# US 7,745,663 B2 · 5-Substituted-2-phenylamino benzamides as MEK inhibitors

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- Number: US 7,745,663 B2
- Document ID: US7745663B2
- Status: Granted
- Kind: B2
- Application number: 11/658,533
- Filed: 2005-07-26
- Published: 2009-09-17
- Granted: 2010-06-29
- Earliest claimed: 2004-07-26
- Assignees: Chugai Seiyaku Kabushiki Kaisha
- Inventors: Yoshiaki Isshiki; Yasunori Kohchi; Eisaku Mizuguchi; Hitoshi Iikura; Yasuaki Matsubara; Shinji Tsujii; Nobuo Shimma; Masanori Miwa; Satoshi Aida; Masami Kohchi; Takeshi Murata; Kosuke Aso
- Web page: https://patentgrep.com/patent/US7745663B2

## CPC

- C07C 259/10: having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/08: Vasodilators for multiple indications
- 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 11/06: Antiasthmatics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- 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
- C07C 317/18: with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C 323/12: the carbon skeleton being acyclic and saturated
- C07D 207/27: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D 211/76: attached in position 2 or 6
- C07D 239/10: Oxygen or sulfur atoms
- C07D 261/04: having one double bond between ring members or between a ring member and a non-ring member
- C07D 263/22: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
- C07D 265/02: 1,2-Oxazines; Hydrogenated 1,2-oxazines
- C07D 265/32: with oxygen atoms directly attached to ring carbon atoms
- C07D 273/00: Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

An objective of the present invention is to provide compounds that exhibit strong MEK-inhibiting activity and are stable in vivo and soluble in water, which can be used as preventive or therapeutic agents for proliferative diseases. The compounds of the present invention and pharmaceutically acceptable salts thereof are represented by the following formula (1): [where R1, R2, R3, R4, and X are the same as defined in the present patent application].

## Claims

### Claim 1

A compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof,
wherein
R1 represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group is optionally substituted by a hydroxyl group;
R3 represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; the alkyl group, the alkenyl group, and the alkynyl group optionally have one to three substituents selected from the group consisting of —ORa, —NRaRb, —NRaCORb, a heterocyclic group, and a heteroaryl group; the heterocyclic group and the heteroaryl group optionally have one to three substituents selected from the group consisting of a C1-5 alkyl group, —ORa, and —NRaRb;
X represents a group represented by the following formula (i):
●-Y—Z—W (i)
wherein
Y represents —O—, —NR8O—, —ONR8—, —NR8CO—, or —NR8SO2—;
Z represents a C1-8 alkylene chain which is optionally substituted by one to three groups represented by W′;
where R8 represents a hydrogen atom, an alkyl group, —ORa, or —COR9; and the alkyl group is optionally substituted by a halogen atom, —ORa, or —NRaRb;
R9 represents a hydrogen atom, an alkyl group, or —ORa; and the alkyl group is optionally substituted by a halogen atom, —ORa, or —NRaRb;
R8 and R9 are optionally linked to the alkylene chain of Z or form a heterocyclic group through a linkage to the substituent represented by Ra or Rb of W,
or alternatively,
X represents a group represented by the following formula (ii):
wherein
Y1 and Y2, which may be the same or different, each represent a single bond, —CO—, —COO—, —O—, —OCO—, —NRa—, or —SO2—;
Z′ represents a C1-5 alkylene chain which is optionally substituted by one to three groups represented by W′;
in the above formulae (i) and (ii),
W and W′, which may be the same or different, each represent a C1-5 alkyl group, a halogen atom, an oxo group, —ORa, —COORa, —COOCORa, —CO-halogen atom, —OCORa, —CONRaRb, —SRa, —SORa, —SO2Ra, —NRaRb, —NRaCORb, —NRaSO2Rb, —SO2NRaRb, a heterocyclic group, or a heteroaryl group; the heterocyclic group and the heteroaryl group optionally have a substituent selected from the group consisting of a C1-5 alkyl group, —ORa, and —NRaRb; the alkyl group is optionally substituted by a hydroxyl group, a C1-5 alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen atom are optionally linked to each other to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group optionally has a substituent selected from the group consisting of —ORa, —NRaRb, and a C1-5 alkyl group that is optionally substituted with ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C1-5 alkyl group; the alkyl group is optionally substituted by one to three groups selected from the group consisting of a hydroxyl group, a C1-5 alkoxy group, and an amino group;
provided that, when X is the group represented by the above formula (i) and Y is not —O—, W is a hydrogen atom or any of the groups assigned to W defined above.

### Claim 2 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents the group —Y—Z—W of the formula (i) and Z represents a C1-5 alkylene chain,
wherein the alkylene chain optionally has one to three substituents selected from the group consisting of a C1-5 alkyl group, a halogen atom, —ORa, —NRaRb, and an oxo group;
the above substituents except the oxo group and the halogen atom are optionally linked to each other to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group optionally has a substituent selected from the group consisting of —ORa, —NRaRb, and a C1-5 alkyl group that is optionally substituted with —ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C1-5 alkyl group; and the alkyl group is optionally substituted by a hydroxyl group, a C1-5 alkoxy group, or an amino group.

### Claim 3 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents the group —Y—Z—W of the formula (i), wherein the alkylene chain of Z is any one of the groups represented by the following formulae:
—CH2—, —(CH2)2—, —(CH2)3—, —(CH2)4—, —CH2CH(Me)—, —CH2C(Me)2-, —C(Me)2CH2—, —(CH2)2CH(Me)—, —(CH2)2C(Me)2-, —CH(Me)(CH2)2—, —C(Me)2(CH2)2—, —CH2CH(Me)CH2—, —CH2C(Me)2CH2—, —CH2C(CH2CH2)CH2—, —CO—, —CH2CO—, —COCH2—, —(CH2)2CO—, —CO(CH2)2—, —CHOH—, —CH2CH(OH)—, —CH(OH)CH2—, —CH2CH(OH)CH2—, —CH(OH)CH2CH2—, and —CH2CH2CH(OH)—.

### Claim 4 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents —Y—Z—W of the formula (i), wherein R8 represents a hydrogen atom, a hydroxyl group, a C1-5 alkyl group, or —COR9;
R9 represents a hydrogen atom, a hydroxyl group, a C1-5 alkyl group, or a C1-5 alkoxy group; and
the alkyl group and the alkoxy group represented by R8 and R9 are optionally substituted by one to three hydroxyl groups at arbitrary positions of the hydrocarbon moiety.

### Claim 5 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents —Y—Z—W of the formula (i), wherein R8 represents a hydrogen atom, a hydroxyl group, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, a sec-butyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a pentyl group, a formyl group, an acetyl group, a 2-methoxyacetyl group, a 2-ethoxyacetyl group, a 2-hydroxyacetyl group, a propionyl group, a 2-methylpropionyl group, a 2-methoxypropionyl group, a 2-ethoxypropionyl group, a 2-hydroxypropionyl group, a 3-methoxypropionyl group, a 3-ethoxypropionyl group, a 3-hydroxypropionyl group, a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, a hydroxymethyl group, or a 2-hydroxyethyl group.

### Claim 6 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents —Y—Z—W of the formula (i), wherein Y represents —O—, —NHO—, —N(COCH3)O—, —N(COCH2OH)O—, —N(COCH2CH3)O—, —N(COCH(OH)CH3)O—, —N(COCH2CH2OH)O—, —N(COCH(OH)CH2OH)O—, —N(COCH2CH2CH3)O—, —N(COCH2CH2CH2OH)O—, —N(COCH(OH)CH2CH3)O—, —N(COCH2CH(OH)CH3)O—, —NHCO—, or —NHSO2—.

### Claim 7 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents a group represented by the formula (ii) and X is any one of the groups represented by the following formulae:
wherein Z′ represents a C1-5 alkylene chain which is optionally substituted by one to three groups represented by W′;
W′ represents a C1-5 alkyl group, a halogen atom, an oxo group, —ORa, —CONRaRb, —SRa, —SORa, —SO2Ra, —NRaRb, —NRaCORb, —NRaSO2Rb, —SO2NRaRb, a heterocyclic group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group optionally have substituents selected from the group consisting of a C1-5 alkyl group, —ORa, and —NRaRb; the alkyl group is optionally substituted by a hydroxyl group, a C1-5 alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen atom are optionally linked to each other to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group optionally has a substituent selected from the group consisting of —ORa, —NRaRb, and a C1-5 alkyl group that is optionally substituted with —ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C1-5 alkyl group; and the alkyl group is optionally substituted by a hydroxyl group, a C1-5 alkoxy group, or an amino group.

### Claim 8 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof wherein X represents the group represented by the formula (ii), wherein W′ represents any one of the groups represented by the formulae:
-Me, -Et, -n-Pr, -i-Pr, —CH2OH, —CH2CH2OH, —CH(OH)CH3, —OH, —OMe, —OEt, —OCH2OH, —O(CH2)2OH, —O(i-Pr), —O(n-Pr), —CONH2, —CONHMe, —CONHEt, —CONH(n-Pr), —CONH(i-Pr), —CONMe2, —CON(Et)Me, —SO2Me, —SOMe, —SMe, —NH2, —NHMe, —NHCH2OH, —NH(CH2)2OH, —N(Me)CH2CH2OH, —NHEt, —NMe2, —N(Et)Me, —NHCOMe, —NMeCOMe, —NHCOEt, —NHCO(n-Pr), and —NHCO(i-Pr).

### Claim 9 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents the group represented by the formula (ii), wherein the alkylene chain of Z′ is any one of the groups represented by the following formulae:
—CH2—, —(CH2)2—, —(CH2)3—, —(CH2)4—, —CH2CH(Me)—, —CH2C(Me)2-, —C(Me)2CH2—, —(CH2)2CH(Me)—, —(CH2)2C(Me)2-, —CH(Me)(CH2)2—, —C(Me)2(CH2)2—, —CH2CH(Me)CH2—, —CH2C(Me)2CH2—, —CHOH—, —CH2CH(OH)—, —CH(OH)CH2—, —CH2CH(OH)CH2—, —CH(OH)CH2CH2—, —CH2CH2CH(OH)—, —CO—, —CH2CO—, —COCH2—, —(CH2)2CO—, —CO(CH2)2—, and —CH2CH(OH)CH2—.

### Claim 10 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents the group represented by the formula (ii) and X is any one of the groups represented by the following formulae:
wherein the alkylene chain is optionally substituted at arbitrary positions by one to three substituents selected from the group consisting of a C1-5 alkyl group, a halogen atom, —ORa, —NRaRb, and an oxo group; Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C1-5 alkyl group; and the alkyl group is optionally substituted by a hydroxyl group, a C1-5 alkoxy group, or an amino group.

### Claim 11 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents the group represented by the following formula (iii) or (iv):
wherein n represents an integer ranging from 1 to 5 and n′ represents an integer ranging from 0 to 5; the repeated units represented by —(CH2)n- or —(CH2)n′- in the formulae optionally are substituted at arbitrary positions in the hydrocarbon moiety by one to three substituents selected from the group consisting of a C1-5 alkyl group, a halogen atom, —ORa, —NRaRb, and an oxo group; Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C1-5 alkyl group; and the alkyl group is optionally substituted by a hydroxyl group, a C1-5 alkoxy group, or an amino group.

### Claim 12 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents a group selected from the group consisting of a 2-hydroxyethoxy group, a 3-hydroxy-2-dimethylpropoxy group, a 3-hydroxypropoxy group, a 2-carbamoylethoxy group, a 2-methylcarbamoylethoxy group, a 2-methanesulfonyl-ethoxy group, a 2-acetylamino-ethoxy group, a 2-hydroxyethoxyamino group, a 3-hydroxypropionylamino group, a 2-hydroxyethanesulfonamide group, a 1-hydroxymethyl-cyclopropylmethoxy group, a 2,3-dihydroxy-propoxy group, a 1H-imidazol-2-ylmethoxy group, a 2-methylcarbamoyl-ethoxyamino group, a 2-acetylamino-ethoxyamino group, a 2-methanesulfonyl-ethoxyamino group, a 1H-imidazol-2-ylmethoxyamino group, a 3-hydroxypropoxyamino group, a hydroxyethoxy)-ethoxy group, a 2-methylaminoethoxy group, a 2-(2-hydroxyethylamino)-ethoxy group, a 2-morpholin-4-yl-ethoxy group, a 2-(4-hydroxy-piperidin-1-yl)-ethoxy group, a 2-methylamino-ethoxyamino group, a 2,3-dihydroxy-propoxyamino group, a formyl-methoxyamino group, an acetyl-methoxyamino group, a methoxy-propionylamino group, an isobutyryl-methoxy-amino group, a (2-hydroxy-acetyl)-methoxyamino group, a methoxy-(2-methoxy-acetyl)-amino group, an acetyl-ethoxy-amino group, an ethoxy-propionyl-amino group, an acetyl-isopropoxy-amino group, an acetylhydroxyamino group, an acetoxy-acetyl-amino group, an acetyl-(2-hydroxy-ethoxy)-amino group, an acetyl-(3-hydroxy-propoxy)-amino group, an acetyl-(2-hydroxy-2-methyl-propoxy)-amino group, an acetyl-(2-acetylamino-ethoxy)-amino group, an acetyl-(2-propionylamino-ethoxy)-amino group, an acetyl-(2-isobutyrylamino-ethoxy)-amino group, an acetyl-(2-methylsulfanyl-ethoxy)-amino group, an acetyl-(3-methylsulfanyl-propoxy)-amino group, a 2-hydroxy-1,1-dimethyl-ethoxy group, a methylcarbamoylmethoxyamino group, an ethylcarbamoylmethoxyamino group, a propylcarbamoylmethoxyamino group, an isopropylcarbamoyl-methoxyamino group, a dimethylcarbamoylmethoxyamino group, a 2-ethylcarbamoyl-ethoxyamino group, a 2-propylcarbamoyl-ethoxyamino group, a 2-isopropylcarbamoyl-ethoxyamino group, a 3-methylcarbamoyl-propoxyamino group, a 2-methoxycarbonyl-ethoxyamino group, a methoxyamino group, a methoxy-methyl-amino group, an ethoxyamino group, an isopropoxyamino group, a 2-hydroxy-2-methyl-propoxyamino group, a 2-methylsulfanyl-ethoxyamino group, a 2-methanesulfinyl-ethoxyamino group, a 3-methylsulfanyl-propoxyamino group, a 3-methanesulfinyl-propoxyamino group, a 2-propionylamino-ethoxyamino group, a 2-isobutyrylamino-ethoxyamino group, a 2-hydroxy-acetylamino group, and an acetyl-(2-hydroxy-ethyl)-amino group.

### Claim 13 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents a group selected from the group consisting of a 3-oxo-[1,2]oxazinan-2-yl group, a 3-oxo-isoxazolidin-2-yl group, a 4,4-dimethyl-3-oxo-isoxazolidin-2-yl group, a 4-hydroxy-3-oxo-[1,2]oxazinan-2-yl group, a 3-oxo-[1,4,2]dioxazinan-2-yl group, a 2-oxo-pyrrolidin-1-yl group, a 2-oxo-piperidin-1-yl group, a 2-oxo-oxazolidin-3-yl group, a 2-oxo-tetrahydro-pyrimidin-1-yl group, and a 2,3-dioxo-morpholin-4-yl group.

### Claim 14 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 represents an iodine atom, a bromine atom, a vinyl group, or an ethynyl group.

### Claim 15 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 represents an iodine atom or an ethynyl group.

### Claim 16 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 represents a chlorine atom, a fluorine atom, a methyl group, or a hydroxymethyl group.

### Claim 17 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 represents a fluorine atom.

### Claim 18 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 represents a fluorine atom.

### Claim 19 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 represents a C1-5 alkyl group substituted by one to three hydroxyl groups.

### Claim 20 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 represents a group selected from the group consisting of the groups represented by the following formulae:

### Claim 21 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ra and Rb, which may be the same or different, each represent a group selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, a sec-butyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a pentyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a 1-hydroxy-1-methylethyl group, a 2-hydroxy-1-methylethyl group, a 2-hydroxy-1,1-dimethylethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, and a 3-hydroxypropyl group.

### Claim 22 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents —Y—Z—W of the formula (i), wherein W and W′, which may be the same or different, each represent a group selected from the group consisting of —OH, —OMe, —OEt, —OCH2OH, —O(CH2)2OH, —O(i-Pr), —O(n-Pr), —COOH, —COOMe, —COOEt, —COOCOMe, —COCl, —CONH2, —CONHMe, —CONHEt, —CONH(n-Pr), —CONH(i-Pr), —CONMe2, —CON(Et)Me, —SO2Me, —SOMe, —SMe, —NH2, —NHMe, —NHCH2OH, —NH(CH2)2OH, —N(Me)CH2CH2OH, —NHEt, —NMe2, —N(Et)Me, —NHCOMe, —NMeCOMe, —NHCOEt, —NHCO(n-Pr), and —NHCO(i-Pr); and
W may be a hydrogen atom when Y is not —O—.

### Claim 23 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the above formula (1) is any one selected from the group consisting of:
(1) B-1
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5(2-hydroxy-ethoxymethyl)-benzamide,
(2) B-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethyl)-benzamide,
(3) B-3
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxymethyl)-benzamide,
(4) B-4
2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethyl)-benzamide,
(5) B-5
3,4-difluoro-2-(2-fluoro-4-vinyl-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethyl)-benzamide,
(6) B-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-hydroxypropoxymethyl)-benzamide,
(7) B-7
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-hydroxy-2,2-dimethyl-propoxymethyl)-N-(2-hydroxy-ethoxy)-benzamide,
(8) B-8
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(1-hydroxymethyl-cyclopropylmethoxymethyl)-benzamide,
(9) B-9
5-(2,3-dihydroxy-propoxymethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(10) B-10
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methylcarbamoyl-ethoxymethyl)-benzamide,
(11) B-11
5-(2-acetylamino-ethoxymethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(12) B-12
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methanesulfonyl-ethoxymethyl)-benzamide,
(13) B-13
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(1H-imidazol-2-yl methoxymethyl)-benzamide,
(14) B-14
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[2-(2-hydroxy-ethoxy)-ethoxymethyl]-benzamide,
(15) B-15
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methylamino-ethoxymethyl)-benzamide,
(16) B-16
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[2-(2-hydroxy-ethylamino)-ethoxymethyl]-benzamide,
(17) B-17
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-morpholin-4-yl-ethoxymethyl)-benzamide,
(18) B-18
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[2-(4-hydroxy-piperidin-1-yl)-ethoxymethyl]-benzamide, and
(19) B-19
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-1,1-dimethyl-ethoxymethyl)-N-(2-hydroxy-ethoxy)-benzamide.

### Claim 24 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the above formula (1) is any one selected from the group consisting of:
(1) C-1
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-benzamide,
(2) C-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-benzamide,
(3) C-3
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-ethoxyamino)-methyl]-benzamide,
(4) C-4
2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy ethoxyamino)-methyl]-benzamide,
(5) C-5
3,4-difluoro-2-(2-fluoro-4-vinyl-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-benzamide,
(6) C-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-ethoxyamino)-methyl]-benzamide,
(7) C-7
5-[(2-acetylamino-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(8) C-8
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfonyl-ethoxyamino)-methyl]-benzamide,
(9) C-9
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(1H-imidazol-2-ylmethoxyamino)-methyl]-benzamide,
(10) C-10
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propoxyamino)-methyl]-benzamide,
(11) C-11
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylamino-ethoxyamino)-methyl]-benzamide,
(12) C-12
5-[(2,3-dihydroxy-propoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(13) C-13
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methylcarbamoylmethoxyamino-methyl)-benzamide,
(14) C-14
5-(ethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(15) C-15
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylmethoxyamino-methyl)-benzamide,
(16) C-16
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoyl-methoxyamino)-methyl]-benzamide,
(17) C-17
5-(dimethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(18) C-18
5-[(2-ethylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(19) C-19
5-[(2-propylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(20) C-20
5-[(2-isopropylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(21) C-21
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-propoxyamino)-methyl]-benzamide,
(22) C-22
3-[N-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxyethoxycarbamoyl)benzyl]aminooxy]propionic acid methyl ester,
(24) C-24
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide,
(25) C-25
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-methyl-amino)-methyl]-benzamide,
(26) C-26
5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(27) C-27
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyamino-methyl)-benzamide,
(28) C-28
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)5-[(2-hydroxy-2-methyl-propoxyamino)-methyl]-benzamide,
(29) C-29
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)5-[(2-hydroxy-2-methyl-propoxyamino)-methyl]-benzamide,
(30) C-30
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-ethoxyamino)-methyl]-benzamide,
(31) C-31
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfinyl-ethoxyamino)-methyl]-benzamide,
(32) C-32
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-propoxyamino)-methyl]-benzamide,
(33) C-33
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methanesulfinyl-propoxyamino)-methyl]-benzamide,
(34) C-34
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylamino-ethoxyamino)-methyl]-benzamide, and
(35) C-35
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-ethoxyamino)-methyl]-benzamide.

### Claim 25 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the above formula (1) is any one selected from the group consisting of:
(1) E-1
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propionylamino)-methyl]-benzamide
(2) E-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propionylamino)-methyl]-benzamide
(3) E-3
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-ethanesulfonylamino)-methyl]-N-(2-hydroxy-ethoxy)-benzamide,
(4) E-4
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-5-[(2-hydroxy-ethanesulfonylamino)-methyl]-N-(2-hydroxy-ethoxy)-benzamide,
(5) E-5
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylamino)methyl]-N-(2-hydroxy-ethoxy)-benzamide, and
(6) E-6
5-{[acetyl-(2-hydroxy-ethyl)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide.

### Claim 26 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the above formula (1) is any one selected from the group consisting of:
(1) F-1
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(formyl-methoxy-amino)-methyl]-N-(2-hydroxy-ethoxy)-benzamide,
(2) F-2
5-[acetyl-methoxy-amino-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(3) F-3
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-amino)-methyl]-benzamide,
(4) F-4
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isobutyryl-methoxy-amino)-methyl]-benzamide,
(5) F-5
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-methyl}-N-(2-hydroxy-ethoxy)-benzamide,
(6) F-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-{[methoxy-(2-methoxy-acetyl)-amino]-methyl}-benzamide,
(7) F-7
5-[(acetyl-methoxy-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide,
(8) F-8
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-amino)-methyl]-benzamide,
(9) F-9
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(isobutyryl-methoxy-amino)-methyl]-benzamide,
(10) F-10
5-[(acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(11) F-11
5-[(ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(12) F-12
5-[(acetyl-isopropoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(13) F-13
5-[(acetyl-hydroxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(14) F-14
5-[(acetoxy-acetyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(15) F-15
5-{[acetyl-(2-hydroxy-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(16) F-16
5-{[acetyl-(3-hydroxy-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(17) F-17
5-{[acetyl-(2-hydroxy-2-methyl-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(18) F-18
5-{[acetyl-(2-acetylamino-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(19) F-19
5-{[acetyl-(2-propionylamino-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(20) F-20
5-{[acetyl-(2-isobutyrylamino-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(21) F-21
5-{[acetyl-(2-methylsulfanyl-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(22) F-22
5-{[acetyl-(3-methylsulfanyl-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(23) F-23
5-[(acetyl-ethoxy-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide,
(24) F-24
5-[(ethoxy-propionyl-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide,
(25) F-25
5-{[acetyl-(2-hydroxy-ethoxy)-amino]-methyl)-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide, and
(26) F-26
5-{[acetyl-(2-hydroxy-2-methyl-propoxy)-amino]-methyl)-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide.

### Claim 27 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the above formula (1) is any one selected from the group consisting of:
(1) G-1
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N(2-hydroxyethoxy)-5-(3-oxo-[1,2]oxazinan-2-ylmethyl)-benzamide,
(2) G-2
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide,
(3) G-3
5-(4,4-dimethyl-3-oxo-isoxazolidin-2-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(4) G-4
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[1,2]oxazinan-2-ylmethyl)-benzamide,
(5) G-5
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide,
(6) G-6
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-oxo-[1,2]oxazinan-2-ylmethyl)-benzamide,
(7) G-7
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide, and
(8) G-8
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(4-hydroxy-3-oxo-[1,2]oxazinan-2-ylmethyl)-benzamide.

### Claim 28 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the above formula (1) is any one selected from the group consisting of:
(1) H-1
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[1,4,2]dioxazinan-2-ylmethyl)-benzamide,
(2) H-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[1,4,2]dioxazinan-2-ylmethyl)-benzamide,
(3) H-3
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-1-ylmethyl)-benzamide,
(4) H-4
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-piperidin-1-ylmethyl)-benzamide,
(5) H-5
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-oxazolidin-3-ylmethyl)-benzamide,
(6) H-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-tetrahydro-pyrimidin-1-ylmethyl)-benzamide, and
(7) H-7
5-(2,3-dioxo-morpholin-4-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide.

### Claim 29 (depends on 1)

A pharmaceutical composition comprising as an active ingredient the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 1)

An MEK inhibitor comprising as an active ingredient the compound according to claim 1 or a pharmaceutically acceptable salt thereof.