BRPI0718520A2 - COMPOSITION, METHODS FOR ADENOSINE A1 RECEPTOR MODULATION AND FOR THE TREATMENT OF CONDITIONS MEDIATED BY ADENOSINE A1 RECEIVER IN MAMMALS, PHARMACEUTICAL COMPOSITION, AND USES OF A COMPOSITION AND A COMPOUND - Google Patents

Description

I “COMPOUND, METHODS FOR ADENOSINE A1 RECEPTOR MODULATION AND FOR THE TREATMENT OF CONDITIONS MEDIATED BY THE ADENOSINE A1 RECEIVER IN MAMMALS, PHARMACEUTICAL COMPOSITION, AND USES OF A COMPOSITION AND A COMPOUND”

The present invention relates to 2-aminothiophene derivatives, pharmaceutical compositions containing them, and methods of treating adenosine A1 receptor mediated conditions including pain, in particular chronic pain such as neuropathic pain, disorder or heart disease. as cardiac arrhythmias, e.g. peroxisomal supraventricular tachycardia, angina, myocardial infarction and stroke, neurological injury or disease, sleep disturbance, epilepsy and depression via the use of such compounds.

Thus, the present invention provides compounds of formula

(I)

(«)

on what

R1 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl or substituted cycloalkyl;

R 2, R 3, and R 4 are, independently of each other, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy or substituted alkoxy;

Q is selected from the group consisting of% R. Rs-X N

.λt7

r N-

K5

M

Ra, R13 - R'12 R13

R10 R?

R «—X

'X N W.

1 ’~ 1 where

R5 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl or substituted acyl;

R6 and R7 are independently hydrogen, C1 -C3 alkyl or substituted C1 -C3 alkyl; or

R 6 and R 7, provided that they are attached to the same carbon atom, combined are alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered spirocyclic ring;

R 8, R 9, R 10, R 11, R 12 and R 13 are independently from each other hydrogen, C 1 -C 3 alkyl or substituted C 1 -C 3 alkyl;

X is N or C-H; or

X is C-NR 14 R 15, wherein R 14 and R 15 are independently from each other hydrogen, C1 -C3 alkyl, substituted C1 -C3 aryl, aryl or substituted aryl; or

X is C-Ri 6, where combined Ri6 and R5 are an oxygen

carbonyl; or

X is C-R 16, where R 16 and R 5 combined are a divalent radical of the formula

<-Y-CHR1 ^ (CH2) n-CHR18-Y-> which together with the carbon atom to which R16 and R5 are attached form a 5- to 7-membered spirocyclic ring and wherein

Y is oxygen or sulfur;

R11 and R18 are independently hydrogen, C1 -C6 alkyl, substituted C1 -C6 alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl;

n is zero, or an integer of 1 or 2; or X is C-R 1, wherein R 6 and R 5 combined are a divalent radical of the formula

which together with the carbon atom to which R16 and R5 are attached form a 5-membered spirocyclic ring, and wherein

Y is oxygen or sulfur;

R19 and R2O are independently hydrogen, halogen, cyano, trifluoromethyl, C1 -C6 alkyl, substituted C1 -C6 alkyl or C1 -C6 alkoxy; or a pharmaceutically acceptable salt thereof.

The compounds of the present invention provide pharmacological agents which are allosteric A 1 adenosine receptor modulators and thus may be employed for the treatment of Aj adenosine receptor mediated conditions. Thus, the compounds of formula (I) may be employed for the treatment of pain, in particular chronic pain, such as neuropathic pain, disorder or heart disease, such as cardiac arrhythmias, e.g. peroxisomal supraventricular tachycardia, angina, myocardial infarction and stroke, neurological injury or disease, sleep disturbance, epilepsy and depression.

Listed below are definitions of various terms used to describe the compounds of the present invention. These definitions apply to terms as they are used throughout this description, unless otherwise limited in specific cases, either individually or as part of a larger group, e.g. wherein a point of attachment of a particular group is limited to a specific atom in that group, the point of attachment 5 is defined by an arrow on the specific atom.

The term "alkyl" refers to a hydrocarbon chain having from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, and more preferably from 1 to 7 carbon atoms. The hydrocarbon chain may be straight, as in the case of a hexyl or n-butyl chain, or branched, such as t-butyl, 2-methylpentyl, 3-propylheptyl. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, and the like.

The term "substituted alkyl" refers to those alkyl groups 15 as described above substituted by one or more, preferably from 1 to 3, of the following groups: halo, hydroxy, alkanoyl, alkoxy, cycloalkyl, cycloalkoxy, alkanoyloxy, thiol alkylthio, alkylthio, sulfonyl, sulfamoyl, carbamoyl, cyano, carboxy, acyl, aryl, aryloxy, alkenyl, alkynyl, aralkoxy, guanidino, optionally substituted amino, heterocyclyl including imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyridyl, analogues.

The term "lower alkyl" refers to those alkyl groups as described above having from 1 to 6, preferably from 1 to 4 carbon atoms.

The term "alkenyl" refers to any of the above alkyl groups having at least two carbon atoms and additionally containing a carbon-carbon double bond at the point of attachment. Groups having from 2 to 6 carbon atoms are preferred.

The term "alkynyl" refers to any of the above alkyl groups having at least two carbon atoms and additionally containing a triple carbon-carbon bond at the point of attachment. Groups having from 2 to 6 carbon atoms are preferred.

The term "alkylene" refers to a straight chain tip of 1 to 6 carbon atoms connected by single bonds, e.g. eg, (CH2) x-, where x is 1-6, in those cases where x is greater than 1, the chain may be interrupted by one or more groups selected from O, S, S (O) Wherein S may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl, acyl, carbamoyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl or S (O) 2. aralkoxycarbonyl and 10 analogs; and alkylene may be further substituted by one or more substituents selected from optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, oxo, halogen, hydroxy, carboxy, alkoxy, alkoxycarbonyl and the like.

The term "cycloalkyl" refers to monocyclic, bicyclic or tricyclic hydrocarbon groups of 3 to 12 carbon atoms, each of which may contain one or more carbon-carbon double bonds.

The term "substituted cycloalkyl" refers to those cycloalkyl groups as described above substituted by one or more substituents, preferably from 1 to 3, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, cyano, carboxy, alkoxycarbonyl, sulfonyl, sulfonamide sulfamoyl, heterocyclyl and the like.

Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 4,4-dimethylcyclohex-1-yl, cyclooctenyl and the like.

Exemplary bicyclic hydrocarbon groups include bomyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, 6,6-dimethylbicyclo [3.1.1] heptyl 2,6,6-trimethylbicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl and the like.

Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

In the definitions listed here, when a reference to a

alkyl, cycloalkyl, alkenyl or alkynyl group is part of the term; it also includes a substituted alkyl, cycloalkyl, alkenyl or alkynyl group.

The term "alkoxy" refers to alkyl-O-.

The term "cycloalkoxy" refers to cycloalkyl-O-.

The term "alkanoyl" refers to C (O) alkyl-.

The term "cycloalkanoyl" refers to C (O) - cycloalkyl.

The term "alkenyl" refers to alkenyl-C (O) -.

The term "alkynoyl" refers to alkynyl-C (O) -.

The term "alkanoyloxy" refers to C (O) -0- alkyl.

The terms "alkylamino" and "dialkylamino" refer to alkyl-NH- and (alkyl) 2N-, respectively.

The term "alkanoylamino" refers to alkyl-C (O) -NH-.

The term "alkylthio" refers to alkyl-S-.

The term "trialkylsilyl" refers to (alkyl) 3 Si.

The term "trialkylsilyloxy" refers to (alkyl) 3 SiO-.

The term "alkylthio" refers to alkyl-S (O) -.

The term "alkylsulfonyl" refers to alkyl-S (O) 2-.

The term "alkoxycarbonyl" refers to alkyl-O-C (O) -.

The term "alkoxycarbonyloxy" refers to alkyl-0-C (0) 0-

The term "carbamoyl" refers to H2NC (O) -, alkyl-NHC (O) -, (alkyl) 2NC (0) -, aryl-NHC (O) -, alkyl (aryl) -NC (0) - , heteroaryl-NHC (O) -, alkyl (heteroaryl) -NC (0) -, aralkyl-NHC (O) -, alkyl (aralkyl) -NC (0) - and the like. The term "sulfamoyl" refers to H2NS (O) 2-, alkyl-NHS (0) 2-, (alkyl) 2NS (0) 2-, aryl-NHS (0) 2-, alkyl (aryl) -NS (0) 2-, (aryl) 2NS (0) 2-, heteroaryl-N HS (O) 2-, aralkyl-NHS (0) 2-, heteroaryl-N HS (O) 2- and the like.

The term "sulfonamido" refers to alkyl-S (O) 2-NH-, aryl-

S (O) 2-NH-, aralkyl-S (0) 2-NH-, heteroaryl-S (0) 2-NH-, heteroaralkyl-S (0) 2-NH-, alkyl-S (0) 2- N (alkyl) -, aryl-S (0) 2-N (alkyl) -, aralkyl-S (0) 2-N (alkyl) -, heteroaryl-S (0) 2-N (alkyl) -, heteroaralkyl- S (0) 2-N (alkyl) - and the like.

The term "sulfonyl" refers to alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.

The term "optionally substituted amino" refers to a primary or secondary amino group which may be optionally substituted by a substituent such as acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,

aralkoxycarbonyl, heteroaralkoxycarbonyl, carbamoyl and the like.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having from 6 to 12 carbon atoms in the ring moiety, such as phenyl, biphenyl, naphthyl, 2,3-dihydro-1H-indenyl and tetrahydronaphthyl.

The term "substituted aryl" refers to those aryl groups as

described above substituted by from 1 to 4 substituents on each ring moiety, such as alkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, methylenedioxy, acyl, alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio, arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthio, sulfonyl, sulfonamido, heterocyclyl and the like.

The term "monocyclic aryl" refers to optionally substituted phenyl as described above under aryl. Preferably the monocyclic aryl is substituted with from 1 to 3 substituents selected from the group consisting of halogen, cyano or trifluoromethyl. In the definitions listed herein, when referring to an aryl group as part of the term, a substituted aryl group is also understood.

The term "aralkyl" refers to an aryl group bonded directly by an alkyl group such as benzyl.

The term "aralkanoyl" refers to aralkyl-C (O) -.

The term "aralkylthio" refers to aralkyl-S-,

The term "aralkoxy" refers to an aryl group bonded directly through an alkoxy group.

The term "arylsulfonyl" refers to aryl-S (O) 2-.

The term "arylthio" refers to aryl-S-.

The term "aroyl" refers to aryl-C (O) -.

The term "aroyloxy" refers to aryl-C (O) -0-.

The term "aroylamino" refers to aryl-C (O) -NH-.

The term "aryloxycarbonyl" refers to aryl-O-C (O) -.

The term "heterocyclyl" or "heterocycle" refers to a fully saturated or unsaturated non-aromatic or aromatic cyclic group, e.g. e.g., which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10 to 15-membered tricyclic ring system having at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing one heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where nitrogen and sulfur heteroatoms may also be optionally oxidized. The heterocyclic group 25 may be attached to a heteroatom or a carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiathiazolidyl thiazolidyl, thiazolidyl, thiazolyl, thiazolyl , piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl (pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thymorpholinyl,

thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, 1,4,4-trioxo-1,2,5-thiadiazolidin-2-yl and the like.

Exemplary bicyclic heterocyclic groups include indolyl, diidroidolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,

decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,2-bjpyridinyl or iuro] -b] pyridinyl), dihydroisoindolyl, 1,3-dioxo-1,3-dihydroisoindol-2-yl, dihydroquinazolinyl (as 3,4-dihydro-4-oxo-quinazolinyl), phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, dibenzoazepinyl, dithenoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl and the like.

The term "substituted heterocyclyl" refers to those heterocyclic groups described above substituted heterocyclic groups substituted by 1, 2 or 3 substituents selected from the group consisting of the following:

(a) alkyl;

(b) hydroxyl (or protected hydroxyl);

(C) halo;

(d) oxo, i.e. = 0;

(e) optionally substituted amino;

(f) alkoxy; (g) cycloalkyl;

(h) carboxy;

(i) heterocyclooxy;

(j) alkoxycarbonyl as non-lower alkoxycarbonyl

substituted;

(k) thiol;

(1) nitro;

(m) cyano;

(n) sulfamoyl;

(o) alkanoyloxy;

(P) aroyloxy;

(q) arylthio;

(r) aryloxy;

(s) alkylthio;

(t) formyl;

(u) carbamoyl;

(v) aralkyl; and

(w) aryl optionally substituted by alkyl, cycloalkyl, alkoxy, hydroxyl, amino, acylamino, alkylamino, dialkylamino or halo.

The term "heterocyclooxy" denotes a heterocyclic group attached

by an oxygen bridge.

The term "heterocycloalkyl" refers to non-aromatic heterocyclic groups as described above.

The term "heteroaryl" refers to an aromatic heterocycle, e.g.

e.g. monocyclic or bicyclic aryl such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, fiiryl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzoylazoline, benzoylazoline, benzofuryl and the like, optionally substituted by e.g. eg halogen, cyano, nitro, trifluoromethyl, lower alkyl or lower alkoxy.

The term "heterocycloalkanoyl" refers to heterocycloalkyl

C (O) -.

The term "heteroarylsulfonyl" refers to methyletheraryl-S (O) 2-.

The term "heteroaryl" refers to heteroaryl-C (O) -.

The term "heteroarylamino" refers to heteroaryl-C (O) NH-.

The term "heteroarylalkyl" refers to a heteroaryl group attached via an alkyl group.

The term "heteroaralkanoyl" refers to heteroaralkyl-C (O) -.

The term "heteroaralkanoylamino" refers to heteroaralkylamino

C (O) NH-.

The term "acyl" refers to alkanoyl, cycloalkanoyl, alkenyl, alkynoyl, aroyl, heterocycloalkanoyl, heteroaryloyl, aralkanoyl, heteroaralkanoyl and the like.

The term "substituted acyl" refers to those acyl groups

described above, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocycloalkyl, heteroaryl, aralkyl or heteroaralkyl group are substituted as described herein above respectively.

The term "acylamino" refers to alkanoylamino, aroylamino, heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine

and iodine.

Pharmaceutically acceptable salts of the compounds of the present invention refer to salts formed with acids, ie acid addition salts such as mineral acids, organic carboxylic acids and organic sulfonic acids, e.g. hydrochloric acid, maleic acid and methanesulfonic acid respectively.

Similarly, pharmaceutically acceptable salts of the compounds of the invention refer to base-formed salts, i.e. cationic salts such as alkaline salts and alkaline earth metal salts, e.g. eg sodium, lithium, potassium, calcium and magnesium, and also ammonium salts, e.g. eg ammonium, trimethylammonium, diethylammonium and tris (hydroxymethyl) methylammonium salts and salts with amino acids provided that an acidic group forms part of the structure.

As described herein above, the present invention provides

2-aminothiophene derivatives of formula (I), pharmaceutical compositions containing them, methods for the preparation of said compounds, and methods of treating Aj adenosine receptor mediated conditions including, but not limited to, pain, in particular chronic pain, as neuropathic pain; heart disorder or disease such as congestive heart failure, cardiac arrhythmias, e.g. peroxisomal supraventricular, tachycardia, angina, myocardial infarction and stroke, neurological injury or disease, sleep disorders, epilepsy, depression, and various inflammatory conditions, by administering a therapeutically effective amount of a compound of the present invention. , or a pharmaceutical composition thereof.

Preferred are compounds of formula (I) wherein

R1 is hydrogen, alkyl, substituted alkyl, aryl or aryl

substituted;

or a pharmaceutical composition thereof.

Further preferred are compounds of formula (I),

designated as group A, where Q is

\ R1

/there is

on what

R5 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl, or substituted acyl; R a and R 7 are independently from each other hydrogen, C 1 -C 3 alkyl, or substituted C 1 -C 3 alkyl; or

R6 and R7, provided that they are attached to the same carbon atom, are combined alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered spirocyclic ring;

X is N or C-H; or

X is C-NR14 R15, wherein R14 and R15 are independently hydrogen, C1 -C3 alkyl, substituted C1 -C3 aryl, aryl, or substituted aryl; or

X is C-Ri6, where combined Ri6 and R5 are oxygen

carbonyl; or

X is C-R 16, where R 16 and R 5 combined are a divalent radical of the formula

Y-CHR17- (CH2) n-CHR18-Y-> which together with the carbon atom to which R16 and R5 are attached form a 5- to 7-membered spirocyclic ring and wherein

Y is oxygen or sulfur;

R 17 and R 18 are independently from each other hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl; n is zero, or an integer of 1 or 2; or X is C-R 16, where R 16 and R 5 combined are a radical

divalent of the formula

Y-

^ 19

which together with the carbon atom to which R16 and R5 are attached form a 5-membered spirocyclic ring, and wherein

Y is oxygen or sulfur;

R19 and R20 are independently from each other hydrogen, halogen, cyano, trifluoromethyl, C1 -C6 alkyl, substituted C1 -C6 alkyl, or C1 -C6 alkoxy;

or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in group A, designated as the group

B, where

XéN;

or a pharmaceutically acceptable salt thereof.

Preferred are compounds in group B having formula

(IA)

on what

R1 is hydrogen, alkyl, substituted alkyl, aryl or aryl

substituted;

R 2, R 3, and R 4 are independently from each other hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy, or substituted alkoxy;

R5 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl, or substituted acyl;

R6 and R7 are independently from each other hydrogen, C1 -C3 alkyl, or substituted C1 -C3 alkyl; or

R6 and R7, provided that they are attached to the same carbon atom, are combined alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered spirocyclic ring;

R8 and R9 are independently from each other hydrogen, C1 -C3 alkyl, or substituted C1 -C3 alkyl; or a pharmaceutically acceptable salt thereof.

Preferred are compounds of formula (IA) wherein R 1 is hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof.

Also preferred are compounds of formula (IA) wherein

R5 is monocyclic aryl optionally substituted by one to three substituents selected from the group consisting of halogen, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof.

Also preferred are compounds of formula (IA), designated as group C, wherein

R2 and R4 are hydrogen; or a pharmaceutically acceptable salt

of the same.

Compounds in group C wherein R 3 is halogen, cyano or trifluoromethyl are preferred;

or a pharmaceutically acceptable salt thereof.

Also preferred are compounds of formula (IA), designated as group D, wherein

R2 and R3 are hydrogen;

or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in group D wherein

R4 is halogen, cyano or trifluoromethyl;

or a pharmaceutically acceptable salt thereof.

Also preferred are compounds of formula (IA), designated as group E, wherein R6, R7, Re and R9 are independently from each other.

hydrogen, or C1 -C3 alkyl; or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in group E, designated as the group

F, wherein R 5 is monocyclic aryl optionally substituted by one to three substituents selected from the group consisting of halogen, cyano, or trifluoromethyl;

or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in group F, designated as the group

G, where

R2 and R4 are hydrogen;

or a pharmaceutically acceptable salt thereof.

Compounds in group G wherein R 3 is halogen, cyano or trifluoromethyl are preferred;

or a pharmaceutically acceptable salt thereof.

Further preferred are compounds in group G, wherein

R1 is hydrogen or C1 -C3 alkyl;

or a pharmaceutically acceptable salt thereof.

Also preferred are compounds in group F, designated as

group H where

R2 and R3 are hydrogen;

or a pharmaceutically acceptable salt thereof.

Preferred are compounds in group H wherein R4 is halogen, cyano or trifluoromethyl;

or a pharmaceutically acceptable salt thereof.

Further preferred are compounds in group H wherein

R1 is hydrogen or C1 -C3 alkyl;

or a pharmaceutically acceptable salt thereof.

Also preferred are compounds in group A, designated

like group I where

X is C-R 16, where R 16 and R 5 combined are a divalent radical of the formula which together with the carbon atom to which R 16 and R 5 are attached form a 5-membered spirocyclic ring and wherein

Y is oxygen;

R19 and R20 are independently from each other hydrogen, halogen, cyano, trifluoromethyl, C1 -C6 alkyl, substituted C1 -C6 alkyl, or C1 -C6 alkoxy;

or a pharmaceutically acceptable salt thereof.

Compounds in group I having formula (IB) are preferred.

substituted;

R 2, R 3, and R 4 are independently from each other hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy, or substituted alkoxy;

hydrogen, C1 -C3 alkyl, or substituted C1 -C3 alkyl; or

R19 and R20 are independently from each other hydrogen, halogen, cyano, trifluoromethyl, C1 -C6 alkyl, substituted C1 -C6 alkyl, or C1 -C6 alkoxy;

on what

10

R1 is hydrogen, alkyl, substituted alkyl, aryl or aryl

15

R6, R7, Rs and R9 are, independently of each other,

20

or a pharmaceutically acceptable salt thereof. Preferred are compounds of formula (IB) wherein R 1 is hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof. Also preferred are compounds of formula (IB) wherein R19 and R2O are independently hydrogen, halogen, cyano, trifluoromethyl, or C1 -C4 alkyl;

or a pharmaceutically acceptable salt thereof.

Also preferred are compounds of formula (IB) designated

like group J where

R2 and R4 are hydrogen;

or a pharmaceutically acceptable salt thereof.

Compounds in group J wherein R 3 is halogen, cyano or trifluoromethyl are preferred;

or a pharmaceutically acceptable salt thereof.

Also preferred are compounds of formula (IB), designated as group K, wherein

R2 and R3 are hydrogen;

or a pharmaceutically acceptable salt thereof.

Preferred are compounds in group K wherein

R4 is halogen, cyano or trifluoromethyl;

or a pharmaceutically acceptable salt thereof.

Also preferred are compounds of formula (IB), designated as group L, wherein

R6, R7, Re and R9 are hydrogen;

or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in group L, designated as the group

M, where

R19 and R20 are, independently of each other, hydrogen,

halogen, cyano, trifluoromethyl, or C1 -C4 alkyl;

or a pharmaceutically acceptable salt thereof.

Compounds in group M, designated as group N, wherein R2 and R4 are hydrogen are preferred; or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in group N, wherein

R3 is halogen, cyano or trifluoromethyl;

or a pharmaceutically acceptable salt thereof.

Further preferred are compounds in group N, wherein

R 1 is hydrogen or C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof.

Also preferred are compounds in group M, designated as group O, wherein

R2 and R3 are hydrogen;

or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in group O wherein

R4 is halogen, cyano or trifluoromethyl;

or a pharmaceutically acceptable salt thereof.

Further preferred are compounds in group O wherein

R 1 is hydrogen or C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof.

The compounds of the invention depending on the nature of the substituents may have one or more asymmetric centers. The resulting diastereoisomers, optical isomers, i.e. enantiomers, and geometric isomers, and mixtures thereof, are encompassed by the present invention.

Particular embodiments of the invention are: {2-Amino-4 - [(4-phenylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4-methylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4- [4 - ((4-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4- [4 - ((4-chlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4- [4 - ((4-methoxyphenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4-p-tolylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (pyridin-2-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (pyrimidin-2-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (3,4-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

4- {4 - [(5-Amino-4- (4-chlorobenzoyl) thiophen-3-yl) methyl] piperazin-1-yl} benzonitrile;

{2-Amino-4 - [(4- (3-chlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (2-chlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4- (2-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

1- {4 - [(5-Amino-4- (4-chlorobenzoyl) thiophen-3-yl) methyl] piperazin-1-yl} -2- (4-

chlorophenyl) ethanone;

{2-Amino-4 - [(4- (4-chlorobenzoyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (pyridin-4-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (benzo [d] dioxol-5-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone; {2-Amino-4 - [(4- (2,3-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (3-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (3,5-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

2- {4 - [(5-Amino-4- (4-chlorobenzoyl) thiophen-3-yl) methyl] piperazin-1-yl} -1- (4-chlorophenyl) ethanone;

{2-Amino-4 - [(4- (2,4-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4- (2,6-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (3-chloro-4-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4-cyclohexylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-chlorophenyl) piperidin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-nitrophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4-isopropyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4-naphthalen-1-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (3,4-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chloro phenyl) methanone;

{2-Amino-4 - [(4-cyclopentylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4-cycloheptylpiperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-chlorobenzyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4-benzylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

(2-Amino-4 - {[4- (2- (4-chlorophenyl) ethyl) piperazin-1-yl] methyl} thiophen-3-yl) (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-fluorobenzyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4-cyclooctylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

(2-Amino-4 - {[4- [3- (4-chlorophenyl) propyl] piperazin-1-yl] methyl} thiophen-3-yl) (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (2,4-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (2,5-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4- (2- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-chloro-3- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (2,4,6-trifluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (2-chloro-4-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4- (2-fluoro-4-chlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone; {2-Amino-4 - [(4- (3,5-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (2,6-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4- (trifluoromethoxy) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (pyridin-3-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4- (2,5-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (2,3-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-chlorophenyl) -3-methylpiperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} [3- (trifluoromethyl) phenyl] methanone;

{2-Amino-4 - [(4- (3-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} [3-

(trifluoromethyl) phenyl] methanone;

{2-Amino-4 - [(4- (2,6-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} [3- (trifluoromethyl) phenyl] methanone;

{2-Amino-4- (spiro [benzo [d] -dioxol-2,4'piperidine] r-ylmethyl) thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4- (5-t-butyl spiro [benzo [d] dioxo-2,4'-piperidine] r-ylmethyl) thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4- (4-fluorospiro [benzo [d] dioxo-2,4'-piperidine] -1'-ylmethyl) thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4- (4-methylspyro [benzo [d] dioxol-2,4'piperidin] r-ylmethyl) thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4- (5-methylspyro [benzo [d] dioxol-2,4'-piperidin] r-ylmethyl) thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4- [4 - ((4-chlorophenylamino) piperidin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-chlorophenyl) methylamino] piperidin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-chlorophenyl) diazepan-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(7- (4-chlorophenyl) -2,7-diaza-spironon-2-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

{2-Amino-4 - [(5- (4-chlorophenyl) hexahydropyrrolo [3,4-c] pyrrol-2-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(5- (4-chlorophenyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-fluorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chloro phenyl) methanone;

{2-Amino-5-methyl-4 - [(4-phenylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-5-methyl-4 - [(4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-chlorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-bromophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-iodophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-5-methyl-4 - [(4- (4-nitrophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-

chlorophenyl) methanone;

4- {4 - [(5-Amino-4- (4-chlorobenzoyl) -2-methylthiophen-3-yl) methyl] piperazin-1-one

yl} benzonitrile {2-Amino-4 - [(4-benzylpiperazin-1-yl) methyl) -5-methylthiophen-3-yl] (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-methoxyphenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-5-methyl-4 - [(4- p -tolylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (3,4-dichlorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-5-methyl-4 - [(4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

10 {2-Amino-4 - [(4- (3-chlorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-chloro-3- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-5-phenyl-4 - [(piperidin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- [4- (4-fluorophenyl) piperazin-1-yl) methyl] -5-ethylthiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-5-ethyl-4 - [(4-phenylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4 - [(4- (4-chlorophenyl) piperazin-1-yl) methyl] -5-ethylthiophen-3-yl} (4-chlorophenyl) methanone; and

{2-Amino-4 - [(4- (3-fluorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-

chlorophenyl) methanone;

or a pharmaceutically acceptable salt thereof.

Preferred embodiments of the present invention include, but are not limited to:

{2-Amino-4 - [(4-phenylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- [4 - ((4-chlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; and

{2-Amino-4- [4 - ((4-trifluoromethylphenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chloro phenyl) methanone;

or a pharmaceutically acceptable salt thereof.

Compounds of formula (I) may be prepared using methods well known in the art, or using modifications thereof, e.g. as outlined below in Scheme 1 for compounds of formula (I), wherein R 1 is hydrogen.

Scheme 1:

hXX

S— 'OH

(ID

protection

ASS)

NH, Ra

(IIi)

halogenation

QH

(SAW'}

halogenation

10

As exemplified in Scheme 1, compounds of formula (I) wherein R 1 is hydrogen, and R 2, R 3, R 4 and Q have a meaning as defined herein above, ie compounds of formula (I ') may be prepared by condensing them. a compound of formula (II) wherein R2, R3 and R4 have a meaning as defined hereinabove with 2,5-dimethyl-dithiane-2,5-diol of formula (N ') in the presence of a base, as triethylamine (TEA), diisopropylethylamine (DIEA), morpholine or N-methylmorpholine (NMM) in an organic solvent, such as a lower alcohol, preferably ethanol (EtOH), giving a compound of formula (III), wherein R2 R 3 and R 4 have a meaning as defined herein above.

Compounds of formula (II) are known, or, if unpublished, they may be prepared using methods well known in the art, or modifications thereof, e.g. as described in United States Patent No. 6,323,214.

A resulting compound of formula (III) may be converted to a compound (IV), wherein R2, R3 and R4 have a meaning as defined hereinabove, and the amino group was protected as a phthalimido group under 15 well-reacted conditions. known in the art, e.g. by treating a compound of formula (III) with phthalic anhydride in the presence of an acid such as acetic acid at an elevated temperature.

A resulting compound of formula (IV) may then be halogenated at the 5-position of the thiophene ring giving a compound of formula (V), wherein R2, R3 and R4 have a meaning as defined hereinbefore, and Hal i represents chloride, bromide or iodide using methods well known in the art, e.g. e.g., a compound of formula (IV) may be treated with a halogenating agent such as N-halosuccinimide, e.g. N-bromosuccinimide, in the presence of a catalyst, such as benzoyl peroxide, and an inert organic solvent, such as an aromatic hydrocarbon, e.g. benzene, giving a compound of formula (V) wherein Hali is, e.g. eg bromide.

Subsequent reaction of a resulting compound of formula (V) with a halogenating agent such as N-halosuccinimide, e.g. N-bromosuccinimide, in the presence of a catalyst such as benzoyl peroxide and an organic solvent such as a halogenated hydrocarbon, e.g. carbon tetrachloride or dichloroethane, gives a compound of formula (VI) wherein R2, R3 and R4 have a meaning as defined hereinabove, and Hali and Hal2 independently represent chloride, bromide or iodide.

A resulting compound of formula (VI) may then be coupled with an amine of formula (VI '), wherein Q has a meaning as defined hereinbefore, in the presence of a base such as TEA, DIEA, NMM, or potassium carbonate. or cesium, and a suitable organic solvent such as dichloromethane (DCM), chloroform (CHCl3) and N, N-dimethylformamide (DMF), giving a compound of formula (VII), wherein R2, R3, R4, Q and Hal1 have a meaning as defined herein above.

Amines of formula (VI ') are known, or, if unpublished, they may be prepared using methods well known in the art, or modifications thereof.

A resulting compound of formula (VII) may then be dehalogenated in the presence of a reducing agent, e.g. e.g. molecular hydrogen in the presence of a catalyst such as palladium on carbon and an organic solvent such as ethyl acetate (EtOAc), a lower alcohol, e.g. EtOH and methanol (MeOH), tetrahydrofuran (THF) or DMF, giving a compound of formula (VIII), wherein R2, R3, R4 and Q have a meaning as defined herein above. Preferably, dehalogenation is conducted in the presence of an extrinsic base, e.g. e.g., TEA.

Finally, a compound of formula (VIII) may be converted to a compound of formula (I '), wherein R2, R3, R4 and Q have a meaning as defined hereinabove by removal of the phthalimide protecting group, P. by treatment with hydrazine in an organic solvent such as lower alcohol, e.g. eg EtOH.

As exemplified in Scheme 2, compounds of formula (I),

15

wherein R1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and R2, R3, R4, and Q have a meaning as defined hereinbefore may be prepared by reacting a compound of formula (II ) wherein R 2, R 3, and R 4 have a meaning as defined hereinabove with a ketone of formula (IX) wherein R 1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl in the presence of sulfur elemental and an appropriate base such as TEA, DIEA, morpholine or NMM, preferably morpholine, in an organic solvent, such as a lower alcohol, preferably EtOH, giving a compound of formula (ΙΙΓ), wherein R1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and R2, R3, and R4 have a meaning as defined herein above.

protection

Alternatively, compounds of formula (II), wherein R2, R3, and R4 have a meaning as defined hereinbefore, may be condensed first (Knoevenagel condensation). ) with a ketone of formula (IX) wherein R 1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl in the presence of a weak base such as piperidine, pyrrolidine, morpholine or β-alanine and a solvent such as benzene or toluene, giving a compound of the formula

Wherein R 1, R 2, R 3, and R 4 have a meaning as defined hereinabove as a mixture of isomers E and Z. Preferably, condensation is conducted in the presence of an organic acid, such as acetic acid, at a temperature close to boiling point of the solvent. A subsequent treatment of a compound of formula (IX ') with an elemental sulfur and an appropriate base, such as TEA, DIEA, morpholine or NMM, preferably TEA, in an organic solvent such as a lower alcohol, preferably EtOH. , then gives a compound of formula (III '), wherein R 1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and R 2, R 3, and R 4 have a meaning as defined herein above.

Compounds of formula (IX) are known or, if

unpublished, they may be prepared using methods well known in the art, or modifications thereof.

A resulting compound of formula (III ') can then be converted to a compound (IV), wherein R1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and R2, R3, and R4 have a meaning as defined hereinabove by treating a compound (III ') with phthalic anhydride in the presence of an acid such as acetic acid at an elevated temperature.

Alternatively, compounds of formula (IV), wherein R 1 is aryl or substituted aryl, and R 2, R 3, and R 4 have a meaning as defined hereinbefore may be obtained by coupling a compound of formula (V) in whereas Hal 1, R 2, R 3, and R 4 have a meaning as defined hereinabove in the presence of a catalyst, preferably a palladium catalyst, e.g. palladium (II) acetate or tetrakis (triphenylphosph) palladium (0), and a base such as sodium hydroxide (NaOH) or sodium potassium or cesium carbonate in a suitable solvent, e.g. acetonitrile, DMF, dimethoxyethane 5 (DME) or toluene, or a mixture of solvents thereof, with a compound of the formula

? "R

.Bn (V)

River

wherein R1 is aryl or substituted aryl, and R 'and R "are hydrogen or lower alkyl, or R1 and R" combined are alkylene which together with boron and oxygen atoms form a 5- or 6-membered ring giving a compound of formula (IV) wherein R 1 is aryl or substituted aryl. Preferably, R 'and R "are hydrogen, and the above coupling reaction, ie, Suzuki reaction, is conducted in toluene in the presence of tetrakis (triphenylphosphine) palladium (0), and potassium carbonate (K2CO3) at a temperature. near the boiling point of the solvent.

Compounds of formula (V) are known, or, if they are

unpublished, they may be prepared using methods well known in the art, or modifications thereof.

A resulting compound of formula (IV) may then be halogenated to the methyl group at the 4-position of the thiophene ring giving a compound 20 of formula (X) wherein R 1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, R 2, R 3, and R 4 have a meaning as defined hereinabove, and Hal 2 represents chloride, bromide or iodide, using methods well known in the art, e.g. by reaction of a compound of formula (IVf) with a halogenating agent such as an N-25 halosuccinimide, e.g. ex. N-bromosuccinimide in the presence of a catalyst such as benzoyl peroxide and an organic solvent such as acetonitrile (ACN) or a halogenated hydrocarbon, e.g. e.g. carbon tetrachloride or dichloroethane. It should be noted that halogenation of the methyl group at the 4-position of the thiophene ring of the compounds of formula (VI ') may be conducted in the absence of a catalyst when ACN is employed as the solvent.

A resulting compound of formula (X) may then be coupled with an amine of formula (VI '), wherein Q has a meaning as defined hereinbefore, in the presence of a base such as TEA, DIEA, NMM, or potassium carbonate. or cesium, and an appropriate organic solvent, such as DCM, CHCl 3 and DMF, giving a compound of formula (XI) wherein R 1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and R 2, R 3, R 4 Q have a meaning as defined herein above.

Finally, a compound of formula (XI) may be converted to a compound of formula (I) wherein R1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and R2, R3, R4 and Q have a meaning as defined hereinabove by removing the phthalimide protecting group as described hereinabove.

The processes described hereinabove may be conducted in an inert atmosphere, preferably in a nitrogen or argon atmosphere.

In starting compounds and intermediates which are converted to the compounds of the present invention in a manner described herein, functional groups present, such as amino, thiol, carboxyl and hydroxyl groups, are optionally protected by conventional protecting groups which are common in preparative organic chemistry. . Protected amino, thiol, carboxyl and hydroxyl groups are those that can be converted under mild conditions to free amino thiol, carboxyl and hydroxyl groups without the molecular structure being destroyed, or other unwanted side reactions occur.

The purpose of introducing protecting groups is to protect functional groups from unwanted reactions with reaction components under conditions used to perform a desired chemical transformation. The necessity and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxyl group, amino group, etc.), the structure and stability of the molecule from which it is present. substituent is a part, and the reaction conditions.

Well-known protecting groups that meet these conditions and their introduction and removal are described, e.g. e.g., in McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, NY (1973); and Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, Inc., NY (1999).

The conditions mentioned above are carried out according to conventional methods, in the presence or absence of diluent, preferably as those which are inert to the reagents and are solvents thereof, catalysts, condensing or said other agents, respectively and / or inert atmospheres, at low temperatures, room temperature (rt) or elevated temperatures, preferably at or near the boiling point of the solvents used, and at atmospheric or superatmospheric pressure. Preferred solvents, catalysts and reaction conditions are given in the accompanying illustrative Examples.

The invention further includes any variant of the present processes, wherein an intermediate obtainable at any stage thereof is used as a starting material, and the remaining steps are performed, or wherein the reaction components are used in the form of their salts.

Compounds of the invention and intermediates may also be converted to one another according to generally known methods.

per se.

The present invention also relates to any unpublished starting materials, intermediates and processes for their manufacture. Depending on the choice of starting materials and methods, the novel compounds may be in the form of one of the possible isomers or mixtures thereof, for example as substantially pure (cis or trans) geometric isomers, diaesteromers, optical isomers, racemized or mixtures thereof. same. The previously indicated possible isomers or mixtures thereof are within the scope of the present invention.

Any resulting mixtures of isomers may be separated based on physicochemical differences of constituents, pure optical or geometric isomers, diaesteromers, for example by fractional crystallization and / or chromatography, e.g. by high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Finally, compounds of the invention are obtained, either in free form or in a salt form thereof, preferably in a pharmaceutically acceptable form thereof.

In particular, compounds of the invention which contain basic groups may be converted to acid addition salts, particularly pharmaceutically acceptable acid addition salts. These are formed, e.g. eg with inorganic acids such as mineral acids e.g. sulfuric acid, phosphoric acid or hydroalic acid, or with organic carboxylic acids such as (C1 -C4) alkanecarboxylic acids which e.g. eg are unsubstituted or substituted by halogen, e.g. acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g. oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, e.g. eg glycolic, lactic, malic, tartaric or citric acid such as amino acids, e.g. aspartic acid or glutamic acid, or with organic sulfonic acids such as (C1 -C4) alkylsulfonic acids, e.g. e.g. methanesulfonic acid; or arylsulfonic acids that are unsubstituted or substituted (for example by halogen). Salts formed with hydrochloric acid, maleic acid and methanesulfonic acid are preferred. Salts may be formed using conventional methods, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alcohol. Of the latter solutions, salts may be precipitated with ethers, e.g. eg with diethyl ether or petroleum ether. Resulting salts may be converted to the free compounds by treatment with an advantageous base, e.g. e.g. sodium hydroxide. These or other salts may also be used for purification of the obtained compounds.

Considering the close relationship between free compounds and compounds in the form of their salts, where a compound is preferred over a corresponding salt is also desired, provided that it is possible or appropriate under the circumstances.

The compounds, including salts thereof, may also be obtained

in the form of their hydrates, or include other solvents used for their crystallization.

As described hereinabove, the compounds of the present invention are allosteric A1 adenosine receptor modulators. Thus, the present invention provides a method for modulating the adenosine A 1 receptor in mammals, wherein said method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I).

Additionally, compounds of formula (I) may be employed for the treatment of adenosine A1 receptor mediated conditions. Therefore, said compounds may be employed therapeutically for the treatment of pain, in particular chronic pain such as neuropathic pain, disorder or heart disease such as cardiac dysrhythmias, e.g. peroxisomal supraventricular tachycardia, angina, myocardial infarction and stroke, neurological injury or disease, sleep disturbance, epilepsy and depression.

In other words, the present invention provides a method for treating adenosine A 1 receptor-mediated conditions which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention.

As used in the description and claims, the term "treatment" encompasses all different forms or modes of treatment as known to those of skill in the relevant art, and in particular includes preventative, curative, retardation of progression and palliative treatment.

The term "therapeutically effective amount" as used herein refers to an amount of a medicament or therapeutic agent that will elicit the desired clinical or biological response of a tissue, system, or animal (including Man) being sought. by a researcher or clinician.

The terms "mammal" or "patient" are used interchangeably herein and include, but are not limited to, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits, mice, and laboratory animals. Preferred mammals are humans.

Preferably, the methods of the present invention are directed to the treatment of pain, generally including pain control, and particularly treatment and control of chronic pain, particularly neuropathic pain. Neuropathic pain has been recognized as pain resulting from some type of pathological damage to the nervous system, or condition related to the nervous system. Various types of neuropathic pain may be treated according to the present invention, e.g. eg, diabetic neuropathy and postherpetic neuralgia. Additional pathological conditions that may give rise to neuropathic pain and which may be treated in accordance with the present invention include trigeminal neuralgia, AIDS-associated neuropathies due to HIV infection and / or treatment, pain associated with cancer treatment, whiplash pain, phantom limb pain, traumatic injury pain, complex regional pain syndrome, and pain due to peripheral vascular disease. Additionally, methods of the present invention will be useful for the control and treatment of postoperative pain.

Preferred methods of the invention also include treating disorder or heart disease, and ischemia-induced lesions, e.g. eg cardiac arrhythmias, angina, myocardial infarction, stroke, and 10 analogs. Typical subjects for such treatments include, e.g. eg, myocardial infarction, stroke, patients with spinal or brain injury, patients undergoing major surgery such as cardiac surgery where cerebral ischemia is a potential complication, and the like.

Similarly, the present invention provides a

method as defined above comprising co-administration, e.g. concomitantly or sequentially, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a second drug substance, wherein said second drug substance is a hypolipidemic agent, an anti-inflammatory agent, an antihypertensive agent or an opioid analgesic agent, e.g. as indicated here below.

The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention alone or in combination with one or more pharmaceutically acceptable carriers.

In carrying out the methods of the present invention, the allosteric A1 adenosine receptor enhancers of the present invention may be formulated into advantageous pharmaceutical compositions for administration by a variety of routes, e.g. enteral, as by oral or rectal, transdermal, intrathecal and parenteral administration to mammals, including humans, for the treatment of adenosine A receptor-mediated conditions]. Such conditions include, but are not limited to, pain, in particular chronic pain such as neuropathic pain, disorder or heart disease such as cardiac arrhythmias, e.g. peroxisomal supraventricular tachycardia, angina, myocardial infarction and stroke, neurological injury or disease, sleep disturbance, epilepsy and depression.

For oral administration the pharmaceutical composition comprising an adenosine A1 allosteric receptor enhancer, or a pharmaceutically acceptable salt thereof, may be in the form of solutions, suspensions, tablets, pills, capsules, powders, microemulsions, unit dose packets and the like.

Thus, the compounds of the present invention may be employed in the manufacture of pharmaceutical compositions comprising an effective amount thereof together or in admixture with advantageous excipients or carriers for administration through a variety of routes, in particular for enteral or parenteral application. Hardcover or soft gelatin tablets and capsules are preferred comprising the active ingredient together with: a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine and / or vegetable oils;

b) lubricants, e.g. e.g. silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets too

c) binders, e.g. aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or

polyvinylpyrrolidone; and if desired

d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or

e) absorbents, colorings, flavorings and sweeteners. Injectable compositions are preferably aqueous isotonic suspensions or solutions, and suppositories are advantageously prepared from suspensions or fatty emulsions.

Said compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, humectants or emulsifiers, solution promoters, osmotic pressure regulating salts and / or buffers. Additionally, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain from about 0.1-75%, preferably from about 1 to 50%, of the active ingredient.

Advantageous formulations for transdermal application include a therapeutically effective amount of a carrier compound of the invention. Advantageous carriers include pharmaceutically acceptable absorbable solvents to aid passage through the skin of the host. Typically, transdermal devices are in the form of a bandage comprising a liner element, a reservoir containing the optionally carrier compound, optionally a rate-controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate to the host. over an extended period of time, and means for attaching the device to the skin.

A unit dosage for a mammal of about 50 to 70 kg may contain from about 0.005 mg to 2000 mg, advantageously from about 1 to 1000 mg of the active ingredient. The therapeutically effective dosage of active compound is dependent on the species of warm-blooded animal (mammal), body weight, age and individual condition, the form of administration, and the compound involved.

Thus, the present invention provides pharmaceutical compositions as described above for the treatment of adenosine A 1 receptor mediated conditions including pain, in particular chronic pain, such as neuropathic pain, disorder or heart disease, such as cardiac arrhythmias, e.g. peroxisomal supraventricular tachycardia, angina, myocardial infarction and stroke, neurological injury or disease, sleep disturbance, epilepsy and depression.

Pharmaceutical compositions may contain a therapeutically effective amount of a compound of the invention as defined above, either alone or in combination with another therapeutic agent, e.g. each at an effective therapeutic dose as reported in the art. Such therapeutic agents include:

a) hypolipidemic agents such as HMG-CoA (3-hydroxy-3-methyl-glutaryl coenzyme A) reductase inhibitors, squalene synthase inhibitors, FXR (famesoid receptor X) and LXR (liver receptor X) ligands, cholestyramine , fibrates, nicotinic acid and aspirin;

b) anti-inflammatory agents;

c) antihypertensive agents, e.g. loop diuretics, angiotensin converting enzyme (ACE) inhibitors, Na-K-ATPase membrane pump inhibitors, NEP (neutral endopeptidase) inhibitors, ACE / NEP inhibitors, angiotensin II antagonists, renin inhibitors ,

β-adrenergic receptor blockers, inotropic agents, calcium channel blockers, aldosterone receptor antagonists, and aldosterone synthase inhibitors; and

d) opioid analgesic agents.

As described above, a compound of the present invention may be administered either simultaneously, before or after the other active ingredient, or separately by the same or different route of administration, or together in the same pharmaceutical formulation.

The structure of the therapeutic agents known by their generic or trade names may be obtained, e.g. eg from the current edition of the conventional compendium "The Merck Index" or databases, p. International Patents (eg, IMS World Publications). Any person skilled in the art is fully capable of identifying active agents and, based on these references, is also able to manufacture and test pharmaceutical indications and properties in conventional test models, both in vitro and in vivo.

Thus, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with another therapeutic agent, preferably selected from hypolipidemic agents, anti-inflammatory agents, hypertensive agents and opioid analgesic agents.

Since the present invention has an aspect which relates to treatment with a combination of compounds which may be co-administered separately, the invention also relates to the combination of separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: (1) a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, plus a pharmaceutically acceptable diluent or carrier; and (2) a composition comprising a hypolipidemic agent, an antiinflammatory agent, an antihypertensive agent, or an opioid analgesic agent, or a pharmaceutically acceptable salt thereof, plus a pharmaceutically acceptable diluent or carrier. The amounts of (1) and (2) are such that, when co-administered separately, a beneficial therapeutic effect (s) is obtained. The kit comprises a container for containing the separate compositions, such as a split vial or a split laminate package, wherein each compartment contains a plurality of dosage forms (e.g. tablets) comprising (1) or (2). Alternatively, instead of separating the active ingredient containing dosage forms, the kit may contain separate compartments, each of which contains an integral dosage which in turn comprises separate dosage forms. An example of such a kit is a blister pack, wherein each individual blister contains two (or more) tablets, one (or more) tablet (s) comprising a pharmaceutical composition (1), and the second (or more) tablet. tablet (s) comprises a pharmaceutical composition (2). Typically the kit comprises instructions for administering the separate components. The kit form is particularly advantageous when the separate components are administered separately in different dosage forms (e.g. oral and parenteral), when they are administered at different dosage intervals, or when the prescribing physician wishes to titrate the components. individual combinations. In the case of the present invention a kit for this comprises:

(1) a therapeutically effective amount of a composition comprising a compound of formula (I), or a salt

pharmaceutically acceptable drug thereof, and a pharmaceutically acceptable diluent or carrier, in a first dosage form;

(2) a composition comprising a hypolipidemic agent, an anti-inflammatory agent, an antihypertensive agent, or

an opioid analgesic agent, or a pharmaceutically acceptable salt thereof, in such amount that upon administration a beneficial therapeutic effect (s) is obtained, and a pharmaceutically acceptable diluent or carrier in a second dosage form; and

(3) a container for containing said first and second dosage forms.

The present invention further relates to pharmaceutical compositions as described above for use as a medicament.

The present invention further relates to the use of pharmaceutical compositions or combinations as described above for the preparation of a medicament for the treatment of adenosine A 1 receptor mediated conditions including pain, in particular chronic pain such as neuropathic pain, disorder or disease. such as cardiac arrhythmias, e.g. peroxisomal supraventricular tachycardia, angina, myocardial infarction and stroke, neurological injury or disease, sleep disturbance, epilepsy and depression.

Thus, the present invention also relates to a compound of formula (I) for use as a medicament, the use of a compound of formula (I) for the preparation of a pharmaceutical composition for the treatment of receptor-mediated conditions. adenosine A 1, and a pharmaceutical composition for use under adenosine A 1 receptor mediated conditions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or diluent therefor.

Finally, the present invention provides a method or use

which comprises administering a compound of formula (I) in combination with a therapeutically effective amount of a hypolipidemic agent, an antiinflammatory agent, an antihypertensive agent or an opioid analgesic agent.

In conclusion, the present invention provides a method or

use comprising administering a compound of formula (I) in the form of a pharmaceutical composition as described herein.

The above properties can be demonstrated in in vitro and in vivo tests using advantageously mammals, e.g. eg 25 mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. Said compounds may be applied in vitro as solutions, e.g. preferably aqueous solutions, and in vivo, either enterally, parenterally, advantageously intrathecally or intravenously, e.g. as a suspension or in aqueous solution. The in vitro dosage may comprise concentrations between about 10 2 molar and 10 10 molar. A therapeutically effective amount in vivo may comprise, depending on the route of administration, from about 0.000001 mg / kg to 1000 mg / kg, preferably from about 0.00001 mg / kg to 100 mg / kg, more preferably. between about 0.001 mg / kg and 10 mg / kg.

The activity of compounds according to the invention may be evaluated using methods well described in the art, e.g. eg as described here below:

Membrane preparation from CHO cells transfected with recombinant human Au Ata and Aβ adenosine receptors:

HCHO-A_i, hCHO-A2A and IiCHO-A3 cell clones are grown adhesively and maintained in Dulbecco's modified Fal nutrient mixture Ealge medium containing 10% fetal calf serum, penicillin (100 U / ml), streptomycin (100 μg / ml), L-glutamine (2 mM), 15 geneticin (G418) 0.2 mg / ml at 37 ° C in 5% CO2 / 95% air. 30 min at 37 ° C (Klotz et al. Naunyn-Schmied. Arch Pharm. 1998, 357, from 1 to 9). Cells are divided two or three times a week in a ratio between 1: 5 and 1:10. For membrane preparation, the culture medium is removed. Cells are washed with PBS and scraped from T75 flasks in cold hypotonic buffer (5 mM Tris HCl, 2 mM EDTA, pH 7.4). The cell suspension is homogenized with Polytron and the homogenate is centrifuged for 10 min at 1,000 x g. The supernatant is then centrifuged for 30 min at 100,000 x g. Membrane pellet is resuspended in 50 mM Tris HCl pH 7.4 buffer for Adenosine Aj receptors, 50 mM buffer 25 Tris HCl pH 7.4, 10 mM MgCl2 for A2a adenosine receptors, 50 mM buffer Tris HCl pH 7.4, 10 mM MgCl 2, 1 mM EDTA to A3 adenosine receptors and incubated with 3 IU / ml adenosine deaminase for 30 min at 37 ° C. Protein concentration is determined according to a Bio-Rad method (Bradford, 1976) with bovine albumin as a standard reference.

Adenosine receptor binding experiments:

To determine the effect of the compounds of the present invention on binding to A1, A2a and A3 receptors, IiCHO-A1i hCHO-5 A2a, hCHO-A3 membranes are incubated in a buffer solution in the absence and presence of the compounds examined. Test agents are dissolved in DMSO and added to the assay from a 100-fold concentrated DMSO solution. Control incubations also contain 1% DMSO. Bound and free radioactivity are separated by filtration of the assay mixture 10 through Whatman GF / B fiberglass filters using a Micro-matte 196 cell cultivator (Packard Instrument Company). Filter bound radioactivity was counted with Top Count Microplate Scintillation Counter (57% efficacy) with Micro-Scint 20.

Saturation Binding of T3HlCCPA to IiCHO-A1:

[3HJCCPA saturation binding experiments (from 0.05

at 20 nM) to human A1 receptors expressed on CHO membranes are performed in triplicate at 25 ° C for 1 h in 50 mM Tris-HCl, pH 7.4, in the absence and presence of the tested compounds (10 μΜ). Nonspecific binding is defined as binding in the presence of 1 μΜ R-PIA.

Competition link from [3HlCCPA to IiCHO-A1:

Competition experiments are performed in triplicate in a final volume of 250 μΐ in test tubes containing 1 nM [3HJCCPA, 50 mM Tris-HCl, pH 7.4 and 100 μΐ diluted membranes and at least six to eight different concentrations of the tested compounds in the range 1 nM 25 to 50 μΜ for 90 min at 25 ° C (Baraldi et al. J. Med. Chem. 2003, 46, 794-809). Nonspecific binding is defined as binding in the presence of 1 μΜ R-PIA. Allosteric increment is measured as the action of different concentrations of the compounds tested to increase specific binding of I nM [3HJCCPA to IiCHO-A1 membranes. Competition binding experiments:

1 nM competition experiments for [H] DPCPX (Borea et al. Life Sciences 1996, 59, 1373-1388), 2 nM [3 H] ZM 241385 (Borea et al. Biochem. Pharmacol. 1995, 49, 461- 469) and 2 nM of [3H] MRE 3008F205 (Varani et al. Mol. Pharmacol. 2000, 57, 968-975) to IiCHO-A1, IiCHO-A2A and IiCHO-A3 are performed by incubating membranes (100 µg protein / assay) at 25 ° C for 90 min, at 4 ° C for 60 min and at 4 ° C for 150 min, respectively. Competition experiments are performed in duplicate in a final volume of 100 μΐ in test tubes containing 50 mM 10 Tris HCl buffer (10 mM MgCl2, 1 mM EDTA for A3), pH 7.4 and 100 μΐ membranes and at least six to eight different concentrations of the test compound. Non-specific binding is defined as binding in the presence of 1 μΜ of DPCPX, ZM 241385 and MRE 3008F20 for A1, A2a and A3, respectively, and is about 30% of total binding.

[3H] DPCPX (specific activity, 120 Ci / mmol) and [3HJCCPA

(specific activity, 55 Ci / mmol) can be obtained from NEN Research Products (Boston, MA); [3H] ZM 241385 (specific activity, 17 Ci / mmol) can be obtained from Tocris Cookson (Bristol, UK); [3HjMRE 3008F20 (specific activity, 67 Ci / mmol) can be obtained from Amersham International (Buckinghamshire, UK).

Measurement of cAMP increment in CHO cells (functional assay):

Allosteric increase is measured as the action of a test compound at different concentrations (0.01, 0.1, 1 and 10 μΜ) to reduce the cAMP content of hCHO-Αμ cells. Growth is removed from the 12-well plates and the cells are washed with hot Hank buffered saline. The wash solution is then removed and replaced with fresh Hank's solution containing forskolin (1 μΜ), rolipram (20 μΜ), N6-cyclopentyladenosine (CPA, 0.01 nM), adenosine deaminase (2 U / ml), and test compound. Forskolin is used to stimulate adenylyl cyclase activity, rolipram to inhibit cAMP phosphodiesterase, adenosine deaminase to degrade endogenous adenosine, and CPA to cause a small increase in the number of activated adenosine receptors. After 6 min incubation at 36 ° C in the presence of a test compound, the incubation solution is removed and hydrochloric acid (50 mM final concentration) is added to determine the action of the drug. The cAMP content in 20 acidified cell extracts is determined by radioimmunoassay as previously described (Kollias-Baker et al. J. Pharmacol. Exp. Ther. 1997, 281, 761-768). Because the magnitude of the effects of 10 allosteric modulators on IiCHO-A1 cells subtly change with the number of passages and differ slightly between different cell fractions, the actions of the test compounds and the action of a reference compound (PD 81,723) are evaluated in 25 each experiment. The effect of each test compound on cAMP content is presented as a percentage of the cAMP content value in the absence of drug (control, 100%).

Model of chronic inflammatory pain:

Intraplantar injection of zymosan-induced mechanical hyperalgesia can be used as a model of chronic inflammatory pain 20 (Meller et al., Neuropharmacology, 33: 1471-1478, 1994). In this model, typically male Sprague-Dawley or Wistar rats (200 to 250 g) receive an intraplantar injection of 3 mg / 100 μΐ zymosan in the hind paw. Marante inflammation occurs in this hind paw. Medicines for efficacy evaluation are usually administered 24 h after inflammatory aggression 25 when mechanical hyperalgesia is considered to be fully established.

Models of chronic neuropathic pain:

It is possible to use two animal models of chronic neuropathic pain that involve some form of peripheral nerve damage. In the Seltzer model (Seltzer et al., Pain, 43: 205-218, 1990) Sprague-Dawley or Wistar rats (200 to 250 g) are anesthetized and a small incision is made midway through a thigh (usually left) to expose the sciatic nerve. The nerve is carefully cleaned from surrounding connective tissues at a site near the trochanter immediately distal to the point at which the posterior biceps semitendinous nerve branches off from the common sciatic nerve. A 7-0 silk suture is inserted into the nerve with an inverted-cut 3/8 curved mini-needle and closely connected such that the dorsal 1/3 to 1/2 the thickness of the nerve is kept within the nerve. bandage. The muscle and skin are closed with sutures and clips, and the wound sprinkled with antibiotic powder. In placebo animals, the sciatic nerve is exposed but not ligated, and the wound closed as in non-placebo animals.

In the Chronic Constriction Injury (CCI) injury model (Bennett, GJ. And Xie, YK Pain, 33: 87-107, 1988) rats 15 are anesthetized, and a small incision is made midway through a Itch (usually left) to expose the sciatic nerve. The nerve is carefully wiped from surrounding connective tissue and four 4/0 chromic bowel ligatures are loosely tied around the nerve approximately 1 mm between each other, so that the ligatures merely clamp the nerve surface. The wound is closed with sutures and clips as described above. In placebo models the sciatic nerve is exposed but not ligated, and the wound is closed as in non-placebo animals.

In contrast to the Seltzer and CCI models, Chung's model involves spinal nerve ligation (Kim, S. O. and Chung, J. M. Pain, 25: 355-363, 1992). In this model, Sprague-Dawley or Wistar rats (200 to 250 g) are anesthetized and placed in an upright position, and an incision is made to the left of the spine at the L4-S2 level. Deep dissection through the paraspinal muscles and separation of the muscles from the spinal processes at the L4-S2 level will reveal part of the sciatic nerve as it branches to form the L4, L5 and L6 spinal nerves. The transverse process L6 is carefully removed with a small rongeur [type of forceps used in surgery] allowing the visualization of these spinal nerves. The L5 spinal nerve is isolated and closely linked with 7-0 silk suture. The wound is closed with a single muscle suture (6-D silk) and one or two skin closure clips, and sprinkled with antibiotic powder. In placebo animals the L5 nerve is exposed as before, but not ligated, and the wound closed as before. behavioral index:

In all models of chronic pain, hyperalgesia is evaluated.

mechanical (inflammatory and neuropathic) by measuring the paw withdrawal thresholds of both hind paws at an increasing pressure stimulus using an analgesometer. Mechanical allodynia is evaluated by measuring withdrawal thresholds for non-harmful mechanical stimuli applied with von 15 Frey hairs on the plantar surface of both hind paws. Thermal hyperalgesia is assessed by measuring withdrawal latencies to a detrimental thermal stimulus applied on the underside of each hind paw. In all models, mechanical hyperalgesia and allodynia and thermal hyperalgesia develop within 1 to 3 days after surgery, and persist for at least 20 50 days. In the case of the trials described here, it is possible to apply medications before and after surgery to assess their effect on the development of hyperalgesia approximately 14 days after surgery to determine their ability to reverse established hyperalgesia.

The percentage of reversal of hyperalgesia is calculated as the

follow:

Post dose dose - Pre dose dose

% reversal = -; -; -

Iim iar without treatment - Pre-dose Iim iar

In the pain models described above, all surgery can be performed under 02 / enflurane inhalation anesthesia. In all cases, the injury is closed after the procedure, and the animals are allowed to recover. In all pain models employed after a few days in all falsely operated animals, a marked thermal and mechanical allodynia and hyperalgesia develop, in which there is a decrease in pain threshold and an increased reflex reflex withdrawal of the hind paw. 5 to touch, pressure or thermal stimuli. After surgery, animals also show characteristic changes in the affected paw. In most animals, the affected hind paw toes are held together, and the foot is turned slightly to one side, and in some mice the toes are also turned down. The gait of the linked mice varies, but it is uncommon to limp. Some rats are observed to lift the affected hind paw off the cage floor and demonstrate unusual rigid extension of the hind limb when held. Rats tend to be very sensitive to touch and can vocalize. Otherwise, the overall health and condition of the mice is good.

As an illustration of the invention, the compound of Example 415 demonstrates an IC 50 value of about 100 nM in a functional assay by measuring the level of cAMP in CHO cells expressing the human adenosine receptor α. Additionally, the compound of Example 4 increases the [H] CCPA agonist Bmax value to human A 1 adenosine receptors by up to 600% at a concentration of 10 μΜ. Similarly, the compound of Example 60 exhibits a 6-fold increase in the Bmax value of the [3 H] CCPA agonist.

The following Examples are intended to illustrate the invention and should not be construed as limitations on it. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 10 mm Hg and 100 mm Hg. The structure of end products, intermediates and starting materials is confirmed by conventional analytical methods, e.g. microanalysis, melting point (m.p.) and spectroscopic characteristics, e.g. MS, IR and NMR (or NMR). The abbreviations used are those conventional in the art. Example I

{2-Amino-4- (4-phenylpiperazin-1-yl) methylthiophen-3-yl-4-chlorophenyl) methanone

A. (2-Amino-4-methylthiophen-3-yl) (4-chlorophenyl) methanone

To a suspension of 3- (4-chlorophenyl) -3-oxo-propionitrile (900 mg, 5 mmol) and 2,5-dimethyl-dithian-2,5-diol (450 mg, 2.5 mmol) in absolute EtOH (10 ml), cooled in a water / ice bath (4 ° C), add TEA (5 mmol, 0.7 ml). After stirring for 10 min at room temperature, the mixture is refluxed for 2 h. The resulting reddish brown solution is cooled and concentrated, and the residue dissolved in EtOAc (10 mL). The organic phase is subsequently washed with 1% w / v aqueous HCl (5 mL), a NaHCO 3 (5 mL), water (5 mL) and brine (5 mL), dried (Na 2 SO 4) and concentrated to give a brown residue. The residue is suspended in ethyl ether (15 mL), the suspension is stirred for 30 min and filtered. The filtrate is concentrated, suspended with petroleum ether and the resulting suspension is stirred for 30 min and filtered. The filtrate is concentrated, and the residue is purified by column chromatography using a mixture of 2-8 EtOAc-petroleum ether as eluent giving (2-amino-4-methylthiophen-3-yl) (4-

° C 1

chlorophenyl) methanone as an orange solid: mp 148-150 ° C. 1 H NMR (CDCl 3) δ: 1.66 (s, 3H), 5.85 (s, 1H), 6.61 (br s, 2H), 7.38 (d, J = 6.4 Hz, 2H) 7.45 (d, J = 6.4 Hz, 2H); IR (KBr) cm -1: 3345, 1589, 1435, 1267.

B. 2- (3- (4-Chlorobenzoyl) -4-methylthiophen-2-ylisoindoline-1,3-dione

The title compound A (755 mg, 3 mmol) is dissolved in acetic acid (20 mL), then phthalic anhydride (3.6 mmol, 533 mg) is added to the solution and the mixture is heated at reflux for 15 h. The solvent is evaporated and the residual material is dissolved in ethyl acetate (20 ml). The organic solution is washed with saturated NaHCO 3 solution (5 mL), water (5 mL) and brine (5 mL), dried (Na 2 SO 4) and concentrated. The residue is stirred for 1 h with petroleum ether (20 mL), and the solids are collected by filtration giving 2- [3- (4-chlorobenzoyl) -4-methylthiophen-2-yl] isoindoline-1,3 - 5 dione as a brown powder: 1H NMR (CDCl3) δ: 2.24 (s, 3H), 7.02 (s, 1H), 7.22 (d, J = 7.2 Hz, 2H), 7 , 62-8.00 (m, 6H).

C. 2-5-Bromo-3- (4-chlorobenzoyl-4-methylthiophen-2-yisoindol-1,3-dione

To a solution of the title compound B (20 mmol, 7.6 g) in benzene (150 mL) is added benzoyl peroxide (484 mg, 2 mmol) and the mixture is heated to reflux. Under reflux conditions, a mixture of N-bromosuccinimide (20 mmol, 3.56 g) and benzoyl peroxide (484 mg, 2 mmol) is added and the mixture is further refluxed for 6 h. The solvent is removed under reduced pressure, and the residue is dissolved in EtOAc (330 mL). The organic solution is subsequently washed with saturated NaHCO 3 solution (200 mL), water (50 mL) and brine (50 mL), dried (Na 2 SO 4) and concentrated to a brown powder. The powder is suspended with petroleum ether (200 ml), the mixture is stirred for 30 min and the solids are collected by filtration giving 2- [5-bromo-3- (4-chlorobenzoyl) -4-methylthiophen-2 -yl] isoindoline-1,3-dione which is used as it is in the next step without further purification: mp 194-195 ° C. 1H-NMR (CDCl3) δ: 2.09 (s, 3H), 7.19 (d, J = 7.4 Hz, 2H), 7.62-7.71 (m, 6H); IR (KBr) cm -1: 1728, 1664, 1587, 1368.717.

D. 2-5-Bromo-4-bromomethyl-3- (4-chlorobenzoylthiophen-2-yisoindol-1,3-dione

To a suspension of the title compound C (20 mmol, 9.2 g) in 25 CCl 4 (150 mL) is added benzoyl peroxide (242 mg, 1 mmol) and the mixture is heated to reflux. Under reflux conditions, a mixture of N-bromosuccinimide (20 mmol, 3.56 g) and benzoyl peroxide (242 mg, 1 mmol) is added and the mixture is refluxed for 1 h. After this period, if the reaction is not terminated, a mixture of N-bromosuccinimide (2 mmol, 356 mg) and benzoyl peroxide (242 mg, 1 mmol) is added and the mixture is refluxed for an additional hour. The resulting yellow solution is cooled to room temperature and the precipitated succinimide is removed by filtration and washed with CCl4 (25 mL). The filtrate is washed with 5% NaHCO 3 solution (50 mL), water (50 mL) and brine (50 mL), dried (Na 2 SO 4) and concentrated to a yellow powder. The powder is suspended with petroleum ether (100 ml), the mixture is stirred for 30 min and the solids are collected by filtration giving 2- [5-bromo-4-bromomethyl-3- (4-chlorobenzoyl) thiophenyl. 2-yljisoindoline-1,3-dione as a yellow solid: mp 173-175 ° C. 1H-NMR (CDCl3) δ: 4.65 (s, 2H), 7.20 (d, J = 6.6 Hz, 2H), 7.66 (d, J = 6.6 Hz, 2H), 7, 62-7.71 (m, 4H). IR (KBr) cm -1: 1727, 1658, 1348, 1330, 1084.

E. 2-R5-Bromo-3- (4-chlorobenzoyl) -4 - (('4-phenylpiperazin-1-yl) methyl) thiophen-2-ylisoindoline-1,3-dione

To a stirred solution of the title compound D (900 mg, 1.6 mmol) in dry DCM (5 mL) is added TEA (1.1 equiv., 1.76 mmol, 243 mg). The mixture is cooled with an ice / water bath, and 4-phenylpiperazine (3 equiv., 5 mmol, 810 mg) is added. The mixture is stirred at room temperature for 2 h, diluted with DCM (5 mL), washed with water (5 mL) and brine (5 mL). The organic layer is dried (Na 2 SO 4) and concentrated in vacuo affording a brown residue which is purified by column chromatography (4-6 EtOAc-petroleum ether as eluent) giving 2- [5-bromo-3- (4 -chlorobenzoyl) -4 - ((4-phenyl-piperazin-1-yl) methyl) thiophen-2-yl] isoindoline-1,3-dione as a yellow solid: mp 186-193 ° C. 1H-NMR (CDCl3) δ: 2.85 (t, J = 5.0 Hz, 2H), 3.14 (s, 2H), 3.34 (t, J = 5.0 Hz, 2H), 3, 42 (t, J = 5.2 Hz, 2H), 3.94 (t, J = 5.2 Hz, 2H), 6.80-6.93 (m, 4H), 6.93-7.28 (m, 4H), 7.39 (d, J = 8.4 Hz, 2H), 7.58-7.62 (m, 2H), 7.82 (d, J = 6.8 Hz, 1H) .

R 1-2-R3- (4-Chlorobenzoyl> 4- (Y4-phenylpiperazin-1-yl) methyl) thiophen-2-one

illisoindoline-1,3-dione

A solution of the title compound E (2 mmol) in DMF (20

5th

10 ml) containing Et 3 N (0.3 ml, 2 mmol, 1 equiv) is hydrogenated over 120 mg of 10% Pd / C at 60 psig (414 kPa man.) For 3 h. The catalyst is removed by filtration, the filtrate is concentrated. The residue is dissolved in DCM (20 mL), washed with water (5 mL) and brine (5 mL), and dried (Na 2 SO 4).

The solvent is removed under reduced pressure and the residue is purified by column chromatography (2-8 EtOAc-DCM as eluent) giving 2- [3- (4-chloro-benzoyl) -4 - ((4- phenylpiperazin-1-yl) methyl) thiophen-2-yl] isoindoline-1,3-dione as a white solid: mp 220-222 ° C. 1H-NMR (CDCl3) δ: 2.92 (t, J = 5.0 Hz, 2H), 3.14 (s, 2H), 3.34 (t, J = 5.0 Hz, 2H), 3, 44 (t, J = 5.2 Hz, 2H), 3.94 (t, 10 J = 5.2 Hz, 2H), 6.69 (s, 1H), 6.87 (d, J = 6, 8 Hz, 2H), 7.21 (d, J = 6.8 Hz, 2H), 7.37-7.52 (m, 4H), 7.52 (t, J = 6.8 Hz, 1H) 7.58-7.60 (m, 3H), 7.83 (d, J = 6.8 Hz, 1H).

G {{2-Amino-4- (4-phenylpiperazin-1-yl) methylthiophen-3-yl H4-

doro feni Dmethanone

A stirred suspension of the title compound F (0.5 mmol) and

100% hydrazine monohydrate (1.2 eq, 0.6 mmol, 29 μΐ) in absolute ethanol (10 mL) is heated at reflux for 3 h. After this time, the resulting solution is left at room temperature for 1 h. The reaction is terminated after complete solubilization of the starting material starting material. The solvent is evaporated and the residue is partitioned between EtOAc (10 mL) and water (5 mL). The organic phase is separated, washed with brine (2 mL), dried and concentrated in vacuo. The residue is purified by column chromatography (EtOAc-DCM / 2-8 as eluent) giving {2-amino-4 - [(4-phenylpiperazin-1-yl) methyl] thiophen-3-yl} (4- chlorophenyl) methanone as a yellow solid: mp 112 ° C. 1H-NMR (CDCl3) δ: 2.04 (m, 4H), 2.94 (m, 4H), 3.00 (s, 2H), 6.07 (br s, 2H), 6.14 (s, 1H), 6.83 (m, 3H), 7.23 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H).

The following compounds are prepared analogously as described in Example 1. Example 2

{2-Ammo-4- (4-methylpiperazin-1-yl) meththiophen-3-yn (4-chlorophenylmethanone

The title compound is purified by column chromatography (MeOH as eluent). Yellow oil. 1H-NMR (CDCl3) 6: 2.24 (s, 3H), 2.32 2.44 (m, 6H), 3.37 (t, J = 5.4 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 6.10 (m, 3H), 7.34 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H) .

Example 3

{2-Amino-4- Γ 4- ((4-fluorophenyl) piperazin-1-yl) methylthiophen-3-yl 1- (4-chlorophenylmethanone

The title compound is purified by flash chromatography.

column (EtOAc: DCM / 2: 8 as eluent). Yellow solid, m.p. 70-72 ° C. 1H-NMR (CDCl3) δ: 2.04 (t, J = 5.2 Hz, 4H), 2.85 (t, J = 5.2 Hz, 4H), 3.00 (s, 2H), 6, 06 (s, 2H), 6.13 (s, 1H), 6.82 (m, 2H), 6.92 (t, J = 9.0 Hz, 2H), 7.38 (d, J = 8 2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H). IR (KBr) cm -1: 3421, 1587, 1509, 1262, 1087.

Example 4

(2-Amino-4- Γ4 - ((4-chlorophenylpiperazin-1-yl) methylthiophen-3-yl 1- (4-chlorophenyl) methanone

/

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 148-150 ° C. 1H-NMR (CDCl3) δ: 2.04 (t, J = 4.6 Hz, 4H), 2.88 (t, J = 4.6 Hz, 4H), 3.00 (s, 2H), 6, 07 (br s, 2H), 6.13 (s, 1H), 6.74 (d, J = 9.2 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 7 , 39 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H). IR (KBr) cm -1: 3366, 1591, 1498, 1426, 1234, 1085,815.

Example 5

{2-Amino-4- [4- (4-methoxyphenyl) piperazin-1-methylmethylthiophen-3-yl] (4-chlorophenylmethanone

v ^

The title compound is purified by column chromatography (EtOAc: DCM / 2: 8 as eluent). Yellow oil. 1H-NMR (CDCl3) 6: 2.04 (t, J = 5.4 Hz, 4H), 2.83 (t, J = 5.4 Hz, 4H), 3.10 (s, 2H), 3, 75 (s, 3H), 6.08 (br s, 2H), 6.14 (s, 1H), 6.82 (d, J = 10.2 Hz, 2H), 6.86 (d, J = 10.2 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H). IR (KBr) cm -1: 3366, 1591, 1498, 1426, 1234, 1085, 815.

Example 6

{2-Amino-4- Γ (4-p-tolylpiperazin-1-yl) methylthiophen-3-yl} (4-chlorophenyl) methanone

Cl

..... / —N

\ _

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, mp 73-75 ° C. 1H-NMR (CDCl3) 6: 2.26 (s, 3H), 2.32 (t, J = 5.6 Hz, 4H), 2.86 (t, J = 5.6 Hz, 4H), 3, 12 20 (s, 2H), 6.10 (br s, 2H), 6.13 (s, 1H), 6.83 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H). IR (KBr) cm -1: 1722, 1614, 1514, 1261, 1089, 1021. Example 7

{2-Ammo-4 - [('4- (pyridin-2-yl) piperazin-1-yl) methylthiophen-3-yl] -4-

chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 4: 6 as eluent). Yellow solid, m.p. 130-131 ° C. 1H-NMR (CDCl3) δ: 2.01 (t, J = 5.0 Hz, 4H), 3.00 (s, 2H), 3.27 (t, J = 5.0 Hz, 4H), 6, 09 (br s, 2H), 6.13 (s, 1H), 6.53-6.61 (m, 3H), 7.40 (d, J = 6.6 Hz, 2H), 7.57 ( d, J = 6.6 Hz, 2H), 8.15 (m, 1H). IR (KBr) cm-1: 2963, 1595, 1434, 1261, 1096, 1022.

Example 8

{2-Amino-4- (4- (pyrimidin-2-yl) piperazin-1-yl) methylthiophen-3-yl H4-chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 1 as eluent). Yellow solid, m.p. 141-143 ° C. 1H-NMR (CDCl3) δ: 1.95 (t, J = 4.8 Hz, 4H), 2.99 (s, 2H), 3.55 (t, J = 4.8 Hz, 4H), 6, 13 (br 15 s, 3H), 6.44 (t, J = 4.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8 , 2 Hz, 2H), 8.26 (d, J = 4.8 Hz, 2H). IR (KBr) cm -1: 3386, 1712, 1586, 1423, 1260, 1084, 798. Example 9

(2-Amino-4-IY4- (3,4-dichlorophenyl) piperazin-1-yl) methylthiophen-3-inf4-chlorophenylmethanone

Ç! The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 102-104 ° C. 1H-NMR (CDCl3) δ: 2.04 (t, J = 4.6 Hz, 4H), 2.90 (t, J = 4.6 Hz, 4H), 3.00 (s, 2H), 6, 08 (br s, 2H), 6.13 (s, 1H), 6.66 (dd, J = 9.0 and 2.8 Hz, 1H), 6.87 (d, 5 J = 2.8 Hz , 1H), 7.21 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 2964, 1591, 1435, 1262, 1096, 1020, 800.

Example 10

4- (4- IY5 - Amino-4- ('4-chlorobenzoyl) thiophen-3-ylmethylpiperazin-1 -

il Ibenzonitrile

The title compound is purified by flash chromatography.

column (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 173-175 ° C. 1H-NMR (CDCl3) δ: 2.01 (t, J = 4.8 Hz, 4H), 3.03 (s, 2H), 3.08 (t, J = 4.8 Hz, 4H), 6, 08 (br s, 2H), 6.14 (s, 1H), 6.78 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7 , 43 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 7.8 Hz, 2H). IR (KBr) cm -1: 2963, 1606,1261,1097,1016,808.

Example 11

{2-Amino-4- (4- (3-chlorophenylpiperazin-1-ylmethylthiophen-3-yl) -4-

chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 197-199 ° C. 1H-NMR (CDCl3) δ: 2.01 (t, J = 5.2 Hz, 4H), 2.93 (t, J = 5.2 Hz, 4H), 3.00 (s, 2Η), 6, 08 (br s, 2H), 6.13 (s, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6 , 81 (s, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8, 4 Hz, 2H). IR (KBr) cmA: 3356, 1587, 1512, 1430 and 1076.

Example 12

{2-Amino-4- Γ (4- (2-chlorophenyl) piperazin-1-yl) methylthiophen-3-yl (4-chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 115-117 ° C. 1H-NMR (CDCl3) δ: 2.04 (t, J = 5.2 Hz, 4H), 2.78 (t, J = 5.2 Hz, 4H), 3.10 (s, 10 2H), 6 .06 (br s, 2H), 6.11 (s, 1H), 6.60 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 6.80 (t, J = 7.4 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7, 52 (d, J = 8.2 Hz, 2H). IR (KBr) cm -1: 3342, 1578, 1534, 1432 and 1084. Example 13

{2-Amino-4- (4- (2-fluorophenyl) piperazin-1-yl) methylthiophen-3-yl-4-chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 102-104 ° C. 1H-NMR (CDCl3) δ: 2.04 (t, J = 5.2 Hz, 4H), 2.86 (t, J = 5.2 Hz, 4H), 3.02 (s, 2H), 6, 04 (s, 2H), 6.12 (s, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 20 6 , 86 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H). IR (KBr) cm -1: 3417, 1578, 1512, 1264, 1092. 10

15

Example 14

{2-Amino-4-r (4- (3- (trifluoromethyl) phenylpiperazin-1-yl) methylthiophen-3-yl) (4-

chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as eluent). Yellow solid, m.p. 167-169 ° C. 1H-NMR (CDCl3) 6: 2.04 (t, J = 5.2 Hz, 4H), 2.97 (t, J = 5.2 Hz, 4H), 3.00 (s, 2H), 6, 07 (br s, 2H), 6.14 (s, 1H), 7.01 (m, 3H), 7.26 (t, J = 9.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), IR (KBr) cm -1: 3346, 1578, 1522, 1424e1082.

Example 15

1- {4- (5-Amino-4- (4-chlorobenzoyl) thiophen-3-yl) methylpiperazin-1-yl} -2- (4-

chloropheniDetanone

The title compound is purified by chromatography.

0C

column (EtOAc: DCM / 2: 8 as eluent). Yellow solid, m.p. 60-61 ° C. 1H-NMR (CDCl3) δ: 1.73 (t, J = 4.8 Hz, 2H), 1.78 (t, J = 4.8 Hz, 2H), 2.93 (s, 2H), 3, 19 (t, J = 5.2 Hz, 2H), 3.64 (t, J = 5.2 Hz, 2H), 3.59 (s, 2H), 6.06 (s, 1H), 6, 09 (s, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), IR (KBr) cm -1: 3342, 1578, 1502, 1442 and 1082.

20 10

15

Example 16

{2-Amino-4- [Y4- (4-chlorobenzoyl) piperazin-1-yl) meththiophen-3-yl) (4-

chlorophenyl) methanone

CL

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 185- 186 ° C. 1H-NMR (CDCl3) δ: 1.83 (t, J = 4.8 Hz, 2H), 1.92 (t, J = 4.8 Hz, 2H),

2.99 (s, 2H), 3.15 (t, J = 5.0 Hz, 2H), 3.49 (t, J = 5.0 Hz, 2H), 6.08 (s, 1H), 6.10 (s, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8 2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H). IR (KBr) cm -1: 3352, 1564, 1512, 1434 and 1068.

Example 17

{2-Amino-4-r (4- (pyridin-4-yl) piperazin-1-yl) methyl] thiophen-3-yl (4-

chlorophenylmethanone

The title compound is purified by column chromatography (EtOAcrMeO H / 7: 3 as eluent). Yellow solid, m.p. 86-88 ° C. 1H-NMR (CDCl3) δ: 2.01 (t, J = 5.2 Hz, 4H), 3.00 (s, 2H), 3.24 (t, J = 5.2 Hz, 4H), 6, 09 (br s, 2H), 6.12 (s, 1H), 6.72 (d, J = 5.6 Hz, 2H), 6.87 (d, J = 5.6 Hz, 2H), 8 .06 (d, J = 7.4 Hz, 2H), 8.19 (d, J = 7.4 Hz, 2H). IR (KBr) cm -1: 2956, 1578, 1445, 1256, 1077, 1012.

20 Example 18

{2-Amino-4- (4- (benzordldioxol-5-yl) piperazin-1-yl) methylthiophen-3-yl} (, 4-

chloropheniDethanone

Clv

r '° \ _ V_ /

° '0 “wn" aI / = 0

VsXnh2

The title compound is purified by column chromatography (EtOAc: DCM / 1: 1 as eluent). Yellow solid, m.p. 85-86 ° C. 1H-NMR (CDCl3) δ: 2.38 (t, J = 5.2 Hz, 4H), 2.66 (t, J = 5.2 Hz, 4H), 3.34 (s, 2H), 5, 72 (s, 2H), 5.84 (s, 2H), 5.86 (dd, J = 8.2 and 2.4 Hz, 1H), 6.05 (d, J = 2.2 Hz, 1H ), 6.24 (d, J = 2.2 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H). IR (KBr) cm -1: 3376, 1577, 1532, 10 1423 and 1054.

Example 19

{2-Amino-4-IY4- (2,3-dichlorophenyl) piperazin-1-yl) methylthiophen-3-yl (4-

chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow oil. 1H-NMR (CDCl3) δ: 2.05 (t, J = 4.4 Hz, 4H), 2.78 (t, J = 4.4 Hz, 4H), 3.01 (s, 2H), 6, 07 (br s, 2H),

6.14 (s, 1H), 6.89 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 5.2 Hz, 2H), 7.43 (t, J = 7.0 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 2978, 1578, 1452, 1267, 1078, 1012.

20 10

15

Example 20

{2-Amino-4-ΙΥ 4- (3-fluorophenylpiperazin-1-yl) methylthiophen-3-yl 1- (4-

chloropheniPmetanone

The title compound is purified by column chromatography (EtOAc: DCM / 2: 8 as eluent). Yellow solid, m.p. 150-152 ° C. 1H-NMR (CDCl3) δ: 2.02 (t, J = 4.8 Hz, 4H), 2.93 (t, J = 4.8 Hz, 4H), 3.00 (s, 2H), 6, 08 (s, 2H), 6.13 (s, 1H), 6.45 (t, J = 7.0 Hz, 1H), 6.53 (m, 2H), 7.17 (q, J = 7 , 6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H). IR (KBr) cm -1: 3434, 1577, 1534, 1256, 1077.

Example 21

(2-Amino-4- Γ (4- (3,5-dichlorophenyl) piperazm-1-methylmethyl] thiophen-3-yl) (4-chlorophenylmethanone

The title compound is purified by column chromatography (EtOAciDCM / 1: 9 as eluent). Yellow solid, m.p. 185-187 ° C. 1H-NMR (CDCl3) δ: 1.99 (t, J = 4.8 Hz, 4H), 2.92 (t, J = 4.8 Hz, 4H), 2.99 (s, 2H), 6, 09 (br s, 2H), 6.13 (s, 1H), 6.64 (s, 2H), 6.76 (s, 1H), 7.38 (d, J = 8.6 Hz, 2H) 7.53 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 2965, 1587, 1444, 1272, 1085 and 1033. Example 22

{2-Amino-4-yl-4- (4- (trifluoromethyl) phenylpiperazin-1-yl) methylthiophen-3-yl} (4-

chloropheniPmetanone

The title compound is purified by 5 column chromatography (EtOAc: DCM / 0.5: 9.5 as eluent). Yellow solid, m.p. 198-200 ° C. 1H-NMR (CDCl3) δ: 2.02 (t, J = 4.8 Hz, 4H), 3.00 (t, J = 4.8 Hz, 4H), 3.04 (s, 2H), 6, 08 (br s, 2H), 6.14 (s, 1H), 6.82 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7 , 42 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H). IR (KBr) cm -1: 3352, 1568, 1512, 1423 and 1077.

Example 23

2- {4- IY5 - Amino-4- (4-chlorobenzoyl) thiophen-3-yl) methylpiperazin-1-yl} -1- (4-chlorophenipetanone

The title compound is purified by column chromatography (EtOAc: MeOH / 9.5: 0.5 as eluent). Yellow solid, m.p. 77-78 ° C.

1H-NMR (CDCl3) 6: 2.73 (t, J = 4.8 Hz, 4H), 3.42 (t, J = 4.8 Hz, 4H), 3.56 (s, 2H), 3, 72 (s, 2H), 6.06 (br s, 2H), 6.08 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H). IR (KBr) cm -1: 3333, 1584, 1512, 1434 and 1074. Example 24

{2-Amino-4-rH- (2,4-difluorophenylpiperazin-1-yl) methyl] thiophen-3-yl) (4-

chloropheniDethanone

The title compound is purified by 5 column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 170-172 ° C. 1H-NMR (CDCl3) δ: 2.04 (t, J = 4.8 Hz, 4H), 2.77 (t, J = 4.8 Hz, 4H), 3.00 (s, 2H), 6, 06 (br s, 2H), 6.13 (s, 1H), 6.80 (m, 3H), 7.35 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 2955, 1592, 1424, 1278, 1092 and 1034. Example 25

{2-Amino-4- [Y4- (2,6-difluorophenyl) piperazin-1-yl) methylthiophen-3-ylH4-chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow oil. 1H-NMR (CDCl3) δ: 1.99 (t, J = 4.8 Hz, 4H), 2.95 (t, J = 4.8 Hz, 4H), 2.98 (s, 2H), 6, 08 (br s, 2H), 6.13 (s, 1H), 6.82 (m, 3H), 7.36 (d, J = 6.6 Hz, 2H), 7.58 (d, J = 6.6 Hz, 2H). IR (neat) cm -1: 2988, 1564, 1433, 1256, 1082 and 1047.

Example 26

{2-Amino-4-IY4- (3-chloro-4-fluorophenyl) piperazin-1-yl) methylthiophen-3-ylH4-

chlorophenylmethanone

c The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 161-163 ° C. 1H-NMR (CDCl3) δ: 2.01 (t, J = 4.6 Hz, 4H), 2.85 (t, J = 4.6 Hz, 4H), 3.00 (s, 2H), 6, 07 (br s, 2H), 6.13 (s, 1H), 6.68 (m, 1H), 6.81 (dd, J = 6.4 and 3.0 Hz, 1H), 6.93 ( t, J = 8.8 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 2972, 1577, 1432, 1271, 1094 and 1032.

Example 27

12-Amino-4- Γ (4-cyclohexylpiperazin-1-yl) methylthiophen-3-yl H4-chlorophenylmethanone

s

The title compound is purified by flash chromatography.

column (EtOAc 3 H / L: 1 as eluent). Yellow solid, m.p. 120-122 ° C. 1H-NMR (CDCl3) δ: 1.17 (m, 6H), 1.64 (m, 5H), 1.78 (t, J = 5.2 Hz, 4H), 2.39 (t, J = 5 , 2 Hz, 4H), 3.13 (s, 2H), 5.69 (br s, 2H), 6.91 (s, 1H), 7.39 (d, J = 7.2 Hz, 2H) 7.48 (d, J = 7.2 Hz, 2H).

Example 28

{2-Amino-4-IY4- (4-chlorophenyl) piperidin-1-yl) methylthiophen-3-yl H 4-chlorophenylmethanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow oil. 1H-NMR (CDCl3) δ: 1.67 (m, 4H), 2.27 (m, 1H), 2.54 (t, J = 5.4 Hz, 4H), 3.04 (s, 2H), 6.09 (s, 2H), 6.16 (s, 1H), 7.33 (s, 4H), 7.39 (d, J = 8.6 Hz, 2H), 7.51 (t, J = 8.6 Hz, 2H). IR (KBr) cm -1: 3378, 1556, 1443, 1412, 1074 and 822. Example 29

(2-Amino-4-r (4- (4-nitrophenyl) piperazin-1-yl) methylthiophen-3-yl} (4-

chloropheniPmetanone

s

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 110-112 ° C. 1 H NMR (CDCl 3) 6: 2.46 (t, J = 5.4 Hz, 4H), 2.84 (t, J = 5.4 Hz, 4H), 3.03 (s, 2H), 6 , 21 (br s, 2H), 6.24 (s, 1H), 6.81 (d, J = 9.6 Hz, 2H), 7.46 (d, J = 9.2 Hz, 2H), 7.65 (d, J = 9.6 Hz, 2H), 8.13 (d, J = 9.2 Hz, 2H). IR (KBr) cm -1: 3455, 1733, 1551, 1533.

Example 30

{2-Amino-4-YY4-isopropylpiperazin-1-ylmethyl) thiophen-3-yl H4-chlorophenylmethane

The title compound is purified by column chromatography (EtOAc: MeO H / 3: 7 as eluent). Yellow oil. 1H-NMR (CDCl3) 6: 1.02 (m, 6H), 1.99 (t, J = 5.2 Hz, 4H), 2.35 (t, J = 5.2 Hz, 4H), 2, 57 (m, 1H), 2.93 (s, 2H), 6.05 (br s, 2H), 6.10 (s, 1H), 7.36 (d, J = 8.6 Hz, 2H) 7.52 (d, J = 8.6 Hz, 2H). Example 31

{2-Amino-4- (4-naphthalen-1-ylpiperazin-1-yl) methylthiophen-3-yl) (4-chlorophenylmethanone) The title compound is purified by column chromatography (EtOAc: DCM / 2: 8 as eluent) Brown solid, mp 178 ° C 1H NMR (CDCl3) δ: 2.42 (t, J = 5.4 Hz, 4H), 2.54 (t, J = 5.4 Hz, 4H) 3.03 (s, 2H), 6.04 (s, 2H), 6.11 (s, 1H), 6.93 (d, J = 7.2 Hz, 2H), 7.06 (d, J = 7.2 Hz, 2H), 7.33 (m, 3H), 7.56 (d, J = 7.8 Hz, 2H), 7.87 (d, J = 7.8 Hz, 2H) .

Example 32

{2-Amino-4- Γ (4- (3,4-difluorophenyl) piperazin-1-yl) methylthiophen-3-yl (4-chlorophenylmethanone)

ct

F \ ^ Q

^ Q-VZ-O = 0

s nh ^

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 143-145 ° C. 1H-NMR (CDCl3) δ: 2.01 (t, J = 4.8 Hz, 4H), 2.84 (t, J = 4.8 Hz, 4H), 3.00 (s, 2H), 6, 07 (br s, 2H), 6.13 (s, 1H), 6.52 (m, 2H), 7.02 (m, 1H), 7.36 (d, J = 8.2 Hz, 2H) 7.53 (d, J = 8.2 Hz, 2H). IR (KBr) cm -1: 2967, 1587, 1433, 1267, 1085 and 1033.

Example 33

{2-Amino-4- Γ (4-cyclopentylpiperazin-1-yl) methylthiophen-3-yl I (4-chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAciMeO H / 6: 4 as eluent). Yellow solid, m.p. 95-97 ° C. 1H-NMR (CDCl3) δ: 1.16 (m, 4H), 1.48 (m, 5H), 1.82 (t, J = 5.2 Hz, 4H), 2.79 (s, 2H), 2.85 (t, J = 5.2 Hz, 4H), 5.72 (br s, 2H), 6.90 (s, 1H), 7.32 (d, J = 7.0 Hz, 2H) , 8.00 (d, J = 7.0 Hz, 2H). Example 34

{2-Amino-4- (4-cycloheptylpiperazin-1-yl) methylthiophen-3-yl (4-one

chloropheniDethanone

THE

The title compound is purified by column chromatography (EtOAc: MeOH / 7: 3 as eluent). Yellow oil. 1H-NMR (CDCl3) δ: 1.26 (m, 12H), 1.79 (t, J = 5.2 Hz, 4H), 2.09 (t, J = 5.2 Hz, 4H), 2, 81 (m, 1H), 3.03 (s, 2H), 6.03 (br s, 2H), 6.09 (s, 1H), 7.31 (d, J = 8.8 Hz, 2H) 7.45 (d, J = 8.8 Hz, 2H).

Example 35

{2-Amino-4-yl-4- (4-chlorobenzylpiperazin-1-yl) methylthiophen-3-yl H4-chlorophenylmethanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 1 as eluent). Yellow solid, m.p. 65-67 ° C. 1H-NMR (CDCl3) δ: 1.88 (t, J = 4.6 Hz, 4H), 2.21 (m, 4H), 2.92 (s, 2H), 3.36 (s, 2H), 6.02 (br s, 2H), 6.09 (s, 1H), 7.24 (m, 4H), 7.34 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 3372, 1589, 1478, 1433, 1241.

Example 36

{2-Amino-4- Γ (4-benzylpiperazin-1-ylmethylthiophen-3-yl} (4-chlorophenylmethanone

\ i

The title compound is purified by column chromatography (DCM: MeOH / 9.5: 0.5 as eluent). Yellow solid, m.p. 153-155 ° C. 1H-NMR (CDCl3) δ: 1.88 (t, J = 4.6 Hz, 4H), 2.24 (t, J = 4.6 Hz, 4H), 3.41 (s, 2H), 3, 48 (s, 2H), 6.01 (br s, 2H), 6.06 (s, 1H), 7.24 (m, 5H), 7.42 (d, J = 8.6 Hz, 2H) ,

7.64 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 3377, 1592, 1468, 1423, 1251.

Example 37

(2-Amino-4- {R4- (2- (4-chlorophenyl) ethyl) piperazin-1-ylmethyl} thiophen-3-yl) (4-

chlorophenipmetanone

The title compound is purified by column chromatography (DCM: MeOH / 9.5: 0.5 as eluent). Yellow oil. 1H-NMR (CDCl3) δ: 1.92 (t, J = 4.6 Hz, 4H), 2.27 (m, 4H), 2.47 (t, J = 7.2 Hz, 2H), 2 , 67 (t, J = 7.2 Hz, 2H), 2.95 (s, 2H), 6.09 (br s, 3H), 7.08 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 3376, 1588, 1456, 1434, 1242.

Example 38

{2-Amino-4-IY4- (4-fluorobenzyl) piperazin-1-yl) methylthiophen-3-yl} (4-chlorophenylmethanone

The title compound is purified by column chromatography (MeOH: DCM / 0.5: 9.5 as eluent). Yellow solid, m.p. 230-231 ° C. 1H-NMR (CDCl3) δ: 1.55 (t, J = 4.6 Hz, 4H), 1.88 (t, J = 4.6 Hz, 4H), 2.92 (s, 20 2H), 2 , 92 (s, 2H), 6.02 (br s, 2H), 6.09 (s, 1H), 6.96 (t, J = 8.8 Hz, 2H), 7.21 (dd, J = 8.8 and 5.6 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H). IR (KBr) cm -1: 3358, 1577, 1468, 1423, 1267. Example 39

{2-Amino-4- (4-cyclooctylpiperazin-1-methoxythiophen-3-yl) (4-

chloropheni Dmetanone

The

The title compound is purified by column chromatography (DCM: MeOH / 0.5: 9.5 as eluent). Yellow oil. 1H-NMR (CDCl3) δ: 1.21 (m, 10H), 1.44 (m, 4H), 1.76 (m, 5H), 2.42 (t, J = 5.2 Hz, 4H), 3.14 (s, 2H), 5.74 (br s, 2H), 6.88 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H). Example 40

(2-Amino-4- (Γ4- Γ3 - (4-chlorophenyl) propylpiperazin-1-ylmethylthiophen-3-yl) (4-chlorophenylmethanone

The title compound is purified by column chromatography (DCM: MeOH / 9.5: 0.5 as eluent). Yellow solid, m.p. 60-61 ° C. 1H-NMR (CDCl3) δ: 1.62 (m, 2H), 1.90 (t, J = 4.8 Hz, 4H), 2.24 (m, 4H), 2.58 (t, J = 4 , 8 Hz, 4H), 2.95 (s, 2H), 6.02 (br s, 2H), 6.09 (s, 1H), 7.10 (d, J = 8.6 15 Hz, 2H ), 7.20 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 3382, 1578, 1455, 1432, 1222.

Example 41

{2-Amino-4- Γ (4- (2,4-dichlorofem-Piperiperin-1-ylmethylHiophen-3-yl (4-chlorophenyl) methanone) The title compound is purified by column chromatography (EtOAc: DCM / l: 9 as eluent) Yellow solid, mp 142-143 ° C 1H NMR (CDCl3) δ: 2.04 (t, J = 4.6 Hz, 4H), 2.76 (t, J = 4.6 Hz , 4H), 3.01 (s, 2H), 6.05 (br s, 2H), 6.14 (s, 1H), 6.88 (d, J = 8.6 Hz, 1H), 7, 14 (dd, J = 11 and 2.6 Hz, 1H), 7.31 (d, J = 2.6 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7 , 56 (d, J = 8.8 Hz, 2H) IR (KBr) cm -1: 2972, 1578.1455, 1265.

Example 42

{2-Amino-4-r (4- (2,5-difluorophenyl) piperazin-1-methylthiophen-3-ylK4-chlorophenyl) methanone

F

The title compound is purified by flash chromatography.

column (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 62-63 ° C. 1H-NMR (CDCl3) 6: 1.99 (t, J = 4.8 Hz, 4H), 2.95 (t, J = 4.8 Hz, 4H), 2.98 (s, 2H), 6, 08 (br s, 2H), 6.13 (s, 1H), 6.82 (m, 3H), 7.36 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H). IR (neat) cm -1: 2976, 1555, 1442, 1265, 1077.

Example 43

{2-Amino-4-r (4- (2- (trifluoromethyl) phenyl) piperazin-1-yl) methylthiophen-3-yl (4-

chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow oil. 1H-NMR (CDCl3) 6: 2.01 (t, J = 4.8 Hz, 4H), 2.67 (t, J = 5.2 Hz, 4H), 3.00 (s, 2H), 6, 05 (br s, 2H), 6.13 (s, 1H), 7.12 (t, J = 8.4 Hz, 1H), 7.18 (m, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.44 (m, 1H), 7.57 (d, J = 8.8 Hz, 2H). IR (KBr) cm -1: 3353, 1563, 1533, 1438 and 1077. Example 44

(2-Amino-4-IY4- (4-chloro-3- (trifluoromethyl) phenyl) piperazin-1-yl) methylthiophen-3-one

yl K 4-chlorophenyl) methanone

-The-

The title compound is purified by 5 column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 141-143 ° C. 1H-NMR (CDCl3) δ: 1.96 (t, J = 4.4 Hz, 4H), 2.87 (t, J = 4.4 Hz, 4H), 2.94 (s, 2H), 6, 01 (br s, 2H), 6.07 (s, 1H), 6.78 (dd, J = 8.2 and 2.8 Hz, 1H), 7.00 (s, 1H), 7.19 ( d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H). IR (KBr) cm -1: 2977, 1578, 1443, 1277, 1078.

Example 45

{2-Amino-4-r (4- (2,4,6-trifluorophenyl) piperazin-1-yl) methylthiophen-3-yl} (4-

chloropheniDethanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 153-155 ° C. 1H-NMR (CDCl3) 6: 1.98 (t, J = 4.6 Hz, 4H), 2.87 (t, J = 4.8 Hz, 4H), 2.98 (s, 2H), 6 , 08 (br s, 2H), 6.13 (s, 1H), 6.58 (t, J = 9.0 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 2977, 1583, 1443, 1277, 1083. Example 46

{2-Amino-4- Γ ('4- (2-chloro-4-fluorophenyl) piperazin-1-yl) methylthiophen-3-yl) (4-chlorophenylmethanone) The title compound is purified by column chromatography (EtOAc : DCM / 1: 9 as eluent Yellow solid, mp 59-61 ° C 1H NMR (CDCl3) δ: 2.06 (t, J = 4.6 Hz, 4H), 2.75 (t, J = 4.6 Hz, 4H), 3.02 (s, 2H), 6.07 (br s, 2H), 6.15 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H ), 7.08 (d, J = 8.4 Hz, 1H), 6.93 δ (t, J = 8.8 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H) , 7.58 (d, J = 8.6 Hz, 2H) IR (KBr) cm -1: 2984, 1583, 1443, 1283, 1123.

Example 47

2-Amino-4- (4- (2-fluoro-4-chloropheninpiperazin-1-methylmethylthiophen-3-yl) (4-chlorophenyl) methanone

The title compound is purified by flash chromatography.

column (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 161-163 ° C. 1H-NMR (CDCl3) δ: 2.04 (t, J = 4.8 Hz, 4H), 2.80 (t, J = 4.8 Hz, 4H), 3.01 (s, 2H), 6, 07 (br s, 2H), 6.14 (s, 1H), 6.78 (t, J = 7.6 Hz, 1H), 7.01 (m, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 2967, 1577, 1452, 1271.1110.

Example 48

{2-Amino-4- Γ (4- (3,5-difluorophenyl) piperazin-1-methylmethylthiophen-3-yl (4-chlorophenylmethanone)

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 162-163 ° C. 1 H NMR (CDCl 3) δ: 2.00 (t, J = 4.8 Hz, 4H), 2.93 (t, J = 4.8 Hz, 4H), 3.00 (s, 2Η), 6, 10 (br s, 2H), 6.13 (s, 1H), 6.26 (m, 3H), 7.38 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H). IR (neat) cm -1: 2982, 1551, 1434, 1255, 1082.

Example 49

{2-Amino-4- [Y4- (2,6-dichlorophenylpiperazin-1-yl) methylthiophen-3-ylH4-

chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 128-130 ° C. 1H-NMR (CDCl3) 6: 2.02 (t, J = 4.8 Hz, 4H), 2.82 (t, J = 4.6 Hz, 4H), 3.02 (s, 2H), 6, 05 (br s, 2H), 6.09 (s, 1H), 7.01 (d, J = 8.6 Hz, 1H), 7.17 (t, J = 8.6 Hz, 10 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H). IR (KBr) cm -1: 2977, 15678, 1466, 1272.

Example 50

{2-Amino-4-r (4- (4- (trifluoromethoxy) phenyl) piperazin-1-yl) methylthiophen-3-ylH4-

chloropheniDethanone

The title compound is purified by flash chromatography.

column (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 151-153 ° C. 1H-NMR (CDCl3) 6: 2.04 (t, J = 4.8 Hz, 4H), 2.92 (t, J = 4.8 Hz, 4H), 3.01 (s, 2H), 6, 09 (br s, 2H), 6.14 (s, 1H), 6.80 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 7 , 38 (d, J = 7.8 Hz, 2H), 7.56 (d, J = 7.8 Hz, 2H). IR (KBr) cm -1: 2973, 1614, 1264, 1087, 1032. Example 51

(2-Amino-4-r (4- (pyridin-3-iPpiperazin-1-iPmethyl-thiophen-3-yl) (4-

chloropheniPmetanone

The title compound is purified by 5 column chromatography (EtOAc: MeOH / 6: 4 as eluent). Yellow solid, m.p. 101-103 ° C. 1H-NMR (CDCl3) δ: 2.01 (t, J = 4.8 Hz, 4H), 2.84 (t, J = 4.8 Hz, 4H), 3.00 (s, 2H), 6, 09 (br s, 2H), 6.13 (s, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.78 (m, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 8.07 (s, 1H), 8.24 (d, J = 9.0 Hz, 1H). IR (KBr) δ: 2958, 1586, 1444, 1270, 1096.

Example 52

{2-Amino-4-IY4- (2,5-dichlorophenyl) piperazin-1-yl) methithiophen-3-ylH4-

chloropheniPmetanone

The title compound is purified by column chromatography (EtOAc: DCMZO, 5: 9.5 as eluent). Yellow solid, m.p. 78-80 ° C. 1H-NMR (CDCl3) δ: 2.07 (t, J = 4.6 Hz, 4H), 2.81 (t, J = 4.6 Hz, 4H), 3.03 (s, 2H), 6, 08 (br s, 2H), 6.15 (s, 1H), 6.93 (s, 1H), 7.24 (d, J = 9.2 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H). IR (KBr) cm -1: 2988, 1568, 1462, 1271.

Example 53

(2-Amino-4- (4- (2,3-difluorophenyl) piperazin-1-yl) methylthiophen-3-yl (4-chlorophenyl) Dmetanone The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as eluent) Yellow solid, mp 138 ° C 1H NMR (CDCl3) 6: 1.99 (t, J = 4.8 Hz, 4H), 2.78 (t, J = 4.8 Hz , 4H), 2.95 (s, 2H), 6.00 (br s, 2H), 6.07 (s, 1H), 6.54 (t, J = 7.6 Hz, 1H), 6, 67 (d, J = 7.8 Hz, 5 1H), 6.85 (t, J = 8.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H) IR (KBr) cm -1: 2981, 1565, 1453, 1254, 1072.

Example 54

{2-Amino-4- [Y4- (4-chlorophenyl-P-3-methylpiperazin-1-yl) methylthiophen-3-yl] (4-chlorophenyl Dmetanone

The title compound is purified by flash chromatography.

column (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 105 c. 1H-NMR (CDCl3) 6: 1.12 (d, J = 6.6 Hz, 3H), 2.12 (t, J = 5.4 Hz, 2H), 2.21 (t, J = 5.4 Hz, 2H), 2.67 (m, 2H), 3.11 (s, 2H), 3.21 (m, 1H), 6.08 (br s, 2H), 6.13 (s, 1H) ,

6.72 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 7, 42 (d, J = 9.0 Hz, 2H). IR (KBr) cm -1: 3372, 1588, 1523, 1233.

Example 55

{2-Amino-4-IY4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methylthiophen-3-yl} Γ3- (trifluoromethylphenylmethanone

The title compound is purified by column chromatography (EtOAc: DCMZO, 25: 9.75 as eluent). Yellow solid, m.p. 143-145 ° C. 1H-NMR (CDCl3) 6: 1.95 (t, J = 4.8 Hz, 4H), 2.94 (s, 2H), 2.98 (t, J = 4.8 Hz, 4H), 6, 14 (s, 1H), 6.28 (br s, 2H), 6.82 (t, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7 , 54 (t, J = 8.0 Hz, 1H), 7.74 (m, 2H), 7.85 (s, 1H). Example 56

{2-Amino-4- (4- (3-fluorophenyl) piperazin-1-yl) methylthiophen-3-ylir3-one

(trifluoromethyl) phenylmethanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 100-102 ° C. 1H-NMR (CDCl3) δ: 1.94 (t, J = 4.8 Hz, 4H), 2.90 (t, J = 4.8 Hz, 4H), 2.93 (s, 2H), 6, 14 (s, 1H), 6.29 (br s, 2H), 6.49 (m, 2H), 6.57 (d, J = 9.6 Hz, 1H), 7.15 (q, J = 7.2 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.74 (m, 2H), 7.84 (s, 1H).

Example 57

{2-Amino-4-yl-4- (2,6-difluorophenyl) piperazin-1-yl) methylthiophen-3-yl} Γ3- (trifluoromethyl) phenylmethanone

PFj

/ \)

Cf CN ^ yy = °

The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as eluent). Yellow solid, m.p. 163-165 ° C. 1H-NMR (CDCl3) 6: 1.92 (t, J = 4.8 Hz, 4H), 2.89 (t, J = 4.8 Hz, 4H), 3.02 (s, 2H), 6, 73 (s, 1H), 6.84 (m, 5H), 7.34 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7, 84 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H).

Example 58

{2-Amino-4- (spiroibenzord1-dioxol-2,4, piperidinal-r-ylmethyl) thiophen-3-ylK4-

chlorophenylmethanone The title compound is purified by column chromatography (DCM: EtOAc / 1: 9 as eluent). Yellow solid, m.p. 209-211 ° C. 1H-NMR (CDCl3) δ: 2.06 (t, J = 6.0 Hz, 4H), 3.02 (t, J = 6.0 Hz, 4H), 3.52 (s, 2H), 6, O (br s, 2H), 6.76 (m, 5H), 7.42 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H).

Example 59

{2-Amino-4- (5-t-butylpyrorbenzordl-dioxol-2,4'-piperidinal-1'-1-imetiDthiophen-3-yl) (4-chlorophenyl Pmetanone

The title compound is purified by flash chromatography.

column (DCM: EtOAc / 1: 9 as eluent). Yellow solid, m.p. 100-102 ° C. 1H-NMR (CDCl3) 6: 1.27 (s, 9H), 1.96 (t, J = 5.6 Hz, 2H), 2.06 (t, J = 5.6 Hz, 2H), 3, 01 (t, J = 6.0 Hz, 4H), 3.67 (s, 2H), 6.15 (br s, 2H), 6.62 (d, J = 8.2 Hz, 1H), 6 , 78 (m, 2H), 6.84 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H).

Example 60

{2-Amino-4- (4-fluorospirorbenzord1-dioxol-2,41-piperidinal-r-ylmethyl) thiophen;

3-ylH4-chlorophenylmethanone

The title compound is purified by column chromatography (DCM: EtOAc / 9.9: 0.1 as eluent). Yellow solid, m.p. 80-81 ° C. 1H-NMR (CDCl3) 6: 1.81 (t, J = 6.0 Hz, 4H), 2.08 (t, J = 6.0 Hz, 4H), 3.03 (s, 2H), 6, 10 (s, 1H), 6.13 (br s, 2H), 6.52 (d, J = 7.6 Hz, 1H), 6.58 (t, J = 7.6 Hz, 1H), 6 72 (m, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H). Example 61

{2-Amino-4- (4-methylpyrorbenzoyl-dioxol-2,4'piperidin-1-ylmethyl) thiophen-3-one

yl j (4-chlorophenyl) methanone

The title compound is purified by column chromatography (DCM: EtOAc / 7: 3 as eluent). Yellow solid, mp 184-186 ° C. 1H-NMR (CDCl3) δ: 1.93 (t, J = 5.6 Hz, 4H), 2.20 (s, 3H), 3.14 (m, 4H), 3.46 (s, 2H), 5.84 (m, 2H), 6.64 (m, 3H), 6.88 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H).

Example 62

{2-Amino-4- (5-methylpiro [benzo [dl-dioxol-2,4'-piperidin-1-ylmethyl) thiophen-3-yl H4-chlorophenylmethanone]

The title compound is purified by column chromatography (petroleum ether: EtOAc / 2: 8 as eluent). White solid, m.p. 119-121 ° C. 1H-NMR (CDCl3) δ: 1.77 (t, J = 5.2 Hz, 4H), 2.06 (t, J = 5.2 Hz, 4H), 2.23 (s, 3H), 3, O (s, 2H), 6.08 (br s, 2H), 6.12 (s, 1H), 6.54 (m, 3H), 7.38 (d, J = 8.4 Hz, 2H) 7.54 (d, J = 8.4 Hz, 2H).

Example 63

{2-Amino-4-F (4- (4-chlorophenylamino) piperidin-1-yl) methylthiophen-3-yl (4-

chlorophenylmethanone The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as eluent). Mass (m / z): 460.48 (M + 1). 1H-NMR (CDCl3) δ: 1.18 (m, 1H), 1.81 (m, 5H), 2.24 (m, 3H), 3.06 (s, 2H), 3.09 (m, 1H) ), 6.04 (br s, 2H), 6.18 (s, 1H), 6.36 (d, 2H, J = 8.8 Hz), 7.07 (d, 2H, J = 8.8 Hz), 7.38 (d, 2H, J = 8.4 Hz), 7.54 (d, 2H, J = 8.4 Hz).

Example 64

(2-Amino-4- (4- (4-chlorophenylmethylamino) piperidin-1-yl) methylthiophen-3-yl)

chloropheniDethanone

The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as eluent). Mass (m / z): 476.47 (M + 1), 1H NMR (CDCl3) δ: 1.40 (m, 3H), 1.67 (m, 3H), 2.20 (m, 2H), 2.70 (s, 3H), 2.92 (s, 2H), 3.30 (m, 1H), 6.02 (br s, 2H), 6.11 (s, 1H), 6.62 ( d, 2H, J = 9.2 Hz), 7.12 (d, 2H, J = 9.2 Hz), 7.39 (d, 2H, J = 8.4 Hz), 7.56 (d, 2H, J = 8.4 Hz). Example 65

{2-Amino-4- Γ (4- (4-chlorophenyl) diazepan-1-yl) methylthiophen-3-yl (4-chlorophenylmethanone

The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as eluent). Mass (m / z): 460.56 (M + 1). 1H-NMR (CDCl3) δ: 1.60 (m, 2H), 2.02 (m, 2H), 2.18 (m, 2H), 3.06 (s, 2H),

3.21 (m, 2H), 3.29 (m, 2H), 5.97 (br s, 2H), 6.11 (s, 1H), 6.49 (d, 2H, J = 8.8 Hz), 7.10 (d, 2H, J = 8.8 Hz), 7.36 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 8.4 Hz) . Example 66

{2-Amino-4-r (7- (4-chlorophenyl) -2,7-diaza-spironon-2-yl) methylthiophen-3-yl} (4-

chlorophenyl) methanone

The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as eluent). Mass (m / z): 486.48 (M + 1). 1H-NMR (CDCl3) 6: 1.61 (m, 2H), 1.84 (m, 2H), 2.01-2.14 (m, 4H), 3.00-3.09 (m, 4H) 3.18 (m, 2H), 6.09 (br s, 2H), 6.11 (s, 1H), 6.39 (d, 2H, J = 8.8 Hz),

7.15 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.4 Hz). Example 67

{2-Amino-4- (5- (4-chlorophenyl) hexahydropyrrolo [3,4-pyrpyr-2-yl) methylthiophen-3-ylH 4-chlorophenyl) methanone

The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as eluent). Mass (m / z): 472.42 (M + 1), 1H NMR (CDCl3) δ: 2.03 (m, 2H), 2.10 (m, 2H), 2.73 (m, 2H), 2.85 (m, 2H), 15 3.06 (s, 2H), 3.34 (m, 2H), 6.06 (br s, 2H), 6.10 (s, 1H), 6.54 (d, 2H, J = 8.8 Hz), 7.20 (d, 2H, J = 8.8 Hz), 7.24 (d, 2H, J = 8.4 Hz), 7.33 (d , 2H, J = 8.4 Hz). Example 68

(2-Amino-4-IY5-f-4-chlorophenyl-2,5-diazabicyclor2.11hept-2-yl) methylthiophen-3-yl (4-chlorophenyl) methanone The title compound is purified by column chromatography ( cyclohexane: EtOAc / 8: 2 as eluent). Mass (m / z): 458.64 (M + 1), 1H NMR (CDCl3) δ: 1.62 (m, 2H), 2.04 (m, 1H), 2.35 (m, 1H), 2.79 (m, 2H), 2.96-3.12 (m, 4H), 6.01 (br s, 2H), 6.29 (d, 2H, J = 8.8 Hz), 6, 36 (m, 1H), 7.06 (d, 2H, J = 8.8 Hz), 7.23 (d, 2H, J = 8.4 Hz), 7.38 (d, 2H, J = 8 , 4 Hz).

Example 69

{2-Αηύηο-4-Γ (4- (4-fluorophenyl) piperazin-1-yl) methyl1 -5-methylthiophen-3-yl I (4-chlorophenipmetanone

A. 2-R3- (4-Chlorobenzoyl) -4,5-dimethylthiophen-2-yl1isoindoline-1,3-dione

To a solution of (2-amino-4,5-dimethylthiophen-3-yl) (4-

chlorophenyl) methanone (532 mg, 2 mmol; prepared as described in United States Patent No. 6,323,214) in acetic acid (15 mL) add phthalic anhydride (360 mg, 2.4 mmol) and the mixture is heated at reflux for 15 h. The solvent is evaporated in vacuo and the residual material is dissolved in ethyl acetate (20 ml). The organic solution is washed with saturated aqueous NaHCO 3 (5 mL), water (5 mL), then brine (5 mL), dried (Na 2 SO 4), filtered, and concentrated in vacuo. The crude product is stirred for 1 h in petroleum ether (20 ml), then filtered to give (2- [3- (4-chlorobenzoyl) -4,5-dimethylthiophen-2-yl] isoindoline-1,3-dione as a yellow powder 1H NMR (CDCl3) δ: 2.10 (s, 3H), 2.43 (s, 3H), 7.24 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.78 (m, 4H).

B. 2-4- (Bromomethyl-3-4-chlorobenzoyl-5-methylthiophen-2-yisoindoline-1,3-dione

To the title compound A (2 mmol, 798 mg) in acetonitrile (10 mL) is added N-bromosuccinimide (2 mmol, 356 mg) and the mixture is heated at reflux for 2 h. After this time, another portion of N-bromosuccinimide (2 mmol, 356 mg) is added and refluxing is continued for a further 2 h. The solvent is then removed under reduced pressure, and the residue dissolved in DCM (15 mL), washed with water (5 mL), brine (5.5 mL), dried (Na 2 SO 4), and concentrated to a dark oil. This residue is then purified by flash chromatography (EtOAc / petroleum ether / 2: 8 as eluent) giving the compound as a yellow solid. The powder is suspended in petroleum ether (10 ml), the mixture is stirred for 30 min, and then filtered to give 2- [4-bromomethyl-3- (4-chlorobenzoyl) -5-methylthiophen-2-10 yl] isoindoline. -1,3-dione: mp 173-175 ° C. 1H-NMR (CDCl3) δ: 2.53 (s, 3H),

4.65 (s, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.63 (m, 2H),

7.73 (m, 2H).

C2- [3- (4-Chlorobenzoyl) -4 - ((4- (4-fluorophenylpiperazin-1-yl) methyl] -4-

methylthiophen-2-yisoindoline-1,3-dione A to a stirred solution of the title compound B (900 mg, 0.5

mmol) in dry DMF (5 mL) is added K 2 CO 3 (0.6 mmol, 83 mg). The mixture is cooled with an ice / water bath, and then added to 1- (4-fluorophenyl) piperazine (3 equiv., 1.5 mmol). The mixture is stirred at room temperature for one hour, the solvent is then removed under reduced pressure, and a mixture of DCM (15 mL) and water (5 mL) is added to the residue. The organic phase is washed with brine (5 mL) and dried (Na 2 SO 4), filtered, then concentrated in vacuo to give a brown residue which is purified by column chromatography (ethyl acetate: DCM / 1: 9 as eluent) giving 2- [3- (4-chlorobenzoyl) -4 - ((4- (4-25 fluorophenyl) piperazin-1-yl) methyl) -5-methylthiophen-2-yl] isoindoline-1,3-dione:

mp 110-112 ° C. 1H-NMR (CDCl3) δ: 2.23 (t, J = 4.8 Hz, 4H), 2.42 (s, 3H), 2.72 (t, J = 4.8 Hz, 4H), 3, 23 (s, 2H), 6.60 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H), 6.85 (t, J = 8.6 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.68 (m, 2H), 7.72 ( m, 2H). D. {2-Amino-4- [4- (4-fluorophenyl) piperazin-1-ylmethyl-5-methylthiophen-3-yl] (4-

chloropheniDethanone

A stirred suspension of the title compound C (0.5 mmol) and hydrazine monohydrate (0.6 mmol, 29 μΐ) in absolute EtOH (10 mL) is heated at reflux for 3 h. The resulting solution is allowed to cool to room temperature for 1 h. The reaction is terminated upon completion of solubilization of the starting material. The solvent is evaporated and the residue partitioned between DCM (10 mL) and water (5 mL). The separated organic phase is washed with brine (2 mL), dried (Na 2 SO 4), filtered, and then concentrated in vacuo to give a residue which is purified by column chromatography (EtOAc: DCM / 0.5: 9 0.5 as eluent) giving {2-amino-4 - [(4- (4-fluorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} - (4-

op 1

chlorophenyl) methanone as a yellow solid: mp 70-72 ° C. 1 H NMR (CDCl 3) δ: 1.99 (t, J = 4.8 Hz, 4H), 2.23 (s, 3H), 2.83 (t, J = 4.8 Hz, 4H), 2, 96 (s, 2H), 5.82 (br s, 2H), 6.76 (d, J = 8.6 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6 94 (t, J = 8.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H).

The following compounds are prepared analogously as described in Example 69.

Example 70

{2-Amino-5-methyl-4- (4-phenylpiperazin-1-yl) methylthiophen-3-yn (4-chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 78-80 ° C. 1H-NMR (CDCl3) δ: 1.98 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 2.91 (t, J = 4.8 Hz, 4H), 2, 95 (s, 2H), 5.80 (br s, 2H), 6.83 (d, J = 8.4 Hz, 2H), 7.23 (t, J = 8.4 Hz, 3H), 7 , 35 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H). Example 71

{2-Amino-5-methyl-4- [4- (4- (trifluoromethylphenyl) piperazin-1-yl) methyl] thiophen-3-one

yl (4-chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 76-78 ° C. 1H-NMR (CDCl3) δ: 2.04 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 2.95 (s, 2H), 3.00 (t, J = 4 , 8 Hz, 4H), 5.82 (br s, 2H), 6.82 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7 , 43 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H).

Example 72

(2-Amino-4- Γ (4- (4-chlorophenyl) piperazin-1-ylmethyl-5-methylthiophen-3-yl) (4-chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 83-85 ° C. 1H-NMR (CDCl3) δ: 1.98 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 2.87 (t, J = 4.8 Hz, 4H), 2, 95 (s, 2H), 5.80 (br s, 2H), 6.73 (d, J = 9.2 Hz, 2H), 7.16 (d, J = 9.2 Hz, 2H), 7 , 36 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H).

Example 73

{2-Amino-4- [Y4- (4-bromophenyl) piperazin-1-yl) methylH-5-methylthiophen-3-yl} (4-

chloropheniDethanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, mp 73-75 ° C. 1H-NMR (CDCl3) 6: 1.96 (t, J = 5.2 Hz, 4H), 2.22 (s, 3H), 2.87 (t, J = 5.2 Hz, 4H), 2, 94 (s, 2H), 5.81 (br s, 2H), 6.68 (d, J = 9.2 Hz, 2H), 7.29 (d, J = 9.2 Hz, 2H), 7 , 35 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H).

Example 74

{2-Amino-4- (4- (4-iodophenyl) piperazin-1-yl) methyl-5-methylthiophen-3-yl | (4-

chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 72-73 ° C. 1H-NMR (CDCl3) 6: 1.99 (t, J = 5.2 Hz, 4H), 2.04 (s, 3H), 2.89 (t, J = 5.2 Hz, 4H), 2, 98 (s, 2H), 5.80 (br s, 2H), 6.58 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7 , 47 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H).

Example 75

{2-Amino-5-methyl-4-yl-4- (4-nitrophenyl) piperazin-1-yl) methylthiophen-3-yl | (4-chlorophenylmethanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 85-87 ° C. 1H-NMR (CDCl3) 6: 1.98 (t, J = 5.4 Hz, 4H), 2.331 (s, 3H), 3.08 (s, 2H), 3.11 (t, J = 5.4 Hz, 4H), 6.26 (br s, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 9.2 Hz, 2H), 8.05 (d, J = 9.2 Hz, 2H), 8.13 (d, J = 8.8 Hz, 2H). Example 76

4- {4 - [(5-Amo-4- (4-chlorobenzoyl) -2-methylthiophen-3-yl) methyl-1-piperazin-1-one

benzonitrile a

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 76-77 ° C. 1H-NMR (CDCl3) 6: 1.96 (t, J = 4.8 Hz, 4H), 2.21 (s, 3H), 2.95 (s, 2H), 3.04 (t, J = 4 , 8 Hz, 4H), 5.84 (br s, 2H), 6.74 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7 , 44 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H).

Example 77

{2-Amino-4- (4-benzylpiperazin-1-yl) methyl) -5-methylthiophen-3-yl (4-chlorophenylmethanone

α

/ - \

r * Ç

The title compound is purified by column chromatography (EtOAc as eluent). Yellow solid, m.p. 48-50 ° C. 1H-NMR (CDCl3) 6: 1.84 (t, J = 5.2 Hz, 4H), 2.18 (s, 3H), 2.86 (t, J = 5.2 Hz, 4H), 3, 40 (s, 2H), 3.49 (s, 2H), 5.79 (br s, 2H), 7.26 (m, 5H), 7.33 (d, J = 8.4 Hz, 2H) 7.51 (d, J = 8.4 Hz, 2H).

Example 78

{2-Amino-4- (4- (4-methoxyphenyl) piperazin-1-yl) methyl-5-methylthiophen-3-yl} (4-chlorophenylmethane) The title compound is purified by column chromatography (EtOAc : DCM / 1.5: 8.5 as eluent Yellow solid, mp 63-65 ° C 1H NMR (CDCl3) δ: 1.98 (t, J = 5.4 Hz, 4H), 2.21 (s, 3H), 2.80 (t, J = 5.4 Hz, 4H), 2.94 (s, 2H), 3.75 (s, 3H), 5.81 (br s, 2H), 6.81 (s, 4H), 7.34 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H).

Example 79

{2-Amino-5-methyl-4-YY4-p-tolylpiperazin-1-yl) methylthiophen-3-ylH4-

chloropheniPmetanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 77-79 ° C. 1H-NMR (CDCl3) δ: 1.98 (t, J = 5.2 Hz, 4H), 2.22 (s, 3H), 2.25 (s, 3H), 2.85 (t, J = 5 , 2 Hz, 4H), 2.94 (s, 2H), 5.81 (br s, 2H), 6.75 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H).

Example 80

{2-Amino-4-r (4- (3,4-dichloropheninpiperazin-1-yl) methyl-5-methylthiophen-3-yn (4-chlorophenylmethane)

a ^ J

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as eluent). Yellow solid, m.p. 63-65 ° C. 1H-NMR (CDCl3) δ: 1.96 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 2.88 (t, J = 4.8 Hz, 4H), 2, 94 (s, 2H), 5.82 (br s, 2H), 6.63 (dd, J = 9.2 and 2.8 Hz, 1H), 6.86 (d, J = 2.8 Hz, IH),

7.22 (d, J = 9.2 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H). Example 81

{2-Amino-5-methyl-4- (4-n- (trifluoromethyl) phenyl) piperazin-1-yl) methylthiophen-3-one

il) (4-chlorophenylmethanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as eluent). Yellow solid, m.p. 60-61 ° C. 1H-NMR (CDCl3) 6: 1.99 (t, J = 5.2 Hz, 4H), 2.22 (s, 3H), 2.96 (m, 6H), 5.81 (br s, 2H) 6.96 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H).

Example 82

{2-Amino-4- Γ (4- (3-chlorophenylpiperazin-1-yl) methyl-5-methylthiophen-3-yl} (4-chlorophenylmethanone

The title compound is purified by column chromatography (EtOAc: DCMZO, 75: 9.25 as eluent). Yellow solid, m.p. 58-60 ° C. 1H-NMR (CDCl3) 6: 1.96 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 2.92 (t, J = 4.8 Hz, 4H), 15 3 .00 (s, 2H), 5.82 (br s, 2H), 6.68 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.78 (s, 1H), 7.12 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8 4 Hz, 2H). Example 83

{2-Amdno-4-IY4- (4-chloro-3- (trifluoromethylphenyl) piperazin-1-yl) methyl1-5-methylthiophen-3-yl H4-chlorophenyl) methanone The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as eluent). Yellow solid, m.p. 133-135 ° C. 1H-NMR (CDCl3) δ: 1.98 (t, J = 4.4 Hz, 4H), 2.22 (s, 3H), 2.93 (t, J = 4.4 Hz, 4H), 2, 96 (s, 2H), 5.82 (br s, 2H), 6.84 (dd, J = 8.8 and 2.8 Hz, 1H), 7.07 (d, 5 J = 2.8 Hz , IH), 7.29 (d, J = 8.8 Hz, IH), 7.37 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H ).

Example 84

{2-Amino-5-ethyl-4- (4- (4-fluorophenyl) piperazin-1-yl) methylthiophen-3-ylH4-

chloropheniDethanone

A. A mixture of (Z) and (Έ) 2- (4-chlorobenzoyl) -3-methylex-2-enenitrile

A mixture of pentan-2-one (20 mmol), 3- (4-chlorophenyl) -3-oxopropanenitrile (3.6 g, 20 mmol), β-alanine (180 mg, 2 mmol), acetic acid (2, 6 ml) and toluene (60 ml) is heated to reflux in a Dean-Stark system for 18 h. The solution is cooled to room temperature, then diluted with EtOAc (50 mL), washed with 5% NaHCO 3 (3 x 20 mL), water (20 mL), brine (20 mL), dried (Na 2 SO 4) and finally concentrated in vacuum. A mixture of the two isomers is obtained as a colorless oil by chromatographic purification of the crude residue on silica gel using EtOAc: petroleum ether (0.5: 9.5) as eluent.

B. (2-Amino-5-ethyl-4-methylthiophen-3-yl) (4-chlorophenyl) methanone

The title compound (s) A (5 mmol), TEA (0.7 mL, 5 mmol) and sulfur (192 mg, 6 mmol) in EtOH (10 mL) are heated at reflux for 2 h . After cooling to room temperature, the solvent is removed and the residue is dissolved in DCM (20 ml). The organic solution is washed with 0.1 N HCl (5 mL), 5% NaHCO 3 (5 mL), water (5 mL), brine (5 mL), dried (Na 2 SO 4) and concentrated in vacuo. The crude residue was purified by chromatography on a silica gel column, eluting with EtOAc: petroleum ether (1: 9) affording (2-amino-5-ethyl-4-methylthiophen-3-yl) ( 4-chlorophenyl) methanone as a yellow oil. 1H-NMR (CDCl3): δ 1.18 (t, 5 J = 7.6 Hz, 3H), 2.18 (s, 3H), 2.55 (q, J = 7.6 Hz, 2H), 5 77 (bs, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H).

C. 2- (3- (4-Chlorobenzoin-4-methyl-5-ethyl-thiophen-2-yl-isoindol-1,3-dione)

The title compound B (4 mmol) is dissolved in acetic acid (25 mL). Phthalic anhydride (5 mmol, 740 mg) is added to the solution and the mixture 10 is heated at reflux for 5 h. The solvent is evaporated in vacuo and the residual material is dissolved in DCM (30 ml). The organic solution is washed with water (10 mL), brine (10 mL), dried (Na 2 SO 4) and concentrated in vacuo. The crude product is first triturated for 1 h in petroleum ether (20 ml), then purified by column chromatography (EtOAc: petroleum ether 15/2: 8 as eluent) giving 2- [3- (4-chlorobenzoyl). ) -4-methyl-5-ethylthiophen-2-yl] isoindol-1,3-dione as a white solid: mp 115-117 ° C. 1H-NMR (CDCl3): δ 1.34 (t, J = 7.6 Hz, 3H), 2.17 (s, 3H), 2.82 (q, J = 7.6 Hz, 2H), 7, 26 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.77 (m, 2H), 7.79 (m, 2H).

D. 2-5-Ethyl-4-bromomethyl-3- (4-chloro-benzoin-thiophen-2-yl-isoindol-1,3-dione) A solution of the title compound C (2 mmol) in CCl4 (40

ml), a mixture of N-bromosuccinimide (784 mg, 4.4 mmol) and benzoyl peroxide (32 mg) is added and the mixture refluxed for 2 h. The resulting yellow solution is then cooled to room temperature, during which the succinimide separates and is removed by filtration. The filtrate is concentrated in vacuo, and the residue is diluted with DCM (20 mL). The organic solution is washed with 5% NaHCO 3 (10 mL), water (10 mL), brine (10 mL), dried (Na 2 SO 4) and concentrated to give a yellow residue which is purified by column chromatography (EtOAc: ether (2: 8 as eluent) giving 2- [5-ethyl-4-bromomethyl-3- (4-chloro-benzoyl) -thiophen-2-yl] -isoindol-1,3-dione as an orange oil. 1H-NMR (CDCl3): δ 1.39 (t, J = 7.6 Hz, 3H), 2.96 (q, J = 7.6 Hz, 2H), 4.66 (s, 2H), 7, 17 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.73 (m, 2H), 7.76 (m, 2H).

K 2- (3- (4-Chlorobenzoyl) -4-R4 - (, 4-fuorophenyl) piperazin-1-ylmethyl-5-ethyl

thiophen-2-yl} -isoindol-1,3-dione

To a stirred ice-water cooled solution of title compound D (0.5 mmol) in dry DMF (2.5 mL) is added TEA (0.12 mL, 1 mmol) and then to 1- (4 mL). -fluorophenyl) piperazine (0.6 mmol). The mixture is then stirred at room temperature for 2 h. The solvent is removed under reduced pressure, the residue is dissolved in DCM (10 mL), washed with water (5 mL), brine (5 mL), and dried (Na 2 SO 4). After evaporation under vacuum, the residue is purified by silica gel column chromatography (EtOAc / Petroleum Ether / 1.5: 8.5 as eluent) giving 2- {3- (4-chlorobenzoyl) -4- [4 - (4-fluorophenyl) piperazin-1-ylmethyl-5-ethyl] thiophen-2-yl} isoindol-1,3-dione 15 as a white solid: mp 122-124 ° C. 1H-NMR (CDCl3): δ 1.20 (t, J = 7.6 Hz, 3H), 1.99 (m, 4H), 2.68 (q, J = 7.6 Hz, 2H), 3, O (m, 4H), 3.22 (s, 2H),

6.84 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7, 52 (d, J = 8.4 Hz, 2H), 7.72 (m, 2H), 7.84 (m, 2H).

F {{2-Amino-4-4- (4-fluorophenyl) piperazin-1-yl) methyl] -5-ethylthiophen-3-ylH4-

chlorine phenipmetanone

A stirred suspension of the title compound E (0.25 mmol) and 100% hydrazine monohydrate (0.3 mmol, 14 μΐ) in absolute EtOH (5 mL) is refluxed for 3 h. The solvent is evaporated and the residue is partitioned between DCM (10 mL) and water (5 mL). The separated organic phase is washed with brine 25 (2 ml) and dried, then concentrated in vacuo to give a residue which is purified by column chromatography (EtOAc: DCM / 8: 2 as eluent) giving {2-amino -4- [4- (4-fluorophenyl) piperazin-1-yl) methyl] -5-ethylthiophenyl

3-yl} (4-chlorophenyl) methanone as a yellow solid: m.p. 123-125 ° C. 1H-NMR (CDCl3): δ 1.21 (t, J = 7.6 Hz, 3H), 1.98 (m, 4H), 2.61 (q, J = 7.6 Hz, 2H), 2, 84 (m, 4Η), 2.96 (s, 2Η), 5.77 (bs, 2H), 6.82 (m, 2H), 6.93 (d J = 9.0 Hz, 2H), 7 , 34 (d J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H).

The following compounds are prepared analogously as described in Example 84.

Example 85

(2-Amino-5-ethyl-4-YY4-phenylpiperazin-1-yl) methylthiophen-3-ylH4-

chlorophenyl) methanone

The title compound is purified by column chromatography (EtOAc: petroleum ether / 1.5: 8.5 as eluent). Yellow solid, m.p. 104-106 ° C. 1H-NMR (CDCl3): δ 1.22 (t, J = 7.6 Hz, 3H), 1.98 (m, 4H), 2.64 (q, J = 7.6 Hz, 2H), 2, 92 (m, 4H), 2.96 (s, 2H), 5.78 (bs, 2H), 6.85 (m 3H), 7.23 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H).

Example 86

{2-Amino-4-r ('4- (4-chlorophenyl) piperazin-1-yl) metin-5-ethylthiophen-3-yl] -4-chlorophenylmethanone

The title compound is purified by column chromatography (EtOAc / petroleum ether / 1.5: 8.5 as eluent). Yellow solid, m.p. 115-117 ° C. 1H-NMR (CDCl3): δ 1.23 (t, J = 7.6 Hz, 3H), 1.97 (m, 4H), 2.61 (q, J = 7.6 Hz, 2H), 2, 88 (m, 4H), 2.96 (s, 2H), 5.77 (bs, 2H), 6.72 (d 20 J = 9.0 Hz, 2H), 7.19 (d J = 9, (Hz, 2H), 7.34 (d J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H). Example 87

{2-Ammo-5-phenyl-4- (piperidin-1-ylmethyl-thiophen-3-ylH-4-chlorophenyl) methanone

A. 2-β-f-4-Chlorobenzoyl) -4-methyl-5-phenylthiophen-2-yl isoindol-1,3-dione

The title compound A is prepared from the title compound C of Example 1 according to a procedure described by Romagnoli et al. in J. Med. Chem. 2006, 49 (13), 3906-3915. The product is purified by column chromatography (eluent EtOAc: petroleum ether / 1.5: 8.5 as eluent) giving 2- [3- (4-chlorobenzoyl) -4-methyl-5-phenylthiophen-2-one. yl] isoindol-1,3-dione as a brown solid, mp 223-225 ° C. 1H-NMR (CDCl3) δ: 2.24 (s, 10 3H), 7.24 (d, J = 8.4 Hz, 2H), 7.74 (m, 5H), 7.80 (m, 6H) .

B. 2-4-Bromomethyl-3- (4-chlorobenzoyl) -5-phenylthiophen-2-ylisoindol-1,3-dione

To a refluxing suspension of the title compound A (458 mg, 1 mmol) in CCl 4 (10 mL) is added NBS (180 mg, 1 mmol) and benzoyl peroxide (14 mg, 0.06 mmol) and the mixture is refluxed for 1 h. After this time, a mixture of N-bromosuccinimide (180 mg, 1 mmol) and benzoyl peroxide (14 mg, 0.06 mmol) is added and the mixture is refluxed for an additional hour. The yellow solution is then cooled to room temperature, and the succinimide which separates after cooling is removed by filtration and the filter cake is washed with CCl4 (5 ml). The filtrate is washed with 5% NaHCO 3 solution (5 mL), water (5 mL), brine (50 mL), dried over Na 2 SO 4, and concentrated to a yellow solid which is suspended with petroleum ether (10 mL). The mixture is stirred for 30 min, and the solid is collected by filtration giving 2- [4-bromomethyl-3- (4-chlorobenzoyl) -5-phenylthiophen-2-yl] isoindol-1,3-dione which is used as it is for the next reaction without further purification, mp 160-161 c. 1H-NMR (CDCl3) δ: 4.73 (s, 2Η), 7.21 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7, 52 (m, 1H), 7.68 (m, 8H).

C. 2- (3- (4-Chlorobenzoyl) -5-phenyl-4- (piperidin-1-yl) methylthiophen-2-ylisoindol-1,3-dione)

To a stirred solution of the title compound B (265 mg, 0.5

mmol) in dry DMF (5 mL) is added K 2 CO 3 (70 mg, 0.5 mmol). The mixture is cooled with an ice / water bath, and then piperidine (4 equiv., 2 mmol) is added. The mixture is stirred at room temperature for 2 h. After this time, the solvent is removed under reduced pressure, and the residue is taken up in a mixture of EtOAc (15 mL) and water (5 mL). The organic phase is washed with brine (5 mL), dried over Na 2 SO 4, and concentrated under vacuum to give a brown residue which is purified by column chromatography (EtOAc: petroleum ether / 1.5: 8.5 as eluent). giving 2- [3- (4-chlorobenzoyl) -5-phenyl-4 - ((piperidin-1-yl) methyl) thiophen-2-yl] isoindol-1,3-dione 15 as a yellow solid, mp 187 ° C. 189 c. 1H-NMR (CDCl3) δ: 1.25 (m, 6H),

1.65 (m, 4H), 2.98 (s, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.53 (m, 3H), 7.73 (m, 8H ).

D- (2-AjTiino-5-phenyl-4- [Ypiperidin-1-methylmethylthiophen-3-yl] -4-

chlorophenyl) methanone

A stirred suspension of the title compound C (0.5 mmol) and

100% hydrazine monohydrate (1.2 eq, 0.6 mmol, 29 μΐ) in absolute ethanol (10 mL) is refluxed for 1 h. After this time, the solvent is evaporated and the residue is partitioned between EtOAc (10 mL) and water (5 mL). The separated organic phase is washed with brine (2 ml), dried, and concentrated in vacuo to give a residue which is purified by column chromatography (EtOAc: petroleum ether / 4: 6 as eluent) giving {2 -amino-5-phenyl-4 - [(piperidin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone as a yellow solid, mp 185-187 ° C. 1H-NMR (CDCl3) 6: 1.24 (m, 6H), 1.66 (m, 4H),

2.99 (s, 2H), 5.69 (br s, 2H), 7.33 (m, 7H), 7.65 (d, J = 8.6 Hz, 2H). Example 88

(Example of a larger scale synthesis)

(2-Amino-4- (4- (4-fluorophenyl) piperazm-1-yl) methyl-5-methylthiophen-3-yl) (4-

chloropheniDethanone

A. (2-Amino-4,5-dimethylthiophen-3-ylX4-chlorophenyl) methanone

A 12-neck, 3-neck, round-neck flask equipped with a mechanical stirrer and thermometer is charged with 3- (4-chlorophenyl) -3-oxopropanenitrile (800 g, 4.46 mol), absolute EtOH (4 1) sulfur (321 g, 4.46 mol) and ethyl methyl ketone (321 g, 4.46 mol). Morpholine (388 g, 4.46 mol) and the thick reaction mixture are added, and the temperature

oC Op

increases from 18 to 30. The reaction mixture is stirred for 1 h at room temperature, heated at reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue is combined with a prior batch of 500 g reaction crude material. The combined residues are collected in EtOAc (121), washed with water (6 I), 10% NaHSO 4 (3 L) and brine (2 L), dried over anhydrous NaSO 4 and filtered through Celite. The filtrate is concentrated in vacuo giving a rubber solid. The solids are collected by filtration, washed with hexanes and air dried giving (2-amino-4,5-dimethylthiophen-3-yl) (4-chlorophenyl) methanone as a tan solid (680 g).

B. 2-β- (4-Chlorobenzoyl) -4,5-dimethylthiophen-2-ylisoindoline-1,3-dione

A 3-neck, round-bottom, 12-liter vial equipped with a mechanical stirrer and thermometer is charged with the title compound A (800 g, 3.01 mol), acetic acid (6 1), and phthalic anhydride ( 535 g, 3.62 mol). The reaction mixture is stirred at reflux overnight, then allowed to cool to room temperature and concentrated in vacuo. Methyl t-butyl ether (MTBE, 2 L) is added to the residue, and the resulting slurry is filtered. The solids are washed with MTBE (500 ml) and hexanes (11), then air dried to give 2- [3- (4-chlorobenzoyl) -4,5-dimethylthiophen-2-yl] isoindoline-1,3-dione. as a solid bronze color (1050 g). The1 H NMR spectrum is consistent with the structure.

C. 2-4- (Bromomethyl) -3- (4-chlorobenzoyl) -5-methylthiophen-2-ylisoindoline-1,3-dione

A 3-neck, round-bottom, 3-liter vial fitted with a mechanical stirrer and thermometer is charged with the title compound B (150 g, 0.38 mol), N-bromosuccinimide (67 g, 0.38 mol) , and acetonitrile (1.5 I). The reaction mixture is stirred at reflux for 2 h, then treated with additional N-bromosuccinimide (67 g, 0.38 mol). Heating under reflux conditions is continued for a further 2 h, and the reaction mixture is allowed to cool to room temperature, and concentrated in vacuo. The residue is taken up in DCM (600 mL) and washed with water (200 mL), saturated NaHCO 3 (200 mL), water (200 mL), and brine (200 mL), dried (Na 2 SO 4), filtered, and concentrated in vacuo. . The dark brown solid is purified by chromatography (DCM as eluent) to give a tan solid which is taken up in diethyl ether (Et 2 O, 300 ml), then filtered and dried to give 2- [4- (bromomethyl) -3- (4-chlorobenzoyl) -5-methylthiophen-2-yl] isoindoline-1,3-dione as an off-white solid (86 g). The1 H NMR spectrum is consistent with the structure.

D-2- (3- (4-Chlorobenzoyl) -4 - ((4- (3-fluorophenylpiperazin-1-yl) methyl) -5-

methylthiophen-2-yl isoindoline-1,3-dione

A 3-neck, round bottom flask with a volume of 2 liters

Equipped with a mechanical stirrer it is charged with the title compound C (80.7 g, 0.17 mol), CHCl 3 (1.2 L), and triethylamine (3 equiv). The mix is

° C j ·

cooled in a ~ 5 ice / water bath, then add the appropriate 4- (3-fluorophenyl) piperazine (0.9 equiv). The reaction mixture is stirred at 0 ° C.

O for 5 min, then at room temperature for 1 h. The reaction mixture is washed with water (500 mL), saturated NaHCO 3 (500 mL), and brine (500 mL), then dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to half volume. The crude material was purified by chromatography (2% EtOAc in DCM). The eluent is concentrated in vacuo, then taken up in Et 2 O (300 ml), filtered and dried to give 2- [3- (4-chlorobenzoyl) -4 - ((4- (3-fluorophenyl) piperazin-1-yl) methyl) -5-methylthiophen-2-yl] isoindoline-1,3-dione (40 g) as an off-white solid.

E. {2-Amino-4- (4- (3-fluorophenyl) piperazin-1-yl) methin-5-methylthiophen-3-yl} (4-chlorophenyl) methanone

A 3-neck, round bottom, 2 liter volume flask is charged with the title compound D (40 g, 0.07 mol), toluene (0.2 M), and EtOH (0.2 M). Hydrazine hydrate (1.5 equiv, 64% hydrazine) is added at one time, and the mixture is heated to reflux. At the reflux temperature, the reaction mixture becomes a clear yellow solution and, upon heating, a precipitate forms. The reaction is monitored by TLC, and when the reaction is complete (usually around ~ 5 h) the reaction mixture is allowed to cool to room temperature and concentrated. The residue is taken up in Et 2 O (600 mL), washed with water (150 mL), saturated NaHCO 3 (150 mL), and brine (150 mL), then dried (Na 2 SO 4). The solvent is removed in vacuo, and the resulting yellow solid is stirred in ethanol (80 ml), then filtered and dried to give {2-amino-4 - [(4- (3-fluorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-

° c

chlorophenyl) methanone as a yellow solid (24 g), m.p. 140-141 ° C. ESI-25 MS: 444 (M + H) +. Elemental analysis: calculated C 62.22%, H 5.22%, N 9.46%; found C 62.21%, H 5.27%, N 9.48%. 1H-NMR (200 MHz, CDCl3): δ 7.54 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz), 7.09-7.21 (m, 1H), 6.46-6.59 (m, 3H), 5.82 (s, 2H), 2.89-2.95 (m, 6H), 2.22 (s, 3H), 1.95 -1.99 (m, 4H).

Claims (46)

A compound, characterized in that it is of formula (I) wherein R1 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl; R 2, R 3, and R 4 are independently from each other hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy, or substituted alkoxy; , Q is selected from the group consisting of <formula> formula see original document page 101 </formula> wherein R5 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl, or substituted acyl; R 6 and R 7 are independently from each other hydrogen, C 1 -C 3 alkyl, or substituted C 1 -C 3 alkyl; or R 6 and R 7, provided that they are attached to the same carbon atom combined are alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered spirocyclic ring; Rs, R9, Rio, R11, R12 and R13 are independently hydrogen, C1 -C3 alkyl, or substituted C1 -C3 alkyl; X is N or C-H; or X is C-NR 14 R 15, wherein R 14 and R 15 are independently from each other hydrogen, C 1 -C 3 alkyl, substituted C 1 -C 3 aryl, aryl, or substituted aryl; or X is C-R1 where R6 and R5 combined are carbonyl oxygen; or X is C-R16, wherein R6 and R5 combined are a divalent radical of the formula -Y-CHR17- (CH2) n-CHR18-Y2 which, together with the carbon atom to which R16 and R5 are attached form a 5- to 7-membered spirocyclic ring wherein Y is oxygen or sulfur; R 17 and R 18 are independently from each other hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl; n is zero, or an integer of 1 or 2; or X is C-R 16, wherein R 16 and R 5 combined are a divalent radical of the formula which together with the carbon atom to which R 16 and R 5 are attached form. a 5-membered spirocyclic ring, wherein Y is oxygen or sulfur; R19 and R2Q are independently hydrogen, halogen, cyano, trifluoromethyl, C1 -C6 alkyl, substituted C1 -C6 alkyl, or C1 -C6 alkoxy; or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein R 1 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; or a pharmaceutically acceptable salt thereof. A compound according to claim 2, wherein Q is <formula> formula see original document page 103 </formula> wherein R5 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl, or substituted acyl; R 6 and R 7 are independently from each other hydrogen, C 1 -C 3 alkyl, or substituted C 1 -C 3 alkyl; or R 6 and R 7, provided that they are attached to the same carbon atom, are combined alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered spirocyclic ring; X is N or C-H; or X is C-NR 14 R 15, wherein R 14 and R 15 are independently from each other hydrogen, C 1 -C 3 alkyl, substituted C 1 -C 3 aryl, aryl, or substituted aryl; or X is C-R16, wherein R16 and R5 combined are a carbonyl oxygen; or X is C-R16, wherein R16 and R5 combined are a divalent radical of the formula <-Y-CHR17- (CH2) n-CHR18-Y -> which, together with the carbon atom to which R16 and R5 are attached form a 5- to 7-membered spirocyclic ring wherein Y is oxygen or sulfur; R17 and R18 are independently hydrogen, C1 -C6 alkyl, substituted C1 -C6 alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl; n is zero, or an integer of 1 or 2; or X is C-R16, wherein R16 and R5 combined are a divalent radical of the formula which, together with the carbon atom to which R16 and R5 are attached, form one. 5-membered spirocyclic ring, wherein Y is oxygen or sulfur; R19 and R20 are independently from each other hydrogen, halogen, cyano, trifluoromethyl, C1-C6 alkyl, substituted C1-C6 alkyl, or C1-C6 alkoxy; or a pharmaceutically acceptable salt thereof. A compound according to claim 3, characterized in that X is N; or a pharmaceutically acceptable salt thereof. A compound according to claim 4 wherein it is of formula (IA) wherein R1 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; R 2, R 3, and R 4 are independently from each other hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy, or substituted alkoxy; R5 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl, or substituted acyl; R6 and R7 are independently from each other hydrogen, C1 -C3 alkyl, or substituted C1 -C3 alkyl; or R 6 and R 7, provided that they are attached to the same carbon atom, are combined alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered spirocyclic ring; R8 and R9 are independently from each other hydrogen, C1 -C3 alkyl, or substituted C1 -C3 alkyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 5, wherein R 1 is hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 5, wherein R 5 is monocyclic aryl optionally substituted by one to three substituents selected from the group consisting of halogen, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof. Compound according to claim 5, characterized in that R2 and R4 are hydrogen; or a pharmaceutically acceptable salt thereof. A compound according to claim 8, characterized in that R 3 is halogen, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 5, wherein R 2 and R 3 are hydrogen; or a pharmaceutically acceptable salt thereof. A compound according to claim 10, characterized in that R 4 is halogen, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof. Compound according to Claim 5, characterized in that R 6, R 7, R 6 and R 9 are independently from each other hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 12, wherein R 5 is monocyclic aryl optionally substituted by one to three substituents selected from the group consisting of halogen, cyano, or trifluoromethyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 13, characterized in that R2 and R4 are hydrogen; or a pharmaceutically acceptable salt thereof. A compound according to claim 14, characterized in that R 3 is halogen, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 15, wherein R 1 is hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof. Compound according to claim 13, characterized in that R2 and R3 are hydrogen; or a pharmaceutically acceptable salt thereof. A compound according to claim 17, characterized in that R 4 is halogen, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 18, characterized in that R 1 is hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 3, wherein X is CR-16, wherein R 1 and R 5 combined are a divalent radical of the formula which together with the carbon atom to which R 6 and R 5 are attached form a compound. 5-membered spirocyclic ring, where Y is oxygen; R19 and R2O are independently hydrogen, halogen, cyano, trifluoromethyl, C1 -C6 alkyl, substituted C1 -C6 alkyl, or C1 -C6 alkoxy; or a pharmaceutically acceptable salt thereof. A compound according to claim 20 wherein it is of formula (IB) wherein R1 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; R 2, R 3, and R 4 are independently from each other hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy, or substituted alkoxy; R6, R7, R6 and R9 are independently hydrogen, C1 -C3 alkyl, or substituted C1 -C3 alkyl; R19 and R20 are independently from each other hydrogen, halogen, cyano, trifluoromethyl, C1 -C6 alkyl, substituted C1 -C6 alkyl, or C1 -C6 alkoxy; or a pharmaceutically acceptable salt thereof. A compound according to claim 21, characterized in that R1 is hydrogen or C1 -C3 alkyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 21, wherein R19 and R2O are independently hydrogen, halogen, cyano, trifluoromethyl, or C1 -C4 alkyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 21, wherein R 2 and R 4 are hydrogen; or a pharmaceutically acceptable salt thereof. A compound according to claim 24, characterized in that R 3 is halogen, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 21, characterized in that R2 and R3 are hydrogen; or a pharmaceutically acceptable salt thereof. A compound according to claim 26, characterized in that R 4 is halogen, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof. Compound according to claim 21, characterized in that R 1, R 7, R 1 and R 9 are hydrogen; or a pharmaceutically acceptable salt thereof. A compound according to claim 28, characterized in that R19 and R2O are independently hydrogen, halogen, cyano, trifluoromethyl or C1 -C4 alkyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 29, wherein R 2 and R 4 are hydrogen; or a pharmaceutically acceptable salt thereof. A compound according to claim 30, characterized in that R 3 is halogen, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof. Compound according to claim 31, characterized in that R 1 is hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 29, characterized in that R2 and R3 are hydrogen; or a pharmaceutically acceptable salt thereof. A compound according to claim 33, characterized in that R 4 is halogen, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 34, characterized in that R 1 is hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that it is selected from the group consisting of: {2-Amino-4 - [(4-phenylpiperazin-1-yl) methyl] thiophen-3-yl} (4 -chlorophenyl) methanone; {2-Amino-4 - [(4-methylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- [4 - ((4-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- [4 - ((4-chlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- [4 - ((4-methoxyphenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- p -tolylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (pyridin-2-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (pyrimidin-2-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (3,4-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; 4- {4 - [(5-Amino -4- (4-chlorobenzoyl) thiophen-3-yl) methyl] piperazin-1-yl} benzonitrile; {2-Amino-4 - [(4- (3-chlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2-chlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; 1- {4 - [(5-Amino -4- (4-chlorobenzoyl) thiophen-3-yl) methyl] piperazin-1-yl} -2- (4-chlorophenyl) ethanone; {2-Amino-4 - [(4- (4-chlorobenzoyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (pyridin-4-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (benzo [d] dioxol-5-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chloro phenyl) methanone; {2-Amino-4 - [(4- (2,3-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (3-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (3,5-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; 2- {4 - [(5-Amino-4- (4-chlorobenzoyl) thiophen-3-yl) methyl] piperazin-1-yl} -1- (4-chlorophenyl) ethanone; {2-Amino-4 - [(4- (2,4-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2,6-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (3-chloro-4-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4-cyclohexylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-chlorophenyl) piperidin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-nitrophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4-isopropyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4-naphthalen-1-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (3,4-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4-cyclopentylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4-cycloheptylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-chlorobenzyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4-benzylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; (2-Amino-4 - {[4- (2- (4-chlorophenyl) ethyl) piperazin-1-yl] methyl} thiophen-3-yl) (4-chloro phenyl) methanone; {2-Amino-4 - [(4- (4-fluorobenzyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4-cyclooctylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; (2-Amino-4 - {[4- [3- (4-chlorophenyl) propyl] piperazin-1-yl] methyl} thiophen-3-yl) (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2,4-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2,5-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-chloro-3- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2,4,6-trifluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2-chloro-4-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2-fluoro-4-chlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (3,5-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2,6-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4- (trifluoromethoxy) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (pyridin-3-yl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2,5-dichlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (2,3-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-chlorophenyl) -3-methylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chloro phenyl) methanone; {2-Amino-4 - [(4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} [3- (trifluoromethyl) phenyl] methanone; {2-Amino-4 - [(4- (3-fluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} [3- (trifluoromethyl) phenyl] methanone; {2-Amino-4 - [(4- (2,6-difluorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} [3- (trifluoromethyl) phenyl] methanone; {2-Amino-4- (spiro [benzo [d] -dioxol-2,4'piperidin] -r-ylmethyl) thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- (5-t-butyl spiro [benzo [d] -dioxol-2,4'-piperidine] -1'-ylmethyl) thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- (4-fluorospiro [benzo [d] dioxol-2,4'-piperidin] r-ylmethyl) thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- (4-methylspiro [benzo [d] -dioxol-2,4'piperidin] -1'-ylmethyl) thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- (5-methylspyro [benzo [d] dioxol-2,4'-piperidin] r-ylmethyl) thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- [4 - ((4-chlorophenylamino) piperidin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-chlorophenyl) methylamino] piperidin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-chlorophenyl) diazepan-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(7- (4-chlorophenyl) -2,7-diaza-spironon-2-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(5- (4-chlorophenyl) hexahydropyrrolo [3,4-c] pyrrol-2-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(5- (4-chlorophenyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-fluorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-5-methyl-4 - [(4-phenylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-5-methyl-4 - [(4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-chlorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-bromophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-iodophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-5-methyl-4 - [(4- (4-nitrophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; 4- {4 - [(5-Amino-4- (4-chlorobenzoyl) -2-methylthiophen-3-yl) methyl] piperazin-1-yl} benzonitrile {2-Amino-4 - [(4-benzylpiperazin-1 (yl) methyl) -5-methylthiophen-3-yl] (4-chlorophenyl) methanone; {2-Amino-4 - [(4-benzylpiperazin-1-yl) methyl) -5-methylthiophen-3-yl] (4-chlorophenyl) methanone; {2-Amino-5-methyl-4 - [(4- p -tolylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (3,4-dichlorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-5-methyl-4 - [(4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (3-chlorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-chloro-3- (trifluoromethyl) phenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-5-phenyl-4 - [(piperidin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4- [4- (4-fluorophenyl) piperazin-1-yl) methyl] -5-ethylthiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-5-ethyl-4 - [(4-phenylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-Amino-4 - [(4- (4-chlorophenyl) piperazin-1-yl) methyl] -5-ethylthiophen-3-yl} (4-chlorophenyl) methanone; and {2-Amino-4 - [(4- (3-fluorophenyl) piperazin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone; or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that it is selected from the group consisting of: [2-Amino-4 - ((4-phenylpiperazin-1-yl) methyl) thiophen-3-yl] (4 -chlorophenyl) methanone; {2-Amino-4- [4 - ((4-chlorophenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; and {2-Amino-4- [4 - ((4-trifluoromethylphenyl) piperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; or a pharmaceutically acceptable salt thereof. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound as defined in any one of claims 1 to 37 in combination with one or more pharmaceutically acceptable carriers. Pharmaceutical composition according to claim 38, characterized in that it is for the treatment of pain, a disorder or heart disease, injury or neurological disease, sleep disorder, epilepsy and depression. Pharmaceutical composition according to claim 39, characterized in that the pain is neuropathic pain. Pharmaceutical composition according to claim 38, characterized in that it is for use as a medicament. Use of a pharmaceutical composition as defined in claim 38, characterized in that it is for the preparation of a medicament for the treatment of adenosine A 1 receptor mediated conditions. Use of a compound as defined in any one of claims 1 to 37, characterized in that it is for the preparation of a pharmaceutical composition for the treatment of adenosine A1 receptor mediated conditions. Use according to claim 42 or 43, characterized in that the adenosine A 1 receptor-mediated condition is selected from pain, a disorder or heart disease, injury or neurological disease, sleep disorder, epilepsy and depression. Use according to claim 44, characterized in that the pain is neuropathic pain. A compound according to any one of claims 1 to 37, characterized in that it is for use as a medicament.