# US 8,772,280 B2 · N-aryl-2-(2-arylaminopyrimidin-4-yl)pyrrol-4-carboxamide derivatives as MPS1 kinase inhibitors

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- Number: US 8,772,280 B2
- Document ID: US8772280B2
- Status: Granted
- Kind: B2
- Application number: 13/260,665
- Filed: 2010-03-23
- Published: 2012-03-15
- Granted: 2014-07-08
- Earliest claimed: 2009-03-27
- Assignees: Nerviano Medical Sciences S.R.L.
- Applicants: Marina Caldarelli; Stefano Adele Nuvoloni; Francesca Quartieri
- Inventors: Marina Caldarelli; Stefano Adele Nuvoloni; Francesca Quartieri
- Web page: https://patentgrep.com/patent/US8772280B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to substituted pyrrolyl-pyrimidines which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular MPS1. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such these compounds or the pharmaceutical compositions containing them.

## Claims

### Claim 1

A compound of the formula (I):
wherein
R1 is a phenyl group;
R2 is hydrogen atom or straight or branched C1-C6 alkyl;
R3 is an aryl group;
R4 is hydrogen atom;
R5 and R7 are each independently hydrogen or halogen atom;
R6 is hydrogen, halogen atom or a C1-C6 alkyl group;
wherein the groups phenyl, aryl and straight or branched C1-C6 alkyl may be optionally substituted,
provided that the compound 1-methyl-5-{2-[4-(1-methyl-piperidin-4-ylcarbamoyl)-2-trifluoromethoxy-phenylamino]-pyrimidin-4-yl}-1H-pyrrole-3-carboxylic acid o-tolylamide is excluded;
and stereoisomers, tautomers, hydrates, solvates, N-oxides and pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

A compound of formula (I) according to claim 1 wherein R1 is a phenyl of the formula:
wherein R′4, R″4 and R′″4 are independently hydrogen or halogen atom, or nitro, cyano, C1-C6 alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl, alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, C3-C6 cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkylideneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfony, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonate or alkylphosphonate group.

### Claim 3 (depends on 2)

A compound of formula (I) according to claim 2 wherein R′4 is not hydrogen atom.

### Claim 4 (depends on 1)

A compound according to claim 1 of formula (Ia):
wherein
R6 is hydrogen, halogen atom or a methyl group, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A compound of formula (I) according to claim 1 which is selected from:
5-[2-(4-Carbamoyl-2-methyl-phenylamino)-pyrimidin-4-yl]-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
1-Methyl-5-{2-[4-(1 -methyl-piperidin-4-ylcarbamoyl)-2-trifluoromethoxy-phenylamino]-pyrimidin-4-yl}-1H-pyrrole-3-carboxylic acid phenylamide;
5-[2-(4-tert-Butoxycarbonyl-2-methyl-phenylamino)-pyrimidin-4-yl]-1-methyl-1H-pyrrole-3-carboxylic acid ethyl ester;
5-{2-[4-(2,6-Diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
4-{4-[4-(2,6-Diethyl-phenylcarbamoyl)-1-methyl-1H-pyrrol-2-yl]-pyrimidin-2-ylamino}-3-methyl-benzoic acid;
2-Chloro-5-{2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
2-Chloro-5-{2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
2-Chloro-5-{5-chloro-2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
2-Bromo-5-{2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{5-Bromo-2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
2-Bromo-5-{5-bromo-2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-[2-(4-Dimethylcarbamoyl-2-methyl-phenylamino)-pyrimidin-4-yl]-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
1-Methyl-5-[2-(2-methyl-4-methylcarbamoyl-phenylamino)-pyrimidin-4-yl]1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[4-(2-Dimethylamino-ethylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[4-(4-Dimethylamino-piperidine-1-carbonyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
1-Methyl-5-{2-[2-methyl-4-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenylamino]-pyrimidin-4-yl}1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-[2-(4-Carbamoyl-2-methyl-phenylamino)-pyrimidin-4-yl]-2-chloro-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-[2-(4-Carbamoyl-2-methyl-phenylamino)-5-chloro-pyrimidin-4-yl]-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-[2-(4-Carbamoyl-2-methyl-phenylamino)-5-chloro-pyrimidin-4-yl]-2-chloro-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-[2-(4-Carbamoyl-2-methyl-phenylamino)-pyrimidin-4-yl]-4-chloro-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-[2-(4-Bromo-2-methoxy-phenylamino)-pyrimidin-4-yl]-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[4-(4-Dimethylamino-piperidin-1-yl)-2-methoxy-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-[2-(2-Methoxy-phenylamino)-pyrimidin-4-yl]-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-[1,4]diazepan-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
4-{4-[4-(2,6-Diethyl-phenylcarbamoyl)-1-methyl-1H-pyrrol-2-yl]-5-methyl-pyrimidin-2- ylamino}-3-methyl-benzoic acid tert-butyl ester;
5-(2-{4-[(2-Dimethylamino-ethyl)-methyl-amino]-2-methoxy-phenylamino}-pyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
4-{4-[4-(2,6-Diethyl-phenylcarbamoyl)-1-methyl- 1H-pyrrol-2-yl]-5-methyl-pyrimidin-2-ylamino}-3-methyl-benzoic acid;
5-[2-(4-Carbamoyl-2-methyl-phenylamino)-5-methyl-pyrimidin-4-yl]-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[4-(4-Dimethylamino-piperidine-l-carbonyl)-2-methyl-phenylamino]-5-methyl-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-(2-{4-[(3-Dimethylamino-propyl)-methyl-amino]-2-methoxy-phenylamino}-pyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-[2-(4-Bromo-2-methoxy-phenylamino)-5-chloro-pyrimidin-4-yl]-1-(2,2,2-trifluoro-ethyl)-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
1-(2-Fluoro-ethyl)-5-{2-[2-methoxy-4-(4-methyl-piperazin-l-yl)-phenylamino]-pyrimidin-4-yl}-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{5-Bromo-2-[2-methoxy-4-(4-methyl-piperazin-l-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-(2-{4-[4-(2-Hydroxy-ethyl)-piperazin-l-yl]-2-methoxy-phenylamino}-pyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2-chloro-6-methyl-phenyl)-amide;
5-[2-(4-Bromo-2-methyl-phenylamino)-pyrimidin-4-yl]-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
1-Methyl-5-{2-[2-methyl-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[4-(4-Dimethylamino-piperidin-1-yl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
1-Methyl-5-(2-o-tolylamino-pyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-dimethyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2-ethyl-6-methyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2-methoxy-6-methyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2-bromo-6-methyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-difluoro-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,4,6-trimethyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1 -yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,4-dimethyl-pyridin-3-yl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1 -yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (4-bromo-2-chloro-6-methyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1 -yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (4-bromo-2,6-diethyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1 -yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (3-chloro-2,6-diethyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1 -yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-4-methyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(4-pyrrolidin-1 -yl-piperidin-1 -yl)-phenylamino]-pyrimidin-4-yl}1 -1 -methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[2-Methoxy-4-(1 -methyl-piperidin-4-ylamino)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide;
5-{2-[4-(2-Dimethylamino-ethylamino)-2-methoxy-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide and 1-Methyl-5-{2-[4-(1 -methyl-piperidin-4-ylcarbamoyl)-2-trifluoromethoxy-phenylamino]-pyrimidin-4-yl}-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide.

### Claim 6 (depends on 1)

A process for preparing a compound of formula (I) or the pharmaceutically acceptable salts thereof, as defined in claim 1, which process comprises:
st.A1) reacting a compound of the formula (II):
with a base in a C1-C4 alcohol;
st.A2) reacting the resultant compound of formula (IV):
with dimethylformamide-di-tert-butylacetale, dimethylformamide-diisopropylacetale or dimethylformamide-diethylacetale;
optionally converting the resultant compound of the formula (VI):
wherein R2 is H, by means of alkylation with a compound of the formula (V):
R2—Y (V)
wherein Y is a suitable leaving group, or halogen atom, and R2 is as defined in claim 1 but not hydrogen, into a compound of the formula (VI) wherein R2 is not hydrogen atom;
st.A3) reacting the compound of the formula (VI) as defined above according to any one of the following alternative steps (st.A3a), (st.A3b) or (st. A3c):
st.A3a) either with guanidine, and then reacting the resultant compound of the formula (VII):
wherein R2 is as defined above, with iso-amylnitrite and diiodomethane or cesium iodide, in the presence of iodine and CuI and then reacting the resultant compound of the formula (VIII):
wherein R2 is as defined above with a compound of formula (IX): R1—NH2 wherein R1 is as defined in claim 1;
st.A3b) or with a guanidine derivative of formula (XI):
wherein R1 is as defined above;
st.A3c) or with guanidine, and then reacting the resultant compound of the formula (VII) as defined above with a compound of the formula (XII): R1—I wherein R1 is as defined above;
st.A4) reacting the resultant compound of the formula (X):
wherein R1 and R2 are as defined above in acidic or basic condition;
st.A5) reacting the resultant compound of the formula (XIII) or a salt thereof:
wherein R1 and R2 are as defined above, with an amine of the formula (XIV):
R3—NH—R4 (XIV)
wherein R3 and R4 are as defined in claim 1, in presence of the suitable condensing agents; and
optionally converting the resultant compound of the formula (I):
wherein R1, R2, R3 and R4 are as defined above and R5, R6 and R7 are hydrogen atoms, into a compound of the formula (I), wherein not all of R5 R6 and R7 are hydrogen atoms; and,
if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into the free compound (I).

### Claim 7 (depends on 1)

A process for preparing a compound of formula (I) or the pharmaceutically acceptable salts thereof, as defined in claim 1, which process comprises:
either
st.D1) reacting a compound of formula (XVIII):
wherein R2, R3 and R4 are as defined in claim 1, with a compound of the formula (XII) R1—I wherein R1 is as defined in claim 1,
or
st.F1) reacting a compound of formula (VII):
wherein R2 is as defined in claim 1 but not hydrogen, with an amine of formula (XIV), R3—NH—R4,
wherein R3 and R4 are as defined in claim 1, in presence of a strong base;
then reacting the resultant compound of the formula (XVIII) as defined above with iso-amylnitrite and diiodomethane or cesium iodide, in the presence of iodine and CuI; finally reacting the resultant compound of the formula (XVI):
wherein R2, R3 and R4 are as defined above, with an arylamine of formula (IX): R1—NH2
wherein R1 is as defined in claim 1;
and optionally converting the resultant compound of the formula (I) as defined above wherein R5, R6 and R7 are hydrogen atoms, into a compound of the formula (I), wherein not all of R5, R6 and R7 are hydrogen atoms; and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into the free compound (I).

### Claim 8 (depends on 1)

A process for preparing a compound of formula (I) as defined in claim 1, characterized in that the conversion of a compound of formula (I) into another compound of formula (I) is carried out with one of the following methods:
conv.b and c) converting a compound of formula (I) wherein R2 is hydrogen and R1, R3, R4, R5 and R6 are as defined in claim 1 into a compound of formula (I) wherein R2 is not hydrogen by reaction either with a compound of the formula (V),
or with an alcohol of formula R2—OH (XIX) wherein R2 is as defined above but not hydrogen;
conv.d) converting a compound of the formula (Ia) wherein one of R′4, R″4 or R′″4 is Br, into a compound of formula (Ia) wherein one of R′4, R″4 or R′″4 is a group of the formula —NR8R9 wherein R8 and R9 are each independently selected from a group consisting of: hydrogen atom, C1-C6 alkyl, polyfluorinated alkyl, alkenyl, alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, C3-C6 cycloalkyl, alkylamino, arylamino, heterocyclylamino, by treatment with an amine of the formula R8R9—NH (XV), wherein R8 and R9 are as defined above;
conv.e) converting a compound of formula (Ia) wherein one of R′4, R″4 or R′″4 is a nitro group into a compound of formula (Ia) wherein one of R′4, R″4 or R′″4, is an amino group (—NH2), by conventional methods of reduction;
conv. f) converting a compound of formula (Ia) wherein one of R′4, R″4 or R′″4 is an amino group (—NH2), into a compound of formula (Ia) wherein one of R′4, R″4 or R′″4 is a group—NHCOR10, wherein R10 is selected from a group consisting of: C1-C6 alkyl, polyfluorinated alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, C3-C6 cycloalkyl, alkylamino, arylamino, heterocyclylamino, by treatment with an acid of the formula R10—COOH (XX), wherein R10 is as defined above, in the presence of suitable condensing agents;
conv.g) converting a compound of formula (Ia) wherein one of R′4, R″4 or R′″4 is t-butyloxycarbonyl in acidic condition, into a compound of formula (Ia) wherein one of R′4, R″4 or R′″4 is —COOH;
conv.h) converting a compound of formula (Ia) wherein one of R′4, R″4 or R′″4 is COOH, into a compound of formula (Ia) wherein one of R′4, R″4 or R′″4 is a group
—CONR8R9 wherein R8 and R9 are as defined above, by treatment with an amine of the formula (XV) as defined above in the presence of the suitable condensing agents;
conv.i) converting a compound of formula (I) wherein R5, R6 and R7 are hydrogen atoms into a compound of formula (I) wherein one or more of R5, R6 and R7 are halogen atoms, by reaction with N-halogen-succinimide;
conv.l) converting a compound of formula (I) wherein one or more of R5, R6 and R7 are halogen into a compound of formula (I) wherein one or more of R5, R6 and R7 are a C1—C6 alkyl group, by treatment with a suitable organo metallic compound.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), as defined in claim 1, and at least one pharmaceutically acceptable carrier or diluent.

### Claim 10 (depends on 9)

A pharmaceutical composition according to claim 9 further comprising one or more chemotherapeutic agents.

### Claim 11 (depends on 1, 11)

A product comprising a compound of formula (I) as defined in claim 1 or a pharmaceutical composition thereof as defined in claim 11, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

### Claim 12 (depends on 1)

A compound of formula (I), as defined in claim 1, for use as a medicament.

### Claim 13 (depends on 1)

An in vitro method for inhibiting protein kinase activity, wherein the protein kinase is selected from the group consisting of human MPS1(TTK), PLK family members, protein kinase C in different isoforms, Met, PAK-4, PAK-5, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, Chk1, Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, PI3K, weel kinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, and Nek, which comprises contacting the kinase with an effective amount of a compound of formula (I) as defined in claim 1.