JP2008514565A - Tricyclic compounds, methods for their production and use as pharmaceutical agents - Google Patents

Abstract

  The object of the present invention is to prepare the compounds represented by formula (I) and their tautomers, pharmaceutically acceptable salts, enantiomeric forms, diastereomers and racemates, the above-mentioned compounds, Pharmaceuticals comprising them and methods for their production, as well as the use of the abovementioned compounds in the management or prevention of illnesses such as cancer or in the manufacture of the corresponding pharmaceuticals.

Description

  The present invention relates to novel tricyclic compounds, processes for their production, pharmaceutical compositions containing them and processes for their production, and the use of these compounds as pharmaceutically active substances.

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

  Aurora kinases are a family of serine / threonine kinases that are thought to play an important role in protein phosphorylation events that are essential for the completion of essential division events. The Aurora kinase family is composed of three main 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 Sugen US 6,207,401 and related patents, as well as in patent applications such as EP 0 868 519 and EP 1 051 500.

  For Aurora A, there is growing evidence that it is a new proto-oncogene. Aurora A gene is amplified and transcript / protein is highly expressed in human tumor cell lines, as well as most primary colorectal, breast, and other tumors. Show that Aurora A overexpression leads to amplified centrosomes in vitro and a marked increase in aneuploidy and genetic instability demonstrated by transformation of rat 1 fibroblasts and mouse NIH3T3 cells Has been. Aurora A transformed NIH3T3 cells grow as tumors in nude mice (Bischoff, J. RM and Plowman, GD, Trends Cell Biol. 9 (1999) 454; Giet, R. and Prigent, C., J. Cell Sci. 112 (1999) 3591-3601; Nigg, EA, Nat. Rev. Mol. Cell Biol. 2 (2001) 21-32; Adams, RR et al., Trends Cell Biol. 11 (2001) Year) pages 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)) and poor prognosis in patients with lymph node-negative breast cancer (Isola, JJ et al., Am. J. Pathol. 147 (1995) pp. 905-911) For these reasons, Aurora A overexpression is related to chromosome segregation and mitosis. It is proposed to contribute to cancer phenotype by participating in mitotic checkpoint control.

  Human tumor cell lines that have lost the Aurora A transcript prevent mitotic fission. Thus, specific inhibition of Aurora kinase by selective inhibitors is recognized as stopping unrestricted growth, reconstructing mitotic checkpoint control and leading to apoptosis of tumor cells. In xenograft models, Aurora inhibitors thereby delay tumor growth and cause regression (Harrington, E.A. et al., Nat. Med. (2004) pp. 262-267).

  Small molecule inhibitors of protein kinases are widely known in the state of the art. For Aurora inhibition, such inhibitors are: quinazoline derivatives according to the following patents and patent applications: WO 00/44728; WO 00/47212; WO 01/21594; WO 01/21595; WO 01/21596; WO WO 01/77085; WO 01/55116; WO 95/19169; WO 95/23141; WO 97/42137; WO 99/06396; Pyrazole derivatives and triazole derivatives according to the following patents and patent applications: WO 02 WO 02/22602; WO 02/22604; WO 02/22605; WO 02/22606; WO 02/22607; WO 02/22608; WO 02/50065; WO 02/50066; WO 02 WO 02/059112; WO 02/062789; WO 02/066461; WO 02/068415; Pyrimidine derivatives: WO 03/077921; WO 03/078423; WO 03/078426; WO 03/078427 WO 04/000833 or derivatives of imidazole, oxazole and thiazole: based on WO 02/96905; WO 04/005283.

  However, there is a need for structurally new compounds with improved therapeutic properties, such as increased activity, reduced toxicity, superior solubility, and improved pharmacokinetic characteristics, to name just a few. There is still.

｛式中、
R¹が、水素、アルキル、又は-C（O）-アルキルであり；
R²が、水素、アルキル、シアノ、又はハロゲンであり；
R³が、水素、アルキル、（C₃-C₆）-シクロアルキル、アルコキシ、又はアルキルスルファニルであり：
Xが、-C（O）-又は-CH₂-であり；
Yが、-NH-、-CH₂-CR⁴R⁵-、-CR⁴R⁵-CH₂-、又は-CR⁴R⁵-である
（式中、
R⁴が、水素又はアルキルであり；そして
R⁵が、水素又はアルキルであるか；あるいは
R⁴及びR⁵が、それらが接続する炭素原子と共にシクロアルキル環を形成する。）。｝によって表される化合物、及び医薬として許容されるそれらの塩の全ての使用に関する。 The invention relates to the following general formula I for the manufacture of a medicament for the treatment of cancer:

{Where,
R ¹ is hydrogen, alkyl, or —C (O) -alkyl;
R ² is hydrogen, alkyl, cyano, or halogen;
R ³ is hydrogen, alkyl, (C ₃ -C ₆ ) -cycloalkyl, alkoxy, or alkylsulfanyl:
X is —C (O) — or —CH ₂ —;
Y is —NH—, —CH ₂ —CR ⁴ R ⁵ —, —CR ⁴ R ⁵ —CH ₂ —, or —CR ⁴ R ⁵ — (wherein
R ⁴ is hydrogen or alkyl; and
R ⁵ is hydrogen or alkyl; or
R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl ring. ). }, And all uses of pharmaceutically acceptable salts thereof.

Another aspect of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Wherein R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl. } Is used.

Another aspect of the present invention provides a compound of formula I as an Aurora family kinase inhibitor:
{Wherein R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl. } Is used.

  Some tricyclic or related compounds are disclosed in US 4,835,280A, EP 0 189 103, US 4,954,498, and likewise Mertens, A. et al., J. Med. Chem. 30 (1987) 1279-1287; Inhibition of hemagglutination from von der Saal, W. et al., J. Med. Chem. 32 (1989) 1481-1491; EP 0 318 902; DE 34 17 643; DE 36 42 315, and DE 37 01 277 Known as an agent. US 5,212,186A describes related tricyclic compounds for the treatment of heart failure, hypertension, and other diseases.

  WO 03/035065 is a benzoate as a kinase inhibitor, in particular as an inhibitor for kinase insertion domains including receptor (KDR) tyrosine kinase, spleen tyrosine kinase (SYK), and inducible T cell kinase (ITK). It relates to imidazole derivatives.

  The compounds according to the present invention exhibit 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, hypersensitivity and asthma, Alzheimer's disease, or hormone related diseases. Therefore, there has been a great effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

  The compounds according to the invention exhibit activity as Aurora family kinase inhibitors, for example Aurora protein kinase A inhibitors, and may therefore be useful in the treatment of diseases mediated by the kinases. Inhibition of Aurora A leads to cell cycle arrest in the G2 phase of the cell cycle and thus exerts an antiproliferative effect in tumor cell lines. This is because Aurora A inhibitors, ie hyperproliferative diseases such as cancer, especially colorectal cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, gastric cancer, bladder cancer, ovarian cancer, melanoma, neuroblastoma, child It has been shown to be useful in the treatment of cervical cancer, kidney cancer (kidney cancer or renal cancer), leukemia, or lymphoma. Treatment of acute myeloid leukemia (AML, acute lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST)) is included.

  The object of the present invention is the compounds of the formula I and their tautomers, pharmaceutically acceptable salts, enantiomeric forms, diastereomers and their use as racemates, Aurora A kinase inhibitors And the use of the compounds described above in the management or prevention of diseases, in particular the diseases and disorders mentioned above, or in the manufacture of corresponding medicaments.

As used herein, the term “alkyl” refers to a saturated straight or branched chain hydrocarbon containing 1 to 6, preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl. , Isopropyl, n-butyl, 2-butyl, t-butyl. Said alkyl is optionally substituted by several halogen atoms, preferably fluorine or chlorine, in particular fluorine. Preferably, the alkyl is substituted 1 to 5 times, more preferably 1 to 3 times with the aforementioned halogen. Examples are trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl and the like, preferably trifluoromethyl. In one embodiment of the invention, only the “alkyl” group used in R ³ is optionally substituted with halogen, whereas R ¹ , R ² , R ⁴ , and R ⁵ are used. Other “alkyl” groups are not substituted by halogen. In other embodiments of the invention, not all “alkyl” groups are substituted by halogen.

  As used herein, the term “alkoxy” means an alkyl group as defined above (alkyl-O—) attached through an oxygen atom.

  As used herein, the term “alkylsulfanyl” means an alkyl group as defined above (alkyl-S—) connected through a sulfur atom.

As used herein, the term “cycloalkyl” means an unsaturated carbocyclic ring system containing 3 to 6, preferably 3 to 5, carbon atoms. The unsaturated carbocyclic ring system can optionally be substituted by alkyl one to three times, preferably once or twice, especially once. Examples are cyclopropyl, 1-methyl-cyclopropyl-1-yl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl. In an embodiment of the invention, the term “cycloalkyl” as used for R ³ means cyclopropyl. The cycloalkyl ring formed by R ⁴ and R ⁵ together with the carbon atom to which they are connected is preferably a cyclopentyl or cyclohexyl ring, in particular a cyclopentyl ring.

  As used herein, the term “halogen” means fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, bromine, and more preferably fluorine and chlorine.

で存在する可能性がある。 The compounds represented by Formula I can exist in various tautomeric forms and in a variety of mixtures thereof. All tautomeric forms of the compounds represented by formula I, and mixtures thereof, are the subject of the present invention. For example, a tricyclic imidazole moiety represented by Formula I, here as shown below, is in two tautomeric forms:

May exist.

を形成する可能性がある。 Also, for example, a pyrazole ring of formula I can be represented in two tautomeric forms, as shown herein below:

May form.

  As used herein, in connection with mass spectrometry (MS), the term “API +” represents a positive pressure ionization mode, the term “API−” represents a negative pressure ionization mode, and the term “ESI +” Expressed in positive electrospray ionization mode.

An embodiment of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Wherein X is -CH _2- . } Is used.

An embodiment of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl; and
X is —CH ₂ —. } Is used.

Embodiments of the present invention are compounds of formula I as Aurora family kinase inhibitors:
{Wherein X is -CH _2- . } Is used.

Another aspect of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
X is —CH ₂ —; and
Y is -CR ⁴ R ^5- . } Is used.

Another aspect of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is —CH ₂ —; and
Y is -CR ⁴ R ^5- . } Is used.

Another aspect of the present invention provides a compound of formula I as an Aurora family kinase inhibitor:
{Where,
X is —CH ₂ —; and
Y is -CR ⁴ R ^5- . } Is used.

Yet another embodiment of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
X is —CH ₂ —; and
Y is —NH—, —CH ₂ —CR ⁴ R ⁵ —, or —CR ⁴ R ⁵ —CH ₂ —. } Is used.

Yet another embodiment of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is —CH ₂ —; and
Y is —NH—, —CH ₂ —CR ⁴ R ⁵ —, or —CR ⁴ R ⁵ —CH ₂ —. } Is used.

Yet another embodiment of the present invention is a compound of formula I as an Aurora family kinase inhibitor:
{Where,
X is —CH ₂ —; and
Y is —NH—, —CH ₂ —CR ⁴ R ⁵ —, or —CR ⁴ R ⁵ —CH ₂ —. } Is used.

Yet another embodiment of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Wherein X is -C (O)-. } Is used.

Yet another embodiment of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl; and
X is -C (O)-. } Is used.

Yet another embodiment of the present invention is a compound of formula I as an Aurora family kinase inhibitor:
{Wherein X is -C (O)-. } Is used.

Another aspect of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
X is -C (O)-; and
Y is —CH ₂ —CR ⁴ R ⁵ — or —CR ⁴ R ⁵ —CH ₂ —. } Is used.

Another aspect of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is —CH ₂ —CR ⁴ R ⁵ — or —CR ⁴ R ⁵ —CH ₂ —. } Is used.

Another aspect of the present invention provides a compound of formula I as an Aurora family kinase inhibitor:
{Where,
X is -C (O)-; and
Y is —CH ₂ —CR ⁴ R ⁵ — or —CR ⁴ R ⁵ —CH ₂ —. } Is used.

Yet another embodiment of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
X is -C (O)-; and
Y is —NH— or —CR ⁴ R ⁵ —. } Is used.

Yet another embodiment of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is —NH— or —CR ⁴ R ⁵ —. } Is used.

Yet another embodiment of the present invention is a compound of formula I as an Aurora family kinase inhibitor:
{Where,
X is -C (O)-; and
Y is —NH— or —CR ⁴ R ⁵ —. } Is used.

Yet another embodiment of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
X is -C (O)-; and
Y is -CR ⁴ R ^5- . } Is used.

Yet another embodiment of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is -CR ⁴ R ^5- . } Is used.

Yet another embodiment of the present invention is a compound of formula I as an Aurora family kinase inhibitor:
{Where,
X is -C (O)-; and
Y is -CR ⁴ R ^5- . } Is used.

Another aspect of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
X is -C (O)-; and
Y is -NH-. } Is used.

Another aspect of the present invention provides a compound of formula I for the manufacture of a medicament for treating cancer:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is -NH-. } Is used.

Another aspect of the present invention provides a compound of formula I as an Aurora family kinase inhibitor:
{Where,
X is -C (O)-; and
Y is -NH-. } Is used.

  In a galenical dosage form with one or more therapeutically inert carriers, one or more of the compounds of the invention, and / or pharmaceutically acceptable salts thereof, and, if desired, one or more Similar to their manufacturing process involving the incorporation of other therapeutically beneficial substances, a medicament comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier It is an object of the invention.

  According to the present invention, the compounds of the present invention, as well as their pharmaceutically acceptable salts, are usually useful in the management or prevention of illnesses. Based on their Aurora tyrosine kinase inhibition and their antiproliferative activity, the compounds are useful in the treatment of human or animal diseases, such as cancer, and in the manufacture of corresponding medicaments. The dosage depends on various factors such as mode of administration, species, age, and / or individual condition.

  Another aspect of the present invention is represented by formula I as an active ingredient together with a pharmaceutically acceptable adjuvant for the treatment of diseases mediated by inappropriate activation of Aurora family tyrosine kinases, in particular Aurora A tyrosine kinase. A pharmaceutical product containing one or more compounds.

  Another aspect of the present invention is a medicament comprising one or more compounds represented by formula I as an active ingredient together with a pharmaceutically acceptable adjuvant for the treatment of cancer.

  Other aspects of the invention include colorectal, breast, lung, prostate, pancreas, stomach, bladder, ovary, melanoma, neuroblastoma, cervix, or kidney (kidney or renal) cancer, leukemia, or lymphoma A pharmaceutical comprising one or more of the compounds represented by formula I as an active ingredient together with a pharmaceutically acceptable adjuvant for the treatment of

  Another aspect of the present invention is a compound as an active ingredient together with a pharmaceutically acceptable adjuvant for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and gastrointestinal stromal tumor (GIST). A pharmaceutical comprising one or more of the compounds represented by I.

  Another aspect of the present invention is the use of one or more compounds of the formula I for the manufacture of a medicament for the treatment of diseases mediated by inappropriate activation of Aurora A tyrosine kinase.

  Another aspect of the invention is the use of a compound represented by Formula I as an Aurora family tyrosine kinase inhibitor.

  Another aspect of the invention is the use of a compound represented by Formula I as an antiproliferative agent.

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

  Another aspect of the invention is effective with a pharmaceutically acceptable adjuvant for the manufacture of a medicament for the manufacture of a medicament for the treatment of a disease mediated by inappropriate activation of Aurora family tyrosine kinases. Use of one or more compounds represented by formula I as a component.

  Another aspect of the invention is the use of one or more compounds represented by formula I as active ingredients together with a pharmaceutically acceptable adjuvant for the manufacture of a medicament for the treatment of cancer.

  Other aspects of the invention include colorectal, breast, lung, prostate, pancreas, stomach, bladder, ovary, melanoma, neuroblastoma, cervix, or kidney (kidney or renal) cancer, leukemia, or lymphoma The use of one or more compounds represented by formula I as an active ingredient together with a pharmaceutically acceptable adjuvant for the manufacture of a medicament for the treatment of

  Other aspects of the invention are pharmaceutically acceptable for the manufacture of a medicament for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and gastrointestinal stromal tumor (GIST) The use of one or more compounds represented by formula I as an active ingredient together with an adjuvant. Another aspect of the present invention is represented by formula I as an active ingredient together with a pharmaceutically acceptable adjuvant for the treatment of diseases mediated by inappropriate activation of Aurora family tyrosine kinases, in particular Aurora A tyrosine kinase. Use of one or more compounds.

  Another aspect of the present invention is a medicament comprising one or more compounds represented by formula I as active ingredients together with a pharmaceutically acceptable adjuvant.

  Other aspects of the invention include colorectal, breast, lung, prostate, pancreas, stomach, bladder, ovary, melanoma, neuroblastoma, cervix, or kidney (kidney or renal) cancer, leukemia, or lymphoma A pharmaceutical comprising one or more of the compounds represented by formula I as an active ingredient together with a pharmaceutically acceptable adjuvant for the treatment of

  Another aspect of the present invention is a compound as an active ingredient together with a pharmaceutically acceptable adjuvant for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and gastrointestinal stromal tumor (GIST). A pharmaceutical comprising one or more of the compounds represented by I.

Another aspect of the invention is a compound of formula I:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
Provided that R ¹ and R ² are hydrogen, X is —C (O) —, and Y is —CR ⁴ R ⁵ — (wherein R ⁴ and R ⁵ are methyl). ,
R ³ is hydrogen, (C ₂ -C ₆ ) alkyl, or (C ₃ -C ₆ ) -cycloalkyl. } Is a compound represented by.

Yet another embodiment of the present invention is a compound of formula I:
{Wherein R ³ is hydrogen, (C ₂ -C ₆ ) alkyl, or (C ₃ -C ₆ ) -cycloalkyl. } Is a compound represented by.

Another aspect of the invention is a compound of formula I:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl; and
X is —CH ₂ —. } Is a compound represented by.

Yet another embodiment of the present invention is a compound of formula I:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -CH _2- and
Y is -CR ⁴ R ^5- . } Is a compound represented by.

The aforementioned compounds are, for example, as follows:
7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -3,5,6,7-tetrahydro-imidazo [4,5-f] indole; and
1- [7,7-Dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -6,7-dihydro-3H-imidazo [4,5-f] indol-5-yl] -ethanone.

Another aspect of the invention is a compound of formula I:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is —CH ₂ —; and
Y is —NH—, —CH ₂ —CR ⁴ R ⁵ —, or —CR ⁴ R ⁵ —CH ₂ —. } Is a compound represented by.

Yet another embodiment of the present invention is a compound of formula I:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl; and
X is -C (O)-;
Provided that R ¹ and R ² are hydrogen, X is —C (O) —, and Y is —CR ⁴ R ⁵ — (wherein R ⁴ and R ⁵ are methyl). ;
R ³ is hydrogen, (C ₂ -C ₆ ) alkyl, or (C ₃ -C ₆ ) -cycloalkyl. } Is a compound represented by.

Yet another embodiment of the present invention is a compound of formula I:
{Wherein R ³ is hydrogen, (C ₂ -C ₆ ) alkyl, or (C ₃ -C ₆ ) -cycloalkyl, and
X is -C (O)-. } Is a compound represented by.

Yet another embodiment of the present invention is a compound of formula I:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-and
Y is —CH ₂ —CR ⁴ R ⁵ — or —CR ⁴ R ⁵ —CH ₂ —. } Is a compound represented by.

The aforementioned compounds are, for example, as follows:
8,8-dimethyl-2- (5-methyl-1H-pyrazol-3-yl) -1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one; and
2- (5-Isobutyl-2H-pyrazol-3-yl) -8,8-dimethyl-1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one.

Another aspect of the invention is a compound of formula I:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is —NH—, —CR ⁴ R ⁵ —;
Provided that R ¹ and R ² are hydrogen, X is —C (O) —, and Y is —CR ⁴ R ⁵ — (wherein R ⁴ and R ⁵ are methyl). ;
R ³ is hydrogen, (C ₂ -C ₆ ) alkyl, or (C ₃ -C ₆ ) -cycloalkyl. } Is a compound represented by.

Another aspect of the invention is a compound of formula I:
{Where,
R ³ is hydrogen, (C ₂ -C ₆ ) alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is —NH— or —CR ⁴ R ⁵ —. } Is a compound represented by.

Yet another embodiment of the present invention is a compound of formula I:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is -CR ⁴ R ^5- ;
Provided that R ¹ and R ² are hydrogen, X is —C (O) —, and Y is —CR ⁴ R ⁵ — (wherein R ⁴ and R ⁵ are methyl). ;
R ³ is hydrogen, (C ₂ -C ₆ ) alkyl, or (C ₃ -Q) -cycloalkyl. } Is a compound represented by.

Yet another embodiment of the present invention is a compound of formula I:
{Where,
R ³ is hydrogen, (C ₂ -C ₆ ) alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is -CR ⁴ R ^5- . } Is a compound represented by.

The aforementioned compounds are, for example, as follows:
2- (5-isobutyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-Methyl-2H-pyrazol-3-yl) -spiro [7,7-cyclopentane-5,7-dihydro-3H-imidazo [4,5-f] indole] -6-one; or actually According to the IUPAC nomenclature of 2- (5-methyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -on;
2- (5-isobutyl-2H-pyrazol-3-yl) -spiro [7,7-cyclopentane-5,7-dihydro-1H-imidazo [4,5-f] indole] -6-one; According to the IUPAC nomenclature, 2- (5-isobutylyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole ] -6 (3H) -on;
5-ethyl-7,7-dimethyl-2- (5-methyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-2- (5-isobutyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one; and
2- (5-Isobutyl-2H-pyrazol-3-yl) -5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one.

Another aspect of the invention is a compound of formula I:
{Where,
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is -NH-. } Is a compound represented by.

The aforementioned compounds are, for example, as follows:
6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one;
3-methyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one; as well as
3-Isopropyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one.

Another aspect of the invention is a compound of formula I:
{Wherein R ¹ is alkyl or —C (O) -alkyl. } Is a compound represented by.

Another aspect of the invention is a compound of formula I:
{Wherein R ¹ is alkyl. } Is a compound represented by.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is alkyl; and
R ² is hydrogen or alkyl. } Is a compound represented by.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is alkyl;
R ² is hydrogen or alkyl; and
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl. } Is a compound represented by.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is alkyl;
X is -C (O)-; and
Y _{^{is, -CH 2 -CR 4 R 5 -}} , - CR 4 R 5 -CH 2 -, or -CR ⁴ R ⁵ - is. } Is a compound represented by.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is alkyl;
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y _{^{is, -CH 2 -CR 4 R 5 -}} , - CR 4 R 5 -CH 2 -, or -CR ⁴ R ⁵ - is. } Is a compound represented by.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is alkyl;
R ² is hydrogen or alkyl;
X is -C (O)-; and
Y is -CR ⁴ R ^5- . } Is a compound represented by.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is alkyl;
R ² is hydrogen;
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is -CR ⁴ R ^5- . } Is a compound represented by.

The aforementioned compounds are, for example, as follows:
5-ethyl-7,7-dimethyl-2- (5-methyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-2- (5-isobutyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;

2- (5-isobutyl-2H-pyrazol-3-yl) -5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-methyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one; Accompanying compounds;

5-isopropyl-7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
5-isopropyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -5-propyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-Dimethyl-5-propyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is alkyl;
R ² is hydrogen or alkyl;
R ³ is alkyl substituted once or several times by halogen;
X is -C (O)-; and
Y is -CR ⁴ R ^5- . } Is a compound represented by.

The aforementioned compounds are, for example, as follows:
5-ethyl-7,7-dimethyl-2- (5-trifluoromethyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-isopropyl-7,7-dimethyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-5-propyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one; as well as
5,7,7-Trimethyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is alkyl;
R ² is hydrogen or alkyl;
R ³ is alkoxy or alkylsulfanyl;
X is -C (O)-; and
Y is -CR ⁴ R ^5- . } Is a compound represented by.

The aforementioned compounds are, for example, as follows:
5-ethyl-2- (5-methoxy-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one; and
5-ethyl-7,7-dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is alkyl;
R ² is hydrogen or alkyl;
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is —CH ₂ —CR ⁴ R ⁵ — or —CR ⁴ R ⁵ —CH ₂ —. } Is a compound represented by.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is alkyl;
R ² is hydrogen or alkyl;
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is -NH-. } Is a compound represented by.

The aforementioned compounds are, for example, as follows:
3-methyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one; as well as
3-Isopropyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one.

Another aspect of the invention is a compound of formula I:
{Where,
R ¹ is —C (O) -alkyl;
R ² is hydrogen or alkyl;
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is —CH ₂ —; and
Y _{^{is, -CH 2 -CR 4 R 5 -}} , - CR 4 R 5 -CH 2 -, or -CR ⁴ R ⁵ - is. } Is a compound represented by.

The aforementioned compounds are, for example, as follows:
1- [7,7-Dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -6,7-dihydro-3H-imidazo [4,5-f] indol-5-yl] -ethanone.

Another aspect of the present invention is that as an active ingredient together with a pharmaceutically acceptable adjuvant, one or more compounds of the formula I, where R ¹ and R ² are hydrogen and X is —C (O) — , And Y is —CR ⁴ R ⁵ — (wherein R ⁴ and R ⁵ are methyl), R ³ is hydrogen, (C ₂ -C ₆ ) alkyl, or (C ₃ -C ₆ ) -Cycloalkyl. } It is a pharmaceutical containing the compound represented by.

Another embodiment of the present invention is an active ingredient together with a pharmaceutically acceptable adjuvant as one or more formula I {wherein R ³ is hydrogen, (C ₂ -C ₆ ) alkyl, (C _3- C ₆ ) -cycloalkyl or fluorine. } It is a pharmaceutical containing the compound represented by.

Another embodiment of the present invention is one or more formula I {wherein R ¹ is alkyl or -C (O) -alkyl as an active ingredient together with a pharmaceutically acceptable adjuvant. } It is a pharmaceutical containing the compound represented by.

Another aspect of the present invention is that one or more formula I {wherein R ¹ is alkyl as an active ingredient together with a pharmaceutically acceptable adjuvant. } It is a pharmaceutical containing the compound represented by.

Another aspect of the invention is the use of one of the following compounds for the manufacture of a medicament for treating cancer:
7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -3,5,6,7-tetrahydro-imidazo [4,5-f] indole;
1- [7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -6,7-dihydro-3H-imidazo [4,5-f] indol-5-yl] -ethanone;
8,8-dimethyl-2- (5-methyl-1H-pyrazol-3-yl) -1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
2- (5-isobutyl-2H-pyrazol-3-yl) -8,8-dimethyl-1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-isobutyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-Methyl-2H-pyrazol-3-yl) -spiro [7,7-cyclopentane-5,7-dihydro-3H-imidazo [4,5-f] indole] -6-one; or actually According to the IUPAC nomenclature of 2- (5-methyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -on;
2- (5-isobutyl-2H-pyrazol-3-yl) -spiro [7,7-cyclopentane-5,7-dihydro-1H-imidazo [4,5-f] indole] -6-one; According to the IUPAC nomenclature of 2- (5-isobutyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -on;
6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one;
2- (4,5-dimethyl-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-2- [5- (3-methyl-butyl) -1H-pyrazol-3-yl] -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-ethyl-4-methyl-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-2- (1H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-cyclopropyl-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-isopropyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
8,8-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
8,8-dimethyl-2- (1H-pyrazol-3-yl) -1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
2- (5-cyclopropyl-1H-pyrazol-3-yl) -8,8-dimethyl-1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
2- (5-isopropyl-2H-pyrazol-3-yl) -8,8-dimethyl-1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
2- (2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -one;
2- (5-isopropyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -one;
2- (5-propyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -one;
7,7-dimethyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one; and
2- (5-Cyclopropyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ', 7-imidazo [4,5-f] indole] -6 (3H) -one .

Another aspect of the invention is the use of one of the following compounds for the manufacture of a medicament for treating cancer:
3-methyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one;
3-isopropyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one;
5-ethyl-7,7-dimethyl-2- (5-methyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-2- (5-isobutyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
2- (5-isobutyl-2H-pyrazol-3-yl) -5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-methyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one; Accompanying compounds;

5-isopropyl-7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
5-isopropyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -5-propyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-5-propyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] -indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-trifluoromethyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-isopropyl-7,7-dimethyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-5-propyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-2- (5-methoxy-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one; and
5-ethyl-7,7-dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one.

｛式中、R¹がアルキル又は-C（O）-アルキルであり、そしてX及びYが式Iについて先に与えられた意味を持つ。｝によって表される化合物を、以下の式（III）：

｛式中、Aが- OH、-Cl、-H、又は-OMeであり、そしてR²及びR³が式Iについて先に与えられた意味を持つ。｝によって表される化合物と反応させて、以下の式I：

｛式中、R¹がアルキル又は-C（O）-アルキルであり、そして、R²、R³、X、及びYが式Iについて先に与えられた意味を持つ。｝によって表される化合物を得、
b）上記反応混合物から上述の式Iによって表される化合物を分離し、そして
c）必要に応じて、それを医薬として許容される塩に変換する、
による、式I：
｛式中、R¹が、アルキル又は-C（O）-アルキルである。｝によって表される化合物の製造方法である。 Another aspect of the invention provides the following steps:
a) The following formula (II):

{Wherein R ¹ is alkyl or —C (O) -alkyl, and X and Y have the meanings given above for formula I. } Is represented by the following formula (III):

{Wherein A is -OH, -Cl, -H, or -OMe, and R ² and R ³ have the meanings given above for formula I. Are reacted with a compound represented by the following formula I:

{Wherein R ¹ is alkyl or —C (O) -alkyl, and R ² , R ³ , X, and Y have the meanings given above for formula I. } Is obtained,
b) separating the compound represented by formula I above from the reaction mixture, and
c) if necessary, convert it to a pharmaceutically acceptable salt,
According to formula I:
{Wherein R ¹ is alkyl or —C (O) -alkyl. } Is a manufacturing method of the compound represented by these.

The compound represented by Formula I, which is the subject of the present invention, or a pharmaceutically acceptable salt thereof may be produced by any method known to be applicable to the preparation of chemically related compounds. it can. When used to prepare a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, the foregoing methods are X, Y, R ¹ , R ² , and R, unless otherwise specified. ³ has the meaning given hereinbefore, the following representative schemes 1 and 2, as well as examples illustrated. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of the aforementioned starting materials is explained in the appended examples. Alternatively, the necessary starting materials can be obtained by procedures analogous to those illustrated which are within the ordinary skill of an organic chemist.

  The benzimidazole ring system represented by Formula I can be synthesized in a variety of ways similar to those described in the literature (Mertens, A. et al., J. Med. Chem. 30 (1987) pages 1279-1287; DE 35 31 678). Can be formed by any synthetic route.

  One of the production routes for the compound represented by Formula I (Scheme 1) begins with a diamine represented by Formula (II), which carboxylic acid (formula (III) {wherein A is OH Compound), acid chloride (A is Cl), aldehyde (A is H), methyl carboxylate (A is OMe), or activated ester (A is, for example, , Hydroxybenzotriazole). See the literature cited above for detailed procedures.

Pyrazoles represented by formula (III) are commercially available or they are standard procedures of organic chemistry (eg, Stanovnik, B. and Svete, J., Science of Synthesis 12 (2002) 15- See page 225), for example, condensation of 1,3-dicarbonyl compounds with hydrazine (eg WO 04/032928 or van Herk, T. et al., J. Med. Chem. 46 (2003) 3945-3951 Page 1), or 1,3-dipolar cycloaddition between a diazo compound and acetylene (see, eg, Sewald, N. et al., Liebigs Ann. Chem. (1992) pages 947-952) Can be manufactured by. Formula (III) {wherein R ³ is alkoxy. } In the presence of a base such as cesium carbonate in a subsequent solvent such as dimethylformamide (DMF), N-methyl-pyrrolidinone (NMP), etc. With O-alkylation of the -hydroxy group (see, for example, WO 03/035065) by 5-hydroxy-pyrazole-3-carboxylic acid esters (see, for example, Ochi, H. et al., Chem. Pharm. Bull. 31 (1983) 1228-1234) or by the procedure of Martins, MAP et al., Synthesis 15 (2003) 2353-2357. Formula (III) {R ³ is alkylsulfanyl. } Can be prepared through the corresponding oxo-ketene dithioacetals according to Mahata, PK et al., Tetrahedron 59 (2003) 2631-2639. Alternatively, for Scheme 1, Formula I {wherein R ³ is alkoxy or alkylsulfanyl. } The 5-alkoxy- or 5-alkylsulfanyl-pyrazole moiety of the compound represented by may be introduced by other pathways of the reaction stage as described in WO 03/035065. Formula (III) {wherein R ² is hydrogen, R ³ is trifluoromethyl, and A is hydroxy. } Is a three-step procedure according to Scheme 1a: condensing 4,4,4-trifluoro-1- (2-furyl) -1,3-butanedione with benzylhydrazine under acidic conditions Oxidatively degrading the furan ring to a carboxylic acid functional group using potassium permanganate (eg, Djuric, SW et al., J. Med. Chem. 43 (2000) 2975-2981; Jia, ZJ et al., Bioorg Med. Chem. Lett. 12 (2002) 1651-1655 or Pruitt, JR et al., J. Med. Chem. 46 (2003) 5298-5315), and the desired 5-tri Cleaving the benzyl protecting group to provide fluoromethyl-2H-pyrazole-3-carboxylic acid.

This procedure with an N-benzyl or p-methoxybenzyl group as an intermediate protecting group (Subramanyam, C., Synth. Comman. 25 (1995) pp. 761-774) can be used for other pyrazoles required as starting materials. It can also be applied to manufacture.

Formula (II) {wherein X is —C (O) —, R ¹ is hydrogen or alkyl, and Y is —CR ⁴ R ⁵ or —NH—. The compounds represented by Mertens, A. et al., J. Med. Chem. 30 (1987) 1279-1287; von der Saal, W. et al., J. Med. Chem. 32 (1989) 1481 -1491 page; 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. Formula (II) {wherein X is —C (O) — or —CH ₂ —, R ¹ is hydrogen or —C (O) alkyl, and Y is —CR ⁴ R ⁵ —. } Can be prepared according to DE 36 42 315. And further, Formula (II) {wherein X is —C (O) — or —CH ₂ —, R ¹ is hydrogen or alkyl, and Y is —CR ⁴ R ⁵ —CH ₂ — or — CH ₂ —CR ⁴ R ⁵ —. } Are described in DE 37 01 277.

For example, formula (II) {wherein X is —C (O) —, R ¹ is hydrogen or alkyl, and Y is —CR ⁴ R ⁵ . Is referred to as IIa and is shown in US Pat. No. 4,666,923A, DE 34 10 168, and Mertens, A. et al., J. Med. Chem. 30 (1987) 1279 as shown in Scheme 1b below. Can be synthesized according to page -1287:

In Scheme 1b, R ¹ , R ⁴ , and R ⁵ have the meanings given above for Formula I, and L represents a leaving group such as, for example, iodine, bromine, chlorine, triflate, and the like. To express.
In an alternative procedure, formula (IIa) {wherein R ¹ is alkyl. Is a diamine represented by formula (IIb) (compound (II) {wherein X is —C (O) — and R ¹ is hydrogen, as shown in Scheme 1c) , And Y is —CR ⁴ R ⁵ }).

  The diamine represented by formula (IIb) can be synthesized according to Scheme 1b with step 5 omitted.

  Another synthesis of the compounds represented by Formula I (Scheme 2) begins with a nitro compound (IV) or (V) that is hydrogenated and subsequently cyclized to the desired benzimidazole derivative using acetic acid or hydrochloric acid. . For detailed procedures, see Mertens, A. et al., J. Med. Chem. 30 (1987) pages 1279-1287; DE 35 31 678.

Formulas (IV) and (V), wherein X is C (O), R ¹ is hydrogen or alkyl, and Y is —CR ⁴ R ⁵ , —NH—. The compounds represented by 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; can be produced in a similar manner as described in EP 0 318 902. Formulas (IV) and (V), wherein X is C (O) or —CH ₂ —, R ¹ is hydrogen or —C (O) alkyl, and Y is —CR ⁴ R ⁵ —. is there. } Can be prepared according to DE 36 42 315. And further, formula (II) {wherein X is C (O) or -CH _2- , R ¹ is hydrogen or alkyl, and Y is -CR ⁴ R ⁵ -CH ₂ -or -CH ₂ -CR ⁴ R ^5- . } Are described in DE 37 01 277.

  The compounds according to the invention may exist in the form of their pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” maintains the biological effectiveness and properties of the compound represented by formula (I) and is from a suitable non-toxic organic or inorganic base, or organic or inorganic acid. Represents a conventional acid addition salt formed. Examples of base addition salts include those obtained from sodium, potassium, ammonium, quaternary ammonium hydroxide (eg, tetramethylammonium hydroxide). Examples of acid addition salts are those obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as organic acids such as p-toluenesulfonic acid , Naphthalenesulfonic acid, naphthalene disulfonic acid, methanesulfonic acid, and those obtained from ethanesulfonic acid. Chemical modification of a pharmaceutical compound (ie, drug) to a salt is a technique well known to pharmacists to obtain improved physical and chemical stability, hygroscopicity, fluidity, and solubility of the compound. . For example, Stahl, PH and Wermuth, G. (Editor), Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta (VHCA), Zurich (2002), or Bastin, RJ. Et al., Organic Proc. Res. Dev. 4 ( 2000), pages 427-435.

  The compounds represented by formula (I) may contain one or several chiral centers and may also exist in racemic or optically active form. Racemates can be separated into enantiomers by known methods. For example, diastereomeric salts that can be separated by crystallization are formed from racemic mixtures, for example, by reaction with optically active acids such as D- or L-camphorsulfonic acid. Alternatively, separation of enantiomers can be achieved by using chromatography on commercially available chiral HPLC-phases.

The compounds represented by the pharmacological activity formula (I) and their pharmaceutically acceptable salts have valuable pharmacological properties. It has also been found that the compounds are active as inhibitors of the Aurora kinase family and show antiproliferative activity. As a result, the compounds of the present invention are useful for the treatment and / or prevention of diseases with known overexpression of Aurora family kinases, preferably Aurora A, in particular the treatment and / or prevention of the diseases mentioned above. Useful. The activity of the compounds as inhibitors of the Aurora kinase family has been demonstrated by the following biological assays:

Measurement of IC ₅₀ for inhibitors of Aurora A
(96MTP-ELISA)
Assay principle
Aurora A is a serine threonine kinase involved in spindle assembly and chromosome segregation.

The assay is usually an ELISA-type assay in which a biotinylated substrate (PKB-GSK2) is phosphorylated. Phosphorylation is detected by peroxidase (POD) labeled polyclonal antibody (PAK <M-Ig> S-IgG-POD) and phosphorylated peptide monoclonal antibody (Mab) (MAK <P-GSK> M-27E5-IgG). The The assay has been validated for IC ₅₀ measurements.

material

Method The assay is performed in a 96-well format for 100 sample IC ₅₀ measurements (each using 8 concentrations in duplicate), 100 μl incubation volume, and the following plate layout:

Step / Measure
1． Sample preparation: 24 μl per well of sample diluted in kinase buffer (descending order) is added to the assay plate (final concentration of DMSO 1%).
2. Add 16 μl of Aurora-A-his-4 diluted in kinase buffer directly into the assay plate.
3. Add 40 μl of PKB_GSK2 / ATP mixture directly into the assay plate (final concentration: Aurora A = 250 ng / ml, GSK2 = 200 nM, ATP = 4 μM) per well. Negative control: no ATP.
Four. Incubate the assay plate at room temperature for exactly 90 minutes.
5. Stop the reaction by adding 20 μl EDTA into all wells.
6． The assay plate is washed 3 times with 200 μl wash buffer per well.
7. 100 μl per well of MAK <P-GSK> M27E5-IgG (1: 10000) and PAK <M-Ig> S-IgG-POD dissolved in 3% BSA / PBS-T (1: 6000) is added to the assay plate.
8． The assay plate is incubated for 60 minutes at room temperature.
9． The assay plate is washed 3 times with 200 μl wash buffer per well.
10. Add 100 μl ABTS solution per well to the assay plate and incubate for about 4 minutes at RT using an MTP shaker.
11. Measure absorption at 405 / 492nm.
12． Calculate percent inhibition as follows:
(1− (E _sample −E _NC ) / (E _PC −E _NC )) × 100
13. IC ₅₀ is calculated using non-linear curve fitting (XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK)).

Antiproliferative activity:
The activity of the compounds as antiproliferative agents is demonstrated by the following biological assays:
CellTiter-Glo® assay in HCT 116 cells
The CellTiter-Glo® Luminescent Cell Viability Assay (Promega) is a homogeneous method for determining the number of viable cells in culture based on the quantification of ATP present, indicating the presence of metabolically active cells.

  HCT 116 cells (human colon carcinoma, ATCC-No. CC1-247) were obtained from GlutaMAX® I (Invitrogen, Cat-No. 61870-010), 2.5% fetal calf serum (FCS, Sigma Cat-No. F4135 (FBS)); cultured in RPMI 1640 medium containing 100 units / ml penicillin / 100 μg / ml streptomycin (= Pen / Strep manufactured by Invitrogen, Cat. No. 15140). For the assay, the cells were seeded in 384 well plates at 1000 cells per well in the same medium. The next day, test compounds were added at various concentrations (10 concentrations, 1: 3 dilution) ranging from 30 μM to 0.0015 μM. After 5 days, the CellTiter-Glo® assay was performed according to the manufacturer's instructions (CellTiter-Glo® Luminescent Cell Viability Assay, Promega). In short: the cell-plate was allowed to equilibrate to room temperature for about 30 minutes, after which CellTiter-Glo® reagent was added. The contents were carefully mixed for 15 minutes to promote cell degradation. After 45 minutes, the luminescence signal was measured by Victor 2 (scanning multiwell spectrophotometer, Wallac).

Details:
First day:
Medium: RPMI 1640 with GlutaMAX® I (Invitrogen, Cat-Nr. 61870), 5% FCS (Sigma, Cat-No. F4135), Pen / Strep (Invitrogen, Cat. No. 15140).
-HCT 116 (ATCC-No. CC1-247): 1000 cells (Greiner 781098, μClear plate, white) in 60 μl per well of a 384 well plate.
-After seeding, the plates are incubated for 24 hours at 37 ° C, 5% CO ₂ .

Day 2: Induction (compound, treatment with 10 concentrations):
To achieve the final concentration of 30 μM, 3.5 μl of 10 mM compound stock solution was added directly to 163 μl of medium. Next, step e) consisting of the dilution procedure described below was then performed.
In order to achieve the second highest concentration to the lowest concentration, serial dilutions with a 1: 3 dilution step were then performed according to procedures (a-e) as described herein below:

a) For the second highest concentration, add 10 μl of a 10 mM stock solution of the compound to 20 μl of dimethyl sulfoxide (DMSO).
b) Dilute 1: 3 in this DMSO dilution series 8 times (always 10 μl vs. 20 μl DMSO) (resulting in 9 wells at concentrations from 3333.3 μM to 0.51 μM).
c) Dilute each concentration 1: 47.6 (3.5 μl compound dilution vs. 163 μl medium).
e) Add 10 μl of all concentrations to 60 μl of medium in the cell plate to give a final concentration of DMSO: 0.3% in all wells and 10 compounds ranging from 30 μM to 0.0015 μM Resulting in a final concentration.
-Each compound is tested in triplicate.
Incubate for 120 hours (5 days) at -37 ° C, 5% CO ₂

analysis:
Add 30 μl of CellTiter-Glo® reagent (prepared from CellTiter-Glo® buffer purchased from Promega and CellTiter-Glo® substrate (lyophilized) per well).
-Shake for 15 minutes at room temperature.
-Incubate for 45 minutes at room temperature without shaking

measurement:
-Victor 2 scanning multiwell spectrophotometer (Wallac), emission mode (0.5 sec / readout, 477 nm).
-Determine IC ₅₀ using non-linear curve fitting (XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK).

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

  The compounds according to the invention and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical compositions. The pharmaceutical composition can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions. Administration can, however, also be achieved rectally, for example in the form of suppositories, or parenterally, for example in the form of infusion solutions.

  The pharmaceutical compositions mentioned above can be obtained by processing the compounds according to the invention together with pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. may be used as the aforementioned carriers for eg tablets, coated tablets, dragees, and hard gelatine capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. Depending on the nature of the active substance, in the case of soft gelatin capsules, however, usually no carrier is necessary. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils 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 composition additionally contains preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, fragrances, salts for altering osmotic pressure, buffers, masking agents, or antioxidants. Can be included. They can also contain other therapeutically valuable substances.

Pharmaceutical compositions include, for example:
a) Tablet formulation (wet granulation):

Manufacturing procedure:
1． Mix items 1, 2, 3, and 4 and granulate with purified water.
2． The granules are dried at 50 ° C.
3． Pass the granules through suitable milling equipment.
Four. Add item 5 and mix for 3 minutes; apply pressure with suitable compression machine.

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 suitable capsules.

c) Micro suspension
1． Weigh out 4.0 g of glass beads in a custom test tube GL, 25.4 cm (the beads fill half of the test tube).
2. Add 50 mg of compound and disperse using spatula and vortex.
3. Add 2 ml gelatin solution (weight, beads: gelatin solution = 2: 1) and vortex.
Four. Cover and wrap with aluminum foil to protect from light.
Five. Prepare the counter balance of the mill.
6． Mill on Retsch mill for 4 hours at 20 / s (for some substances up to 24 hours at 30 / s).
7. Extract the suspension from the beads using a two-layer filter (100 μm) on a filter holder integrated with the receiving vial by centrifuging at 400 g for 2 minutes.
8． Transfer the extract to a graduated cylinder.
9． Repeat washing with a small amount (here 1 ml step) until the final volume is reached or the extract is clear.
Ten. Fill up to the final volume with gelatin and homogenize.

  The following examples and references 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 described without departing from the essence of the invention.

A: Starting material
Preparation of 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one
i) 1-ethyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one 3,3-dimethyl-6- in anhydrous N, N-dimethylformamide (DMF) (35 ml) A solution of nitro-1,3-dihydro-indol-2-one (6 g, 29.10 mmol) was treated with sodium hydride. The resulting suspension was stirred at 60 ° C. for 1 hour. A solution of bromo-ethane (2.17 mL, 3.17 g, 29.10 mmol) in DMF (10 ml) was added. The mixture was cooled to room temperature and stirred for 1 hour. After solvent removal, the mixture was quenched with water (100 ml) and extracted with ethyl acetate (3 × 100 ml). The extract was dried over Na ₂ SO ₄ , evaporated and the crude product was purified by column chromatography on silica gel. Elution with ethyl acetate / n-heptane (1: 3) gave 5.94 g (87%) of a yellow solid.

ii) 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one in methanol / tetrahydrofuran (THF) (1: 1, 80 ml) in 1-ethyl-3,3- To a solution of dimethyl-6-nitro-1,3-dihydro-indol-2-one (5.9 g, 25.19 mmol) was added palladium on charcoal (10%, 1.2 g) and the mixture was stirred at room temperature for 4 hours. Hydrogenated. After filtration and evaporation of the solvent, 5.05 g (98%) of 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one was isolated as a white solid.

iii) N- (1-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -acetamide 6-amino-1-ethyl-in acetic anhydride (80 ml) A solution of 3,3-dimethyl-1,3-dihydro-indol-2-one (5.05 g, 24.72 mmol) was stirred at room temperature for 4 hours. The mixture was poured into ice water (150 ml), warmed to room temperature and stirred again for 2 hours. After extraction with ethyl acetate (3 × 100 ml), the combined organic layers were washed with saturated NaHCO ₃ solution (3 × 100 ml), brine (100 ml) and dried over sodium sulfate. After removal of the solvent, the crude product was purified by column chromatography on silica gel (ethyl acetate / n-heptane, 1: 1) to yield 5.6 g (91%) of N- (1-ethyl- 3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -acetamide was obtained.

iv) N- (1-Ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-1H-indol-6-yl) -acetamide In acetic anhydride (70 ml), N- (1 To a solution of -ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -acetamide (5.6 g, 22.73 mmol), nitric acid (100%, 1.96 g, 1.29 ml) 31.2 mmol) at 0 ° C. The mixture was stirred for 30 minutes and then poured into ice water (150 ml). After stirring for 4 hours, the mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic layers were washed with sodium hydroxide solution (1M, 100 ml) and water (100 ml), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate / n-heptane, 1: 1) and 5.2 g (78%) N- (1-ethyl-3,3-dimethyl- as a yellow solid. 5-Nitro-2-oxo-2,3-dihydro-1H-indol-6-yl) -acetamide was obtained.

v) 6-amino-1-ethyl-3,3-dimethyl-5-nitro-1,3-dihydro-indol-2-one
N- (1-Ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-1H-indol-6-yl) -acetamide (5.2 g, 17.85 mmol) in ethanol (40 ml) Dissolved in. After the addition of hydrochloric acid (25%, 8 ml, 81.44 mmol), the mixture was stirred at reflux for 3 hours. The reaction mixture was cooled to room temperature and then quenched with water (80 ml). The yellow precipitate was separated by suction and washed with ethanol / water (1: 1). The solid was dissolved in ethyl acetate, dried over sodium sulfate and concentrated to give 4.15 g (93%) of 6-amino-1-ethyl-3,3-dimethyl-5-nitro-1 as an orange solid , 3-Dihydro-indol-2-one was obtained.

vi) 5,6-Diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one 6-amino-1-ethyl-3,3-dimethyl-5 in ethanol (80 ml) To a solution of -nitro-1,3-dihydro-indol-2-one (4.15 g, 16.65 mmol) was added PtO ₂ (0.4 g) and the mixture was hydrogenated at room temperature for 3.5 hours. After filtration and evaporation of the solvent, 3.25 g (89%) of 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one is isolated as an orange solid did.

Preparation of 5,6-diamino-1,3,3-trimethyl-1,3-dihydro-indol-2-one
5,6-diamino-1,3,3-trimethyl-1,3-dihydro-indole-2-one is converted to 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indole Prepared by a 6-step synthesis similar to that described for 2-one.

Preparation of 5,6-diamino-3,3-dimethyl-1-propyl-1,3-dihydro-indol-2-one
5,6-diamino-3,3-dimethyl-1-propyl-1,3-dihydro-indol-2-one is converted to 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro -Prepared by a 6-step synthesis similar to that described for indol-2-one.

Preparation of 5,6-diamino-1-isopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one
5,6-diamino-3,3-dimethyl-1-isopropyl-1,3-dihydro-indol-2-one is converted to 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro -Prepared by a 6-step synthesis similar to that described for indol-2-one.

Preparation of 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid
i) 1-Benzyl-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole 50g (0.240mol) 4,4,4-tri in 1ml hydrogen chloride solution in ethanol 24ml (0.024mol) To a solution of fluoro-1- (2-furyl) -1,3-butanedione and an additional 520 ml of EtOH, 50 g (0.248 mol) of benzylhydrazine dihydrochloride was added in small portions at room temperature. The reaction mixture was then heated at reflux for 7 hours. After cooling to room temperature, the reaction mixture was neutralized with saturated NaHCO ₃ , EtOH was separated by distillation and the residual oil / water mixture was extracted with 300 ml of dichloromethane. The organic phase was washed twice with 100 ml water, dried over Na ₂ SO ₄ and concentrated in vacuo to give 73.7 g 1-benzyl-5-furan-2-yl-3 as a brown oil. -Trifluoromethyl-1H-pyrazole was obtained and used crude in the next reaction. MS: M = 293.0 (API +).

ii) 2-Benzyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid
In a solution of 9.5 g (0.0325 mol) 1-benzyl-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole in 350 mL acetone, 27.2 g (0.172 mol) permanganese in 450 ml water Potassium acid was added. The reaction mixture was heated at 60 ° C. for 4 hours. After cooling to room temperature, 200 ml of 2-propanol was added and the mixture was stirred overnight, it was filtered through a celite pad and washed with 1 l of acetone. The filtrate was concentrated in vacuo to 150 ml. The residue was dissolved in 20 mL 2M NaOH and 150 mL water. The resulting aqueous phase was washed twice with 70 ml of ethyl ether, then it was acidified with 30 ml of 5M HCl solution. The suspension was extracted with 200 and 50 ml of ethyl acetate (EtOAc). The combined organic extracts were washed with 30 mL water and 5 mL brine and concentrated. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ with 1% acetic acid) to give 6.1 g (0.022 mol, 67%) of 2-benzyl-5-trifluoromethyl as an off-white solid -2H-pyrazole-3-carboxylic acid was obtained. MS: M = 271.1 (ESI +).

iii) 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid About 50 ml of ammonia was liquefied in a three-necked flask in an ethanol-dry ice bath and 100 mg (3.70 mmol) of 2- Benzyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid was added. To the solution, sodium was added in portions (about 260 mg, 11.3 mmol) until the blue color lasted longer than 5 minutes. Ammonia was distilled off overnight. Water was added and acidified with 2N HCl solution. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over Na ₂ SO ₄ and the solvent was removed in vacuo to give 560 mg (3.11 mmol, 84%) of 5-tris as a yellow solid. Fluoromethyl-2H-pyrazole-3-carboxylic acid was obtained and used without further purification. MS: M = 179.0 (API-)

5-Methoxy-1H-pyrazole-3-carboxylic acid ethyl ester
5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, 1.92 mmol) was dissolved in anhydrous N, N-dimethylformamide (DMF) (35 ml) and cesium carbonate (626 mg, 1.92 mmol) was dissolved. added. The resulting suspension was treated with iodomethane (120 μl, 273 mg, 1.92 mmol) and stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated potassium hydrogen sulfate solution and extracted with ethyl acetate (3 × 100 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml). The extract was dried over sodium sulfate, evaporated and the crude product was purified by column chromatography on silica gel. Elution with ethyl acetate / n-heptane (1: 3) gave 124 mg (38%) of a white solid.

5-Methoxy-1H-pyrazole-3-carboxylic acid
5-Methoxy-1H-pyrazole-3-carboxylic acid ethyl ester (120 mg, 0.71 mmol) was dissolved in tetrahydrofuran (THF) (2 mL). After the addition of sodium hydroxide (2M in water, 1 mL), the mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature, acidified by addition of hydrochloric acid (pH 3) and extracted with ethyl acetate (3 × 20 ml). The extract was dried over sodium sulfate and evaporated to give 86 mg (86%) of a white solid.

Preparation of 2- (3,3-bis-methylsulfanyl-acryloyl) -5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one (i ) 5-ethyl-2- (1-hydroxy-ethyl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one in hydrochloric acid (100 mL, 4N), A mixture of 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (10 g, 46 mmol) and 2-hydroxy-propionic acid (9.13 g, 91.2 mmol) Reflux for hours. After cooling, neutralize with aqueous ammonia (25%) and stir for 1.5 hours, filter the precipitate and dry in vacuo at 50 ° C., 12.29 g (95%) of gray A solid was obtained.

(Ii) 2-acetyl-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-one
5-ethyl-2- (1-hydroxy-ethyl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one (13 g, 47.6 mmol) and manganese dioxide (IV) (16.54 g, 190 mmol) was suspended in chloroform (400 mL) and stirred at 65 ° C. for 16 hours. The mixture was cooled, filtered through celite, and the filtrate was concentrated in vacuo to give 11.6 g (90%) of a beige solid.

(Iii) 2-acetyl-5-ethyl-7,7-dimethyl-1- (tetrahydro-pyran-2-yl) -5,7-dihydro-1H-imidazo [4,5-f] indole-6-one
2-acetyl-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one (11.7 g, 43.1 mmol) and p-toluenesulfonic acid monohydrate The Japanese product (0.82 g, 4.3 mmol) was dissolved in dichloromethane (200 mL). To this solution was added 3,4-dihydro-2H-pyran (4.81 g, 56 mmol) and the mixture was stirred at reflux for 24 hours. The mixture was filtered and the filtrate was washed with water (2 × 100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica (dichloromethane / methanol 93: 3) to give 6.8 g (44%) of a light yellow solid.

  (Iv) 2- (3,3-Bis-methylsulfanyl-acryloyl) -5-ethyl-7,7-dimethyl-1- (tetrahydro-pyran-2-yl) -5,7-dihydro-1H-imidazo [ 4,5-f] Indole-6-one

  To a suspension of sodium hydride (0.57 g, 22.5 mmol) in toluene (20 mL) was added tert-butanol (0.88 g, 11.8 mmol) at 80 ° C. and the mixture was stirred for 2 h. After cooling to room temperature, 2-acetyl-5-ethyl-7,7-dimethyl-1- (tetrahydro-pyran-2-yl) -5,7- in N, N-dimethylformamide (DMF) (12 mL) A suspension of dihydro-1H-imidazo [4,5-f] indole-6-one (2 g, 5.63 mmol) and carbon disulfide (0.43 g, 5.63 mmol) was added in portions and the mixture was allowed to reach room temperature for 30 minutes. Stir and finally stir at 80 ° C. for 30 minutes. After cooling to room temperature, water (20 mL) and ethyl acetate (15 mL) were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic phases are washed with water (3 × 10 mL) and concentrated in vacuo to give 2.27 g (88%) of 2- (3,3-bis-methylsulfanyl-acryloyl) -5-ethyl. -7,7-dimethyl-1- (tetrahydro-pyran-2-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one was obtained in a series of reactions. And partially deprotected. It was used in the next step without any further purification.

(V) 2- (3,3-bis-methylsulfanyl-acryloyl) -5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indole-6-one Purified 2- (3,3-bis-methylsulfanyl-acryloyl) -5-ethyl-7,7-dimethyl-1- (tetrahydro-pyran-2-yl) -5,7-dihydro-1H-imidazo [4 , 5-f] indol-6-one (2.25 g, 4.9 mmol) and p-toluenesulfonic acid monohydrate (0.5 g, 2.6 mmol) in methanol (25 mL) and water (3 mL), and Stir at reflux for 3 hours. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water and concentrated in vacuo. The crude product was recrystallized from methanol to give 2- (3,3-bis-methylsulfanyl-acryloyl) -5-ethyl-7,7-dimethyl-5,7-dihydro-1H- as a yellow solid) Imidazo [4,5-f] indol-6-one (0.71 g, 39%) was obtained.

B: Final product
Examples 1-43
Standard procedure:
1-isopropyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d '] diimidazol-2-one ( Production of Example 11)

5-methyl-1H-pyrazole-3-carboxylic acid (126 mg, 1 mmol) and 5,6-diamino-1-isopropyl-1,3-dihydro-benzimidazol-2-one (206 mg, 1 mmol) were added to polyphosphoric acid ( 5 g) and phosphorus pentoxide (500 mg, 3.5 mmol) was heated at 160 ° C. for 6 hours. The mixture was poured into water (20 ml) and kept stirring until a precipitate formed. After filtration, the crude product was suspended in water and neutralized by the addition of aqueous ammonia (25%). The precipitate was collected, washed with water and dried in vacuo. Purification was achieved by chromatography on silica (dichloromethane / methanol 95: 5) to give 1-isopropyl-6- (5-methyl-1H-pyrazol-3yl) -3,5-dihydro-1H as a pale yellow solid -Benzo [1,2-d; 4,5-d '] diimidazol-2-one was obtained. Yield 36 mg (12%).
Using the previously reported experimental conditions and appropriate starting materials, the following derivatives 1-43 were prepared:

Example 44:
5-Ethyl-2- (5-methoxy-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indole-6-one
5-Methoxy-1H-pyrazole-3-carboxylic acid (86 mg, 0.61 mmol), 1-hydroxybenzotriazole hydrate (111 mg, 0.73 mmol), and triethylamine (253 μl, 184 mg, 1.82 mmol) were added to N, N— After dissolving in dimethylformamide (DMF) (2 ml) and adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (139 mg, 0.73 mmol) in DMF (2 ml), The reaction mixture was stirred at room temperature. After 1 hour, a solution of 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one in DMF (2 ml) was added and the reaction mixture was allowed to cool at room temperature. Stir for 16 hours. The solvent was removed under reduced pressure and the residue was quenched with water (20 ml) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (15 ml), dried over sodium sulfate and evaporated. The residue was dissolved in ethanol (5 ml) and after adding hydrochloric acid (10M, 2 ml) it was stirred at reflux for 2 hours. Ethanol was distilled off and the residue was adjusted to pH 9-10 with ammonium hydroxide. After adding water (20 ml), the aqueous phase was extracted with ethyl acetate (3 × 20 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and evaporated. The crude product was purified by column chromatography on silica gel. Elution with ethyl acetate / n-heptane (9: 1) gave 56 mg (28%) off-white solid.

Example 45:
5-ethyl-7,7-dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indole-6-one hydrazine Hydrate (0.92 g, 1.8 mmol) was dissolved in acetonitrile (15 mL) in 2- (3,3-bis-methylsulfanyl-acryloyl) -5-ethyl-7,7-dimethyl-1- (tetrahydro-pyran- 2-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one (0.68 g, 1.81 mmol) was added to a suspension and stirred for 24 hours. After cooling to room temperature, the precipitate was collected and washed with acetonitrile and ether to give 0.5 g (81%) of a pale white powder.

Claims (12)

Formula I:

{Where,
R ¹ is hydrogen, alkyl, or —C (O) -alkyl;
R ² is hydrogen, alkyl, cyano, or halogen;
R ³ is hydrogen, alkyl, (C ₃ -C ₆ ) -cycloalkyl, alkoxy, or alkylsulfanyl:
X is —C (O) — or —CH ₂ —;
Y is —NH—, —CH ₂ —CR ⁴ R ⁵ —, —CR ⁴ R ⁵ —CH ₂ —, or —CR ⁴ R ⁵ —, where
R ⁴ is hydrogen or alkyl; and
R ⁵ is hydrogen or alkyl; or
R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl ring. }
And the pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of cancer. R ³ is hydrogen, alkyl, or (C ₃ -C ₆₎ - cycloalkyl, a compound of formula I according to claim 1, for the manufacture of a medicament for the treatment of cancer. X is, -CH ₂ - which is, of a compound of formula I according to claim 1 or 2, for the manufacture of a medicament for the treatment of cancer.   Use of a compound of formula I according to claim 1 or 2 wherein X is -C (O)-for the manufacture of a medicament for the treatment of cancer. 7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -3,5,6,7-tetrahydro-imidazo [4,5-f] indole;
1- [7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -6,7-dihydro-3H-imidazo [4,5-f] indol-5-yl] -ethanone;
8,8-dimethyl-2- (5-methyl-1H-pyrazol-3-yl) -1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
2- (5-isobutyl-2H-pyrazol-3-yl) -8,8-dimethyl-1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-isobutyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-methyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -one;
2- (5-isobutyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -one;
6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one;
2- (4,5-dimethyl-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-2- [5- (3-methyl-butyl) -1H-pyrazol-3-yl] -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-ethyl-4-methyl-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-2- (1H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-cyclopropyl-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-isopropyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
8,8-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
8,8-dimethyl-2- (1H-pyrazol-3-yl) -1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
2- (5-cyclopropyl-1H-pyrazol-3-yl) -8,8-dimethyl-1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
2- (5-isopropyl-2H-pyrazol-3-yl) -8,8-dimethyl-1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-6-one;
2- (2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -one;
2- (5-isopropyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -one;
2- (5-propyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ′, 7-imidazo [4,5-f] indole] -6 (3H) -one;
7,7-dimethyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
2- (5-Cyclopropyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [cyclopentane-1 ', 7-imidazo [4,5-f] indole] -6 (3H) -one .
3-methyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one;
3-isopropyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one;
5-ethyl-7,7-dimethyl-2- (5-methyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-2- (5-isobutyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
2- (5-isobutyl-2H-pyrazol-3-yl) -5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-methyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one; Accompanying compounds;
5-isopropyl-7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
5-isopropyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -5-propyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-5-propyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] -indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-trifluoromethyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-isopropyl-7,7-dimethyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-5-propyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-2- (5-methoxy-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one; and
5-ethyl-7,7-dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indole-6-one,
Use of a compound of formula I according to claim 1 selected from the group consisting of for the manufacture of a medicament for the treatment of cancer. Formula I:

{Where,
R ¹ is alkyl or —C (O) -alkyl;
R ² is hydrogen, alkyl, cyano, or halogen;
R ³ is hydrogen, alkyl, (C ₃ -C ₆ ) -cycloalkyl, alkoxy, or alkylsulfanyl:
X is —C (O) — or —CH ₂ —;
Y is —NH—, —CH ₂ —CR ⁴ R ⁵ —, —CR ⁴ R ⁵ —CH ₂ —, or —CR ⁴ R ⁵ —, where
R ⁴ is hydrogen or alkyl; and
R ⁵ is hydrogen or alkyl; or
R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl ring. }
And all pharmaceutically acceptable salts thereof. 5-ethyl-7,7-dimethyl-2- (5-methyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-2- (5-isobutyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
2- (5-isobutyl-2H-pyrazol-3-yl) -5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-methyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one; Accompanying compounds;
5-isopropyl-7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
5-isopropyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -5-propyl-5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-5-propyl-2- (5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-trifluoromethyl-1H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-isopropyl-7,7-dimethyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
7,7-dimethyl-5-propyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
5,7,7-trimethyl-2- (5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-2- (5-methoxy-1H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-imidazo [4,5-f] indol-6-one;
5-ethyl-7,7-dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -5,7-dihydro-1H-imidazo [4,5-f] indol-6-one;
3-methyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one;
3-isopropyl-6- (5-methyl-1H-pyrazol-3-yl) -3,5-dihydro-1H-benzo [1,2-d; 4,5-d ′] diimidazol-2-one;
1- [7,7-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -6,7-dihydro-3H-imidazo [4,5-f] indol-5-yl] -ethanone,
7. A compound according to claim 6 selected from the group consisting of: R ¹ is alkyl;
R ² is hydrogen or alkyl;
X is -C (O)-; and
The compound according to claim 6, wherein Y is -CR ⁴ R ^5- . R ¹ is alkyl;
R ² is hydrogen or alkyl;
R ³ is hydrogen, alkyl, or (C ₃ -C ₆ ) -cycloalkyl;
X is -C (O)-; and
Y is -CR ⁴ R ^5-
7. A compound according to claim 6. a) Formula II:

A compound of formula (wherein R ¹ is alkyl or —C (O) -alkyl, and X and Y have the meanings given above for formula I) is represented by formula III:

Reacting with a compound of formula I: wherein A is —OH, —Cl, —H, or —OMe, and R ² and R ³ have the meanings described above for I,

Wherein R ¹ is alkyl or —C (O) -alkyl, and R ² , R ³ , X, and Y have the meanings described above for Formula I,
b) isolating the compound of formula I described above from the reaction mixture;
Converting it to a pharmaceutically acceptable salt, if necessary,
A process for the preparation of compounds of formula I wherein R ¹ is alkyl or —C (O) -alkyl.   A medicinal product comprising one or more compounds according to any one of claims 6 to 9 as an active ingredient together with a pharmaceutically acceptable adjuvant.   A medicament for the treatment of cancer comprising one or more compounds according to any one of claims 6 to 9 as active ingredients together with a pharmaceutically acceptable adjuvant.