# US 8,541,575 B2 · 3,4-diarylpyrazoles as protein kinase inhibitors

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- Number: US 8,541,575 B2
- Document ID: US8541575B2
- Status: Granted
- Kind: B2
- Application number: 13/054,853
- Filed: 2009-07-23
- Published: 2011-06-16
- Granted: 2013-09-24
- Earliest claimed: 2008-07-24
- Assignees: Nerviano Medical Sciences S.R.L.
- Applicants: Maurizio Pulici; Fabio Zuccotto; Alessandra Badari; Stefano Nuvoloni; Giovanni Cervi; Gabriella Traquandi; Sonia Biondaro; Paolo Trifiro'; Chiara Marchionni; Michele Modugno
- Inventors: Maurizio Pulici; Fabio Zuccotto; Alessandra Badari; Stefano Nuvoloni; Giovanni Cervi; Gabriella Traquandi; Sonia Biondaro; Paolo Trifiro'; Chiara Marchionni; Michele Modugno
- Web page: https://patentgrep.com/patent/US8541575B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- 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 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 407/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 513/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

3,4-diarylpyrazole derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

## Claims

### Claim 1

A compound of formula (I):
wherein:
m is an integer from0 to 6;
R1 is hydrogen, trichloromethyl, trifluoromethyl, halogen, cyano, OH, OR8, NR9R10, NR21COR22, COOH, COOR11, CONR12R13, or a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, heterocyclyl, aryl and heteroaryl, wherein:
R8 and R11 are each independently a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C3-C8) cycloalkyl, heterocyclyl, aryl and heteroaryl;
R9, R10, R12 and R13 the same or different, are each independently hydrogen or a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C3-C8) cycloalkyl, heterocyclyl, aryl and heteroaryl, or taken together with the nitrogen atom to which they are bonded either R9 and R10 as well as R12 and R13 may form an optionally substituted heterocyclyl or heteroaryl, optionally containing one additional heteroatom or heteroatomic group selected from S, O, N or NH;
R21 and R22 the same or different, are each independently hydrogen or a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C3-C8) cycloalkyl, heterocyclyl, aryl and heteroaryl, or taken together with the atoms to which they are bonded R21 and R22 may form an optionally substituted heterocyclyl, optionally containing one additional heteroatom or heteroatomic group selected from S, O, N or NH;
X is —CH or N;
R2 is hydrogen, halogen, NR14R15, SR23 or SO2R23, wherein:
R14 and R15 are independently hydrogen or a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C3-C8) cycloalkyl, heterocyclyl, aryl and heteroaryl; or taken together with the nitrogen atom to which they are bonded R14 and R15 may form an optionally substituted 3 to 8 membered heterocyclyl or heteroaryl, optionally containing one additional heteroatom or heteroatomic group selected from S, O, N or NH; or R14 is hydrogen and R15 is COR 16,
wherein:
R16 is OR17, NR18R19 or a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cylcoalkenyl, heterocyclyl, aryl and heteroaryl, wherein:
R17 is a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C3-C8) cycloalkyl, heterocyclyl, aryl and heteroaryl;
R18 and R19 are each independently a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C3-C8) cycloalkyl, heterocyclyl, aryl and heteroaryl, or taken together with the nitrogen atom to which they are bonded R18 and R19 may form an optionally substituted 3 to 8 membered heterocyclyl or heteroaryl, optionally containing one additional heteroatom or heteroatomic group selected from S, O, N or NH;
R23 is a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C3-C8) cycloalkyl, heterocyclyl, aryl and heteroaryl;
R3, R4, R5 and R6 are each independently hydrogen, halogen, trifluoromethyl, trichloromethyl, cyano, OR20 or a group optionally substituted selected from straight or branched (C1-C8) alkyl, and (C3-C8) cycloalkyl, wherein:
R20 is a group optionally substituted selected from straight or branched (C1-C8) alkyl and (C3-C8) cycloalkyl ;
A is —CON(Y)—, —CON(Y)O—, —CON(Y)N(Y)—, —CON(Y)SO2—, —SO2N(Y)—, —SO2N(Y)O—, —SO2N(Y)N(Y)—, —SO2N(Y)CO—, —SO2N(Y)CON(Y)—, —SO2N(Y)SO2—, —N(Y)CO—, —N(Y)SO2—, —N(Y)CON(Y)—, —N(Y)CSN(Y)—, —N(Y)CON(Y)N(Y)—, —N(Y)COO—, —N(Y)CON(Y)SO2—, —N(Y)SO2N(Y)—, —C(R′R″)CON(Y)—, —C(R′R″)CSN(Y)—, —C(R′R″)CON(Y)O—, —C(R′R″)CON(Y)N(Y)—, —C(R′R″)CON(Y)SO2—, —C(R′R″)SO2N(Y)—, —C(R′R″)SO2N(Y)O—, —C(R′R″)SO2N(Y)N(Y)—, —C(R′R″)SO2N(Y)CO—, —C(R′R″)SO2N(Y)SO2—, —C(R′R″)N(Y)CO, —C(R′R″)N(Y)SO2—, —C(R′R″)N(Y)CON(Y)—, —C(R′R″)N(Y)CSN(Y)—, —C(R′R″)N(Y)COO—, —C(R′R″)N(Y)SO2N(Y)—or —N(Y)C(R′R″)—, wherein:
Y is hydrogen or an optionally substituted straight or branched (C1-C3) alkyl;
and R′ and R″ are independently hydrogen or an optionally further substituted straight or branched (C1-C6) alkyl, or taken together with the carbon atom to which they are bonded R′ and R″ may form an optionally substituted (C3-C8) cycloalkyl;
R7 is hydrogen or an optionally substituted group selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl, or (C3-C8) cycloalkyl, (C2-C8) alkynyl, (C3-C8) cylcoalkenyl, heterocyclyl, aryl and heteroaryl;
or a pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

A compound of formula (I) as defined in claim 1 wherein:
m is an integer from 0 to 2; or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound of formula (I) as defined in claim 1 wherein:
A is —CON(Y)—, —CON(Y)O—, —CON(Y)N(Y)—, —CON(Y)SO2—, —SO2N(Y)—, —N(Y)CO—, —N(Y)SO2—, —N(Y)CON(Y)—, —N(Y)CSN(Y)—, —N(Y)COO—, —C(R′R″)CON(Y)—, —C(R′R″)N(Y)CO, —C(R′R″)N(Y)CON(Y)—,
wherein:
Y, R′ and R″ are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

A compound of formula (I) as defined in claim 1 wherein:
R1 is hydrogen, trichloromethyl, trifluoromethyl, halogen, cyano, OH, OR8, NR9R10, CONR12R13, or a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, heterocyclyl, aryl and heteroaryl, wherein:
R8, R9, R10, R12 and R13 are as defined in claim 1; or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 3)

A compound of formula (I) as defined in claim 3, wherein:
R1 is hydrogen, trichloromethyl, trifluoromethyl, halogen and cyano; or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 3)

A compound of formula (I) as defined in claim 3 wherein:
R2 is hydrogen or NR14R15, wherein:
R14 and R15 are independently hydrogen or a group optionally substituted selected from straight or branched (C1-C8) alkyl, (C3-C8) cycloalkyl, heterocyclyl, aryl and heteroaryl; or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 6)

A compound of formula (I) as defined in claim 6 wherein:
R3, R4, R5 and R6 are each independently hydrogen, halogen, trifluoromethyl, trichloromethyl or cyano; or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

A compound of formula (I) as defined in claim 1 wherein:
R7 is an optionally substituted group selected from straight or branched (C1-C8) alkyl, (C3-C8) cylcoalkyl, (C3-C8) cycloalkenyl, heterocyclyl, aryl and heteroaryl; or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 which is selected from the group consisting of:
1-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea, 2,5-difluoro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide, N-(4-chloro-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide,
N-(4-tert-Butyl-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide,
1-(4-chloro-3-trifluoromethyl-phenyl)-3-{3-[1-(2-fluoro-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-urea,
furan-2-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,
thiophene-3-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,
1-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-p-tolyl-urea,
1-(4-chloro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,
1-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,
1-[3-(1-cyanomethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,
1-{3-[4-(2-amino-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,
1-{3-[1-(2-fluoro-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,
1-{3-[1-(2-hydroxy-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,
1-{3-(1-piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,
N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide,
N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-acetamide,
N-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,
thiophene-3-sulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,
furan-2-sulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,
propane-1-sulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,
1-(4-tert-butyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,
1-[4-(cyano-dimethyl-methyl)-phenyl]-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,
1-[2-ffluoro-5-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,
1-(2-fluoro-4-trifluoromethyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,
cyclopropanesulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,
2,2,2-trifluoro-ethanesulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,
N-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-trifluoro-methanesulfonamide,
cyclohexanesulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,
1-[3-(4-pyrimidin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,
1-{3-[4-(2-amino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,
N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)- pyrimidin-2-yl]-acetamide,
2,5-difluoro-N-[3-(4-pyrimidin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide,
N-{3-[4-(2-amino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,
N-(4-{3-[3(2,5-difluoro-benzenesulfonylamino)-phenyl]-1H-pyrazol-4-yl}-pyrimidin-2-yl)-acetamide,
N-[2,4-difluoro-3-(4-pyrimidin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,
N-{3-[4-(2-amino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,
N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-1H-pyrazol-4-yl}-pyrimidin-2-yl)-acetamide,
N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-propionamide,
N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-isobutyramide,
cyclopentanecarboxylic acid[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-amide,
2-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-N-(4-trifluoromethyl-phenyl)-acetamide,
4-hydroxy-N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-butyramide,
N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-phenyl]-1H-pyrazol-4-yl}-pyridin-2-yl)-acetamide,
N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-1H-pyrazol-4-yl}-pyridin-2-yl)-acetamide,
3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-N-(4-trifluoromethyl-phenyl)-benzamide,
4-pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazole-1-carboxylic acid ethyl ester
1-[3-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifuoromethyl-phenyl)-urea,
1-[3-(1-butyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifuoromethyl-phenyl)-urea,
1-[3-(1-Isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,
N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide,
N-[2,4-difluoro-3-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,
N-{2,4-difluoro-3-[4-(2-methylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,
N-{3-[4-(2-ethylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,
N-{3-[4-(2-ethylamino-pyrimidin-4-yl)-1H-pyrazol3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,
N-[2,4-difluoro-3-(1-isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,
N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide,
N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide,
N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-4-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide,
N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide,
N-{3-[4-(2-amino-pyrimidin-4-yl)-1-ethyl-1H-pyrazol3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,
N-{2,4-difluoro-3-[1-(2-piperidin-1-yl-ethyl)-4-pyridin-4-yl-1H-pyrazol3-yl]-phenyl}-2,5-difluoro-enzenesulfonamide,
N-{2,4-difluoro-3-[1-(2-morpholin-4-yl-ethyl)-4-pyridin-4-yl-1H-pyrazol3-yl]-phenyl}-2,5-difluoro-enzenesulfonamide,
N-(2,4-difluoro-3-{1-[2-(4-methyl-piperazin-1-yl)-ethyl]-4-pyridin-4-yl-1H-pyrazol-3-yl}-phenyl)-2,5-difluoro-benzenesulfonamide,
N-{3-[1-(2-dimethylamino-ethyl)-4-pyridin-4-yl-1H-pyrazol3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,
(2,5-difluoro-benzyl)-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-amine,
4-{3-[3-(2,5-difluoro-benzyloxy)-2,6-difluoro-phenyl]-1-ethyl-1H-pyrazol4-yl}-pyridine and
N-{3-[4-(2-Amino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide.

### Claim 10 (depends on 1)

A method for treating a disease caused by and/or associated with a deregulated protein kinase activity which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

### Claim 11 (depends on 10)

The method according to claim 10 for treating a disease caused by and/or associated with a deregulated Raf family kinase activity.

### Claim 12 (depends on 10)

The method according to claim 10 wherein the disease is selected from the group consisting of cancer and cell proliferative disorders.

### Claim 13 (depends on 12)

The method according to claim 12 wherein the cancer is selected from the group consisting of carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage including leukaemia, acute lymphocitic leukaemia, acute lymphoblastic leukaemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukaemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.

### Claim 14 (depends on 12)

The method according to claim 12 wherein the cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis.

### Claim 15 (depends on 10)

The method according to claim 10 further comprising subjecting the mammal in need thereof to a radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.

### Claim 16 (depends on 10)

The method according to claim 10 wherein the mammal in need thereof is a human.

### Claim 17 (depends on 1)

An in vitro method for inhibiting the RAF family activity which comprises contacting the said receptor with an effective amount of a compound as defined in claim 1.

### Claim 18 (depends on 10)

The method according to claim 10 which provides tumor angiogenesis and metastasis inhibition.

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 19)

A pharmaceutical composition according to claim 19 further comprising one or more chemotherapeutic agents.

### Claim 21 (depends on 1)

A product or kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, or a pharmaceutical compositions comprising a therapeutically effective amount of a compound accordinq to claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, carrier or diluent, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.