OA16301A - New aminopyrazoloquinazolines. - Google Patents

Abstract

The present invention encompasses compounds of general formula (I) <img file="OA16301A_A0001.tif"/> wherein the groups R1 to R3 and X are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, pharmaceutical preparations which contain such compounds and their use as medicaments.

Description

NEW AMINOPYRAZOLOQUINAZOLINES

The présent invention relates to new aminopyrazoloquinazolines of general formula (I) (I) wherein the groups R¹ to R³ and X hâve the meanings given in the ciaims and spécification, which are suitable for the treatment of diseases characterised by excessive or abnormal cell prolifération, pharmaceutical préparations which contain such compounds and their use as médicaments. The compounds according to the invention display an inhibitory effect on the phosphorylation activity of the IGF-1 receptor located in cell membranes.

Background to the invention

WO 2005/037843 describes partially saturated quinazolînes anellated with heteroaryls as kinase inhibitors.

The aim of the présent invention is to indicate new compounds which can be used for the prévention and/or treatment of diseases characterised by excessive or abnormal cell prolifération. The compounds according to the invention are characterised by a powerful inhibitory effect on the phosphorylation activity of the IGF-1 receptor located in cell membranes and a potent efficacy against tumour cells, e.g. glioblastoma cells, which is mediated through the inhibition of phosphorylation of the receptor. ln addition to the inhibitory effect and cell activity the compounds hâve good solubility and good PK properties.

The insulin-like growth factor (IGF) and insulin signalling network is a highly conserved and essential pathway involved in biological processes including growth, metabolism and homeostasis. ln addition, dereguîated signalling via this network can enhance tumorigenesis and metastasis of certain cancers. _x

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The ligands IGF-1, IGF-2 and insulin are highly homologous and activate spécifie hetero or homodimère of the IGF-1 R and IR. Following ligand binding, the IGF-1R and IR undergo autophosphorylation mediated via the receptor tyrosine kinase domains. The phosphorylated receptors activate the canonical Ras-Raf-MEK-ERK1/2 and PI3K- PDK1Akt intracellular signaling cascades, which leads to cell prolifération and survival. In addition, activation of the IR by insulin stimulâtes the uptake of glucose and storage of glycogen in metabolic tissues such as the liver, adipose and muscle.

Published research articles as well as medical and epidemiological investigations hâve identified a strong corrélation between expression of the 1GF-1R and IR and ligands for these receptors in tumor development and progression. Developing a small molécule compétitive inhibitor of the ATP-binding pocket of the IGF-1 R and IR as a means of blocking growth and survival signaling cascades in cancer is therefore désirable. The anticipated clinical benefit of blocking such an interaction would be to reduced tumor growth rate and potentially sensitize tumors to cytotoxîc agents or targeted thérapies.

Detailed description of the invention

Surprisingly it has been found that compounds of general formula (I), wherein the groups R¹ to R³ and X hâve the meanings stated hereinafter act as inhibitors of receptors that are involved in controlling cell prolifération. Thus, the compounds according to the invention may be used for example for the treatment of diseases associated with the activity of these receptors and characterised by excessive or abnormal cell prolifération.

The présent invention therefore relates to compounds of general formula (I)

, wherein (AO)

R¹ dénotés hydrogen or a group optionally substituted by one or more identical or different

R^a and/or R^b, selected from among Ci «alkyl, C₂«alkenyl, C2_6alkynyl, QHocycloalkyl, C^wcycloalkenyl, C₆-₁₀aryl, 5-12 membered heteroaryl and 3- to 14-membered Z

-216301 heterocyclyl;

(B0)

R^z dénotés hydrogen or a group optionally substituted by one or more îdentical or different R^a and/or R^b, selected from among C^alkyl, C₂^alkenyl, C₂__ealkynyl, C₃.₁₀cycloalkyl, C₄.₁₀cycloalkenyl, C₆.ioaryl> 5-12 membered heteroaryl and 3- to 14-membered heterocyclyl;

R³ dénotés a group

(CO)

A is selected from among C₆.ioaryl and 5-12 membered heteroaryl;

B dénotés a 5- to 7-membered, non-aromatic hetero ring with at Ieast one heteroatom, selected from among nitrogen, sulphur and oxygen, which optionally carries one or more substituents selected from among C^alkyl and =O;

(DO) each R⁴ is independently selected from among R^a and R^b; m dénotés 0, 1, 2 or 3;

R⁵ is selected from among R^a and R^b;

n dénotés 0 or 1;

(E0)

X dénotés a bond or is selected from among -CH₂- and -CH₂-CH₂- and in the abovementioned -CH₂- and -CH₂-CH₂- one or two hydrogen atoms are optionally substituted X

-316301 independently of one another by C_Malkyl, C₁.₄haloalkyl, -O-C_;.zalkyl or halogen;

each R^a independently dénotés a group optionally substituted by one or more identical or different R^b and/or R^c, selected from among C^alkyl, C^alkenyl, C2-6alkynyl, C₃-i₀cycloalkyl, C₄.₁₀cycloalkenyl, C₆-ioaryl, 5-12 membered heteroaryl and 3- to 14membered heterocyclyl;

each R^b is independently selected from among -OR^C, -SR^C, -NR^CR^C, halogen, -CN, -NO21 -C(O)R^c, -C(O)OR^C, -C(O)NR^CR^C, -C(NR^h)NR^cR^c, -OC(O)R^C, -OC(0)OR^C, -S(O)2R^e, -S(O)2NR^cR^c, -NR^hC(O)R^c, -NR^hC(O)OR^c, -NR^hC(O)NR°R^c, -NR^hC(NR^h)NR^cR^c and -NR^hS(O)2R^c, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R^c independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^d and/or R^e, selected from among C^alkyl, C_2J6alkenyl, C^alkynyl, C₃.₁₀cycloalkyl, C₄-i₀cycloalkenyl, C₆j_Oaryl, 5-12 membered heteroaryl and 3- to 14membered heterocyclyl;

each R^d is independently selected from among -OR^e, -SR^e, -NR^eR^e, halogen, -CN, -NO2, -C(O)R^e, -C(O)OR^e, -C(O)NR^eR^e, -C(NR^h)NR^eR^e, -OC(O)R^e, -OC(O)OR^e, -S(O)2R^e, -S(O)2NR^eR^e, -NR^hC(O)R^e, -NR^hC(O)0R^e, -NR^hC(O)NR^eR^e, -NR^tlC(NR^h)NR^eR^e and -NR^hS(O)2R^e, as well as the bivalent substituent =O, while the latter may only be a substituent in non-aromatic ring Systems, each R® independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^f and/or R^fl, selected from among C^alkyl, C₂^alkenyl, C₂^alkynyl, C₃.₁₀cycloalkyl, C4-iocycloalkenyl, C₆.₁₀aryl, 5-12 membered heteroaryl and 3- to 14membered heterocyclyl;

each R^f is independently selected from among -OR⁹, -SR⁹, -NR⁹R⁹, halogen, -CN, -NO21 -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁹R⁹, -C(NR^h)NR⁹R⁹, -OC(O)R⁹, -OC(O)OR⁹, -S(O)2R⁹, -S(O)2NR⁹R⁹, -NR^hC(O)R⁹, -NR^hC(O)OR⁹, -NR^hC(O)NR⁹R⁹, -NR^hC(NR^h)NR⁹R⁹ and -NR^hS(O)2R⁹, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R⁹ is independently selected from among hydrogen, C^alkyl, C^alkenyl, C_2j6alkynyl, Ci_₆haloalkyl, C₃.i₀cycloalkyl, C₄.i₀cycloalkylalkyl, C₄.₁₀cycloalkenyl, C₆-ioaryl, /

-416301

5-12 membered heteroaryl and 3- to 14-membered heterocyclyl, and each R^h is independently selected from among hydrogen and C^alkyl, while the compounds (I) may optionally also be présent in the form of their tautomers, their racemates, their enantiomers, their diastereomers or their mixtures or as the respective salts of ali the above-mentioned forms.

In one aspect (A1 > the invention relates to compounds (I), wherein

R¹ is a group optionally substituted by one or more identical or different R^a1 and/or R^b1, selected from among C^elkyl, C₃.₁₀cycloalkyl, Ce-ioaryl, 5-12 membered heteroaryl and 3to 14-membered heterocyclyl;

each R^a1 independently dénotés a group optionally substituted by one or more identical or different R^b1 and/or C^alkyl, selected from among C^alkyl, C₃.₁₀cycloalkyl and C₆.i₀aryl, and each R^b1 is independently selected from among -OH, -O-C₁₃-alkyl, halogen and -CN.

In another aspect (A2) the invention relates to compounds (I), wherein

R¹ is a group optionally substituted by one or more identical or different R^a1 and/or R^b1, selected from among C^alkyl, C_3ecycloalkyl, phenyl, 5- to 6-membered heteroaryl and

3-7 membered heterocyclyl;

each R^a1 independently dénotés a group optionally substituted by one or more identical or different R^b1 and/or C_Malkyl, selected from among C^alkyl, C₃._scycloalkyl and phenyl, and each R^b1 is independently selected from among -O-C^alkyl, halogen and -CN.

In another aspect (A3) the invention relates to compounds (1), wherein

R¹ dénotés C_3Îalkyl.

In another aspect (A4) the invention relates to compounds (I), wherein

R¹ dénotés phenyl or benzyl, while the above-mentioned phenyl and benzyl optionally carry one or more substituents selected from among C^alkyl, halogen, -O-C^ealkyl and -CN.

-516301

In another aspect (A5) the invention relates to compounds (I), wherein

R¹ dénotés phenyl or benzyl, while the above-mentioned phenyl and benzyl optionally carry one or more substituents selected from among Cj^alkyl, Ci.₄haloalkyl, halogen,

-O-Cualkyl, -O-Ci.haloalkyl and -CN.

In another aspect (A6) the invention relates to compounds (I), wherein

R¹ dénotés thienyl, this thienyl optionally carrying one or more substituents selected from among C^alkyl and halogen.

In another aspect (B1) the invention relates to compounds (I), wherein

R² is hydrogen or a group optionally substituted by one or more identical or different R^b2 and/or C6-ioaryl selected from among C^alkyl, C26alkenyl and 5-12 membered heteroaryl; each R^b2 is independently selected from among -OH, -O-C^alkyl, -NH2, -NH(C^alkyl) and -N(Ci^alkyl)₂.

In another aspect (B2) the invention relates to compounds (I), wherein

R² is a group optionally substituted by one or more identical or different R^b2 and/or phenyl selected from among C^alkyl, and 5- to 6-membered heteroaryl;

each R^b2 is independently selected from among -O-C_Malkyl and -N(C^alkyl)₂.

In another aspect (B3) the invention relates to compounds (I), wherein

R² dénotés methyl or ethyl.

In another aspect (E1 ) the invention relates to compounds (I), wherein

X dénotés a bond or is selected from among -CH₂- and -CH₂-CH₂- and in the abovementioned -CH₂- and -CH₂-CH₂- optionally one or two hydrogen atoms are substituted by C_Malky1.

In another aspect (E2) the invention relates to compounds (I), wherein

X is selected from among -CH₂- and -CH₂-CH₂- and in the above-mentioned -CH₂- and -CH₂-CH₂- optionally one or two hydrogen atoms are substituted by Ci_₄alkyl.

In another aspect (E3) the invention relates to compounds (1), wherein S

-616301

X is selected from among -CH₂, -CH(CH₃), -C(CH₃)2- and -CH2-CH2-.

In another aspect (E4) the invention relates to compounds (I), wherein

X dénotés -CH₂ or -CH(CH₃)-.

In another aspect (C1) the invention relates to compounds (I), wherein

A is selected from among phenyl, naphthyl, 5- to 6-membered, monocyclic heteroaryl and 9- to 10-membered bicyclic heteroaryl.

In another aspect (C2) the invention relates to compounds (I), wherein

A is selected from among phenyl, benzofuryl, benzothienyl, naphthyl, isoquinolinyl, pyrazolyl, indazolyl, isoxazolyl and imidazo[1,2-a]pyrîdyl.

In another aspect (C3) the invention relates to compounds (I), wherein

A dénotés phenyl.

In another aspect (C4) the invention relates to compounds (I), wherein

A dénotés pyrazolyl.

In another aspect (D1 > the invention relates to compounds (l), wherein each R⁴ is independently selected from among R^a3 and R^b3;

m dénotés 0, 1, 2 or 3;

each R^a3 independently dénotés a group optionally substituted by one or more identical or different R^b3 and/or R^c3 selected from among C^alkyl, C₃.₁₀cycloalkyl and 3- to 14membered heterocyclyl;

each R^b3 is independently selected from among -OR^c3, -NR^c3R^c3, halogen, -C(O)R^c3, -C(O)OR^c3, -C(O)NR^c3R^c3 and -S(O)₂R^c3;

each R^c3 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^d3 and/or R^e3 selected from among C^alkyl, C_2üalkenyl. C₃_i₀cycloalkyl and 3- to 14-membered heterocyclyl;

each R^d3 is independently selected from among -OR^e3, -NR^e3R^e3, halogen, -C(O)R^e3, -C(O)OR^e3 and -C(O)NR^e3R^e3; /

-Ί16301 each R^e3 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R*³ and/or R⁹³ selected from among C^alkyl, C₃__wcycloalkyl and 3- to 14-membered heterocyclyl;

each R^f3 is independently selected from among -OR⁹³, -NR⁹³R⁹³, halogen, -C(O)R⁹³, -C(O)OR⁹³ and -C(O)NR⁸³R⁹³ and each R⁹³ is independently selected from among hydrogen, Ci^alkyl, Cvehaloalkyl, C₃.i₀cycloalkyl, CZ i_ycyc(oaikylaikyl, C₆₁₀aryl, and 5-12 membered heteroaryl.

In another aspect (D2) the invention relates to compounds with the structural aspect (D1), wherein m dénotés 1,2 or 3.

In another aspect (D3) the invention relates to compounds with the structural aspect (D1), wherein m dénotés 2.

In another aspect (CD1) the invention relates to compounds (l), wherein R³ dénotés a group

A is selected from among C_{e 1cl}aryl and 5-12 membered heteroaryl; each R⁴ is independently selected from among R^a and R^b;

m dénotés 0,1, 2 or 3 and

R^a and R^b are as hereinbefore defined.

In another aspect (CD2) the invention relates to compounds (I), wherein R³ dénotés a group

-816301

A is selected from among C₆.ioaryl and 5-12 membered heteroaryl;

each R⁶ îs independently selected from among C_Malkyl, -O-C, ?.alkyl and halogen;

p dénotés 0,1 or 2;

R^c4 dénotés hydrogen or a group optionally substituted by one or more identical or different R^d4 and/or R⁶⁴ selected from among C^alkyl, C₂^alkenyl, C_?salkynyl, C₃-iocycloalkyl, C₄ i_Ccycloalkenyl, C₆-ioaryl, 5-12 membered heteroaryl and 3- to 14membered heterocyclyl;

each R^d4 is independently selected from among -OR^e4, -SR^e4, -NR^e4R^e4, halogen, -CN, -NO2, -C(O)R^e4, -CiCQOR*⁴, -C(O)NR^e4R^e4, -CiNR^NR^R®⁴, -OC(O)R^e4, -OC(O)OR^e4, -S(O)2R^e4, -S(O)2NR^fl-R^e4, -NR^h4C(O)R'-‘⁴, -NR^h4C(O)OR^e4, -NR^hC(O)NR^e/‘R^e\ -NR^h4C(NR^h4)NR^e4R^e4 and -NR^h4S(O)2R^e4, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R®⁴ independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^f4 and/or R⁹⁴ selected from among C^alkyl, C₂^alkenyl, C₂-₆alkynyl, C₃.₁₀cycloalkyl, C₄₁₀cyclcalkenyl, Ce-waryl, 5-12 membered heteroaryl and βίο 14-membered heterocyclyl;

each R^f4 is independently selected from among -OR⁹⁴, -SR⁹⁴, -NR^g4R⁹⁴, halogen, -CN, -NO21 -C(O)R⁹⁴, -C(O)OR⁹⁴, -C(O)NR⁹⁴R⁹⁴, -C(NR^h4)NR⁹⁴R⁹⁴, -OC(O)R^g4, -OC(O)OR⁹⁴, -S(O)2R⁹⁴, -S(O)₂NR⁹⁴R⁹⁴, -NR^h4C(O)R⁹⁴, -NR^h4C(O)OR⁹⁴, -NR^r4C(O)NR⁹-R^g\

-NR^h4C(NR⁹⁴)NR⁹⁴R⁹⁴ and -NR^h4S(O)_?R^q4, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R⁹⁴ is independently selected from among hydrogen, C^alkyl, C₂^alkenyl, C₂.₆alkynyl, Ci_₆haloalkyl, C₃_i₀cycloalkyl, C^iocycloalkylalkyl. C₄.i₀cycloalkenyl, C₆_i₀aryl, 5-12 membered heteroaryl and 3- to 14-membered heterocyclyl and each R^m is independently selected from among hydrogen and C^elkyl.

In another aspect (CD3) the invention relates to compounds (I), wherein

R³ dénotés a group >

-916301

R⁰⁴, R⁶ and p are as hereinbefore defined.

[n another aspect (CD4) the invention relates to compounds (I), wherein

R³ dénotés a group

R⁰⁴, R⁶ and p are as hereinbefore defined.

In another aspect (CD5) the invention relates to compounds (I), wherein

R³ dénotés a group

to R^{6 1} and R⁶'² is independently selected from among hydrogen, Ci^alkyl, -O-Ci_₄alkyl and halogen and

R^c4 is as hereinbefore defined.

In further aspects (CD6), (CD7), (CD8) and (CD9) the invention relates to compounds with the structural aspect (CD2), (CD3), (CD4) and (CD5), wherein

R⁰⁴ dénotés hydrogen or a group optionally substituted by one or more identical or 2

-1016301 different R⁰⁴ and/or R®⁴ selected from among C^alkyi, C₃_i₀cycloalkyl and 3- to 14membered heterocyclyl;

each R^d4 is independently selected from among -OR®⁴, -NR^e4R^e4, halogen, -C(O)R®⁴ and -C(O)NR®⁴R®⁴;

each R®⁴ independently dénotés hydrogen or a group optionally substituted by one or more identical or different R⁽⁴ and/or R^fl4 selected from among Ci-ealkyl, C₃-₃cycloalkyl and 3- to 14-membered heterocyclyl;

each R^f4 is independently selected from among -OR⁹⁴, -NR⁹⁴R⁹⁴, halogen, -C(O)R⁹⁴, -C(O)NR⁹⁴R⁹⁴ and each R⁹⁴ is independently selected from among hydrogen, C^alkyl, Ci-ehaloalkyl, C₃.₁₀cycloalkyl, C₄₁₀cycloalkylalkyl, C_e.i_Oaryl and 5-12 membered heteroaryl.

In further aspects (CD10), (CD11), (CD12) and (CD13) the invention relates to compounds with the structural aspect (CD2), (CD3), (CD4) and (CD5), wherein

R®⁴ dénotés a group optionally substituted by one or more identical or different R^d4 and/or R®⁴ selected from among C^alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrralidinyl, tetrahydropyranyl, 1-aza-bicyclo[2.2.2]octyl, 8-methyl-8-azabicyclo[3.2.1]octyl, morpholinyl, piperidinyl and piperazinyl;

each R^d4 is independently selected from among -OR®⁴, -NR®⁴R®⁴, halogen, -C(O)R®⁴ and -C(O)NR^e4R®⁴;

each R®⁴ independently dénotés a group optionally substituted by one or more identical or different R^f4 and/or R⁹⁴ selected from among C^alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, 1-aza-bicyclo[2.2.2]octyl, 8-methyl-8aza-bicyclo[3.2.1]octyl, morpholinyl, piperidinyl and piperazinyl;

each R^f4 is independently selected from among -OR⁹⁴, -NR⁹⁴R⁹⁴, halogen, -C(O)R⁹⁴, -C(O)NR⁹⁴R⁹⁴ and each R⁹⁴ is independently selected from among hydrogen, C_1j6alkyl, Ci_₆haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl and 5- to 6membered heteroaryl.

In further aspects (CD14), (CD15), (CD16) and (CD17) the invention relates to compounds with the structurai aspect (CD2), (CD3), (CD4) and (CD5), wherein /

-1116301

R^c4 is selected from among methyl, methoxyethyl, Ν,Ν-dimethyl-ethyl, A/,N-dimethylpropyl,

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-1216301

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f

In another aspect (CD18) the invention relates to compounds (I), wherein

R³ dénotés a group

each R^{5 6 * * * 10 * * * * 15} is independently selected from among C₄^alkyl. -O-C_Malkyl and halogen;

p dénotés 0,1 or 2;

R^cS dénotés hydrogen or a group optionally substituted by one or more îdentical or different R^d5 and/or R^e5 selected from among C^alkyl, C_2ealkenyl, C₂_₆alkynyl,

C₃._1Qcycloalkyl, C₄.₁₀cycloalkenyl, C₆.i₀aryl, 5-12 membered heteroaryl and 3- to 1410 membered heterocyclyl;

each R^d5 is independently selected from among -OR^e5, -SR^e5, -NR^e5R^e5, halogen, -CN,

-NOz, -C(O)R^e5, -C(0)OR^e5, -C(O)NR^e5R^e5, -C(NR^h5)NR^e5R^e5, -OC(O)R^e5, -OC(O)OR^e5,

-S(O)₂R^e5, -S(O)₂NR^e5R^e5, -NR^h5C(O)R^e5, -NR^h5C(O)OR^e5, -NR^h5C(O)NR^e5R^e5,

-NR^h5C(NR^h5)NR^e5R^e5 and -NR^h5S(O)₂R^e5, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R^e5 independently dénotés hydrogen or a group optionally substituted by one or more îdentical or different R^f5 and/or R^gS selected from among C^alkyl, C₂^alkenyl,

-1316301

Cï^alkynyl, C₃.₁₀cycloalkyl, C₄ iocycloalkenyl, C₆-ioaryl. 5-12 membered heteroaryl and 3to 14-membered heterocyclyl;

each R^f5 îs independently selected from among -OR⁹⁵, -SR⁹⁵, -NR^g5R⁹⁵, halogen, -CN, -NO2, -C(O)R⁹⁵, -C(0)OR⁹⁵, -C(O)NR⁹⁵R⁹⁵, -C(NR^h5)NR⁹⁵R⁹⁵, -OC(O)R⁹⁵, -OC(O)OR⁹⁵, -S(O)2R⁹⁵, -S(O)₂NR^g5R⁹⁵, -NR^h5C(O)R^g5, -NR^CfOJOR⁹⁵, -NR^h5C(O)NR^g5R⁹⁵,

-NR^h5C(NR^h5)NR^a5R^g5 and -NR^h5S(O)₂R⁹⁵, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R⁹⁵ is independently selected from among hydrogen, Ci^alkyl, C₂₆alkenyl, C₂.₆alkynyl, C-^haloalkyl, C₃.₁₀cycloalkyl, C₄.₁₀cycloalkylalkyl, C^iocycloalkenyl, C₆-ioaryl, 5-12 membered heteroaryl and 3- to 14-membered heterocyclyl and each R^h5 is independently selected from among hydrogen and C^alkyl.

In another aspect (CD 19) the invention relates to compounds (I), wherein

R³ dénotés a group

R^{6 1} and R^{6 2} is independently selected from among hydrogen, C^alkyl, -O-C^alkyl and halogen and

R^cS are as hereinbefore defined.

In further aspects (CD20) and (CD21) the invention relates to compounds with the structural aspect (CD18) and (CD19), wherein

R^c5 dénotés hydrogen or a group optionally substituted by one or more identical or different R^d5 and/or R®⁵, selected from among C^alkyl, C₃.₁₀cycloalkyl and 3- to 14membered heterocyclyl;

each R^dS is independently selected from among -OR®⁵, -NR^eSR^e5, halogen, -C(O)R^e5 and -C(O)NR^e5R®⁵ and X

-1416301 each R^eS is independently selected from among hydrogen, Ci _calkyl. C₃.₁₀cycloalkyl and 3to 14-membered heterocyclyl.

In further aspects (CD22) and (CD23) the invention relates to compounds with the structural aspect (CD18) and (CD19), wherein

R^c5 dénotés a group optionally substituted by one or more identical or different R^ds and/or R*⁵ selected from among C^alkyl and 5- to 6-membered, nitrogen-containing heterocyclyl;

each R^ds is independently selected from among -OR^e5, -NR^e5R^e5, halogen, -C(O)R^e5 and -C(O)NR^e5R^e5 and each R^e5 is independently selected from among Ci._galkyl and 5- to 6-membered, nitrogencontaining heterocyclyl.

In further aspects (CD24) and (CD25) the invention relates to compounds with the structural aspect (CD 18) and (CD 19), wherein

R^c5 is selected from among A/.N-dimethylethyl, A/.N-dimethyl-propyl,

In another aspect (CD26) the invention relates to compounds (I), wherein

R³ dénotés a group

each R⁶ is independently selected from among C_Malkyl, -Ο-Ci ₄alkyl and halogen;

R^T is selected from among R^b6 and R^c6; /

-1516301 p dénotés 0,1 or 2;

R^b6 is selected from among -C(O)R^c6, -C(O)OR^c8, -C(O)NR^c6R“ -S(O)2R^c6 and -S(O)2NR^c6R^c6;

each R^c6 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^d6 and/or R^e6 selected from among C^alkyl, C₂.₆alkenyl, C₂.₆alkynyl, C₃.₁₀cycloalkyl, C4_₁₀cycloalkenyl, C₆-ioaryl, 5-12 membered heteroaryl and 3to 14-membered heterocyclyl;

each R^d6 is independently selected from among -OR®⁶, -SR⁶⁶, -NR^e6R^e6, halogen, -CN, -NO2, -CÎOJR®⁶, -C(O)OR^cfi, -C(O)NR^e6R^e6, -CiNR^'^NR^R^, -OC(O)R^eC, -OCiOJOR⁶⁶, -SiO^R⁶⁶, -S(O)?NR^e6R^e(’, -NR^h6C(O)R-, -NR^h6C(O)OR^e6, -NR^C(O)NR^eCR^ei,

-NR^CiNR^NR^R®⁶ and -NR^h6S(O)₂R^eS, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R^e6 is independently selected from among hydrogen, C^alkyl, C₂.₆alkenyl, C₂.₆alkynyl, C₃_₁₀cycloalkyl, C₄.₁₀cycloalkenyl, C₆-ioaryl, 5-12 membered heteroaryl and βίο 14-membered heterocyclyl, and each R^h6 is independently selected from among hydrogen and Ci.₄alkyl.

In another aspect (CD27) the invention relates to compounds (I), wherein

R³ dénotés a group

R^{6 1} and R^{6 2} is independently selected from among hydrogen, C_Malkyl, -O-C,.₄alkyl and halogen and

R⁷ are as hereinbefore defined.

In further aspects (CD28) and (CD29) the invention relates to compounds with the structural aspect (CD26) and (CD27), wherein /

-1616301

R⁷ is selected from among R^b6 and R^c6;

R^b6 is selected from among -C(O)R^ce, -C(O)NR^c6R^cS and -S(O)₂R^c6;

each R^c6 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^d6 and/or R^e6 selected from among C^alkyl, C₃._scycloalkyl and 5- to 6-membered heterocyclyl;

each R^d6 is independently selected from among -OR^e6, -NR^iÆR^L’⁶, halogen, -C/OJR⁶⁶ and -C(O)NR^eCR^e6 and each R^e6 is independently selected from among hydrogen, C^alkyl, C₃^cycloalkyl and 5to 6-membered heterocyclyl.

In another aspect (CD30) the invention relates to compounds (l), wherein

R³ dénotés pyrazolyl, which is optionally mono- or disubstituted by C-.₄alkyl or C₃.₅cycloalkyl.

In another aspect (CD31) the invention relates to compounds (I), wherein

R³ dénotés a group

R?

R⁸ dénotés a group optionally substituted by one or more identical or different R^b7 and/or R^c7 selected from among C^alkyl, C₃.₆cycloalkyl and 5- to 7-membered heterocyclyl;

each R^b7 is independently selected from among -OR^c7, -NR^c7R^c7, halogen, -C(O)R^c7 and -C(O)NR^c7R^c7;

each R^c7 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^d7 and/or R^e7 selected from among C^alkyl, C₃«cycloalkyl, 5to 6-membered heteroaryl and 5- to 7-membered heterocyclyl;

each R^dT is independently selected from among -OR^e7, -NR^e7R^e7, halogen, -C(O)R^e7 and -C(O)NR^e7R^e7; /

-1716301 each R^e7 independently dénotés hydrogen or a group optionally substituted by one or more identical or different Rⁿ and/or R⁹⁷ selected from among C_1j6alkyl, C₃₆cycloalkyl. 5to 6-membered heteroaryl and 5- to 7-membered heterocyclyl;

each R⁷⁷ is independently selected from among -OR⁹⁷, -NR^a7R⁰⁷, halogen, -C(O)R⁹⁷ and -C(O)NR^g7R⁹⁷;

each R^g7 independently dénotés hydrogen or C^alkyl;

R⁹ is selected from among hydrogen, C, .-alkyl and C₃.₅cycloalkyl.

In another aspect (CD32) the invention relates to compounds (I), wherein

R³ dénotés a group

R?

R⁸ is selected from among C^alkyl, C₃_₅cycloalkyl, C· ,-alkoxy-C-./.alkyl, (C-i^lkyONH-C-Malkyl and (Ct ₄alkyl)₂N-C_t />alkyl;

R⁹ is selected from among hydrogen, CL.-.alkyl and C₃.₅cycloalkyl.

Ail the structural aspects A1 to A6, B1 to B3, C1 to C4, D1 to D3, E1 to E4 and CD1 to CD32 mentioned hereinbefore are preferred embodiments of the respective aspects AO, B0, CO, DO, E0 and CDO, while CDO is a combination of CO and DO. The structural aspects AO to A6, B0 to B3, CO to C4, DO to D3, E0 to E4 and CDO to CD32 with respect to different molecular parts of the compounds (I) according to the invention may be permutated with one another as desired to form ABCDE combinations, thus obtaining preferred compounds (I). Each ABCDE combination represents and defines individual embodiments or generic partial amounts of compounds A0B0C0D0E0 according to the invention. Every individual embodiment or partial quantity defined by this combination is expressly included in and a subject of the invention.

Preferred compounds (I) are:

1-168 (5S)-N-[1-(2-methoxyethyl)pyrazol-3-yl]-5,8-dimethyl-9-phenyl-5,6- >

-1816301

1-194

1-201

I-204

I-222

1-271

I-225

I-205

1-198

1-197

1-195

1-193

1-189

1-187

1-186

1-185

1-171 dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-5,8-dimethyl-9-phenyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-8-methyl-9-phenyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amîne;

N-[1-(2-methoxyethyl )pyrazol-3-yl]-5,8-dimethyl-9-phenyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-[4-(difluoromethoxy)phenyi]-N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-8methyl-5,6-dîhydropyrazolo[3,4-h]quinazolin-2-amine;

( 5S)- N-[1 -( 2-methoxyethyl )pyrazol-3-yl]-5,8-dimethyl-9-p heny I-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-methoxyethyl )pyrazol-3-yl]-8-methyl-9-[(3-methylphenyl)methyl]-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine

1-[4-[4-[[9-[4-(difluoromethoxy)phenyl]-8-methyl-5,6-dihydropyrazolo[3,4-

h]quinazolin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]ethanone;

N-[1-[2-[2-methoxyethyl(methyl)amino]ethyl]pyrazol-3-yl]-8-methyl-9-phenyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

8- methyl-9-phenyl-N-[1-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-8-methyl-9-(naphthalen-1-ylmethyl)-

5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine;

9- [(2-chlorophenyl)methyl]-N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-8-methyl-

5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-8-methyl-9-(3-methylthiophen-2-yl)-

5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-methoxyethyl )pyrazol-3-yl]-8-methyl-9-[(2-methyl phenyl )methyl]-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

1-[4-[4-[(5_i8-dimethyl-9-phenyl-5,6-dihydropyrazolo[3_I4-h]qiiinazolin-2yl)amino]pyrazol-1-yl]piperidin-1-yl]ethanone;

8- methyl-N-[1-[2-(4-methylpiperazin-1-yl)ethyl]pyrazol-3-yl]-9-phenyl-5,6dîhydropyrazolo[3,4-h]quinazolin-2-amine;

9- (4-chlorophenyl)-N-[1-(2-methoxyethyl)pyrazol-3-yl]-8-methyl-5,6- dihydropyrazolo[3,4-h]quinazolin-2-amine; z

-1916301

1-166

1-167

1-217

1-210

I-208

1-192

1-182

1-180

1-176

1-175

1-181

I-202

I-224

I-237

I-236

I-30

1-112

2-[4-[2-[3-[(8-methyl-9-phenyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2yl)amino]pyrazol-1-yl]ethyl]piperazin-1-yl]ethanol;

N-[1-[2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl]pyrazol-3-yl]-8-methyl-9-phenyl5_i6-dihydropyrazolo[3,4-h]quinazolin-2-aniine,

9-[(3-methoxyphenyl)methyl]-8-methyl-N-(1-methylpyrazol-3-yl)-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-[4-(difluoromethoxy)phenyl]-N-[1-(2-methoxyethyl)pyrazol-3-yl]-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-benzyl-N-[1-(2-dimethylamÎnoethyl)pyrazol-3-yl]-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-[(2-οήΙθΓορήθη^)πθίήνΙ]-Ν-[1-(2-πβ^οχνβίήνΙ)ρνΓ3Ζθ!-3-νΙ]-8-πθίή^-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

8- methyl-9-phenyl-N-[1-(2-piperazin-1-ylethyl)pyrazol-3-yl]-5,6- dihydropyrazolo[3,4-h]quinazolin-2-amine;

9- (3-chlorothiophen-2-yl)-N-[1-(2-methoxyethyl)pyrazol-3-yl]-8-methyl-5,6- dihydropyrazolo[3,4-h]quinazolin-2-amine;

1-[4-[4-[[9-(4-methoxyphenyl)-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2yl]amino]pyrazol-1-yl]piperidin-1-yl]ethanone;

N-[1-[2-[4-(dimethylamino)piperidin-1-yl]ethyl]pyrazol-3-yl]-8-methyl-9-phenyl-

5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-(3-chlorothiophen-2-yl)-N-(1-ethylpyrazol-3-yl)-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-[(2-chlorophenyl)methyl]-N-(1-ethylpyrazol-3-yl)-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-(1-ethylpyrazol-3-yl)-8-methyl-9-[(3-methylphenyl)methyl]-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-[4-(difluoromethoxy)phenyl]-N-(1-ethylpyrazol-3-yl)-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-[4-(difiuoromethoxy)phenyl]-N-[1-(2-dimethylaminoethyl)pyrazol-4-yl]-8methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amÎne;

9-(2-chlorophenyl)-N-(1-ethylpyrazol-3-yl)-8-methyl-5,6-dihydropyrazolo[3,4-

h]quinazolin-2-amine;

4-[[9-(2-chloro phenyl )-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2- y

-2016301

1-40

1-42

1-97

I- 157

II- 8 yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide; 9-(2-chlorophenyl)-5,8-dimethyl-N-(1-propane-2-ylpyrazol-3-yl)-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-(2-chlorophenyl)-5,8-dimethyl-N-(1-methylpyrazol-3-yl)-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-(2-chlorophenyl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-5,8dimethyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amîne;

4-[[9-(2-chlorophenyl)-5,8-dimethyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2yl]amino]-3-methoxy-N-(1-methylpiperidîn-4-yl)benzamide;

4-[[9-(2-chlorophenyl)-5,8-dimethyl-5,6-dihydropyrazolo[3_I4-h]quinazolin-2yl]amino]-3-methoxybenzoic acid;

The présent invention further relates to hydrates, solvatés, polymorphs, métabolites, dérivatives and prodrugs of compounds of general formula (I).

In another aspect the invention relates to compounds of general formula (I) - or the 5 pharmaceutically acceptable salts thereof - as médicaments.

In another aspect the invention relates to compounds of general formula (I) - or the pharmaceutically acceptable salts thereof - for use in the treatment and/or prévention of cancer, infections, inflammations and autoimmune diseases.

In another aspect the invention relates to compounds of general formula (I) - or the 10 pharmaceutically acceptable salts thereof - for use in the treatment and/or prévention of cancer.

In another aspect the invention relates to compounds of general formula (I) - or the pharmaceutically acceptable salts thereof - for use in the treatment and/or prévention of non-small-cell lung cancers (NSCLC) and hepatocellular carcinomas (HCC).

In another aspect the invention relates to a method for the treatment and/or prévention of cancer comprising administering a therapeutically effective amount of a compound of general formula (I) - or one of the pharmaceutically acceptable salts thereof - to a human.

In another aspect the invention relates to a pharmaceutical préparation containing as active substance one or more compounds of general formula (I) - or the pharmaceutically

-2116301 acceptable salts thereof - optionally in combination with conventional excipients and/or carriers.

In another aspect the invention relates to a pharmaceutical préparation comprising a compound of general formula (!) - or one of the pharmaceutically acceptable salts thereof - and at least one further cytostatic or cytotoxic active substance, different from formula (I).

Définitions

Terms that are not specifically defined here hâve the meanings that are apparent to the skilled man in the light of the overall disclosure and the context as a whole.

As used herein, the following définitions apply, unless stated otherwise:

The use of the prefix C_xy, wherein x and y each represent a naturel number (x < y), indicates that the chains or ring structure or combination of chains and ring structure as a whole, specified and mentioned in direct association, may consist of a maximum of y and a minimum of x carbon atoms.

The indication of the number of members in groups that contain one or more heteroatom(s) (heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl) relates to the total atomic number of ail the ring members or chain members or the total of ail the ring and chain members.

Alkyl dénotés monovalent, saturated hydrocarbon chains, which may be présent in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on ail the hydrogen-carrying carbon atoms.

The term C^s-alkyl includes for example H₃C-, H₃C-CH₂-, H₃C-CH2-CH₂-,

H₃C-CH(CH₃)-, H₃C-CH₂-CH₂-CH₂-, H₃C-CH₂-CH(CH₃)-, H₃C-CH(CH₃)-CH₂-, H₃C-C(CH₃)₂-, H₃C-CH₂-CH₂-CH₂-CH₂-, H₃C-CH₂-CH₂-CH(CH₃)-, H₃C-CH₂-CH(CH₃)-CH₂HaC-CHiCHaî-CHrCHz-, H₃C-CH₂-C(CH₃)₂-, H₃C-C(CH₃)₂-CH₂-, H₃C-CH(CH₃)-CH(CH₃)and H₃C-CH₂-CH(CH₂CH₃)-.

Further examples of alkyl are methyl (Me; -CH₃), ethyl (Et; -CH₂CH₃), 1-propyl (n-propyl; n-Pr; -CH₂CH₂CH₃), 2-propyl (/-Pr; /so-propyl; -ΟΗ(ΟΗ₃)₂), 1-butyl (n-butyl; n-Bu; /

-2216301

-CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (/so-butyl; /-Bu; -CH2CH(CH₃)₂), 2-butyl (sec-butyl; sec-Bu; -CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (tert-butyl; t-Bu; -C(CH₃)₃), 1-pentyl (n-pentyl; -CH₂CH₂CH₂CH₂CH₃), 2-pentyl (-CH(CH₃)CH₂CH₂CH₃), 3-pentyl (-CH(CH₂CH₃)₂), 3-methyl- 1-butyl (/so-pentyl; -CH₂CH₂CH(CH₃)₂), 2-methyl-2-butyl (-C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (-CH(CH₃)CH(CH₃)₂), 2,2-dimethyl-1-propyl (neo-pentyl; -CH₂C(CH₃)₃), 2-methyl-1-butyl (-CH₂CH(CH₃)CH₂CH₃), 1-hexyl (n-hexyl; -CH2CH₂CH2CH2CH₂CH₃), 2-hexyl (-CH(CH₃)CH₂CK₂CH₂CH₃), 3-hexyl (-CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (-C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (-CH(CH₃)CH₂CH(CH₃)₂),

3-methyl-3-pentyl (-C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (-CH(CH₂CH₃)CH(CH₃)₂),

2.3- dimethyl-2-butyl (-C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (-CH(CH₃)C(CH₃)₃),

2.3- dimethyl-1-butyl (-CH₂CH(CH₃)CH(CH₃)CH₃), 2,2-dimethyl-1-butyl (-CH₂C(CH₃)₂CH₂CH₃), 3,3-dimethyl-1-butyl (-CH₂CH₂C(CH₃)₃), 2-methyl-1-pentyl (-CH₂CH(CH₃)CH₂CH₂CH₃), 3-methyl-1-pentyl (-CH₂CH₂CH(CH₃)CH₂CH₃), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl,

2.3- dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl,

3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl) etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further définition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein ail isomeric forms are included.

The above définition for alkyl also applies if alkyl is a part of another group such as for example C_x._y-alkylamino or C_xy-alkyloxy.

The term alkylene can also be derived from alkyl. Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is produced by removing a hydrogen atom in an alkyl. Corresponding groups are for example -CH₃ and -CH₂, -CH₂CH₃ and -CH₂CH₂ or >CHCH₃ etc.

The term C; ^-alkylene includes for example -(CH₂)-, -(CH₂-CH₂)-, -(CH(CH₃))-, -(CH₂-CH₂-CH₂)-, -(C(CH₃)₂)-, -(CH(CH₂CH₃))-, -(CH(CH₃)-CH₂)-, -(CH₂-CH(CH₃))-. -(CH₂-CH₂-CH2-CH₂)-, -(CH₂-CH₂-CH(CH₃))-, -(CH(CH₃)-CH₂-CH₂)-, -(CH₂-CH(CH₃)-CH₂)-, -(CH₂-C(CH₃)₂)-, -(C (CH₃)₂-CH₂)-, -(CH(CH₃)-CH(CH₃))-, -(CH₂-CH(CH₂CH₃))-, -(CH(CH₂CH₃)-CH₂)-, -(CH(CH₂CH₂CH₃))-, -(CHCH(CH₃)₂)- and -C(CH₃)(CH₂CH₃)-.

-2316301

Other examples of alkylene are methylene, ethylene, propylene, 1-methylethylene, butylène, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,

1,1-dimethyl propylene, 2,2-dîmethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene etc.

By the generic terms propylene, butylène, pentylene, hexylene etc. without any further définition are meant ail the concevable isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene and butylène includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene. The above définition for alkylene also applies if alkylene is part of another group such as for example in HO-C_x._y-alkylenamino or HzN-Cx-y-alkylenoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed.

Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-l-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl,

3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl,

2.3- dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene-3-methylbutyl,

2.3- dimethyl-but-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, penta-1,4-dienyl, penta-

1.3- dienyl, b uta-1,3-dienyl, 2,3-dîmethylbuta-1,3-diene etc.

By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. without any further définition are meant ail the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenyl includes prop-1-enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl etc.

Alkenyl may optionally be présent in the c/s or trans or E or Z orientation with regard to the double bond(s).

The above définition for alkenyl also applies when alkenyl is part of another group such as for example in C_x._y-alkenylamîno or C,._y-alkenyloxy. A

-2416301

Unlike alkylene, al ken vie ne consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond. If in an alkylene as hereinbefore defîned having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenylene is formed.

Examples of alkenylene are ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene,

1.1- dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene,

1,3-dimethylpropenylene, hexenylene etc.

By the generic terms propenylene, butenylene, pentenylene, hexenylene etc. without any further définition are meant ail the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and

1.2- dimethylethenylene.

Alkenylene may optionally be présent in the cis or trans or E or Z orientation with regard to the double bond(s).

The above définition for alkenylene also applies when alkenylene is a part of another group as in for example HO-C_x._y-alkenylenamino or H₂N-C_x._y-alkenylenoxy.

Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkyl as hereinbefore defîned having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed.

Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl,

3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl etc.

By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. without any further définition are meant ail the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.

If a hydrocarbon chain carries both at least one double bond and also at least one triple ✓·

-2516301 bond, by définition it belongs to the alkynyl subgroup.

The above définition for alkynyl also applies if alkynyl is part of another group, as in C_x._y-alkynylamino or C_x._y-alkynyloxy, for example.

Unlike alkylene, alkynylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynylene is formed.

Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene,

1.1- dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene,

1,3-dimethylpropynylene, hexynylene etc.

By the generic terms propynylene, butynylene, pentynylene, hexynylene etc. without any further définition are meant ail the conceivable isomérie forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and

1.2- dimethylethynylene.

The above définition for alkynylene also applies if alkynylene is part of another group, as in HO-C_xy-alkynyleneamino or H_zN-C_xy-alkynyleneoxy, for example.

By heteroatoms are meant oxygen, nitrogen and sulphur atoms.

Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon atoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF₃, -CHFi, -CH₂F, -CF2CF₃, -CHFCF₃, -CH2CF3, -CF_ZCH₃, -CHFCH3, -cf₂cf₂cf₃, -cf₂ch₂ch₃, -cf=cf₂, -cci=ch₂, -CBr=CH₂, -CI=CH₂, -CeC-CF₃, -CHFCH₂CH₃, -CHFCH₂CF₃ etc.

From the previously defined haloalkyl (haloalkenyl, haloalkynyl) are also derived the terms haloalkylene (haloalkenvlene. haloalkynylene) Haloalkylene (haloalkenyl,

-2616301 haloalkynyl), unlike haloalkyl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from a haloalkyl.

Corresponding groups are for example -CH₂F and -CHF-, -CHFCH₂F and -CHFCHF- or >CFCH₂F etc.

The above définitions also apply if the corresponding halogen groups are part of another group.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The Systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they hâve at least two carbon atoms together. In spiro-hydrocarbon rings a carbon atom (spiroatom) belongs to two rings together. If a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molécule via every suitable position of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0lhexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthalene), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo-[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.

The above définition for cycloalkyl also applies if cycloalkyl is part of another group as in Cx y-cycloalkylamino or C_x._y-cycloalkyloxy, for example.

If the free valency of a cycloalkyl is saturated, then an alicyclic group is obtained.

The term cycloalkvlene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are for example cyclohexyl and

(cyclohexylene).

The above définition for cycloalkylene also applies if cycloalkylene is part of another s

-2716301 group as in HO-C_x._y-cycloalkyleneamino or H₂N-C_x ,.-cycloalkyleneoxy, for example.

Cvcloalkenyl is also made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However, the Systems are unsaturated, i.e. there is at least one C-C double bond but no aromatic system. If in a cycloalkyl as hereinbefore defined two hydrogen atoms at adjacent cyclic carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl is obtained. If a cycloalkenyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked as a substituent to the molécule via every suitable position of the ring system.

Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl. cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4.5]dec-2-ene etc.

The above définition for cycloalkenyl also applies when cycloalkenyl is part of another group as in C_x._y-cycloalkenylamino or C_x._y-cycloalkenyloxy, for example.

If the free valency of a cycloalkenyl is saturated, then an unsaturated alicyclic group is obtained.

The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two binding partners. Formally the second valency is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are for example cyclopentenyl and

or

(cyclopentenylene)

The above définition for cycloalkenylene also applies when cycloalkenylene is part of another group as in HO-C_x.y-cycloalkenyleneamÎno or H₂N-C_x__y-cycloalkenyleneoxy, for

-2816301 example.

Ary! dénotés a mono-, bi- or tricyclic group with at least one aromatic carbocycle. Preferably it dénotés a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or, however, may also be saturated or partially saturated. If an aryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon atoms. Aryl itself may be linked as a substituent to the molécule via every suitable position of the ring System.

Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2- dihydronaphthyl), fluorenyl etc.

The above définition of aryl also applies when aryl is part of another group as in arylamino or aryloxy, for example.

If the free valency of an aryl is saturated, then an aromatic group is obtained.

The terrn arylene can also be derived from the previously defined aryl. Arylene, unlike aryl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups are e.g.

The above définition for arylene also applies when arylene is part of another group as in HO-aryleneamino or H₂N-aryleneoxy for example.

Heterocyclyl dénotés ring Systems, which are derived from the previously defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the groups -CH₂independently of one another in the hydrocarbon rings by the groups -O-, -S- or -NH- or by replacing one or more of the groups =CH- by the group =N-, wherein a total of not more than fîve heteroatoms may be présent, at least one carbon atom may be présent /

-2916301 between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the ring as a whole must have chemical stability. Heteroatoms may optionally be présent in ail the possible oxidation stages (sulphur sulphoxide -SO-, su Iphone -SO₂-; nitrogen -> N-oxide). In a heterocyclyl there is no heteroaromatic ring, i.e. no heteratom is part of an aromatic System.

A direct resuit of the dérivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl is made up of the subgroups monocyclic heterorings, bicyclic heterorings, tricyclîc heterorings and spiro-heterorings, which may be présent in saturated or unsaturated form. By unsaturated is meant that there is at Ieast one double bond in the ring System in question, but no heteroaromatic System is formed. In bicyclic heterorings two rings are linked together so that they have at Ieast two (hetero)atoms in common. In spiro-heterorings a carbon atom (spiroatom) belongs to two rings together. If a heterocyclyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogencarrying carbon and/or nitrogen atoms. Heterocyclyl itself may be linked as a substituent to the molécule via every suitable position of the ring System.

Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholtnyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl, tetrahydrothienyl, homothiomorpholinyl-S,Sdioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2H-pyrrolyl, 4Hpyranyl, 1,4-dihydropyridînyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, 2-oxa-5azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1 joctyl, 3,8-diaza-bicyclo[3.2.1 joctyl, 2,5diaza-bicyclo-[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1 joctyl, 3,9diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl, 1-oxa-

3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diazaspiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2,8-diaza-spiro[4.5]decyl etc.

Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen): -

-3016301

Û Û ü^N ô ô ô

H

-3116301

-3216301

The above définition of heterocyclyl also applies if heterocyclyl is part of another group as in heterocyclylamino or heterocyclyloxy for example.

If the free valency of a heterocyclyl is saturated, then a heterocyclic group is obtained.

The term heterocyclylene is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners.

-3316301

Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are for example

etc.

The above définition of heterocyclylene also applies if heterocyclylene is part of another group as in HO-heterocyclyfeneamino or H₂N-heterocyclyleneoxy for example.

Heteroaryl dénotés monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring, which compared with the corresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, wherein the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system. If a heteroaryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogencarrying carbon and/or nitrogen atoms. Heteroaryl itself may be linked as a substituent to the molécule via every suitable position of the ring system, both carbon and nitrogen. Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-AZ-oxide, pyrrolyl-M-oxide, pyrimidinyl-Noxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-/V-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-Noxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazoly), benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolînyl, phthalazinyl, quînazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, purinyl, pteridînyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N□xide, isoquinolyÎ-A/-oxide, quinazolinyl-W-oxide, quinoxalinyl-/V-oxide, phthalazinyl-/Voxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N- >

-3416301 oxide etc.

Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

-3516301

The above définition of heteroaryl also applies when heteroaryl is part of another group as in heteroarylamino or heteroaryloxy, for example.

If the free valency of a heteroaryl is saturated, a heteroaromatic group is obtained.

The term heteroarylene can therefore be derived from the previously defined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are for example

The above définition of heteroarylene also applies when heteroarylene is part of another group as in HO-heteroaryleneamino or H₂N-heteroaryleneoxy, for example.

The above-mentioned bivalent groups (alkylene, alkenylene, alkynylene etc.) may also be a part of composite groups (e.g. H₂N-Ci^alkylene or HO-Cwalkylene-). In this case one of the valencies is saturated by the attached group (in this case: -NH₂, -OH), so that a composite group of this kind in this nomenclature amounts in total to only a monovalent substituent.

By substituted is meant that a hydrogen atom which is bound directly to the atom under considération, is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place on one atom. Substitution with a particular substituent is only possible if the permitted valencies of the substituent and of the atom that is to be substituted correspond to one another and the substitution leads to a stable compound (i.e. to a compound which is not converted spontaneously, e.g. by rearrangement, s

-3616301 cyclisation or élimination).

Bivalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N₂ or the like, may only be substituents at carbon atoms, wherein the bivalent substituent =0 may also be a substituent at sulphur. Generally, substitution may be carried out by a bivalent substituent only at ring Systems and requires replacement by two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom that is saturated prior to the substitution. Substitution by a bivalent substituent is therefore only possible at the group -CH₂_ or sulphur atoms of a ring system,

Stereochemistry/Solvates/Hydrates: Unless stated otherwîse a structural formula given in the description or in the claims or a chemical name refers to the corresponding cornpound itself, but also encompasses the tautomers, stereoisomers, optical and géométrie isomers (e.g, enantiomers, diastereomers, E!Z isomers, etc.), racemates, mixtures of separate enantiomers in any desired combinations, mixtures of diastereomers, mixtures of the forms mentioned hereinbefore (if such forms exist) as well as salts, particularly pharmaceutically acceptable salts thereof. The compounds and salts according to the invention may be présent in solvated form (e.g. with pharmaceutically acceptable solvents such as e.g. water, éthanol etc.) or in unsolvated form. Generally, for the purposes of the présent invention the solvated forms, e.g. hydrates, are to be regarded as of equal value to the unsolvated forms.

Salts: The term pharmaceutically acceptable is used herein to dénoté compounds, materials, compositions and/or formulations which are suitable, according to generally recognised medical opinion, for use in conjunction with human and/or animal tissue and do not have or give rise to any excessive toxicity, irritation or immune response or lead to other problems or complications, i.e. correspond overall to an acceptable risk/benefit ratio. The term pharmaceutically acceptable salts relates to dérivatives of the chemical compounds disclosed in which the parent cornpound is modified by the addition of acid or base. Examples of pharmaceutically acceptable salts include (without being restricted thereto) salts of minerai or organic acids in relation to basic functional groups such as for example amines, alkali métal or organic salts of acid functional groups such as for example carboxylic acids, etc. These salts include in particular acetate, ascorbate, benzenesulphonate, benzoate, besylate, bicarbonate, bitartrate, bromide/hydrobromide, Ca-edetate/edetate, camsylate, carbonate, chloride/hydrochloride, citrate, edisylate, ethane disulphonate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate,

-3716301 glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, methanesulphonate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, oxalate, pamoate, pantothenate, phenyl acetate, phosphate/diphosphate, polygalacturonate, prapionate, salicylate, stéarate, subacetate, succinate, sulphamîde, sulphate, tannate, tartrate, teoclate, toluenesulphonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumin and procaine. Other pharmaceutically acceptable salts may be formed with cations of metals such as aluminium, calcium, lithium, magnésium, potassium, sodium, zinc, etc, (ci, also Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19),

The pharmaceutically acceptable salts of the présent invention may be prepared starting from the parent compound which carries a basic or acidic functionality, by conventional chemical methods, Generally, such salts may be synthesised by reacting the free acid or base form of these compounds with a sufficient amount of the corresponding base or acid in water or an organic solvent such as for example ether, ethyl acetate, éthanol, isopropanol, acetonitrile (or mixtures thereof).

Salts of acids other than those mentioned above, which are useful for example for purifying or isolating the compounds from the reaction mixtures (e.g. trifluoroacetates), are also to be regarded as part of the invention.

In a représentation such as for example or ^N or the letter A has the function of a ring désignation in order to make it easier, for example, to indicate the attachment of the ring in question to other rings.

For bivalent groups in which it is crucial to détermine which adjacent groups they bind and with which valency, the corresponding binding partners are indicated in brackets, where necessary for clarification purposes, as in the following représentations: s

-3816301

or (R²)-C(O)NHor (R²)-NHC(0)-;

Groups or substituents are frequently selected from among a number of alternative groups/ substituents with a corresponding group désignation (e.g. R®, R^b etc). If such a group is used repeatedly to define a compound according to the invention in different 5 molecular parts, it must always be borne in mind that the various uses are to be regarded as totally independent of one another.

By a therapeutically effective amount for the purposes of this invention is meant a quantity of substance that is capable of obviating symptoms of illness or of preventing or alleviating these symptoms, or which prolong the survival of a treated patient.

List of abbreviations

aa	amino acid
Ac	acetyl
equiv.	equivalent(s)
Ar	aryl
ATP	adenosine triphosphate
Boc	tert-butyloxycarbonyl
BSA	bovine sérum aîbumin
Bu	butyl
d	day(s)
TLC	thin layer chromatography
DCC	dicyclohexylcarbodiimÏde
DCM	dichloromethane
DEA	diethylamine
DIC	diisopropylcarbodiîmide
DI PEA	/V-ethyl-/V,/V-diisopropylamine (HÜNiG-base)
DMA	/V./V-dimethylacetamide
DMAP	4-d i methylaminopyrid i ne
DMF	Ν,/V-dimethylformamide

-3916301

DMF-DMA	N,N-dimethylfomnamide-dimethylacetal
DMSO	dimethylsulphoxide
dppf	1,T-bis(diphenylphosphino)ferrocene
EDC	N-(3-dimethylaminopropyl)-N4-ethylcarbodiimide hydrochloride
ESI	électron spray ionization
Et	ethyl
EtOH	éthanol
h	hour(s)
HATU	O-(7-azabenzotriazol-1-yl)-A/,A/,N',N-Îetramethyluronium hexafluorophosphate
HCl	hydrochloric acid
het	hetero
HPLC	high performance liquid chromatography
Hünig base	/V-ethyl-N,/V-diisopropy]amine
i	iso
/PrzNEt	diisopropylethylamine (Hünig base)
/PrOH	isopropanol
cat.	catalyst, catalytic
conc.	concentrated
LC	liquid chromatography
sln.	solution
M	molar
Me	methyl
MeOH	methanol
min	minute(s)
mL	millilitres
MPLC	medium pressure liquid chromatography
MS	mass spectrometry
MW	microwave
N	normal
NMP	/V-methyl pyrrolid inone
PBS	phosphate-buffered saline

-4016301

Pd-dppf	1 ,r-bis(diphenylphosphino)ferrocene palladium(ll)dichloride dichloromethane
Ph	phenyl
PK	pharmacokinetics
Pr	propyl
Rf (Rf)	rétention factor
RP	reversed phase
RT	ambient température
s	second(s)
TBTU	0-(benzotriazol-1 -y\)-N,N, N’, N -tetramethyl-uronium tetrafluoroborate
TEA	triethylamine
tert	tertîary
Tf	triflate
TFA	trifluoroacetic acid
THF	tetrahydrofuran
TMS	trimethylsilyl
Tos	tosyl
tRet.	rétention time (HPLC)
TRIS	tris(hydroxymethyl)-aminomethane
uv	ultraviolet

Features and advantages of the présent invention will become apparent from the following detailed Examples, which illustrate the fundamentals of the invention by way of example, without restricting its scope:

Préparation of the compounds according to the invention

General

Unless stated otherwise, ail the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and io corresponding reactions and manipulations therewith are carried out under protective gas

-4l16301 (nitrogen or argon).

The compounds are named according to the Beilstein rules using the Autonom software (Beilstein). If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is décisive.

Microwave reactions are carried out in an initiator/reactor made by Biotage or Synthos 3000 and Monowave 300 made by the company Anton Paar in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring.

Chromatography

Thin layer chromatography is carried out on ready-made TLC plates of silica gel 60 on glass (with fluorescence indicator F-254) made by Merck.

The préparative high pressure chromatography (HPLC) of the example compounds according to the invention is carried out with columns made by Waters (names: Sunfire C18, 5 pm, 30 x 100 mm Part. No. 186002572; X-Bridge C18, 5 pm, 30 x 100 mm Part. No. 186002982).

The compounds are eluted using either different gradients of H₂O/acetonitrile or H₂O/MeOH, wherein preferably 0.1 % HCOOH is added to the water (acid conditions). For chromatography under basic conditions H₂0/acetonitrile gradients are also used, and the water is made basic according to the following recipe; 5 mL of an ammonium hydrogen carbonate solution (158 g to 1 L H₂O) and 2 mL ammonia (7M in MeOH) are made up to 1 L with H₂O.

The normal-phase préparative high pressure chromatography (HPLC) of the example compounds according to the invention is carried out with columns made by Macherey & Nagel (name: Nucleosil, 50-7, 40 x 250 mm) and VDSoptilab (name: Kromasil 100 NH₂, 10 μΜ, 50 x 250 mm). The compounds are eluted using different gradients of DCM/ MeOH, with 0.1 % NH₃ added to the MeOH.

The analytical HPLC (reaction monitoring) of intermediate compounds is carried out with columns made by Agilent, Waters and Phenomenex. The analytical equipment is also provided with a mass detector in each case.

HPLC mass spectroscopy/UV spectrometry

The rétention times/MS-ESr for characterising the example compounds according to the invention are produced using an HPLC-MS apparatus (high performance liquid -4216301 chromatography with mass detector) made by Agilent. Compounds that elute at the injection peak are given the rétention time t_Ret. = 0.00.

HPLC-methods

Préparative

prep. HPLC1 HPLC:	333 and 334 Pumps
Column:	Waters X-Bridge C18, 5 pm, 30 x 100 mm, Part. No. 186002982
Eluant:	A: 10 mM NH4HCO3 in H2O; B; acetonitrile (HPLC grade)
Détection:	UV/Vis-155
Flow;	50 mL/min
Gradient:	0.00 min: 5 % B 3.00 - 15.00 min: variable (see individual methods) 15.00-17.00 min: 100 % B
prep. HPLC2 HPLC:	333 and 334 Pumps
Column:	Waters Sunfire C18, 5 pm, 30 x 100 mm, Part. No. 186002572
Eluant:	A: H2O + 0.2 % HCOOH; B: acetonitrile (HPLC grade) + 0.2 % HCOOH
Détection:	UV/Vis-155
Flow:	50 mL/min
Gradient;	0.00 min: 5 % B 3.00 - 15.00 min: variable (see individual methods) 15.00-17.00 min: 100% B

analytical

Method A

HPLC	Agilent 1100 Sériés
MS	1100 Sériés LC/MSD SL (MM-ES + APCI, + 3000 V, Quadrupol, G1956B)

MSD signal settings Scan pos 120 - 750

column	Waters, XBridge, C18, 3.5 pm, 135 A, 30 x 2.1 mm column, Part. No: 186003020
eluant	A: 5 mM NH4HCO3/20 mM NH3 (pH = 9.5)

-4316301 détection signal spectrum peak width injection flow column température gradient

B: acetonitrile (HPLC grade)

UV 254/214 nm (bandwidth 8, reference off) range: 190 - 400 nm; step: 2.0 nm > 00025 min (0.05 s) pL standard injection

1.0 mL/mîn

35°C

0.0- 1.0 min

1.0-1.6 min

1.6 -1.7 min

1.7 - 2.3 min

15% ->95% B % B

95% -> 15% B

15% B

Method B

HPLC

MS

MSD signal settings column eluant détection signal spectrum peak width injection flow column température gradient

Agitent 1100 Sériés

1100 Sériés LC/MSD SL (MM-ES + APCI, + 3000 V, Quadrupol,

G1956B)

Scan pos 120 - 750

Waters, XBridge, C18, 3.5 pm, 135 Â, 30x2.1 mm column,

Part. No.; 186003020

A: 5 mM NH4HCO3/ 20 mM NH₃ (pH = 9.5)

B:MeOH (HPLC grade)

UV 254/214 nm (bandwidth 8, reference off) range: 190 - 400 nm; step: 2.0 nm > 00025 min (0.05 s) pL standard injection

1.0 mL/min

40°C

0.0 - 1.0 min

1.0-2.0 min

2.0 - 2.1 min

2.1 -2.3 min % 95 % B % B % 20 % B % B

-4416301

Method C

HPLC

MS

MSD signal settings column éluant détection signal spectrum peak width injection flow column température gradient

Method D

HPLC

MS

MSD signal settings column éluant détection signal spectrum peak width injection

Agilent 1100 Sériés

1200 Sériés LC/MSD (API-ES + 3000 V, Quadrupol, G6140A)

Scan pos 150 - 750

Agilent. Zorbax SB, C8, 3.5 pm, 80 Â, 50 x 2.1 mm column, Part.

No.: 871700-906

A: water + 0.11 % formic acid

B: acetonitrile (HPLC grade) + 0.1 % formic acid

UV 254/214/230 nm (bandwidth 8, reference off) range: 190-450 nm; step: 4.0 nm > 0.01 min (0.2 s)

1.5 pL standard injection

1.1 mL/min

45°C

0.0 -1.75 min

1.75 -1.9 min

1.9-1.92 min

1.92-2.1 min

15% Z 95% B % B

95% Z 15% B % B

Agilent 1100 Sériés

1100 Sériés LC/MSD SL (MM-ES + APCI, + 2500 V, Quadrupol, G1956B)

Scan pos 70 - 500

Agilent Zorbax SB, C8, 3.5 pm, 80 Â, 50 x 2.1 mm column, Part.

No.: 871700-906

A: water + 0.11 % formic acid

B: MeOH (HPLC grade)

UV 254/214/230 nm (bandwidth 8, reference off) range: 190 - 450 nm; step; 4.0 nm > 0.01 min (0.2 s)

1.5 pL standard injection Z

-4516301 flow column température gradient

1.0 mL/min

45°C

0.0 -1.5 min

1.5 - 2.1 min

2.1 -2.2 min

2.2-2.4 min % -> 95 % B % B % 20 % B % B

Method E

HPLC

MS

MSD signal settings column eluant détection signal spectrum peak width injection flow column température gradient

Agitent 1100 Sériés

1100 Sériés LC/MSD SL (MM-ES + APCI, + 3000 V, Quadrupol,

G1956B)

Scan pos 100-750

Waters, XBridge, C18, 3.5 pm, 135 A, 30 x 2.1 mm column,

Part. No.; 186003020

A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5)

B. acetonitrile (HPLC grade)

UV 254/214 nm (bandwidth 8, reference off) range: 190 - 400 nm; step: 2.0 nm > 0005 min (0.1 s) pL standard injection

1.0 mL/min

35°C

0.0 - 1.0 min

1.0 -1.6 min

1.6 -1.7 min

1.7-2.3 min

15% 95% B % B % -> 15 % B

15% B

Method F

HPLC

MS

MSD signal settings column

Agilent 1100 Sériés

1200 Sériés LC/MSD (API-ES + 2500 V, Quadrupol, G6140A)

Scan pos 75 - 500

Agilent Zorbax SB, C8, 3.5 pm, 80 A, 50 x 2.1 mm column, >

-4616301

	Part. No.: 871700-906
eluant	A: water + 0.11 % formic acid B: acetonitrile (HPLC grade) + 0.1 % formic acid
détection signal spectrum peak width injection flow	UV 254/214/230 nm (band width 8, reference off) range: 190 - 450 nm; step: 4.0 nm > 0.01 min (0.2 s) 1.5 pL standard injection 1.1 mL/min

column température 45°C gradient

0.0 -1.75 min

1.75 -1.9 min

1.9-1.92 min

1.92-2.1 min

15%->95% B % B %-> 15% B % B

Method G

HPLC

Agitent 1100 Sériés

MS

1100 Sériés LC/MSD (APl-ES +/- 3000 V, Quadrupol, G1946D)

MSD signal settings

Scan pos 120 - 900, Scan neg 120 - 900

column	phenomenex; Part. No. OOM-4439-BO-CE; Gemini 3 pm, C18, 110 Â; 20 x 2.0 mm column
eluant	A: 5 mM NH4HCO3/2O mM NH3 (pH = 9.5) B: acetonitrile (HPLC grade)
détection signal	UV 254 nm (bandwidth 1, reference off)
spectrum peak width injection flow	range: 250 - 400 nm; step: 1 nm < 0.01 min (0.1 s) 10 pL standard injection 1.0 mL/min

column température 40°C gradient

0.0 - 2.5 min

2.5 - 2.8 min % 95 % B % B

2.8 - 3.1 min % -> 5 % B

The compounds according to the invention are prepared by the methods of synthesis

-4716301 described hereinafter, in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the préparation of starting compounds is not described, they are 5 commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis.

-4816301

General formula scheme and summary of the synthesis route

Var. 2a

O O

c ^D Var. 2b E

Novel compounds of general structure (I) may be prepared starting from cyclic 1,3diketones A by two different synthesis routes leading to the central component B:

-4916301

The first variant (Var. 1) makes the intermediates B available by the reaction of suitable diketones A with substituted hydrazines R¹NHNH₂ and dimethylformamide-dimethylacetal or analogous reagents.

The second variant (Var. 2) converts the starting compounds A by reaction with acid chlorides R’COCI and subséquent rearrangement of the intermediate enol esters into the triketones C, which can be converted with oxalyl chloride into the vinyl chlorides D. Substitution with protected hydrazines R^ÎNHNH₂ (Var. 2a) leads to the intermediates E, which cyclise in the hydrochloric acid medium after the cleaving of the protective group to form the central component B. When arylhydrazines are used there is no need for the protective group (Var. 2b). Here, the reaction of the chlorine compound D yields the intermediate B directly.

By reacting B with dimethylformamide-dimethylacetal or formic acid esters in the presence of bases the intermediate compounds F1 or F2 are obtained, which may in turn be reacted to form the end compounds (I) by reaction with guanidines available from amines using known methods. Altematively B may be reacted with phosphorus oxychloride in the presence of DMF to form the intermediate F3 which may be cyclised with corresponding guanidines to form (I).

The compounds (I) may be on the one hand end compounds according to the invention or on the other hand may also be prepared using correspondingly protected components, deprotected by conventional methods and then converted into other compounds (I) according to the invention by derivatisation steps such as e.g. amide formation, alkylation or amination reactions. Instead of protected reagents it is also possible to use synthesîs compounds which can be directly functionalised or derivatised without recourse to protective groups.

-5016301

1. Préparation of the pyrazole fragments B

1.1. Préparation ofthe pyrazole fragments B starting from diketones A according to Variant 1

O

A

The pyrazole fragments B are prepared analogously to the method of Kennedy L. J., Lawrence J. Synlett 2008 (4), 600 - 604.

Préparation of B-01

Cyclohexane-1,3-dione (6.00 g, 53.5 mmol) in MeOH (15 mL) is combined at 0°C with methylhydrazine (2.82 mL, 53.0 mmol) in THF (15 mL) and the mixture is stirred for 1.5 h. It is heated to RT, dimethylformamide-dimethylacetal (15 mL, 113.3 mmol) is added and the reaction mixture is heated in a microwave reactor (120^oC, 10 min). The solvent is spun off in vacuo and the residue is purified by chromatography.

The libération of hydrazinium salts is carried out either analogously to the Kennedy method with triethylamine or by the addition of potassium-tert-butoxide.

Reactions with dimethylacetamide-dimethylketal are carried out analogously to dimethylformamide-dimethylacetal. Optionally potassium-tert-butoxide may also be added to the cyclisation reaction here.

Analogously to B-01 further pyrazole fragments B are synthesised using the corresponding educts (Table 1).

Table 1

No.	Structure	fret [min]	[M+H]+	Method of analysis
B-01		0.35	151.2	C
B-02	4 X	0.29	165.0	A

-5116301

No.	Structure	fret [min]	[M+H]+	Method of analysis
B-03		0.49	165.2	F
B-04	ëA	0.59	179.1	C
B-05	A-	0.46	165.2	F
B-06	AA '-N \	0.24	208.0	E
B-07		0.59	179.3	F
B-08	c?A	0.57	179.3	F
B-09	AA. N— /	0.35	236.2	E
B-10	ÔA	0.69	193.1	F
B-11		0.58	179.3	F

-5216301

No.	Structure	fret [min]	[M+H]*	Method of analysis
B-12		0.67	193.1	F

1.2. Préparation of the pyrazole fragments B via triketones C (Variant 2/2a)

O

A

1. R¹COCI

N H, [ 2	O O Il II
^NBoc	ÂX,
R	H R
Method D	X^NH _2xNHBoc r\

Method E

E

HCl

Préparation of C-01 (method A, method B)

Cyclohexane-1,3-dione (2.00 g, 17.3 mmol), propionic acid chloride (2.07 mL, 23.2 mmol) and DMAP (360 mg, 3.21 mmol) are stirred in anhydrous toluene (60 mL) for 30 min at RT and refluxed for 1 h. The cooled reaction mixture is washed 3 x with water and once with saturated saline, dried on sodium sulphate, filtered and evaporated down. The residue is taken up in anhydrous toluene (100 mL), combined with DMAP (290 mg, 2.23 mmol) and io refluxed for 3 h with stirring. The cooled reaction mixture is washed 3 x with water and once with saturated saline, dried on sodium sulphate, filtered and evaporated down.

Alternatîvely the second partial step may be carried out in the presence of triethylamine with catalytic amounts of potassium cyanide or 1,2,4-trîazole in acetonitrile.

Analogously to C-01 further triketones C are synthesised using the corresponding educts (Table 2). /

-5316301

Table 2

No.	Structure	fret [min]	[M+H]*	Method of analysis
	0 II	0 II
C-01	δ	c	0.77	169.1	F
	o	0 L
C-02	e	t	0.68	169.2	C
	0 II	0 II
C-03	ô	^0	0.84	181.2	C
	0 II	o
C-04	ô	C?	0.97	183.2	F
	0 II	0 II
C-05	ô	δ3	0.99	195.0	C
	o II	0
C-06	ά	'0	0.94	183.3	C
C-07	ά	0	0.46	185.0	F
		'0
	0 II	s
C-08	ώ	δο	0.74	217.2	C
	0 II	o II
C-09	δ	δ'	0.87	197.3	D

-5416301

No.	Structure	Let [min]	[M+H]*	Method of analysis
C-10	0 °	1.09	231.2	F
C-11		1.16	245.0	F
C-12	0 O cXo	1.12	209.1	C
C-13	0 0 dto	1.19	223.2	C
C-14	0 0	0.43	207.0	C
C-15	0 0 cXq	0.74	225.0	c
C-16	î:	0.97	195.2	F
C-17	άΐύ	0.97	231.2	C

-5516301

No.	Structure	fret [min]	[M+H]*	Method of analysis
C-18	0 0 Cl w	1.00	251.0	C
C-19	0 0 0^ w	0.85	247.2	C
C-20	dd	0.89	221.0	C
C-21	0 0 I 'Vù	1.09	245.2	c
C-22	O O Cl	1.11	265.2	c
C-23	0 °	1.24	259.2	c
C-24	9 o ci cXû0 I	1.04	281.0	c
C-25	0 0 Cl όύψ F	1.05	269.0	c

-5616301

No.	Structure	tret [min]	[M+H]+	Method of analysis
C-26	0 0 Cl ά»	1.10	265.0	C
C-27	Q o ci	1.05	269.0	C
C-28	0 0	1.14	245.2	C
C-29		1.08	261.2	c
C-30	o 0	1.06	261.2	c
C-31	0 0 Cl zeô	1.12	265.2	c
C-32	ο o	0.90	261.2	c

Préparation of D-01 by chlori nation (method C)

C-01 (525 mg, 3.22 mmol) and oxalyl chloride (515 pL, 5.84 mmol) are stirred in anhydrous DCM for 12 h at RT. The reaction mixture is evaporated to dryness and further 5 reacted immediately.

For the HPLC analysis the reaction mixture is mixed with morpholine and the product is

-5716301 detected as alkylated morpholine dérivative. The [M+H]⁺ value found relates to this compound.

Analogously to D-01 further chlorinated diketones D are synthesised using the corresponding intermediate C (Table 3).

Table 3

No.	Structure	trot [min]	[M+H]*	Method of analysis
	0 II	î
D-01	i	é Cl	0.23	224.3	F
	0 II	0
D-02	ô	'Cl	0.33	238.1	F
	0	o L
D-03	d	f	0.20	238.2	C
	0 II	0 II
D-04	ô	'V ^Cl	0.45	252.3	C
	0 II	o II
D-05	ά	Cl	0.51	264.3	C
	0 II	0
D-06	ô	i	0.30	252.2	E
	O II	o II
D-07	ύ	A 'Cl °'	0.10	254.0	A

-5816301

No.	Structure	fret [min]	[M+H]+	Method of analysis
	O II	0 II
D-08	Λ	Λ,	·>	0.54	286.2	C
	m	XI
	0 II	0 II
D-09	k			0.42	266.2	A
	O	0 i
D-10	Oc	'Cl		0.66	300.2	F
	O	0
D-11	Oc	'Cl >	1	0.75	314.1	C
	0	0 II
D-12	ô	6	fi)	0.64	278.2	B
	O II	0 II
D-13	ô	ù	D	0.74	292.2	B
	0 II	O II
D-14	ô	ά	fi	0.32	276.3	C
	O II	0 II
D-15	ô	ù	?o	0.35	294.3	C

-5916301

No.	Structure	tret [min]	[M+H]*	Method of analysis
D-16	0 0 Λ Λ,	0.50	264.3	C
D-17	e*	0.59	300.2	C
D-18	9 o ci ôOô	0.76		C
D-19	0 0 θ' «ό	0.48	316.2	c
D-20	0 0 , : Z*	0.43	290.2	c
D-21	0 0 I 'ôi	0.73	314.2	c
D-22		0.67	334.2	c
D-23	0 0	1.26	277.2 (product mass)	c

-6016301

No.	Structure	trel [min]	[M+H]+	Method of analysis
D-24	0 0 Cl o, I	0.64	350.2	C
D-25	F	0.61	338.2	C
D-26		0.65	334.2	C
D-27	0 0 Cl ωχ	0.62	338.2	C
D-28	° ° Ja'j)	0.76	314.2	c
D-29	0 0 77 ÔvXi	0.68	330.2	c
D-30	° 0 ΓΓ	0.66	330.2	c
D-31	O 0 Cl Æô	0.67	334.2	c

-6116301

No.	Structure	fret [min]	[M+H]*	Method of analysis
	O O r^ji
D-32	UUk	0.57	330.2	C

Préparation of E-01 by substitution with Boc-protected hydrazines (method D, Variant 2a)

Chlorine compound D-01 (1.20 g, 6.43 mmol) in anhydrous THF (10 mL) is combined at 5 -35°C with N-ethyldiisopropylamine (1.10 mL, 6.43 mmol) and 1-Boc-1-methylhydrazine (0.969 mL, 6.43 mmol), heated to RT and stirred for 12 h at RT. The reaction mixture is evaporated down, the residue is taken up in EtOAc, washed with saturated ammonium chloride solution, water and saturated sodium chloride solution, dried (Na₂SO₄), filtered and evaporated down. Optionally the crude product may be purified by chromatography.

Analogously to E-01 further intermediate compounds E are synthesised using the corresponding intermediate D and a hydrazine component (Table 4).

Table 4

No.	Structure	fret [min]	[M+H]*	Method of analysis
E-01	O O ec I ^NBoc	1.03	297.3	C
E-02	θ o Anh J ^NBoc	0.96	297.3	C

-6216301

No.	Structure	tret [min]	[M+H]+	Method of analysis
E-03	O 0 ûS I ^NBoc	1.02	309.3	C
E-04	O O àS I \^/NBoc 1	1.13	323.4	C
E-05	0 0 I \q/\^NBoc	1.07	353.4	C
E-06	0 0 ÙV NH I ^NBoc	1.11	311.1	c
E-07	0 0 I /NBoc	1.15	323.1	c
E-08	0 0 ee I ^NBoc	1.11	311.4	c

-6316301

No.	Structure	tret [min]	[M+H]+	Method of analysis
E-09	0 0 I N B oc	0.84	313.1	F
E-10	όάο I ^NBoc	0.67	345.2	A
E-11	0 0 ÔcV NH I ^NBoc	1.07	325.1	F
E-12	0 0 NH I /-.....NBoc n	1.36	339.2	F
E-13	0 0 zy I \^NBoc	1.31	339.3	C
E-14	0 0 I ^NBoc	1.26	359.3	F

-6416301

No.	Structure	fret [min]	[M+H]*	Method of analysis
E-15	êÇo /NBoc	1.31	373.1	F
E-16	O O tYn NH I ^NBoc	1.24	337.2	C
E-17	: I ^NBoc	1.28	351.3	C
E-18	0 O NH I /NBoc	0.76	335.1	C
E-19	όάα I xNBoc	0.92	353.4	c
E-20	O 0 ôC I \/NBoc	1.16	311.2	F
E-21	P θ Ôô I \ox^/NBoc	0.95	327.3	C

-6516301

No.	Structure	fret [min]	[M+H]+	Method of analysis
E-22	0 0 ôC I \q/\^NBoc	1.10	341.3	F
E-23	O O NH I \^NBoc	1.22	325.2	C
E-24	0 0 λ ! ,,NBoc	1.12	323.3	F
E-25	0 0 i ÙV I /NBoc	1.10	359.2	C
E-26	0 O Cl ôCô I ^NBoc	1.14	379.2	C
E-27	0 0 0^ I ^NBoc	1.02	375.2	C

-6616301

No.	Structure	fret [min]	[M+H]1	Method of analysis
E-28	0 O , I xNBoc	0.84	349.2	C
E-29	I .N B oc	1.19	373.2	C
E-30	0 O Cl γ xNBoc	1.21	393.2	c
E-31	j? ° I ,,NBoc	1.37	387.2	c
E-32	O 0 Cl ôôX I /NBoc	1.15	409.2	c
E-33	0 O Cl /NBocF	1.19	397.2	c

-6716301

No.	Structure	tret [min]	[M+H]+	Method of analysis
E-34	0 0 Cl AA ) ^NBoc	1.21	393.2	C
E-35	O 0 Cl AA ^NBoc	1.19	397.2	C
E-36	Â Â jQ I ^NBoc	1.26	373.2	C
E-37	° 0 ^Anh /° I ^NBoc	1.21	389.2	c
E-38	0 5 I ^NBoc	1.20	389.2	c
E-39	0 0 Cl AA I ^NBoc	1.22	393.2	c

-6816301

No.	Structure	fret [min]	[M+H]+	Method of analysis
E-40	0 0 H ^-^'NHOx·' I ^NBoc	1.07	389.2	C

¹ Brosse, Nicolas et al., Préparation of multiply protected alkylhydrazine dérivatives by Mitsunobu and PTC approaches”; Europ. J. Org. Chem. 2003, 4757-4764;

² Brosse, Nicolas et al., New synthesis of 1,1-substituted hydrazines by alkylation of

N-acyl or N-[(alkyloxycarbonyl)amino]phthalîmide using the Mitsunobu protocol”; J. Org. Chem. 2000, 4370-4374.

Préparation of B-13 by cyclisation (method E)

The protected hydrazine E-01(1.5 g, 5.06 mmol) in anhydrous dioxane (3 mL) is combined with 4 N HCl in dioxane (5 mL) and stirred for 1 h at RT. The reaction mixture is 10 evaporated down, the residue is taken up in DCM, washed with saturated potassium carbonate solution and saturated sodium chloride solution, dried (Na₂SO₄), filtered and evaporated down. Optionally the crude product may be purified by chromatography.

Analogously to B-13 further întermediate compounds E are cyclised (Table 5).

Table 5

No.	Structure	fret [min]	[M+H]+	Method of analysis
B-13	M	0.60	179.1	C
B-14		0.60	179.1	C

-6916301

No.	Structure	fret [min]	[M+H]+	Method of analysis
B-15	° p [ nN~	0.62	191.1	C
B-16	° P [ N—	0.72	205.2	C
B-17	° P f 'N V-o \	0.66	235.2	C
B-18	° V [ TN~	0.74	193.2	c
B-19	° / 1 N	0.81	205.2	c
B-20	Ο Γ [ PN— X/n	0.71	193.2	c
B-21	.	0.48	195.2	F

-7016301

No.	Structure	Let [min]	[M+H]+	Method of analysis
B-22	o [ PN	0.79	227.1	C
B-23	0 Vc [ N—	0.87	207.2	C
B-24	0 V f PN~\	0.95	221.1	C
B-25	° [ n—\	0.95	221.1	c
B-26	θ rO [ ΓN	0.892	241.2	c
B-27	Ο Γ [ pN-	0.96	255.3	c

-7116301

No.	Structure	tret [min]	[M+HJ*	Method of analysis
B-28	O Γ [ N—	0.91	219.3	C
B-29	o \ i n~	1.02	233.1	C
B-30	o °p Γ LN~	0.79	217.2	C
B-31	rQ o y-P [ 1N“ V''N	0.59	235.2	c
B-32	PP	0.68	193.2	c
B-33		0.46	165.2	F
B-34	Pk V_o \	0.53	209.1	C

-7216301

No.	Structure	fret [min]	[M+H]+	Method of analysis
B-35	ÔÀ. V-O \	0.64	223.2	C
B-36	° [ ΓN\ \	0.80	237.3	C
B-37	0 V	0.84	207.3	C
B-38	ο Γ Γn—	0.95	205.2	c
B-39	0 Γ\ [ Γ 'N-	0.85	241.2	c
B-40	o y=\ JL7 Cl [ n—	0.88	261.2	c

-7316301

No.	Structure	tret [min]	[M+H]*	Method of analysis
B-41	o V o- f ΓN—	0.80	257.2	C
B-42	o yk l 1 n-	0.80	231.2	C
B-43	0 f JVN—	1.00	255.2	C
B-44	o M AJ ci [ N-	1.00	275.2	c
B-45	θ w [ 'Γ N”	1.08	269.2	c
B-46	0 o Va JL7 ci [ n—	0.94	291.0	c

-7416301

No.	Structure	fret [min]	[M+H]+	Method of analysis
B-47	F ο Va ci [ L N— aV	0.92	279.2	C
B-48	o Va JV7 ci l ΊνN A^N	0.99	275.2	C
B-49	F o Va JL7 ci L JVN_	0.92	279.0	c
B-50	o vO [ TN_ aV	0.98	255.2	c
B-51	/ O 9 vO i Ίνn_ aa^n	0.95	271.2	c
B-52	O [ N— AA'N	0.90	271.2	c

-7516301

No.	Structure	fret [min]	[M+H]+	Method of analysis
B-53	o ci f PN~	0.99	275.2	C
B-54	oP) f P'N—	1.00	271.2	C

1.3. Préparation of (hetero)arylpyrazole fragments B via triketones C (Variant 2/2b)

O

A

1. R¹C0CI

H N NH, (Het)Ar

Method D ,1

O

N-(Het)Ar ( = R2)

N

Préparation of pyrazole fragment B-55 by cyclisation with (hetero)arylhydrazine (method D)

The réaction of the chiorinated diketones with (hetero )arylhydrazi nés is carried out according to method E and yields the corresponding (heteroJarylpyrazole fragment

-7616301 directly.

Table 6

No.	Structure	fret [min]	[M+H]*	Method of analysis
B-55	0 N	0.93	256.2	C
B-56	0 V- OXXX N	0.85	256.2	C

2. Préparation of the starting compounds for the pyrimidine cyclisation reaction

2.1. Reaction of B to obtain intermediates F1 and F2

Préparation of F1-01: Condensation with dimethylformamide-dimethylacetal (method F)

Pyrazole fragment B-01 (7.5 g, 49.9 mmol) and DMF-DMA (15 mL, 113.3 mmol) in DMA 10 (15 mL) are stirred in a microwave reactor for 30 min at 180’C. The solvent is spun off in vacuo and the residue is purified by chromatography.

Analogously to F1-01 further intermediate compounds F1 are obtained by condensation of pyrazole fragments B with DMF-DMA (Table 7). /

-ΊΊ16301

Table 7

No.	Structure	fret [min]	[M+H]+	Method of analysis
F1-01	ί< o w	0.45	179.0 (hydrolysis)	C
F1-02	\ r° V../'N	0.74	193.1 (hydrolysis)	F
F1-03	0 YXH	0.34	220.2	E
F1-04	\ c° ( T N-^	0.42	234.2	E
F1-05	X o Yr-v: N \	0.33	263.2	E
F1-06	X 0	0.67	207.3	C
F1-07	X O , YY» x	0.39	234.2	E

-7816301

No.	Structure	fret [min]	[M+H]*	Method of analysis
F1-08	0	0.56	282.0	A
F1-09	n o I T n—	0.40	234.2	E
F1-10	° X'' N—7	0.81	311.2	B
F1-11	0 \_rXXo —N	0.75	311.2	B
F1-12	° V- \X^N O \	0.53	292.2	A
F1-13	0 V i L X N^x	0.84	262.2	B
F1-14	θ \ i L X N	0.74	260.2	B
F1-15	0 r i L X N_	0,64	234.3	B

-7916301

No.	Structure	fret [min]	[M+H]*	Method of analysis
F1-16	\ 0 (ζ /N—	0.45	234.3	A
F1-17	0 i l L ·Ν_	0.41	246.2	A
F1-18	° F i L X ·Ν	0.48	260.2	A
F1-19	0 R i L £ ·Ν^\ X 0 \	0.45	290.2	A
F1-20	° V Υ^γΧγ\ [ I N-	0.49	248.2	A
F1-21	0 f Ν^ΛγΧΜ i L X ·Ν_	0.76	260.2	B
F1-22	0 Γ Ν^ΛγΧ i l X ·Ν_	0.49	248.2	A
F1-23	/ 0 O xnWm i L JX N_	0.34	250.2	A

-8016301

No.	Structure	tret [min]	[M+H]+	Method of analysis
F1-24	o dAX i L X N_ AA N	0.52	282.2	A
F1-25	° Xa '''ΝΑγΑΧ i L X -N_ AA'N	0.60	262.2	A
F1-26	0 V aaXU i L X na	0.64	276.2	A
F1-27	0 V vAA / i L X N \	0.86	276.2	B
F1-28	θ rO aAA [ [ n— A'N	0.82	296.2	B
F1-29	0 Γ ^VyÎ i L X N_ aA'-n	0.87	310.2	B
F1-30	0 r AaXU ! 1 X ·Ν“ AA'n	1.11	247.2 (hydrolysis)	C

-8116301

No.	Structure	fret [min]	[M+HJ*	Method of analysis
F1-31	0 s L X N	1.21	261.2 (hydrolysis)	C
F1-32	o <0 i l X N~	0.75	272.0	B
F1-33	Λ0 0 i I n— \A'N	0.66	290.2	B
F1-34	o r i L N AA	0.71	248.2	B
F1-35	'tVA AA-?n V o \	0.37	264.2	A
F1-36	0 [ I N-y \A?N Vo \	0.43	278.2	A

Préparation of F2-01: reaction with formic acid esters (method G)

KOtBu (100 mg, 0.89 mmol) is added at 0°C to pyrazole fragment B-09 (100 mg, 0.43 mmol) in anhydrous dioxane (0.5 mL) and stirred for 5 min. Ethyl formate (60 pL) is added and the mixture is stirred until the starting compound is completely reacted. KOiBu and ethyl formate are optionally metered in subsequently. The crude product may be ,χ

-8216301 reacted further directly in the next step.

Analogously to F2-01 further intermediate compounds F2 are obtained by reacting formic acid esters with pyrazole fragments B (Table 8).

Table 8

No.	product	fret [min]	[M+H]+	Method of analysis
F2-01	c° ( Γ N-	0.84	207.3	C
F2-02	OH O YïK N- /	0.13	264.2	E

2.2. Formylation and chlorination of B to form intermediates F3

Préparation of F3-01 by reaction with phosphorus oxychloride/DMF (method H)

DMF (2.7 mL) is added at 0°C to POCI₃ (2.4 mL) in anhydrous DCM (10 mL) and stirred 10 for 20 min. Pyrazole fragment B-22 (2.0 g, 8.8 mmol) is added, the mixture is stirred for min at RT and for 10 min at 100°C in a microwave reactor. The reaction mixture is added dropwise to semisaturated potassium carbonate solution and the product is extracted with DCM. The organic phase is washed with water, dried on sodium sulphate, filtered and evaporated down.

Analogously to F3-01 further intermediate compounds F3 are obtained by reacting pyrazole fragments B with POCI₃/DMF (Table 9).

-8316301

Table 9

No.	Structure	fret [min]	[M+H]+	Method of analysis
	0	Cl	yA
F3-01	HT		F N_	1.15	273.2	C
			Γδ
	0	Cl
F3-02			N—	1.22	287.2	C
			P)
	O	Cl
F3-03	H Ίί	Av	Λ	1.11	303.2	C
	L N— v/:::N
			ΓΛ
	0	CI
F3-04	H I	AA	Λ Cl	1.20	307.0	C
		N—
			~N
	0	Cl'	“yo
F3-05	H		L N_ 'N	1.14	277.2	C
			r$
F3-06	O	Cl	\===/	1.32	301.2	C
			Γ n—

-8416301

No.	Structure	tret [min]	[M+H]*	Method of analysis
F3-07	O Cl X 1 / ci hTTn-	1.32	321.0	C
F3-08	o ci yxj H ΤχΝ-	1.36	315.2	C
F3-09	o-· o ci X 1 / ci H rfN-	1.24	337.0	C
F3-10	o ci v=/ X 1 / ci HYrN- X/'N	1.23	325.0	c
F3-11	0 Cl X X / ci ηΥγν-	1.30	321.0	c

-8516301

No.	Structure	tret [min]	[M+Hf	Method of analysis
F3-12	F O Cl A A j ci H Tr^	1.24	325.0	C
F3-13	o ci yyy Hir N-	1.25	301.0	C
F3-14	/ 0 O CI z— H IP-	1.21	317.2	C
F3-15	° ci /ΆΑ°χ pv	1.16	317.2	c
F3-16	o ci \=4 JL JL / ci H iJA-	1.26	321.0	c
F3-17	0 Cl °v-JJ H lAn-	1.27	317.2	c

-8616301

3. Guanidine synthèses

HjNCN

Method J

NH

nh₂

The préparation of the guanidine compounds (method J) takes place in the Parallel

Synthesis Microwave Reactor (Synthos 3000, Anton Paar GmbH). The aniline (0.5 mmol) 5 in dioxane (300 pL) is combined with cyanamide (1.5 mmol) in dioxane (125 pL) and HCl (4 N in dioxane, 188 pL) and stirred for 1 h at 120°C.

The reaction solutions are used in the next step without any further purification.

Complexly substituted guanidines are prepared analogously to or using the methods of

C. E. Stephens, J. Med. Chem. 2001, 1741-1748 and H. Ube, J. Organomet. Chem. 10 2007, 545-549 using isothiourea components. '

-8716301

4. Préparation of novel compounds (I) by pyrimidine cyclisation and optionally derivatisation

4.1. Pyrimidine cyclisation on intermediates F1

F2 and F3 using guanidine (method I, type I)

F3

Method I: The reaction mixture of the guanidine synthesis is combined with pyridine (200 pL) and the corresponding pyrazole component F1, F2 or F3 (0.5 mmol) in dioxane (150 pL) and stirred for 1 h at 120°C in a parallel synthesis microwave reactor. The reaction mixture is purifîed by préparative HPLC-MS. The fractions containing the reaction 10 product are freeze-dried. The compounds 1-1 to I-295 according to the invention (Table

10) are prepared in this way.

Protected intermediate stages or guanidine intermediates intended for further derivatisation are prepared analogously and purifîed by conventional methods. The synthesis components required for this are synthesised from commercial reactants using 15 standard methods.

-8816301

Table 10

No.	Structure	fret [min]	[M+H]1	Method of analysis
1-1	0uljCQ v O N	1.33	442.2	C
I-2	x_ °\1X0Q V	1.39	456.2	C
I-3	•x- H	1.36	476.2	C
I-4	0Vt jCO U N V Cl H X-r^	1.50	460.2	c
I-5	'X- 0 lOl x0Cl ci H	1.54	460.2	c

-8916301

No.	Structure	fret [min]	[M+H]+	Method of analysis
I-6	°Ί λ	1.53	484.2	C
I-7	0jCO T H N °xH	1.46	470.2	C
I-8*	θΎΙΐΊυι Μ Ja νΑ'θ1	1.40	490.2	C
I-9	(ζΧό of°' ο-	2.07	456.3	G
1-10	’W. 0 Η rO V-ci	2.05	476.3	G

-9016301

No.	Structure	tret [min]	[M+H]*	Method of analysis
1-11	tS Vs z-P N\ z ° CJ	1.25	482.2	C
1-12	Xi îÛQ M « n >n n ° o c'	2.04	482.0	G
1-13	jO. ΓΟ μ h N7> ° o çy	2.05	466.0	G
1-14	cXn^i T N N X > Y A	0.90	538.4	C
1-15	«Z XWA T H N ï Z Οχ /ΖΛ VZ~c|	0.93	544.2	C

-9116301

No.	Structure	fret [min]	[Μ+Η]+	Method of analysis
1-16	O	1.84	538.3	G
1-17	I H N 1 > ci H s--< \	1.66	528.2	C
1-18	H / \ Νχ	1.88	354,3	G
1-19	<1 αΊΟ N N NVn Λ Η VÀci	1.66	420.3	G
I-20	[ίΆ Q'NAN*Mn ° Η ΖΛ	1.99	384.3	G
1-21	3.¾ CJFci	1.91	388.3	G

-9216301

No.	Structure	tret [min]	[M+H]*	Method of analysis
I-22	qnçq UAci	2.04	418.3	G
I-23	H /---/χ ÎJ^CI	1.54	392.3	G
I-24	r°TY ^ύί /-NJ V'NAN<SYn \_J JD H >-N 0	2.05	497.3	G
I-25	ιί^ι ν'Ν^Ί A JL λ X A /TnnVn \_° H	1.97	396.0	G
I-26	VnAnVn /Ο H ^Λν	1.83	482.3	G
I-27	γ°ίΓΥ νΎΊ γ,Ν S^N'V'YpN °-H /—( \ C/-CI	2.11	531.2	G

-9316301

No.	Structure	fret [min]	[M+H]+	Method of analysis
I-28	LXxJM T N N YN ci H /γ	2.14	388.0	G
I-29*	o,X	1.96	402.3	G
I-30	F'N N%r% X-U H /=< N\ vAci	1.65	406.3	G
1-31	JÛL 3ÛQ Y H	2.11	408.0	G
I-32	NXt'Î unvVn H An z \	1.79	350.3	G
I-33	ÇlÇQ Xh nVnn / O '	2.15	410.3	G

-9416301

No.	Structure	fret [min]	[M+Hf	Method of analysis
I-34	ÇVAX H A \ Νχ	1.97	368.0	G
I-35	I WM ,Ο H ΛΝ^ N- /	1.83	409.3	G
I-36	QXQ Th NZjN P H	2.08	382.0	G
I-37	T N N N -^o A~\	2.13	398.0	G
I-38	Z cT	2.21	438.0	G
I-39	Λ ΓΟ CN H nVn H Z=<A 1X~CI	1.51	428.3	G

-9516301

No.	Structure	Let [min]	[M+H]+	Method of analysis
I-40*	H J-N UAi	1.82	434.3	G
1-41*	n-n ναΛ AMmM N ν%Γν H N\ PAci	1.69	420.3	G
I-42*	n-n naA N N vn H _An VYci	1.64	406.3	G
I-43*	N-NZ n%Z ΆΧ,χΛΑ n H _AN W~CI	1.64	420.3	G
I-44	^νΎϊι nY> vP H AN	1.53	390.3	G
I-45	snA o ^n^YA νΎί h PAM a A^A. x N Ν·Ν /O H z-Y \	2.16	516.3	G

-9616301

No.	Structure	fret [min]	[M+Hf	Method of analysis
I-46	AV - r· λ N N'k N /O H	2.28	530.5	G
I-47	nV na Yh^Vn exH Vn Chiral rçA V/	1.78	510.5	G
I-48	nV ΑΝγ% nY> YnVà ex H „ An Chiral V/	1.94	510.3	G
I-49	O i Yvr° N W H ΜαΑΛΛ n N ίΓν H )Ln	1.77	538.3	G

-9716301

No.	Structure	tret [min]	[M+H]*	Method of analysis
I-50	H N ï\ N H Kn	1.86	496.3	G
1-51	NX νΎΊ XnAnXN Ox H >-N	1.94	510.3	G
I-52	OUCÛ N N^N H —(	2.05	382.3	G
I-53	./9¾	2.16	525.3	G
I-54	X'CQ h An	2.01	402.2	G

-9816301

No.	Structure	tret [min]	[M+HJ*	Method of analysis
I-55	? « Ny	1.64	386.0	G
I-56	W H	1.67	359.0	G
I-57	û? h N y	2.11	418.0	G
I-58	N-n nAA h N y	1.56	372.3	G
I-59	XX £Xk nrn n+cn nU h Iff1	1.77	419.0	G

-9916301

No.	Structure	fret [min]	[M+H]+	Method of analysis
1-60	O H T N N^Tn °-H οΛ	1.90	568.2	G
1-61	N'V'l °-H 0->Nx	1.94	526.2	G
I-62	Γ°Ί^ΪΙ ΝΑ^Ί /N^ S^NAnS^n O. H o An z°~( '	2.16	541.3	G
I-63	ί°¥^ι ΝΎ^ι <τ PA P	2.01	541.5	G
I-64	O-XQ ü nP/n H JL^ O<*\ z V?	1.77	398.3	G

-10016301

No.	Structure	Let [min]	[M+H]+	Method of analysis
Ι-65	Νζνχ Wn CVΗ Αν	1.73	526.5	G
Ι-66	A ΝΎΊ A Η Ν L Ν Ο. Η Αν '°Ό	1.80	568.5	G
Ι-67	αχα ΰ Ν ΤΝ η Αν Ο-ΑΑ ' XJ	1.87	428.5	G
Ι-68	r°Tdi '.Ad <y SVnYn VJ Ck H ^k-N	2.21	539.2	G
Ι-69	r°YY NXX Z'NJ X/nAn VJ Ck H AN O-	2.07	541.3	G

-ΙΟΙ16301

No.	Structure	tret [min]	[M+H]+	Method of analysis
I-70	ClÇQ h N L N H An 0-	1.93	398.3	G
1-71	PnW V N VN CK H An Q CK	1.86	526.2	G
I-72	w H ŸKo„H Ai^ o~	1.81	568.2	G
I-73	AA ,0 H A^ 0-	2.02	428.3	G

-10216301

No.	Structure	tret [min]	[M+H]+	Method of analysis
I-74	N'A WM Ck H ,Λ-Ν	2.00	524.3	G
I-75	Oit Y n n^v> Ox h ^An	1.95	566.2	G
I-76	r°n A V>ASjN VJ XO H	2.14	511.3	G
I-77	Uy-AA H f \	1.97	368.0	G
I-78	N^·) ^ΝγΆ Υ^ζα ° h f~\Νχ	1.91	496.3	G

-10316301

No.	Structure	fret [min]	[M+H]*	Method of analysis
I-79	^NH d FM1	1.84	538.3	G
I-80	ΝΎδ WM x0 H	2.08	398.3	G
1-81	roY^i nV> σ tFnVnn Λ'	2.05	527.2	G
I-82	CVXi ΰ N VN H zVNx VpO	1.87	384.3	G
I-83	^νΆι nAi MPn'Vn /O H do' \	1.82	512.3	G

-10416301

No.	Structure	trei [min]	[M+H]+	Method of analysis
I-84	XX VnVyn O H >N LZo	1.76	554.2	G
I-85	N '°H rO ίλο —' \	1.98	414.0	G
I-86	fn ioû. <fN t N N VN VJ ex h .An Vj-ci	2.12	545.3	G
I-87	O-JXl N N Vn H z-Y N\ ν^Λει	1.98	402.0	G
I-88	νΎ> ° H /Χλ XXci	1.92	530.2	G

-I0516301

No.	Structure	fret [min]	[M+Hf	Method of analysis
I-89	Ό S AA νυί H MaAAX T N N AN ° ηΑΛ n\ ~Ά~α	1.82	572.3	G
I-90	ÇUXi y sjXn AJA	2.09	432.3	G
1-91	rMi a xA	2.25	525.3	G
I-92	0.Λ0 ü N VN H f \ N'	2.01	382.3	G
I-93	Aw y» ”Xn	1.94	510.3	G

-10616301

No.	Structure	tret [min]	[M+H]+	Method of analysis
I-94	nX o Χ^Ν^γχ nXX Au N °'H Νχ	1.82	552.2	G
I-95	iîX nXX	2.12	412.3	G
I-96*	/X VJ 0. H ΧΛα	2.12	545.3	G
I-97*	NX i ^NYX nX'X WM H Xn x XXci	1.91	530.2	G
I-98*	ffli Cil Xn^m'Xn XXci	2.08	432.3	G

-10716301

No.	Structure	tret [min]	[M+HJ*	Method of analysis
I-99	Vo	2.04	501.3	G
1-100	AA Ço	1.86	358.3	G
1-101	°'H \=r N\ Ço	1.81	486.3	G
1-102	'Ν~Ί O AA νΎ> An AO °' H \=ZA Ço	1.73	528.3	G
1-103	QXQ Ço	1.99	388.3	G
1-104	<1DO Th vYci	1.58	406.3	G

-I0816301

No.	Structure	fret [min]	[M+Hf	Method of analysis
1-105	Vz~ci	1.89	448.3	G
1-106	H /==/ X κΛα	1.62	407.3	G
1-107	N-|\T N νΎν H /=/\ W-CI	1.69	432.3	G
1-108	Jn-n Νγ> Cz B '“X VÀci	1.75	442.3	G
1-109	n-n νΎΧ —^Α.,Α .JLA H Xu* VÀci	1.62	406.3	G
1-110	VnvQn CX H CJFci	1.88	516.3	G

-10916301

No.	Structure	fret [min]	[M+H]*	Method of analysis
1-111	' H N 1 N	1.55	372.3	G
1-112	o 04 WCI	1.80	558.5	G
1-113	QXQ H N 1 < \	1.94	368.3	G
1-114	H _/-N.	2.13	360.3	G
1-115	Q ΓΥ0	1.85	320.3	G
1-116	QXT) 0H JPn \	1.90	336.3	G

-I ΙΟ16301

No.	Structure	tret [min]	[M+H]+	Method of analysis
1-117	''b N—	1.88	413.0	G
1-118	QfX> Yh N7¾	1.89	326.3	G
1-119	æÇQ H z°	1.66	322.3	G
1-120	n co '(ΜόΑλ	2.04	413.0	G
1-121	w V N—	1.88	383.0	G
1-122	rbk N/Vb ULaAa Jb NbÛ_ Λ Q	1.97	413.0	G

-lll16301

No.	Structure	fret [min]	[M+H]*	Method of analysis
1-123	XJCQ.	1.98	413.0	G
1-124	αχηΝ	1.97	320.3	G
1-125	OUCÛ fi N '/ n'·	1.94	334.3	G
1-126	OAQ N N \\ N H ?-N	1.90	332.3	G
1-127	WM °' H r-Z N\	1.82	460.3	G
1-128	o ro N YN H M	1.87	332.0	G

-11216301

No.	Structure	fret [min]	[Μ+Η]+	Method of analysis
1-129	xn 0 γΛΎΙ Pl	1.74	502.0	G
1-130	νύί H Vav» /0 H An	2.15	552.5	G
1-131	νΎΊ	2.03	510.20	G
1-132	αχα Η Λ\ Ο	2.06	382.3	G

-11316301

No.	Structure	Let [min]	[M+H]*	Method of analysis
1-133	N^N ,o H Kn O	2.19	412.3	G
1-134	nY> / N |A N N Ό XO H Kn	2.14	525.5	G
1-135	Pi vp 0 JLN /0 h Ço	1.97	374.2	G
1-136	^νίΡι VnAVn /0 H /=/ N\ vo	1.81	472.30	G
1-137	ΓΟνΡι /TM ^ΡνΛνΑ^ν VJ 'Q H Kn Co	2.04	487.3	G
1-138	Pl ΝΑΊ h r-M Vo	1.87	344.0	G

-11416301

No.	Structure	Let [min]	[M+H]*	Method of analysis
1-139	O-ÆQ N N v n H Cz-	1.93	480.0	G
1-140	0. H UæCI o \	2.08	561.3	G
1-141	O/Z K N XXci o	1.89	418.3	G
1-142	U^N'ïZ*l ΝΥΊ Α'νΛν''Μν CK H —A A=/~CI 9	1.86	546.3	G
1-143	A N_ H αΑα,Ά x N N Vn CK H UXci 9	1.78	588.3	G

-11516301

No.	Structure	fret [min]	[M+H]+	Method of analysis
1-144	Xn X* UAci o \	2.00	448.3	G
1-145	q πω. Ω^ΙΜν H z==< k kV^N	1.68	379.0	G
1-146	Γ°Τ^ι ΥΛ YN VA Os H A N	2.02	545.3	G
1-147	OJX1 ΰ N N H ^Z~N <Y x vVci	1.84	402.2	G
1-148	TXÇQ n H N LN °- H N YAci	1.77	530.5	G

-1I616301

No.	Structure	tret [min]	[M+H]*	Method of analysis
1-149	9¾ Xci	1.93	432.0	G
1-150	? Y/W, O^H X-N Xci	1.69	572.3	G
1-151	γ°ίΓ^ nX> /X yVnXn V Ck H ^Λν X'CI F	1.94	549.3	G
1-152	αχα H /V UJ^CI F	1.76	406.2	G
1-153	XX <ΝγΧ ΝΎ> Wm °' H -r-f N\ ΥΛ-ci F	1.71	534.5	G

-11716301

No.	Structure	fret [min]	[M+H]*	Method of analysis
1-154	Çlçq XQ F	1.87	436.2	G
1-155	O NVd T N N VN ° H /A\ YjAci F	1.64	576.2	G
1-156	O R ^N Vx nX^ T n \'^x, Ό H _/-m O '	1.75	524.3	G
1-157*	X^NH i oXdA ny\ VnWn H /XN\ vAci	1.82	572.3	G
[-158	V ¥vVN	1.72	490.3	G

-11816301

No.	Structure	tret [min]	[M+H]*	Method of analysis
1-159	ç H to H	1.70	488.3	G
1-160	νΆ ° Άά 500 ŸN N-y^N CKH /-jy	1.72	490.3	G
1-161	ApH o r’Ai T N N γΆ to H J^N	1.72	476.3	G
1-162	Av» Jo H Y	1.80	504.3	G
1-163	Ph °Ύ1 ΓΟ p Nn O. H	1.78	502.3	G

-11916301

No.	Structure	fret [min]	[M+H]+	Method of analysis
1-164	ΊΑ O h ^AAaA. γ N N X N ,O H JM cA	1.66	532.3	G
1-165	H PN	1.76	363.3	G

No.	Structure	têt [min]	[M+Hf	Analysis
1-166		1.07	500	G
1-167		1.17	514	G
1-168	Ά1 jfrS A AS	1.67	416	G
1-169	y<yOYXl Z H Cl .U P's	1.25	509	G

-12016301

No.	Structure	Ut [min]	[M+Hf	Analysis
1-170	V FF	1.76	488	G
1-171	θ-^id jOQ N » d? cr^	1.29	436	G
1-172	~w H V/ \ Vs	1.37	392	G
1-173	KW N N A m H ClvA{ ds	1.25	398	G
1-174	ouôx N N T N H αμΛ\ dxS	1.54	394	G
1-175	>0^0. jCQ n H AS	1.29	498	G

-12116301

No.	Structure	tret [min]	[M+H]+	Analysis
1-176	o c	1.14	499	G
1-177	νΛΛχΑ H ανΛ\ Xs	1.35	455	G
[-178		1.19	497	G
1-179	H>W Ps	1.24	489	G
1-180	x°^a jûQ H ανΛ\ Ps	1.33	442	G
1-181	Έχα N N X N H Clx{ Ps	1.37	412	G

-12216301

No.	Structure	tret [min]	[M+H]*	Analysis
1-182	jCQ N ü N ïPn a ;	1.10	456	G
1-183	''b—\ N\^ A N N °Ύ 7s	1.28	442	G
1-184	nAAXl H kQ	1.24	378	G
1-185	N LY	1.14	470	G
1-186*		1.18	483	G
1-187	N N N Jxl H Z \	1.29	430	G

-12316301

No.	Structure	Ui [min]	[M+H]*	Analysis
Μ 88	OXQ N N N H WA Ys	1.55	374	G
1-189	Ys	1.34	435	G
1-190	Aam N N AT ' m H WA	1.28	422	G
1-191	JûQ N^N N Y H / \	1.16	457	G
1-192	N « Cl¥	1.30	450/452	G
1-193	rwQ. jOQ N N nY% c¥	1.29	463	G

-12416301

No.	Structure	fret [min]	[M+H]+	Analysis
1-194*		1.25	429	G
1-195	H	1.32	479	G
1-196	X-S	1.32	422	G
1-197	CNVN^ YQ	1.26	441	G
1-198	-~0χ—\ jcq H \\ ' 7^/ \	1.22	459	G
1-199	h>axqp	1.16	483	G

-12516301

No.	Structure	Ut [min]	[M+H]+	Analysis
I-200	JOQ VAS	1.30	386	G
1-201	Αχ ΓΥΊ A AS	1.19	415	G
I-202	AO VAS	1.34	420/422	G
I-203	XN-\ V fY) / O JL JL A vA'nanASn H W ’ c,A	1.27	463/465	G
I-204*	'°^O. 1Ύ1	1.25	416	G
I-205	c> o fXf	1.65	535	G

-12616301

No.	Structure	t™, [min]	[M+H]*	Analysis
1-206	WX/ÇQ N °\	1.19	459	G
1-207	KuÇQ h 8 Z	1.14	388	G
1-208	Kl 1Ύ1 n rKS	1.26	429	G
1-209	-XJÇQ N N^Y^l	1.12	358	G
1-210	0 λ-F F	1.72	468	G

-12716301

No.	Structure	fret [min]	[M+H]*	Analysis
1-211	A 1 1	1.26	430	G
1-212	ΛΆΑ JOQ	1.52	443	G
1-213		1.35	497	G
1-214	>χ-Λ ΧΥΊ NAS	1.18	445	G
1-215	Ο^Ύΐ XXI V AS.	1.99	503	G
1-216*		2.05	477	G

-12816301

No.	Structure	Ut [min]	[M+H]+	Analysis
1-217	c N\ c	1.20	402	G
1-218	Al JOQ n VAS	1.26	416	G
1-219	H A\ CI^O	1.41	434/436	G
I-220	Ml χγ> n VAS ,ow	1.25	459	G
1-221*	N Va	1.27	386	G

-12916301

No.	Structure	tret [min]	[M+H]*	Analysis
I-222		1.72	481	G
I-223	x'X W A CX	1.25	483	G
I-224	AÎYl N VnM, A	1.57	400	G
I-225	f N\	1.54	430	G
I-226	nVXS	1.54	463	G

-13016301

No.	Structure	tret [min]	[M+H]*	Analysis
1-227	wa H W ' f \	1.24	429	G
1-228	A A	1.25	416	G
1-229	i \	1.37	400	G
1-230	Ha jCQ N^N n \\ N H zV	1.19	402	G
1-231	HW»- /0O	1.16	513	G
I-232	>O“Zm Ά	1.19	503/505	G

-13116301

No.	Structure	t„t [min]	[M+H]*	Analysis
I-233	A-W	1.17	483	G
I-234	F	1.24	433	G
I-235	-OlJCCl N h °?z	1.16	388	G
I-236	N N X A	1.71	481	G
I-237	A ΙΎΊ Z=»f \ o f/3'f	1.76	438	G
I-238	N N cr^	1.21	392	G

-13216301

No.	Structure	tret [min]	[M+H]*	Analysis
1-239	N N A\ N H M	1,44	386	G
1-240	θνχχτχ N N ΐ N H Λ\ A	1.27	450/452	G
1-241	j! 'T Ί '°~b	1.25	446	G
1-242	N VN1 a~O	1.26	449/451	G
1-243	H N θΓ	1.24	449	G
1-244	o~ci	1.58	420	G

-13316301

No.	Structure	tret [min]	[M+H]*	Analysis
I-245	XQ n 0 VA Cs/'CI	1.54	450	G
I-246	UW JLXX / H NX> O-c.	1.39	517	G
I-247	VwCQ. h LJx	1.24	429	G
I-248	Kn XQ N H LM F	1.23	420	G
I-249	XXQ H NQ + /0W	1.31	416	G
I-250	x°-wx XQ N N Xm o \	1.20	432	G

-13416301

No.	Structure	Ut [min]	[M+H]+	Analysis
1-251	'V ΧΥΊ AAS C	1.11	459	G
I-252	-w	1.49	386	G
I-253	AW, F	1.61	497	G
I-254	Kl ajQ N N N'A	1.33	479	G
I-255	χ°Άα xxi A <Λ '°~Q>	1.22	446	G

-13516301

No.	Structure	Ut [min]	[M+H]+	Analysis
1-256	o—	1.13	499	G
1-257	XajQ N fi A	1.71	416	G
1-258	-ΧχΙΥΊ A Y Ô+c,	1.49	406	G
1-259	N N ''f'p '°~Q	1.22	459	G
1-260	N N v N H z=O F	1.22	433	G

-13616301

No.	Structure	tret [min]	[M+H]+	Analysis
1-261*	XXX	1.15	443	G
I-262	VO.XXX	1.22	372	G
I-263	-O. xxx N F	1.20	376	G
I-264*	αχώ N N X n H X~\	1.92	334	G
I-265	-n^xxx N Ρχ cr^	1.25	392	G
I-266	n	1.45	406	G

-13716301

No.	Structure	tre, [min]	[M+H]*	Analysis
I-267	Ύ rxi nVAS ciP	1.33	420	G
I-268	Am H Y	1.08	443	G
I-269	A AQ A AS	1.29	386	G
I-270	°Λ /A NAS i N\ F F	1.58	484	G
1-271		1.67	416	G
I-272	A AS	1.30	406/408	G

-13816301

No.	Structure	tre( [min]	[M+H]+	Analysis
1-273	XXX N XQ	1.20	445	G
I-274	jOCX N^N N H -O	1.18	477	G
I-275	_ N=, CIU	1.26	551	G
I-276	XXX νΑΧΑΧ h XA\	1.25	416	G
I-277	-nXxxq	1.55	400	G
I-278	>-Xq. xxi A AS o A	1.60	495	G

-13916301

No.	Structure	tret [min]	[M+H]*	Analysis
I-279	N N F F	1.64	454	G
I-280	Ά. joq N « n'NS	1.28	386	G
1-281	-ο,χά N N Y N H	1.13	388	G
I-282	jCQ N Am C,~O	1.26	436/438	G
I-283	Qj F	1.45	551	G
1-284	_o. jcn N¥y> qt F	1.57	440	G

-14016301

No.	Structure	tre( [min]	[M+Hf	Analysis
I-285*	Ad	2.04	364	G
I-286	^χχχχ H NA> /Ov	1.19	432	G
I-287	NNN H z-AA	1.09	429	G
I-288	Axxx H Λ\ O~c,	1.55	420	G
I-289	XXJÇQ N N >4 X M F	1.52	440	G
I-290	-rdk xük N N '°~b	1.29	416	G

-14116301

No.	Structure	Ut [min]	[M+H]*	Analysis
1-291	\ P N~\ Ό N N N H V ' F	1.13	447	G
I-292	AQ n h AS F	1.26	390	G
I-293	AQ A AS	1.22	402	G
I-294	AQ AAAS 0 f^f	1.73	438	G
I-295	QjQQ A« AS	1.94	390	G

* Structure includes both enantiomers in each case, i.e.

-14216301

4.2. Préparation of other novel compounds (I) by derivatisation of carboxylic acids (method K/method L)

Préparation of compound 11-1 by ester cleaving

Ester cleaving (method K). Compound 1-1 (2.5 g, 5.66 mmol) in MeOH (25 mL) is combined with 10 N NaOH (2.8 mL, 28 mmol) and stirred at 50°C until the reaction is complété. The reaction mixture is acidified with conc. hydrochloric acid (pH = 3). The precipitated solid is isolated by filtration, digested several times with water and dried.

Analogously to 11-1 further free acids are obtained by ester cleaving (Table 11). The io product may optionally be isolated by extraction and purified by chromatography.

Table 11

No.	Structure	tret [min]	[M+H]+	Method of analysis
11-1	OH Y N N YpN 0^ z--/\	1.06	428.2	C
II-2	OH T N N X N O..	1.10	442.2	C

-14316301

No.	Structure	Ut [min]	[M+H]+	Method of analysis
		OH I
	O'			u
		UL		II
II-3		T	N N H		A ,N λ-Ν	1.11	462.2	C
				X
			Y	d	-ci
		OH I
	0'	Vf		|T
		M		II
Il-4		T Cl	N N' H		AN z~N	1.21	446.2	C
				' X
				o
		OH I
	0	Ua	N?'
		UL		II	AN >-N
II-5		T Cl	N N H		1.25	446.2	C
				X
			v	d
		ÎH
	0	Ua		iT
		UL	x.. .X	II
		T	N N		A,N Λ-Ν
II-6		o.	H		1.17	456.3	c
		Ί			X
				o
		OH I
	0	Ua	A'
		UL		IL	AN )-N
		I	'N N'
II-7		Οχ	H		1.18	456.2	c
					X
				F	d

-14416301

No.	Structure	fret [min]	[Μ+Η]+	Method of analysis
ll-8*	OH i YXXXp i h N Ύ > °· ζ=/Λ	1.14	476.2	C
JI-9	A-kA-M Η Η Ν ο HOk Ζ7 χ ο V/	0.97	468.2	C
11-10	οΖ ~ΎΊ À Η Ν k Ν \^Ο Η	1.13	442.0	G
11-11*	ΟΗ 0 <Π ΉΎι Ο-ΌΙ	1.16	476.3	G
11-12	Η0 τΥ Ν^Ί Υ^νΥν |-° Η	1.29	470.3	G

-14516301

No.	Structure	tret [min]	[M+H]+	Method of analysis
11-13	OH A H N VN	1.24	456.3	G
11-14	μ h nXn H0 0 ( '	1.21	468.3	G
11-15	o Ηθ\χ W-Vn ci h An	1.20	446.0	G
11-16	ΗοΧχ nX^X t n n Xn Cl H	1.18	446.3	G
11-17	°χ 0. H /=<N\	1.06	442.3	G

-14616301

No.	Structure	tret [min]	[M+H]*	Method of analysis
11-18	V/-ci	1.07	462.0	G

* Structure includes both enantiomers in each case, i.e.

Préparation of cornpound 111-1 by amidation

Amide formation (method L). The starting cornpound 11-1 (75 mg, 0.18 mmol) and TBTU (87 mg, 0.27 mmol) in anhydrous DMSO (0.5 mL) are combined with triethylamine (124 pL, 0.90 mmol) and 2-methoxyethylamine (17 mg, 0.23 mmol) and stirred at RT until the reaction is complété. The reaction mixture is purified by préparative HPLC-MS. The fractions containing the reaction product are freeze-dried.

Analogously to 111-1 further novel compounds are obtained by amidation or estérification (Table 12). x

-14716301

Table 12

No.	Structure	tret [min]	[M+H]+	Method of analysis
111-1	X VnKi 1 n /O CK H	1.73	485.3	G
III-2	9> H x N N V p-O H A=YN\	1.89	608.0	G
I1I-3	H W	1.76	455.0	G
III-4	'Z A «-T, b y?A	1.81	510.3	G
III-5	Ό v, NV> A H N Ύν H ç~X~^	2.00	564.3	G

-14816301

No.	Structure	tret [min]	[M+H]*	Method of analysis
III-6	n4 ? A ÎfN	1.85	538.0	G
III-7	O O SV H UxaAU· Ah N Vn pO H	1.86	608.3	G
III-8	HN TM NVrA / W'nAX .N. O_ H >4	1.78	498.3	G
III-9	+J-^J'NJSr^jl ΝΎΊ h υι.Λ..ο. Ah νΎν Οχ. H Λν Chiral /V \	1.84	536.2	G
111-10	rN 0. H LN N ° G '	1.91	524.3	G

-14916301

No.	Structure	tret [min]	[M+H]+	Method of analysis
111-11	5¾ ϊύκ .r sn i« n °s H An	1.85	512.3	G
111-12	? h XkAiKX Chiral °'H	1.96	647.5	G
111-13	nA'' h MnWn Ox H __ΛΝ O '	1.86	538.3	G
111-14	9 H Γ B NV ox H WN\ Chiral	1.93	550.2	G
111-15	’% m. A H N V ° H /=A N\	1.79	568.2	G

-15016301

No.	Structure	fret [min]	[M+H]*	Method of analysis
111-16	m ΓΗ XV	1.66	554.2	G
111-17	Y o ''ΆΆ'ί N'X V « A	1.92	550.2	G
111-18	'^ν'γΊι νΎΊ h LAhA.ikAK, X» XQ	1.78	594.2	G
111-19	-n v Vi rn n Yn nVn W-ci	1.87	546.5	G
III-20	O î H ΆμΧ,ΑΊ· Υΐ N L^N Ck H λ/ν\ VXci	1.81	628.7	G

-15I16301

No.	Structure	tret [min]	[M+H]*	Method of analysis
111-21	W	Αχ O V'nxna <ah ~	Y N An < X	1.68	588.5	G
		VAci
III-22	0	w CkH	VN An X	1.84	628.5	G
		G	kCl
	Q
III-23	H	o or N> O. H	A x	1.95	584.5	G
		O	Cl
	XV	ΧΊι
III-24	H	t'n'SA 0. H	VN An X	1.81	602.5	G
		O	^Cl
		Ml
III-25	H	ΟνλΛ <XH ,	L N x	1.91	584.2	G
		o	'Cl

-15216301

No.	Structure	tret [min]	[M+H]+	Method of analysis
III-26	'x-/ n Y h ΧΧ.Λ..ΧΛ °x UA Chiral V^CI	1.83	627.2	G
III-27	''N'XX o hFjl. STjQ. Ah IA Vz~ci	1.92	586.2	G
III-28	O A °χ Ar ÎYci	2.10	574.2	G
III-29	zyXX m X ÎA Chiral O~Cl'	1.88	628.3	G
Hl-30	H WÀ CX H ^Λν vF~ci	1.71	574.2	G

-15316301

No.	Structure	fret [min]	[M+H]+	Method of analysis
111-31	O znJ h L 1 λ JL JL Vn nVn CX H	1.83	572.3	G
III-32	AnV o V«A VAci	2.01	600.2	G
III-33	0 ΑνΎί nV$ AH VnIAA y o. h vAci	1.68	601.3	G
III-34	^°«\ιχη x N N<N es H ,/-N vAci	1.82	635.2	G
III-35	f^nV A-N^, o H ΑΑΑκ.ΑΥ n H N VN °- H z=Y N x VAci	1.74	645.3	G

-15416301

No.	Structure	fret [min]	[M+H]*	Method of analysis
111-36	νύί Ah n Os. H XX vX~Ci	1.81	635.2	G
111-37	rP ΝΡΤΡ A H ' Ck H ^Λν VpCI	1.95	598.2	G
111-38	H rxZ Ck H VÀCI	1.71	613.3	G
111-39	xw. H /^CN\ VAci	1.74	600.2	G

-15516301

No.	Structure	Ut [min]	[M+H]+	Method of analysis
III-40*	AA h LA a Al T N N Vn O. H CJ£ci	2.07	614.2	G
111-41*	væ jY H T'A îS W~CI	2.20	612.3	G
III-42*	î i AA h LJL a JL 1 in n An o. h X-nJ yRci	1.91	586.2	G
III-43*	ΠΊ O 1 ÛXW Xh NXn YAci	1.85	616.2	G
III-44*	GO V, -a ιΡί νΎΊ H U-nAAU °'H À OCI	1.88	642.3	G

-15616301

No.	Structure	fret [min]	[M+H]*	Method of analysis
111-45*	w Vmci	1.72	602.2	G
111-46*	^NO L· Λ h V VJ YicnVm Os h it? V/-CI	2.00	696.3	G
111-47*	<Q 0 i °- H /Ai /v V-ci	1.84	642.3	G
111-48*	2 i N iP Ci] T N N X N Os H M-N w~ci	1.78	544.2	G
111-49*	oP-nP 5 1 H T N N X N O. H λΝ Chiral CæC|X	1.84	628.3	G

-15716301

No.	Structure	fret [min]	[M+H]+	Method of analysis
111-50	X 0 Cl H QXn'XjN OX Q	1.73	510.3	G
111-51	W nQQ H ULaAU· I H N k? vo	1.69	498.3	G
III-52	A. SAQQx y h 0-n	1.86	508.0	G
III-53	τά XQ Ψ .0 H	1.72	504.3	G
III-54	m 9 i h LA X A A T Ν ΝΎν ,O H 1N^	1.74	548.3	G
III-55	Q VAX y h A	1.79	524.3	G

-15816301

No.	Structure	tret [min]	[M+H]*	Method of analysis
111-56	YnA ? <?' /0 NAfA T N N r m Ό H	1.81	568.3	G
111-57	1 P o Z 1	2.13	539.2	G
111-58	Ό î Pnm Ah AS çO H	1.86	552.2	G
111-59	O hn^vA nAtA <S γΑρι y Cl H A	1.96	542.0	G
111-60	NASpi îfYS H ΡνΛν*1N fO H An	1.86	524.3	G

-15916301

No.	Structure	tret [min]	[M+H]*	Method of analysis
111-61	Xi 0 TiA NAA T N NYn ,O H Kn	2.02	578.3	G
III-62	AA NXX Vs H Tn ° /N“ b	1.86	495.0	G
III-63	Ai nAA ά A πΛνA NS ( ' H 0 f\	1.81	525.0	G
III-64	A NAA (r N^N YHI ys h os \ ' ΛΗ Q	1.76	481.0	G
III-65	-n ΑΑκΛλΧ ( ys h ln n NS \ ' H ° O	1.84	538.3	G

-16016301

No.	Structure	Vet [min]	[M+H]*	Method of analysis
III-66	H N H F\'	1.78	522.2	G
III-67	QX XX nXX H XX A ,<ΧΧ i ü N \Tn H	1.71	538.3	G
Hl-68	ΗΝ^Ά Q y N N \\ N °'H /XN? ÎAci	1.65	601.3	G
III-69	YYjTq H-jQ YNX Vz~CI	1.78	614.2	G
III-70	oœx. _ h MxJM A N Νχ H χΑ xXci	2.09	634.2	G

-16116301

No.	Structure	tret [min]	[M+H]*	Method of analysis
m-71	hiv0l aJO. U AS	1.67	441.3	G
III-72	XL· νΎΊ Ck H	1.75	496.3	G
III-73	S»L· ΝΎΊ Ah N \'n ° H	1.84	608.5	G
III-74	'VVl JQQ Ah AS	1.82	512.5	G
III-75	oSOnAx Ν-γΧ H UWU A N N^fN OsH CFA	1.68	568.5	G

-16216301

No.	Structure	tret [min]	[M+H]*	Method of analysis
III-76	o νύί À ü N 1 N Ox H	1.98	661.5	G
III-77		1.82	582.5	G
III-78	A, î ^'ν'τΊι T N ΝγΎν ° H /==< ^	1.81	608.5	G
III-79	H UkAhAU- T N NAT Ox H	1.78	499.5	G
III-80	O χν^^γ/Ύϊ] )AA h AvA Q.. H ,^Ν	1.87	526.5	G

-16316301

No.	Structure	fret [min]	[M+H]+	Method of analysis
111-81	h Ck H	1.76	510.5	G
III-82	5 Ά rii HCl h kXNMu γ N N X N °H CL·''	1.96	564.5	G
III-83	m¥i rp Ah n V νΛοι	1.81	532.5	G
III-84	VæN XN'/\ 0 mm xh m V¥ci	1.98	681.7	G
III-85	N^iO °' H χΛ vAci	1.78	519.5	G

-16416301

No.	Structure	fret [min]	[M+H]*	Method of analysis
111-86	A W N 1 n VÀci	1.76	530.5	G
111-87	l\T> o H UkArk/t T N N lpN Cl H N	1.90	542.3	G
111-88	ν^ιΛα nVP 1 H LA,A.,AJ. Y h An	1.96	530.2	G
111-89	YuOO Y H *XN	1.92	516.3	G
111-90	<jj> H M-mAAA· Cl H Υ“Ν	2.06	568.2	G

-16516301

No.	Structure	fret [min]	[M+H]*	Method of analysis
111-91	O V	1.90	612.3	G
lli-92	H WM CI H ^Λν	1.91	586.2	G
lli-93	vqxû Y N N^N Cl H	1.76	572.3	G
III-94	m H Mx.aAT t N n»n ci H	1.97	514.2	G
III-95	SlYi ΧΊΟ H V'N^'N^Vn oT	1.81	594.2	G

-16616301

No.	Structure	tret [min]	[M+H]+	Method of analysis
III-96	rpYHQ S?B “X	1.83	536.2	G
III-97	oÇl ΝΑΟ JA M M Ç-zl T N N T\ N ,O H o-	1.61	506.3	G
III-98	sNA x^nh oY^ïl NVJJ L£ A Yn nVOn ,o H 0 /	1.57	492.3	G
lil-99	xNj £Anh °\1 DOi t n ÀnVn x0 H /~N^ o-	1.71	532.3	G

-16716301

No.	Structure	tret [min]	[M+H]+	Method of analysis
111-100	ΊμΑ oaA nAP τ^νλνΜν A H ^/Nv_	1.77	502.3	G
111-101	ΊΑ Uh °Ύ1 αΊΟ VN nVN ,O H	1.95	476.3	G
111-102	a °Ύ1 AQ V/nVm zO H	1.92	518.2	G

No.	Structure	tret [min]	[M+H]+	Analysis
111-103	Ά m ’ H C? c< M CI\Z~Y As	1.48	564	G

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No.	Structure	fret [min]	[M+H]*	Analysis
111-104	n A , 0 uXQ H Λ\ C!'\X	1.37	572	G
111-105	Aa T N N H νΛ\ Xs	1.47	544	G
111-106*	Aa a γ AnAA	1.78	504	G
111-107	Άζ M P CI~O	1.51	606	G
111-108	XnX î JJaXzk nAA h 1 JL JL A LL jaaaa A s^	1.7	530	G

-16916301 * Structure includes both enantiomers in each case, i.e.

4.3. Préparation of other novel compounds (I) by derivatisation of amines (method M/method N/method 0/method P)

Préparation of compound IV-1 by amide cleavîng

Amide cleavîng (method M). The startîng compound 1-14 (1.2 g, 2.23 mmol) is stirred in conc. HCl (3 mL)/EtOH (3 mL) for 10 min. at 120°C in a microwave reactor. The reaction mixture is made basic with potassium carbonate solution and exhaustively extracted with 10 DCM. The organic phase is washed with water, dried on sodium sulphate, filtered and evaporated down. The crude product is purified by column chromatography .

Analogously to IV-1 further free amines are obtained by amide cleavîng (Table 13). '

-17016301

Table 13

No.	Structure	tret [min]	[M+H]+	Method of analysis
IV-1	HN% jÇ AΎν	1.85	496.3	G
IV-2	«O w A Y/ Cl	0.71	502.2	A

No.	Structure	Ut [min]	[M+Hf	analysis
IV-2a*	^=\ il ΎΊ hM h Kn; ci-n VA	1.29	489	G

* Structure includes both enantiomers in each case, i.e.

-17116301

Préparation of compound IV-3 by reductive amination (method N)

NaBH(OAc)₃ (Method N)

Reductive amination (method N). The starting compound IV-1 (80 mg, 0.16 mmol) in anhydrous NMP (500 μ!_) is combined with tetrahydro-4/-f-pyran-4-one (45 pL, 0.48 mmol) and sodium triacetoxyborohydride (107 mg, 0,48 mmol) and stirred for 1.5 h at RT. The reaction mixture is purified by préparative HPLC-MS. The fractions containing the réaction product are freeze-dried.

Analogously to IV-3 further novel compounds are obtained by reductive amination (Table 14).

Table 14

No.	Structure	fret [min]	[Μ+Η]+	Method of analysis
IV-3	OA Xkx νύί °ΊΗ Ρ	1.99	580.3	G
IV-4	Υ'ί VPVn °Ί Ρ Ο	1.97	510.3	G

-17216301

No.	Structure	fret [min]	[M+H]+	Method of analysis
IV-5	Αχ ΝΎΊ AVA °Ί C '	2.19	538.3	G
IV-6	O ΆμΛμΜ A h N 1 N Wl	1.58	586.2	G
IV-7	Aj XnyV nW WÀ Ck H ^Λν CAci	1.48	627.5	G
IV-8	An nV> ΥνΛΝ γΝ ΟΧ Λν n. Xci	1.92	544.5	G

-17316301

No.	Structure	fret [min]	-------------------------------------------------------------------------------------1 [M+H]+	Method of analysis
IV-9	νΎ> À H N tN ° H /y ΥΛ-CI	1.81	530.2	G

No.	Structure	tret [min]	[M+H]+	Analysis
IV-9a		1.46	573	G
IV-9b	A	1.33	614	G
IV-9c	N y? CIY	1.37	533	G

* Structure includes both enantiomers in each case, i.e.

-I7416301

Préparation of compound IV-10 by sulphonamidation (method O)

II

-_S-a o (Method O)

Sulphonamide formation (method O). The starting compound IV-1 (100 mg, 0.20 mmol) 5 in anhydrous DCM (0.5 mL) is combined with methanesulphonic acid chloride (22 pL,

0.28 mmol) and triethylamine (90 pL, 0.62 mmol) and stirred for 3 h at RT. The reaction mixture is evaporated down, the residue is taken up in DMSO (500 pL) and purified by préparative HPLC-MS. The fractions containing the reaction product are freeze-dried.

Analogously to IV-10 further novel compounds are obtained by reaction with sulphonic 10 acid chlorides.

Table 15

No.	Structure	tret [min]	[M+H]+	Method of analysis
IV-10	ôY χνά νχί °Ί Ο	1.94	574.0	G

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Préparation of compound IV-11 by amidation (method P)

Amide formation (method P). The starting compound IV-1 (100 mg, 0.20 mmol) in anhydrous DCM (0.5 mL) is combined with dimethylcarbamyl chloride (30 mg, 0.28 mmol) and triethylamine (90 pL, 0.62 mmol) and stirred for 3 h at RT. The reaction mixture is evaporated down, the residue is taken up in DMSO (0.5 mL) and purifîed by préparative HPLC-MS. The fractions containing the reaction product are freeze-dried. Alternatively method L may be used for the amide linking.

Analogously to IV-11 further novel compounds may be obtained by reaction with acid 10 chlorides or amide coupling of acids.

Table 16

No.	Structure	fret [min]	[M+H]+	Method of analysis
IV-11	N ΊΎΊ °iH σ	1.96	567.3	G

-17616301

4.4. Préparation of other novel compounds (I) by alkoxylation catalysed by transition metals (method Q)

Préparation of compound V-1

I

mmol), caesium carbonate (92 mg,

0.28 mmol),

Educt 1-17 (75 mg,

1,10-phenanthroline (5 mg, 0.03 mmol) and copper-l-iodide (3 mg, 0.015 mmol) are stirred in 3-dimethylamino-2,2-dimethyl-1-propanol (95 mg, 0.71 mmol) for 60 h at 100°C under argon. The reaction mixture is taken up in DMSO, filtered and purified by préparative HPLC-MS. The fractions containing the reaction product are freeze-dried.

Analogously to V-1 further novel compounds (I) are obtained (Table 17).

Table 17

No.	Structure	fret [min]	[M+H]*	Method of analysis
V-1	V ^°ΤΊ HQ	2.63	531.2	G
V-2	AW .N. Cl H JL-rT	2.21	503.3	G

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No.	Structure	fret [min]	[M+H]+	Method of analysis
V-3	Cl H	2.16	515.2	G
V-4	/xw n t^n rrypN Cl H «A	2.11	489.3	G
V-5	Xi O d \	2.26	517.3	G
V-6	AW N Cl H _>N ° A'	2.38	529.3	G
V-7	(°Ά /A SAAAA \_J „0 H	2.17	491.3	G
V-8	r°Aîi Va .0 h An \ r	2.18	491.3	G

-17816301

The following Examples describe the biological activity of the compounds according to the invention, without restricting the invention to these Examples.

Compounds of general formula (1) are characterised by their many possible applications in the therapeutîc field. Particular mention should be made of those applications in which the inhibiting effect on the prolifération of cultivated human tumour cells but also on the prolifération of other cells such as endothélial cells, for example, are involved.

Insulin-like Growth Factor-1 Receptor (IGF-IR)-Kinase Assay

The kinase activity is measured by DELFIA® assay (dissociation-enhanced lanthanide fluorescence immunoassay, Perkin Elmer). The cytoplasmic kinase domain of human IGF-1R (amino acids 964 - 1370) is expressed as a fusion protein with a glutathione-Stransferase tag (IGF-1R-GST) in High Five™ Cells (invitrogen). Enzyme activity is measured in the presence of substances and a control substance. Poly-glutamatetyrosine peptide (pEY, Sigma Aldrich) and biotinylated pEY (bio-pEY) are used as reaction substrates.

pL of substance in 25 % DMSO are mixed with 30 pl_ of IGF-1R-GST solution (67 mM HEPES pH 7.4, 15 pg/mL pEY, 1.7 pg/mL bio-pEY, 13.3 mM MgCI₂, 3.3 mM dithiothreitol, 0.0033% Brij 35, 2 ng IGF-1R-GST) in 96-well plates. The reactions are started with 10 pL of a 750 pM ATP solution. After 40 min at RT the reactions are stopped with 50 pL of stop solution (250 mM EDTA, 20 mM HEPES pH 7.4). 90 pL from each reaction are transferred onto streptavidin-coated 96-well plates. After 120 min incubation at RT the plates are washed three times with 200 pL phosphate-buffered saline (PBS) per well. The plates are incubated for 60 min with 100 pL of europium-coupled antibody against phospho-tyrosine (diluted 1/2000 in Perkin Elmer DELFIA assay buffer) per well. The plates are washed three times with 200 pL per well of DELFIA washing buffer. 100 pL DELFIA Enhancement Solution (Perkin Elmer) is added to each well, and the plates are incubated for 10 min. The fluorescence signal is measured with a Wallac Victor TRF Reader. IC₅₀ values for the inhibition of the IGF-1R-kinase activity are calculated using the programmes Fifty (Version 2) and GraphPad (Version 3.0).

Table 18 shows the IC» values of the example compounds determined using the above assay. Z

-17916301

Table 18

No.	IGF1R IC50 [nM]
1-2	73
1-3	25
1-9	73
1-10	25
1-12	14
1-13	13
1-14	4
1-15	3
1-16	4
1-18	15
1-19	50
I-20	62
1-21	2
I-22	12
I-23	2
I-24	5
1-25	48
1-26	2
1-27	0.18
1-28	179
1-29	5
1-30	2
1-31	34
I-32	433
I-33	398
I-34	226
1-35	242
1-36	409
1-37	264
1-38	299

No.	1GF1R ICM [nM]
1-39	63
1-40	3
1-41	4
I-42	1
I-43	3
I-44	196
I-45	11
I-46	9
I-47	89
I-48	0.69
I-49	2
I-50	1
1-51	4
I-52	475
I-53	11
I-54	91
I-55	22
I-56	120
I-57	91
I-58	11
I-59	36
I-60	226
1-61	207
I-62	155
I-63	1
I-64	37
I-65	1
I-66	2
I-67	30
I-68	219

No.	IGF1R IC50 [nM]
1-69	9
1-70	231
1-71	5
I-72	11
I-73	208
I-74	169
I-75	219
I-76	1
l-77	7
I-78	0.92
I-79	2
I-80	43
1-81	20
I-82	56
I-83	21
I-84	38
I-85	437
I-86	15
I-87	60
I-88	11
I-89	20
I-90	700
1-91	2
I-92	23
I-93	1
I-94	2
I-95	106
I-96	0.8
I-97	0.19
I-98	13

-18016301

No.	IGF1R ICM [nM]
1-99	13
1-100	50
1-101	11
1-102	17
1-103	169
1-104	11
1-105	500
1-106	1000
1-107	17
1-108	1000
1-109	6
1-110	0.19
1-111	12
1-112	0.87
1-113	29
1-114	140
1-115	471
1-116	785
1-117	922
1-118	1939
1-119	2035
1-120	2354
1-121	2612
1-122	2613
1-123	2976
1-124	135
1-125	27
1-126	77
1-127	7
1-128	96
1-129	11

No.	IGF1R IC5D [nM]
1-130	54
1-131	22
1-132	1132
1-133	1000
1-134	46
1-135	264
1-136	23
1-137	108
1-138	131
1-139	63
1-140	0.5
1-141	4
1-142	0.3
1-143	0.4
1-144	15
1-145	277
1-146	1
1-147	13
1-148	1
1-149	39
1-150	2
1-151	2
1-152	13
1-153	1
1-154	71
1-155	2
1-156	16
1-157	1
1-158	4
1-159	42
1-160	25

No.	IGF1R IC50 [nM]
1-161	148
1-162	8
1-163	13
1-164	71
1-165	105
II-2	73
II-3	21
ll-7	246
II-8	29
11-10	282
11-11	29
11-12	244
11-13	246
11-14	94
11-15	61
11-16	500
11-17	73
11-18	21
111-1	10
III-2	17
III-3	92
III-4	17
III-5	44
III-6	13
III-7	21
JII-8	7
III-9	4
111-10	8
111-11	4
111-12	11
111-13	3

-18116301

No.	IGF1R IC5o [nM]
111-14	3
111-15	5
111-16	5
HI-17	5
111-18	9
111-19	0.75
III-20	1
111-21	0.54
IU-22	0.27
III-23	2
III-24	2
III-25	1
III-26	2
III-27	2
III-28	1
III-29	1
III-30	2
111-31	1
III-32	1
III-33	2
III-34	4
III-35	3
III-36	3
III-37	3
III-38	1
III-39	2
III-40	1
111-41	2
III-42	1
III-43	1
III-44	2

No.	IGF1R IC50 [nM]
111-45	1
111-46	3
111-47	1
111-48	1
111-49	2
111-50	26
111-51	183
III-52	6
III-53	8
III-54	11
III-55	7
III-56	8
III-57	36
III-58	5
III-59	2
III-60	0.57
111-61	5
III-62	76
III-63	22
III-64	21
III-65	4
III-66	6
III-67	117
III-68	3
III-69	2
IH-70	6
111-71	15
III-72	2
III-73	6
III-74	3
III-75	4

No.	IGF1R IC50 [nM]
III-76	10
III-77	5
III-78	4
111-79	12
111-80	3
111-81	4
III-82	8
III-83	1
111-84	2
111-85	3
111-86	0.87
111-87	7
111-88	6
111-89	6
111-90	13
111-91	11
III-92	10
III-93	10
III-94	7
III-95	9
III-96	4
III-97	387
III-98	34
III-99	193
111-100	21
111-101	64
111-102	54
IV-1	0.63
IV-3	0.43
IV-4	0.31
IV-5	0.26

-18216301

No.	IGF1R IC50 [nM]
IV-6	1
IV-7	1
IV-8	0.5
IV-9	1
IV-10	14

No.	IGF1R ICM [nM]
ÎV-11	2
V-1	12
V-2	13
V-3	5
V-4	7

No.	IGF1R ICM [nM]
V-5	8
V-6	7
V-7	180
V-8	109

No.	IGF1R IC50 [nM]
1-166	0.6
1-167	0.6
1-168	1
1-169	0.2
1-170	3
1-171	0.2
1-172	0.3
1-173	0.3
1-174	0.4
1-175	0.4
1-176	0.4
1-177	0.5
1-178	0.5
1-179	0.6
1-180	0.6
1-181	0.6
1-182	0.6
1-183	0.7
1-184	1
1-185	1
1-186*	1
1-187	1
1-188	2

No.	IGF1R ICW [nM]
1-189	2
1-190	2
1-191	2
1-192	2
1-193	2
1-194*	2
1-195	2
1-196	3
1-197	3
1-198	3
1-199	3
I-200	3
1-201	3
I-202	3
I-203	3
I-204*	3
I-205	3
I-206	3
I-207	3
I-208	4
I-209	4
1-210	4
1-211	4

No.	IGF1R ICM [nM]
1-212	4
1-213	4
1-214	4
1-215	5
1-216*	5
1-217	5
1-218	5
1-219	5
I-220	5
1-221*	5
I-222	5
I-223	5
I-224	5
1-225	5
1-226	5
1-227	6
1-228	6
1-229	6
1-230	6
1-231	6
I-232	6
I-233	6
I-234	6

-18316301

No.	IGF1R ICso [nM]
1-235	6
1-236	6
1-237	6
1-238	6
1-239	7
1-240	8
1-241	8
I-242	8
I-243	8
I-244	8
I-245	8
I-246	8
I-247	9
I-248	9
I-249	10
I-250	10
1-251	10
I-252	10
I-253	10
I-254	10
I-255	12
I-256	12
I-257	12
I-258	12

No.	IGF1R ΙΟ» [nM]
1-259	13
1-260	13
1-261*	13
I-262	14
I-263	14
(-264*	15
I-265	15
I-266	15
I-267	16
I-268	16
I-269	17
I-270	17
1-271	18
I-272	18
I-273	18
I-274	18
I-275	18
I-276	19
I-277	19
I-278	21
I-279	22
I-280	23
1-281	23
I-282	23

No.	IGF1R IC50 [nM]
1-283	23
1-284	25
1-285*	28
1-286	31
1-287	36
1-288	48
1-289	51
1-290	57
1-291	58
I-292	59
I-293	70
I-294	70
I-295	89
111-103	0.3
111-104	0.4
111-105	1
111-106*	5
111-107	5
111-108	8
IV-2a*	2
IV-9a	1
IV-9b	1
IV-9c	1

Cellular IGF-IR-phosphorylation assay

The activity of substances against the phosphorylation of 1GF-1R in activated cells is measured as follows: mouse fibroblast cells (transfected with human IGF-1R, Fibro-hlGF5 1R) are cultivated in standard medium (DMEM, 10 % foetal calf sérum (FCS, Gibco),

1x MEM Non-Essential Amino Acids (NEAA, Gibco), 7.5 % sodium hydrogen carbonate (Gibco) and 0.3 mg/mL Puromycin (Sigma)) in a humid incubator at 37°C with 5 %

-18416301

CO₂/95 % air.

10000 Fibro-hlGF-1R cells per well in 200 μΙ_ of standard medium are seeded into 96-well plates and cultivated overnight. The next day, the medium is suction filtered and the cells are cultivated in 90 pL serum-reduced medium (DMEM, 0.5 % FCS, 1x MEM NEAA,

7.5 % sodium hydrogen carbonate) for a further 24 h. 10 pL of substance solution (diluted in serum-reduced medium) is added thereto, and the cells are incubated for a further 120 min in the incubator. The phosphorylation of IGF-1R is activated for 30 min by the addition of IGF-1 (20 ng/mL in serum-reduced medium). Ail further incubations are carried out at RT. The supernatant is suction filtered from the wells, and the cells are fixed in 100 pL per well of 4 % paraformaldéhyde (diluted in PBS). The supernatant in the well is suction filtered and the cells are permeabilised for 5 min in 300 pL per well of 0.1 % TrîtonX-100 (diluted in PBS). The supernatants are suction filtered once again and the cells are incubated for 20 min in quenching buffer (PBS with 0.1 % TritonX-100 and 1.2 % hydrogen peroxide), to inhibit the endogenous peroxidase of the cells. The cells are washed for 5 min with 300 pL per well of PBS with 0.1 % TritonX-100 and then incubated for 60 min with 100 pL per well of blocking buffer (PBS with 0.1 % TritonX-100 and 5 % Bovine Sérum Album in (BSA)). The blocking buffer is exchanged for 50 pL of the first antibody buffer (1/1000 dilute anti-phospho-IGF-1 receptor β (Tyr1135/1136) / insulin receptor β (Tyr1150/1151) (19H7) rabbit monoclonal antibody from Cell Signaling Technology in blocking buffer) and the plates are incubated overnight at 4°C. The next day the plates are washed for 5 min with 300 pL PBS/0.1 % TritonX-100 at RT and then incubated for 60 min with 50 pL per well of the second antibody buffer (1/500 diluted Goat Anti-Rabbit Immunoglobulin-Horseradish Peroxidase (HRP) (Dako) in blocking buffer) at RT. The plates are washed first for 5 min with 300 pL PBS/0.1 % TritonX-100 and then for a further 5 min with 300 pL PBS at RT . The plates are developed for 10 min with 100 pL per well of a peroxidase solution (1:1 mixture of TMB Peroxidase Substrate and Peroxidase Solution B from Kirkegaard & Perry Laboratories, Inc.). The reactions are stopped with 100 pL per well of stop solution (1M phosphoric acid). The absorbance in each well is measured at 450 nm with a SpectraMax Absorbance Reader. EC50 values for inhibiting the phosphorylation of the IGF-1R in activated cells are calculated using the programmes Fifty (Version 2) and GraphPad (Version 3.0).

Compounds (I) according to the invention generally display a good inhibitory effect in the cellular assay described above, i.e. for example an ECso value of less than 5 pmol/L, often

-18516301 less than 3 pmol/L.

Cell Prolifération Assavs

Compounds were tested for their anti-proliferative effects in the TC-71 (Ewing’s sarcoma) and HCT 116 (colorectal carcinoma) cancer cell lines in vitro. Published scientific data has described that interférence with the Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway reduces the prolifération of TC-71 cells [1]. Therefore TC-71 cells served as a positive control cell line for monitoring the activity of compounds against IGF1R-mediated cell prolifération. In contrast, published data has demonstrated that the prolifération of HCT 116 cells is independent of IGF-1R signaling [2]. Therefore the HCT 116 cell line served as a négative control.

2000 TC-71 cells or 1000 HCT 116 cells were seeded per well in 180 pl. IMDM + 10 % foetal calf sérum (FCS) + penicillin/streptomycin into 96-well microtitre plates. The plates were placed in a cell culture incubator (37°C in a humidified atmosphère of 95 % O₂/5 % CO₂) overnight. The following day, serial dilutions of compounds, prepared in duplicates, were transferred onto the cell layers (controls without compound). The cells were cultivated for a further 72 h in the cell culture incubator. 20 pL of Alamar Bluet™ (Serotec Ltd, Düsseldorf, Germany) was added to each well and the plates incubated for 7 h in the cell culture incubator. Fluorescence (extinction wavelength of 544 nm and émission at 590 nm) was then measured and the normalized data fitted by itérative calculation with a sigmoidal curve analysis program (Graph Pad Prism) with a variable Hill slope to détermine the IC₅o values.

The ECæ values of the following compounds were determined on TC-71 cells: I-23, 1-30,

I-40, I-42, I-97, 1-109, 1-112, 1-147, 1-157, 1-166 - 1-168, 1-171, 1-172, f-175 - 1-178, 1-180 -

1-182, 1-185 - 1-187, 1-189, 1-191 - 1-214,1-217 - I-263, I-265 - I-284, I-286 - I-289, I-293,

I-294, il-3,11-18, III-38,111-105,111-107, IV-2a, IV-9a, IV-9b and IV-9c.

The EC50 values for ail these compounds are less than 3 pM, very often less than 500 nM.

In addition to TC-71, several other cancer cell lines from diverse tissue origins, which hâve previously been demonstrated to be sensitive to IGF-1 R inhibition, were shown to be sensitive to compounds (I). Examples include COLO 205 (colorectal cancer) [3], LP-1 (multiple myeloma) [4] and HL-60 (acute myeloid leukemia) [5]. λ

-18616301

Reference List

Manara.M.C., Landuzzi.L., Nanni,P., Nicoletti.G., Zambelli,D., Lollini.P.L., Nanni.C., Hofmann.F., Garcia-Echeverrîa,C., Picci.P. and Scotlandi.K. (2007) Preclinical in vivo study of new insulin-like growth factor-l receptor-specific inhibitor in Ewing’s sarcoma. Clin.Cancer Res., 13,1322-1330.

Pitts.T.M., Tan,A.C., Kulikowski.G.N., Tentler.J.J., Brown,A.M., Flanigan.S.A., Leong.S., Coldren.C.D., Hirsch,F.R., Varella-Garcia,M., Korch.C. and Eckhardt.S.G. (2010) Development of an integrated genomic classifier for a novel agent in colorectal cancer; approach to individualized therapy in early development. Clin Cancer Res., 16, 31933204.

Haluska.P., carboni.J.M., Loegering.D.A., Lee,F.Y., Wittman.M., Saulnier.M.G., Frennesson.D.B., Kalli.K.R., Conover.C.A., Attar.R.M., Kaufmann.S.H., Gottardis.M. and Erlichman.C. (2006) In vitro and in vivo antitumor effects of the dual insulin-like growth factor-l/insulin receptor inhibitor, BMS-554417. Cancer Res., 66, 362-371.

Georgii-Hemming.P., Wiklund.H.J., Ljunggren.O. and Nilsson.K. (1996) Insulin-like growth factor I is a growth and survival factor in human multiple myeloma cell lines. Blood, 88, 2250-2258.

Wahner Hendrickson,A.E., Haluska,P., Schneider,P.A., Loegering.D.A., Peterson.K.L., Attar.R., Smîth.B.D., Erlichman.C., Gottardis,M., Karp.J.E., carboni.J.M. and Kaufmann.S.H. (2009) Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukemia: effect of the dual-receptor inhibitor BMS-536924 in vitro. Cancer Res., 69, 7635-7643.

On the basis of their biological properties the compounds of general formula (I) according to the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of ail the above-mentioned forms are suitable for treating diseases characterised by excessive or abnormal cell prolifération.

Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer’s disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g. psoriasis); diseases based on hyperplasia which are characterised by an increase in the number of cells (e.g. fîbroblasts, hépatocytes, bones and bone marrow

-18716301 cells, cartilage or smooth muscle cells or épithélial cells (e.g. endométrial hyperplasia)); bone diseases and cardiovascular diseases (e.g. restenosis and hypertrophy). They are also suitable for protecting proliferating cells (e.g. haïr, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment.

For example, the following cancers may be treated with compounds according to the invention, without being restricted thereto: brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphomas, brain métastasés, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as e.g. tumours of the végétative nervous System such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumours on the peripheral nervous System such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumours of the central nervous System such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon carcinoma, colorectal carcinoma, anal carcinoma, carcinoma of the large bowel, tumours of the small intestine and duodénum; eyelid tumours such as basalioma or basal cell carcinoma; pancreatic cancer or carcinoma of the pancréas; bladder cancer or carcinoma of the bladder; lung cancer (bronchial carcinoma) such as for example small-cell bronchial carcinomas (oat cell carcinomas) and ποπ-small cel! bronchial carcinomas (NSCLC) such as plate épithélial carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as for example mammary carcinoma such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma; non-Hodgkin's lymphomas (NHL) such as for example Burkitt’s lymphoma, low-malignancy non-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endométrial carcinoma or corpus carcinoma; OU P syndrome (Cancer of Unknown Primary); ovarian cancer or ovarian carcinoma such as mucinous, endométrial or serous cancer; gall bladder cancer; bile duct cancer such as for example Klatskin tumour; testicular cancer such as for example seminomas and non-seminomas; lymphoma (lymphosarcoma) such as for example malignant lymphoma, Hodgkin's

-18816301 disease, non-Hodgkin’s lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, éosinophilie granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulo-sarcoma, plasmocytoma, fibrous dysplasia, juvénile bone cysts and aneurysmatic bone cysts; head and neck tumours such as for example tumours of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as for example liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); stomach cancer or gastric carcinoma such as for example papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, smallcell carcinoma and undifferentiated carcinoma; melanomas such as for example superficially spreading, nodular, lentigo-maligna and acral-lentiginous melanoma; rénal cancer such as e.g. kidney cell carcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer or carcinoma of the oesophagus; penile cancer; prostate cancer; throat cancer or carcinomas of the pharynx such as for example nasopharynx carcinomas, oropharynx carcinomas and hypopharynx carcinomas; retinoblastoma; vaginal cancer or vaginal carcinoma; plate épithélial carcinomas, adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid carcinomas such as for example papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, epidormoid carcinoma and plate épithélial carcinoma of the skin; thymomas, cancer of the urethra and cancer of the vulva.

The new compounds may be used for the prévention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other state-of-the-art compounds, such as e.g. cytostatic or cytotoxic substances, cell prolifération inhibitors, anti-angiogenic substances, steroids or antibodies.

The compounds of general formula (I) may be used on their own or in combination with -18916301 other active substances according to the invention, optionally also in combination with other pharmacologically active substances.

Chemotherapeutic agents which may be administered in combination with the compounds according to the invention, include, wîthout being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raioxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutéthimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors (growth factors such as for example platelet derived growth factor (PDGF)”, “fibroblast growth factor (FGF)”, “vascular endothélial growth factor (VEGF)”, “epidermal growth factor (EGF)”, “insulinelike growth factors (IGF)”, “human epidermal growth factor (HER, e.g. HER2, HER3, HER4)” and hépatocyte growth factor (HGF)), inhibitors are for example growth factor antibodies, growth factor receptor antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antîtumour antibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum dérivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example Vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron), serine/threonine kinase inhibitors (e.g. PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors, PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g. PTK2/FAK inhibitors), protein protein interaction inhibitors (e.g. IAP, Mcl-1, MDM2/MDMX), MEK inhibitors, rapamycin analogs (e.g. everolimus, temsirolimus) and various chemotherapeutic agents such as amifostin,

-19016301 anagrelid, clodronat, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mîtotane, pamidronate and porfimer.

Other possible combination partners are 2-chlorodesoxyadenosine, 2-fluorodesoxycytidine, 2-methoxyoestradiol, 2C4, 3-alethine, 131-I-TM-601, 3CPA, 7-ethyl-10hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, aldesleukin, alitretinoin, altretamîne, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, ARRY-300, ARRY-142886/AZD-6244, ARRY-704/AZD-8330, AS703026, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BBR-3464, BBR-3576, bevacizumab, biricodar dicitrate, BCX-1777, bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BNP-1350, BNP-7787, BIBW 2992, BIBF 1120, Bl 836845, Bl 2536, Bl 6727, Bl 847325, bleomycinic acid, bleomycin A, bleomycin B, bryostatin-1, bortezomib, brostallicin, busulphan, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCI-779, CEP-701, CEP-751, CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655/RO4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-ll, CDC-394, CKD-602, clofarabin, colchicin, combretastatin A4, CHS-828, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CP461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine, deoxorubîcin, deoxyrubicîn, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, E7010, E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EKB-569, EKB-509, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18OCH3, ethynylcytidine, ethynyloestradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, floxuridine, folie acid, FOLFOX, FOLFIRI, formestane, galarubicin, gallium maltolate, gefînitib, gemtuzumab, gimatecan, glufosfamide, GCS-IOO, G17DT immunogen, GMK, GPX-100, GSK-5126766, GSK-1120212, GW2016, granisetron, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxy progestérone caproate, ibandronate, ibritumomab, idatrexate, idenestrol, IDN-5109, IMC-1C11, immunol, indisulam, interferon alpha-2a, interferon alpha-2b, interleukin-2, ionafarnib, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated oestrogens, kahalid F, kétoconazole, KW-2170, lobaplatin, leflunomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone,

-19116301

LU 223651, lurtotecan, mafosfamide, marimastat, mechloroethamine, methyltestosteron, méthylprednisolone, MEN-10755, MDX-H210, MDX-447, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MLN518, motexafin gadolinium, MS-209, MS-275, MX6, neridronate, neovastat, nimesulide, nîtroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, omeprazole, oncophage, ormiplatin, ortataxel, oxantrazole, oestrogen, patupilone, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PEG-paclitaxel, PEP-005, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine, perillylalcohol, PG-TXL, PG2, PLX-4032/RO-5185426, PT-100, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol Ο, PKI166, plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY 869766, rebeccamycin analogues, revimid, RG-7167, rhizoxin, rhu-MAb, risedronate, rituximab, rofecoxib, Ro-31-7453, RO-5126766, RPR 109881 A, rubidazone, rubitecan, R-flurbiprofen, S-9788, sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, SU5416, SU6668, SDX-101, semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SRL-172, sorafenib, spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAS-103, tacedinaline, talaporfîn, tariquitar, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinic acid, traszutumab, tretinoin, triacetyluridine, triapine, trimetrexate, TLK-286TXD 258, urocidin, valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1, vectibix, xeloda, XELOX, XL-281, XL-518/R-7420, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZDI839, zoledronat and zosuquidar.

Suitable préparations include for example tablets, capsules, suppositories, solutions particularly solutions for injection (s.c., i.v., i.m.) and infusion - élixirs, émulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.

Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as

-19216301 starch or gélatine, lubricants such as magnésium stéarate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or élixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonie agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali métal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gélatine capsules.

Suîtable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the dérivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctîonal alcohols (e.g. éthanol or glycerol), carriers such as e.g. natural minerai powders (e.g. kaolins, clays, talc, chalk), synthetic minerai powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch s

-19316301 and polyvinylpyrrolidone) and lubricants (e.g. magnésium stéarate, talc, stearic acid and sodium lauryl sulphate).

The préparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gélatine and the like. Moreover, lubricants such as magnésium stéarate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

For parentéral use, solutions of the active substances with suitable liquid carriers may be used.

The dosage for intravenous use is from 1 - 1000 mg per hour, preferably between 5 and 500 mg per hour.

However, it may sometimes be necessary to départ from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may hâve to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.

The formulation examples which follow îllustrate the présent invention without restricting its scope:

Examples of pharmaceutical formulations

A)	Tablets	per tablet
active substance according to formula (1)	100 mg
	lactose	140 mg
	corn starch	240 mg .

-19416301 polyvinylpyrrolidone 15 mg magnésium stéarate 5 mg

500 mg

The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnésium stéarate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

B) Tablets____________________________________________________________per tablet

active substance according to formula (1)	80 mg
lactose	55 mg
corn starch	190 mg
microcrystalline cellulose	35 mg
polyvinylpyrrolidone	15 mg
sodium-carboxymethyl starch	23 mg
magnésium stéarate	2 mg

400 mg

The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnésium stéarate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution active substance according to formula (I) 50 mg sodium chloride 50 mg water for inj. 5 ml

-19516301

The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonie. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptie conditions into ampoules which are 5 then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance. -D 9 J AN 2013

-19616301

Patent Claims

Claims (15)

Patent Claims

1-175 N-[1-[2-[4-(dimethylamino)piperidin-1-yl]ethyl]pyrazol-3-yl]-8-methyl-9-phenyl5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine; 1-181 9-(3-chlorothiophen-2-yl)-N-(1-ethylpyrazol-3-yl)-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine; I-202 9-[(2-chlorophenyl)methyl]-N-(1-ethylpyrazol-3-yl)-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine; I-224 N-( 1 -eth ylpyrazol-3-yl )-8-methyl-9-[(3-methyl phenyl )methyl]-5,6dîhydropyrazolo[3,4-h]quinazolin-2-amine; I-237 9-[4-(difluoromethoxy)phenyl]-N-(1-ethylpyrazol-3-yl)-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine; I-236 9-[4-(difluoromethoxy)phenyl]-N-[1-(2-dimethylaminoethyl)pyrazol-4-yl]-8methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine; I-30 9-(2-chlorophenyl)-N-(1-ethylpyrazol-3-yl)-8-methyl-5,6-dihydropyrazolo[3,4h]quinazolin-2-amine; 1-112 4-[[9-(2-chlorophenyl)-8-methyl-5,6-d ihyd ropyrazolo[3,4-h]quinazolin-2yl]amino]-3-methoxy-N-(1-methyl piperidin-4-yl)benzamide; I-40 9-(2-chlorophenyl)-5,8-dimethyl-N-(1-propane-2-ylpyrazol-3-yl )-5,6dihydropyrazolo[3,4-h]quînazolin-2-amine; I-42 9-(2-chlorophenyl)-5,8-dimethyi-N-(1-methylpyrazol-3-yl)-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine; I-97 9-(2-chlorophenyl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-5,8d i meth yl-5,6-d ihyd ropyrazolo[3,4-h]quinazolin-2-a mine; 1-157 4- [[9-(2-chloro phenyl )-5,8-d imethyl-5,6-d ihyd ropyrazolo[3,4-h]q u i nazo I i n-2yl]amino]-3-methoxy-N-(1-methyipiperidin-4-yl)benzamide; II-8 4- [[9-(2-chlorophenyl)-5,8-d imethyl-5,6-dihydropyrazolo [3,4-h]quinazoli n-2yl]amino]-3-methoxybenzoic acid;

42. Compounds of general formula (I) according to one of claims 1 to 41 - or the pharmaceutically acceptable salts thereof - as médicaments.

43. Compounds of general formula (I) according to one of claims 1 to 41 - or the

1-[4-[4-[[9-(4-methoxyphenyl)-8-rnethy]-5,6-dihydropyrazo)o[3,4-h]quinazolin-2yl]amino]pyrazol-1-yllpiperidin-1-yl]ethanone;

-21416301

1- [4~[4-[(5,8-dimethyl-9-phenyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2yl)amino]pyrazol-1-yl]piperidin-1-yl]ethanone;

1-176 dihydropyrazolo[3,4-hIquinazolin-2-amine;

N-[1 -( 2-d imethylaminoethyl )pyrazol-3-yl]-8-methyl-9-(naphtha len-1 -yl methyl )-

1-180

1-182

1-192

1-210

I-208

1-217

1-166 [-167

1-171

1-185

1-186

1-187

1-189

1-193

1-195

1 -[4-[4-[[9-[4-(difluoromethoxy)phenyl]-8-methyl-5,6-d ihyd ropyrazolo[3,4-

h]quinazolin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]ethanone;

N-[1-[2-[2-methoxyethyl( methyl )amino]ethyl]pyrazol-3-yl]-8-methyl-9-phenyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

1-197

R⁸ is selected from among C^alkyl, C₃-₅cycloalkyl, C-.^alkoxy-C^alkyl, 5 (C_Malkyl)NH-C_Malkyl and (C^lkylkN-C^alkyl;

R⁹ is selected from among hydrogen, Ci^alkyl and C_{3 b}cycloalkyl.

41. Compounds according to claim 1 (5S)-N-[1-(2-methoxyethyl)pyrazol-3-yl]-5,8-dimethyl-9-phenyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-5,8-dimethyl-9-phenyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-8-methyl-9-phenyl-5,6dîhydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-methoxyethyl)pyrazol-3-yl]-5,8-dimethyl-9-phenyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

1-198

1-271

I-225

I-205

1-201

I-204

I-222

1-194

1-168

1. Compounds of general formula (I) (I) , wherein

R¹ dénotés hydrogen or a group optionally substituted by one or more identical or different R^a and/or R^b, selected from among C^alkyl, C_?balkenyl, C₂_₆alkynyl, C₃_₁₀cycloalkyl, C₄.₁₀cycloalkenyl, C₆_₁₀aryl, 5-12 membered heteroaryl and 3- to 14-membered heterocyclyl;

R² dénotés hydrogen or a group optionally substituted by one or more identical or different R^a and/or R^b, selected from among C₁₆alkyl, C₂-6alkenyl, C^alkynyl, C₃.₁₀cycloalkyl, C4-i₀cycloalkenyl, C₆.waryl, 5-12 membered heteroaryl and 3- to 14-membered heterocyclyl;

R³ dénotés a group

A is selected from among C₆_₁₀aryl and 5-12 membered heteroaryl;

B dénotés a 5- to 7-membered, non-aromatic hetero ring with at least one heteroatom, selected from among nitrogen, sulphur and oxygen, which optionally carries one or more substituents selected from among C^alkyl and =0;

each R⁴ is independently selected from among R^a and R^b;

m dénotés 0, 1,2 or 3; z

-19716301

R⁵ is selected from among R^a and R^b;

n dénotés 0 or 1;

X dénotés a bond or is selected from among -CH₂- and -CH₂-CH₂- and in the abovementioned -CH₂- and -CH₂-CH₂- one or two hydrogen atoms are optionally substituted independently of one another by C^alkyl, Ckhaloalkyl, -O-C₁.4alkyl or halogen;

each R^a independently dénotés a group optionally substituted by one or more îdentical or different R^b and/or R^c, selected from among C^alkyl, C^alkenyl, C₂^alkynyl, C₃--[Qcycloalkyl, C₄.₁₀cyc[oalkenyl, C₆.-i₀aryl, 5-12 membered heteroaryl and 3- to 14membered heterocyclyl;

each R^b is independently selected from among -OR^C, -SR^C, -NR^CR^C, halogen, -CN, -NO2, -C(O)R^C, -C(O)OR^C, -C(O)NR^CR^C, -C(NR^h)NR^cR^c, -OC(O)R^C, -OC(O)OR^C, -S(O)2R^C, -S(O)2NR^cR^c, -NR^hC(O)R^c, -NR^hC(O)OR^c, -NR^hC(O)NR^cR^c, -NR^hC(NR^h)NR^cR^c and -NR^hS(O)2R^c, as well as the bivalent substituent =O, while the latter may only be a substituent in non-aromatic ring Systems;

each R^c independently dénotés hydrogen or a group optionally substituted by one or more îdentical or different R^d and/or R^e, selected from among C^alkyl, C^alkenyl, C₂.₆alkynyl, C₃-i₀cycloalkyl, C^ocycioalkenyl, C₆-ioaryl, 5-12 membered heteroaryl and 3- to 14membered heterocyclyl;

each R^d is independently selected from among -OR^e, -SR^e, -NR^eR^e, halogen, -CN, -NO2, -C(O)R^e, -C(O)OR^e, -C(O)NR^eR^e, -C(NR^h)NR^eR^e, -OC(O)R^e, -OC(O)OR^e, -S(O)2R^e, -S(O)2NR^eR^e, -NR^hC(O)R^e, -NR^hC(O)OR^e, -NR^hC(O)NR^eR^e, -NR^hC(NR^h)NR^eR^e and -NR^hS(O)2R^e, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R^e independently dénotés hydrogen or a group optionally substituted by one or more îdentical or different R* and/or R⁹, selected from among C^alkyl, C₂-(,alkenyl, C₂.₆alkynyl, C₃-i₀cycloalkyl, C₄.₁₀cycloalkenyl, C₆.i₀aryl, 5-12 membered heteroaryl and 3- to 14membered heterocyclyl;

each R^f is independently selected from among -OR⁹, -SR⁹, -NR^SR⁹, halogen, -CN, -NO2, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁹R⁹, -C(NR^h)NR⁹R⁹, -OC(O)R⁹, -OC(O)OR⁹, -S(O)2R⁹, -S(O)2NR⁹R⁹, -NR^hC(O)R⁹, -NR^hC(O)OR⁹, -NR^hC(O)NR⁹R^a, -NR^hC(NR^h)NR⁹R⁹ and -NR^hS(O)2R⁹, as well as the bivalent substituent =0, while the latter may only be a

-19816301 substituent in non-aromatic ring Systems;

each R⁹ is independently selected from among hydrogen, C^alkyl, C^alkenyl, C2-₆alkynyl, C^haloalkyl, C₃.₁₀cycloalkyl, C₄_₁₀cycloalkylalkyl, C₄._Klcycloalkenyl, C₆.ioaryl,

2- [4-[2-[3-[(8-methyl-9-phenyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2yl)amino]pyrazol-1-yl]ethyl]piperazin-1-yl]ethanol;

N-[1-[2-[4-(2-methoxyethyl)piperazin-1-y!]ethyl]pyrazol-3-yl]-8-methyl-9-phenyl-

2. Compounds according to claim 1, wherein

R¹ is a group optionally substituted by one or more identical or different R^a1 and/or R^b1, selected from among C^alkyl, C₃.₁₀cycloalkyl, Ce-ioaryl, 5-12 membered heteroaryl and 3to 14-membered heterocyclyl;

each R^a1 independently dénotés a group optionally substituted by one or more identical or different R^b1 and/or C^alkyl, selected from among Ci^alkyl, C₃.₁₀cycloalkyl and Ce-ioaryl, and each R^b1 is independently selected from among -OH, -O-C_1j6alkyl, halogen and -CN.

3-7 membered heterocyclyl;

each R^a1 independently dénotés a group optionally substituted by one or more identical or different R^b1 and/or C_Malkyl, selected from among C^alkyl, C₃.₆cycloalkyl and phenyl, and each R^b1 is independently selected from among -O-C_Malkyl, halogen and -CN.

3. Compounds according to one of daims 1 or 2, wherein

R¹ is a group optionally substituted by one or more identical or different R^a1 and/or R^b1, selected from among C^alkyl, C₃.₆cycloalkyl, phenyl, 5- to 6-membered heteroaryl and

4. Compounds according to one of daims 1 to 3, wherein

R¹ dénotés C₃-ealkyl. x-19916301

5 pharmaceutically acceptable salts thereof - for use in the treatment and/or prévention of non-small cell lung cancers (NSCLC) and hepatocellular carcinomas (HCC).

46. Use of a compound of general formula (I) according to one of claims 1 to 41 - or one of the pharmaceutically acceptable salts thereof in the manufacture of a médicament for the treatment and/or prévention of cancer.

io

47. Pharmaceutical préparation containing as active substance one or more compounds of general formula (I) according to one of claims 1 to 41 - or the pharmaceutically acceptable salts thereof - optionally in combination with conventional excipients and/or carriers.

48. Pharmaceutical préparation comprising a compound of general formula (I) according

5 pharmaceutically acceptable salts thereof - for use in the treatment and/or prévention of cancer, infections, inflammations and autoimmune dîseases.

-21516301

44. Compounds of general formula (I) according to one of claims 1 to 41 - or the pharmaceutically acceptable salts thereof - for use in the treatment and/or prévention of cancer.

45. Compounds of general formula (I) according to one of claims 1 to 41 - or the

5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine;

5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-methoxyethyl)pyrazol-3-yl]-8-methyl-9-[(2-methylphenyl)methyl]-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-8-methyl-9-(3-rnethylthiophen-2-yl)-

5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine;

5 each R^{5 6} is independently selected from among C^alkyl, -O-C-.₄alkyl and halogen;

p dénotés 0, 1 or 2; x

-20716301

R^c5 dénotés hydrogen or a group optionally substituted by one or more identical or different R^ds and/or R^eS selected from among Ci _üalkyl, C₂.₆alkenyl, C₂^alkynyl, C₃.₁₀cycloalkyl, Ci.₁₀cycloalkenyl, Ce.₁₀aryl, 5-12 membered heteroaryl and 3- to 14membered heterocyclyl;

each R^d5 is independently selected from among -OR^e5, -SR^e5, -NR^e5R^e5, halogen, -CN, -NO2, -C(O)R^e5, -C(O)OR^e5, -C(O)NR^e5R^e5, -C(NR^h5)NR^e5R^e5, -OC(O)R^e5, -OC(O)OR^e5, -S(O)2R^e6, -S(O)2NR^e5R^e5, -NR^h5C(O)R^e5, -NR^h5C(O)OR^e5, -NR^h5C(O)NR^e5R^e5, -NR^h5C(NR^h5)NR^e5R^e5 and -NR^h5S(O)2R^eS, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R^e5 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^K and/or R^e5 selected from among C^alkyl, C₂^alkenyl, C_2ealkynyl, C₃.₁₀cycloalkyl, C_{4 t0}cycloalkenyl, C₆.₁₀aryl, 5-12 membered heteroaryl and βίο 14-membered heterocyclyl;

each R^f5 is independently selected from among -OR⁹⁵, -SR⁹⁵, -NR⁹⁵R⁹⁵, halogen, -CN, -NO2, -C(O)R⁹⁵, -C(O)OR⁹⁵, -C(O)NR^g5R⁹⁵, -C(NR^h5)NR⁹⁵R⁹⁵, -OC(O)R⁹⁵, -OC(O)OR⁹⁵, -S(O)2R⁹⁵, -S(O)_zNR⁹⁵R³⁵, -NR^h5C(O)R⁹⁵, -NR^h5C(O)OR⁹⁵, -NR^h5C(O)NR^s5R⁹⁵,

-NR^h5C(NR^h5)NR⁹⁵R⁹⁵ and -NR^h5S(O)₂R⁹⁵, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each _RgS is independently selected from among hydrogen, C^alkyl, C^alkenyl, C₂₆alkynyl, C-._fihaloalkyl, C₃.₁₀cycloalkyl, C4.₁₀cycloalkylalkyl, C^ocycloalkenyl, C₆.ioaryl, 5-12 membered heteroaryl and 3- to 14-membered heterocyclyl and each R^h5 is independently selected from among hydrogen and Ci^alkyl.

31. Compounds according to one of claims 1 to 14, wherein

R³ dénotés a group

-20816301

R^{6 1} and R^{6 2} are each independently selected from among hydrogen, C_Malkyl, -O-C- ₄alkyl and halogen and

R^c5 is defined as in claim 30.

32. Compounds according to one of claims 30 or 31, wherein

R^c5 dénotés hydrogen or a group optionally substituted by one or more identical or different R^d5 and/or R®⁵ selected from among Ci^alkyl, C_3Wcycloalkyl and 3- to 14membered heterocyclyl;

each R^d5 is independently selected from among -OR®⁵, -NR^e5R^e5, halogen, -C(O)R^e5 and -C(O)NR^e5R®⁵ and each R®⁵ is independently selected from among hydrogen, C^alkyl, C₃.i₀cycloalkyl and 3to 14-membered heterocyclyl.

33. Compounds according to one of claims 30 or 31, wherein

R^c5 dénotés a group optionally substituted by one or more identical or different R^dS and/or R®⁵ selected from among C^alkyl and 5- to 6-membered, nitrogen-containing heterocyclyl;

each R^d5 is independently selected from among -OR®⁵, -NR^e5R^e5, halogen, -C(O)R®⁵ and -C(O)NR^e5R®⁵ and each R*⁵ is independently selected from among Ci._salkyl and 5- to 6-membered, nitrogencontaining heterocyclyl.

34. Compounds according to one of claims 30 or 31, wherein

R^cS is selected from among Ν,Ν-dimethylethyl, N,N-dimethyl-propyl, and

-20916301 each R⁶ is independently selected from among C^alkyl, -O-C-.,_;alkyl and halogen;

R⁷ is selected from among R^b6 and R^c6;

p dénotés 0, 1 or 2;

R^b6 is selected from among -C(O)R^c6, -C(O)OR^c6, -C(O)NR^c6R^c6, -S(O)₂R^c6 and

-S(O)₂NR^c6R^c6;

each R^c6 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^d6 and/or R®⁶, selected from among C^alkyl, C^alkenyl, C_2üalkynyl, C₃_i₀cycloalkyl, C₄ wcycloalkenyl, C₆.i₀aryl, 5-12 membered heteroaryl and 3to 14-membered heterocyclyl;

each R^d6 is independently selected from among -OR®⁶, -SR®⁶, -NR^e6R^e6, halogen, -CN, -NO2, -CfOJR®⁶, -CiOJOR®⁶, -C(O)NR^eËR^ee, -C(NR^h6)NR®⁶R®⁶, -OCiOJR®⁶, -OCtOJOR®⁶, -StO^R®⁶, -SÎO^NR^R®⁶, -NR^h6C(O)R^e6, -NR^h6C(O)OR®\ -NR^h6C(O)NR®⁶R®⁶, -NR^h6C(NR^h6)NR^e6R®⁶ and -NR^h6S(O)?R^eS, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R®⁶ is independently selected from among hydrogen, C^alkyl, C₂.₆alkenyl, C_z6alkynyl, C3.₁₀cycloalkyl, C^ocycloalkenyl, C₆.ioaryl, 5-12 membered heteroaryl and 3to 14-membered heterocyclyl, and each R^he is independently selected from among hydrogen and C_walkyl.

-21016301

36. Compounds according to one of claims 1 to 14, wherein

R³ dénotés a group

R^{6 1} and R^{6 2} are independently selected from among hydrogen, C_Malkyl, -O-C, ₄alkyl and 5 halogen and

R⁷ is defined as in claim 35.

37. Compounds according to one of claims 35 or 36, wherein

R⁷ is selected from among R^b6 and R^c6;

R^be is selected from among -CiOÏR®⁶, -C(O)NR^c6R^c6 and -S(O)₂R^c6;

5 each R^m is independently selected from among hydrogen and Ci_₄alkyl.

24. Compounds according to one of daims 1 to 14, wherein

R³ dénotés a group and

R⁰⁴, R⁶ and p are defined as in claim 23.

25. Compounds according to one of daims 1 to 14, wherein

R³ dénotés a group (R^e)p and

R^c4, R⁶ and p are defined as in claim 23.

26. Compounds according to one of daims 1 to 14, wherein

R³ dénotés a group

-20416301

R^{6 1} and R⁶’² is independently selected from among hydrogen, C-t^alkyl, -O-C<.ialkyl and halogen and

R^c4 is defined as in claim 23.

27. Compounds according to one of daims 23 to 26, wherein

R^c4 dénotés hydrogen or a group optionally substituted by one or more identical or different R^d4 and/or R⁶⁴ selected from among Ci.₆alkyl, C₃₁₀cycloalkyl and 3- to 14membered heterocyclyl;

each R^d4 is independently selected from among -OR^e4, -NR^R⁶⁴, halogen, -C(O)R^e4 and -C(O)NR^e4R^e4;

each R*⁴ independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^f4 and/or R⁹⁴ selected from among C,__balkyl, C₃.i₀cycloalkyl and 3- to 14-membered heterocyclyl;

each R*⁴ is independently selected from among -OR⁹⁴, -NR^g4R⁹⁴, halogen, -C(O)R⁹⁴, -C(O)NR^a4R⁹⁴ and each r₉4 is independently selected from among hydrogen, C^alkyl, Ci_₆haloalkyl, C₃.iocycloalkyl, C₄.₁₀cycloalkylalkyl, C₆.ioaryl and 5-12 membered heteroaryl.

28. Compounds according to one of daims 23 to 26, wherein

R^c4 dénotés a group optionally substituted by one or more identical or different R^d4 and/or R⁶⁴ selected from among C^alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, 1-aza-bicyclo[2.2.2]octyl, 8-methyl-8-azabicyclo[3.2.1]octyl, morpholinyl, piperidinyl and piperazinyl;

each R^d4 is independently selected from among -OR^e4, -NR^e4R^e4, halogen, -C(O)R“ and

-20516301

-C(O)NR^e4R^e4;

each R®⁴ independently dénotés a group optionally substituted by one or more identical or different R^f4 and/or R⁹⁴ selected from among C, ₆alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, 1-aza-bicyclo[2.2.2]octyl, 8-methyl-85 aza-bicyclo[3.2.1]octyl, morpholinyl, piperidinyl and piperazinyl;

each R^f4 is independently selected from among -OR⁹⁴, -NR⁹⁴R⁹⁴, halogen, -C(O)R⁹⁴, -C(O)NR⁹⁴R⁹⁴ and each R^g4 is independently selected from among hydrogen, C^alkyl, Cvehaloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl and 5- to 610 membered heteroaryl.

29. Compounds according to one of claims 23 to 26, wherein

R^c4 is selected from among methyl, methoxyethyl, A/,A/-dimethyl-ethyl, A/./V-dimethylpropyl,

> x. / ‘CX y ï 0 y -O, r f ^χ f ^ΌνΌ,/ NX ^χ. ^x

-20616301

A 1 /a oÎU, J Ά ï m,· / y °cxx i Sx / 1 oj A J OX σα αα cm.

and

30. Compounds according to one of claims 1 to 14, wherein

R³ dénotés a group

5-12 membered heteroaryl and 3- to 14-membered heterocyclyl and

5. Compounds according to one of claims 1 to 3, wherein

R¹ dénotés phenyl or benzyl, wherein the above-mentioned phenyl and benzyl optionally carry one or more substituents selected from among C-^alkyl, halogen, -O-C- ₆alkyl and -CN.

5-12 membered heteroaryl and 3- to 14-membered heterocyclyl, and each R^h is independently selected from among hydrogen and C;__ealky1, while the compounds (I) may optionally also be présent in the form of their tautomers, their racemates, their enantiomers, their diastereomers or their mixtures or as the respective salts of ail the above-mentioned forms.

6. Compounds according to one of claims 1 to 3, wherein

R¹ dénotés phenyl or benzyl, wherein the above-mentioned phenyl and benzyl optionally carry one or more substituents selected from among C^alkyl, Ci_₄haloalkyl, halogen, -O-Ci^alkyl, -O-C-.-.haloalkyl and -CN.

7. Compounds according to one of claims 1 to 3, wherein

R⁴ dénotés thîenyl, wherein this thienyl optionally carries one or more substituents selected from among C₁₄alkyl and halogen.

8- methyl-9-phenyl-N-[1-(2-piperazin-1-ylethyl)pyrazol-3-yl]-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

8- methyl-N-[1-[2-(4-methy1piperazin-1-yl)ethyl]pyrazol-3-yl]-9-phenyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

8-methyl-9-phenyl-N-[1-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]-5,6-21316301

8. Compounds according to one of claims 1 to 7, wherein

R² is hydrogen or a group optionally substituted by one or more identical or different R^b2 and/or C₆-io3ryl selected from among C^alkyl, C₂-ealkenyl and 5- to 12-membered heteroaryl;

each R^b2 is independently selected from among -OH, -O-Ci_6alkyl, -NH₂, -NHfC^alkyl) and -N(Ci^alkyl)2.

9- (3-chlorothiophen-2-yl)-N-[1-(2-rnethoxyethyl)pyrazol-3-yl]-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-[(2-chlorophenyl)methyl]-N-[1-(2-methoxyethyl)pyrazol-3-yl]-8-methyl-5,6dîhydropyrazolo[3,4-h]quinazolin-2-amine;

9-benzyl-N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-[4-(difluoromethoxy)phenyl]-N-[1-(2-methoxyethyl)pyrazol-3-yl]-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-[(3-methoxyphenyl)methylJ-8-methyl-N-(1-methylpyrazol-3-yl )-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9- (4-chlorophenyl)-N-[1-(2-methoxyethyl)pyrazol-3-yl]-8-methyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

9-[(2-chlorophenyl)methyl]-N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-8-methyl-

9-[4-(difluoromethoxy)phenyl]-N-[1-(2-dimethylaminoethyl)pyrazol-3-yl]-8methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine;

(5S)-N-[1-(2-methoxyethyl)pyrazol-3-yl]-5,8-dimethyl-9-phenyl-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine;

N-[1-(2-methoxyethyl)pyrazol-3-yl]-8-methyl-9-[(3-methylphenyl)methyl]-5,6dihydropyrazolo[3,4-h]quinazolin-2-amine

9. Compounds according to one of claims 1 to 7, wherein

R² is a group optionally substituted by one or more identical or different R^b2 and/or phenyl, selected from among C^alkyl, and 5- to 6-membered heteroaryl;

each R^b2 is independently selected from among -O-C^alkyl and -N(C_walkyl)₂.

10 each R^c6 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^de and/or R^e6, selected from among C^alkyl, C₃.₆cycloalkyl and 5- to 6-membered heterocyclyl;

each R^de is independently selected from among -OR®⁶, -NR^e6R^e6, halogen, -CiOJR®⁶ and -C(O)NR^e6R^eü and

15 each R^e6 is independently selected from among hydrogen, C^alkyl, C₃^cycloalkyl and 5to 6-membered heterocyclyl.

38. Compounds according to one of claims 1 to 14, wherein

R³ dénotés pyrazolyl, which is optionally mono- or disubstituted by Ci /.alkyl or C₃.₅cycloalkyl. y

-21116301

39. Compounds according to one of claims 1 to 14, wherein

R³ dénotés a group

R⁸ dénotés a group optionally substituted by one or more identical or different R^b7 and/or 5 R^cT, selected from among C^alkyl, C_{3 g}cycloalkyl and 5- to 7-membered heterocyclyl;

each R^b7 is independently selected from among -OR⁰⁷, -NR^o7R°⁷, halogen, -C(0)R^c7 and

-C(0)NR^o7R°⁷;

each R^c7 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^d7 and/or R^e7, selected from among C^alkyl, C₃__ecycloalkyl, 510 to 6-membered heteroaryl and 5- to 7-membered heterocyclyl;

each R^d7 is independently selected from among -OR^e7, -NR^e7R^e7, halogen, -C(O)R^e7 and -C(O)NR^e7R^e7;

each R^e7 independently dénotés hydrogen or a group optionally substituted by one or more identical or different Rⁿ and/or R⁹⁷, selected from among C^alkyl, C₃«cycloalkyl, 515 to 6-membered heteroaryl and 5- to 7-membered heterocyclyl;

each Rⁿ is independently selected from among -OR⁹⁷, -NR⁹⁷R^g7, halogen, -C(O)R^9? and -C(O)NR^g7R⁹⁷;

each R⁹⁷ independently dénotés hydrogen or C_1j6alkyl;

R⁹ is selected from among hydrogen, C_Malkyl and C₃^cycloalkyl.

-21216301

40. Compounds according to one of claims 1 to 14, wherein

R³ dénotés a group

10. Compounds according to one of claims 1 to 7, wherein

R² dénotés methyl or ethyl.

11. Compounds according to one of claims 1 to 10, wherein

X dénotés a bond or is selected from among -CH₂- and -CH₂-CH₂- and in the above

-20016301 mentioned -CH₂- and -CH₂-CH₂- one or two hydrogen atoms are optionally substituted by CMalkyl.

12. Compounds according to one of claims 1 to 10, wherein

X is selected from among -CH₂- and -CH₂-CH₂- and in the above-mentioned -CH₂- and -CH₂-CH₂- one or two hydrogen atoms are optionally substituted by C_lJtalkyl.

13. Compounds according to one of claims 1 to 10, wherein

X is selected from among -CH₂-, -CH(CH₃)-, -C(CH₃)₂- and -CH₂-CH₂-.

14. Compounds according to one of claims 1 to 10, wherein

X dénotés -CH₂- or -CH(CH₃)-.

15. Compounds according to one of claims 1 to 14, wherein

A is selected from among phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl and 9- to 10-membered bicyclic heteroaryl.

16. Compounds according to one of claims 1 to 14, wherein

A is selected from among phenyl, benzofuryl, benzothienyl, naphthyl, isoquinolinyl, pyrazolyl, indazoiyl, isoxazolyl and imidazo[1,2-a]pyridyl.

17. Compounds according to one of claims 1 to 14, wherein

A dénotés phenyl.

18. Compounds according to one of claims 1 to 14, wherein

A dénotés pyrazolyl.

19. Compounds according to one of claims 1 to 18, wherein each R⁴ is independently selected from among R^a3 and R^bî;

m dénotés 0, 1,2 or 3;

each R^a3 independently dénotés a group optionally substituted by one or more identical or

-20116301 different R^b3 and/or R^c3, selected from among C^alkyl, C₃.₁₀cycloalkyl and 3- to 14membered heterocyclyl;

each R^b3 is independently selected from among -OR^c3, -NR^c3R^c3, halogen, -C(O)R^c3, -C(O)OR^c3, -CXOJNR^R⁸³ and -S(O)₂R^c3;

each R^c3 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^d3 and/or R^e3 selected from among Cj^alkyl, C^alkenyl, C₃-₁₀cycloalkyl and 3- to 14-membered heterocyclyl;

each R^d3 is independently selected from among -OR^e3, -NR^e3R^e3, halogen, -C(O)R^e3, -C(O)OR^e3 and -C(O)NR^e3R^e3;

each R^e3 independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^f3 and/or R®³ selected from among C^alkyl, C₃._wcycloalkyl and 3- to 14-membered heterocyclyl;

each R^f3 is independently selected from among -OR®³, -NR®³R®³, halogen, -C(O)R⁹³, -C(O)OR⁹³ and -C(O)NR®³R®³ and each R®³ is independently selected from among hydrogen, C^alkyl, C, _bhaloalkyl, C₃.₁₀cycloalkyl, C₄.₁₀cycloalkylalkyl, Ce_₁₀aryl, and 5-12 membered heteroaryl.

20. Compounds according to claim 19, wherein m dénotés 1,2 or 3.

21. Compounds according to claim 19, wherein m dénotés 2.

22. Compounds according to one of claims 1 to 14, wherein

R³ dénotés a group

A is selected from among C₆.₁₀aryl and 5-12 membered heteroaryl; each R⁴ is independently selected from among R^a and R^b; x

-20216301 m dénotés 0, 1, 2 or 3 and

R^a and R^b are defined as in claim 1.

23. Compounds according to one of ciaims 1 to 14, wherein

R³ dénotés a group

A is selected from among C₆.iûaryl and 5-12 membered heteroaryl;

each R^e is independently selected from among C-i.₄alkyl, -O-Cwalkyl and halogen;

p dénotés 0,1 or 2;

R^c4 dénotés hydrogen or a group optionally substituted by one or more identical or different R'*⁴ and/or R⁶⁴ selected from among Ci^alkyl, C₂₆alkenyl, C₂.₆alkynyl, C₃.₁₀cycloalkyl, C₄.i₀cycloalkenyl, C_e.ioaryl, 5-12 membered heteroaryl and 3- to 14membered heterocyclyl;

each R^d4 is independently selected from among -OR^e4, -SR⁶⁴, -NR^e4R^e4, halogen, -CN, -NO2, -C(O)R^e4, -C(0)OR⁶⁴, -C(O)NR^e4R⁶⁴, -C(NR^M)NR^e<R^el· -OC(O)R^e4, -OC(O)OR^e4, -S(O)2R⁶⁴, -S(O)₂NR^l'V; -NR^COJR·⁴, -NR^MC(O)OR^e4, -NR^h4C(O)NR^e4R^e4, -NR^h4C(NR^h4)NR^e4R^e4 and -NR^SiO^R⁶⁴, as well as the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring Systems;

each R®⁴ independently dénotés hydrogen or a group optionally substituted by one or more identical or different R^f4 and/or R⁹⁴ selected from among C_1j6alkyl, C₂₆alkenyl, C₂.₆alkynyl, C₃.₄₀cycloalkyl, C₄.i₀cycloalkenyl, C₆-waryl, 5-12 membered heteroaryl and 3to 14-membered heterocyclyl;

each R^f4 is independently selected from among -OR⁹⁴, -SR⁹⁴, -NR⁹⁴R^g4, halogen, -CN, -NO2, -C(O)R⁹⁴, -C(O)OR⁹⁴, -C(O)NR⁹⁴R⁹⁴, -C(NR^h4)NR⁹⁴R⁹⁴, -OC(O)R⁹⁴, -OC(O)OR⁹⁴, -S(O)2R⁹⁴, -S(O)2NR^g4R^g4, -NR^h4C(O)R^g4, -NR^h4C(O)OR⁹⁴, -NR^h4C(O)NR^g4R^g4, -NR^h4C(NR^g4)NR⁹⁴R⁹⁴ and -NR^MS(O)2R⁹⁴, as well as the bivalent substituent =0, while the

-20316301 latter may only be a substituent in non-aromatic ring Systems;

each R⁹⁴ is independently selected from among hydrogen, C^alkyl, C2^alkenyl,

C2-6alkynyl, Ci.₆haloalkyl, C₃-i₀cycloalkyl, C₄.₁₀cycloalkylalkyl, C4-₁₀cycioalkenyl, C₆.₁₀aryl,

15 to one of claims 1 to 41 - or one of the pharmaceutically acceptable salts thereof - and at least one other cytostatic or cytotoxic active substance different from formula (I).