(19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0143382 A1

Aulinger-Fuchs et al.

US 2005O143382A1

(43) Pub. Date: Jun. 30, 2005

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(75)

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(60)

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HETEROCYCLIC COMPOUNDS AS PHARMACEUTICALLY ACTIVE COMPOUNDS

Inventors: Katharina Aulinger-Fuchs, Neuried (DE); Thomas Herz, Stockdorf (DE); Rolf Krauss, Planegg-Martinsried (DE); Michael Kubbatat, Schallstadt (DE); Martin Lang, Grafelfing (DE); Christoph Schachtele, Freiburg (DE); Frank Totzke, Freiburg (DE)

Correspondence Address: OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C. 1940 DUKE STREET ALEXANDRIA, VA 22314 (US)

Assignee: 4SC AG, Martinsried (DE)

Appl. No.: 10/978,353

Filed: Nov. 2, 2004

Related U.S. Application Data

Provisional application No. 60/516,743, filed on Nov. 4, 2003.

Foreign Application Priority Data

Nov. 4, 2003 (EP)........................................ O3O25380.1

Publication Classification

(51) Int. Cl." ...................... A61K 31/498; CO7D 491/02 (52) U.S. Cl. ............................................ 514/249; 544/350

(57) ABSTRACT

The present invention relates to furazanopyrazine deriva tives of the general formula (I):

N R N n

o e 2 N N R"

R" represents -NR'R' or -OR wherein:

R" represents -NR-NRR", -NR-OR, -O-NRR";

wherein R' to R' in formula (I) represent independently of each other a variety of different Substituents comprising alkyl, aryl, aralkyl, alkylaryl, heteroaryl groupS and mono functional moieties.

US 2005/0143382 A1

HETEROCYCLIC COMPOUNDS AS PHARMACEUTICALLY ACTIVE COMPOUNDS

0001. The present invention relates to furazanopyrazine derivatives, the use of the furazanopyrazine derivatives as pharmaceutically active agents, especially to treat protein kinase-dependent diseases and conditions, Such as cancer, angiogenesis, atherosclerosis, inflammatory diseases, neu rodegenerative diseases and the like in mammals, as well as compositions containing at least one furazanopyrazine derivative and/or pharmaceutically acceptable Salt thereof, and methods for preventing and/or treating Such diseases. Furthermore, a proceSS for preparing Said furazanopyrazine derivatives is disclosed.

BACKGROUND OF THE INVENTION

0002 Protein kinases play a central role in the regulation of cellular functions. This includes processes like cell growth and division, cell differentiation and cell death, but also many other cellular activities. Protein kinases catalyse the transfer of phosphate residues from ATP on target proteins which as a consequence of this protein kinase mediated phosphorylation change their three-dimensional Structure and thereby their physiological function. Depend ing on the amino acid which becomes phosphorylated by a protein kinase these enzymes are grouped in two families, the So-called Serine/threonine protein kinases and the tyrosine protein kinases. 0.003 Based on the human genome project it is known that in human beings their exist 518 DNA sequences which encode for a protein kinase-like protein Sequence. In the last about 20 years for several of this 518 proteins it could be shown that modifications in their related gene Sequences (e.g. point mutations, deletions or gene amplifications) result in pathological changes of the cellular activities of the corresponding protein kinase. This is in particular true for protein kinases which are involved in cell proliferation and cell cycle control, in Survival of cells and cell death, in tumor angiogenesis, and in formation of tumor metastases. 0004 Several so-called oncogenes are pathologically modified genes which in their proto-oncogenic form encode for protein kinases involved in normal, physiological regu lation of cell growth and division. 0005 Since protein kinases are key regulators of cell functions and Since they can show dysregulated enzymatic activity in cells they are promising targets for the develop ment of therapeutic agents. There are many ongoing drug discovery projects in the pharmaceutical industry with the goal to identify modulators of protein kinases. The major focus is currently on protein kinases involved in inflamma tion and cancer, but besides this protein kinases are currently discussed as promising targets in almost every disease area.

0006. In the tumor field the first protein kinase inhibitor (Gleevec) has already reached the market. In addition, a great number of protein kinase inhibitors are currently in various phases of clinical development. In most cases these compounds are either targeting Subtypes of the EGF (Epi dermal Growth Factor) receptor or of the VEGF (Vascular Endothelial Growth Factor) receptor. All these compounds have been developed with the goal to specifically inhibit one particular protein kinase, for which there is evidence that it interferes with one of the four major molecular processes of

Jun. 30, 2005

tumor progression. These four processes are (1) cell prolif eration/cell cycle control, (2) regulation of programmed cell death (apoptosis) and cell Survival, (3) tumor angiogenesis and (4) tumor metastasis. The present invention relates to furazanopyrazine derivatives which may be useful for inhi bition of protein kinases involved in diseases besides cancer, but which are especially useful as anti-tumor agents. This includes monospecific protein kinase inhibitors, which pref erentially inhibit one protein kinase which is causatively involved in tumor progression, but also So-called multi target protein kinase inhibitors, which inhibit at least two different protein kinases which play a role in two or more different molecular mechanism of tumor progression. AS an example, Such a compound could be an inhibitor of tumor angiogenesis and, in addition, also a Stimulator of apoptosis. 0007. The concept of multi-target protein kinase inhibi tors is a new approach although the idea of developing “multiplex protein kinase inhibitors' has already been described by J. Adams et al., Current Opinion in Chemical Biology 6, 486-492, 2002. Therein compounds are described, which, at the same time, inhibit Several protein kinases, which however all are involved in one molecular mechanism of tumor progression, namely tumor angiogen CSS.

0008. In WO 02/44378, “WNT signalling assay, method and uses thereof, 5,6-diaminofurazanopyrazines as poten tial kinase inhibitors are mentioned. Furazanopyrazine derivatives are known to be antimicrobials, antibacterials, herbicides and plant growth regulators (E. Fernandez et al., Tetrahedron Lett., 43, 2002, 4741-4745, GB 2122492, U.S. Pat. No. 3,850,929). The synthesis of 5,6-disubstituted fura Zanopyrazines is described by different groups (I.B. Starch enkov, Chemistry of Heterocyclic Compounds, 33(10), 1997, 1219-1233, A. Gasco et al., Journal of Heterocyclic Chemistry, 6, 1969, 769-770). 0009. The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.

0010 Considering the lack of currently available treat ment options for the majority of the conditions associated with protein kinases like ABL1, AKT1, AKT2, AKT3, Aurora-A, Aurora-B, Aurora-C, BRK, CDK1/CycB, CDK2/ CycA, CDK2/CycE, CDK3/CycE, CDK4/CyclD1, CDK5, CDK6/CycD1, CK2, COT, EGF-R, EPHA1, EPHB2, EPHB4, ERBB2, ERBB4, FAK, FGF-R1, FGF-R3, FGF R4, FGR, FLT3, IGF1-R, IKK-beta, INS-R, IRAK4, JAK2, KIT, MET MUSK, PBK, PCTAIRE1, PDGFR-alpha, PDGFR-beta, PIM1, PKC-alpha, PKC-beta1, PKC-beta2, PKC-delta, PKC-epsilon, PKC-eta, PKC-gamma, PKC-iota, PKC-mu, PKC-theta, PKC-Zeta, PLK1, PRK1, RET, SGK3, SNK, S6K, SNK, SRC, SYK, TIE2, TSF1, TSK2, VEGF R1, VEGF-R2, VEGF-R3, WEE1, especially with protein kinases like EGF-R (cell proliferation), Aurora-B (cell cycle control), IGF1-R (apoptosis), VEGF-R2 (angiogenesis) and SRC kinase (metastasis), there is still a great need for new therapeutic agents that inhibit these protein targets. Furaza nopyrazine derivatives are a new group of protein kinase inhibitors which show differential inhibition of protein kinases, each of which can be assigned to one of the four molecular mechanisms of tumor development.

US 2005/0143382 A1

0.011 The present invention is also directed to novel compounds of the general formula (I) and pharmaceutically acceptable Salts thereof:

N R N N V e 2 N N R"

0012 wherein: 0013) R' represents -NR'R' or -OR 0014) R" represents -NR-NR'R'', -NR-OR, -O-NRR';

0015) R' represents hydrogen, C-C-alkyl, C-C-alk enyl, C-C-alkinyl, C-C-Cycloalkyl, -COOR", -SOR", -CO-R, -SONHR, -SON(R), -OH, -SH, C-C-alkoxy, C-C-alkylthio, C-C- hydroxyalkyl, C-C-haloalkyloxy, Cs-C-aryl, het eroaryl or R together with R form a 5-6- or 7-mem bered unsaturated or Saturated heterocyclic ring, which has optionally 1 to 3 substituents R;

0016 R represents hydrogen, C-C-alkyl, C-C-alk enyl, C-C-alkinyl, Cs-Cs-cycloalkyl, -COOR", -SOR"; -SONHR, -SON(R), C-C-alkoxy, C-C-alkylthio, C-C-hydroxyalkyl, C-C-haloalky loxy, C-C-aryl or heteroaryl;

0017 R represents hydrogen, C-C-alkyl, C-C-alk enyl, C-C-alkinyl, C-Cs-cycloalkyl, -COOR", -SOR", -CO-R, -SONHR, -SON(R), -OH, -SH, C-C-alkoxy, C-C-alkylthio, C-C- hydroxyalkyl, C-C-haloalkyloxy, Cs-C-aryl het eroaryl, or R represents a double bond to the carbon ylic carbon atom of a mono- or oligosaccaride and R' is absent, or R represents

NR9 ,

0018 which has optionally 1 to 3 substituents Rand R' is absent or R represents

0.019 and is bonded to N via a single or double bond, and wherein

0020 R and R are each independently hydrogen, C-C-alkyl, C-C-alkenyl, C-C-alkinyl, C-C-cy cloalkyl, -COOR7, -SOR", -CO-R',

Jun. 30, 2005

-SONHR', -SO2N(R), -OH, -SH, C, -Co alkoxy, C-C-alkylthio, C-C-hydroxyalkyl, C-C- haloalkyloxy, Cs-C-aryl, heteroaryl, or R together with R' form a 5-, 6- or 7-membered unsaturated or Saturated heterocyclic ring, which has optionally 1 to 3 Substituents R,

0021 or R together with R form a 5-, 6- or 7-mem bered unsaturated or Saturated heterocyclic ring, which has optionally 1 to 3 substituents R;

0022) R' represents hydrogen, C-C-alkyl, C-C-alk enyl, C-C-alkinyl, Cs-Cs-cycloalkyl, -COOR", -SOR", -SO2NHR'. -SO2N(R), C-C-alkoxy, C-C-alkylthio, C-C-hydroxyalkyl, C-C-haloalky loxy, Cs-C-s-aryl, or heteroaryl or R' together with R form a 5-, 6- or 7-membered unsaturated or Saturated heterocyclic ring, which has optionally 1 to 3 Substitu ents R, or R' represents a bond in case R' and R' form a ring System, and R' is absent in case R is bonded to N via a double bond;

0023 R represents hydrogen, C-C-alkyl, C-C-alk enyl, C-C-alkinyl, Cs-Cs-cycloalkyl, -COOR", -SOR", -SONHR, -SON(R), C-C-alkoxy, C-C-alkylthio, C-C-hydroxyalkyl, C-C-haloalky loxy, Cs-Cis-aryl, heteroaryl or R represents a bond in case R and R' or R and R' or R and R' form a ring System;

0024) R' represents hydrogen, C-C-alkyl, C-C-alk enyl, C-C-alkinyl, C-C-cycloalkyl, Cs-C-aryl or heteroaryl;

0025 The C-C-alkyl, C-C-Cycloalkyl, Cs-Cs aryl, and heteroaryl group can optionally be Substituted by one or more substituents R.

0026 R represents independently of each other hydro gen, -COOR, -CONHR'. -F, -Cl, -Br, -I, –CO-R, -SONR'R'', -NR'R'', -NR-NR, -O-CO-NR'R'', -NR -CO-NR, -NO, CN, -OH, -SH, -NR-CO-(C-C)haloalkyl,

-NR'-SO-(C-C)-haloalkyl, C-C-alkyl, C-C-aminoalkyl, C-C-alkoxy, C-C-alkylthio, C-C-hydroxyalkylamino, C-C-hydroxyalkyl, amine, C-C-haloalkyloxy, Cs-C-aryl or heteroaryl;

0027 R represents independently of each other hydrogen, -COOR. -CONHR'. -F, -Cl, -Br, –I, -CO-R, -SONR'R'', -NR'R'', -NR NR, -O-CO-NR'R'', -NR-CO-NR, -NR'-CO-(C-C)-haloalkyl, -NO, -CN, -NR-SO-(C-C)-haloalkyl, C-C-alkyl, C-C-aminoalkyl, -OH, -SH, C-alkoxy, C-C- alkylthio, C-C-hydroxyalkylamino, C-C-hydroxy alkyl, amine, C-C-haloalkyloxy, Cs-C-aryl or het eroaryl;

0028) R' represents hydrogen, C-C-hydroxyalkyl, C-C-alkyl, C-C-aminoalkyl, Cs-C-aryl or het eroaryl;

0029) R' represents hydrogen, C-C-hydroxyalkyl, C-C-alkyl, C-C-aminoalkyl, Cs-C-aryl or het eroaryl.

0030. An alkyl group denotes a C-C-alkyl, C-C- alkenyl, C-C-alkinyl, or C-C-cycloalkyl residue.

US 2005/0143382 A1

-continued

N

R y N NN X-X S. N

e

N \ N

M 0-2

-continued

- N 1. R3 S-2 R3 V

Jun. 30, 2005

US 2005/0143382 A1

-continued

- \

R31 Y-1.

R3 V N-N

/ W N N

-continued

Jun. 30, 2005

US 2005/0143382 A1 Jun. 30, 2005 6

-continued -continued

X X

3 R3 ls R r

* O-3 Y N-11, X

X ls A ls A N N 3 N R31 Y1, R O-3 Y

R3 N X n

Y t Y A. 1. N-X n N N N

-s-s y R3 0-3 X X

, 3

- / - 0-2 sy Y X

*N- RNN }-x. N R y ". 0-2

-N

a -s, 0043 or tautomers thereof N X

R31 N-11, 0044) wherein X represents O, S or NR; Y represents OR, SR or NR'R'; Z represents CRR, SO, SO, O, S or NR.

US 2005/0143382 A1

0048 wherein R. R. and R have the meanings as defined above; and R" represents independently of each other hydrogen, -COOR, -CONHR'. -F, -Cl, -Br, -I, -NO, -CO-R, -SONHR, -SON(R), -NR'-CO-(C-C)-haloalkyl, -OH, -SH, -CN, -NR-SO-(C-C)-haloalkyl, CC-alkyl, C-C-ami noalkyl, C-C-alkoxy, C-C-alkylthio, C-C-hydroxy alkylamino, C-C-haloalkyloxy, Cs-C-aryl or heteroaryl.

0049. In a preferred embodiment of the invention, in compounds of formula (I), the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;

0050. In a further particularly preferred embodiment of the invention, in compounds of formula (I), R' is NR'R''. 0051. In a further particularly preferred embodiment of the invention, in compounds of formula (I), R" is NR NR'R''.

0.052 In a further particularly preferred embodiment of the invention, in compounds of formula (I), R', R' or Rare independently of each other are hydrogen or methyl.

0053. In a further preferred embodiment of the invention, in compounds of formula (I), R is aryl or heteroaryl more preferred R is an optionally substituted phenyl. 0054. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with one or two halogen groups.

0055. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with a halogen group, preferably Substituted in meta or para position to the amine.

0056. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with two halogen groups, preferably Substituted in 3,4-position to the amine.

0057. In a further preferred embodiment of the invention, in compounds of formula (I), R" is aryl or heteroaryl more preferred R' is an optionally substituted phenyl. 0.058. In a further particularly preferred embodiment of the invention, in compounds of formula (I), R is

NR9 O Ra

0059. In a further preferred embodiment of the invention, in compounds of formula (I), R is aryl or heteroaryl, more preferred R is an optionally by R substituted phenyl, an optionally by Rsubstituted 5-phenyl-furan-2-yl, an option ally by R substituted furan-2-yl, or an optionally by R substituted benzofuranoyl.

0060. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with one or two or three hydroxy groups.

Jun. 30, 2005

0061. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with a hydroxy group in ortho position to the amino group. 0062. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with a hydroxy group and one or two halogen groups.

0063. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with a hydroxy group in ortho position to the amino group and one or two halogen groups.

0064. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with a hydroxy group, a methoxy group and a halogen group.

0065. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with a hydroxy group in ortho position to the amino group and a halogen group and a methoxy group.

0066. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with one or more methoxy groups. 0067. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with a methoxy group in meta or para position to the amino grOup.

0068. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with a methoxy group in meta or para position to the amino group and a hydroxy group in Ortho position to the amino group.

0069. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with a methoxy group in meta or para position to the amino group and a hydroxy group in ortho position to the amino group and a halogen group.

0070. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with one or more caboxyl groups.

0071. In a further preferred embodiment of the invention, in compounds of formula (I), R is phenyl substituted with a carboxyl group in para position to the amino group.

0072. In a further preferred embodiment of the invention, in compounds of formula (I), R is 5-phenyl-furan-2-yl Substituted by a carboxyl, an amide or a nitro group. 0073. In a further preferred embodiment of the invention, in compounds of formula (I), R is 5-phenyl-furan-2-yl Substituted by a carboxyl and a halogen group.

0074. In a further preferred embodiment of the invention, in compounds of formula (I), R is 5-phenyl-furan-2-yl Substituted by a carboxyl and a hydroxy group.

0075. In a further preferred embodiment of the invention, in compounds of formula (I), R is 5-phenyl-furan-2-yl Substituted by a carboxyl and a methoxy group.

0076) One possibility for the synthesis of compounds of formula (I), wherein R' is -NR'R'' and R" is -NR NR'R' comprises the step of reacting a compound of for mula (II) with a compound of formula (III). This reaction is described for example in Starchenkov, I. B.; Andrianov, V.

US 2005/0143382 A1

G. Chem. Heterocycl. Compa. 1997, 33, 1219-1233, Khim. Geterotsikl. Soedin. 1997, 1402-1416.

N n R5 R3 o -- N2 2 HN-N-R Hess

N Cl Formula (III)

Formula (II) R1

N N N-R2 / N n O R3 \ -2 2 N N NRS-N-R

Formula (I)

0.077 One possibility for the synthesis of compounds of formula (II) comprises the Step of reacting 5,6-dichloro-1, 2.5oxadiazolo 3,4-bipyrazine with a compound of formula (IV). This reaction is described for example in Starchenkov, I. B.; Andrianov, V. G. Chem. Heterocycl. Compa. 1997, 33, 1219-1233, Khim. Geterotsikl. Soedin. 1997, 1402-1416, and in Fernández, E., García-Ochoa, S.; Huss, S.; Mallo, A.; Bueno, J. M.; Micheli, F.; Paio, A.; Piga, E.; Zarantello, P. Tetrahedron Lett. 2002, 43, 4741-4745.

N N Cl M NS n O \2n 2 + HN-R N N Cl

Formula (IV)

N N o e N 4.

Formula (II)

---

R1

0078. Alternatively, 5,6-dichloro-1,2.5oxadiazolo 3,4- bipyrazine can be first reacted with a compound of formula (III) and then with a compound of formula (IV). 0079. One possibility for the synthesis of derivatives of compounds of formula (I), wherein R is -NR'R'' and R" is -NR-N=CRR comprises the step of reacting a com pound of formula (I), wherein R is -NR'R'' and R" is -NR-NH2, with a compound of formula (V). Instead of a compound of formula (V), Synthetic equivalents thereof Such as acetals, ketals, imines can also be used. Such reactions are described for example in: Duni?, M., Korun cev, D.; Kovacevic, K., Polak, L. In Methoden der Orga nischen Chemie (Houben-Weyl), Vol. E14b, Teil 1, Georg Thieme-Verlag, Stuttgart, New York, 1990, pp. 461-506, and literature cited herein. These furazanopyrazines of formula (I) can be separated by precipitation from the reaction mixture, or by chromatography, for example by HPLC

Jun. 30, 2005

chromatography. The Synthesis includes that the terminal amino group of compounds of formula (I), wherein R is -NR'R'' and R" is -NR-NH), or salts thereof, can be protected by one or two of the usual protecting groups like tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz, Z), 2,2,2-trichloro-ethoxycarbonyl (Troc), carbamates, cyclic imides and other groups well known to those skilled in the art. Further protecting groups are also described in Greene, T. W.; Wuts, P. G. M. “Protective Groups in Organic Synthesis”, 3' edition, John Wiley & Sons, New York, 1999, and in Kocienski, P. J., “Protecting Groups", 2" edition, Thieme Verlag, Stuttgart, 2000.

R1

N N N-R2 O / s n

O \ -2 2 + R Rb -> N N NR-NH

Formula (V) Formula (I)

R = R = H R1

N N N-R2 M s n O

N2 1 N NR-N

yo Rb Ra

Formula (I)

R = NRR2, R" = NRNR'R''. R== CRR: R absent

0080 Compounds of formula (I) can also be prepared by reacting 5,6-dichloro-1,2.5oxadiazolo 3,4-bipyrazine with a compound of formula (III) and Subsequently with other nucleophiles Such as alcohols, thiols and the like, or Vice Versa. Examples are described in Starchenkov, I. B., Andri anov, V. G. Chem. Heterocycl. Compa. 1997, 33, 1219 1233, Khim. Geterotsikl. Soedin. 1997, 1402-1416.

0081. The starting material, 5,6-dichloro-1,2.5oxadia Zolo3,4-bipyrazine can be prepared from 1,2,5oxadiazolo 3,4-bpyrazine-5,6-diol, for example by applying a mixture of phosphorus pentachloride and phosphorus oxychloride. This Step is for example described in Fernández, E., García Ochoa, S.; Huss, S.; Mallo, A.; Bueno, J. M.; Micheli, F., Paio, A.; Piga, E.; Zarantonello, P. Tetrahedron Lett. 2002, 43, 4741-4745, or in Starchenkov, I. B.; Andrianov, V. G.; Chem. Heterocycl. Compa. 1997, 33, 1219-1233, Khim. Geterotsikl. Soedin. 1997, 1402-1416.

N N OH / NS n

O + PCls + POCl3

Y2N4 N OH

US 2005/0143382 A1

-continued N N C

M s n

R le 2 N N C

0082 Instead the mixture of phosphorus pentachloride and phosphorus Oxychloride thionylchloride can be used. 0.083 1,2.5oxadiazolo 3,4-bipyrazine-5,6-diol is com mercially available. Alternatively, this compound can be prepared according to Gasco, A., Ruá, G., Menziani, E., Nano, G. M.; Tappi, G. J. Heterocycl. Chem. 1969, 6, 769-770.

0084. One method for the synthesis of compounds of formula (V), wherein R is 5-arylfuryland R'=H comprises the Step of reacting the diazonium Salt of an arylamine with substituted or unsubstituted furfural. This step is for example described in Burch, H. A.; White, R. E.; Wright, G. C.; Goldenberg, M. M. J. Pharm. Sci. 1980, 69, 107-110, in Pong, S. F.; Pelosi, S. S.; Wessels, F. L.; Yu, C.-N.; Burns, R. H.; White, R. E.; Anthony, Jr., D. R.; Ellis, K.O.; Wright, G. C.; White, Jr., R. L. Arzneim.-Forsch./Drug Res. 1983, 33(II), 1411–1416, and in Belagali, S. L.; Kumar, K. H.; Boj a, P.; Himaja, M. Ind. J. Chem. 1998, 37b, 370-375. 0085 Another method for the synthesis of compounds of formula (V), wherein R is 5-arylfuryland R'=H represents the croSS coupling reaction of boronic acid derivatives with substituted or unsubstituted 5-halogenofurfurals. This reac tion is described for example in Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2001, 42,5659-5662. Another method for the synthesis of compounds of formula (V), wherein R is 5-arylfuryl and R=H represents the cross coupling reaction of an aryl halogenide with a 5-formylfu ran-2-boronic acid derivative. This reaction is for example described in McClure, M. S.; Roschangar, F.; Hodson, S.J.; Millar, A.; Osterhout, M. H. Synthesis 2001, 1681-1685. 0.086 Another method for the synthesis of compounds of formula (V), wherein R is 5-arylfuryland R=H represents the palladium-catalyzed reaction of an aryl halogenide with furfural. This reaction is for example described in McClure, M. S.; Glover, B., McSorley, E., Millar, A., Osterhout, M. H., and Roschangar, F. Org. Lett. 2001, 3, 1677-1680. 0087. Other aspects of the present invention relate to furazanopyrazine derivatives of the general formula (I) as new pharmaceutically active agents, especially for the preparation of a pharmaceutical composition for the treat ment of diseases which are cured or relieved by the inhibi tion of one or Several kinases and/or phosphatases. The compounds of the general formula (I) were Surprisingly identified as potent inhibitors. 0088 Another method is directed to the prophylaxis and/or treatment of infectious diseases, including opportu nistic 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 (I) or compounds of the general formula (Ia) and/or pharmaceu tically acceptable Salts thereof, effective to prevent and/or treat Said infectious disease and/or opportunistic infection. 0089. The infectious disease can be selected from the group comprising AIDS, Alveolar Hydatid Disease (AHD,

11 Jun. 30, 2005

Echinococcosis), Amebiasis (Entamoeba histolytica Infec tion), AngioStrongylus Infection, Anisakiasis, Anthrax, Babesiosis (Babesia Infection), Balantidium Infection (Bal antidiasis), Baylisa Scaris Infection (Raccoon Roundworm), Bilharzia (Schistosomiasis), Blastocystis hominis 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, CJD (Creutzfeldt-Jakob Disease), Clonorchiasis (Clonorchis Infection), CLM (Cutaneous Larva Migrans, Hookworm Infection), Coccidioidomycosis, Conjunctivitis, Coxsackievirus A16 (Hand, Foot and Mouth Disease), Cryp tococcosis, Cryptosporidium Infection (Cryptosporidiosis), Culex mosquito (Vector of West Nile Virus), Cutaneous Larva Migrans (CLM), Cyclosporiasis (Cyclospora Infec tion), Cysticercosis (Neurocysticercosis), Cytomegalovirus Infection (CMV), Dengue/Dengue Fever, Dipylidium Infec tion (Dog and Cat Flea Tapeworm), Ebola Virus Hemor rhagic Fever, Echinococcosis (Alveolar Hydatid Disease), Encephalitis, Entomoeba coli Infection, Entomoeba dispar Infection, Entamoeba hartmanni Infection, Entamoeba his tolytica Infection (Amebiasis), Entamoeba polecki Infec tion, Enterobiasis (Pinworm Infection), Enterovirus Infec tion (Non-Polio), Epstein-Barr Virus Infection, Escherichia coli Infection, Foodborne Infection, Foot and mouth Dis ease, Fungal Dermatitis, Gastroenteritis, Group A Strepto coccal Disease, Group B Streptococcal Disease, 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 Ehrlichio sis, Human Parainfluenza Virus Infection, Influenza, Isos poriasis (ISOspora Infection), Lassa Fever, Leishmaniasis, Kala-azar (Kala-azar, Leishmania Infection), Leprosy, Lice (Body lice, Head lice, Pubic lice), Lyme Disease, Malaria, Marburg Hemorrhagic Fever, Measles, Meningitis, Mos quito-borne Diseases, Mycobacterium avium Complex (MAC) Infection, Naegleria Infection, Nosocomial Infec tions, Nonpathogenic Intestinal Amebae Infection, Onchocerciasis (River Blindness), Opisthorciasis (Opisthor cis Infection), Parvovirus Infection, Plague, PCP (Pneu mocystis carinii Pneumonia), Polio, Q Fever, Rabies, Res piratory Syncytial Virus (RSV) Infection, Rheumatic Fever, Rift Valley Fever, River Blindness (Onchocerciasis), Rotavi rus Infection, Roundworms Infection, Salmonellosis, Sal monella Enteritidis, Scabies, Shigellosis, Shingles, Sleeping Sickness, Smallpox, Streptococcal Infection, Tapeworm Infection (Taenia Infection), Tetanus, Toxic Shock Syn drome, 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. 0090. Furthermore, the present invention refers to a method for preventing and/or treating diseases like cell proliferation disorders, cardiovascular disorders, immuno logical diseases, inflammatory diseases, neuroimmunologi cal diseases, autoimmune diseases preferably in mammal, most preferably in human. Said method comprises admin istering to the mammal an amount of at least one furazan opyrazine derivative of the general formula (I) and/or phar

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maceutically acceptable Salts thereof, effective to prevent and/or treat cell proliferation disorders, cardiovascular dis orders, immunological diseases, inflammatory diseases, neuroimmunological diseases, and/or autoimmune diseases.

0.091 The compounds of the present invention are also useful for the treatment of diseases which are caused by malignant cell proliferation, Such as all forms of hemato logical and Solid cancer. Therefore the compounds accord ing to the invention and pharmaceutical compositions pre pared therewith are generally useful for regulating cell activation, cell proliferation, cell Survival, cell differentia tion, cell cycle, cell maturation and cell death or to induce Systemic changes in metabolism Such as changes in Sugar, lipid or protein metabolism.

0092. They can also be used to support cell generation poiesis, including blood cell growth and generation (prohe matopoietic effect) after depletion or destruction of cells, as caused by, for example, toxic agents, radiation, immuno therapy, 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.

0093. The compounds according to the invention and pharmaceutical compositions prepared therewith are gener ally useful for the treatment of cell proliferation disorders, for the treatment or prophylaxis of cardiovascular disorders, immunological diseases and conditions (as for instance inflammatory diseases, neuroimmunological diseases, autoimmune diseases or other). 0094. These diseases and conditions include but are not limited to cancer as hematological (e.g. leukemia, lym phoma, myeloma) or Solid tumors (for example breast, prostate, liver, bladder, lung, esophageal, Stomach, colorec tal, genitourinary, gastrointestinal, Skin, pancreatic,-brain, uterine, colon, head and neck, ovarian, melanoma, astrocy toma, Small cell lung cancer, glioma, basal and Squameous cell carcinoma, Sarcomas as Kaposi's Sarcoma and Osteosa rcoma), tumor angiogenesis or metastasis, treatment of disorders involving T-cells Such as acute or chronic graft rejection or other host verSuS graft or graft verSuS host reactions, aplastic anaemia and DiGeorge Syndrome, Graves disease, lupus erythematosus, Sjogren's Syndrome, fibrosis, uveitis, rhinitis, asthma or athropathy, in particular, arthrosis, all forms of rheumatism or arthritis as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthri tis, multiple Sclerosis, pancreatitis, glomerulonephritis, ulcerative colitis, Sickle cell anaemia or other forms of anaemia progressive retinal atrophy, inflammatory bowel disease, Morbus Crohn, chronic pulmonary inflammatory disease as well as other chronic or acute inflammations or inflammatory diseases, chronic diarrhea, insulin dependent diabetes mellitus and non-insulin dependent diabetes melli tus as well as diabetic conditions as glaucoma, retinopathy or microangiopathy and other metabolic diseases, ocular conditions as ocular or macula edema, ocular neovascular disease, Scleritis, radial keratomy, uveitis, vitritis, myopia, chronical retinal detachment, post-laser treatment compli cations, conjunctivitis, Stargardt's disease, Eales disease or retinopathy, dermatological disorderS Such as psoriasis and acute immunological events and disorderS Such as Sepsis, Septic shock, endotoxic shock, Gram-negative Sepsis, toxic

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Shock Sydrome, acute respiratory distress Syndrome, Stroke, reperfusion injury, CNS injury, Serious forms of allergy, Alzheimer's disease or pyresis, atherosclerosis, ischemia/ reperfusion injury as for instance Stroke or infarct, cardio vascular diseases, vascular Smooth muscle proliferation con ditions as postSurgical vascular Stenosis, restenosis, angina pectoris chronic pulmonary inflammatory disease, Silicosis, pulmonary Sarcosis, fibrosis, Heppel-Lindau disease, gan grene, necrosis, benign prostate hyperplasia, bone resorption disease as Osteoporosis as well as neurodegenerative disor derS.

0095 The inventive furazanopyrazine compounds of the general formula (I) and/or pharmaceutically acceptable Salts thereof are administered in a dosage corresponding to an effective concentration in the range of 0.001-50 uM, pref erably in the range of 0.001-10 uM, more preferably in the range of 0.001-1 uM, and most preferably in the range of 0.001-0.1 uM. 0096. In a further aspect the present invention relates to pharmaceutical compositions comprising at least one com pound of the general formula (I) as an active ingredient together with one or more pharmaceutically acceptable carrier(s), excipient(s) and/or diluent(s). 0097. The furazanopyrazine compounds of the present invention can form pharmaceutically acceptable Salts with organic and inorganic acids. Examples of Suitable acids for Such acid addition Salt formation are hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, acetic acid, citric acid, Oxalic acid, malonic acid, Salicylic acid, p-aminoSalicylic acid, malic acid, fumaric acid, Succinic acid, ascorbic acid, maleic acid, Sulfonic acid and other mineral or carboxylic acids well known to those skilled in the art. The Salts are prepared by contacting the free base form with a Sufficient amount of the desired acid to produce a Salt in the conventional manner.

0098. It is also possible to obtain acid addition salts with amino acids like methionine, tryptophane, lysine or arginine, especially with furazanopyrazine compounds of the general formula (I) containing a carboxylic acid residue. 0099. Depending upon the substituents on the inventive furazanopyrazine compounds, one can form Salts with bases too. Thus, for example, if there are carboxylic acid Substitu ents in the molecule, Salts may be formed with inorganic as well as organic bases such as, for example, NaOH, KOH, NHOH, tetraalkylammonium hydroxide, guanidinium, and the like.

0100 The compounds of formula (I) can also be used in the form of a precursor (prodrug) or a Suitably modified form, that releases the active compound in Vivo. Such precursors can be obtained for example by masking an amine with an alkyl group or as an imine, or a free acid group or hydroxy group with an ester group, which is then in turn transformed into the free amino group or acid group or hydroxy function in vivo F. W. Sum et al. Bioorg. & Med. Chem. Lett. 9 (1999), 1921-1926; Ada Rephaeli et al. Drug Development Research 50 (2000) 379-391; H. Ishikawa, Current Med. Chem. 6 (1999), 575-597). 0101 The compounds of the general formula (I) or compounds can also be administered in form of their phar maceutically active Salts optionally using Substantially non toxic pharmaceutically acceptable carriers, excipients or

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diluents. The medications of the present invention are pre pared in a conventional Solid or liquid carrier or diluents and a conventional pharmaceutically-made adjuvant at Suitable dosage level in a known way. The preferred preparations are in administratable form which is Suitable for oral applica tion. These administratable forms, for example, include pills, tablets, film tablets, coated tablets, capsules, powders and deposits. 0102). Furthermore, the subject of the present invention also includes pharmaceutical preparations for parenteral, including dermal, intradermal, intragastrical, intracutane ous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, Subcutaneous, Sublingual, topical or transdermal applica tion, which in addition to typical vehicles and diluents contain a furazanopyrazine compound of the general for mula (I) and/or a pharmaceutically acceptable Salt thereof as active ingredient. Within the disclosed methods the phar maceutical compositions of the present invention, contain ing furazanopyrazine derivatives of the general formula (I) as active ingredients, will typically be administered in admixture with Suitable carrier materials Selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, Syrups, Suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral nontoxic pharmaceutically acceptable inert carrier, Such as lactose, Starch, Sucrose, cellulose, magnesium Stear ate, dicalcium phosphate, calcium Sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. 0103 Moreover, when desired or needed, suitable bind ers, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition. 0104 Suitable binders include starch, gelatin, natural Sugars, corn Sweeteners, natural and Synthetic gums Such as acacia, Sodium alginate, carboxymethylcellulose, polyethyl ene glycol and waxes. Among the lubricants, there may be mentioned for use in these dosage forms, boric acid, Sodium benzoate, Sodium acetate, Sodium chloride, and the like. Disintegrants include Starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Some of the terms noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below. 0105 Additionally, the compositions of the present invention may be formulated in Sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. antihistaminic activity and the like. Suitable dosage forms for Sustained release include layered tablets containing layers of varying disintegration rates or con trolled release polymeric matrices impregnated with the active components and Shaped in tablet form or capsules containing Such impregnated or encapsulated porous poly meric matrices.

0106 Liquid form preparations include solutions, sus pensions and emulsions. AS an example may be mentioned

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water or water-propylene glycol Solutions for parenteral injections or addition of Sweeteners and opacifiers for oral Solutions, Suspensions and emulsions. Liquid form prepara tions may also include Solutions for intranasal administra tion.

0107 Aerosol preparations suitable for inhalation may include Solutions and Solids in powder form, which may be in combination with a pharmaceutically acceptable carrier Such as inert compressed gas, e.g. nitrogen. 0.108 For preparing suppositories, a low melting wax Such as a mixture of fatty acid glycerides Such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by Stirring or Similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidifies. 0109) Also included are solid form preparations which are intended to be converted, Shortly before use, to liquid form preparations for either oral or parenteral administra tion. Such liquid forms include Solutions, Suspensions and emulsions.

0110. The inventive furazanopyrazine compounds of the present invention may also be deliverable transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. 0111. The term capsule refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or Starch for holding or containing com positions comprising the active ingredients. Hard shell cap Sules are typically made of blends of relatively high gel Strength bone and pork skin gelatins. The capsule itself may contain Small amounts of dyes, opaquing agents, plasticizers and preservatives. 0112 Tablet means compressed or molded solid dosage form containing the active ingredients with Suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction well known to a person skilled in the art. 0113 Oral gels refers to the active ingredients dispersed or Solubilized in a hydrophilic Semi-Solid matrix. 0114 Powders for constitution refer to powder blends containing the active ingredients and Suitable diluents which can be Suspended in water or juices.

0115 Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include SugarS Such as lactose, Sucrose, mannitol and Sorbitol, Starches derived from wheat, corn rice and potato, and celluloses Such as microcrystalline cellulose. The amount of diluents in the composition can range from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight. 0116. The term disintegrants refers to materials added to the composition to help it break apart (disintegrate). Suitable disintegrants include starches, “cold water soluble” modified Starches Such as Sodium carboxymethyl Starch, natural and Synthetic gums Such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives Such as methylcellulose and

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Sodium carboxymethylcellulose, microcrystalline celluloses and croSS-linked microcrystalline celluloses Such as Sodium croScarmellose, alginates Such as alginic acid and Sodium alginate, clayS. Such as bentonites, and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 5 to about 10% by weight.

0117 Binders characterize substances that bind or “glue” powders together and make them cohesive by forming granules, thus Serving as the “adhesive' in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include Sugars Such as Sucrose, Starches derived from wheat, corn rice and potato, natural gums Such as acacia, gelatin and tragacanth; derivatives of Seaweed Such as alginic acid, Sodium alginate and ammonium calcium alginate, cellulosic materials Such as methylcellulose and Sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinyl-pyrrollidone; and inorganics Such as magnesium aluminum Silicate. The amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more pref erably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight. 0118 Lubricant refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic Stear ates Such as magnesium Stearate, calcium Stearate or potas sium Stearate, Stearic acid; high melting point waxes, and water Soluble lubricants Such as Sodium chloride, Sodium benzoate, Sodium acetate, Sodium oleate, polyethylene gly cols and D.L-leucine. Lubricants are usually added at the very last Step before compression, Since they must be present on the Surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.

0119 Glidents are materials that prevent caking and improve the flow characteristics of granulations, So that flow is Smooth and uniform. Suitable glidents include Silicon dioxide and talc. The amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight. Coloring agents are excipients that provide colora tion to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a Suitable adsorbent Such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.

EXAMPLES

0120) The following compounds (examples 1 to 61) were commercially available.

Example 1

(6-N'-5-(4-Chloro-3-nitro-phenyl)-furan-2-ylmeth ylenel-hydrazino-1,2.5loxadiazolo 3,4-bipyrazin

5-yl)-(2,3-dimethyl-phenyl)-amine

Jun. 30, 2005

Example 2

2-Chloro-5-(5-6-(2,3-dimethyl-phenylamino)-11.2, 5oxadiazolo 3,4-bipyrazin-5-yl)-hydrazonom

ethyl-furan-2-yl)-benzoic acid Example 3

5-6-N'-(2-Benzyloxy-3,5-dibromo-benzylidene)- hydrazino-1,2.5oxadiazolo 3,4-bpyrazin-5- ylamino-1,3-dihydro-benzoimidazol-2-one

Example 4

2-Chloro-5-(5-6-(2-fluoro-phenylamino)-1,2.5 oxadiazolo 3,4-bipyrazin-5-yl)-hydrazonomethyl

furan-2-yl)-benzoic acid

Example 5

(4-Iodo-phenyl)-6-N'-(5-methyl-furan-2-ylmethyl ene)-hydrazino-1,2.5oxadiazolo 3,4-bipyrazin-5-

yl)-amine Example 6

3-(5-6-(2,3-Dimethyl-phenylamino)-1,2,5oxadia Zolo 3,4-bipyrazin-5-yl)-hydrazonomethyl-furan-2-

yl)-benzoic acid Example 7

4-6-(2-Fluoro-phenylamino)-1,2.5oxadiazolo 3, 4-bipyrazin-5-yl)-hydrazonomethyl)-2-methoxy-6-

nitro-phenol

Example 8

{6-N'-(4-Chloro-3-nitro-benzylidene)-hydrazino 1,2,5oxadiazolo 3,4-bipyrazin-5-yl)-(2-fluoro

phenyl)-amine

Example 9

(2-Methoxy-phenyl)-(6-N'-1-(4-methyl-furazan-3- yl)-ethylidenel-hydrazino-1,2.5oxadiazolo 3,4-b

pyrazin-5-yl)-amine

Example 10

2-6-(2,3-Dimethyl-phenylamino)-1,2.5oxadia Zolo 3,4-bipyrazin-5-yl)-hydrazonomethyl-4-nitro

phenol

Example 11

{6-N'-(4-Nitro-benzylidene)-hydrazino-1,2.5oxa diazolo 3,4-bipyrazin-5-yl)-m-tolyl-amine

Example 12

(4-Chloro-phenyl)-(6-N'-5-(3-nitro-phenyl)-furan 2-ylmethylenel-hydrazino-1,2.5oxadiazolo 3,4-b

pyrazin-5-yl)-amine

Example 13

2-Chloro-5-(5-6-(2-fluoro-phenylamino)-1,2.5 oxadiazolo 3,4-bipyrazin-5-yl)-hydrazonomethyl

furan-2-yl)-benzoic Acid

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0121 The following section describes the synthesis of compounds of formula (I). 0122) NMR spectra: Bruker Avance 300 MHz. The spec tra were recorded in DMSO-d at 300 MHz ("H NMR) and 75 MHz (CNMR), respectively, using the residual solvent peak as an internal Standard (Ö=2.49, 6 =39.70). 0123. Analytical LC/ESI-MS: 2x Waters 600 Multisol vent Delivery System. 50 ul sample loop. Column, Chro molith Speed ROD RP18e (Merck, Darmstadt), 50x4.6 mm, with 2 um prefilter (Merck). Eluent A, HO+0.1% HCOH: eluent B, MeCN. Gradient, 5% B to 100% B within 5 min; flow, 3 mil/min. WaterS LCZ Single quadrupol mass Spec trometer with electrospray source. MS method, MS8minPM-80-800-20V; positive/negative ion mode scan ning, m/z 80-800 in 1s; 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 W. Absorbance Detector, set to 254 nm.

0124 Preparative HPLC-MS: Waters 600 Multisolvent Delivery System with peparative pump heads. 2000 ul or 5000 ul sample loop. Column, Waters X-Terra RP18, 7 um, 19x150 mm with X-Terra RP18 guard cartridge 7tum, 19x10 mm; used at flow rate 20 ml/min or YMC ODS-A, 120 A, 40x150 mm with X-Terra RP18 guard cartridge 7 um, 19x10 mm; used at flow rate 50 ml/min. Make-up solvent: MeCN-HO-HCOH80:20:0.05 (v:v:v). Eluent A, H2O+ 0.1% HCOH; eluent B, MeCN. Different linear gradients from 5-100% Eluent B, adapted to sample. Injection vol ume: 500 ul-2000 ul depending on sample. Waters ZQ single quadrupol mass spectrometer with electrospray Source. Posi tive or negative ion mode Scanning m/Z 80-800 in 1 S; capillary, 3.5 kV 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-triggered fraction collection. Waters 996 photo diode array detector.

5,6-Dichloro-1,2.5oxadiazolo 3,4-bpyrazine

0.125. In a flask with reflux condenser and stirring bar, a mixture of phosphorus oxychloride (5.6 mL, 64.1 mmol), phosphorus pentachloride (12.5g, 59.8 mmol), and 12.5 oxadiazolo 3,4-bipyrazine-5,6-diol (4.39 g, 28.5 mmol) was heated to 95 C. for 2 h (caution: HCl development). After cooling, the condenser was replaced with a distillation bridge and POCl was distilled off with heating. The remain ing residue was cooled in an ice bath and treated with cold water (caution: Violent reaction of residual phosphorus chlo rides may occur). The precipitate was filtered off and washed with two portions of cold water. The solid was largely dissolved by addition of acetone (15 mL) and then precipi tated by addition of water (25 mL). The precipitate was filtered off and washed with cold water (2x). After drying in vacuo, a beige Solid (2.42 g, 12.7 mmol, 44%) was obtained which was used without further purification. 0126 General synthesis of compounds of formula (1) wherein R' is -NR'R'' and R" is -NH-NHBoc (Boc= tert-butyloxycarbonyl).

0127. In a flask with stirring bar, 5,6-dichloro-1,2.5 oxadiazolo 3,4-bipyrazine (0.420 g, 2.20 mmol) was dis solved in THF (2 mL). After cooling to 0°C., a solution of the appropriate amine (formula (IV); 2.00 mmol) in THF (2

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mL) was added dropwise. After stirring for 10 min at 0°C., triethylamine (0.28 mL, 2.00 mmol) was added. After stir ring for 1 h at 0° C., a solution of tert-butyl carbazate (formula (III); 0.291 g, 2.2 mmol) in THF (2 mL) was added followed by triethylamine (0.31 mL, 2.2 mmol). The order of adding the amine and tert-butyl carbazate may also be reversed. The mixture was stirred overnight at r.t. After removal of the Solvent in vacuo, the residue was agitated with water (5 mL). The solid was filtered off and washed with water (2x). The crude products weres purified by preparative HPLC or by recrystallisation. Yields covered a range between 20 and 80%. 0128 N'-(6-Amino-1,2.5oxadiazolo 3,4-bipyrazin-5- yl)-hydrazinecarboxylic acid tert-butyl ester was prepared from 5,6-dichloro-1,2.5oxadiazolo 3,4-bpyrazine, tert butyl carbazate, and ammonia (large excess, 7 M Solution in methanol). 0129 HNMR: 8=1.46 (s, 9H), 7.04 (s, br., 1H), 8.07 (s, br., 1H), 9.62 (s, br., 1H), 11.19 (s, br., 1H); LC/(+)-ESI-MS: m/z=268 M+H, 253 (268-CH, 212 268-isobutene", 168 (212-CO"; LC/(-)-ESI-MS: m/z=266 M-H, 192 266-t-BuOH]. 0130 N'-(6-Methoxy-1,2.5loxadiazolo 3,4-bipyrazin-5- yl)-hydrazinecarboxylic acid tert-butyl ester. This com pound was obtained as a Second product in the course of the preparation of N'-(6-amino-1,2.5oxadiazolo 3,4-b pyrazin-5-yl)-hydrazinecarboxylic acid tert-butyl ester.

0131 HNMR: 8=1.43 (s, 9H), 4.12 (s, 3H), 9.34 (s, br., 1H), 10.42 (s, br., 1H). 0132) LC/(+)-ESI-MS: m/z=283 M+H, 268 (283 CH", 227 (283-isobutene", 183227-CO". 0133) LC/(-)-ESI-MS: m/z=281 M-H, 207 281-t- BuOH]. 0134) N'-(6-Phenylamino-1,2.5oxadiazolo 3,4-b pyrazin-5-yl)-hydrazinecarboxylic acid tert-butyl ester was prepared from 5,6-dichloro-1,2.5oxadiazolo 3,4-bipyra Zine, aniline, and tert-butyl carbazate.

0135 HNMR: 8=1.49 (s, 9H), 7.17 (t, 1H, J-7.7 Hz), 7.41 (t, 2H, J=7.7 Hz), 7.80 (d. 2H, J=7.7 Hz), 9.32 (s, br., 1H), 9.79 (s, br., 1H), 11.40 (s, br., 1H); LC/(+)-ESI-MS: m/z=344 M+H", 288 .344 isobutene", 244 288-CO"; LC/(-)-ESI-MS: m/z=342 M-H, 268 (342-t-BuOH]. 0136 N'-(6-Benzylamino-1,2.5oxadiazolo 3,4-b pyrazin-5-yl)-hydrazinecarboxylic acid tert-butyl ester was prepared from 5,6-dichloro-1,2.5oxadiazolo 3,4-bipyra Zine, benzylamine, and tert-butyl carbazate.

0137 H NMR: 8=1.46 (s, 9H), 4.64 (d. 2H, J=6.4 Hz), 7.20-7.40 (m, 5H), 8.27 (s, br., 1H), 9.70 (s, br., 1H), 11.29 (s, br., 1H); LC/(+)-ESI-MS: m/z=358 M+H, 302 358 isobutene, 258 302-CO; LC/(-)-ESI-MS: m/z=356 M-H, 282 (M-t-BuOH]. 0138 N'-6-(4-Fluoro-phenylamino)-1,2.5oxadiazolo 3,4-bpyrazin-5-yl)-hydrazinecarboxylic acid tert-butyl ester was prepared from 5,6-dichloro-1,2.5oxadiazolo.3, 4-bipyrazine, 4-fluoroaniline, and tert-butyl carbazate. 0139 H NMR: 8=1.49 (s, 9H), 7.24 (dd, 2H, Js Jrs9Hz), 7.81 (dd, 2H, J-9.2 Hz, Jr.-5.0 Hz), 9.40 (s, br., 1H), 9.78 (s, br., 1H), 11.40 (s, br., 1H);

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Example 197 0440 (3,4-Dichloro-phenyl)-6-(N-furan-2-ylmethyl ene-hydrazino)-1,2,5-oxadiazolo 3,4-bipyrazin-5-yl)- amine was prepared from (3,4-dichloro-phenyl)-(6-hy drazino-1,2.5oxadiazolo 3,4-bpyrazin-5-yl)-amine hydrochloride and furan-2-carbaldehyde.

0441) H NMR: 8=6.75 (dd, 1H, J-34 Hz, J=1.7 Hz), 7.31 (d. 1H, J=3.4 Hz), 7.68 (d. 1H, J=8.9 Hz), 7.98-8.00 (m, 1H), 8.00 (dd, 1H, J=8.9 Hz, J=2.5 Hz), 8.34 (d. 1H, J=2.5 Hz), 8.52 (s, 1H), 10.01 (s, br., 1H), 12.17 (s, br., 1H); LC/(+)-ESI-MS: m/z-390 M+H".

Example 198 0442 3-(5-6-(3,4-Dichloro-phenylamino)-1,2.5oxa diazolo 3,4-bipyrazin-5-yl)-hydrazonomethyl-furan-2-yl)- benzamide was prepared from (3,4-dichloro-phenyl)-(6-hy drazino-1,2.5oxadiazolo 3,4-bpyrazin-5-yl)-amine hydrochloride and 3-(5-formyl-furan-2-yl)-benzamide. 0443) "H NMR: 8–7.30 (d. 1H, J=3.6 Hz), 7.43 (d. 1H, J=3.6 Hz), 7.48 (s, br., 1H), 7.59 (dd, 1H, J=J=7.8 Hz), 7.68 (d. 1H, J=8.9 Hz), 7.87 (“d”, 1H, J=7.9 Hz), 8.01 (dd, 1H, J=8.9 Hz, J-2.5 Hz),8.04 (“d”, 1H, J=7.9 Hz), 8.33-8.37 (m, 2H), 8.56 (s, 1H), 10.04 (s, br., 1H), 12.16 (s, br., 1H); LC/(+)-ESI-MS: m/z=509 M+H".

Example 199 0444) 4-(5-6-(3,4-Dichloro-phenylamino)-1,2,5oxa diazolo 3,4-bipyrazin-5-yl)-hydrazonomethyl-furan-2- yl)-benzoic acid was prepared from (3,4-dichloro-phenyl)- (6-hydrazino-1,2.5oxadiazolo 3,4-bpyrazin-5-yl)-amine hydrochloride and 4-(5-formyl-furan-2-yl)-benzoic acid. 0445 H NMR: 8–7.41 (d. 1H, J=3.6 Hz), 7.44 (d. 1H, J=3.6 Hz), 7.69 (d. 1H, J=8.9 Hz), 7.98-8.07 (m, 5H), 8.36 (d. 1H, J=2.5 Hz), 8.56 (s, 1H), 10.04 (s, br., 1H), 12.17 (s, br., 1H), 13.03 (s, br., 1H).

Example 200 0446 (6-N-5-(4-Chloro-phenyl)-furan-2-ylmethyl enel-hydrazino-1,2,5-oxadiazolo 3,4-bipyrazin-5-yl)-(3, 4-dichloro-phenyl)-amine was prepared from (3,4-dichloro phenyl)-(6-hydrazino-1,2.5oxadiazolo 3,4-bipyrazin-5- yl)-amine hydrochloride and 5-(4-chloro-phenyl)-furan-2- carbaldehyde.

0447 "H NMR: 8=7.29 (d. 1H, J=3.6 Hz), 7.40 (d. 1H, J=3.6 Hz), 7.57 (d. 1H, J=8.7 Hz), 7.69 (d. 1H, J=8.9 Hz), 7.93 (d. 1H, J=8.7 Hz), 8.01 (dd, 1H, J=8.9 Hz, J=2.5 Hz), 8.35 (d. 1H, J=2.5 Hz), 8.54 (s, 1H), 10.03 (s, br., 1H), 12.17 (s, br., 1H).

Example 201 0448. 3-6-(3,4-Dichloro-phenylamino)-1,2.5oxadia Zolo 3,4-bipyrazin-5-yl)-hydrazono-1,3-dihydro-indol-2- one was prepared from (3,4-dichloro-phenyl)-(6-hydrazino 1,2,5oxadiazolo 3,4-bipyrazin-5-yl)-amine hydrochloride and isatin.

0449) H NMR: 8=6.90 (d. 1H, J=7.6 Hz), 7.01 (td, 1H, J=7.6 Hz, J=0.8 Hz), 7.39 (td, 1H, J=7.6 Hz, J=1.2 Hz), 7.69 (d. 1H, J=8.9 Hz), 7.96 (d, br., 1H, J=7.6 Hz), 8.01 (dd, 1H, J=8.9 Hz, J=2.5 Hz), 8.35 (d. 1H, J=2.5 Hz), 10.21 (s, br., 1H), 10.81 (s, br., 1H), 12.22 (s, br., 1H).

34 Jun. 30, 2005

Example 202 0450 (3,4-Dichloro-phenyl)-6-N'-(1H-indol-3-ylmeth ylene)-hydrazino-1,2.5loxadiazolo 3,4-bipyrazin-5-yl)- amine was prepared from (3,4-dichloro-phenyl)-(6-hy drazino-1,2.5oxadiazolo 3,4-bipyrazin-5-yl)-amine hydrochloride and 1H-indole-3-carbaldehyde.

0451) "H NMR: 8=7.21 (dd, 1H, J=7.1 Hz, J=1.5 Hz), 7.26 (dd, 1H, J=7.1 Hz, J=1.5 Hz), 7.48 (“d”, 1H, J=7.1 Hz), 7.68 (d. 1H, J=8.9 Hz), 8.02 (dd, 1H, J=8.9 Hz, J=2.5 Hz), 8.08 (d. 1H, J=2.9 Hz), 8.38 (d. 1H, J=2.5 Hz), 8.62 (“d”, 1H, J-7 Hz), 8.91 (s, 1H), 10.00 (s, br., 1H), 11.75 (s, br., 1H), 11.90 (s, br., 1H); LC/(+)-ESI-MS: m/z=439 M+H". 0452. Materials and Methods 0453 Protein Kinase Assay 0454. The effect of the farazanopyrazine derivatives was tested on recombinant, human protein kinases. All protein kinases were expressed in Sf9 insect cells as human recom binant GST-fusion proteins or as His-tagged proteins by means of the baculovirus expression System. Protein kinases were purified by affinity chromatography using either GSH agarose or Ni-NTH-agarose. The purity and identity of each was checked by SDS-PAGE/silver staining and by western blot analysis with Specific antibodies. 0455) A proprietary protein kinase assay ( PanOinase(R) Activity Assay) was used for measuring the kinase activity. All kinase assays were performed in 96-well FlashPlatesTM in a 50 til reaction volume. The assay for all enzymes contained 60 mM HEPES-NaOH, pH 7.5, 3 mM MgCl, 3 mM MnCl, 3 uM Na-Orthovanadate, 1.2 mM DTT, 50 ag/ml PEGoooo and 1 uMy-P-ATP (approx. 5x10 cpm per well). 0456. The reaction cocktails were incubated at 30° C. for 80 minutes. The reaction was stopped with 50 ul of 2% (v/v) HPO, plates were aspirated and washed two times with 200 ul of 0.9% (w/v) NaCl. Incorporation of 33P, was determined with a microplate Scintillation counter. All assays were performed with a BeckmanCoulter/Sagian robotic System. 0457. Results 0458) i) The following compounds are efficient inhibitors of Aurora B kinase showing ICso values <10 uM: Examples 6, 7, 13, 23,47, 52,53,58, 60, 81, 89, 95, 111,117, 126, 147, 154, 165, 173, 176, 181, 189, 194, 196, 199. 0459) ii) The following compounds are efficient inhibi tors of EGF-R showing ICs values <1 uM: Examples 2, 7, 13, 14, 15, 23, 52,53,55, 60, 135,139, 151, 152, 154, 155, 160, 161,169, 172, 175, 176, 178, 179, 180, 182, 185, 186, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 2O1.

0460) iii) The following compounds are efficient inhibi tors of IGF-1 R showing ICs values <1 uM: Examples 2, 14, 23, 29, 30, 35,36, 39, 52,53,55, 60, 95, 134, 135,139,143, 151,152, 154, 155, 172,173, 174, 175,176, 178,179, 180, 182, 186, 191, 192, 193, 194, 196, 197, 198, 199, 200, 201. 0461) iv) The following compounds are efficient inhibi tors of VEGF-R2 showing ICs values <2 uM: Examples 2, 6, 7, 13, 14, 15, 23, 35, 52, 53, 60, 134, 152, 154, 155, 165, 172, 174, 176, 178, 179, 180, 182, 186, 191, 193, 194, 196, 198, 199, 200, 201.

US 2005/0143382 A1 Jun. 30, 2005 35

0462 v) The following compounds are efficient inhibitors and is bonded to N via a single or double bond, and of SRC kinase showing ICs values <1 uM: Examples 2, 7, wherein 13, 14, 15, 23, 29, 30, 33,35, 36, 37, 39, 52,53,55, 60, 88, R" and Rare each independently hydrogen, C-C-alkyl, 90, 135,139,151,152, 154, 155, 167, 172,173, 174, 175, 176, 178,179, 180, 182, 186, 191, 193, 194, 195, 196, 197 C-C-alkenyl, C-C-alkinyl, C-C-cycloalkyl,

s u- Y-s -- . 1 s -- Yo Y's u-Y-a-s u-Y-ws --- us -- 1 - 3 -u- ~ is u- ~ as u-1 ws --- is -COOR7, -SOR", -CO-R, -SONHR,

198, 199, 200, 201. -SON(R), -OH, -SH, C-C-alkoxy, C-C- alkylthio, C-C-hydroxyalkyl, C-C-haloalkyloxy,

1. A compound of the general formula (I) C-C-aryl, heteroaryl, or R together with R' form a 5-, 6- or 7-membered unsaturated or Saturated hetero cyclic ring, which has optionally 1 to 3 substituents R,

N or R together with R form a 5-, 6- or 7-membered /S1 n O unsaturated or Saturated heterocyclic ring, which has \ 2 2 optionally 1 to 3 substituents R;

R" represents hydrogen, C-C-alkyl, C1-Co-alkenyl, C-C-alkinyl, C-Cs-cycloalkyl, -COOR",-SOR",

wherein: -SONHR, -SON(R), C-C-alkoxy, C-C- R" represents -NR'R' or -OR alkylthio, C-C-hydroxyalkyl, C-C-haloalkyloxy,

Cs-Cis-aryl, or heteroaryl or R' together with R form R" represents NR-NR'R'', -NR-OR,-NR'R'; a 5-, 6- or 7-membered unsaturated or Saturated het

erocyclic ring, which has optionally 1 to 3 Substituents R" represents hydrogen, C-C-alkyl, C-C-alkenyl, C-C-alkinyl, C-Cs-cycloalkyl, -COOR", -SOR", —CO-R, -SONHR, -SON(R), -OH, -SH, C-C-alkoxy, C-C-alkylthio, C-C-hydroxyalkyl, C-C-haloalkyloxy, C5-C1s-aryl, or heteroaryl, or R' together with R form a 5-, 6- or 7-membered unsat urated or Saturated heterocyclic ring which has option ally 1 to 3 substituents R;

R represents hydrogen, C1-Co-alkyl, C-C-alkenyl, C-C-alkinyl, C-C-cycloalkyl, -COOR7, -SOR"; -SONHR, -SO2N(R), C-C-alkoxy, C-C-alkylthio, C-C-hydroxyalkyl, C-C-haloalky loxy, C-C-aryl or heteroaryl;

R represents hydrogen, C1-Co-alkyl, C-C-alkenyl, C-C-alkinyl, C-C-cycloalkyl, -COOR7, -SOR", —CO-R, -SONHR, -SON(R), -OH, -SH, C-C-alkoxy, C-C-alkylthio, C-C-hydroxyalkyl, C-C-haloalkyloxy, or Cs-Cis-aryl heteroaryl, or R represents a double bond to the carbonylic carbon atom of a mono- or oligosaccaride and R" is absent, or R represents

which has optionally 1 to 3 substituents R and R' is absent, or R represents

R, or R' represents a bond in case R" and R' form a ring system, and R' is absent in case R is bonded to N via a double bond;

R represents hydrogen, C-C-alkyl, C-C-alkenyl, C-C-alkinyl, C-Cs-cycloalkyl, -COOR",-SOR", -SONHR, -SON(R), C-Calkoxy, C-C-alky lthio, C-C-hydroxyalkyl, C-C-haloalkyloxy, Cs-Cis-aryl, heteroaryl or R represents a bond in case RandR' or RandR' or RandR form a ring system;

R" represents hydrogen, C-C-alkyl, C-C-alkenyl, C-C-alkinyl, C-C-cycloalkyl, Cs-C-aryl or het eroaryl;

R represents independently of each other hydrogen, -COOR,-CONHR,-F, -Cl,-Br, -, -CO R, -SONR'R'', -NR'R'', -NR -NR, –O-CO-NR'R'', -NR -CO-NR, -NO, CN, OH, SH, NR'-CO-(C-C)-ha

loalkyl, -NR-SO-(C-C)-haloalkyl, C-C- alkyl, C-C-aminoalkyl, C-C-alkoxy, C-C-alky lthio, C-C-hydroxyalkylamino, C-C-hydroxyalkyl, amine, C-C-haloalkyloxy, Cs-C-aryl or heteroaryl;

R represents independently of each other hydrogen, -COOR,-CONHR,-F, -Cl,-Br, -, -CO R, -SONR'R'', -NR'R'', -NR -NR, -O-CO-NR'R'', -NR -CO-NR, NR CO-(C-C)-haloalkyl, -NO, -CN, -NR'- SO-(C I-C)-haloalkyl, C-C-alkyl, C-C-ami noalkyl, -OH, -SH, C-C-alkoxy, C-C-alkylthio, C-C-hydroxyalkylamino, C-C-hydroxyalkyl, amine, C-C-haloalkyloxy, Cs-C-aryl or heteroaryl;

R” represents hydrogen, C-C-hydroxyalkyl, C-C- alkyl, C-C-aminoalkyl, Cs-C-aryl or heteroaryl;

R” represents hydrogen, C1-Co-hydroxyalkyl, C-C- alkyl, C-C-aminoalkyl, Cs-C-aryl or heteroaryl;

an alkyl group denotes a C-C-alkyl, C-C-alkenyl, C-C-alkinyl, or C-C-cycloalkyl residue,

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;

US 2005/0143382 A1

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 hydroxyalkyl group denotes an HO-alkyl group, 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 chlorine, bromine, fluorine or iodine, a mono- or oligosaccharide, which is bonded through the

double bond of the carbonyl to the nitrogen atom, wherein one or more of the OH groups could be protected by an acetyl or benzyl group;

a C-C-aryl group represents -Ph, -CHPh, -CHPh, -CH=CH-Ph, -C=C-Ph, -CH-R, -m-CH R, -p-CH-R, -o-CH-CH-R, -m-CH CH-R, -p-CH-CH-R, wherein R is as defined above or 1-naphthyl, 2-naphthyl, 1-anthracyl, 2-anthracyl optionally substituted by one or more R, which is as defined above;

a heteroaryl group represents a 5- or 6-membered hetero cyclic group which contains at least one heteroatom selected from O, N, or S wherein this heterocyclic group can be fused to another ring,

and pharmaceutically acceptable Salts thereof for the use as a medicament.

2. The compounds of claim 1, wherein R' is NR'R''. 3. The compounds of claim 1, wherein R" is NR

NR'R''.

36 Jun. 30, 2005

4. The compounds of claim 1, wherein R" is NR'R'' and R" is NR-NR'R''.

5. The compounds of claim 1, wherein R' is NR'R'' and R" is NR-NR'R'' and R is optionally substituted phenyl and R is

6. A method for preventing and/or treating diseases which are cured or relieved by the inhibition of kinases and/or phosphatases in a mammal, including a human, which method comprises administering to the mammal an amount of at least one compound as defined in claim 1 and/or pharmaceutically acceptable Salts thereof, effective to pre vent and/or treat Said diseases which are cured or relieved by the inhibition of one or Several kinases and/or phosphatases.

7. A method for preventing and/or treating diseases like cell proliferation disorders, cardiovascular disorders, immu nological diseases, inflammatory diseases, neuroimmuno logical diseases, neurodegenerative disorders, autoimmune diseases in a mammal, including a human, which method comprises administering to the mammal an amount of at least one compound as defined in claim 1 and/or pharma ceutically acceptable Salts thereof, effective to prevent and/ or treat Said disease.

8. A method of inhibiting at least two different protein kinases which play a role in two or more different molecular mechanims of tumor progression by compounds as defined in claim 1 and/or pharmaceutically acceptable Salts thereof.

9. A method of inhibiting at least two different protein kinases which play a role in one molecular mechanims of tumor progression by compounds as defined in claim 1 and/or pharmaceutically acceptable Salts thereof.