WO2008022747A1

WO2008022747A1 - Tricyclic lactam derivatives, their manufacture and use as pharmaceutical agents

Info

Publication number: WO2008022747A1
Application number: PCT/EP2007/007277
Authority: WO
Inventors: Birgit Bossenmaier; Richard Engh; Guy Georges; Eike Hoffmann; Matthias Koerner; Hans-Rainer Voelger; Stefan Weigand
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2006-08-21
Filing date: 2007-08-17
Publication date: 2008-02-28

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-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above-mentioned compounds in the control or prevention of illnesses such as cancer.

Description

Tricyclic lactam derivatives, their manufacture and use as pharmaceutical agents

The present invention relates to novel tricyclic 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, J. J., 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.

WO 02/079192, WO 2004/031401, WO 2004/063151 and WO 2005/021510 relate to benzimidazole pyridone derived kinase inhibitors.

WO 2006/032519 and WO 2006/063841 relate to pyrazolylbenzimidazole derivatives and tricyclic heterocycle imidazole derivatives as antitumor agents.

Summary of the Invention

The present invention relates to tricyclic 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, -CF₃, -OCF₃, -CN, -NO₂, -NRR', -alkylene-NRR', -NR- C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C(O)NRR', - S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR\ heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; b) heteroaryl optionally substituted one or several times by alkyl, phenyl, halogen, -OR, -NRR\-alkylene-NRR',-CN, -CF₃ or -

OCF₃; or c) heterocyclyl optionally substituted one or several times by alkyl, -C(O)-alkyl or -S(O)₂-alkyl;

Y is a single bond, -alkylene-NH- or alkylene optionally substituted once or twice by -OR or oxo;

R³ and R⁴ are alkyl;

R and R' independently represent 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

1. Definitions:

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 and more preferably chlorine.

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, ethylene, methyl-ethylene (1,2- propylene) or trimethylene (1,3-propylene) and more preferably methylene or ethylene.

The term "alkylene optionally substituted by oxo" as used herein means a alkylene group as described above which can be substituted by oxo. Examples include e.g. 1- oxo- 1,3-propylene, 3-oxo- 1,3-propylene 2-oxo- 1,3-propylene, 1 -oxo- 1,2- propylene, 1-oxo-ethylene, 2-oxo-ethylene, and the like.

The term "heterocyclyl" as used herein means a saturated, monocyclic ring 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. Preferably at least one heteroatom of the ring is N and the remaining heteroatoms are selected independently from N, O or S and such heterocyclyl group is preferably attached via the ring N atom. Examples of such saturated heterocyclic groups include pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, oxazolidinyl, thiazolidinyl, and the like, preferably morpholinyl, piperazinyl, piperidyl or pyrrolidinyl.

The term "heterocyclyl optionally substituted once or twice by oxo " as used herein means a heterocyclyl as described above wherein a ring atom can by substituted , if possible, by an oxo group. Examples include e.g. 2-oxo-pyrrolidin-l-yl, 2-oxo- piperidine-1-yl, 2-oxo-piperazine-l-yl, 3-oxo-piperazine-l-yl, 2,5-dioxo- piperazine-1-yl and the like.

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, benzo furanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl and the like, preferably pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl or pyrimidyl.

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.

2. Detailed Description:

R¹ is hydrogen or alkyl, preferably (Ci-C₃)alkyl, and more preferably ethyl .

R² is a) phenyl optionally substituted one or several times by alkyl, halogen, -CF₃, -OCF₃,

-CN, -NO₂, -NRR', -alkylene-NRR', -NR-C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', - alkylene-C(O)NRR', -S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR', heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; preferably the phenyl being optionally substituted one to three times , more preferably once or twice, by alkyl, halogen, -NO₂, -NR-C(O)alkyl, -OR, -C(O)OR, -S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR', heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; b) heteroaryl optionally substituted one or several times by alkyl, phenyl, halogen,

-OR, -NRR',-alkylene-NRR',-CN, -CF₃ or -OCF₃, alkyl, phenyl, alkylene-NRR' or -CN; preferably the heteroaryl being optionally substituted once or twice by alkyl, phenyl, alkylene-NRR' or -CN; or c) heterocyclyl optionally substituted one or several times by alkyl, -C(O)-alkyl or -S(O)₂-alkyl; preferably the heterocyclyl being optionally substituted once or twice by alkyl.

Y is a single bond, -alkylene-NH- or alkylene optionally substituted once or twice by -OR or oxo; preferably a single bond or alkylene optionally substituted once or twice by -OR.

R³ and R⁴ are alkyl, preferably methyl.

R and R' independently represent hydrogen or alkyl. A preferred embodiment of the invention are the compounds according to formula I, wherein

R¹ is alkyl, preferably ethyl.

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

R¹ is alkyl, preferably ethyl; and

R³ and R⁴ are methyl.

Another embodiment of the invention are the compounds according to formula I, wherein Y is a single bond.

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

R² is phenyl optionally substituted one to three times by alkyl, halogen, -CF₃, -OCF₃, -CN, -NO₂, -NRR', -alkylene-NRR', -NR- C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C( O)NRR', -

S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR', heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; preferably the phenyl being optionally substituted by alkyl, -NO₂, -NR- C(O)alkyl, -OR, -C(O)OR, -S(O)₂-NRR', -alkylene-S(O)₂-NRR', heteroaryl, or heterocyclyl optionally substituted once or twice by alkyl or oxo.

Another embodiment of the invention are the compounds according to formula I, wherein R² is phenyl optionally substituted one to three times by alkyl, halogen, -CF₃, -OCF₃, -CN, -NO₂, -NRR', -alkylene-NRR', -NR- C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C(O)NRR', - S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR\ heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; preferably the phenyl being optionally substituted by alkyl, -NO₂, -NR- C(O)alkyl, -OR, -C(O)OR, -S(O)₂-NRR', -alkylene-S(O)₂-NRR', heteroaryl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; and Y is a single bond. Such compounds, for example, may be selected from the group consisting of:

4-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-/|indol-2-yl)-2- oxo-l,2-dihydro-pyridin-4-ylamino] -benzoic acid;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[3-(lH-tetrazol-5-yl)-phenylamino]-l,2- dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[4-(2-oxo-pyrrolidin-l-yl)-phenylamino]-l,2- dihydro-pyridm-3-yl}-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one;

C-{4-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3,5₎6,7-tetrahydro-imidazo[4,5-/]indol-2- yl)-2-oxo-l,2-dmydro-pyridin-4-ylamino]-phenyl}-N-methyl- methanesulfonamide;

5-Ethyl-7,7-dimethyl-2-[4-(2-methyl-6-nitro-phenylamino)-2-oxo-l,2-dihydro- pyridin-3-yl]-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[3-(lH-pyrazol-3-yl)-phenylamino]-l,2- dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/|indol-6-one; N-{4-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4₎5-/]indol-2- yl)-2-oxo-l,2-dihydro-pyridin-4-ylamino]-phenyl}-N-methyl-acetamide; and

3-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3₎5,6,7-tetrahydro-imidazo[4,5-/]indol-2-yl)-2- oxo-l,2-dihydro-pyridin-4-ylamino]-4-methoxy-N,N-dimethyl- benzenesulfonamide. Another embodiment of the invention are the compounds according to formula I, wherein

R¹ is alkyl;

R² is phenyl optionally substituted one to three times by alkyl, halogen, -CF₃, -OCF₃, -CN, -NO₂, -NRR', - alkyl ene- NRR', -NR- C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C(O)NRR', -

S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR', heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; preferably the phenyl being optionally substituted by alkyl, -NO₂, -NR- C(O)alkyl, -OR, -C(O)OR, -S(O)₂-NRR', -alkylene-S(O)₂-NRR\ heteroaryl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; and Y is a single bond. Another embodiment of the invention are the compounds according to formula I, wherein

R² is heteroaryl optionally substituted once or twice by alkyl, phenyl, halogen, -OR, -NRR', -alkylene-NRR', -CN, -CF₃ or -OCF₃; preferably the heteroaryl being optionally substituted by alkyl, alkylene-NRR' or -CN.

R² is heteroaryl optionally substituted once or twice by alkyl, phenyl, halogen, -OR, -NRR', -alkylene-NRR', -CN, -CF₃ or -OCF₃; preferably the heteroaryl being optionally substituted by alkyl, alkylene-NRR' or -CN; and

Y is a single bond.

Such compounds, for example, may be selected from the group consisting of: 5-[3-(5-Ethyl-7₎7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-/]indol-2-yl)-2- oxo-l,2-dihydro-pyridin-4-ylamino]-3-(3-methylamino-propyl)-lH-pyrazole-4- carbonitrile; and

5-Ethyl-7,7-dimethyl-2-[2-oxo-4-(pyridin-4-ylamino)-l,2-dihydro-pyridin-3-yl]- 5,7-dihydro-3H-imidazo[4,5-/]indol-6-one. Another embodiment of the invention are the compounds according to formula I, wherein

R¹ is alkyl;

R is heteroaryl optionally substituted once or twice by alkyl, phenyl, halogen, -OR, -NRR', -alkylene-NRR', -CN, -CF₃ or -OCF₃; preferably the heteroaryl being optionally substituted by alkyl, alkylene-NRR' or -CN; and

Y is a single bond.

Another embodiment of the invention are the compounds according to formula I, wherein Y is alkylene optionally once or twice substituted by -OR or oxo, preferably by -OR.

R² is phenyl optionally substituted one to three times by alkyl, halogen, -CF₃, -OCF₃, -CN, -NO₂, -NRR', -alkylene-NRR', -NR- C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C(O)NRR', - S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR', heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo, preferably the phenyl being optionally substituted by halogen, -OR or -

S(O)₂-alkyl.

R² is phenyl optionally substituted one to three times by alkyl, halogen, -CF₃, -OCF₃, -CN, -NO₂, -NRR', -alkylene-NRR', -NR-

C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C(O)NRR\ - S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR\ heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; preferably the phenyl being optionally substituted by halogen, -OR or -

S(O)₂-alkyl; and

Y is alkylene optionally once or twice substituted by -OR or oxo, preferably by -OR.

Such compounds, for example, may be selected from the group consisting of: 2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-l,2-dihydro- pyridin-3-yl}-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one;

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-l,2-dihydro- pyridin-3-yl}-5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-/| indol-6-one;

5-Ethyl-2-[4-((R)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-l,2-dihydro-pyridin-3- yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one;

5-Ethyl-2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-l,2-dihydro-pyridin-3- yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-/] indol-6-one;

5-Ethyl-2-{4-[2-hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-2-oxo-l,2-dihydro- pyridin-3-yl}-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one; 2-{4-[2-(3-Chloro-phenyl)-ethylamino]-2-oxo-l,2-dihydro-pyridin-3-yl}-5-ethyl-

7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-2-[4-((lS,2S)-2-hydroxy-l-methoxymethyl-2-phenyl-ethylamino)-2-oxo- l,2-dihydro-pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-/]indol-6- one; 5-Ethyl-2-[4-((lS,2S)-2-hydroxy-l-hydroxymethyl-2-phenyl-ethylamino)-2-oxo- l,2-dihydro-pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-/]indol-6- one;

2-(4-Benzylamino-2-oxo-l,2-dihydro-pyridin-3-yl)-5-ethyl-7,7-dimethyl-5,7- dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-7,7-dimethyl-2-(2-oxo-4-phenethylamino-l,2-dihydro-pyridin-3-yl)-5,7- dihydro-3H-imidazo [4,5-/] indol-6-one;

2-[4-(3-Chloro-benzylamino)-2-oxo-l,2-dihydro-pyπdin-3-yl]-5-ethyl-7,7- dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one; 5-Ethyl-7_>7-dimethyl-2-[2-oxo-4-(2-[l,2,4]triazol-l-yl-benzylamino)-l,2- dihydro-pyridin-3-yl]-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[(l-phenyl-lH-tetrazol-5-ylmethyl)-amino]-l,2- dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/| indol-6-one;

5-Ethyl-2-[4-((lR,2S)-2-hydroxy-l-methyl-2-phenyl-ethylammo)-2-oxo-l,2- dihydro-pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-2-[4-((lS,2R)-2-hydroxy-l-methyl-2-phenyl-ethylamino)-2-oxo-l,2- dihydro-pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-/] indol-6-one; and

5-Ethyl-2-[4-(3-methanesulfonyl-benzylamino)-2-oxo-l,2-dihydro-pyridin-3-yl]- 7_>7-dimethyl-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one.

R¹ is alkyl;

C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C(O)NRR\ - S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR', heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; preferably the phenyl being optionally substituted by halogen, -OR or -

S(O)₂-alkyl; and

Y is alkylene optionally once or twice substituted by -OR or oxo, preferably by -OR. Another embodiment of the invention are the compounds according to formula I, wherein

R² is heteroaryl optionally substituted once or twice by alkyl, phenyl, halogen, -OR, -NRR', -alkylene-NRR', -CN, -CF₃ or -OCF₃; preferably the heteroaryl being optionally substituted by phenyl.

R² is heteroaryl optionally substituted once or twice by alkyl, phenyl, halogen, -OR, -NRR', -alkylene-NRR', -CN, -CF₃ or -OCF₃; preferably the heteroaryl being optionally substituted by phenyl; and

Y is alkylene.

Such compounds, for example, may be selected from the group consisting of:

5-Ethyl-7,7-dimethyl-2-[2-oxo-4-(2-pyridin-2-yl-ethylamino)-l,2-dihydro- pyridin-3-yl]-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[(pyridin-2-ylmethyl)-amino]-l,2-dihydro- pyridin-3-yl}-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-2-{4-[2-(3H-imidazol-4-yl)-ethylamino]-2-oxo-l,2-dihydro-pyridin-3- yl} -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one; 5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[(pyridin-4-ylmethyl)-amino]-l,2-dihydro- pyridin-3-yl}-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[(pyridin-3-ylmethyl)-amino]-l,2-dihydro- pyridin-3-yl}-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one; and

5-Ethyl-2-{4-[(lH-imidazol-2-ylmethyl)-amino]-2-oxo-l,2-dihydro-pyridin-3- yl}-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one.

R¹ is alkyl;

Y is alkylene. Another embodiment of the invention are the compounds according to formula I, wherein

R² is heterocyclyl optionally substituted once or twice by alkyl,

-C(O)-alkyl or -S(O)₂-alkyl; preferably the heterocyclyl being optionally substituted by alkyl.

R² is heterocyclyl optionally substituted once or twice by alkyl,

-C(O)-alkyl or -S(O)₂-alkyl; preferably the heterocyclyl being optionally substituted by alkyl; and

Y is alkylene optionally once or twice substituted by -OR or oxo, preferably by oxo.

Such a compound is for example:

5-Ethyl-7,7-dimethyl-2-{4-[3-(4-methyl-piperazin-l-yl)-3-oxo-propylamino]-2- oxo-l,2-dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one.

Y is -alkylene-NH-.

R² is heteroaryl optionally substituted once or twice by alkyl, phenyl, halogen, -OR, -NRR\-alkylene-NRR',-CN, -CF₃ or -OCF₃; preferably the heteroaryl being unsubstituted; and

Y is -alkylene-NH-. Such a compound is for example:

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[2-(pyridin-2-ylamino)-ethylamino]-l,2- dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one.

Another embodiment of the invention are the compounds according to formula I, wherein R¹ is alkyl; and

R² is a) phenyl optionally substituted one to three times by alkyl, halogen, -CF₃, -OCF₃, -CN, -NO₂, -NRR', -alkylene-NRR', -NR- C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C(O)NRR\ - S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR\ heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; preferably the phenyl being optionally substituted by alkyl, halogen, -NO₂, - NR-C(O)alkyl, -OR, -C(O)OR, -S(O)₂-alkyl, -S(O)₂-NRR', - alkylene-S(O)₂-NRR\ heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo, or b) heteroaryl optionally substituted once or twice by alkyl, phenyl, halogen, -OR, -NRR\-alkylene-NRR',-CN, -CF₃ or -OCF₃; preferably the heteroaryl being optionally substituted by alkyl, phenyl, alkylene-NRR' or -CN.

R¹ is alkyl; and R² is a) phenyl optionally substituted one to three times by alkyl, halogen, -CF₃, -OCF₃, -CN, -NO₂, -NRR', -alkylene-NRR', -NR- C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C(O)NRR', - S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR', heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; preferably the phenyl being optionally substituted by alkyl, halogen, -NO₂, - NR-C(O)alkyl, -OR, -C(O)OR, -S(O)₂-alkyl, -S(O)₂-NRR', - alkylene-S(O)₂-NRR', heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo, or b) heteroaryl optionally substituted once or twice by alkyl, phenyl, halogen, -OR, -NRR',-alkylene-NRR',-CN, -CF₃ or -OCF₃; preferably the heteroaryl being optionally substituted by alkyl, phenyl, alkylene-NRR' or -CN; and Y is a single bond or alkylene optionally substituted once or twice by -OR.

Another embodiment of the invention is a process for the preparation of the compounds of formula I comprising the steps of a) reacting a compound of formula V,

formula V,

wherein R¹, R³ and R⁴ have the meaning as defined for formula I above, and X is a halogen selected from chlorine, bromine or iodine, preferably chlorine or iodine, with a compound of formula Va,

^H2^N \ 2

Y-R formula Va,

wherein R² and Y have the meaning as defined for formula I above to give the compounds of formula I,

formula I, wherein R¹, R², R³, R⁴ and Y have the meaning as defined for formula I above

b) isolating the compounds of formula I; and c) if desired, converting the compounds of formula I into their pharmaceutically acceptable salts.

The 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 , R³, R⁴ and Y 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.

The benzimidazole ring system of formula I can be formed by different synthetic pathways in analogy to methods described in the literature (Mertens, A., et al., J.

Med. Chem. 30 (1987) 1279-1287; DE 35 31 678).

One route for the preparation of compounds of formula I (Scheme 1) starts from diamines of formula II which can be reacted with carboxylic acids (compounds of formula III wherein A is OH and X represents a halogen), acid chlorides (A is Cl), aldehydes (A is H), methyl carboxylates (A is OMe) or activated esters (A is e.g. hydroxybenzotriazole) to form intermediates of formula IV. For detailed procedures see the literature cited above.

The intermediate of formula IV can be further reacted to compounds of formula I by two different ways (Scheme 1):

a) Cleavage of the methoxy group of the pyridine residue by e.g. treatment with a strong inorganic acid in an appropriate solvent (for instance hydrochloric acid in 1,4-dioxane) to form the pyridinone intermediates of formula V and subsequent introduction of the amino side chain of the compounds of formula I by nucleophilic substitution with suitable amines of formula Va at elevated temperatures to yield the compounds of formula

I. This strategy is described in e.g. WO 2002/079192, US 2004/0044203, WO 2004/031401, WO 2004/063151, and Wittman, M., et al., J. Med. Chem. 2005, 48, 5639-5643.

b) Introduction of the amino side chain of compound I by nucleophilic substitution with suitable amines of formula Va applying e.g. a Pd-catalyzed cross-coupling reaction (based on general procedures for C-N-bond formation with aromatic iodides described in e.g. Kwong, F.Y., et al., Org. Lett. 2002, 4, 581 -584, and Kwong, F.Y. and Buchwald, S.L., Org. Lett. 2003, 5, 793-796) to form the methoxypyridine intermediates VI, and subsequent cleavage of the methoxy group of the pyridine residue by e.g. treatment with a strong inorganic acid in an appropriate solvent (for instance hydrochloric acid in 1,4-dioxane) to form the compounds of formula I.

III IV

Scheme 1

Pyridine carboxylates of formula III wherein A is either OH (free acids), Cl (acid chlorides), hydrogen (aldehydes), OAIk (alkyl carboxylates ) or hydroxybenzotriazole (activated esters) and X represents a halogen selected from chlorine, bromine or iodine, can be prepared according to literature procedures.

Pyridine aldehydes of formula III (A is H and X is halogen selected from chlorine, bromine or iodine) can for example be prepared according to procedures described in WO 95/29917 or Gabarda, A.E., Tetrahedron 2002, 58, 6329-6341.

Pyridine carboxylates of formula III (A is OH and X is halogen selected from chlorine, bromine or iodine) can for example be prepared according to procedures described in WO 2004/063151.

Alkyl pyridine carboxylates of formula III (A is e.g. OMe and X is halogen selected from chlorine, bromine or iodine) can for example be prepared according to procedures described in WO 2004/063151. The synthesis of the corresponding diamines of formula II or precursors thereof wherein R¹ is hydrogen or alkyl can be achieved in an analogous manner as described in Mertens, A., et al., J. Med. Chem. 30 (1987) 1279-1287; von der Saal, W., et al., J. Med. Chem. 32 (1989) 1481-1491; DE 34 17 643; EP 0 318 902, US 4,666,923A, US 4,695,567A, US 4,863,945A and US 4,985,448A. Furthermore the compounds of formula II wherein R¹ is alkyl are described in DE 37 01 277.

For instance, the diamines of formula II, wherein R¹ is alkyl are named Ha and can be synthesized according to US 4,666,923A, DE 34 10 168 and Mertens, A., et al., J. Med. Chem. 30 (1987) 1279-1287 as shown in Scheme Ib:

Scheme Ib

In scheme Ib, R¹ has the significance as given above for formula I, R³ and R⁴ represent an alkyl group, and L represents a leaving group as e.g. iodine, bromine, chlorine, triflate and the like.

In an alternative procedure diamines of formula Ha, wherein R¹ is alkyl, can be obtained by an alkylation of diamines of formula lib (compounds II wherein R¹ is hydrogen) as shown in scheme Ic. L represents a leaving group as e.g. iodine, bromine, chlorine, triflate and the like.

Scheme Ic

Diamines of formula lib can be synthesized according to scheme Ib under omission of step 5.

Another synthesis of compounds of formula IV (Scheme 2) wherein X is a halogen selected from chlorine, bromine or iodine, starts from nitro-compounds VII or VIII which are hydrogenated and subsequently cyclized with acetic acid or hydrochloric acid to the desired benzimidazole intermediate. For detailed procedures see Mertens, A., et al, J. Med. Chem. 30 (1987) 1279-1287; DE 35 31 678.

VIII

Scheme 2

Compounds of formulas VII and VIII wherein R¹ is hydrogen or alkyl can be prepared in an analogous manner as described in Mertens, A., et al., J. Med. Chem. 30 (1987) 1279-1287; von der Saal, W., et al., J. Med. Chem. 32 (1989) 1481-1491; DE 34 17 643; EP 0 318 902. Certain substituents on the groups Y and R² may not be inert to the conditions of the synthesis sequences described above and may require protection by standard protecting groups known in the art. For instance, an amino or hydroxyl group may be protected as an acetyl or tert.-butoxycarbonyl derivative. Alternatively, some substituents may be derived from others at the end of the reaction sequence. For instance, a compound of formula I may be synthesized bearing a nitro-, an ethoxycarbonyl, an ether, a sulfonic acid substituent on the groups Y and R², which substituents are finally converted to an amino- (e.g. by reduction of a nitro group or cleavage of a suitable amino protective group (e.g. removal of a Boc group with TFA)), alkylamino- (e.g. by reductive amination of an amino group), dialkylamino-

(e.g. by alkylation of an amino group, reduction of an appropriate acylamino group with lithium aluminum hydride or Eschweiler-Clarke reaction with an appropriate amino or alkylamino group), acylamino- (by amide formation from an amino group e.g. with appropriate acyl halides or with appropriate carboxylic acids after their activation with CDI, EDC etc.), alkylsulfonylamino (e.g. by reaction of an amino group with sulfonyl chlorides), arylsulfonylamino substituent (e.g. by reaction of an amino group with sulfonyl chlorides), hydroxyl- (by cleavage of a suitable hydroxy protective group (e.g. hydrogenolytic removal of a benzyl ether or oxidative cleavage of a p-methoxy benzyl ether), ether- (e.g. by Williamson's ether synthesis from a hydroxyl group) or to a carboxamide substituent (e.g. by amide formation from a carboxylic acid group with appropriate amines after activation of the carboxylic acid group with CDI, EDC etc. or conversion to an acyl chloride), or to a sulfonamide substituent by standard procedures.

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, citric acid, ascorbic 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, R.J., 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, enantiomeric or diastereomeric, 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:

1C50 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 typical 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-phosphopeptide 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.

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-Glo™ Luminescent Cell Viability Assay (Promega) is a homogeneous method of determining the number of viable cells in culture based on quantification of the ATP present, which indicates 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), 5 % Fetal Calf Serum (FCS, Sigma Cat-No. F4135 (FBS)) and 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). 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, day:

- 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 -d) 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) d) 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.

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, dragees, 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 inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragέes 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, emulsifϊers, 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

Intermediate 1

2-(4-Iodo-2-methoxy-pyridin-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5- f]indol-6-one

To a solution of 5,6-Diamino-3,3-dimethyl-l,3-dihydro-indol-2-one (200 mg, 1.04 mmol) in methanol (3 mL) was added at 0 ⁰C a suspension of 4-Iodo-2-methoxy- pyridine-3-carbaldehyde (247 mg, 0.94 mmol) in MeOH (2 mL). The unclosed flask was stirred over night at room temperature. Concentration and purification by silica column chromatography followed. The resulting solid was dissolved in ethyl acetate and then precipitated with heptane, filtered and dried. This gave the title compound as a light brown solid. Yield: 200 mg (44 %).

¹H-NMR (400 MHz, D^-DMSO): δ= 12.44 (d, IH, NH, benzimidazole), 10.26 (d, IH, NH, indolone), 7.98 (m, IH, 5-H-pyridine), 7.64 (m, IH, 6-H-pyridine), 7.57 (s, 0.59H, Ar-H, 4-H-benzimidazole, tautomeric form), 7.42 (s, 0.41H, Ar-H, 4-H- benzimidazole, tautomeric form), 7.03 (s, 0.52H, Ar-H, 8-H-benzimidazole, tautomeric form), 6.89 (s, 0.59H, Ar-H, 8-H-benzimidazole, tautomeric form), 3.80

(s, 3H, CH₃, methoxy), 1.31 (s, 6H, CH₃). MS: M = 435.1 (ESI+)

Intermediate 2 2-(4-Chloro-2-oxo-l,2-dihydro-pyridin-3-yl)-7,7-dimethyl-5,7-dihydro-3H- imidazo[4,5-f]indol-6-one

To a solution of 2-(4-Iodo-2-methoxy-pyridin-3-yl)-7,7-dimethyl-5,7-dihydro-3H- imidazo[4,5-f]indol-6-one (200 mg, 0.46 mmol) in Dioxane (4 mL) cone. HCl (0.66 mL) was added. The reaction mixture was stirred at 50 ⁰C for 2 h. Threefold extraction with saturated NaHCθ₃ and dichloromethane followed. The combined organic layers were dried over Na₂CO₃, filtered and concentrated and gave the title compound as a brown solid. Yield: 250 mg (165 %). The high yield results from a mixture of chloro- and iodo- containing compound.

¹H-NMR (400 MHz, Dg-DMSO): δ= 14.8 (m, IH, NH, benzimidazole), 10.07 (bs, 2H, NH, pyridine, indolone), 7.66 (d, IH, 6-H-pyridone), 7.47 (s, IH, Ar-H, 7-H- benzimidazole), 6.98 (s, IH, Ar-H, 4-H-benzimidazole), 6.27 (d, IH, Ar-H, 5-H- pyridone), 1.28 (s, 6H, CH₃).

MS: M = 329.1 (ESI+)

Example 1

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-l,2-dihydro- pyridin-3-yl}-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one

2-(4-Iodo-2-oxo-l,2-dihydro-pyridm-3-yl)-7,7-dimethyl-5,7-dihydro-3H- imidazo[4,5-f]indol-6-one (250 mg, 0.59 mmol), 2-Amino-l-(3-chloro-phenyl)- ethanol (255 mg, 1.48 mmol) and N-methylmorpholine (228 μl, 2.08 mmol) were dissolved in DMF (2.5 ml) and stirred at 80 ⁰C for 6 h. Concentration to dryness and purification by preparative HPLC/MS gave the title compound as a light brown solid.

Yield: 80 mg (29 %). 1H-NMR (400 MHz, D_ά-DMSO): δ= 12.75 (m, IH, NH, benzimidazole), 11.08 (m, IH, NH, pyridone), 11.01 (m, IH, NH, ethylamine), 10.24 (d, IH, NH, indolone),

7.62 (d, IH, Ar-H, 2-H-3-Cl-Ph), 7.54 (m, 0.38H, Ar-H, 7-H-benzimidazole, tautomeric form), 7.48 (m, IH, Ar-H, 6-H-3-Cl-Ph), 7.41 (m, 0.62H, Ar-H, 7-H- benzimidazole, tautomeric form), 7.38 (t, IH, Ar-H, 5-H-3-Cl-Ph), 7.33 (d, IH, Ar-H, 4-H-3-Cl-Ph), 7.27 (m, IH, 6-H-pyridone), 7.14 (m, 0.65H, Ar-H, 4-H- benzimidazole, tautomeric form), 6.98 (m, 0.3 IH, Ar-H, 4-H-benzimidazole, tautomeric form), 6.15 (d, IH, Ar-H, 5-H-pyridone), 5.58 (d, IH, OH, hydroxy- ethyl), 4.93 (m, IH, CH, ethyl), 3.67 (m, IH, CH₂, ethyl), 3.56 (m, IH, CH₂, ethyl), 1.13 (d, 6H, CH₃). MS: M = 464.1 ( ESI+)

Example 2

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-l,2-dihydro- pyridin-3-yl}-5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one

5-Ethyl-2-(4-iodo-2-oxo-l,2-dihydro-pyridin-3-yl)-7,7-dimethyl-5,7-dihydro-3H- imidazo[4,5-f]indol-6-one (200 mg, 0.44 mmol), 2-Amino-l-(3-chloro-phenyl)- ethanol (382 mg, 2,23 mmol) and N-methylmorpholine (171 μL, 1.56 mmol) were dissolved in DMF (2 mL) and heated in the microwave at 80 ⁰C for 135 min. Concentration and purification by preparative HPLC/MS gave the title compound as a light yellow solid. Yield: 180 mg (82%).

¹H-NMR (400 MHz, D^-DMSO): δ= 12.85 (m, IH, NH, benzimidazole), 11.13 (m, IH, NH, pyridone), 10.95 (m, IH, NH, ethylamine), 7.63 (d, IH, Ar-H, 2-H-3-C1- Ph), 7.61 (m, 0.4H, Ar-H, 7-H-benzimidazole, tautomeric form), 7.49 (m, IH, Ar- H, 6-H-3-Cl-Ph), 7.47 (m, 0.6H, Ar-H, 7-H-benzimidazole, tautomeric form), 7.37 (m, IH, Ar-H, 5-H-3-Cl-Ph), 7.33 (m, 0.6H, Ar-H, 4-H-benzimidazole, tautomeric form), 7.31 (m, IH, Ar-H, 4-H-3-Cl-Ph), 7.27 (m, IH, 6-H-pyridone), 7.09 (m, 0.4H, Ar-H, 4-H-benzimidazole, tautomeric form), 6.17 (t, IH, Ar-H, 5-H- pyridone), 5.87 (m, IH, OH, hydroxy-ethyl), 4.93 (m, IH, CH, ethyl), 3.73 (m, 2H, CH₂, N-ethyl), 3.66 (m, IH, CH₂, ethyl), 3.57 (m, IH, CH₂, ethyl), 1.31 (d, 6H, CH₃), 1.21 (m, 3H, CH₃, N-ethyl).

MS: M = 492.32 (ESI+)

Using the experimental conditions reported above for example 2 and the appropriate starting materials, the following examples 3 to 34 were prepared:

Claims

Patent Claims

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, -CF₃, -OCF₃, -CN, -NO₂, -NRR', -alkylene-NRR', -NR- C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C(O)NRR', - S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR', heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo; b) heteroaryl optionally substituted one or several times by alkyl, phenyl, halogen, -OR, -NRR\-alkylene-NRR\-CN, -CF₃ or - OCF₃; or c) heterocyclyl optionally substituted one or several times by alkyl, -C(O)-alkyl or -S(O)₂-alkyl;

Y is a single bond, -alkylene-NH- or alkylene optionally substituted once or twice by -OR or oxo; R³ and R⁴ are alkyl;

2. The compounds according to claim 1, wherein Y is alkylene optionally once or twice substituted by -OR or oxo.

3. The compounds according to any one of claims 1 or 2, wherein

R¹ is alkyl.

4. The compounds according to claim 3, wherein

R² is a) phenyl optionally substituted one to three times by alkyl, halogen, -CF₃, -OCF₃, -CN, -NO₂, -NRR', -alkylene-NRR', -NR- C(O)alkyl, -OR, -C(O)OR, -C(O)NRR', -alkylene-C(O)NRR', - S(O)₂-alkyl, -S(O)₂-NRR', -alkylene-S(O)₂-NRR\ heteroaryl optionally substituted once or twice by alkyl, or heterocyclyl optionally substituted once or twice by alkyl or oxo, or b) heteroaryl optionally substituted once or twice by alkyl, phenyl, halogen, -OR, -NRRValkylene-NRR'.-CN, -CF₃ or -OCF₃.

5. The compounds according to claim 1, selected from the group consisting of:

4-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-/]indol-2- yl)-2-oxo-l,2-dihydro-pyridin-4-ylamino] -benzoic acid; 5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[3-(lH-tetrazol-5-yl)-phenylamino]-l,2- dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[4-(2-oxo-pyrrolidin-l-yl)-phenylamino]- 1 ,2-dihydro-pyridin-3-yl} -5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

C-{4-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5- /]indol-2-yl)-2-oxo-l,2-dihydro-pyridin-4-ylamino]-phenyl}-iV-methyl- methanesulfonamide;

5-Ethyl-7,7-dimethyl-2-[4-(2-methyl-6-nitro-phenylamino)-2-oxo-l,2- dihydro-pyridin-3-yl]-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[3-(lH-pyrazol-3-yl)-phenylamino]-l,2- dihydro-pyridm-3-yl}-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

N-{4-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5- /]indol-2-yl)-2-oxo-l,2-dihydro-pyridin-4-ylamino]-phenyl}-N-methyl- acetamide;

3-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-/]indol-2- yl)-2-oxo-l,2-dihydro-pyridin-4-ylamino]-4-methoxy-N,N-dimethyl- benzenesulfonamide;

5-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-/]indol-2- yl)-2-oxo-l,2-dihydro-pyridin-4-ylamino]-3-(3-methylamino-propyl)-lH- pyrazole-4-carbonitrile; 5-Ethyl-7,7-dimethyl-2-[2-oxo-4-(pyridin-4-ylamino)-l,2-dihydro-pyridin- 3-yl]-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-l,2-dihydro- pyridin-3-yl}-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one;

2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-l,2-dihydro- pyridin-3-yl}-5-ethyl-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-/]indol-6- one;

5-Ethyl-2-[4-((R)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-l,2-dihydro- pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one; 5-Ethyl-2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-l,2-dihydro- pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-2-{4-[2-hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-2-oxo-l,2- dihydro-pyridin-3-yl}-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-/]indol-6- one; 2-{4-[2-(3-Chloro-phenyl)-ethylamino]-2-oxo-l,2-dihydro-pyridin-3-yl}-5- ethyl-7_>7-dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-2-[4-((lS,2S)-2-hydroxy-l-methoxymethyl-2-phenyl-ethylamino)- 2-oxo-l,2-dihydro-pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5- /] indol-6-one; 5-Ethyl-2-[4-((lS,2S)-2-hydroxy-l-hydroxymethyl-2-phenyl-ethylamino)-2- oxo-l,2-dihydro-pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo[4_>5- f\ indol-6-one;

2-(4-Benzylamino-2-oxo-l,2-dihydro-pyridin-3-yl)-5-ethyl-7,7-dimethyl- 5,7-dihydro-3H-imidazo[4,5-/] indol-6-one; 5-Ethyl-7,7-dimethyl-2-(2-oxo-4-phenethylamino-l,2-dihydro-pyridin-3- yl)-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

2-[4-(3-Chloro-benzylamino)-2-oxo-l,2-dihydro-pyridin-3-yl]-5-ethyl-7,7- dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-7,7-dimethyl-2-[2-oxo-4-(2-[l,2,4]triazol-l-yl-benzylamino)-l,2- dihydro-pyridin-3-yl]-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one; 5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[(l-phenyl-lH-tetrazol-5-ylmethyl)- amino]-l,2-dihydro-pyτidin-3-yl}-5,7-dihydro-3H-imidazo[4₎5-/]indol-6- one;

5-Ethyl-2-[4-((lR,2S)-2-hydroxy-l-methyl-2-phenyl-ethylamino)-2-oxo- l,2-dihydro-pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-

/jindol-6-one;

5-Ethyl-2-[4-((lS,2R)-2-hydroxy-l-methyl-2-phenyl-ethylamino)-2-oxo- l₎2-dihydro-pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo[4₎5- /] indol-6-one; 5-Ethyl-2-[4-(3-methanesulfonyl-benzylamino)-2-oxo-l,2-dihydro-pyridin-

3-yl]-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one;

5-Ethyl-7,7-dimethyl-2-[2-oxo-4-(2-pyridin-2-yl-ethylamino)-l,2-dihydro- pyridin-3-yl]-5,7-dihydro-3H-imidazo[4,5-/|indol-6-one;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[(pyridin-2-ylmethyl)-amino]-l,2- dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one;

5-Ethyl-2-{4-[2-(3H-imidazol-4-yl)-ethylamino]-2-oxo-l,2-dihydro- pyridin-3-yl}-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[(pyridin-4-ylmethyl)-amino]-l,2- dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/]indol-6-one; 5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[(pyridin-3-ylmethyl)-amino]-l,2- dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/|indol-6-one;

5-Ethyl-2-{4-[(lH-imidazol-2-ylmethyl)-amino]-2-oxo-l,2-dihydro- pyridin-3-yl}-7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-/] indol-6-one;

5-Ethyl-7,7-dimethyl-2-{4-[3-(4-methyl-piperazin-l-yl)-3-oxo- propylamino]-2-oxo-l,2-dihydro-pyridin-3-yl}-5,7-dihydro-3H- imidazo [4,5-/] indol-6-one;

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[2-(pyridin-2-ylamino)-ethylamino]-l,2- dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/] indol-6-one; and

5-Ethyl-7,7-dimethyl-2-{2-oxo-4-[2-(pyridin-2-ylamino)-ethylamino]-l,2- dihydro-pyridin-3-yl}-5,7-dihydro-3H-imidazo[4,5-/| indol-6-one.

6. A process for the preparation of the compounds of formula I comprising the steps of:

a. reacting a compound of formula V,

formula V,

wherein R¹, R³ and R⁴ have the meaning as defined for formula I above, and X is a halogen selected from chlorine, bromine or iodine, with a compound of formula Va,

H₂N-

Υ-FT formula Va,

formula I,

wherein R¹, R², R³, R⁴ and Y have the meaning as defined for formula

I above,

b. isolating the compounds of formula I; and c. if desired, converting the compounds of formula I into their pharmaceutically acceptable salts.

8. A pharmaceutical composition, containing one or more compounds according to claims 1 to 5 as active ingredients together with pharmaceutically acceptable carriers.

9. The pharmaceutical composition according to claim 8 for the treatment of cancer.

10. Use of a compound according to claims 1 to 5, for the manufacture of corresponding pharmaceutical compositions for the inhibition of tumor growth.

11. Use of one or more compounds according to claims 1 to 5 for the treatment of cancer.