of the formula (la), (Ib), (Jo), (ID, or (I) or their pharmacologically acceptable salts and also other therapeutically active substances,
Thus, the compounds of the present invention can be used in the form of one compound alone or in combination with other active compounds — for example with medicaments already known for the treatment of the aforementioned diseases, whereby in the latter case a favorable additive, amplifying effect is noticed. Suitable amounts to be administered to humans may range from 5 to 500 mg.
To prepare the pharmaceutical preparations, pharmaceutically inert inorganic or organic excipients can be used. To prepare pills, tablets, coated tablets and hard gelatin capsules, for example, lactose, corn starch or derivatives thereof, tale, stearic acid or its salts, etc. can be used. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable excipients for the production of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols etc. Suitable excipients for the production of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.
The dose can vary within wide limits and is to be suited to the individual conditions in each individual case. For the above uses the appropriate dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, however, satisfactory results are achieved at dosage rates of about 1 to 100 mg/kg animal body weight preferably 1 to 50 mg/kg. In general, suitable dosage rates for larger mammals, for example humans, may be of the order of from about 10 mg to 3 g/day, conveniently administered onoe, in divided doses 2 to 4 times a day, or in sustained release form.
In general, a daily dose of approximately 10 mg to 5000 mg, preferably 50 to 500 mg, per human individual is appropriate in the case of the oral administration. In the case of other : administration forms too, the daily dose is in similar ranges. For topical delivery, depending on the permeability of the skin, the type and the severity of the disease and dependent on the type of formulation and frequency of application, different concentrations of active compounds within the medicament can be sufficient to elicit a therapeutic effect by topical application. Preferably the concentration of an active compound or a pharmaceutically acceptable salt thereof or a physiologically functional derivative or a stereoisomer thereof within a medicament according to the invention is in the range of between 1 pmol/l and 100 mmol/l.
The following examples and figures are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skiil in the art that the techniques disclosed in. the examples that follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed without departing from the spirit and scope of the invention as set out in the appended claims. All references cited are incorporated herein by reference.
Examples
Abbreviations: min, minute(s); h, hour(s); r.t., room temperature; t-, tert-,
NMR. spectra: Bruker Avance 300 MHz. The spectra were recorded at 300 MHz (‘H-
NMR), respectively, using the residual solvent peak as an internal standard (DMSO-d; Ou = 2.49; CD;0D, 8 = 3.31; CDCl, 8x = 7.26; CD3CN, 8g = 1.93; (CD3):CO, 6x = 2.05).
Analytical LC/BSI-MS: 2 x Waters 600 Multisolvent Deiivery System. 50 tl sample loop.
Column, Chromolith Speed ROD RP18e (Merck, Darmstadt), 50 x 4.6 mm, with 2 pum prefilter (Merck). Eluent A, H,O + 0.1% HCO,H; eluent B, MeCN. Gradient, 5 % B to 100 % B within 5 min; flow, 3 ml/min. Waters LCZ single quadrupol mass spectrometer with electrospray source. MS method, MS8minPM-80-800-20V; positive/negative ion mode scanning, m/z 80 - 800 in 1 s; capillary, 3.5 kV; cone voltage, 20 V; multiplier voltage, 400
V; probe and desolvation gas temperature, 120° C and 350° C, respectively. Waters 2487
Dual Absorbance Detector, set to 254 nm.
Preparative HPLC-MS: Waters 600 Multisolvent Delivery System with peparative pump heads. 2000 ul or 5000 pl sample loop. Column, Waters X-Terra RP18, 7 um, 19 x 150 - mm with X-Terra RP18 guard cartridge 7 um, 19 x 10 mm; used at flow rate 20 ml/min or
YMC ODS-A, 120 A, 40 x 150 mm with X-Terra RP 18 guard cartridge 7 pm, 19 x 10 mm; used at flow rate 50 ml/min. Make-up solvent: MeCN — HO — HCO.H 80 : 26 : 0.05 (viviv). Eluent A, HoO + 0.1% HCOH; eluent B, MeCN. Different linear gradients from 5
— 100% eluent B, adapted to sample. Injection volume: 500 pl = 2000 ul depending on sarnple. Waters ZQ single quadrupol mass spectrometer with electrospray source. Positive or negative jon mode scanming m/z 80 - 800 in 1 s; capillary, 3.5 XV or 3.0 kV; cone voltage, 20 V; multiplier voltage, 400 V; probe and desolvation gas temperature, 120° C and 350° C, respectively. Waters Fraction Collector II with mass-iriggered fraction : collection. Waters 996 photo diode array detector. : Synthesis of 4-(Methoxy-methyl-carbamoyl-piperidine-1-carboxylic acid t-butyl ester
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethyl- hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0°C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at0°Cforlhandatrt for 18h
The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO; and filtered.
The solvent was removed and the residue was purified by distillation resulting in a yield of 80%.
Synthesis of 4-Formyl-piperidine-1-carboxylic acid t-butyl ester 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 16.4 mmel) was dissolved in 100 ml dry tefrahydrofurane under inert atmosphere. This solution was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 ml dry tetrahydrofurane at 50°C. During the adding of the mixture, the temperature was held at — 50°C and then allowed to warm to 0°C within 3 h.
The mixture was cooled to ~78 °C and quenched carefully with 100 ml 1 M citric acid. The mixture was warmed up to r.t. and diluted with 400 ml ethylacetate. The phases were separated and the aqueous phase was extracted 3 times with 70 ml ethylacetate, The combined organic layers were extracted 3 times with 100 ml 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml brine, dried over MgSOy4 and filirated. The solvent was removed and the residue was purified by distillation resulting in a yield of 85%
Synthesis of 4-(4-Ethoxycarbenyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylic acid t-butyl ester 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution L~cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap.
The solvent was removed and the residue was dissolved in 100 ml ethylacetate. The organic layer was extracted 3 times with 50 ml 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with 50 ml brine, dried over MgSO, and filtrated. The solvent was removed and the residue was purified by silica gel chromatography using a
PE/ EA 4:1 gradient. Yield: 75%
Synthesis of 4.(4-Ethoxycarbonyl-thinzol-2-yl)-piperidine-I-carboxylic acid t-butyl ester 4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 8.7 mmol) was solved in 160 ml toluene under inert conditions. To this solution
MnO; (15.0 eq, 130 mmol) was added. The reaction was heated to 70 °C under stirring for 5 h. The mixture was filtered over celite and the filtration agent was washed 3 times with 30 ml toluene and ethylacetate. The combined organic layers wers distilled in vacuo. The residue was purified by silica gel chromatography using a DCM/MeOH 95:5 gradient.
Yield: 30%
C-terminal functionalisation 4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 2.9 mmol) was dissolved under inert gas in 40 ml dioxane. Under stirring 1.5 ml aqueous 2 N © NaOH was added dropwise over a period of 10 min. Afterwards the mixture was stirred for 2hatrt
The reaction was neutralized with 2 N HCI and the solvent was evaporated in vacuo. The residue was dissolved in 50 ml ethylacetate. The organic layer was extracted 3 times with 10 ml of 1 M citric acid and water, dried over MgSOy and filtered. The solvent was removed and the residue was dried in vacuo. Yield 95% 4-(4-Carboxy-thiazol-2-yI)-piperidine-1-carboxylic acid tert-butyl ester (1 -eq) was " dissolved under inert conditions in dry dimethylacetamide (0,03 mmol/ml). To this solution aryl- or alkylamine (1 eq), diisopropylethylamine (2 eq) and O-benzotriazol-1-yl-
N,N, N',N'-tetramethyluronium hexafluorophosphate (2 eq) was added. The reaction mixture was stirred for 12 hat r.t.
The solvent was removed in vacuo and the residue was dissolved in sthylacetate. The organic layer was extracted 3 times with 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with brine, dried over MgSO4 and filtred. The solvent was removed and the residue was purified by silica gel chromatography using. a DCM/MeOH 95:5gradient. Yield: 40-80% : N-terminal functionalisation oo
The N-protected substrate was treated under inert condition with 4 M HCl/dioxane (conc. 0,03 mmol substrate in 1 mb HCl/dioxane) and was stirred for Z h at rt,
The solvent was removed in vacuo to yield the HCI salt of the free amine without further purification.
The free amino compound (1 eq) was dissolved under inert conditions in dry dimethylacetamide (0,03 mmol/ml). To this solution aryi- or alkylcarboxylic acid (1 eq), : diisopropylethylamine (2 eq) and O-benzotriazol-1-yI-N,N,N',N'-tetramethyluronium hexafluorophosphate (2 eq) was added in this sequence and the reaction mixture was stirred for 12 h atr.t.
The solvent was removed in vacuo and the residue was dissolved in ethylacetate. The organic layer was extracted 3 times with 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with brine, dried over MgSO and filtred. The solvent was removed and the residue was purified by silica gel chromatography using a DCM/MeOH 95:5 gradient. Yield: 40-80%
General synthesis for compounds of type (JII) and (II)
Procedure for the synthesis of compounds of type (Ila), (Hc), (Ila) and (116) 7,3%10™ mol of the benzoic acid derivative (VI) was dissolved in 5 ml DMF and 1 eq. of
Hiinig’s base was added, stirring the reaction mixture for a few minutes, followed by the addition of 1 eq. of HBTU and further stirring at r.t. for 2 min. Afterwards 1 eq. 2-Amino- thiazole-4-carboxylic acid ethyl ester was added, stirring the mixture overnight at the same temperature. Subsequently, the solvent was removed by filtration and the residue redissolved in 5 ml dioxane and treated with 0,5 mi of a IM NaOH solution. After the reaction was complete, the pH was decreased to 1-2 with a IM HCI solution and the precipitated product (VII) filtered and dried in vacuo. For the next step, intermediate (VII) was dissolved in 3 ml DMF and 1 eq. of Hilnig’s base was added, stirring the reaction mixture for a few minutes, followed by the addition of 1 eq. of HBTU and further stirring at r.t. for 2 min. Afterwards 1 eq. the amino component was added, stirring the mixture overnight at the same temperature. Subsequently, the solvent was removed by filtration and the crude product redissolved in 10 ml ethyl acetate, washed twice with 10 ml citric acid {1M solution), 10 ml sat. NaHCO; solution and 10 ml water. The organic phase was then evaporated and the residue dried over MgS8Q04 The solvent was removed and final purification was realised by preparative HPLC as described above.
As a second variante for the first step, the corresponding acid chloride derivative of (VI) could be reacted. with the 2-Amino-thiazole-4-carboxylic acid ethyl ester (1:1) using 1,1 eq. of Hiinig’s base.
Procedure for the synthesis of compounds of type (IIIb, d, e, J) and (IIc, d} 6,3%x10% mol of 2-Bromo-thiazole-4-carboxylic acid ethyl ester (X) was dissolved in 10 ml
THF together with 2,2 eq. of the respective piperazine (IX), allowing to reflux overnight.
Afterwards the solvent was removed in vacuo and the residue purified by pTLC (PE/EE 2/1).
The second and the third step of the reaction were accomplished as described above under the procedure for the synthesis of compounds of type (IIa) and (IIIc).
For as synthesis-protocol of type (Ib, 4, e, f and Ic, d) compounds with Z = CH, see WO 2004/058750. Examplary compounds of formula (Ta) of the present invention include, but are not limited to, the followings:
Mass | LC/(+)-ESI- | Biological nis: activity 1 piperazine-1-carbonyl]-thiazol-2-y1}- M-+HT piperidine-1-carboxylic acid (7-fluoro-2,3- dihydro-benzo[1,4]dioxin-5-yD-amide piperazine-1-~carbonyl]-thiazol-2-y1}- ME] - piperidine-1-carboxylic acid (2,3-dihydro- benzol1,4]dioxin-6-yi)-amide piperazine-1-carbonyl]-thiazol-2-y1}~ IME] piperidine-1-carboxylic acid (5-methyl-2-
TT |4-{4-[4-(3-Trifluoromethyl-phenyl)- 577 578 +H piperazine~1-carbonyl}-thiazol-2-y1}~ TMAH] piperidine-1-carboxylic acid (2-thiophen-2- yi-ethyl)-amide EE _
78 |4-{4-[4-(3-Trifluoromethyl-phenyl})- 509 [510 + piperazine-1-carbonyl]-thiazol-2-y1}- DMAHHTT piperidine-1-carboxylic acid isopropylamide
79 | 4-{4-[4-(3-Trifluoromethyi-phenyl)- 627 628 ++ piperazine-1-carbonyl]-thiazol-2-y1}- IM+HT" piperidine-1-carboxylic acid (2- trifluoromethoxy-phenyl)-amide
80 |4-{4-[4-(3-Trifluoromethyl-phenyl)- 573 |574 + piperazine-1-carbonyl]-thiazol-2-y1}- [MAH] piperidine-I-carboxylic acid (3-methoxy- pheny)-amide
81 |4-{4-[4-(3-Trifluoromethyl-phenyl)- 633 (634 At piperazine-1-carbonyl}-thiazol-2-y1}- [M+H]" piperidine-1-carboxytic acid (3,4,5- trimethoxy-phenyl)-amide
114 |4-(4-{4-[4-(3-Trifluoromethyl-phenyl}- 568 1569 + piperazine-1-carbonyl]-thiazol-2-y1}- MAH]
piperidine-1-carbonyl)-benzoniirile piperazine-1-carbonyl]-thiazol-2-y1}- MH] piperidine-1-carboxylic acid phenylamide
142 | 4-{4-[4-(3-Trifluoromethyl-phenyl)- 561 [562 fe piperazine-1-carbonyl]-thiazol-2-y1}- [M-+HT" piperidine~1-carboxylic acid (3-fluoro- : phenyl)-amide LL
143 | 4-{4-[4-(3-Trifluoromethyl-phenyl)- 561 [562 + piperazine-1-carbonyl]-thiazol-2-y1}- [MH] piperidine-1-carboxylic acid {(4-fluoro- phenyl)-amide
> The biological data refer to results obtained from the NF-xB inflammation assay. [#4 stands for 50-80% inhibition, “++” means 80-50% and “4+ stands for 90-100% ixthibition]
Examplary compounds of formula (Ib) of the present invention include, but are not limited to, the followings:
LL Ms: activity” 163 | 2-{5-Methyl-2-[1-(2-trifluoromethoxy- 640 | 641 Coit benzoyD-piperidin-4-y1j-thiazol-4-yi}-1-[4- MH] (3-trifluoromethyl-phenyl)-piperazin-1-y1]- : sthanone _ ne 128 | 1-[4-(3-Chloro-phenyl-piperazin-1-yi]-2- 606 |607 Se {5-methyl-2-[1-(2-trifluoromethoxy- TMAH] benzoyl)-piperidin-4-y1}-thiazol-4-yi}- ethanone bH The biological data refer to results obtained from the NF-xB inflammation assay. [+ stands for 50-80% inhibition, “++” means 80-90% and “+++” stands for 90-100% inhibition]
Examplary compounds of formula (Ic) of the present invention include, but are not limited to, the followings:
Name Mass | LC/(H-EST-
MS: activity? “1150 | [1-(5-Chloro-2-methylamino-phenyl)-3,4- 654 [655 ++ trifluoromethoxy-benzoy!)-piperidin-4-yl}- thiazol-4-yl}-methanone 160 |1-{4-[4-(6,7-Dihydroxy-3,4-dihydro-1H- {495 [496 + isoquinoline-2-carbonyl)-thiazol-2-y1]- [MH] : piperidin-1-y1}-2-(4-fluoro-phenyl)- : ethanone 161 | 1-{4-4-(6,7-Dimethoxy-3,4-dihydro-1H- |523 |524 +
EEE piperidin-1-y1}-2~(4-fluoro-phenyl)- ) ethanone 163 | 1-{4-[4-(3,4-Dihydro-1H-isoquinoline-2- | 463 |464 + 4-fluoro-phenyl)-ethanone dihydro-1H-isoquinoline-2-carbonyl)- IM-HET :
meee pheny))-ethanone _ ] a 233 | 1-{4-[4-(6,7-Dihydroxy-1-methyl-3,4~ 509 (510 + dihydro-1H-isoquinoline-2-carbonyl)- MH] thiazol-2-yl]-piperidin-1~y1}-2-(4-fluorc- phenyl)-ethanone 234 | 1-{4-[4-(6,7-Dimethoxy-1-methyl-3,4- 537 |538 + dihydro-1H-isoquinoline-2-carbonyl)- MH thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 235 | 1-(4-{4-[1-(5-Chloro-2-methylamino- 602 |603 + phenyl)-3,4-dihydro-1 H-isoquinoline-2- [MET carbonyl)-thiazol-2-y1}-piperidin-1-yl)-2- 4-fluoro-phenyl)-ethanone b The biological data refer to results obtained from the NF-kB inflammation assay. [#4 stands for 50-80% inhibition, “++” means 80-90% and “++” stands for 90-100% inhibition]
FExamplary compounds of formula (IT) of the present invention include, but are not limited to, the followings:
MS: activity” 3 N-{4-[4-(4-Fluoro-phenyl)-piperazine-1- 1494 1495 ++ carbonyl}-thiazol-2-y1}-2-trifluoromethoxy- [MAH] benzamide 5 N-[5-(4-Pyrimidin-2-yl-piperazine-1- 478 |47% +
Ei benzamide | 2-Methoxy-N-{4-[4-(3-trifluoromethyl- 490 [491 +H phenyl)-piperazine-1-carbonyl}-thiazol-2- [MHI y1}-benzamide 16 |3-Fluoro-4-trifluoromethyl-N-(1-{4-[4-(3- 1643 |644 ++ trifluoromethyl-phenyl)-piperazine-1- [M+HT carbonyl]-thiazol-2-y1}piperidin-4- - yImethyl)-benzamide 17 |3-Cyclopentyl-N-(1-{4~[4-(3- 577 |578 ++ trifluoromethyl-phenyl)-piperazine-1- | [MAH] carbonyl]-thiazel-2-y1} -piperidin-
18 | 2-Trifluoromethoxy-N-(1-{4-[4~(3- 641 (642 he trifluoromethyl-phenyl)-piperazine-1- [MVE carbonyl]-thiazol-2-v1}-piperidin- 4yImethyl)-benzamide .
1% |4-Cyano-N-(1-{4-[4-(3-trifluoromethyl- 582 | 583 At phenyl}-piperazine-1-carbonyl]-thiazol-2- IME] : vi}-piperidin-4-vimethyl)-benzamide ~~ | i
[4-(3-Trifluoromethyl-phenyl)-piperazin-1-
1 yl]-{2-[4-(4-triflucromethyl-phenyl)- MH] piperazin-1-yl}-thiazol-4-y1}-methanone
21 | {2-[4-(4-Trifluoromethoxy-phenyl)- 585 [586 + piperazin-1-y1]-thiazol-4-y1}-[4-(3- [MET trifluoromethyl-phenyl)-piperazin-1-y1]- methanone
122 | {2-[4-(2-Trifluoromethoxy-benzyl)- 599 | 600 ++ piperazin-1-yI}-thiazol-4-y1}-[4-(3- IM-HHT triffnoromethyl-phenyl)-piperazin-1-y1]- : methanone
23 | {2-[4-(4-Bromo-benzyl)-piperazin-1-y1]- |593 {594 A thiazol-4~y1}-[4-(3-triffuoromethyl-phenyl)- IM-FHTY piperazin-1-yl}-methanone
24 | {2-[4-(3-Trifluoromethoxy-benzyl)- 58% 1600 ++ piperazin-1-yl]-thiazol-4-yl}-[4-(3- [M+H] ) trifiuoromethyl-phenyl)-piperazin-1-yi]- methanone 32 | 2-Trifluoromethoxy-N-{4-[4-(3- 544 1545 eff ® trifluoromethyl-phenyl)-piperazine-1- carbonyl]-thiazol-2-y1}-benzamide 33 |3-Cyclopentyl-N-{4-[4-(3-trifluoromethyl- [480 [481 bt phenyl)-piperazine-1-carbonyl]-thiazol-2- [MH] y1}-propionamide 134 | 3-Fluoro-4-trifluoromethyl-N-{4-[4-(3~ 546 [547 opt trifluoromethyl-phenyl)-piperazine-1- [MFHT carbonyl]-thiazol-2-y1}-benzamide
37 | 3-Cyclopentyi-1-(4-{4-[4-(3- triffuoromethyl-pheny!)-piperazine-1- | pag
BN carbonyl ]-thiazol-2-y1}-piperazin-1-y1)- propancl-one EE 38 | {2-[4-(2-Methoxy-benzoyl)-piperazin-1- 559 | 560 + yl]-thiazol-4-y1}-[4-(3-triflucromethyl- VE phenyl)-piperazin-1-vi}-methanone 38 | {2-[4-(2-Trifluoromethoxy-benzoyi)- 613 1614 +++ piperazin-1-yl]-thiazol-4-y1}[4-(3- [MH] triflnoromethyl-pheny!)-piperazin-1-yi}- 41 | N-{4-[4-(3,4-Dichloro-phenyl)-piperazine- |544 |545 bE 1-carbonyl]-thiazol-2-yl}-2- IM+HT trifluoromethoxy-benzamide 44 IN-{4-[4-(2-Methoxy-phenyl)-piperazine-1- |506 |507 + carbonyl]-thiazol-2-y1}-2-trifluoromethoxy- IM-+HHT' benzamide 155 1-(2-Trifluoromethoxy-phenyl)-3-{4-[4-(3- |559 |560 ++ trifluoromethyl-phenyl)-piperazine-1- M+] carbonyl]-thiazol-2-y1}-urea _
N-[4-(4-Benzhydryl-piperazine-1- 566 |3567 + carbonyl)-thiazol-2-y1]-2-frifluoromethoxy- IM+HT benzamide 59 | {2-[4-(3,5-Bis-trifluoromethyl-benzoyi)- 665 666 + piperazin-1-yl]-thiazol-4-y1}-[4-(3- MH] trifluoromethyl-phenyl)-piperazin-1-yi]- methanone 60 | {2-[4-(3-Fluoro-4-trifluoromethyi- 615 |616 ++ benzoyl)-piperazin-1-yl]-thiazol-4-y1}-[4- M+] (3-frifluoromethyl-phenyl)-piperazin-1-yi]- methanone 61 |4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 554 |555 +++ piperazine-1-carbonyl]-thiazol-2-y1}- [MAH] piperazine-1-carbonyl)-benzonitrile LL 62 | 4-(4-{4-[4~(3-Trifluoromethyl-phenyl)- 540 (541 pete piperazine-1-carbonyl}-thiazol-2-yl}- [MFI] piperazine-1-ylmethyD)-benzonitrile piperazine-1-carbonyl}-thiazol-2-yi}- +H]
triftucromethyl-phenyl)-piperazin-1-yij- IM+HT __| mothanone Lo 65 | {2-[4-(2-Methoxy-phenyl)-piperazin-1-v1]- |531 |532 A+ __|piperazin-1-ylj-methanone | _ 66 | 1-[4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- {543 |544 ef
EE FE piperazin-1-yl)-phenyl]-cthanone 67 | [4-(3-Triffuoromethyl-phenyD-piperazin-i- 570 + yi]-{2-[4-(3-trifluoromethyl-phenyl)- MH] piperazin-1-yl]-thiazol-4-y1}-methanone [4-(3-trifluoromethyl-phenyl)-piperazin-1- IM+H]" vil-methanone 69 | {2-[4-(4-Fluoro-phenyl)-piperazin-1-y1}- 519 520 ++ :
Emre piperazin-1-yl]-methanone i benzyl-piperazin-1-yl)-thiazol-4-yl]- [MET methanons 72 | [2-(4-Benzyl-piperazin-i-y)-thiazol-4-y1]- [515 [516 ++ [4-(3-trifluoromethyl-phenyl)-piperazin-1- TMAH] yil-methanone : 99 | 3-Fluoro-4-trifluoromethyl-N-(1-{4-[4-(3- |642 [643 + triflucromethyl-phenyl)-piperazine-1- IM+HHT carbonyl]-thiazo!-2-y1}-piperidin-4- yimethyD-benzamide ] 160 | 3-Cyclopentyl-N-{1-{4-[4-(3- 576 |577 + trifluoromethyl-phenyl)-piperazine-1- MEH] carbonyl}-thiazol-2-y1}-piperidin-4- vimethy!)-propionamide _ - 101 | Z2-Trifluoromethoxy-N-(1-{4-[4-(3- 640 [641 + trifluoromethyl-phenyl)-piperazine-1- MH] carbonyl]-thiazol-2-y1}-piperidin-4- vlmethyl)-benzamide LL —
102 | 4-Cyano-N-(1-{4-[4-(3-trifluoromethyl- 581 [582 + phenyl)-piperazine-1-carbonyl]-thiazo}-2- MET y1}-piperidin-4-ylmethyl -benzamide : 241 | {2-[1-(2,6-Dimethoxy-pyrimidin-4-yI)- 576 |577 [M+H'] {++ piperidin-4-yi}-5-methoxy-oxazol-4-y1}-[4- (3-trifiuoromethyl-phenyl)-piperazin-1-y1]- 242 | {2-[1-(4,6-Dimethoxy-[1,3,5jtriazin-2-y1)- |577 578 [M+H'] |++ piperidin-4-yl]-5-methoxy-oxazol-4-y1}-[4- (3-trifluoromethyl-phenyl)-piperazin-1-y13- methanone : piperidin-4-yl]-5-methoxy-oxazol-4-yl}-[4- (5-trifluoromethyl-benzotriazol-1-y1)- piperidin-1-yl]-methanone 244 | {2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yI)}- |617 [618 [M+H'] {++ piperidin-4-yl]-5-methoxy-oxazol-4-yl}-[4- (5-trifluoromethyl-benzotriazol-1-y1)- viperidin-1-yi]-methanone 245 | 4-(4-{4-[4-(5-Trifluoromethyl-benzotriazol- | 580 | 581 ++
I-yl)-piperidine-1-carbonyl}-thiazol-2-y1}- IMA+H]+ piperazin-1-yl-methyl)-benzonitrile triftucromethyl-phenyl)-piperazin-1-yij- [M+H]+ methanone : 2 The biological data refer to results obtained from the NF-xB inflammation assay. [“+" stands for 50-80% inhibition, “++” means 80-30% and “++ stands for 90-100% inhibition]
Examplary compounds of formula (ITT) of the present invention include, but are not Hrnited to, the followings:
MS: activity 0 2-Morpholin-4-yl-thiazole-d-carboxylic ~~ |357 1358 ; acid (5,6-dimethyl-1H-benzoimidazol-2- [M+H] yl)-amide thiazole-4-carboxylic acid (IH-1 |p 3
4 |2-(2-Fluoro-benzoylamino)-thiazole-4- 409 [410 + carboxylic acid (5,6-dimethyl-1H- MET benzoimidazol-2-yl)-amide _ 6 N-{4-[N'-(1 H-Benzoimidazol-2-y1)- 441 1442 ++ difluoro-benzamide | _ : 7 | N-{4.N-(1H-Benzoimidazol-2-y1)- 423 424 + i goanidinocarbonyl]-thiazol-2-yl }-4-flucro- [M+HT benzamide guanidinocarbonyl]-oxazol-2-y1}-2~ MAHT trifluoromethoxy-benzamide thiazole-4-carboxylic acid (4- [M+H] dimethylamino-[1,3,5 triazin-2-yl)-amide 16 | N-{4-[N'-(1H-Benzoimidazol-2-yl}- 483 1484 ++ .
EEE TE benzamide 11 | N-{4-[N-(1H-Benzoimidazol-2-yl)- 435 1436 ++ guanidinocarbonyl]-thiazol-2-y1}-2- [M+HT methoxy-benzamide 12 | N-{4-[N'-(1H-Benzoimidazol-2-yl)- 489 1490 H+ guanidinocarbonyl]-thiazol-2-y1}-2~ [MH] trifluoromethoxy-benzamide 13 |N-(1H-Benzoimidazol-2-yl)-N'-{2-[4-(2- |558 |559 +
EE thiazole-4-carbonyl}-guanidine 14 | N-(1H-Benzoimidazol-2-y])-N'-[2(2,3- dihydro-benzo[1,4]dioxin-2-yl)-thiazole-4- [MET carbonyl]-guanidine : | 2-(2-Trifluoromethoxy-benzoylamino)- 475 |476 Hr. - thiazole-4-carboxylic acid (5,6-dimethyl- IME 1H-benzoimidazol-2-y])-amide LL benzoylamino)-oxazole-4-carboxylic acid IME] ethyl ester
27 IN-{4-[N'-(1H-Benzoimidazol-2-yl)- 475 (476 +t :
guanidinocarbonyl]-oxazol-2-y1}-3-fluoro- IMHH]T 4-trifluoromethyl-benzamide LL ] 3
|N-(1H-Benzoimidazol-2-y1)-N'-[2-(4- 1460 1461 + benzyl-piperazin-1-yI)-thiazole-4- MH] carbonyl]-guanidine
31 | 2-(2-Trifluoromethoxy-benzoylamino)- 447 1448 +
" thiazole-d-carboxylic acid (1H-~ Ce 7 benzoimidazol-2-yl)-amide _
36 | N-(1H-Benzoimidazol-2-y1)-N'-{2-[1-(2- trifluoromethoxy-benzoyl)-piperidin-4-y1}- MH] thiazole-4-carbonyi}-guanidine oxazole-4-carboxylic acid (5,6-dimethyl- IM-+HT 1H-benzoimidazol-2-y1)-amide
42 |2-(2-Triftuoromethoxy-benzoylamino)- thiazole-4-carboxylic acid [6-(4-methyl- TMH] piperazin-1-y)-benzothiazol-2-yi]-amide
43 2-(2-Trifluoromethoxy-benzoylamino)- 492 1493 H+ thiazole-4-carboxylic acid (5-nitro-1H- fr 7 benzoimidazol-2-yl}-amide
45 |N-{4-[N'-(1H-Benzoimidazol-2-yl)~ 487 488 ++ guanidinocarbonyl]-thiazol-2-yl1}-2- M+HT cyclohexyl-benzamide
46 2-(2-Trifluoromethoxy-benzoylamino)- 461 (462 Lr thiazole-4-carboxylic acid (1-methyl-1H- MET benzoimidazol-2-yl}-arnide
47 | 2-(2-Trifluoromethoxy-benzoylamino)- 553 554 Naas thiazole-4-catboxylic acid [3-(propane-1- MAH] sulfonyl)-1H-benzoimidazol-2-y1l-amide
4% | N-(1H-Benzoimidazol-2-y1}-N'-(2- 371 (372 Ff
- | goanidine
51 |N-{4-[N'-(1H-Benzoimidazol-2-y1)- 473 1474 Fort guanidinocarbonyl]-thiazol-2-y1}-4- [M+HT triffuoromethyl-benzamide . ]
piperidin-4-yl]-thiazole-4-carboxylic acid VHT [5-(propane-1-sulfonyl)-1H-benzoimidazol- 2-yi]-amide _ LL
N-{4-[N'(1H-Benzoimidazol-2-yI)- guanidinocarbonyl]-thiazol-2-y1}-2-fluoro- MET 4-trifluoromethyl-benzamide guanidinocarbonyl]-thiazol-2-y1}-3-(2- | pET trifluoromethoxy-phenyl)-urea _ guanidinocarbonyl]-thiazol-2-yl1}-3-fluoro- M-+HHT
A-rifluoromethyl-benzamide guanidinocarbonyl]-thiazol-2-y1}-2,6- M+] difluoro-benzamide 91 | N-(IH-Benzoimidazol-2-yi)-N'-(2- 371 [372 + morpholin-4-yl-thiazole-4-carbonyl)- [M-+H]
EE rr re - 250 | N-(1H-Benzoimidazol-2-y1)-N'-{2-[1-(4- 484 [485 ++ cyano-benzyl)-piperidin-4-y1}-thiazole-4- [MFI] carbonyl }-guanidine 251 | N-Benzothiazol-2-yl-N'-{2-[1-(4-cyano- 501 1502 ++ benzyl)-piperidin-4-yi]-thiazole-4- [M+H]+ carbonyl }-guanidine ¢yano-benzyl)-piperazin-1-yi]-thiazole-4- [MH carbonyl }-guanidine 2583 | N-{2-[4-(4-Cyano-benzyl)-piperazin-1-yi}- 1466 467 +b
PE
2-yD-guanidine 4-yl-thiazole-4-carbonyl)-guanidine IMAHHT+ 255 i N-(1H-Benzoimidazol-2-y1}-N'-(2- 371 1372 dt morpholin-4-yl-thiazole-4-carbonyl)- [MAH guanidine thiazole-4-carbonyl)~guanidine [MAH]
morpholin-4-yl-oxazole-4-carbonyl)- M--HE+ guanidine Lo SR ; thiazole-4-carbonyl)-guanidine [MAH]+
N'-(5-nitro-benzooxazol-2-yD-guanidine | |[M+H}+ LL morpholin-4-yl-thiazole-4-carbonyl)- [M-H]+ guanidine morpholin-4-yl-thiazole-4-carbonyl)- TMH : guanidine BN 262 |N-{2-[1-(4-Cyano-benzyl)-piperidin-4-vi]- |465 1466 +
Em 2-yI)-guanidine 263 |N-(6-Chloro-1H-benzoimidazol-2-yl)-N'- {391 i592 hep
IE piperidin-4-ylj-thiazole-4-carbonyl}- guanidine 264 | N-(5,6-Dichloro-1H-benzoimidazel-2-yI)- |625 [626 ++
Cm Te piperidin-4-yl]-thiazole-4~carbomnyl}- guanidine acid [4-(5-trifluoromethyl-benzothiazol-2- IM-+H]+ yl}-phenyl]-amide acid (5-benzothiazol-2-yl-pyridin-2-y1)- [M+H]+ amide 267 | 2-Morpholin-4-yl-thiazole-4-carboxylic 440 1441 acid (4-benzothiazol-2-y1-2-fluoro-phenyt)- [M+H]+ 268 | 2-Morpholin-4-yl-thiazole-4-carboxylic ~~ {506 |507 acid (4-benzothiazol-2-yl-2-trifluorometh- [M+H]+ oxy-phenyl}-amide 269 [2-01-Fwol23-clpyridin4-yl.piperidin-4- [548 |s49
Em ee] ee 1H-benzoimidazol-2-y1)-amide 276 | 2-[1-(4,6-Dimethoxy-[1,3,5 trlazin-2-y1)- {570 1571 "pen In fe (5-benzoyl-1H-benzoimidazol-2-y1}-amide 271 | 2-[1-(4,6-Dimethoxy-[1,3,5triazin-2-yI}» |501 (502 piperidin-4-yi]-thiazole-4-carboxylic acid MHH]+
B-fluoro-benzothiazol-2-yl)-amide 2-11 (4-Cyano-benzyl)-piperidin-4-yij- thiazole-4-carboxylic acid (5-benzoyl-1H- benzoimidazol-2-yl) -amide 273 |2~(1-Thieno[3,2-dIpyrimidin-4-yl- 565 |566 [M+H] |++ piperidin-4~yl)-thiazole-4-carboxylic acid (5-benzoyl-1H-benzoimidazol-2-yl)-amide piperidin-4-yl}-thiazole-4-carboxylic acid
S-benzoyl-1H-benzoimidazol-2-y1)-amide 275 | 2.[1-(6-Trifluoromethyl-pyrimidin-4-yD- {577 578 [M+H']
FE
5-benzoyl-1H-benzoimidazol-2-yl)-amide "ESE. thiazole-4-carboxyiic acid (5-ethoxy-1H- benzoimidazol-2-yl)}-amide : 277 |2-[1-(4-Cyano-benzyl)-piperidin-4-y1}- 476 1477 [MAH] A
FE re benzoimidazol-2-yl)-amide thiazole-4-catboxylic acid (5.6-dichloro- 1H-benzoimidazol-2-yl)-amide
D The biological data refer to results obtained from the NF-«B inflammation assay. [4 stands for 50-80% inhibition, “++ means 80-90% and “+++ stands for 90-100% inhibition]
Proteasome assay:
The chymofryptic activity of the 208 proteasome (Immatics, Tilbingen) was determined using a Tecan Ultra plate reader and Suc-LLVT-AMC as substrate (Bachem). In the wells of a black 96 well polypropylene plate, 2 ul of the respective inhibitor dissolved in DMSO were mixed with 50 pl substrate solution (25 mM HEPES pH 7.5 at 20°C, 0.5 mM EDTA and Suc-LLVI-AMC (in the appropriate concentration) and the reaction was initiated by adding 150 pl proteasome solution (1.3 pg/ml 208 proteasome in 25 mM HEPES pH 7.5 at 20°C, 0.5 mM EDTA, 0.033% (w/v) SDS). Substrate hydrolysis was followed by fluorescence spectroscopy {excitation wavelength: 360 nm; emission wavelength: 465 nm) for 20 min at 30°C and initial velocities were calculated and expressed as change in relative fluorescence units (RFU) per second.
For the determination of the ICs values {concentration of inhibitor required for 50% inhibition) at least four different inhibitor concentrations were applied. Each data point was recorded in triplicates. Curves were fitted with the a suitable program.
The Compounds have average activities between 1 and 30 pM : T-Lymphocyte Proliferation Assay:
Inhibition of stimulated peripheral blood monocytes (PBMC).
PBMCs were isolated from the blood of healthy volunteers with the help of ACCUSPIN™
System Histopaque®-1077 tubes, washed and resuspended with 10° cells/ml in Dulbecco's modified eagles medium, containing 10 % fetal calf serum and 2 mM Glutamine.
The cells were stimulated with 2 pg/ml phytohemoagglutinin in the presence of test compound or blank vehicle for 72 h. 4 h prior to the end of the incubation period, 5-bromo- 2’-desoxyuridine (BrdU) was added to label the proliferating cells. After the incubation, the cells were separated by centrifugation and the culture supernatant removed.
Incorporated BrdU was quantified with the help of an enzyme-linked immunosorbent assay.
For the determination of the ICsp values {concentration of inhibitor required for 50% inhibition) at least four different inhibitor concentrations were applied. Each data point was recorded in triplicates. Curves were fiited with the a suitable program.
Influence of compounds according to the invention on proliferation of T-cells
Compounds according to Examples 1-24 resulted in an inhibition of more than 50% compared to control experiments,
The average ECsq of the compounds were between 3 and 40 uM.
Thus, the compounds of formula T are suitable for treating inflammatory diseases or diseases associated with Teells.
Inhibition of NF-«B-induced inflammation:
For the determination of anti-inflammatory activity of the compounds the PRINCESS®
NINA. Instant Assay from Cell Culture Service GmBH was used. This assay is based on recombinant A549-NF-«B-SEAP reporter cells preseeded in 96-well flat bottom plates. As the transfected reportergen for SEAP (secreted embryonic alkaline phosphatase) is under transcriptional comtrol of a NF-«xB-responsive element, the expression of this reporter is activated upon stimulation with TNF-a. SEAP secretion into the culture supernatant can be detected by the chemiluminescent substrate CSPD®. Test compounds that inhibit the NF- «B activation show reduced SEAP activity and reduced luminescent readout.
Following 18 h of reactivation at 37 °C, 5 % CO. and $0 % relative humidity, the cells were incubated with 0.01 up to 100 uM of test compound for 4.5 h before stimulation with ng/ml TNF-o.. After stimulation with TNF-a for 22 h endogenous phosphatases were inactivated and CSPD® substrate was supplied for 40 min. SEAP activity then was quantified by measuring luminescence as relative light units (RLU) using a Tecan Ultra reader. Each data point was. recorded in quadruplicates and EC50 values were calculated via fitting function and the Microsoft Excel Solver. :

Claims (1)

  1. CLAIMS i. A compound of the general formula (II) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereocisomer thereof, RA Ne N N\ No R! PY Re ~ z X re iy wherein R'is -C(O)R™, -C(O)CHR'R®, -C(ONR'R®, -C{O)OR!, R'C(O)R®, or CHR, R* is 1, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or R' and R? together with the N-atom or the C-atom to which they are attached form a 3 to 8 membered saturated or at least partially unsaturated monocycloc or polycyclic ring system, wherein at least one or more of the carbon atoms in the ring is a heteroatom selected from O, N, and S and the ring can be substituted by one or more R’; R® is H, -C(O)NR'R®, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SEH NR*OR”, NH,, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, hetero- cycloalkyl, hydroxyalkyl, or haloalkyloxy; R'is H, OH, SH, NH,, alkoxy, haloalkoxy, halogen, alkyl, -CONR/)NR'R?, - (CHoparyl, -(CHppNR'R®, -C(ONR'R!, -N=CR'R®, -NR'C(O)RS, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; } SE R® ishalogen, alkyl, -CONRNR'R®, -(CHy)paryl, (CH), NR'RS, -C(ONR'R®, N=CR'R®, NR'C(O)R®, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxy- alkyl, hydroxyalkylamino, atkylamino, heteroaryl, or aryl;
    oo R® is H, halogen, alkyl, -CONR')NR'R®, «(CHy)aryl, -(CH2),NR'R®, aryl, -CONR'RE, -N=CR'R®, -NR'C(O)R®, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, or heteroaryl;
    R® independently represents H, -CN, -OH, -SH, -CO,R¥, -C(O)R?, -80,NR?,
    NR¥RY, -C(ONR'R®, -SO,-alkyl, -80,RY, SOsRY, -N=CRYRY, - NRYC(O)RY”, -NR¥-CO-haloalkyl, -NO,, -NR*-§0,-haloalkyl, -NR*-80,- alkyl, NR*-CO-alkyl, -NRY(CHy)beteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O(CHy),[O(CH2)p]qOCHs, -CINR* INR benzimidazolyl, -CNR*INR*-
    benzthiazolyl, -C(NR* INR¥benzoxazolyl, hydroxyalkyl, hydroxy- cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;
    R*, RY, R” independently are H, halogen, alkyl, -CONR")NR'R®, -(CHy)parvl, haloalkyl, -CH2),NR'RE, -C(C)NR'R®, -N=CRR?, -NR'C(O)R?, cycloalkyl, heterocycloallkyl, hydroxyalleyl, hydroxyalkylamino, alkylamino, heteroaryl,
    oraryl;
    RR”, R® independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamine, alkylamino, arylamino heteroaryl, or aryl;
    R™ iscycloalkyl, haloalkyl, hydroxyaliyl, hydroxyalkylamino, heteroaryl, or aryl;
    R™® isH, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl;
    A is CO or SO»,
    X isNR*, 0,01 S; Z isNorCR%; RY is H, alkyl, ~C(O)NR, -C(O)R®, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; p is 1 to 6; q is 1 to 6; ’ } R? independently represents’ H, -CN, -OH, -SH, alkoxy, alkylthio, -CO.R*, -C(OR™, -C(O)NR'R, -SONRY, -NR*R¥, -S0,-alkyl, -SO,RY, SOR?
    N=CR*R*, NRYC(OR?, -NR¥-CO-haloalkyl, -NO, -NR*-SO,- haloalkyl, -NR¥-SOz-alkyl, -NR"-CO-alkyl, -NR* (CH) heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, ~O(CHp),[O(CH,),J,0CH;, ~CNR* INR benzimidazolyl, -CNR*INR*- benzthiazolyl, -C(NR* INR benzoxazolyl, hydroxycycloalkyl, hydroxy- alkylamino, haloalkyloxy, heterocycloalkyl, ~(CHy),NR'COR®, aryl, or heteroaryl; : R®™ is H, C;-Cealkyl, Co-Cealkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -COMNR)NR'R?, ~(CHp)aryl, - C10 (CH),NR'RS, -C(O)NR'R®, -N=CR'R®, -NR'C(O)R®, halogen, heteroaryl, or aryl; wherein an Cy-Cg-alkyl group, if not stated otherwise, denotes a linear or branched C-Cg- allyl, which can optionally be substituted by one or more substituents R’; R' is independently H, -COR™, -CONHR', CRO, -SONR™, -NR“-CO- haloalkyl, -NO,, -NR-S0,-haloalkyl, -NR -S0z-alkyl, -SO-alkyl, -NR"-CO- ; alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, arvl, or heteroaryl; R'is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl;
    an Cp—Cealkenyl group, if not stated otherwise, denotes a linear or branched Co— Ce—alkenyl, which can optionally be substituted by one or more substituents R"; an alkyl group, if not stated otherwise, denotes a linear or branched Cy-Ce-alkyl, a linear or branched Cy-Ce-alkenyl or a linear or branched Cp-Cy-alkynyl group, which "can be substituted by one or more substituents R:R being defined as above.
    a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by one or more substituents R; R being defined as above;
    a heterocycloalkyl group denotes a non-aromatic ring system containing two fo ten carbon atoms and at least one heteroatom selected from OQ, N, and S, wherein one or more of the carbon atoms in the ring can be substituted by R being as defined above;
    an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; an alkylthio group denotes an S-alky!l group, the alkyl group being as defined above;
    an haloalkyl group denotes an alkyl group which is substituted by one to five halogen ators, the alkyl group being as defined above;
    a hydroxyalkyl group denotes an HO-atkyl group, the alkyl group being as defined above;
    an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above;
    a hydroxyalkylamino group denotes an (HO-alkyl)>-N- group or HO-alkyl-NH-
    group, the alkyl group being as defined above;
    an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above;
    a halogen group is fluorine, chlorine, bromine, or iodine; )
    an aryl group denotes an aromatic group having five to fifieen carbon atoms, which can be substituted by one or more substituents R, where R is as defined above;
    an arylamino group denotes an HN-aryl or N-diaryl group, the aryl group being as defined above; a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic group which contains at least one heteroatom selected from O, N, and 8, wherein the heterocyclic group may be fused to another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R , wlan R is as defined above;
    with the proviso that the following compounds are excluded O N R2 5 @ wherein Rr! independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloatkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl; R* independently represents -NR’R?, $y $n N—R® , Or _/ : rR? independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl, R* independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkylexy, aryl or heteroaryl; . R’ independently represents H, CORS, CO.R®, SORS, SO.R®, SOsRS, alkyl, cycloalkyl, alkoxy, -NHp, alkylamine, -NR’CORS, halogen, -OH, -SH, alkylthio, hydroxyalleyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
    RS independently represents H, alkyl, cycloalkyl, -NH,, alkylamine, aryl or Fy : heteroaryl; rR’ independently represents H, alkyl, cycloalkyl, alkoxy, ~-OH, -8H, alkylthio, hydroxyalkyl, aryl, or heteroaryl; p is, or I; q isf, ori; x is CO or SO,
    2. A compound of the general formula (Ih) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, i A SS IR I, RI N NR32 4 | R2a \ N / SAR R? X R3 © Yooh wherein A isNR?,Sor0; : t 180 to 4; : r is 0, orl; R* is independently H, OH, SH, NH, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyallylamino, halogen, aryl, or heteroaryl; : R* is independently H, OH, SH, NH, -COMRHNR'RE, -(CHy)aryl, - (CH), NRTR®, -C(ONR'R®, -N=CR'R®, -NR'C(O)R}, alkyl, cycloalkyl, . hydroxyalkyl, haloalkyl, haloatkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; RY is H, halogen, alkyl, -CONR)NR'R®, ~(CHa)paryl, -(CHa),NR'R?, - C(ONR'R?, N=CR'R?, -NR'C(O)R®, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl.
    R'is -C(OR™, -COCHRR®, -CONR'R®, -C(O)OR’, -R'C(OR®, or ) CER, R? is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamine, alkylamino, heteroaryl,
    or R* and R? together with the N-atom or the C-afom to which they are attached form a 3 to 8 membered saturated or at least partially unsaturated monocycloc or polycyclic ring system, wherein at least one or more of the carbon atoms in the ring is a heteroatom selected from O, N, and S and the ring can be substituted by one or more R”;
    R® is H, -C(O)NR®R®, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NRYOR®, NH,, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, hetero- cycloalkyl, hydroxyalkyl, or haloalkyloxy;
    R* is H, halogen, alkyl, -CORNR'R®, ~(CHp)paryl, ~(CHo),NR'R?, aryl, ~ -C(O)NRR®, -N=CR'R®, -NR'C(O)R®, cycloalkyl, heterocyclioalkyl,
    haloatkyl, hydroxyalkyl, hydroxyalkylamino, atkylamino, or heteroaryl;
    R® independently represents H, -CN, -OH, -SH, -CO.R*, -C(O)R¥, -SO,NR¥, NRYRY, -C(ONR'R®, -8C,-alkyl, -SOR¥, SCRY, -N=CR'R’, -
    - NRYC(ORY, -NR¥-CO-haloalkyl, -NO,, -NR*-S0,-haloalkyl, -NR¥-SO,- alkyl, -NR*-CO-alkyl, -NR*(CHp)heteroaryl, alkyl, cycloalkyl,
    alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O(CHy),[O(CH,),],OCH;s, -CNR* NR? benzimidazolyl, -CONR* INR- benzthiazolyl, -CONRYINR*benzoxazolyl, hydroxyalkyl, hydroxy- cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;
    R¥, R*, R* independently are H, halogen, alkyl, -CONR)NR"R®, -(CHy)yaryl, haloalkyl, -CH),NR'R®, -C(ONR'R®, -N=CR'R®, NR'C(O)R?, cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; rR’, R”, R® independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyallyl, hydroxyalkylamino, alkylamino, arylamino heteroaryl, or aryl; ) R™ is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl;
    R™ is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; X isNRY, 0,018; Z is N or CR? RY is H, alkyl, -C(O)NR, -C(O)R®, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; p islto6; : q islto6;
    rR’ independently represents H, -CN, -OH, -SH, alkoxy, alkylthio, -CO,R¥, -C(O)R™, -C(ONR'RS, -SO,NRY, NBR, -50z-alkyl, -SORY, SO4RY, N=CR*R%, NR¥C(O)R*", -NR¥-CO-haloalkyl, -NO,, -NR*-80,- haloalkyl, -NR*-SO,-alkyl, -NR¥-CO-alkyl, -NR*(CHp),heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, “O(CH)p O(CHy),];OCH;, -C(NR* NR" benzimidazolyl, -CNR*)NR*- benzthiazolyl, CNR INR benzoxazolyl, hydroxyeycloalkyl, hydroxy- alkylamino, haloatkyloxy, heterocycloalkyl, -(CHp),NR’COR®, aryl, or heteroaryl; R® is H, C;-Cealkyl, Co—Cgalkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyallylamino, ~ alkylamino, -CONRHNR'R!, -(CHp)aryl, - (CH),NR'R®, -C(OINR'R?, -N=CR'R?, NR'C(O)R®, halogen, heteroaryl, or aryl; wherein an Ci-Ce-alkyl group, if not stated otherwise, denotes a linear or branched Cy-Cy- alkyl, which can optionally be substituted by one or more substituents R'; R'is independenily H, -CO;R, -CONHR™, -CR“0, -SO.NR™, -NR-CO- haloalkyl, -NO;, -NR-8Oj-haloalkyl, -NR™-80s-alkyl, -SOy-alkyl, -NR**-CO- alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalicylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
    R™ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; an Cp,—Ce—alkenyl group, if not stated otherwise, denotes a linear or branched Co~ C—alleenyl, which can optionally be substituted by one or more substituents R; an alkyl group, if not stated otherwise, denotes a linear or branched C;-Ce-alkyl, a linear or branched Cyp-Ce-alkenyl or a linear or branched Cp-Cg-alkynyl group, which can be substituted by one or more substituents RR being defined as above. a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by one or more substituents R ; R being defined as above;
    a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atoms and at least one heteroatom selected from CG, N, and S, wherein one or more of the carbon atoms in the ring can be substituted by R being as defined above;
    an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; an alkylthio group denotes an S-alky! group, the alicy! group being as defined above;
    an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; - an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above;
    a hydroxyalkylamino group denotes an (HO-alkyl)-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes an HN-alkyl or N-dialky] group, the alky! group being as defined above; a halogen group is fluorine, chlorine, bromine, or iodine; an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R, where R is as defined above; an arylamino group denotes an FN-aryl or N-diaryl group, the aryl group being as defined above;
    a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic group which contains at least one heteroatom selected from O, N, and §, wherein the heterocyclic group may be fused to another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R, wherein R. is as defined above; with the proviso that the following compounds are excluded : Q N RZ ito ffdn / Pp q 8 @ wherein R! independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl; R* independently represents -NR*R,
    O40 ~5-N RS —-N N—R3 R® independently represents allcyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, : alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl, R* independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R® independently represents H, CORS, COR®, SORS, SORS, SO:R®, alkyl, cycloalkyl, alkoxy, -NH,, alkylamine, -NR'CORS, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; RS independently represents H, alkyl, cycloalkyl, -NH,, alkylamine, aryl or heteroaryl; R’7 independently represents H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, aryl, or heteroaryl; P isO, ort; 13 q is, orl; . xX 18 CO or 80s.
    3. A compound of the general formula (I) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, AN YE pA No
    RI . ~, x kh w wherein R! is-COR, -C(O)CHR'R?, -C(O)NR'R®, -C(O)OR”, R'C(O)RE, -C(SHR,
    R* is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkyl amino, hydroxyalkylamino, heteroaryl,
    or R! and R? together with the N-atom or the C-atom to which they are attached form a 3 to 8 membered saturated or at least partially unsaturated monocyclic or polycyclic ring system, wherein at least one or more of the carbon atoms in the ring is a heteroatom selected from O, N, and S, and the
    : ring can be substituted by one or more rR’
    Ris H, -C(O)NRRY, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NRYOR’? NH,, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl,
    heterocycloalkyl, hydroxyalkyl, or haloalkyloxy;
    R* is H, halogen, alkyl, -CONRTNR'R?, ~(CHp)aryl, -(CHu)NR'R®, aryl, C(ONRRE, -N=CR'R®, -NR'C(O)R®, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, or heteroaryl;
    RP independently represents H, -CN, -OH, ~SH, -CO,R¥, -C(O)RY, -SO,NRY,
    NRYRY, -C(ONR'R, -SO.-alkyl, -SO;RY, SOY, -N=CR‘R", -
    NRYC(O)RY, -NR*-CO-haloalkyl, -NO,, -NR¥-SO,-haloalkyl, -NR*-S0,-
    alkyl, -NRY-CO-alkyl, -NRY(CHp) heterocycle, alkyl, cycloalkyl,
    alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy,
    -O(CHy)p[O(CH,), OCH, -CNR*"NR*benzimidazolyl, -C(NR*)NR*-
    benzthiazolyl, -CONR*‘NR*benzoxazolyl, hydroxyalkyl, hydroxy- alkylamino, aryl, heterocycloalkyi, or heteroaryl;
    RS is halogen, -C(OR’, -C(O)CHR'RS, -C{ONR'RY, -C(O)OR', -R'C(OIRY, - CSR’, -CNRHNR'RS, ~(CHpparvl, ~(CH),NR'R?, -C(O)NR'RE, -
    N=CR'R®, -NR'C(O)R”, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
    R’ R”, R® independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -NHaryl, heteroaryl, or aryl;
    A is CO or 80,
    xX is NR? QO, or S;
    Y isN, CR* orif Vis O then RS is absent;
    Z isNor CR%;ifZis CH then X is O or NR”
    RY is H, allyl, -C(O)NR?, -C(O)R?, cycloalkyl, heterocycloaikyl, haloalkyl, hydroxyalkyl, hydroxyallcylamino, alkylamino, heteroaryl, or aryl; mn is0to 2; p isltoé, q is 1 to 6; : R’ independently represents H, -CN, -OH, -SH, -CO.RY, -C(O)R*, -C(O)NR'RE, - SONRY, -NRYRY, .SOp-alkyl, -SORY, SO;RY, N=CRRY, - NR¥C(O)R"", -NR¥-CO-haloalkyl, -NO,, -NR¥-80,-haloalkyl, -NR*-S0,- alkyl, -NR*-CO-alkyl, -NR*(CHj)heteroaryl, alkyl, cycloalkyl, ~ heterocycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, hydroxyalkylamino, hydroxyalkyl, hydroxycycloalkyl, aryl, -O(CHy)p[O(CH2)pJ{OCH;, -CNR* “NR benzimidazolyl, -CONR* NR?- benzthiazolyl, -C(NR* YNR* benzoxazolyl, (CH2),NR'CORS, or heteroaryl; R*,R*, R” independently are H, halogen, alkyl, -CONR"YNR”'R®, -(CHa)aryl, ~(CH),NRR®, -C(O)NRR®, -N=CR'R®, -NR'C(O)R?, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R*® is H, C-Cealkyl, Cr-Cealkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, aryl, alkylamino, -C(NRHNR'R?, -(CHp)aryl, -(CH),NR'RY, -C(ONR'R®, -N=CR'R}!, -NR'C(O)R}, halogen, or heteroaryl; wherein an C;-Cg-alkyl group, if not stated otherwise, denotes a linear or branched Cy-Ce~ alkyl, which can optionally be substituted by one or more substituents R: R’ is independently H, -CO.R™, -CONHR", -CR™0, -SO,NR, -NR-CO- haloalkyl, -NO,, -NR-8Oy-haloalkyl, -NR -§0;-alkyl, -SOp-alkyl, -NR>*-CO- alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or . heteroaryl; R™ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl;
    an Cyp-Ce-alkenyl group, if not stated otherwise, denotes a linear or branched Co Cg—alkenyl, which can optionally be substituted by one or more substituents R;
    an alkyl group, if not stated otherwise, denotes a linear or branched C;-Ce-alkyl, 2 linear or branched Co-Cg-alkenyl or a linear or branched Co-Ce-alkynyl group, which . can be substituted by one or more substituents R'; R" being defined as above.
    a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by one or more substituents RR being defined as above;
    a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atoms and at least one heteroatom selected from O, N, and S, wherein one or more of the carbon atoms in the ring can be substituted by R being as defined above; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above;
    an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; : an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above;
    a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above;
    an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms; the alkyl group being as defined above;
    a hydroxyalkylamino group denotes an (HO-alkyl)s-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes an FiN-alkyl or N-dialkyl group, the alkyl group being as defined above; a halogen group is fluorine, chlorine, bromine, or iodine; : an aryl group denotes an aromatic group having five to fifteen carbon atoms, which 1¢ can be substituted by one or more substituents R", where R is as defined above; a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclic group may be fused fo another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R’, wherein Ris as defined above: 4, A compound of the general formula (Ia) or a pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, J N ~~ R2 {—<U R z Re (Ia) ~~ R is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; Rr! is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; X is CO, CS or SO; Y i8CO, CS or SOy;
    Z is NR%, 8, or O; RZ is H, alkyl, -C(O)NR', -C(O)R®, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamine, alkylamine, heteroaryl, or aryl;
    R® is independenfly H, OH, SH, NROR, NH, alkylamino, hydroxyalkylamino, halogen, CONRR®, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
    RY is H, halogen, alkyl, CONRNR RS, ~(CH)garyl, -(CHz),NR'RY, - C(OINR'R?, -N=CR'R®, NR'C(O)R, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;
    R’ R” independently represent H, alkyl, cycloatkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;
    RE is H, NHy, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;
    R® independently represents H, -CN, -OH, -SH, -COR", -C(O)RY, -SO;NRY, NRYRY, -C(ONR'R®, -SOpalkyl, -SO:RY, SORRY, N=CR'R’, - NRY CORY, -NR*-CO-haloalkyl, -NOj, -NR¥-SOy-haloallyl, -NR"-S0»- alkyl, -NR¥-CO-alkyl, -NRY(CHy)beteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl hydroxyalkylamino, alkoxy, alkylthio, -O(CHy)p[O(CHz),){OCHs, -CNRYINRY benzimidazolyl, -CONR* INR” benzthiazolyl, -CONR*YNR* benz-oxazolyl, or heteroaryl; RY RY", R¥ independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -CQNRYNR” RY, -(CHz)paryl, - CH), NR'RE, -C(O)NR'R’, -N=CR'R’, NR'C(O)RS, halogen, heteroaryl, or aryl p is 1to 6; } 30 q islto6; R? isindependently fo ye SN N——R® , OF \__/ R® is independently H, COR’, COR, SOR, SO,R®, SOR’, alkyl, cycloalkyl, alkoxy, -NH,, alkylamine, -NR'CORS, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl R¢ is independently H, alkyl, cycloalkyl, amino, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, aryl or heteroaryl; wherein an alkyl group, if not stated otherwise, denotes a linear or branched C;-Ce-alkyl, a linear or branched Cy-Cg-alkenyl or a linear or branched Cp-Co-allynyl group, which can be substituted by one or more substituents R’, R°, being defined as above. R' is independently H, -CO,R", -CONHR™, -CR"O, -SO,NR"™, -NR™-CO- haloalkyl, -NOj, ~NR*-SO0;-haloalkyl, -NR*-80;-alkyl, -50;-alkyl, -NR™-CO- alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OIL -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl; R™ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; : a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group B, E being O, S, SO, SO,, N, or NR”, R™ being as defined above; : an alkoxy group denotes an O-allyl group, the alkyl group being as defined above;
    . an alkylthio group denotes an S-alkyl group, the alkyl group being as defined : above;
    08 oo an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkylamino group denotes an (HO-alkyl),-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes an HN-alkyl or N-dialky! group, the allyl group being as defined above; a halogen group is fluorine, chlorine, bromine, or iodine; an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R', where R” is as defined above; a heteroaryl group denotes a 5- fo 10-membered aromatic heterocyclic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclic group may be fused to another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R, wherein R is as defined above.
    5. A compound of the general formula (Ib) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, | }
    Re R° 2 Rl N 1 i \ — x ? R® (Ib) wherein R' is COR’, -C(OXCHR'RS, -COINR'RS, -C(O)OR’, -R'C(OR®, or -C(S)R, R® independently represents H, -CN, -OH, -SH, -CORY, -C(O)RY, -SO,NR?, NRYR”, -C{ONR'R®, -SO,-alkyl, -SO,R¥, SO;RY, -N=CR*R", - NRYC(ORY, -NR*-CO-haloalkyl, -NO,, -NR*¥-S0,-haloalkyl, -NR¥-SO,- alkyl, -NR*-CO-alkyl, -NR*(CHa)heteroaryl, heteroaryl, hydroxyalkyl, cycloalkyl, alkylamino, aryl hydroxyalkylamino, alkoxy, alkylthio, ~O(CH),[O(CHL), 1, OCH; -CONRY INR benzimidazolyl, -CNR* INR¥" benzthiazolyl, CORY INR? benzoxazolyl, (CHy),NR'CORS, or alkyl R* is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamine, i5 alkylamino, heteroaryl, aryl or R! and R* together with the X to which they are attached forma3 to § membered saturated or at least partially unsaturated monocyclic or polycyclic ring system, wherein at least one ring atom is a heteroatom selected from O, N, and 8, and the ring optionally has one or more substituents R%; ; X isN, or CR%; Y isCO, CS or SO; Z isNRY, 8, or 0;
    25 . ; R¥ is H, alkyl, -C(OYNR', <C(O)R®, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
    R? is H, alkyl, -C(O)N R¥, -C(0) R*, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxy-alkylamino, alkylamino, heteroaryl, or ary];
    RY, RY, R independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -CNR)NR"R, -(CH)paryl, -
    CH), NR'R, -C(O)NR'R?, -N=CR'R®, NR'C(O)R?, halogen, heteroaryl, or aryl p is 1 to 6;
    q islto 6;
    R* is independently H, OH, SH, NH, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl;
    RP is independently H, OH, SH, NH, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen,
    aryl, or heteroaryl;
    R® is independently H, OH, 8H, NRYOR®, NH, alkylamino, hydroxyalkylamino, halogen, CONRR®, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or hetercaryl;
    RY is H, halogen, alkyl, -C(NR")NR" R®, (CHy)aryl, -(CH2),NR'R?, - CORRE, N=CRRE, NR'C(O)R?, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;
    R7, R" independenily represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;
    RP is H, NH, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;
    R® independently represents H, -CN, -OH, -SH, -CO,RY, -C(O)RY, -SO.NRY, NRYRY, -CONR'RE, -S0p-alkyl, -SO;R*, SORY, N=CR'R’, -
    NRY CORY, NR¥-CO-haloalkyl, -NO;, -NR*-80,-haloalkyl, -NR*¥-S0,- alkyl, -NRY-CO-alkyl, -NR*(CH)heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxy-alkylamino, alkoxy, alkylthio,
    -O(CHy)o O(CH),]OCHs, ~CONR' INR" benz-imidazolyl, -CONR® NR? benzthiazolyl, -C(NR* INR" benzoxazolyl, aryl or heteroaryl; R* isindependently $n A——RS Hla A iN, 0, or CR; R® is independently H, SOR’, SOR’, SOR’, -CO)R’, -C(O)CHR'R®, - C(ONR'RE, -C(O)OR?, -R'C(O)R®, -C(S)R7, -CNRINR RE, ~(CHy)paryl, -(CHp),NR'R®, -C(O)NR'R®, -N=CR'R®, -NR'C(O)R”, alkyl, cycloalkyl, alkoxy, . -NHp, alkylamino, hydroxyalkylamino, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; n is 0 to2; wherein an alkyl group, if not stated otherwise, denotes a linear or branched C;-Cg-alleyl, a . Linear or branched C,-Cs-alkeny! or a linear or branched Co-Cy-alliynyl group, which can be substituted by one or more substituents R'; R* being defined as above.
    R'is independenily H, -CO,R™, -CONHR™, -CR™O, -SO,NR™, -NR™-CO- haloalkyl, -NO;, -NR™-5O0,-haloalkyl, -NR *-50;-alkyl, -SOz-alkyl, -NR**-CO- alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, : hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl; R™ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group E, E being 0, 8, SO, SO, N, or NR", R* being as defined above;
    an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; an, alkylthio group denotes an S-alkyl group, the alkyl group being as defined above;
    an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkylamino group denotes an (HG-alkyl),-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above;
    a halogen group is fluorine, chlorine, bromine, or iodine; an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R', where R” is as defined above;
    a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclic group may be fused to another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R, wherein R’ is as defined above. ’
    6. A. compound of the general formula (Ic) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, Nee ir ~~ xX NA | ®1n J ; ; \ Ra rbot} AN “ / z R® dc)
    wherein rR! independently represents H, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halo- alkyloxy, aryl, or heteroaryl; X isCO,CSorSOy oo Y is CO, CS or 804; Z isNR¥,S,0r0; RY is H, alkyl, -C(OINR', -C(O)RS, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; RY, RY, RY independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -CNR)NR” R?, «(CH,)aryl, - (CH), NR'R?, -C(OYNR'R?, -N=CRRE, -NR'C(O)R®, halogen, heteroaryl, or aryl. p ig Ito 6; q isito6: . m isto 4 . r is0, ori; - . 1 is 0, or 1; S ig, orl;
    R® is. independently H, OH, SH, NRYORY, NH, alkylamino, hydroxyalkylamino, halogen, CONR'R®, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
    R® is independently H, OH, SH, NRYOR®, NH; alkylamino,
    hydroxyalkylamino, halogen, CONRIR®, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
    R* is H, halogen, alkyl, -CONR)NR'R®, -(CHparyl, ~(CEL),NR'RS, ~C(ONR'R?, N=CR'R?, -NR'C(O)R®, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyallcylamino, alkylamino, heteroaryl or aryl;
    R’, R” independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, : hydroxyalkylamino, alkylamine, heteroaryl or aryl; R® is H, NH,, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, : allcylamino, heteroaryl or arvl; R® independently represents H, -CN, -OH, -SH, -CO»R¥, -C(O)RY, -SO;NR?, NRYRY, -CONR'R®, -SOpalkyl, -SO.RY, SOR*, N=CRYRY, -. NRYC(O)RY, -NR-CO-haloalkyl, -NO,, -NR*-SO,-haloalkyl, -NR*.50,- alkyl, -NRY-CO-alkyl, -NR*(CHy)heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkyl-amino, alkoxy, alkylthio, ~O(CH),[O(CH,),];0CH;, -CONRYINR* benzimidazolyl, -CONR* INR*- benzthiazolyl, -CONR* YNR* benz-oxazolyl, aryl or heteroaryl;
    rR? is independently HM, OH, SH, NRYOR”>, Ni, hydroxyalkylamino,
    alkylamino, halogen, CONRR®, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
    wherein ~ an alkyl group, if not stated otherwise, denotes a linear or branched C;-Cg-alkyl, a linear or branched C-Cs-alkeny! or a linear or branched Co-Cy-alkyny! group, which can be substituted by one or more substituents R'; R' being defined as above.
    R'is independently H, -CO,R™, -CONHR™, -CR™Q, -SONR, -NR-CO- haloalkyl, -NOj, -NR-80;-haloalkyl, “NR -S§Os-alkyl, -S0;-alkyl, -NR *-CO- alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio,
    hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroatyi; R™ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group E, E being 0, 8, SO, SO, N, or NR**, R*" being as defined above; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; an haloalkyl group denotes an alkyl group which is substituied by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the allyl group being as defined above;
    a hydroxyalkylamino group denotes an (HO-alkyl);-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above; - a halogen group is fluorine, chlorine, bromine, or iodine;
    an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substitated by one or more substituents R*, where R is as defined above; a heteroaryl group denotes a 5- 40 10-membered aromatic heterocyclic group which contains at least one heferoatom selected from 0, N, and S, wherein the heterocyclic group may be fused to another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R*, wherein R” is as defined above, a 7, The compound according to any one of claims 1 to 6 for the use as a medicament.
    g. A composition containing a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or diluent. 9, The use of a compound according to any one of claims 1 10 6 or a composition of claim § for the preparation of a medicament for the treatment or prevention of a disease characterized by hyperproliferation of cells.
    10. The use of a compound according to any of claims 1 to 6 or a composition of claim 8 for the preparation of a medicament for the treatment or prevention of a disease resulting f rom ischemia and/or reperfusion injury of organs and/or of parts of the body selected from the group comprising heart, brain, peripheral limb, kidney, liver, spleen and lung, and/or wherein the endothelial dysfunction is associated with diseases selected from a group comprising infarctions such as myocardial infarction and critical limb ischemia, and/or wherein the endothelial dysfunction is associated with diseases selected from the group comprising ischemic diseases, myocardial infarction and ischemic diseases of organs.
    11. Theuseofa compound according to any of claims 1 fo 6 or a composition of claim 8 for the preparation of a medicament for the treatment or prevention of a ) neurological diseases or disorders selected from the group comprising Alzheimer's disease, Parkinson's disease, Creutzfeld-Jacob Disease, Lewy Body Dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, Huntington's Disease, Down's Syndrome, nerve deafness, and Meniere's disease. :
    12. The use according to claim 9, wherein the disease is selected from the group consisting of psoriasis, atopic dermatitis, alopecia areata, alopecia totalis, alopecia subtotalis, alopecia universalis, alopecia diffusa, lupus erythematodes of the skin, lichen planus, dermatomyostis of the skin, atopic eczema, morphea, sklerodermia, psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa, alopecia areata ophiasis-type, androgenetic alopecia, allergic contdct eczema, irritative’ contact eczema, contact eczema, pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, scarring mucosal pemphigoid, bullous pemphgoid, mucous pemphigoid, dermatitis, dermatitis herpetiformis duhring, urticaria, necrobiosis lipoidica, erythema nodosum, lichen vidal, prurigo simplex, prurigo nodularis, prurigo acuta, linear IgA dermatosis, polymorphic light dermatoses, erythema solaris, lichen sclerosus et afrophicans, exanthema of the skin, drug exanthema, purpura chronica progressiva, dihidrotic ekzema, Ekzema, fixed drug exanthema, photoallergic skin reaction, lichen simplex eriorale, dermatitis and "Graft versus Host-Disease®, acne, rosacea, scarring, keloids, vitiligo, actinic keratoses, hyperkeratoses like epidermolytic hyperkeratosis, Hyperkeratosis Lenticularis Perstans, Keratosis pilaris and Ichthyoses.
    13. The use according to claim 9, wherein the disease is selected from the group consisting of hematological or solid tumors. :
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