# US 8,541,406 B2 · Thiadiazole derivatives for the treatment of neurodegenerative diseases

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,541,406 B2
- Document ID: US8541406B2
- Status: Granted
- Kind: B2
- Application number: 12/187,115
- Filed: 2008-08-06
- Published: 2009-02-26
- Granted: 2013-09-24
- Earliest claimed: 2006-02-07
- Assignees: Remynd NV
- Applicants: Gerard Griffioen; Kristel Marie Edith Coupet; Hein Roger Duhamel; Stefaan Wera; Ellen Gommé; Nele Van Damme; Ingrid Van Der Auwera; Marleen Lox; Tom Van Dooren; Tine Decruy
- Inventors: Gerard Griffioen; Kristel Marie Edith Coupet; Hein Roger Duhamel; Stefaan Wera; Ellen Gommé; Nele Van Damme; Ingrid Van Der Auwera; Marleen Lox; Tom Van Dooren; Tine Decruy
- Web page: https://patentgrep.com/patent/US8541406B2

## CPC

- A61K 31/497: containing further heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61P 25/00: Drugs for disorders of the nervous system
- 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

This invention provides specifically substituted 1,2,4-thiadiazole derivatives for use in the treatment of an α-synucleopathy such as Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, multiple system atrophy and Alzheimer's disease. This invention also provides various methods for producing such substituted 1,2,4-thiadiazole derivatives.

## Claims

### Claim 1

A pharmaceutical composition comprising a therapeutically effective amount of a 1,2,4-thiadiazole derivative according to the structural formula (A)
wherein the divalent group schematically represented by the structural formula (A′)
includes an optionally mono-substituted or poly-substituted, saturated or partly unsaturated heterocyclic ring with at least two nitrogen atoms in the said heterocyclic ring and with a total of 5 to 7 atoms in the said heterocyclic ring, and further wherein:
R6 is a substituent independently selected from the group consisting of oxo and C1-4 alkyl;
n is selected from the group consisting of 0, 1, 2 and 3;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkoxy, aryl, aryloxy, aryl-C1-4 alkyloxy, heteroaryloxy, benzenesulfonate, amino, hydroxy, nitro, trifluoromethyl, trifluoromethoxy and halogen, or any two adjacent substituents selected from the group consisting of R1, R2, R3, R4 and R5 form, together with the phenyl ring carbon atoms to which they are attached, a saturated or unsaturated ring fused to said phenyl ring and having from 5 to 7 ring members, said saturated or unsaturated ring optionally having one or two oxygen atoms and being optionally substituted with one or more halogen atoms;
R7, R8, R9, R10 and R11 are each independently selected from the group consisting of hydrogen, C1-10 alkyl, C1-6 alkoxy, C1-4 alkylthio, C2-4 alkenyl, C3-8 cycloalkyl, aryl, hydroxy, acetyl, nitro, trifluoromethyl and halogen; or any two adjacent substituents selected from the group consisting of R7, R8, R9, R10 and R11 form, together with the phenyl ring carbon atoms to which they are attached, a saturated or unsaturated ring fused to said phenyl ring and having from 5 to 7 ring members, said saturated or unsaturated ring optionally having one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; and each of said C1-6 alkyl, C1-6 alkoxy, aryl or fused ring is optionally substituted with one or more halogen atoms;
R12 and R13 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, aryl-C1-4 alkyl, aryl and N-containing heterocyclic rings, or R12 and R13 together form a C3-6 cycloalkyl or heterocyclic group; and
X is a linking moiety selected from the group consisting of —C(═O)—; —S(═O)2—; divalent saturated or unsaturated non-cyclic hydrocarbon groups having from 1 to 6 atoms in the main chain, each of said atoms in the main chain being independently selected from the group consisting of carbon, nitrogen and sulfur, each of said carbon atoms in the main chain being optionally substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, C1-4 alkyl and halogen, and each of said sulfur atoms in the main chain being optionally substituted with oxo, provided that the number of heteroatoms in the main chain of said divalent saturated or unsaturated non-cyclic hydrocarbon group is 0, 1 or 2, wherein a first terminal atom of the main chain is connected to the structural formula (A′) and a second terminal atom of the main chain is connected to the
group of structural formula (A); and divalent saturated or unsaturated heterocyclic groups having from 2 to 6 carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen in the said heterocyclic group; or X together with one of R7 and R11 forms a saturated or unsaturated ring having from 5 to 7 ring members and being fused to the phenyl ring bearing said one of R7 and R11, said saturated or unsaturated ring optionally having one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, and said saturated or unsaturated ring optionally having one or more substituents independently selected from the group consisting of C1-4 alkyl and trifluoromethyl or is selected from the group consisting of —CO—CH═CH—, —CH2—CH═CH— and —SO2—CH═CH—;
or a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.

### Claim 2 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the divalent group represented by the structural formula (A′) includes one or more further heteroatoms in the heterocyclic ring or attached to one or more carbon atoms of the heterocyclic ring.

### Claim 3 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the divalent group represented by the structural formula (A′) is selected from the group consisting of piperazinyl, 2,3-dioxopiperazinyl, 2,5-dioxopiperazinyl, 2-methylpiperazinyl, trans-2,5-dimethylpiperazinyl, 3,6-dimethyl-2,5-dioxopiperazinyl, 3-isopropyl-2,5-dioxo-piperazinyl, 3-tert-butyl-2,5-dioxopiperazinyl, 2,4-dioxoimidazolidinyl, 2,4,5-trioxoimidazolidinyl and homopiperazinyl.

### Claim 4 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the 1,2,4-thiadiazole derivative is represented by the structural formula (A1)
wherein X, R1, R2, R3, R4, R5, R7, R8, R9, R10 and R11 are as defined in claim 1, R6 is hydrogen or is as defined in claim 1, or a stereoisomer or a solvate thereof, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The pharmaceutical composition according to claim 1, wherein X is a divalent saturated or unsaturated non-cyclic hydrocarbon group having from 1 to 3 carbon atoms but no heteroatom in the main chain, and wherein each of said carbon atoms in the main chain is optionally substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, C1-4 alkyl and halogen.

### Claim 6 (depends on 1)

The pharmaceutical composition according to claim 1, wherein X is selected from the group consisting of C1-6 alkylene, —CO—CH2—, —CO—(CH2)2—, —CO—CHR14— and —CO—CHX′—, wherein R14 is C1-4 alkyl and wherein X′ is halogen.

### Claim 7 (depends on 1)

The pharmaceutical composition according to claim 1, wherein X is a divalent saturated or unsaturated non-cyclic hydrocarbon group having from 1 to 5 carbon atoms and one single nitrogen, oxygen or sulfur atom in the main chain, wherein each of said carbon atoms in the main chain is optionally substituted with one or more substituents independently selected from the group consisting of oxo, thioxo and C1-4 alkyl, and wherein a sulfur atom in the main chain is optionally substituted with oxo.

### Claim 8 (depends on 7)

The pharmaceutical composition according to claim 7, wherein X is selected from the group consisting of —CO—NH—, —(CH2)2—NH—CO—, —(CH2)2—NH—CO—CH2—, —(CH2)2—NH—CO—(CH2)2—, —(CH2)2—NH—CO—CHR14—, and —SO2—CH2—, wherein R14 is C1-4 alkyl.

### Claim 9 (depends on 1)

The pharmaceutical composition according to claim 1, wherein X is a divalent saturated or unsaturated non-cyclic hydrocarbon group having from 1 to 5 carbon atoms and one single oxygen atom in the main chain, wherein said oxygen atom is not adjacent to the nitrogen atom of the divalent group (A′).

### Claim 10 (depends on 9)

The pharmaceutical composition according to claim 9, wherein X is —C(═O)—O—CH2—.

### Claim 11 (depends on 1)

The pharmaceutical composition according to claim 1, wherein X is a divalent saturated or unsaturated non-cyclic hydrocarbon group having from 1 to 4 carbon atoms and two non-adjacent nitrogen atoms in the main chain, wherein none of said nitrogen atoms is adjacent to the nitrogen atom of the divalent group (A′).

### Claim 12 (depends on 11)

The pharmaceutical composition according to claim 11, wherein X is —(CH2)2—NH—CO—NH—CH2—.

### Claim 13 (depends on 1)

The pharmaceutical composition according to claim 1, wherein X is 1,2,4-thiadiazolyl.

### Claim 14 (depends on 1)

The pharmaceutical composition according to claim 1, wherein each of R1, R2, R3, R4 and R5 is fluoro.

### Claim 15 (depends on 1)

The pharmaceutical composition according to claim 1, wherein at least two of R1, R2, R3, R4 and R5 are hydrogen.

### Claim 16 (depends on 1)

The pharmaceutical composition according to claim 1, wherein three of R1, R2, R3, R4 and R5 are methoxy.

### Claim 17 (depends on 1)

The pharmaceutical composition according to claim 1, wherein three of R1, R2, R3, R4 and R5 are hydrogen, and wherein two of R1, R2, R3, R4 and R5 are identical and are selected from the group consisting of halogen, C1-4 alkoxy and trifluoromethyl.

### Claim 18 (depends on 1)

The pharmaceutical composition according to claim 1, wherein three of R1, R2, R3, R4 and R5 are hydrogen, and wherein two of R1, R2, R3, R4 and R5 are halogen and are independently selected from the group consisting of fluoro, chloro and bromo.

### Claim 19 (depends on 1)

The pharmaceutical composition according to claim 1, wherein three of R1, R2, R3, R4 and R5 are hydrogen, and wherein two adjacent substituents selected from the group consisting of R1, R2, R3, R4 and R5 form, together with the phenyl ring carbon atoms to which they are attached, a phenyl or methylenedioxy ring fused to said phenyl ring.

### Claim 20 (depends on 1)

The pharmaceutical composition according to claim 1, wherein four of R1, R2, R3, R4 and R5 are hydrogen, and wherein one of R1, R2, R3, R4 and R5 is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, aryl, aryloxy, aryl-C1-4 alkyloxy, heteroaryloxy, benzenesulfonate, amino, hydroxy, nitro, trifluoromethyl, trifluoromethoxy and halogen.

### Claim 21 (depends on 1)

The pharmaceutical composition according to claim 1, wherein R12 and R13 together form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and piperidinyl.

### Claim 22 (depends on 1)

The pharmaceutical composition according to claim 1, wherein R12 is hydrogen and R13 is selected from the group consisting of piperidinyl and morpholinyl.

### Claim 23 (depends on 1)

The pharmaceutical composition according to claim 1, wherein two adjacent substituents selected from the group consisting of R7, R8, R9, R10 and R11 form, together with the phenyl ring carbon atoms to which they are attached, a methylenedioxy group fused to said phenyl ring.

### Claim 24 (depends on 1)

The pharmaceutical composition according to claim 1, wherein at least three of R7, R8, R9, R10 and R11 are hydrogen, and wherein at most two of R7, R8, R9, R10 and R11 are independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, phenyl, hydroxy, acetyl, nitro, trifluoromethyl and halogen.

### Claim 25 (depends on 1)

The pharmaceutical composition according to claim 1, wherein said 1,2,4-thiadiazole derivative is selected from the group consisting of:
4-phenylacetyl-1-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
4-(4-fluorophenylacetyl), 1-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-fluorophenylacetyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(4-methoxyphenylacetyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-phenylacetyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine
1-(4-fluorophenylacetyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[chloro(phenyl)acetyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(2-phenylbutanoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
N-(3-fluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,
N-(2-methylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine-1-carboxamide,
N-(4-ethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,
N-(2-ethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,
N-phenyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,
N-(4-ethoxyphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine-1-carboxamide,
N-(2-methylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,
N-(2-fluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,
N-(2-trifluoromethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,
N-(2-trifluoromethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine-1-carboxamide,
N-(2,6-dimethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine-1-carboxamide,
N-(2,4-dimethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine-1-carboxamide,
N-(2,6-dichlorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine-1-carboxamide,
N-(3-cyanophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,
N-(2,4-difluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine-1-carboxamide,
N-(2,6-dimethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,
N-1-naphtyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine-1-carboxamide,
N-(3,4-difluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine-1-carboxamide,
N-(2,4-dimethoxyphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,
N-(3,4-difluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxamide,
N-(3,5-dimethoxyphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine-1-carboxamide,
1-[4-tert-butylphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-methoxyphenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-methoxyphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-fluorophenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-chlorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[1-naphtylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[2,5-dichlorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[2,4,6-trimethylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,
1-[2-naphtylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[2,5-dichlorophenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,
1-[4-bromophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-3-methyl-piperazine,
1-[1-naphtylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-3-methyl-piperazine,
1-[4-tert-butylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[1-naphtylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[3-methoxyphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[2,4,6-trimethylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[3-trifluorophenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-phenylsulfonyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[4-acetamidophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[4-acetamidophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,
1-[4-methylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[4-methoxyphenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[2-naphtylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-methoxyphenylsulfonyl]-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-tert-butylphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[4-acetamidophenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[3-trifluoromethylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[4-fluorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-fluorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[4-fluorophenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[4-methoxyphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[4-ter-butylphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[3-trifluoromethylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,
1-[4-methylphenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-bromophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[2-naphtylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-chlorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-tert-butylphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,
1-[4-methoxyphenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine
1-[4-tert-butylphenylsulfonyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine
1-[quinoline-8-sulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[4-nitrophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[3-nitro-4-chlorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[4-nitrophenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-[4-methoxyphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[3-nitro-4-chlorophenylsulfonyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-piperazine
1-(benzylsulfonyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(benzylsulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(phenylprop-2-ensulfonyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(phenylprop-2-ensulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine
1-(phenylprop-2-ensulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(butylsulfonyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(octylsulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(butylsulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(ethylsulfonyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(isopropylsulfonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[(2E)-3-phenylprop-2-enoyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[(2E)-3-phenylprop-2-enoyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-[(2E)-3-phenylprop-2-enoyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,
1-(3-phenylpropanoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(3-phenylpropanoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[3-phenylprop-2-enyl]-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[3-phenylprop-2-enyl]-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-[3-phenylprop-2-enyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
4-pentyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
4-butyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
4-hexyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
4-chloro-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
3,5-dichloro-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
2-methyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
3-fluoro-N-{2-[4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
4-methyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
4-fluoro-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
4-ethyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}benzamide,
3-fluoro-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-benzamide,
3-fluoro-N-{2-[4-[3-benzyl-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}benzamide,
2-(4-fluorophenyl)-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}acetamide,
2-phenyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-acetamide,
2-(4-fluorophenyl)-N-{2-[4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}acetamide,
N-benzyl-N′-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl urea
2-phenyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-butanamide,
3-phenyl-N-{2-[4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazin-1-yl]ethyl}-propanamide,
1-benzyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(1,3-benzodioxol-5-ylmethyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-piperazine,
1-(2-fluorobenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(4-ethylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-butylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-methoxybenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(1,3-benzodioxol-5-ylcarbonyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-butylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-hexylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(3-chlorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine
1-(4-fluorobenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-methylbenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(3-fluorobenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine
1-benzoyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-fluorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-tert-butylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(1,1′-biphenyl-4-ylcarbonyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-methoxybenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-ethylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(2-naphthoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(2-methoxybenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(4-pentylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(4-bromobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine
1-(2,4-dimethoxybenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(3,5-dichlorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(3-chlorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(2-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(3-bromobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine
1-(4-ethylbenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(3-methylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(3-trifluoromethylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(4-tert-butylbenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-ethylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(2-bromobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine
1-(2-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(3-fluorobenzoyl)-4-[3-benzyl-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(2-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-fluorobenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-fluorobenzoyl)-4-[3-benzyl-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-chlorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(3-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(3-fluorobenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-benzoyl-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(2-fluorobenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(1,3-benzodioxol-5-ylcarbonyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(3-fluororbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-fluorobenzoyl)-4-[3-benzyl-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-bromobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-ethylbenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(2-chlorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine
1-(2-fluorobenzoyl)-4-[3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine
1-(4-trifluoromethylbenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-benzoyl-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-bromobenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(4-trifluoromethylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(3-nitro-4-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-benzoyl-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-chlorobenzoyl)-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(2-fluorobenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-hexylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(2-chloro-4-nitrobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methyl-piperazine,
1-(1,3-benzodioxol-5-ylcarbonyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine
1-(3-fluorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(4-tert-butylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-benzoyl-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-butylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-tert-butylbenzoyl)-4-[3-(4-methylbenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-nitrobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-2-methylpiperazine,
1-(2-methylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(2-ethoxyphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(2-fluorophenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(3-trifluoromethylphenyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine,
1-(4-chlorobenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-1,4-diazepane,
1-(4-methylbenzoyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-1,4-diazepane,
1-(1,3-benzodioxol-5-ylcarbonyl)-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]-1,4-diazepane,
1-[4-methoxyphenylsulfonyl]-4-[3-(3-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(2-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[2-methoxyphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-ethoxyphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-ethylphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-phenylsulfonyl-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-(4-propionyloxy)benzene-sulfonyl-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]-piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(3-methyl-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(2-methyl-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(2-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(3-methyl-4-fluoro-benzyl-1,2,4-thiadiazol-5-yl]-piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(4-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-bromophenylsulfonyl]-4-[3-(3-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(3-methoxybenzyl)-1,2,4-thia-diazol-5-yl]-2-methyl-piperazine;
1-(4-hydroxybenzenesulfonyl)-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine; and 1-(thien-2-ylsulfonyl)-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine.

### Claim 26

A 1,2,4-thiadiazole derivative selected from the group consisting of:
1-[3-methoxyphenylsulfonyl]-4-[3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(3-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(2-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[2-methoxyphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-ethoxyphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-ethylphenylsulfonyl]-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-phenylsulfonyl-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-(4-propionyloxy)benzene-sulfonyl-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]-piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(3-methyl-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(2-methyl-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(2-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(3-methyl-4-fluoro-benzyl-1,2,4-thiadiazol-5-yl]-piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(4-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-bromophenylsulfonyl]-4-[3-(3-methoxy-benzyl-1,2,4-thiadiazol-5-yl]piperazine;
1-[4-methoxyphenylsulfonyl]-4-[3-(3-methoxybenzyl)-1,2,4-thia-diazol-5-yl]-2-methyl-piperazine; and
1-(4-hydroxybenzenesulfonyl)-4-[3-(4-fluoro-benzyl)-1,2,4-thiadiazol-5-yl]piperazine.

### Claim 27 (depends on 1)

The pharmaceutical composition according to claim 1, further comprising a therapeutic amount of one or more drugs selected from the group consisting of neuro-protective agents and α-synuclein deposition inhibitors.

### Claim 28

A method of treating an α-synucleopathy, comprising the administration of a therapeutic effective amount of a 1,2,4-thiadiazole derivative to a patient in need thereof, optionally in combination with one or more pharmaceutically acceptable carriers, and optionally in combination with a therapeutic amount of one or more drugs selected from the group consisting of neuro-protective agents and α-synuclein deposition inhibitors, wherein said α-synucleopathy is selected from the group consisting of Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, multiple system atrophy and Alzheimer's disease and wherein said 1,2,4-thiadiazole derivative is according to the structural formula (A)
wherein the divalent group schematically represented by the structural formula (A′)
includes an optionally mono-substituted or poly-substituted, saturated or partly unsaturated heterocyclic ring with at least two nitrogen atoms in the said heterocyclic ring and with a total of 5 to 7 atoms in the said heterocyclic ring, and further wherein:
R6 is a substituent independently selected from the group consisting of oxo and C1-4 alkyl;
n is selected from the group consisting of 0, 1, 2 and 3;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkoxy, aryl, aryloxy, alkyloxy, aryl-C1-4 alkloxy, heteroaryloxy, benzenesulfonate, amino, hydroxy, nitro, trifluoromethyl, trifluoromethoxy and halogen, or any two adjacent substituents selected from the group consisting of R1, R2, R3, R4 and R5 form, together with the phenyl ring carbon atoms to which they are attached, a saturated or unsaturated ring fused to said phenyl ring and having from 5 to 7 ring members, said saturated or unsaturated ring optionally having one or two oxygen atoms and being optionally substituted with one or more halogen atoms;
R7, R8, R9, R10, and R11 are each independently selected from the group consisting of hydrogen, C1-10 alkyl, C1-6 alkoxy, C1-4 alkylthio, C2-4 alkenyl, C3-8 cycloalkyl, aryl, hydroxy, acetyl, nitro, trifluoromethyl and halogen; or any two adjacent substituents selected from the group consisting of R7, R8, R9, R10 and R11 form, together with the phenyl ring carbon atoms to which they are attached, a saturated or unsaturated ring fused to said phenyl ring and having from 5 to 7 ring members, said saturated or unsaturated ring optionally having one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; and each of said C1-6 alkyl, C1-6 alkoxy, aryl or fused ring is optionally substituted with one or more halogen atoms;
R12 and R13 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, aryl-C1-4 alkyl, aryl and N-containing heterocyclic rings, or R12 and R13 together form a C3-6 cycloalkyl or heterocyclic group; and
X is a linking moiety selected from the group consisting of —C(═O)—; —S(═O)2—; divalent saturated non-cyclic hydrocarbon groups having from 1 to 6 atoms in the main chain, each of said atoms in the main chain being independently selected from the group consisting of carbon, nitrogen and sulfur, each of said carbon atoms in the main chain being optionally substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, C1-4 alkyl and halogen, and each of said sulfur atoms in the main chain being optionally substituted with oxo, provided that the number of heteroatoms in the main chain of said divalent saturated or unsaturated non-cyclic hydrocarbon group is 0, 1 or 2, wherein a first terminal atom of the main chain is connected to the structural formula (A′) and a second terminal atom of the main chain is connected to the
group of structural formula (A): and divalent saturated or unsaturated heterocyclic groups having from 2 to 6 carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen in the said heterocyclic group; or X together with one of R7 and R11 forms a saturated or unsaturated ring having from 5 to 7 ring members and being fused to the phenyl ring bearing said one of R7 and R11, said saturated or unsaturated ring optionally having one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, and said saturated or unsaturated ring optionally having one or more substituents independently selected from the group consisting of C1-4 alkyl and trifluoromethyl or is selected from the group consisting of —CO—CH═CH—, —CH2—CH═CH— and —SO2—CH═CH—.