WO2008017465A1

WO2008017465A1 - Bicyclic lactam derivatives, their manufacture and use as pharmaceutical agents

Info

Publication number: WO2008017465A1
Application number: PCT/EP2007/007006
Authority: WO
Inventors: Guy Georges; Bernhard Goller; Anja Limberg; Petra Rueger; Matthias Rueth
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2006-08-10
Filing date: 2007-08-08
Publication date: 2008-02-14

Abstract

Objects of the present invention are the compounds of formula (I) their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above compounds, medicaments containing them and their manufacture, as well as the use of the above compounds in the control or prevention of illnesses such as cancer.

Description

Bicyclic lactam derivatives, their manufacture and use as pharmaceutical agents

The present invention relates to novel bicyclic lactam derivatives, to a process for their manufacture, pharmaceutical compositions containing them and their manufacture as well as the use of these compounds as pharmaceutically active agents.

Background of the Invention

Protein kinases regulate many different signaling processes by adding phosphate groups to proteins (Hunter, T., Cell 50 (1987) 823-829); particularly serine/threonine kinases phosphorylate proteins on the alcohol moiety of serine or threonine residues. The serine/threonine kinase family includes members that control cell growth, migration, differentiation, gene expression, muscle contraction, glucose metabolism, cellular protein synthesis, and regulation of the cell cycle.

The Aurora kinases are a family of serine/threonine kinases that are believed to play a key role in the protein phosphorylation events that are essential for the completion of essential mitotic events. The Aurora kinase family is made up of three key members: Aurora A, B and C (also known as Aurora-2, Aurora-1 and

Aurora-3 respectively). Aurora-1 and Aurora-2 are described in US 6,207,401 of Sugen and in related patents and patent applications, e.g. EP 0 868 519 and EP 1 051 500.

For Aurora A there is increasing evidence that it is a novel proto-oncogene. Aurora A gene is amplified and transcript/protein is highly expressed in a majority of human tumor cell lines and primary colorectal, breast and other tumors. It has been shown that Aurora A overexpression leads to genetic instability shown by amplified centrosomes and significant increase in aneuploidy and transforms Ratl fibroblasts and mouse NIH3T3 cells in vitro. Aurora A-transformed NIH3T3 cells grow as tumors in nude mice (Bischoff, J.R. and Plowman, G.D., Trends Cell Biol. 9

(1999) 454-459; Giet, R. and Prigent, C, J. Cell Sci. 112 (1999) 3591-3601; Nigg,

E.A., Nat. Rev. MoI. Cell Biol. 2 (2001) 21-32; Adams, R.R. et al., Trends Cell Biol.

11 (2001) 49-54). Moreover, amplification of Aurora A is associated with aneuploidy and aggressive clinical behavior (Sen, S. et al., J. Natl.Cancer Inst. 94 (2002) 1320-1329) and amplification of its locus correlates with poor prognosis for patients with node-negative breast cancer (Isola, JJ. et al., Am. J. Pathology 147

(1995) 905-911). For these reasons it is proposed that Aurora A overexpression contributes to cancer phenotype by being involved in chromosome segregation and mitotic checkpoint control.

Human tumor cell lines depleted of Aurora A transcripts arrest in mitosis. Accordingly, the specific inhibition of Aurora kinase by selective inhibitors is recognized to stop uncontrolled proliferation, re-establish mitotic checkpoint control and lead to apoptosis of tumor cells. In a xenograft model, an Aurora inhibitor therefore slows tumor growth and induces regression (Harrington, E.A. et al, Nat. Med. 10 (2004) 262-267).

Low molecular weight inhibitors for protein kinases are widely known in the state of the art. For Aurora inhibition such inhibitors are based on i.e. pyrazole or quinazoline derivatives as claimed in the following patents and patent applications: WO 00/44728 or WO 02/22601.

3-Amino-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles were described by Pevarello, P. et al., Bioorg. Med. Chem. Lett. 16 (2006) 1084-1090 as cdk2 and Aurora A kinase inhibitors. Fancelli, D. et al., J. Med. Chem. 48 (2005) 3080-3084 relates to 1,4,5,6- tetrahydropyrrolo[ 3, 4-c] pyrazole bicycles as Aurora kinase inhibitors. WO 2002/012242, WO 2004/080457, WO 2004/056827 and WO 2005/005427 relate to bicyclo-pyrazole derivatives as kinase inhibitors

Summary of the Invention

The present invention relates to bicyclic lactam derivatives of the general formula I,

formula I

wherein R¹ is hydrogen or alkyl; R² is a) phenyl optionally substituted one or several times by alkyl, halogen, cyano, -NO₂, -NRR', -NR-C(O)alkyl, -OH, -OR, -CF₃ or -OCF₃; b) heteroaryl optionally substituted one or several times by alkyl; or c) alkyl;

R³ and R⁴ independently are alkyl; X is -NH-, -O- or alkylene;

R and R' independently are hydrogen or alkyl; and all pharmaceutically acceptable salts thereof.

The compounds according to this invention show activity as protein kinase inhibitors. Many diseases are associated with abnormal cellular responses triggered by protein kinase mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone- related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

The compounds according to this invention in particular show activity as Aurora family kinase inhibitors, especially as Aurora A kinase inhibitors, and may therefore be useful for the treatment of diseases mediated by said kinase. Aurora A inhibition leads to cell cycle arrest in the G2 phase of the cell cycle and exerts an antiproliferative effect in tumor cell lines. This indicates that Aurora A inhibitors may be useful in the treatment of i.e. hyperproliferative diseases such as cancer and in particular colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas. Treatment of acute- myelogenous leukemia (AML, acute lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST) is included.

Objects of the present invention are the compounds of formula I and their tautomers, pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, their use as Aurora kinase inhibitors, the preparation of the above- mentioned compounds, medicaments or pharmaceutical compositions containing them and their manufacture as well as the use of the above-mentioned compounds in treatment, control or prevention of illnesses, especially of illnesses and disorders as mentioned above like tumors or cancer (e.g. colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas) or in the manufacture of corresponding medicaments or pharmaceutical compositions.

Detailed Description of the Invention

The term "alkyl" as used herein means a saturated, straight-chain or branched-chain hydrocarbon containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2 -butyl, t-butyl, n- pentyl, n-hexyl.

The term "halogen" as used herein means fluorine, chlorine or bromine, preferably fluorine or chlorine.

The term "heteroaryl" as used herein means a mono- or bicyclic aromatic ring with

5 to 10 ring atoms, preferably with 5 to 6 ring atoms, which contains up to 3 heteroatoms, preferably 1 or 2 heteroatoms, selected independently from N, O or S and the remaining ring atoms being carbon atoms. Examples of such heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl and the like, preferably pyrazolyl, triazolyl, tetrazolyl, thienyl, pyridyl or pyrimidyl and more preferably thienyl.

The term "alkylene" as used herein means a saturated, straight-chain or branched- chain, preferably straight-chain, hydrocarbon containing from 1 to 5 carbon atoms, preferably from 1 to 3 carbon atoms, such as methylene, ethylene, trimethylene

(1,3 -propylene); tetramethylene (butylene), pentamethylene, methyl-methylene, ethyl-methylene, methyl-ethylene (1,2-propylene), ethyl-ethylene, propyl-ethylene,

1-methyl-trimethylene, 2-methyl-trimethylene, 1-ethyl-trimethylene, 2-ethyl- trimethylene and the like, preferably methylene or ethylene and more preferably methylene.

The term "N-protecting group" as used herein means a blocking group for the amino functional group (which is introduced before a reaction and) which prevents the amino group to react in side reaction e.g. during acylation reactions. Such N- protecting group can be cleaved after the reaction to give the free amine again.

Examples such as t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Z), allyloxycarbonyl, ethyloxycarbonyl and others are described e.g. in Greene, T. W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, third edition, Wiley, New York (1999) or Kocienski, P., Protecting Groups, third edition, Georg Thieme Verlag, Stuttgart (2004) including the reaction conditions for introduction and cleavage. Preferred examples of N-protecting groups are e.g. t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Z), allyloxycarbonyl, ethyloxycarbonyl and the like. For PG¹ a preferred group is ethyloxycarbonyl and for PG² a preferred group is t- butyloxycarbonyl (BOC).

As used herein, a "pharmaceutically acceptable carrier" is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions of the invention are contemplated. Supplementary active compounds can also be incorporated into the compositions.

As used herein, the term "a therapeutically effective amount" of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.

The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion. R¹ is hydrogen or alkyl.

R² is a) phenyl optionally substituted one or several times, preferably once or twice, by alkyl, halogen, cyano, -NO₂, -NRR', -NR-C(O)alkyl, -OH, -OR, -CF₃ or -OCF₃, preferably by alkyl ; b) heteroaryl optionally substituted one or several times by alkyl, said heteroaryl being preferably unsubstituted and if substituted, being preferably substituted once or twice by alkyl; or c) alkyl.

R³ and R⁴ independently are alkyl, preferably methyl.

X is -NH-, -O- or alkylene.

R and R' independently are hydrogen or alkyl.

An embodiment of the invention are the compounds according to formula I, wherein

X is -NH-.

Another embodiment of the invention are the compounds according to formula I, wherein

R² is phenyl optionally substituted one or several times, preferably once or twice, by alkyl, halogen, cyano, -NO₂, -NRR', -NR-C(O)alkyl, -OH, -OR, -CF₃ or -OCF₃, preferably by alkyl.

X is -NH-; and

Such compounds, for example, may be selected from the group consisting of: l-Isopropyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2,6- diethyl-phenylcarbamoyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl] -amide;

l-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2,6- diethyl-phenylcarbamoyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl] -amide; and

3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2,6-diethyl- phenylcarbamoyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl] -amide. Another embodiment of the invention are the compounds according to formula I, wherein

X is alkylene.

R² is heteroaryl optionally substituted one or several times by alkyl, said heteroaryl being preferably unsubstituted and if substituted, being preferably substituted once or twice by alkyl.

X is alkylene; and

Such compounds, for example, may be selected from the group consisting of: l-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2- thiophen-2-yl-acetyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl] -amide; and

3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2-thiophen-2-yl- acetyl)- l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl] -amide.

X is -O-.

R² is alkyl.

X is -O-; and R² is alkyl.

Such a compound is for example:

3-[(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl)-amino]-4,6-dihydro- lH-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester. Another embodiment of the invention is a process for the preparation of the compounds of formula I comprising the steps of

a) converting a compound of formula II,

formula II,

wherein R¹, R³ and R⁴ have the significance given above for formula I and PG¹ is a N-protecting group, to give the compounds of formula III

formula III,

wherein R¹, R², R³, R⁴ and X have the significance given above for formula I and PG¹ is a N-protecting group, b) cleaving the N-protecting group PG¹ of the compounds of formula III to give the corresponding derivatives of formula I,

formula I wherein R¹, R², R³, R⁴ and X have the significance given above for formula I, c) isolating the compounds of formula I; and d) if desired, converting the compounds of formula I into their pharmaceutically acceptable salts.

The bicyclic compounds of formula I, or a pharmaceutically acceptable salt thereof, which are subject of the present invention, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula I, or a pharmaceutically- acceptable salt thereof, are illustrated by the following representative schemes 1 to 2 and examples in which, unless otherwise stated, R¹, R² and X have the significance given herein before for formula I. Necessary starting materials are either commercially available or they may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying examples or in the literature cited below with respect to schemes 1 to 2. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

Scheme 1: Preparation of intermediates One route for the preparation of compounds of formula VI starts from carboxylic acids of formula IV and suitable protected aminopyrazoles of formula V which were reacted to give the corresponding amides VI.

Scheme 1

In scheme 1, R¹, R³ and R⁴ have the significance as given above for formula I and

PG¹ and PG² are two different N-protecting groups, which are cleavable independently from each other.

Such N-protecting groups are e.g. t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Z), allyloxycarbonyl, ethyloxycarbonyl and the like. These and other appropriate N-protecting groups are described e.g. in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, third edition, Wiley, New York (1999) or Kocienski, P., Protecting Groups, third edition, Georg Thieme Verlag, Stuttgart (2004).

The carboxylic acids of formula IV can be prepared by standard procedures of organic chemistry and are described in DE 39 32 953 and EP 0 344 634 (one method for the alleviation of such compounds is described in scheme 2, step 3). The synthesis of compounds of formula V wherein PG¹ and PG² are two different oxycarbonyl groups (e.g. as in a preferred embodiment, PG¹ is ethyloxycarbonyl and PG² is t- butyloxycarbonyl) can be prepared as described in Fancelli, D. et al., J.

Med. Chem. 48 (2005) 3080-3084 or analogously thereto.

Before the reaction with the compounds of formula V, the carboxylic acids of formula IV are either converted into their acid chlorides using standard reagents well known to someone skilled in the art, such as thionyl chloride, oxalyl chloride, phosphoryl chloride and the like. Those reagents can be used in presence of bases such as N.N-diisopropylethylamine, triethylamine or pyridine in inert solvent such as dichloromethane or dimethylformamide. The resulting acid chloride is then reacted with the amines of formula V to give the compounds of formula VI in an inert solvent such as dimethylformamide (DMF), dichloromethane tetrahydrofuran and the like at temperatures between 0 ⁰C and 60 ⁰C eventually in the presence of a base such as N,N-diisopropylethylamine, triethylamine or pyridine and the like.

Or the carboxylic acids of formula IV are converted in situ into activated acids by different peptide coupling procedures known to those skilled in the art. These activated acids were reacted directly with the amines of formula V to give the compounds of formula VI. Said activation with those peptide coupling procedures can involve the use of an activating agent like l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) (or dicyclohexylcarbodiimide (DCC)), hydroxybenzotriazole (HOBt) with or without di-isopropylethylamine (DIPEA) in an inert solvent such as dimethylformamide (DMF) or dichloromethane at temperatures between 0 ⁰C and 60 ⁰C. The reaction may alternatively be carried out in presence of O-(7-azabenzotriazol-l-yl)-N,JV,N',N'-tetramethyluronium hexafluorophosphate (HATU) or l-hydroxy-7-azabenzotriazole (HOAt) and triethylamine or di-isopropylethylamine in dimethylformamide or tetrahydrofuran. Scheme 2: Preparation of compounds of formula I

In scheme 2 the preparation of the compounds of formula I is described starting from derivatives of formula VI, wherein PG¹ is ethyloxycarbonyl, PG² is t- butyloxycarbonyl and R¹ is hydrogen, and which are named Via.

agent CDI

Scheme 2

In scheme 2, R¹, R², R³ and R⁴ have the significance as given above for formula I, X is alkylene for Methods A, B and C, X is NH or O for Methods E and F and X' is N for Method D. Removal of the Boc protecting group PG² (step 1) can be achieved by standard methods well know to someone skilled the art. For example acids like HCl or trifluoro acetic acid in solvents like ethyl acetate or methanol at ambient temperature can be used in this reaction.

Depending on the nature of X different methods for the acylation of amines of formula Ha in step 2 , scheme 2 can be used: IfX is alkylene, Methods A, B and C can be used:

Acid anhydrides (Method A) and acid chlorides(Method B) used in the formation of compounds of formula IHa are either commercially available or can be prepared using standard methods well known to someone skilled in the art. Those reagents can be used in presence of bases such as N,N-diisopropylethylamine, triethylamine or pyridine in inert solvent such as dichloromethane or dimethylformamide.

In scheme 2 (step 2), activated acids (Method C) can be prepared by different peptide coupling procedures known to those skilled in the art. Activation with those procedures can involve the use of an activating agents like l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (or dicyclohexylcarbodiimide

(DCC)), hydroxybenzotriazole (HOBt) with or without di-isopropylethylamine (DIPEA) in an inert solvent such as dimethylformamide (DMF) or dichloromethane at temperatures between 0 ⁰C and 60 ⁰C. The reaction may alternatively be carried out in presence of O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) or l-hydroxy-7- azabenzotriazole (HOAt) and triethylamine or di-isopropylethylamine in dimethylformamide or tetrahydrofuran.

IfX is NH or O, Methods D, E and F can be used:

Compounds of formula IHa wherein X is NH or O can be prepared using standard methods for the synthesis of ureas or carbamates (Scheme 2, step2- Methods

D,E,F). For example ureas of formula I can be synthesized by addition of amines of formula Ha to isocyanates of formula R²-X'CO (Method D, X' is N, scheme 2, step

2) in the presence of a base such as N,N-diisopropylethylamine, pyridine, triethylamine and the like in an inert solvent like dichloromethane, dimethylformamide (DMF), tetrahydrofuran (THF) and the like.

Ureas or carbamates can be obtained by reaction of the corresponding carbamoyl chlorides (X is NH) or chloroformates (X is O) of formula R²-X-C(O)C1 with amines of formula Ha (Method E, scheme 2, step 2) in the presence of a base such as N,N-diisopropylethylamine, pyridine, triethyl amine and the like in an inert solvent like dichloromethane, dimethylformamide (DMF), tetrahydrofuran (THF) and the like.

In another procedure for the preparation of compounds of formula I an amine of formula Ha is reacted with carbonyldiimidazole (CDI) and then amines (X is NH) or alcohols(X is O) of formula R²-X-H are added to the reactive intermediate to form urethanes or carbamates (Method F, scheme 2, step 2).

Compounds of formula I wherein R¹ is alkyl can be obtained by alkylation of the corresponding amides of formula IHa by methods well known to someone skilled in the art (scheme 2, step 3). For example alkyl chlorides or alkyl bromides can be used as alkylating reagents after deprotonation with bases like NaH or LiHMDS and the like in solvents like dimethylformamide (DMF), tetrahydrofuran (THF) and the like. This alkylation can alternatively be performed at any stage before step 1 (scheme 2).

Compounds of formula I can be obtained be deprotection of the corresponding precursors (scheme 2, step 4). In the case of ethyloxycarbonyl as protecting group deprotection is achieved by standard methods known to someone skilled in the art, e.g. treatment with bases like triethyl amine, potassium hydroxide potassium carbonate and the like, in solvents like water, methanol and the like.

Pharmaceutical compositions containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of the present invention and/or pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable carriers.

In accordance with the invention the compounds of the present invention as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses. Based on their Aurora tyrosine kinase inhibition and their antiproliferative activity, said compounds are useful for the treatment of diseases such as cancer in humans or animals and for the production of corresponding pharmaceutical compositions. The dosage depends on various factors such as manner of administration, species, age and/or individual state of health.

An embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I as active ingredients, together with pharmaceutically acceptable carriers.

Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable carriers for the treatment of diseases mediated by an inappropriate activation of Aurora family tyrosine kinases.

Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I as active ingredients, for the inhibition of tumor growth.

Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I as active ingredients, for the treatment of cancer.

Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable carriers for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.

Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable carriers for the treatment of acute-myelogenous leukemia (AML, acute lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST).

Another embodiment of the invention is the use of one or more compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of diseases mediated by an inappropriate activation of Aurora family tyrosine kinases.

Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of corresponding pharmaceutical compositions for the inhibition of tumor growth.

Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of corresponding pharmaceutical compositions for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.

Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of pharmaceutical compositions for the treatment of acute-myelogenous leukemia (AML, acute lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST).

Another embodiment of the invention is the use of the compounds of formula I as Aurora A tyrosine kinase inhibitors.

Another embodiment of the invention is the use of the compounds of formula I as anti-proliferating agents.

Another embodiment of the invention is the use of one or more compounds of formula I for the treatment of cancer.

Another embodiment of the invention is a method of treating cancer comprising administering to a person in need thereof a therapeutically effective amount of a compound of formula I.

Another embodiment of the invention is a method of treating cancer comprising administering to a person in need thereof a therapeutically effective amount of a compound of formula I, wherein the cancer is colorectal cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, gastric cancer, bladder cancer, ovarian cancer, melanoma, neuroblastoma, cervical cancer, kidney cancer or renal cancer, leukemia, or lymphoma.

The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like. The chemical modification of a pharmaceutical compound (i.e. a drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g. Bastin, RJ. et al., Organic Proc. Res. Dev. 4 (2000) 427-435.

The compounds of formula I can contain one or several chiral centers and can then be present in a racemic or in an optically active form. The racemates can be separated according to known methods into the enantiomers. For instance, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L- camphorsulfonic acid. Alternatively separation of the enantiomers can also be achieved by using chromatography on chiral HPLC-phases (HPLC: High Performance Liquid Chromatography) which are commercially available.

Pharmacological activity

The compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been found that said compounds show activity as inhibitors of the Aurora kinase family and also show anti-proliferative activity. Consequently the compounds of the present invention are useful in the therapy and/or prevention of illnesses with known over-expression of kinases of the Aurora family preferably Aurora A, especially in the therapy and / or prevention of illnesses mentioned above. The activity of the present compounds as inhibitors of the Aurora kinase family is demonstrated by the following biological assay:

IC50 determination for inhibitors of Aurora A

Assay principle

Aurora A is a serine threonine kinase involved in spindle assembly and chromosome segregation.

The assay is a typically ELISA-type assay where substrate (GST-Histone H3) is coupled to the assay-plate and is phosphorylated by the kinase. Phosphorylation is detected by a mouse anti-Phosphopeptid mAb and an HRP-labeled anti-mouse pAb. The assay is validated for IC₅₀ -determination.

Kinase activities were measured by Enzyme-Linked Immunosorbent Assay (ELISA): Maxisorp 384-well plates (Nunc) were coated with recombinant fusion protein comprising residues 1-15 of HistoneH3 fused to the N-terminus of Glutathione-S-

Transferase. Plates were then blocked with a solution of 1 mg/mL I-block (Tropix cat# T2015 - highly purified form of casein) in phosphate-buffered saline. Kinase reactions were carried out in the wells of the ELISA plate by combining an appropriate amount of mutant Aurora A kinase with test compound and 30 μM ATP. The reaction buffer was 1OX Kinase Buffer (Cell Signaling cat # 9802) supplemented with 1 μg/mL I-block. Reactions were stopped after 40 minutes by addition of 25 mM EDTA. After washing, substrate phosphorylation was detected by addition of anti-phospho-Histone H3 (Ser 10) 6G3 mAb (Cell Signaling cat #9706) and sheep anti-mouse pAb-HRP (Amersham cat# NA931V), followed by colorimetric development with TMB (3,3',5,5'-tetramethylbenzidine from Kirkegaard & Perry Laboratories). After readout of the adsorbance, IC50 values were calculated using a non-linear curve fit (XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK)). The results are shown in Table 1.

Results: Table 1

Antiproliferative activity

The activity of the present compounds as antiproliferative agents is demonstrated by the following biological assay:

CellTiter-Glo™ assay in HCT 116 cells The CellTiter- GIoTM Luminescent Cell Viability Assay (Promega) is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.

HCT 116 cells (human colon carcinoma, ATCC-No. CCl-247) were cultivated in RPMI 1640 medium with GlutaMAX™ I (Invitrogen, Cat-No. 61870-010), 2,5 %

Fetal Calf Serum (FCS, Sigma Cat-No. F4135 (FBS)); lOOUnits/ml penicillin/ lOOμg/ml streptomycin (= Pen/Strep from Invitrogen Cat. No. 15140).

For the assay the cells were seeded in 384 well plates, 1000 cells per well, in the same medium. The next day the test compounds were added in various concentrations ranging from 30 μM to 0.0015 μM (10 concentrations, 1:3 diluted). After 5 days the

CellTiter-Glo™ assay was done according to the instructions of the manufacturer

(CellTiter-Glo™ Luminescent Cell Viability Assay, from Promega). In brief: the cell-plate was equilibrated to room temperature for approximately 30 minutes and than the CellTiter-Glo™ reagent was added. The contents were carefully mixed for 15 minutes to induce cell lysis. After 45 minutes the luminescent signal was measured in Victor 2, (scanning multiwell spectrophotometer, Wallac). Details: 1st, dav:

- Medium: RPMI 1640 with GlutaMAX™ I (Invitrogen, Cat-Nr. 61870), 5 % FCS (Sigma Cat.-No. F4135), Pen/Strep (Invitrogen, Cat No. 15140). - HCTl 16 (ATCC-No. CCl-247): 1000 cells in 60 μl per well of 384 well plate

(Greiner 781098, μClear-plate white)

- After seeding incubate plates 24 h at 37°C, 5% CO₂

2nd, day : Induction (Treatment with compounds, 10 concentrations): In order to achieve a final concentration of 30 μM as highest concentration 3,5 μl of

10 mM compound stock solution were added directly to 163 μl media. Then step e) of the dilution procedure described below, was followed.

In order to achieve the second highest to the lowest concentrations, a serial dilution with dilution steps of 1:3 was followed according to the procedure (a -e) as described here below:

a) for the second highest concentration add 10 μl of 10 mM stock solution of compound to 20 μl dimethylsulfoxide (DMSO) b) dilute 8x 1:3 (always 10 μl to 20 μl DMSO) in this DMSO dilution row (results in 9 wells with concentrations from 3333,3 μM to 0.51 μM) c) dilute each concentration 1: 47,6 (3,5 μl compound dilution to 163 μl media) e) add 10 μl of every concentration to 60 μl media in the cell plate resulting in final concentration of DMSO : 0.3 % in every well and resulting in 10 final concentration of compounds ranging from 30 μM to

0.0015 μM.

Each compound is tested in triplicate.

Incubate 120 h (5 days) at 37°C, 5% CO₂

Analysis: -Add 30 μl CellTiter-Glo™ Reagent (prepared from CellTiter-Glo™ Buffer and

CellTiter-Glo™ Substrate (lyophilized) purchased from Promega) per well, -shake 15 minutes at room temperature -incubate further 45 minutes at room temperature without shaking Measurement:

-Victor 2 scanning multiwell spectrophotometer (Wallac), Luminescence mode (0.5 sec/read, 477 nm)

-Determine IC50 using a non-linear curve fit (XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK))

With all compounds a significant inhibition of HCT 116 cell viability was detected, which is exemplified by the compounds shown in Table 2.

Results: Table 2

The compounds according to this invention and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions. The pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragέes, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The above-mentioned pharmaceutical compositions can be obtained by processing the compounds according to this invention with pharmaceutically acceptable, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or it's salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

A pharmaceutical compositions comprise e.g. the following:

a) Tablet Formulation (Wet Granulation):

Manufacturing Procedure:

1. Mix items 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50⁰C.

3. Pass the granules through suitable milling equipment.

4. Add item 5 and mix for three minutes; compress on a suitable press.

b) Capsule Formulation:

Manufacturing Procedure:

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule. c) Micro suspension

1. Weigh 4.0 g glass beads in custom made tube GL 25, 4 cm (the beads fill half of the tube).

2. Add 50 mg compound, disperse with spatulum and vortex. 3. Add 2 ml gelatin solution (weight beads: gelatin solution = 2:1) and vortex.

4. Cap and wrap in aluminum foil for light protection.

5. Prepare a counter balance for the mill.

6. Mill for 4 hours, 20/s in a Retsch mill (for some substances up to 24 hours at 30/s). 7. Extract suspension from beads with two layers of filter (100 μm) on a filter holder, coupled to a recipient vial by centrifugation at 400 g for 2 min.

8. Move extract to measuring cylinder.

9. Repeat washing with small volumes(here 1 ml steps) until final volume is reached or extract is clear. 10. Fill up to final volume with gelatin and homogenize.

The following examples are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims. It is understood that modifications can be made in the procedures set forth without departing from the spirit of the invention.

Experimental Procedures: Examples

A: starting materials i) 3-[(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-mdole-6-carbonyl)-amino]-4,6- dihydro-pyrrolo[3_>4-c]pyrazole-l,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester

3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid (3.0 g, 14.62 mmol) was dissolved in thionylchloride (19.1 mL, 163 mmol) and after addition of N,N- dimethylformamide (DMF) (200 μL) the mixture was refluxed for 1.5 hours. The volatiles were carefully removed under reduced pressure and the resulting 3,3- dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl chloride was added portionwise to a mixture of 3-amino-4,6-dihydro-pyrrolo[3,4-c]pyrazole-l,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (4.33 g, 14.62 mmol) in dry dichloromethane (DCM) (40 mL) and ethyl-diisopropyl-amine (DIEA) (2.53 mL, 14.62 mmol). The resulting mixture was stirred for 30 minutes, washed with water (20 mL) and brine (20 mL) and evaporated to dryness. Purification by flash chromatography over silica gel eluting with ethyl acetate/«-heptane (2:1), afforded the title compound as a white solid (5.5 g, 78 %).

MS: M = 482.0 (ESI-)

¹H-NMR (400 MHz, DMSO): δ (ppm) = 1.28 (s, 6H), 1.34 (t, 3H), 1.46 (s, 9H),

4.41 (q, 2H), 4.51 (br, 2H, rotamers), 4.60 (br, 2H, rotamers), 7.42 (m, IH), 7.47 (s, IH), 7.71 (m, IH), 10.58 (s, IH), 11.45 (s, IH)

ii) 3-[(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl)-amino]-5,6- dihydro-4H-pyrrolo[3,4-c]pyrazole-l-carboxylic acid ethyl ester hydrochloride

A 4 N solution of HCl in dioxane (3.88 mL, 15.51 mmol) was added dropwise to a stirred solution of 3-[(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl)- amino]-4,6-dihydro-pyrrolo[3,4-c]pyrazole-l,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (600 mg, 1.24 mmol) in dry DCM (10 mL) and the resulting suspension was stirred 20 hours at room temperature. After dilution with Et2O (10 mL), the solid was filtered, extensively washed with Et2O and dried under vacuum at 50⁰C to give 520 mg (99%) of the title compound, used in the next step without further purification.

MS: M = 384.3 (ESI+)

¹H-NMR (400 MHz, DMSO): δ (ppm) = 1.28 (s, 6H), 1.35 (t, 3H) 4.42 (q, 2H), 4.48 (s, 2H), 4.55 (s, 2H), 7.43 (m, IH), 7.47 (s, IH), 7.73 (m, IH), 10.19 (br, 2H),

10.62 (s, IH), 11.60 (s, IH)

iii) 5-(2,6-Diethyl-phenylcarbamoyl)-3-[(3,3-dimethyl-2-oxo-2,3-dihydro-lH- indole-6-carbonyl)-amino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-l-carboxylic acid ethyl ester

A solution of l,3-diethyl-2-isocyanato-benzene (158 μL, 0.91 mmol) in DCM (4 mL) was added dropwise to a suspension of 3-[(3_>3-Dimethyl-2-oxo-2,3-dihydro- lH-indole-6-carbonyl)-amino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-l- carboxylic acid ethyl ester hydrochloride (320 mg, 0.76 mmol) in DCM (6 mL) and DIEA (396 μL, 2.29 mmol). The resulting suspension was stirred at room temperature for 18 hours. The solvent was evaporated to dryness to give a crude solid. Purification by flash chromatography over silica gel eluting with ethyl acetate/rc-heptane (9:1), afforded the title compound as a white solid (312 mg, 73 %). MS: M = 559.4 (ESI+)

¹H-NMR (400 MHz, DMSO): δ (ppm) = 1.13 (t, 6H), 1.28 (s, 6H), 1.36 (t, 3H), 2.57 (q, 4H), 4.42 (q, 2H), 4.70 (br, 2H, rotamers), 4.75 (br, 2H, rotamers), 7.08 (m, 2H), 7.16 (m, IH), 7.42 (m, IH), 7.48 (m, IH), 7.74 (m, IH), 7.86 (s, IH), 10.59 (br, IH), 11.48 (br, IH)

iv) 5-(2,6-Diethyl-phenylcarbamoyl)-3-[(l-isopropyl-3,3-dimethyl-2-oxo-2,3- dihydro-lH-indole-6-carbonyl)-amino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole- 1-carboxylic acid ethyl ester

5-(2,6-Diethyl-phenylcarbamoyl)-3-[(3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole- 6-carbonyl)-amino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-l-carboxylic acid ethyl ester (156 mg, 0.28 mmol) was dissolved in DMF (3 mL) and after addition of sodium hydride (10.7 mg 0.47 mmol) the reaction mixture was stirred at room temperature for 30 minutes. A solution of 2-bromo-propane (37.8 μL, 0.31 mmol) dissolved in DMF ( 1 mL) was added and the reaction mixture was stirred at 50⁰C for 2 hours. After dilution with water (4 mL) it was extracted with ethyl acetate (3 x

15 mL). The organic layer was washed with brine and dried over Na₂SO₄. The solvent was evaporated. The crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/methanol yielded 12 mg (7 %) of title compound as a white solid.

MS: M = 601.3 (ESI+)

v) 5-(2,6-Diethyl-phenylcarbamoyl)-3-[(l-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro- lH-indole-6-carbonyl)-amino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-l- carboxylic acid ethyl ester

5-(2,6-Diethyl-phenylcarbamoyl)-3-[(3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole- 6-carbonyl)-amino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-l-carboxylic acid ethyl ester (150 mg, 0.27 mmol) was dissolved in DMF (2 mL) and after addition of sodium hydride (10 mg, 0.42 mmol) the mixture was stirred at room temperature for 45 minutes. A solution of bromo-ethane (32 mg, 0.30 mmol) dissolved it DMF (1 mL) was added and the reaction mixture was stirred at 50⁰C for 1 hours. After dilution with of water (3 mL) it was extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with brine and dried over Na₂SO₄. The solvent was evaporated. The crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/n-heptane yielded 56 mg (36 %) of the title compound as a white solid. MS: M = 587.2 f ESI+)

vi) 3- [ ( l-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro- 1 H-indole-6-carbonyl)- amino]-4,6-dihydro-pyrrolo[3,4-c]pyτazole-l,5-dicarboxylic acid 5-tert-butyl ester 1 -ethyl ester

3-[(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl)-amino]-4,6-dihydro- pyrrolo[3,4-c]pyrazole-l,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (530 mg, 1.1 mmol) was dissolved in DMF (12 mL) and after addition of sodium hydride (33 mg, 1.32 mmol) the mixture was stirred at room temperature for 30 minutes. A solution of bromo-ethane (90 μL, 1.21 mmol) dissolved it DMF (3 mL) was added and the reaction mixture was stirred at 50⁰C for 1 hours. After dilution with of water (15 mL) it was extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine and dried over Na₂SO₄. The solvent was evaporated. The crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/rc-heptane 2:1 yielded 117 mg (21 %) of title compound as a white solid.

MS: M = 510.4 (ESI-)

¹H-NMR (400 MHz, DMSO): δ (ppm) = 1.18 (t, 3H), 1.29 (s, 6H), 1.34 (t, 3H), 1.47 (s, 9H), 3.75 (q, 2H), 4.40 (q, 2H), 4.53 (br, 2H, rotamers), 4.60 (br, 2H, rotamers), 7.50 (m, IH), 7.77 (m, 2H), 11.45 (br, IH)

vii) 3-[(l-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl)- amino] -5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-l-carboxylic acid ethyl ester hydrochloride

A 4 N solution of HCl in dioxane (764 μL, 3.05 mmol) was added dropwise to a stirred solution of 3-[(l-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6- carbonyl)-amino]-4,6-dihydro-pyrrolo[3,4-c]pyrazole-l,5-dicarboxylic acid 5-tert- butyl ester 1-ethyl ester (125 mg, 0.24 mmol) in dry DCM (5 mL) and the resulting suspension was stirred 20 hours at room temperature. After dilution with Et₂O (5 mL), the solid was filtered, extensively washed with Et₂O and dried under vacuum at 50⁰C to give 76 mg (70%) of the title compound, used in the next step without further purification.

MS: M = 412.1 (ESI+) viii) 3-[(l-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl)- amino]-5-(2-thiophen-2-yl-acetyl)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-l- carboxylic acid ethyl ester

A suspension of 3-[(l-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6- carbonyl)-amino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-l-carboxylic acid ethyl ester hydrochloride (76 mg, 0.17 mmol) in tetrahydrofuran (2 mL) was cooled to

0⁰C and DIEA (73 μL, 0.42 mmol) and thiophen-2-yl-acetyl chloride (23 μL, 0.19 mmol) were added before stirring the mixture for 20 hours. After dilution with water (5 mL) and NaOH (IM, 1 mL) it was extracted with ethyl acetate (2 x 15 mL). The organic layer was washed with brine and dried over Na₂SO₄. The solvent was evaporated. The crude product was used in the next step without further purification.

ix) 3-[(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl)-amino]-5-(2- thiophen-2-yl-acetyl)-5,6-dihydro-4H-pyrrolo [3,4-c] pyrazole- 1-carboxylic acid ethyl ester

A suspension of 3-[(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl)- amino]-5,6-dihydro-4H-pyrrolo [3,4-c] pyrazole- 1-carboxylic acid ethyl ester hydrochloride (200 mg, 0.48 mmol) in tetrahydrofuran (2 mL) was cooled to 0⁰C and DIEA (206 μL, 1.19 mmol) and thiophen-2-yl-acetyl chloride (65 μL, 0.52 mmol) were added before stirring the mixture for 20 hours. After dilution with water (10 mL) and NaOH (IM, 1 mL) it was extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with brine and dried over Na₂SO^ The solvent was evaporated. The crude product was used in the next step without further purification.

MS: M = 508.3 (ESI+)

B: Final products

Example 1 l-Isopropyl-3,3-dimethyl-2-oxo-2,3-dihydro- lH-indole-6-carboxylic acid [5-(2,6- diethyl-phenylcarbamoyl)- 1 ,4,5,6-tetrahydro-pyrrolo [3,4-c] pyrazol-3-yl] -amide

A solution of 5-(2,6-diethyl-phenylcarbamoyl)-3-[(l-isopropyl-3,3-dimethyl-2- oxo-2,3-dihydro-lH-indole-6-carbonyl)-amino]-5,6-dihydro-4H-pyrrolo[3,4- c] pyrazole- 1-carboxylic acid ethyl ester (12 mg, 0.02 mmol) in methanol (500 μL) and Et₃N (33 μL, 0.24 mmol)was stirred at 30⁰C for 3 hours. The resulting mixture was evaporated under reduced pressure and the residue taken up with Et₂O and evaporated (three times). This procedure yielded 10 mg (95 %) of the title compound as a white solid.

MS: M = 529.2 (ESI+) 1H-NMR (400 MHz, DMSO): δ (ppm) = 1.13 (t, 6H), 1.27 (s, 6H), 1.45 (d, 6H),

2.57 (q, 4H), 4.57 (m, IH), 4.65 (br, 4H, rotamers), 7.08 (m, 2H), 7.15 (m, IH), 7.49 (m, IH), 7.73 (m, 3H), 10.98 (br, IH), 12.45 (br, IH)

Example 2 l-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2- thiophen-2-yl-acetyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide

In an analogous manner as described for example 1 l-Ethyl-3,3-dimethyl-2-oxo- 2,3-dihydro-lH-indole-6-carboxylic acid [5-(2-thiophen-2-yl-acetyl)-l ,4,5,6- tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide was prepared from the appropriate starting material.

MS: M = 462.2 (ESI-)

¹H-NMR (400 MHz, DMSO): δ (ppm) = 1.18 (t, 3H), 1.29 (s, 6H), 3.77 n(q, 2H), 3.98 (d, 2H), 4.53 (m, 2H), 4.81 (m, 2H), 6.97 (m, 2H), 7.39 (m, IH), 7.49 (m, IH), 7.23 (m, 2H), 10.92 and 10.96 (br, IH, two tautomeric forms), 12.30 and 12.45 (br, IH, two tautomeric forms)

Example 3 l-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2,6- diethyl-phenylcarbamoyl)-l,4,5₎6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide

In an analogous manner as described for example 1 l-Ethyl-3,3-dimethyl-2-oxo- 2,3-dihydro- lH-indole-6-carboxylic acid [5-(2,6-diethyl-phenylcarbamoyl)- l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide was prepared from the appropriate starting material.

MS: M = 515.2 (ESI+)

¹H-NMR (400 MHz, DMSO): δ (ppm) = 1.13 (t, 6H), 1.22 (t, 3H), 1.29 (s, 6H), 2.57 (q, 4H), 3.75 (q, 2H), 4.56 (br, 2H, rotamers), 4.64 (br, 2H, rotamers), 7.08 (m, 2H), 7.15 (m, IH), 7.50 (m, IH), 7.73 (m, 3H), 10.92 (br, IH), 12.45 (br, IH) Example 4

3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2-thiophen-2-yl- acetyl)- 1 ,4,5,6-tetrahydro-pyrrolo [3,4-c] pyrazol-3-yl] -amide

In an analogous manner as described for example 1 3,3-Dimethyl-2-oxo-2,3- dihydro-lH-indole-6-carboxylic acid [5-(2-thiophen-2-yl-acetyl)-l,4,5,6- tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide was prepared from the appropriate starting material.

MSl M = 436.1 (ESI+)

¹H-NMR (400 MHz, DMSO): δ (ppm) = 1.28 (s, 6H), 3.98 (d, 2H), 4.51 (br, 2H, rotamers), 4.80 (br, 2H, rotamers), 6.97 (m, 2H), 7.40 (m, 3H), 7.66 (s, IH), 10.57

(br, IH), 10.85 and 10.95 (br, IH, two tautomeric forms), 12.25 and 12.41 (br, IH, two tautomeric forms)

Example 5

3,3-Dimethyl-2-oxo-2,3-dihydro- lH-indole-6-carboxylic acid [5-(2,6-diethyl- phenylcarbamoyl)- 1 ,4,5,6-tetrahydro-pyrrolo [3,4-c] pyrazol-3-yl] -amide

In an analogous manner as described for example 1 3,3-Dimethyl-2-oxo-2,3- dihydro-lH-indole-6-carboxylic acid [5-(2,6-diethyl-phenylcarbamoyl)- 1,4,5,6- tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide was prepared from the appropriate starting material.

MS: M = 487.3 f ESI+)

¹H-NMR (400 MHz, DMSO): δ (ppm) = 1.13 (t, 6H), 1.28 (s, 6H), 2.57 (q, 4H), 4.55 (br, 2H, rotamers), 4.62 (br, 2H, rotamers), 7.08 (m, 2H), 7.15 (m, IH), 7.43 (m, 2H), 7.70 (m, 2H), 10.57 (br, IH), 10.85 (br, IH), 12.30 and 12.45 (br, IH, two tautomeric forms)

Example 6

3-[(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl)-amino]-4,6-dihydro- lH-pyrrolofS^-cJpyrazole-S-carboxylic acid tert-butyl ester

In an analogous manner as described for example 1 3-[(3,3-Dimethyl-2-oxo-2,3- dihydro-lH-indole-6-carbonyl)-amino]-4,6-dihydro-lH-pyrrolo[3,4-c]pyrazole-5- carboxylic acid tert-butyl ester was prepared from the appropriate starting material.

Mil M = 410.2 (ESI-) ¹H-NMR (400 MHz, DMSO): δ (ppm) = 1.28 (s, 6H), 1.45 (s, 9H), 4.41 (br, 2H, rotamers), 4.44 (br, 2H, rotamers), 7.41 (m, 2H), 7.64 (m, IH), 10.57 (br, IH), 10.85 (br, IH), 12.23 and 12.35 (br, IH, two tautomeric forms)

Claims

Patent Claims

1. A compound of formula I,

formula I

wherein

R¹ is hydrogen or alkyl;

R² is a) phenyl optionally substituted one or several times by alkyl, halogen, cyano, -NO₂, -NRR', -NR-C(O)alkyl, -OH, -OR, -CF₃ or -OCF₃; b) heteroaryl optionally substituted one or several times by alkyl; or c) alkyl;

R³ and R⁴ independently are alkyl; X is -NH-, -O- or alkylene; R and R' independently are hydrogen or alkyl; and all pharmaceutically acceptable salts thereof.

2. The compounds according to claim 1, wherein X is -NH-.

3. The compounds according to any one of claims 1 or 2, wherein R² is phenyl optionally substituted one or several times by alkyl, halogen, cyano, -NO₂, -NRR', -NR-C(O)alkyl, -OH, -OR, -CF₃ or -OCF₃.

4. The compounds according to claim 1, selected from the group consisting of: l-Isopropyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5- (2,6-diethyl-phenylcarbamoyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3- yl] -amide;

l-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5- (2,6-diethyl-phenylcarbamoyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3- yl] -amide;

3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2,6- diethyl-phenylcarbamoyl)- 1,4,5,6-tetrahydro-pyrrolo [3,4-c] pyrazol-3-yl] - amide;

l-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2- thiophen-2-yl-acetyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl] -amide;

3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid [5-(2- thiophen-2-yl-acetyl)-l,4,5,6-tetrahydro-pyrrolo [3,4-c] pyrazol-3-yl] -amide; and

3-[(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl)-amino]-4,6- dihydro-lH-pyrrolo^^-cJpyrazole-S-carboxylic acid tert-butyl ester.

5. A process for the preparation of the compounds of formula I comprising the steps of a) converting a compound of formula II,

formula II,

wherein R¹, R³ and R⁴ have the significance given above for formula I in claim 1 and PG¹ is a N-protecting group, to give the compounds of formula III

formula III,

wherein R¹, R², R³, R⁴ and X have the significance given above for formula I in claim 1 and PG¹ is a N-protecting group,

b) cleaving the N-protecting group PG¹ of the compounds of formula III to give the corresponding derivatives of formula I in claim 1,

formula I

wherein R¹, R², R³, R⁴ and X have the significance given above for formula I in claim 1.

6. A pharmaceutical composition, containing one or more compounds according to claims 1 to 4 as active ingredients together with pharmaceutically acceptable carriers.

7. The pharmaceutical composition according to claim 6 for the treatment of cancer.

8. The use of one or more compounds according to claims 1 to 4 for the treatment of cancer

9. The use of a compound according to claims 1 to 4, for the manufacture of corresponding pharmaceutical compositions for the inhibition of tumor growth.