# US 9,751,825 B2 · TAK1 kinase inhibitors, compositions, and used related thereto

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- Number: US 9,751,825 B2
- Document ID: US9751825B2
- Status: Granted
- Kind: B2
- Application number: 14/234,127
- Filed: 2012-07-19
- Published: 2014-09-04
- Granted: 2017-09-05
- Earliest claimed: 2011-07-19
- Assignees: Emory University
- Applicants: Huw M. L. Davies; Spandan Chennamadhavuni; Andrei Bakin
- Inventors: Huw M. L. Davies; Spandan Chennamadhavuni; Andrei Bakin
- Web page: https://patentgrep.com/patent/US9751825B2

## CPC

- C07C 69/73: of unsaturated acids
- A61K 31/194: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A61K 31/357: having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K 31/36: Compounds containing methylenedioxyphenyl groups, e.g. sesamin
- A61K 31/405: Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
- C07C 51/00: Preparation of carboxylic acids or their salts, halides or anhydrides (of acids by hydrolysis of oils, fats or waxes C11C)
- C07C 57/42: having unsaturation outside the rings
- C07C 67/31: by introduction of functional groups containing oxygen only in singly bound form
- C07C 69/604: Polycarboxylic acid esters, the acid moiety containing more than two carboxyl groups
- C07C 69/618: having unsaturation outside the six-membered aromatic ring
- C07C 69/65: of unsaturated acids
- C07C 69/732: of unsaturated hydroxy carboxylic acids
- C07C 69/734: Ethers
- C07C 69/736: the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
- C07C 69/738: Esters of keto-carboxylic acids {or aldehydo-carboxylic acids}
- C07C 201/12: by reactions not involving the formation of nitro groups
- C07C 205/56: having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
- C07C 259/06: having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 209/24: with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
- C07D 209/26: with an acyl radical attached to the ring nitrogen atom
- C07D 209/34: in position 2
- C07D 307/79: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 307/80: Radicals substituted by oxygen atoms
- C07D 317/60: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 317/68: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 319/18: Ethylenedioxybenzenes, not substituted on the hetero ring
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The disclosure relates to TAK1 inhibitors, compositions, and uses related thereto. In certain embodiments, the disclosure relates to compounds of formula (I), pharmaceutical compositions having a compound of formula (I), and methods of treating or preventing cancer by administering an effective amount of a pharmaceutical composition having a compound of formula (I) to a subject in need thereof.

## Claims

### Claim 1

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound of formula IC,
or salt or prodrug thereof wherein,
R1 is hydrogen, hydroxy, alkyl, alkoxy, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R10;
R2 is formyl, carboxy, or phosphonate, wherein R2 is optionally substituted with one or more, the same or different, R10;
R5 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R10;
R6 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R10;
R7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R10;
R8 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R10;
R9 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11;
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R13; and
R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the compound is selected from:
(2Z,4Z)-dimethyl 2-(3,4-dichlorophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-bromophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-iodophenyl)hexa-2,4-dienedioate, and
(2Z,4Z)-dimethyl 2-(4-nitrophenyl)hexa-2,4-dienedioate.

### Claim 3

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound of formula IC,
or salt or prodrug thereof wherein,
R1 is hydrogen, hydroxy, alkyl, alkoxy, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R10;
R2 is formyl, carboxy, or phosphonate, wherein R2 is optionally substituted with one or more, the same or different, R10;
R5 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R10;
R6 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R10;
R7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R10;
R8 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R10;
R9 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11;
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R13; and
R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, and
wherein the pharmaceutical composition is in the form of a tablet, capsule, or granules.

### Claim 4 (depends on 3)

The pharmaceutical composition of claim 3, wherein the compound is selected from:
(2Z,4Z)-dimethyl 2-(3,4-dichlorophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-bromophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-iodophenyl)hexa-2,4-dienedioate, and
(2Z,4Z)-dimethyl 2-(4-nitrophenyl)hexa-2,4-dienedioate.

### Claim 5

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound of formula IC,
or salt or prodrug thereof wherein,
R1 is hydrogen, hydroxy, alkyl, alkoxy, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R10;
R2 is formyl, carboxy, or phosphonate, wherein R2 is optionally substituted with one or more, the same or different, R10;
R5 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R10;
R6 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R10;
R7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R10;
R8 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R10;
R9 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11;
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R13; and
R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, and
wherein the pharmaceutical composition comprises an enteric coating.

### Claim 6 (depends on 5)

The pharmaceutical composition of claim 5, wherein the compound is selected from:
(2Z,4Z)-dimethyl 2-(3,4-dichlorophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-bromophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-iodophenyl)hexa-2,4-dienedioate, and
(2Z,4Z)-dimethyl 2-(4-nitrophenyl)hexa-2,4-dienedioate.

### Claim 7

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound of formula IC,
or salt or prodrug thereof wherein,
R1 is hydrogen, hydroxy, alkyl, alkoxy, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R10;
R2 is formyl, carboxy, or phosphonate, wherein R2 is optionally substituted with one or more, the same or different, R10;
R5 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R10;
R6 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R10;
R7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R10;
R8 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R10;
R9 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11;
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R13; and
R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, and
wherein the excipient is selected from maltodextrin, xanthan, scleroglucan, dextran, starch, alginates, pullulan, hyaloronic acid, chitin, chitosan, albumin, gelatin, poly-L-lysine, sodium poly(acrylic acid), poly(hydroxyalkyl methacrylates), poly(hydroxyethylmethacrylate), carboxypolymethylene, carbomer, polyvinylpyrrolidone, gum, guar gum, gum arabic, gum karaya, gum ghatti, locust bean gum, tamarind gum, gellan gum, gum tragacanth, agar, pectin, gluten, poly(vinyl alcohol), ethylene vinyl alcohol, polyethylene glycol, cellulose ether, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, carboxyethylcellulose, ethylhydroxyethylcellulose, carboxymethylhydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, and sodium carboxymethylcellulose.

### Claim 8 (depends on 7)

The pharmaceutical composition of claim 7, wherein the compound is selected from:
(2Z,4Z)-dimethyl 2-(3,4-dichlorophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-bromophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-iodophenyl)hexa-2,4-dienedioate, and
(2Z,4Z)-dimethyl 2-(4-nitrophenyl)hexa-2,4-dienedioate.

### Claim 9

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound of formula IC,
or salt or prodrug thereof wherein,
R1 is hydrogen, hydroxy, alkyl, alkoxy, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R10;
R2 is formyl, carboxy, or phosphonate, wherein R2 is optionally substituted with one or more, the same or different, R10;
R5 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R10;
R6 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R10;
R7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R10;
R8 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R10;
R9 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11;
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R13; and
R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, and
wherein the pharmaceutical composition is in the form of an alcoholic solution, oily solution, sugar solution, physiological saline solution, or isotonic sodium chloride solution.

### Claim 10 (depends on 7)

The pharmaceutical composition of claim 7, wherein the compound is selected from:
(2Z,4Z)-dimethyl 2-(3,4-dichlorophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-bromophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-iodophenyl)hexa-2,4-dienedioate, and
(2Z,4Z)-dimethyl 2-(4-nitrophenyl)hexa-2,4-dienedioate.

### Claim 11

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound of formula IC,
or salt or prodrug thereof wherein,
R1 is hydrogen, hydroxy, alkyl, alkoxy, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R10;
R2 is formyl, carboxy, or phosphonate, wherein R2 is optionally substituted with one or more, the same or different, R10;
R5 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R10;
R6 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R10;
R7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R10;
R8 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R10;
R9 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10;
R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11;
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
R12 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R13; and
R13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl, and
wherein the pharmaceutical composition comprises another active ingredient.

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, wherein the compound is selected from:
(2Z,4Z)-dimethyl 2-(3,4-dichlorophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-bromophenyl)hexa-2,4-dienedioate,
(2Z,4Z)-dimethyl 2-(4-iodophenyl)hexa-2,4-dienedioate, and
(2Z,4Z)-dimethyl 2-(4-nitrophenyl)hexa-2,4-dienedioate.

### Claim 13

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound (2Z,4Z)-dimethyl 2-(3,4-dichlorophenyl)hexa-2,4-dienedioate.

### Claim 14

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound (2Z,4Z)-dimethyl 2-(4-iodophenyl)hexa-2,4-dienedioate.

### Claim 15

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound (2Z,4Z)-dimethyl 2-(4-nitrophenyl)hexa-2,4-dienedioate.