SUBSTITUTED AMIDO PHENOXYBENZAMIDES

1 . A compound of general formula (I):

in which:

A is a ring which is aryl or heteroaryl;

R1 is selected from the group comprising, preferably consisting of, a halogen atom, cyclopropyl, —CF 3 or —C≡C—H;

R2 is selected from the group comprising, preferably consisting of, a hydrogen atom, a halogen atom, alkyl or cyclopropyl;

R3 is selected from the group comprising, preferably consisting of, a hydrogen atom, alkyl, cycloalkyl or heterocycloalkyl, wherein alkyl is optionally substituted one or more times, independently from each other, with hydroxyl, —NR b1 R b2 , heterocycloalkyl, a halogen atom, cyano or alkoxy;

R4 is a halogen atom or cyano;

R5 is a hydrogen atom or alkyl, wherein alkyl is optionally substituted with hydroxyl, cyano or an amino group;

R6 is alkyl or heterocycloalkyl, wherein alkyl is substituted one or more times, independently from each other, with a group selected from hydroxyl, a halogen atom, alkoxy, cyano, haloalkoxy, thioalkyl, heterocycloalkyl, cycloalkyl, NR b1 R b2 , NH—C(O)R c , —C(O)OR c , —C(O)NH 2 , —C(O)NHR c , —C(O)N(R c ) 2 or —S(O) 2 R c ; or

R6 is a moiety selected from the group comprising, preferably consisting of, —O—, —C(O)—, —CH 2 —, —N(R a )—, —N(R a )—C(O)—, —O—C(O)—, and —N(R a )—CH 2 —, said moiety being bound directly to the above-mentioned ring A, thus forming a ring fused to said ring A;

R7 is selected from the group comprising, preferably consisting of, a hydrogen atom, a halogen atom, cyano, alkyl, cycloalkyl, heterocycloalkyl;

R8 and R9 independently from each other are a hydrogen atom or a halogen atom;

R a is a hydrogen atom or C 1 -C 6 -alkyl;

R b1 and R b2 independently from each other are selected from the group comprising, preferably consisting of a hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl; or

R b1 and R b2 together with the nitrogen atom to which they are attached, form a 3 to 7 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with alkyl, a halogen atom, haloalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, alkoxy, hydroxy; the carbon backbone of said heterocycloalkyl ring being optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NR b3 , an oxygen or sulphur atom, and being optionally interrupted one or more times, the same way or differently, with a —C(O)—, —S(O)—, and/or —S(O) 2 — group, and optionally containing one or more double bonds;

R b3 is selected from the group comprising, preferably consisting of a hydrogen atom, alkyl, cycloalkyl, wherein C 1 -C 6 -alkyl is optionally substituted one or more times with cycloalkyl, hydroxyl, a halogen atom, haloalkyl or alkoxy;

R c is alkyl or cycloalkyl; and

n is an integer of 0, 1 or 2.

2 . The compound according to claim 1 , wherein:

A is an aryl ring;

R1 is a halogen atom or —C≡C—H;

R2 is a halogen atom or methyl;

R3 is a hydrogen atom;

R4 is a halogen atom;

R5 is a hydrogen atom;

R6 is alkyl or heterocycloalkyl, wherein alkyl is substituted one or more times, independently from each other, with a group selected from hydroxyl, a halogen atom, alkoxy, cyano, haloalkoxy, thioalkyl, heterocycloalkyl, cycloalkyl, NR b1 R b2 , NH—C(O)R c , —C(O)OR c , —C(O)NH 2 , —C(O)NHR c , —C(O)N(R c ) 2 or —S(O) 2 R c ; or

R6 is a —O— moiety, said moiety being bound directly to the above-mentioned ring A, thus forming a ring fused to said ring A;

R7 is selected from the group comprising, preferably consisting of, a hydrogen atom, a halogen atom, alkyl;

R8 and R9 independently from each other are a hydrogen atom or a halogen atom;

R b1 and R b2 independently from each other are selected from the group comprising, preferably consisting of a hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl; or

R b1 and R b2 together with the nitrogen atom to which they are attached, form a 3 to 7 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with alkyl, a halogen atom, haloalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, alkoxy, hydroxy; the carbon backbone of said heterocycloalkyl ring being optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NR b3 , an oxygen or sulphur atom, and being optionally interrupted one or more times, the same way or differently, with a —C(O)—, —S(O)—, and/or —S(O) 2 — group, and optionally containing one or more double bonds;

R b3 is selected from the group comprising, preferably consisting of a hydrogen atom, alkyl, cycloalkyl, wherein C 1 -C 6 -alkyl is optionally substituted one or more times with cycloalkyl, hydroxyl, a halogen atom, haloalkyl or alkoxy;

R c is alkyl or cycloalkyl; and

n is an integer of 0 or 1.

3 . The compound according to claim 1 , wherein:

A is an aryl ring;

R1 is an iodine atom;

R2 is a fluorine atom;

R3 is a hydrogen atom;

R4 is a fluorine atom;

R5 is a hydrogen atom;

R6 is alkyl or heterocycloalkyl, wherein alkyl is substituted one or more times, independently from each other, with a group selected from hydroxyl, a halogen atom, alkoxy, cyano, haloalkoxy, thioalkyl, heterocycloalkyl, cycloalkyl, NR b1 R b2 , NH—C(O)R c , —C(O)OR c , —C(O)NH 2 , —C(O)NHR c , —C(O)N(R c ) 2 or —S(O) 2 R c ; or

R6 is a —O— moiety, said moiety being bound directly to the above-mentioned ring A, thus forming a ring fused to said ring A;

R7 is a hydrogen atom;

R8 and R9 are both a hydrogen atom;

R b1 and R b2 independently from each other are selected from the group comprising, preferably consisting of a hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl; or

R b1 and R b2 together with the nitrogen atom to which they are attached, form a 3 to 7 membered heterocycloalkyl ring, which is optionally substituted one or more times, the same way or differently, with alkyl, a halogen atom, haloalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, alkoxy, hydroxy; the carbon backbone of said heterocycloalkyl ring being optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NR b3 , an oxygen or sulphur atom, and being optionally interrupted one or more times, the same way or differently, with a —C(O)—, —S(O)—, and/or —S(O) 2 — group, and optionally containing one or more double bonds;

R b3 is selected from the group comprising, preferably consisting of a hydrogen atom, alkyl, cycloalkyl, wherein C 1 -C 6 -alkyl is optionally substituted one or more times with cycloalkyl, hydroxyl, a halogen atom, haloalkyl or alkoxy;

R c is alkyl or cycloalkyl; and

n is an integer of 0 or 1.

4 . The compound according to claim 1 , which is selected from the group consisting of:

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(2-hydroxy-2-methyl-propionylamino)phenoxy]-benzamide;

2-[3-((R)-2-Amino-3-hydroxy-propionylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;

2-[3-((S)-2-Amino-3-hydroxy-propionylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;

2-[3-((S)-2-Amino-propionylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)benzamide;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(2-hydroxy-acetylamino)-phenoxy]-benzamide;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(2-methoxy-acetylamino)-phenoxy]-benzamide;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(2-methylsulfanyl-acetylamino)-phenoxy]-benzamide;

5-Oxo-pyrrolidine-2-carboxylic acid {3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)phenoxy]-phenyl}-amide;

Tetrahydro-pyran-4-carboxylic acid {3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)phenoxy]-phenyl}-amide;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(-2-hydroxy-propionylamino)-phenoxy]-benzamide;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(2-morpholin-4-yl-acetylamino)-phenoxy]-benzamide;

2-[3-(2-Acetylamino-acetylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)benzamide;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(3-morpholin-4-yl-propionylamino)-phenoxy]-benzamide;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(3-hydroxy-propionylamino)-phenoxy]-benzamide;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-{3-[2-(4-methyl-piperazin-1-yl)-acetylamino]-phenoxy}-benzamide;

Tetrahydro-furan-2-carboxylic acid {3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)phenoxy]-phenyl}-amide;

2-[3-(2-Diethylamino-acetylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)benzamide;

2-[3-(2-Dimethylamino-acetylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)benzamide;

N-{3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-succinamic acid methyl ester;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-{3-[2-(4-methyl-piperidin-1-yl)-acetylamino]-phenoxy}-benzamide

1-Methyl-piperidine-4-carboxylic acid {3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-1-phenylamino)-phenoxy]-phenyl}-amide;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(2-oxo-2,3-dihydro-benzooxazol-5-yloxy)benzamide;

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(2-oxo-2,3-dihydro-benzooxazol-6-yloxy)benzamide; and

4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(2,2,2-trifluoro-acetylamino)-phenoxy]-benzamide.

5 . A method of preparing a compound of general formula (I) according to claim 1 , said method comprising the step of allowing an intermediate compound of general formula 8:

in which R1, R2, R3, R4, R5, R7, R8, R9, A and n are as defined in claim 1 ,

to react with a carboxylic acid of formula 9:

in which R6 is as defined in claim 1 ;

optionally in the presence of a carboxylic acid-activating agent thus yielding a compound of general formula (I):

In which R1, R2, R3, R4, R5, R6, R7, R8, R9, A and n are as defined in claim 1 .

6 . A method of preparing a compound of general formula (Ib) according to claim 1 , said method comprising the step of allowing an intermediate compound of general formula (Ia):

in which R2, R3, R4, R5, R6, R7, R8, R9, A and n are as defined in claim 1 ,

to react with an alkyne of formula 17:

in the presence of a catalyst, such as a Pd catalyst in the presence of copper iodide and a base, optionally followed by desilylation, thus yielding a compound of general formula (Ib):

In which R2, R3, R4, R5, R6, R7, R8, R9, A and n are as defined in claim 1 .

7 . A pharmaceutical composition comprising a compound according to claim 1 , or a tautomer, stereoisomer, physiologically acceptable salt, hydrate, solvate, metabolite, or prodrug thereof, and a pharmaceutically acceptable diluent or carrier.

8 . The pharmaceutical composition according to claim 7 wherein said compound is present in a therapeutically effective amount.

9 . The pharmaceutical composition according to claim 8 which further comprises at least one further active compound.

10 . The pharmaceutical composition according to claim 9 , in which said further active compound is an anti-hyperproliferative agent, an anti-angiogenic agent, a mitotic inhibitor, an alkylating agent, an anti-metabolite, a DNA-intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme inhibitor, a toposisomerase inhibitor, a biological response modifier, or an anti-hormone.

11 . A packaged pharmaceutical composition comprising a container, the pharmaceutical composition of claim 7 , and instructions for using the pharmaceutical composition to treat a disease or condition in a mammal.

12 . A method of inhibiting mitogen extracellular kinase enzymes in a cell comprising contacting a cell with one or more compounds according to claim 1 .

13 . The method according to claim 12 , wherein said cell is a mammalian cell.

14 . A method for treating a hyperproliferative disorder or abnormal cell growth in a mammal comprising administering a compound according to claim 1 to a patient in need thereof.

15 . A method according to claim 14 , wherein said hyperproliferative disorder is cancer.

16 . A method according to claim 15 , wherein said cancer is a cancer of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, endocrine system or a distant metastasis of a solid tumor.

17 . A method according to claim 16 , wherein said cancer is a sarcoma, a melanoma or a hematological malignancy.

18 . A method according to claim 17 , wherein said haematological malignancy is lymphoma, leukaemia or multiple myeloma.

19 . A method for treating an angiogenesis disorder in a mammal comprising administering a compound of claim 1 to a patient in need thereof.

20 . A method according to claim 14 , wherein said hyperproliferative disorder is psoriasis, restenosis, autoimmune disease, atherosclerosis, rheumatoid arthritis, chronic pain, neuropathic pain, osteoarthritis, benign prostate hyperplasia, hyperproliferative disease of the eye.

21 . A method according to claim 20 , wherein said hyperproliferative disease of the eye is cataract, conjunctival epithelial cell hypermitosis or goblet cell hyperplasia.