KR20090112627A - Allosteric Modulators of the A1 Adenosine Receptor - Google Patents

Abstract

The present invention provides compounds of Formula I in R1, R2, R3, R4 and Q, which have meanings as defined herein. Compounds of formula (I) are allosteric modulators of A1 adenosine receptors and thus can be used for the treatment of diseases mediated by A1 adenosine receptors. Thus, the compounds of formula (I) are particularly useful for those chronic pains such as neuropathic pain; Such heart diseases or heart disorders as deep vein, such as paroxysmal loss tachycardia, angina, myocardial infarction and stroke; Neurological diseases or injuries; Sleep disorders; epilepsy; And can be used for the treatment of pain such as depression.

Description

Adenosine Modulators of the A1 Adenosine Receptor

Allosteric Modulators of A1 Adenosine Receptors

[001] The present invention refers to a pharmaceutical composition containing 2-aminothiophene derivatives, 2-aminothiophene derivatives, and by using such compounds, in particular, such chronic pain as neuropathic pain, such as deep vein Treatment of diseases controlled by A1 adenosine receptors that include such heart diseases or disorders, such as paroxysmal ventricular tachycardia, angina, myocardial infarction and stroke, neurological diseases or injuries, sleep disorders, epilepsy and depression Means the way.

Thus, the present invention provides compounds of formula (I).

R 1 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl or substituted cycloalkyl;

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

Q is selected from the following stages.

R 5 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 each, independently, hydrogen, C 1 -C 3 alkyl or C 1 -C 3 substituted alkyl; Also

R6 and R7 are alkylene which together with the carbon atom to which R6 and R7 are attached if they are attached to a carbon atom and form a 3- to 7-spirocyclic ring;

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

X is N or C-H; Also

Each X is C-NR14R15 at R14 and R15 each independently being hydrogen, C1-C3 alkyl, C1-C3 substituted alkyl, aryl or substituted aryl; Also

X is C-R16 at combined R16 and R5 which is a carbonyl group oxygen; Also

X is C-R16 in the combined R16 and R5 of the divalent group of the formula ← Y-CHR17- (CH2) n-CHR18-Y → with the carbon atom to which R16 and R5 are attached. Forming seven spirocyclic rings, Y is oxygen or sulfur;

R 17 and R 18 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl;

n is 0, or an integer of 1 or 2; Also

X is a chemical formula

C-R16 at the combined R16 and R5 which is a divalent group of, together with the carbon atom to which R16 and R5 are attached, forms five spirocyclic rings, Y is oxygen or sulfur;

R 19 and R 20 are each independently hydrogen, halogen, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl or C 1 -C 6 alkoxy;

Or a pharmaceutically acceptable salt therefrom.

The compounds of the present invention provide a pharmaceutical agent that is an allosteric modulator of the A1 adenosine receptor and thus can be used for treating diseases controlled by the A1 adenosine receptor. Thus, the compounds of formula (I) are particularly useful for such chronic pain as neuropathic pain, such heart diseases or disorders as deep vein, e.g. paroxysmal tachycardia, angina, myocardial infarction and stroke, neurological disease or injury, sleep It can be used for the treatment of pain such as disorders, epilepsy and depression.

Listed below are definitions of various terms used to describe the compounds of the present invention. These definitions are, for example, defined as the junction of a given stage to a particular atom within that stage, which is part of a larger stage as defined by the arrowhead at that particular atom. Applicable to the term when used throughout the specification unless otherwise defined in a particular example.

[005] The term "alkyl" refers to a hydrocarbon chain having 1-20 carbon atoms, preferably 1-10 carbon atoms, and more preferably 1-7 carbon atoms. The hydrocarbon chain may be hexyl or n-butyl chain, or branched chain, for example continuous with t-butyl, 2-methyl-phenyl, 3-propyl-heptyl. Representative alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4, 4-dimethylpentyl, octyl, and the like. .

[006] The term "substituted alkyl" means, as described above, substituted with one or more, preferably 1-3, such alkyl groups of the following stages: halo, Hydroxy, alkanoyl, alkoxy, cycloalkyl, cycloalkoxy, alkanoyloxy, thiol, alkylthio, alkylthiono, sulfonyl, sulfamoyl, carbamoyl, cyano, carboxy, acyl, aryl, aryloxy, alkenyl , Alkynyl, aralkyloxy, guanidino, optionally substituted amino, heterocyclyl including imidazolyl, furyl, thienyl, thiazolyl, pyrrolonidyl, pyridyl, and the like.

[007] The term "lower alkyl" refers to such alkyl groups as described above having 1-6, preferably 1-4 carbon atoms.

[008] The term "alkenyl" refers to any of the above alkyl groups having at least two carbon atoms and further including carbon-carbon double bonds at the contacts.

Preference is given to a stage having 2-6 carbon atoms.

[009] The term "alkynyl" refers to any of the above alkyl groups having at least two carbon atoms and further including a carbon-carbon triple bond at the junction.

Preference is given to a stage having 2-6 carbon atoms.

[010] The term "alkylene" refers to-(CH2) x-, a straight-chain bridge of 1-6 carbon atoms linked by a single bond, as for example in which x is greater than 1 in which x is 1-6 It means a bridge.

The term "cycloalkyl" refers to a monocyclic, bicyclic or tricyclic hydrocarbon group of 3-12 carbon atoms, each of which comprises one or more carbon-carbon double bonds. Can be.

[012] The term "substituted cycloalkyl" refers to alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, cyano, carboxy, alkoxycarbo Cyclo of those as described above substituted by one or more substituents, preferably 1-3 substituents, such as nil, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the like It means an alkyl stage.

Representative monocyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 4,4-dimethylcyclohex-1-yl, cyclooctenyl and the like. It includes, but is not necessarily limited to these.

[014] Representative bicyclic hydrocarbon groups include carbonyl, indyl, hexahydroindanyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, Rho [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 It includes.

Representative tricyclic hydrocarbon stages include adamantyl and the like.

[016] In the definitions enumerated herein, when reference is made to alkyl, cycloalkyl, alkenyl or alkynyl groups as part of the term, substituted alkyl, cycloalkyl, alkenyl or alkynyl groups It is also intended.

[017] The term "alkoxy" means alkyl-O-.

[018] The term "cycloalkoxy" means cycloalkyl-O-.

[019] The term "alkanoyl" means alkyl-C (O)-.

[020] The term "cycloalkanoyl" means cycloalkyl-C (O)-.

[021] The term "alkenoyl" refers to alkenyl-C (O)-.

The term "alkynoyl" means alkynyl-C (O)-.

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

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

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

[026] The term "alkylthio" means alkyl-S-.

[027] The term "trialkylsilyl" means (alkyl) 3 Si-.

The term "trialkylsilyloxy" means (alkyl) 3SiO-.

[029] The term "alkylthiono" means alkyl-S (O)-.

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

The term "alkoxycarbonyl" means alkyl-O-C (O)-.

The term "alkoxycarbonyloxy" means alkyl-O-C (O) O-.

[033] The term "carbamoyl" refers to H2NC (O)-, alkyl-NHC (O)-, (alkyl) 2NC (O)-, aryl-NHC (O)-, alkyl (aryl) -NC (O)- , Heteroaryl-NHC (O)-, alkyl (heteroaryl) -NC (O)-, aralkyl-NHC (O)-, alkyl (aralkyl) -NC (O)-and the like.

The term "sulfonyl" refers to H2NS (O) 2-, alkyl-NHS (O) 2-, (alkyl) 2NS (O) 2-, aryl-NHS (O) 2-, alkyl (aryl) -NS (O) 2-, (aryl) 2NS (O) 2-, heteroaryl-NHS (O) 2-, aralkyl-NHS (O) 2-, heteroaralkyl-NHS (O) 2- and others it means.

The term "sulfonamide" refers to alkyl-S (O) 2-NH-, aryl-S (O) 2-NH-, aralkyl-S (O) 2-NH-, heteroaryl-S (O) 2-NH-, heteroaralkyl-S (O) 2-NH-, alkyl-S (O) 2-N (alkyl)-, aryl-S (O) 2-N (alkyl)-, aralkyl-S (O) 2-N (alkyl)-, heteroaryl-S (O) 2-N (alkyl)-, heteroaralkyl-S (O) 2-N (alkyl)-and the like.

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

The term "optionally substituted amino" means that the primary or secondary amino group is optionally acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbon It can be substituted by such substituents such as nil, heteroaralkyloxycarbonyl, carbamoyl and the like.

[038] The term "aryl" is a monocyclic ring having 6-12 carbon atoms in such rings, such as phenyl, biphenyl, naphthyl, 2,3-dihydro-1H-indenyl and tetrahydronaphthyl. Hydrocarbon stage of a formula or bicyclic aromatic is meant.

[039] The term "substituted aryl" refers to alkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, methylenedioxy, acyl, alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio, By 1-4 substituents at each ring such as arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl, sulfonamide, heterocyclyl, and the like By an aryl group of those as described above being substituted.

[040] The term "monocyclic aryl" refers to phenyl optionally substituted as described above under aryl. Preferably, monocyclic aryl is substituted by 1-3 substituents selected from the stages constituting halogen, cyano or trifluoromethyl.

In the definitions enumerated herein, when reference is made to allyl groups as part of the term, substituted aryl groups are also intended.

[042] The term "aralkyl" refers to an aryl group bonded directly through an alkyl group, such as benzyl.

[043] The term "arkanoyl" means aralkyl-C (O)-.

[044] The term "aralkylthio" means aralkyl-S-.

[045] The term "aralkyloxy" means an aryl group linked directly through an alkoxy group.

[046] The term "arylsulfonyl" means aryl-S (O) 2-.

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

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

[049] The term "aroyloxy" means aryl-C (O) -0-.

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

The term "aryloxycarbonyl" means aryl-O-C (O)-.

The term "heterocyclyl" or "heterocyclo" refers to fully saturated or unsaturated, aromatic or non-aromatic cyclic stages, eg, 4 to 7 monocyclic ( One to seven, twelve bicyclic or ten to fifteen tricyclic systems, having at least one heteroatom in a ring containing at least one carbon atom. Each ring of the heterocyclic group containing heteroatoms may have 1, 2 or 3 heteroatoms selected from hydrogen, oxygen and sulfur atoms in which hydrogen and sulfur heteroatoms may be optionally oxidized. have. Heterocyclic groups can be attached to heteroatoms or carbon atoms.

Representative monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazoli Neil, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-jade Sofiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazinyl, azepinyl, 4-piperidonyl, pyridinyl (pyridyl), pyrazinyl, pyrimidinyl, pyri Dazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1, 1-dioxothienyl, 1 , 1,4-trioxo-1,2,5-tridiazolidin-2-yl and the like.

Representative bicyclic heterocyclic groups include indolyl, dihydroidolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl, Decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl , Cynolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furypyridinyl (puro [2,3-c] pyridinyl, puro [3,2-b] pyridinyl or puro [2,3-b ] Such as pyridinyl), dihydroisoindolyl, 1,3-dioxo-1,3-dihydroisoindol-2-yl, dihydroquinazolinyl (3,4-dihydro-4-oxo- Such as quinazolinyl), phthalazinyl and the like.

Representative tricyclic heterocyclic groups include carbazolyl, dibenzoazinyl, dithianozepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl , Carbolinyl and the like.

The term "substituted heterocyclyl" means such a heterocyclic group as described above substituted with 1,2 or 3 substituents selected from the groups consisting of

(a) alkyl;

(b) hydroxyl (or protected hydroxyl);

(c) halo;

(d) oxo, such as = O;

(e) optionally substituted amino;

(f) alkoxy;

(g) cycloalkyl;

(h) carboxy;

(i) heterocyclooxy;

(j) such alkoxycarbonyls as unsubstituted lower alkoxycarbonyls;

(k) thiols;

(l) 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 with alkyl, cycloalkyl, alkoxy, hydroxyl, amino, acylamino, alkylamino, dialkylamino or halo.

[057] The term "heterocyclooxy" refers to a heterocyclic group bonded through an oxygen bridge.

[058] The term "heterocycloalkyl" refers to a non-aromatic heterocyclic group as described above.

[059] The term "heteroaryl" refers to aromatic hetero rings, such as monocyclic or bicyclic aryl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl , Thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl and others Such as, for example, halogen, cyano, nitro, trifluoromethyl, lower alkyl or lower alkoxy.

[060] The term "heterocycloalkanoyl" refers to heterocycloalkyl-C (O)-.

[061] The term "heteroarylsulfonyl" refers to heteroaryl-S (O) 2-.

[062] The term "heteroaroyl" refers to heteroaryl-C (O)-.

[063] The term "heteroaroylamino" refers to heteroaryl-C (O) NH-.

[064] The term "heteroaralkyl" refers to a heteroaryl group bonded through an alkyl group.

[065] The term "heteroaralkylanoyl" means heteroaralkyl-C (O)-.

[066] The term "heteroaralkanoylamino" refers to heteroaralkyl-C (O) NH-.

[067] The term "acyl" means alkanoyl, cycloalkanoyl, alkenoyl, alkinoyl, aroyl, heterocycloalkanoyl, heteroaroyl, aralcanoyl, heteroarkanoyl and the like.

[068] The term "substituted acyl" is used above in the substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocycloalkyl, heteroaryl, aralkyl or heteroaralkyl groups as described separately herein above. Means such acyl groups as described.

The term "acylamino" means alkanoylamino, aroylamino, heteroaroylamino, arkananoylanimo, heteroarkananoylamino and the like.

[070] The term "halogen" or "halo" means fluorine (fluorine), chlorine (chlorine), bromine (bromine) and iodine (iodine).

Pharmaceutically acceptable salts of the compounds of this invention are salts formed with acids, ie inorganic acids, organic carboxylic acids and organic sulfonic acids, such as hydrochloric acid, maleic acid and methanesulfonic acid, such acid additions, respectively. Salt.

Similarly, pharmaceutically acceptable salts of the compounds of the present invention are salts formed with bases, i.e. alkali and alkaline earth metal salts, such as those cationic salts such as sodium, lithium, potassium, calcium and magnesium By way of example, it is meant salts of such ammonium salts, such as ammonium, trimethylammonium, diethylammonium and tris (hydroxymethyl) -methyl-ammonium salts, salts of amino acids provided with acidic stages constituting part of their structure.

As described herein above, the present invention relates to 2-aminothiophene derivatives of formula (I), pharmaceutical compositions containing derivatives, methods for preparing the compounds mentioned, and compounds of the invention or Such chronic pain, such as pain, in particular neuropathic pain, by therapeutically effective amount administration of a pharmaceutical composition thereto; Congestive heart failure, cardiac arrhythmias such as paroxysmal ventricular tachycardia, angina pectoris, myocardial infarction and such heart diseases or disorders as stroke, neurological diseases or injuries, sleep disorders, epilepsy, depression, and various inflammatory diseases, but not necessarily these Methods of treating disease controlled by an unrestricted A1 adenosine receptor are provided.

[074] The compound of formula (I) is a compound wherein R1 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; Or a pharmaceutical composition thereof.

[075] Compounds of formula (I) specified in the

And 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 from each other, hydrogen, C1-C3 alkyl, or C1-C3 substituted alkyl; Also

Bonded R 6 and R 7 are alkylene which together with the carbon atom to which they are attached form a 3 to 7 spiro cyclic ring if they are attached to the same carbon atom;

X is N or C-H; Also

X is C-NR14R15 in that R14 and R15 are each independently hydrogen, C1-C3 alkyl, C1-C3 substituted alkyl, aryl, or substituted aryl; Also

X is C-R16 at the point that bonded R16 and R5 are carbonyl oxygen; Also

X is a carbon atom to which R 16 and R 5 are attached to form a 5 to 7 spiro cyclic ring, and in that ring Y is oxygen or sulfur, and R 16 and R 5 bonded together are of the formula ← Y-CHR 17-(CH 2) n- C-R16 in that it is a divalent radical of CHR18-Y →; Also

R 17 and R 18 are, independently from each other, hydrogen, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl;

n is 0 or an integer of 1 or 2; Also

X is a carbon atom to which R 16 and R 5 are attached to form five spiro cyclic rings, and R 16 and R 5 bonded together with Y being oxygen or sulfur in the ring

Is C-R16 in that 2 is a radical;

R 19 and R 20 are each independently hydrogen, halogen, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, or C 1 -C 6 alkoxy; Or a pharmaceutically acceptable salt thereof.

Compounds in the A stage, designated as the B stage, wherein X is N; Or a pharmaceutically acceptable salt thereof.

[077] Formula (IA)

The compound in B stage which has

R 1 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;

R2, R3 and R4 are each independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy, or substituted alkoxy;

R 5 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl, or substituted acyl;

If R 6 and R 7 are attached to the same carbon atom, the bonded R 6 and R 7 are alkylene which together with the carbon atom to which they are attached form a 3 to 7 spiro cyclic ring;

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

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

The compound of formula (IA) is also monocyclic aryl optionally substituted by three substituents from one selected from the group wherein R5 constitutes halogen, cyano or trifluoromethyl; It is also preferable in that it is a pharmaceutically acceptable salt.

[080] The compound of formula (IA), designated as C stage, also wherein R2 and R4 are hydrogen; It is also preferable in that it is a pharmaceutically acceptable salt.

The compound at the C stage wherein R 3 is halogen, cyano or trifluoromethyl; It is also preferable in that it is a pharmaceutically acceptable salt.

A compound of formula (IA) designated as D stage, also wherein R 2 and R 3 are hydrogen; It is also preferable in that it is a pharmaceutically acceptable salt.

The compound at the D stage wherein R 4 is halogen, cyano or trifluoromethyl; It is also preferable in that it is a pharmaceutically acceptable salt.

Compounds of formula (IA) designated as E group are also independently of each other hydrogen, or C1-C3 alkyl, R6, R7, R8 and R9; It is also preferable in that it is a pharmaceutically acceptable salt.

The compound in the E stage designated as the F stage is monocyclic aryl optionally substituted by three substituents on one selected from the stage in which R 5 comprises halogen, cyano, or trifluoromethyl; It is also preferable in that it is a pharmaceutically acceptable salt.

In the F stage designated as the G stage, R 2 and R 4 are hydrogen; It is also preferable in that it is a pharmaceutically acceptable salt.

In the G group, R 3 is halogen, cyano or trifluoromethyl; It is also preferable in that it is a pharmaceutically acceptable salt.

Compounds in the G stage wherein R 1 is hydrogen or C 1 -C 3 alkyl; It is also more preferable in that it is a pharmaceutically acceptable salt for it.

The compound in the F stage designated as the H stage also wherein R 2 and R 3 are hydrogen; It is also preferable in that it is a pharmaceutically acceptable salt.

In the H group, R 4 is halogen, cyano or trifluoromethyl; It is also preferable in that it is a pharmaceutically acceptable salt.

In the H group, R 1 is hydrogen or C 1 -C 3 alkyl; It is also more preferable in that it is a pharmaceutically acceptable salt for it.

[092] the compound in the A stage, also designated as the I stage;

The carbon atom to which R 16 and R 5 are attached to form five spiro cyclic rings, and R 16 and R 5 bonded together with Y being oxygen in the ring

In that is a divalent radical and X is C-R16;

R 19 and R 20 independently of one another are hydrogen, halogen, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, or C 1 -C 6 alkoxy; It is also preferable in that it is a pharmaceutically acceptable salt.

[093] Formula (IB)

The compound in stage I having

R 1 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;

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;

R 6, R 7, R 8 and R 9 are each independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 substituted alkyl; Also

R 19 and R 20 are each independently hydrogen, halogen, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, or C 1 -C 6 alkoxy; Or a pharmaceutically acceptable salt thereof.

Compounds of formula (IB) are those wherein R 1 is hydrogen or C 1 -C 3 alkyl;

It is also preferable in that it is a pharmaceutically acceptable salt.

Compounds of formula (IB) are also independently of each other hydrogen, halogen, cyano, trifluoromethyl, or C1-C4 alkyl;

It is also preferable in that it is a pharmaceutically acceptable salt.

[0096] Compounds of formula (IB) designated as J stages, wherein R2 and R4 are hydrogen;

It is also preferable in that it is a pharmaceutically acceptable salt.

The compound at the J terminus is where R3 is halogen, cyano or trifluoromethyl; It is also preferable in that it is a pharmaceutically acceptable salt.

[098] The compound of formula (IB) designated as K stage, also wherein R2 and R3 are hydrogen;

It is also preferable in that it is a pharmaceutically acceptable salt.

The compound at the K stage is such that R4 is halogen, cyano or trifluoromethyl; It is also preferable in that it is a pharmaceutically acceptable salt.

[100] The compound of formula (IB), specified in L stage, also wherein R6, R7, R8 and R9 are hydrogen; It is also preferable in that it is a pharmaceutically acceptable salt.

[101] The compound in the L stage, designated as the M stage, wherein R 19 and R 20 are, independently from each other, hydrogen, halogen, cyano, trifluoromethyl, or C 1 -C 4 alkyl;

It is also preferable in that it is a pharmaceutically acceptable salt.

[102] The compound in the M stage designated as the N stage is wherein R2 and R4 are hydrogen;

It is also preferred in that it is a pharmaceutically acceptable salt thereof.

[103] The compound at the N stage is a compound wherein R3 is halogen, cyano or trifluoromethyl; It is also preferred in that it is a pharmaceutically acceptable salt thereof.

The compound at the N terminus is where R 1 is hydrogen or C 1 -C 3 alkyl;

It is also more preferable in that it is a pharmaceutically acceptable salt thereof.

[105] The compound in the M stage designated as O stage is also R2 and R3 are hydrogen;

It is also preferred in that it is a pharmaceutically acceptable salt thereof.

[106] The compound at the O stage is a compound wherein R4 is halogen, cyano or trifluoromethyl; It is also preferred in that it is a pharmaceutically acceptable salt thereof.

[107] The compound in the O group is that R 1 is hydrogen or C 1 -C 3 alkyl;

It is also more preferable in that it is a pharmaceutically acceptable salt thereof.

Compounds of the invention that depend on the nature of the substituents may have one or more asymmetric centers. The resulting diastereomers, optical isomers, such as the optical isomers, and geometric isomers, and mixtures thereof, are achieved by the instant invention.

[109] The detailed composition of the invention is:

{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;

{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] [1,3] 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-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-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- (trifluorophenyl) 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] methane On;

{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] [1,3] -dioxol-2,4'piperidin] -1'-ylmethyl) thiophen-3-yl} (4-chlorophenyl Methanone;

{2-Amino-4- (5-tert-butylspiro [benzo [d] [1,3] -dioxol-2,4'-piperidin] -1'-ylmethyl) thiophen-3-yl } (4-chlorophenyl) methanone;

{2-amino-4- (4-fluorospiro [benzo [d] [1,3] -dioxol-2,4'-piperidin] -1'-ylmethyl) thiophen-3-yl} (4-chlorophenyl) methanone;

{2-Amino-4- (4-methylspiro [benzo [d] [1,3] -dioxol-2,4'piperidin] -1'-ylmethyl) thiophen-3-yl} (4 -Chlorophenyl) methanone;

{2-amino-4- (5-methylspiro [benzo [d] [1,3] -dioxol-2,4'-piperidin] -1'-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)-[1,4] diazepan-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone;

{2-amino-4-[(7- (4-chlorophenyl) -2,7-diaza-spiro [4.4] non-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) methane On;

{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-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- (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- (prefluoromethyl) 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) -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;

Also a pharmaceutically acceptable salt for it.

[111] The compound of formula (I) is a compound of formula (I), in which R1 is hydrogen, by way of example in the Table 1 below, using modifications to it or methods well known in the art. Can be prepared.

Table 1:

As illustrated in Table 1, a compound of Formula (I) is a compound of Formula (I ′) wherein R 2, R 3, R 4 and Q are for example R 1 is hydrogen, as defined herein above. In this regard, N-methylmorpholine (NMM) or morpholine in an organic solvent such as ethanol (EtOH), lower alcohol, so that R2, R3 and R4 can provide a compound of formula (III), Under such bases, such as disopropylethylamine (DIEA), triethylamine (TEA), diol of 2,5-dimethyl- [1,4] dithiane-2,5-formula (II ′), as defined herein above In the sense having the meaning as described above, R 2, R 3 and R 4 have the meaning as defined herein above, and can be prepared by condensing the compound of formula (II).

[113] Compounds of formula (II) are known, for example, as described in US Pat. No. 6,323,214, or if they are new, can be prepared using methods well known in the art, or using modifications thereto. Can be prepared.

[114] The resulting compound of formula (III) can be converted to compound (IV) in which R 2, R 3 and R 4 have the meaning as defined herein above and the amino group is for example an elevated temperature. Under the reaction conditions well known in the art, by treating compounds of formula (III) with phthalic anhydride under such acids as acetic acid, phthalimides have also been protected as sweet.

[115] The resulting compound of formula (IV) is an iodide, or bromide, in which R2, R3 and R4 have the meanings as defined herein above and Hal1 employs methods well known in the art. , Such as aromatic hydrocarbons, such inert organic solvents such as benzene and such catalysts such as benzoyl peroxide, for example so that the compounds of formula (IV) can provide compounds of formula (V) By way of example below, N-bromosuccinimide, N-halosuccinimide can be treated with such a activating agent, and in that Hal1 is, for example, bromide, it will provide a compound of formula (V). Can be halogenated at the 5-position of the thiophene ring.

[116] halogenated hydrocarbons, for example, such organic solvents as carbon tetrachloride, dichloroethane and such catalysts as benzoyl peroxides, such as, for example, such halogenating agents as N-bromosuccinimide, N-halosuccinimide and The following reaction of the compound of the formula (V) results in that R2, R3 and R4 have the meaning as defined herein above, and Hal1 and Hal2 independently represent chloride, bromide, or iodide independently of one another. In the presence of the compounds of formula (VI).

[117] The resulting compound of formula (VI) is such a suitable compound such as N, N-dimethylformamide (DMF), chloroform (CHCl3) and dichloromethane (DCM) so that Q can provide a compound of formula (VII). R2, R3, R4, Q and Hal1 are defined herein above in that they have the meaning as defined herein above under organic solvents and potassium or cesium carbonate or such bases as TEA, DIEA, NMM, It may be associated with an amine of formula (VI ′) in that it has the meaning as it is.

The amines of formula (VI ′) are known or can be formulated if they are new, using methods well known in the art or using modifications to them.

The resulting compound of formula (VII) is ethyl acetate (R) in order to be able to provide a compound of formula (VIII) in that R 2, R 3, R 4 and Q have the meaning as defined herein above. EtOAc), lower alcohols such as EtOH and methanol (MeOH), tetrahydrofuran (THF) or such organic solvents, such as molecular hydrogen under such catalysts, for example palladium on carbon, to be dehalogenated under reducing agents. Can be. Preferably, dehalogenation is carried out in the presence of an exogenous base such as TEA.

[120] Finally, compounds of formula (VIII) may be prepared by treatment of R2, R3, R4 and Q with hydrazine in the removal of phthalimido protecting groups, for example in lower alcohols such as organic solvents such as EtOH. It can be converted to a compound of formula (I ′) in that it has the meaning as defined herein.

As an example in Table 2, the compound of formula (I) is

R2, R3 and R4 in which R1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and R2, R3, R4 and Q have the meaning as defined herein above Has a meaning as defined herein above as a ketone of formula (IX), in order that R 1 can provide a compound of formula (III ′) such organic solvents as lower alcohols, preferably EtOH R1 is alkyl in that alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl under such elemental sulfur with such a suitable base such as TEA, DIEA, morpholine or NMM, preferably morpholine , In which substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and R2, R3, and R4 have the meaning as defined herein above,

It may be prepared by a compound reaction of formula (II).

Table 2:

[122] Alternatively, the compound of formula (II)

In which R2, R3 and R4 have the meanings as defined herein above, R1 is

In order to be able to provide compounds of these, organic solvents such as toluene or benzene, and alkyl, substituted alkyl, cycloalkyl, under such weak bases such as piperidine, pyrrolidine, morpholine or β-alanine, A ketone of formula (IX) in that R 1, R 2, R 3 and R 4 have a meaning as defined herein above as a mixture of E and Z isomers in the sense of substituted cycloalkyl, aryl or substituted aryl Can be condensed first. Preferably, the condensation can be carried out under such organic acid as acetic acid at the temperature near the boiling point of the solvent. Compounds of formula (IX ') with such elemental sulfur and appropriate bases, such as TEA, DIEA, morpholine or NMM, preferably TEA, in such organic solvents as lower alcohols, preferably EtOH, are described in which R1 is alkyl, substituted Provided that the compound is alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and that R2, R3 and R4 have the meaning as defined herein above.

[123] Compounds of formula (IX) are known, or if they are new, can be formulated using methods well known in the art, or using modifications thereto.

The resulting compound of formula (III ′) is a compound wherein R 1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and at elevated temperatures, R 2, R 3, and R 4, with acetic acid By treating compound (III ') with phthalic anhydride under such an acid, it can be converted to compound (IV') in that it has the meaning as defined herein above.

[125] Alternatively, the compound of formula (IV ′) is a compound wherein R 1 is aryl or substituted aryl, and R 2, R 3 and R 4 have the meaning as defined herein above.

Hal 1, R 2, R 3 and R 4 are

As a compound of a solvent, for example, acetonitrile, DMF, dimethoxyethane (DME) or toluene or a mixture of solvents thereof, a catalyst, preferably a palladium catalyst, for example, palladium (II) acetate or tetrakis ( Under such salts as triphenylphosphine) palladium (0) and sodium hydroxide (NaOH) or sodium, potassium or cesium carbonate, in that it has the meaning as defined herein above,

5 or 6 rings to allow R 1 to be aryl or substituted aryl, R 'and R "to hydrogen or lower alkyl, and to be bonded R' and R" to provide compounds of formula (IV ') In the point that it is alkylene with boron and oxygen atom which formed

In that R 1 is aryl or substituted aryl,

It can be achieved by coupling a compound of formula (V).

Preferably, R 'and R "are hydrogen, and the coupling reaction, e.g., the Suzuki reaction, is toluene under tetrakis (triphenylphosphine) palladium (0) and potassium carbonate (K2CO3) at a temperature near the boiling point of the solvent. Is performed in

Compounds of formula (V ′) are known, or if they are new, can be formulated using methods well known in the art, or using modifications thereto.

[127] The resultant compound of formula (IV ') is

 R 1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, R 2, R 3 and R 4 have the meanings as defined herein above and Hal 2 is well known in the art. By using these examples, such organic solvents as dichloroethane or carbon tetrachloride, halogenated hydrocarbons or acetonitrile (ACN) and such catalysts such as benzoyl peroxide, such as N-halosuccinimide, N-bromosuccinimide In view of the fact that such a halogenating agent clearly represents chloride, bromide or iodide by the compound reaction of formula (IV '),

It may be halogenated at the methyl end at the 4-position of the thiophene ring in order to be able to provide the compound of formula (X).

It should be noted that the halogenation of the methyl group at the 4-position of the thiophene ring of the compound of formula (VI ′) can be carried out under a catalyst when ACN is used as the solvent.

The resulting compound of formula (X) may be formulated with such suitable organic solvents as DCM, CHCl 3, such as cesium carbonate or potassium carbonate or with NMM, DIEA, TEA, in order to be able to provide compounds of formula (XI). Under the base, R 1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and R 2, R 3, R 4, Q is here as having the meanings as defined herein above. It may be associated with an amine of formula (VI ′) in that it has the meaning as defined in.

[129] Finally, the compound of formula (XI) is a compound wherein R1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and R2, R3, R4 and Q as described herein above. Phthalimido can also be converted to a compound of formula (I) in that it has the meaning as defined herein above by the removal of the protecting stage.

The process as described herein above may be performed in an inert environment, preferably in a nitrogen or argon environment.

[131] In the intermediates and starting compounds which are converted to the compounds of the present invention in the manner described herein, functional groups exhibiting such such as amino, thiol, carboxyl and hydroxyl groups are conventional protective groups common in preparative organic chemistry. Is arbitrarily protected by Protected amino, thiol, carboxyl and hydroxyl groups are those that can be converted to free amino, thiol, carboxyl and hydroxyl groups under mild conditions without causing molecular structure or other side effects in the broken state.

The purpose of introducing a protection stage is to protect the functional groups from the adverse effects of the reaction elements under the conditions used to effect the desired chemical modification. The need and selection of protective stages for detailed reactions are known to those skilled in the art and the functionality of the substituents is such that the substituents will be protected by some of the molecular structure and stability and reaction conditions (eg, amino groups, hydroxyl groups). Depends on

[133] Well-known protection steps that meet these conditions and their introduction and removal are, for example, Plenum Press, London, NY (1973), "Protection Steps in Organic Chemistry," McOmie and John Wiley and Sons. , Inc., NY (1999), “Groups to Protect in Organic Synthesis,” Greene and Wuts ,.

[134] The above-mentioned reactions are carried out at elevated or room temperature (RT), at low temperatures, individually and / or in an inert environment at superatmospheric or atmospheric pressure and preferably at or near the boiling point of the solvent used. , Diluents, preferably inert of reagents and in the presence or absence of such things as solvents, catalysts, condensation or other agents mentioned for them, can be carried out according to the usual methods. Preferred solvents, catalysts and reaction conditions are set forth in the examples of the accompanying examples.

[135] Furthermore, the present invention encompasses any modification of this process in the intermediate product achievable at any stage for that used as starting material and in the remaining stages to be carried out or in the reaction materials used in their salt formation.

The compounds and intermediates of the invention can also be converted from one another according to generally known methods.

The invention also refers to any new starting materials, intermediates and processing for their production.

[138] Depending on the choice of starting materials and methods, the new compounds are possible isomers or mixtures thereof, such as substantially purified cis or trans, diastereomers, optical isomers, racemic compounds, In one of the mixtures thereof. The aforementioned isomers, or mixtures thereof, are within the scope of the present invention.

[139] Any resulting mixture of isomers may be prepared by purification techniques or optical isomers, diastereomers such as fractional crystallization and / or chromatography, eg by high pressure liquid chromatography (HPLC) using chiral adsorbents. Can be separated on the basis of differences in physical chemistry.

Finally, the compounds of the invention can be achieved in free form or in salt form thereof, preferably in pharmaceutically acceptable salt form thereof.

In particular, the compounds of the invention, including the basic stages, can be converted to acid addition salts, in particular pharmaceutically acceptable acid addition salts. These include, for example, inorganic acids such as sulfuric acid, phosphoric acid or hydrochloric acid, such inorganic acids such as, for example, halogen, such as acetic acid, unsubstituted or unsubstituted (C1-C4) -alkancarboxylic acids. Saturated or unsaturated dicarboxylic acids such as, for example, hydroxycarboxylic acids such as oxalic acid, succinic acid, maleic acid or fumaric acid, such as glycolic acid, lactic acid, malic acid, tartaric acid or citric acid (citric acid) Such, amino acids such as aspartic acid or glutamic acid, such as unsubstituted or substituted (eg by halogen) (C1-C4) -alkylsulfonic acids, such as methanesulfonic acid or aryl With such organic sulfonic acids, such as sulfonic acids. The salt is preferably formed with hydrochloric acid, maleic acid, and methanesulfonic acid. Salts may advantageously be formed using conventional methods under such etheric or alcoholic solvents such as lower alcohols. From the latter dissolution, the salts can be precipitated with ethers such as diethyl ether or petroleum ether. As a result, the salt can be converted into a free compound by treatment with a suitable base such as sodium hydroxide. These or other salts may also be used for the purification of the compounds achieved.

[142] It is also intended whenever a compound is mentioned in a rising salt, if appropriate or possible under its circumstances, taking into account the intimate connection between the compound and the free compound in their salt formation.

Compounds containing their salts may also be obtained in their hydrate formation, or may include other solvents used for their crystallization.

As described herein above, the compounds of the present invention are allosteric modulators of the A1 adenosine receptor. In addition, the present invention provides a method for the regulation of A1 adenosine receptors in a mammal, which method comprises administering to a mammal in need of a therapeutically effective amount of a compound of formula (I).

In addition, the compound of formula (I) may be used as a therapeutic agent for diseases regulated by A1 adenosine receptors. Such compounds are thus therapeutically painful, in particular such chronic pain as neuropathic pain, deep vein, e.g. paroxysmal loss tachycardia, angina pectoris, myocardial infarction, and stroke, neurological diseases or disorders, sleep disorders It can be used as a treatment for such heart disease or disorders such as epilepsy and depression.

In other words, the present invention provides a method for the treatment of a disease modulated by A1 adenosine receptor which comprises administering to a mammal a therapeutically effective amount of a compound of the invention.

[147] When the term "treatment" is used throughout the specification and claims, it encompasses methods or all other forms of treatment known to those of skill in the art and, in particular, prevents prophylactic and curative delays in conventional treatment and progression. It is included.

[148] As used herein, the term "therapeutically effective amount" refers to the amount of drug or therapeutic agent that is intended to elicit a desired biological or medical response in an animal, system, or tissue, including humans, obtained by a researcher or clinician. .

[149] The term "mammal" or "patient" is used interchangeably herein and includes, but is not necessarily limited to, humans, dogs, cats, horses, pigs, cattle, monkeys, rabbits, rats, and laboratory animals. Preferred mammals are humans.

[150] Preferably, the methods of the present invention relate to the treatment of pain, generally pain management, and to detailed treatment and management of chronic pain, in particular neuropathic pain. Neuropathic pain has been recognized as pain resulting from some form of abnormality or pathological damage associated with the nervous system. Various forms of neuropathic pain can be treated in accordance with the present invention, eg, diabetic neuropathy and postherpetic neuralgia. Additional pathological abnormalities that can cause neuropathic pain that can be treated in accordance with the present invention include trigeminal neuralgia, AIDS associated with neuropathy resulting from HIV infection and / or treatment, pain associated with cancer treatment, wheezing pain, hallucinogenic pain , Traumatic injury pain, complex site pain syndrome, and pain due to peripheral vascular disease. Moreover, the methods of the present invention will be useful for the treatment and treatment of postoperative pain.

[151] Preferred methods of the present invention also include the treatment of heart disease or disorders, and injuries induced by injuries such as deep vein, angina pectoris, myocardial infarction, stroke, and the like. Typical subjects for such treatment include such patients as, for example, myocardial infarction, stroke, brain or spinal cord injury patients, patients undergoing such major surgery, such as cardiac surgery, in which cerebral anemia may be a potential complication, and the like.

[152] Similarly, the present invention provides, for example, concurrently or subsequently, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a second drug substance, Hyperlipidemic Therapeutic Agents in Second Drug Substance Provided herein are methods as defined above comprising anti-inflammatory, antihypertensive or anesthetic analgesic, eg, combined administration as indicated herein below.

Furthermore, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, alone or in combination with one or more pharmaceutically acceptable carriers.

[154] In carrying out the methods of the present invention, the allosteric adenosine A1 receptor enhancers of the present invention can be administered to mammals, including humans, for the treatment of diseases controlled by the A1 adenosine receptor. For example, it may be formulated into a pharmaceutical composition suitable for oral or rectal, transdermal, intrathecal and parenteral administration. These diseases are pains, especially those chronic pains such as neuropathic pain, deep veins, such as paroxysmal ventricular tachycardia, stenosis, myocardial infarction and stroke, neurological diseases or disorders, sleep disorders, epilepsy and depression Include, but are not necessarily limited to, diseases or disorders.

[155] Oral administration of an allosteric adenosine A1 receptor enhancer or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof includes: solution, suspension, tablet, pill, capsule, powder, microemulsion, 1 It may take the form of recovery dose classification packaging and others.

[156] In addition, the compounds of the present invention contain a mixture or an effective amount associated with a carrier or additive suitable for administration via various routes, in particular for enteral or parenteral use. It can be used for the preparation of pharmaceutical compositions.

Preference is given to tablets and solid or soft-shelled gelatin capsules containing the following active ingredients:

a) diluents, such as lactose, glucose, sucrose, mannasaccharide, sorbitol, cellulose, glycine and / or vegetable oils;

b) lubricants, such as silica, talcum, stearic acid, magnesium or calcium salts thereof and / or polyethyleneglycol; Also for tablets

c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and also Polyvinylpyrrolidone; And if desired

d) disintegrants, eg, starches, agar, alginic acid or sodium salts thereof, or effervescent mixtures; And / or

e) absorbents, colorants, seasonings and sweeteners.

The administrable composition is preferably a solution or suspension of water isotonic, and suppositories are advantageously prepared from fatty emulsions or suspensions.

[158] The compositions mentioned may contain and / or disinfect such adjuvants, such as protective, stable, wet or emulsion agents, solvent promoters, salts, for controlling osmotic pressure and / or buffers. have. In addition, such may also include therapeutically other valuable substances. The mentioned compositions are individually formulated according to traditional mixing, granulating or coating methods and contain about 0.1-75%, preferably about 1-50%, of the active ingredient.

[159] Suitable formulations for transdermal use include compounds of the invention having a therapeutically effective carrier. Advantageous carriers include acceptable solutions of absorbent pharmacology to aid passage through the skin of the host. Characteristically, the percutaneous instrument can be used with an optionally proportioned barrier, optionally with a carrier, to enable the release of the host's dermal compound over a prolonged period of time and in a controlled manner. A reservoir containing a compound, a bandage that includes supporting a body part, and a form of means for safeguarding the instrument of the skin.

[160] Single dose sorting packaging for about 50-70 kg mammals may be between about 0.005 mg and 2000 mg, advantageously between 1-1000 mg of the active ingredient. The therapeutically effective dosage of the active compound depends on the mammalian species, body weight, age and individual conditions, the form of administration and the compound involved.

[161] Accordingly, the present invention is directed to pain, especially such chronic pain, such as neuropathic pain, deep veins, e.g. paroxysmal ventricular tachycardia, angina pectoris, myocardial infarction and stroke, neurological diseases or disorders, sleep disorders, epilepsy and depression. A pharmaceutical composition as described above is provided for the treatment of a disease modulated by an A1 adenosine receptor comprising such heart disease or disorder.

[162] The pharmaceutical composition may comprise a therapeutically effective amount of a compound of the invention, as defined above, alone or in combination with other therapeutic agents, such as each in effective therapeutic dosages as reported in the art. Can be.

Such therapeutics include:

a) HMG-CoA (3-hydroxy-3-methyl-glutaryl coenzyme A), reductase inhibitors, squalene synthase inhibitors, FXR (panasoid X receptor): therapeutic agents for such hyperlipidemia, such as farnesoid X receptor and LXR (liver X receptor) ligands, cholesterolyramine, fibrates, nicotinic acid and aspirin;

b) anti-inflammatory drugs;

c) antihypertensives such as loop diuretics, angiotensin converting enzyme (ACE) inhibitors, inhibitors of Na-K-ATPase membrane pumps, neutral endopeptidase (NEP) inhibitors, ACE / NEP inhibitors, angiotesin II antagonists, renin inhibitors, β-adrenergic receptor blockers, muscle contractile agents, calcium antagonists, aldosterone receptor antagonists, and aldosterone synthase inhibitors; And

d) narcotic analgesics.

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

[164] The structure of a therapeutic agent, known by its name or trade name, can be extracted, for example, from an international patent (e.g. IMS World Publications) database, for example, by substantial editing of the standard specification "The Merck Index". Any person skilled in the art will be able to fully identify the active agent, and likewise, anyone based on this description will be able to test pharmaceutical signs and features on standard test forms in both in vivo and in vitro experiments. And can be prepared.

Thus, the present invention preferably comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in conjunction with another therapeutic agent selected from a hyperlipidemic agent, an anti-inflammatory agent, an antihypertensive agent and an anesthetic analgesic agent. To provide.

[166] Since the present invention relates to treatment with the combination of compounds that can be co-administered individually, the invention also means combining 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, in addition to a pharmaceutically acceptable carrier or diluent; And

(2) A composition comprising a therapeutic agent for hyperlipidemia, an anti-inflammatory agent, an antihypertensive agent, or an anesthetic analgesic agent, or a pharmaceutically acceptable salt thereof, in addition to a pharmaceutically acceptable carrier or diluent.

When co-administered separately, the amounts of (1) and (2) are such that a beneficial therapeutic effect is achieved. Kits include such discrete compositions as discrete foil packets or discrete bottles, in that each membrane is a plurality of dosage dosage forms (e.g. tablets) comprising (1) or (2). It contains a container for. Alternatively, rather than separating the active ingredient, including the dosage form, the kit may alternately comprise each separate cell membrane containing the entire dosage, including the separate dosage form. Examples of such forms of kits are that each individual bleb comprises two (or more) tablets, one (or more) tablets, and a pharmaceutical composition (2) containing the pharmaceutical composition (1) It is a blister pack. Typically the kit includes instructions for the administration of the separate components. The kit shape may be such that when separate components are preferably administered in different dosage forms (eg, oral and parenteral) administered in different dosage dosage forms, or titration of the individual components of the compound is desired by the prescribing therapist. Is particularly advantageous.

In the case of the present invention the kit comprises:

(1) In the first dosage form, the amount of a therapeutically effective composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;

(2) In subsequent doses, a pharmaceutically acceptable carrier or diluent, hyperlipidemic agent, anti-inflammatory agent, antihypertensive agent, or anesthetic analgesic agent, at such an amount that a beneficial therapeutic amount can be achieved, and in a second dosage form. Or a pharmaceutically acceptable salt thereof; And

(3) a container for containing the first and second dosage forms mentioned

The present invention furthermore refers to a pharmaceutical composition as described above for use as a medicament.

[168] The invention furthermore relates to pain, in particular such chronic pain, such as neuropathic pain, deep veins, e.g. paroxysmal loss tachycardia, angina pectoris, myocardial infarction and stroke, neuropathic diseases or disorders, sleep disorders, epilepsy and depression. By the use of a pharmaceutical composition or compound as described above for the preparation of a medicament for the treatment of a disease controlled by an A1 adenosine receptor comprising such heart disease or disorder.

As such, the present invention also refers 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 diseases controlled by A1 adenosine receptors. For use in a disease state controlled by an A1 adenosine receptor comprising a pharmaceutically acceptable salt or a compound of formula (I), in connection with a pharmaceutically acceptable diluent or carrier thereto It means a pharmaceutical composition.

Finally, the present invention provides a method or use comprising administering a compound of formula (I) in combination with a therapeutically effective amount of a hyperlipidemic, anti-inflammatory, antihypertensive or anesthetic analgesic .

[171] Finally, 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.

[172] The features recited above are advantageously in vivo and in vitro tests using mammals such as mice, rats, dogs, monkeys or isolated organs, tissues and preparations for them. The compounds mentioned can be applied in vitro in the formation of solutions, preferably solutions of physical properties, and orally, parenterally, advantageously in vivo, as a solution of dura or veins, eg suspensions or properties. Can be. In vitro dosages may range between approximately 10-2 molar and 10-10 molar concentrations. The therapeutically effective amount in vivo depends on the route of administration and is approximately 0.000001 mg / kg and 1000 mg / kg, preferably approximately 0.0001 mg / kg and 100 mg / kg, more preferably approximately 0.001 mg / kg and 10 mg It can range between / kg.

[173] The active compounds according to the invention can be assessed in the art, for example using methods well described in the art, as described herein below:

Cell membrane preparation from CHO cells infected with human recombination A1, A2A and A3 adenosine receptors :

[174] The hCHO-A1, hCHO-A2A and hCHO-A3 cell clones were allowed to attach and grow for 30 minutes at 37 ° C. (Klotz et al. Naunyn-Schmied. Arch Pharm. 1998, 357, 1-9) Air 95 %, Carbon dioxide 5%, 10% fetal stage bovine serum at 37 ° C., penicillin (100 U / mL), streptomycin (100 μg / mL), L-glutamine (2 mM), geneticin (G418) 0.2 mg / mL It is maintained in Dulbecoo's modified Eagle's medium (DMEM) with a nutrient mixture F12 containing. Cells split two or three times a week at a ratio of 1: 5 and 1:10. The medium is removed for cell membrane preparation. Cells are washed with PBS and detached from T75 flasks in ice-cold osmotic buffer (5mM Tris HCl, 2 mM EDTA, pH 7.4). The cell suspension is homogenized with a homogenizer and the homogenate is stirred for 10 minutes at 1,000 x g. The supernatant is then separated by a 30 minute centrifuge at 100,000 x g. Cell membrane pellets are resuspended in 50 mM Tris HCl buffer pH 7.4 for A1 adenosine receptors, resuspended in 50 mM Tris HCl buffer pH 7.4 10 mM MgCl2 for A2A adenosine receptors, and for A3 adenosine receptors. Resuspend in 50 mM Tris HCl buffer pH 7.4, 10 mM MgCl 2, 1 mM EDTA and incubate with 3 Ul / mL of adenosine deaminase at 37 ° C. for 30 minutes. Protein concentrations are determined in bovine albumin according to standard references according to the Bio-Rad method (Bradford, 1976).

Adenosine Receptor Binding Experiments:

[175] To determine the effect of the compounds of the present invention on the binding of A1, A2A and A3 receptors, cell membranes from hCHO-A1, hCHO-A2A, hCHO-A3 were cultured in buffer solution in the presence and absence of the tested compounds. do. Experimental agents are dissolved by DMSO and added to the test evaluation from a solution of 100-fold concentration in DMSO. Control cultures also contain 1% DMSO. Bound and free radioactivity is fractionated by filtering the test evaluation mixture through a Whatman GF / B glass fiber filter using a Micro-mate 196 Cell Instrument Company. The filter binding radioactivity is Micro-Scint 20, which depends on the Top Count Microplate Scintillation Counter (57% efficiency).

hCHO [3H] of -A1 CCPA  Saturation Bundle

[176] Saturation bundle experiments of [3H] CCPA of human A1 receptors revealed in CHO cell membranes were tripled at 25 ° C. for 1 hour in 50 mM Tris-HCl, pH 7.4, in the presence and absence of the tested compound (10 μm). Can be performed. Non-specific binding can be characterized as binding in the presence of 1 μm R-PIA.

[3H] CCPA of hCHO Competitive combination for -A1:

[177] Competition experiments included 1 nM [3H] CCPA, 50 mM Tris-HCl, pH 7.4 and 100 μl of diluted cell membrane, and 25 ° C. (Baraldi et al. J. Med. Chem. 2003, 46, 794 -809) can be performed three times in the final 250 μl volume in a test tube containing at least 6 to 8 differential concentrations of the tested compound within the range between 1 nM and 50 μm for 90 minutes. Nonspecific binding can be clarified by binding in the presence of 1 μm R-PIA. Allosteric increase can be measured by the effect of different concentrations of compound tested to increase hCHO-A1 cell membrane specific binding of 1 nM [3H] CCPA.

Competitive Combination Experiments:

[178] 1 nM [3H] DPCPX (Borea et al. Life Sciences 1996, 59, 1373-1388), 2 nM [3H] ZM 241385 (Borea et al. Biochem. Pharmacol. 1995, 49, 461-469) and Competition experiments with nM [3H] MRE 3008F20 (Varani et al. Mol. Pharmacol. 2000, 57, 968-975) for 2 hCHO-A1, hCHO-A2A, hCHO-A3 were carried out individually at 150 ° C. Cell culture (100 μg of protein per test) is carried out at 4 ° C. for min and 25 ° C. for 90 min. Competition experiments consisted of 50 mM Tris HCl buffer (10 mM MgCl 2, 1 mM EDTA for A3), pH 7.4 and 100 μl of cell membranes and containing at least 6 to 8 differences in concentrations of the test compound. This can be done twice at a final volume of 100 μl. Non-specific binding is individually defined as binding under 1 μm DPCPX, ZM 241385 and MRE 3008F20 for A1, A2A and A3 and is approximately 30% of the total binding.

[179] [3H] DPCPX (specific activity, 120 Ci / mmol) and [3H] CCPA (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); [3H] MRE 3008F20 (Special Activities, 67 Ci / mmol) can be obtained from Amersham International (Buckinghamshire, UK).

CHO  In cells (functional test) cAMP  Increase measurement

Allosteric increase is measured as the effect of the test compound at different concentrations (0.01, 0.1, 1 and 10 μm) to reduce the cAMP content of hCHO-A1 cells. To begin the experiment, the medium is removed from the twelve grooves and the cells are washed with warm Hanks' buffered saline. The wash was then removed and a new Hanks' containing forskolin (1 μm), rolipram (20 μm), N6-cyclopentyladenosine (CPA, 0.01 nM), adenosine deaminase (2U / mL), and the test compound. Replaced by a solution. Forskolin is used to stimulate activity 15 of adenylyl cyclase, rolipram is used to inhibit cAMP phosphodiesterase, and adenosine deaminase is responsible for endogenous adenosine. It is used to drop and CPA is used to cause a small increase in the number of activated adenosine receptors. After 6 min incubation at 36 ° C. under the test compound, the culture solution is removed and hydrochloric acid (final concentration 50 mM) is added to stop drug activity. The cAMP content in 20 acidified extractions of cells is determined by radioimmunoassay as previously described (Kollias-Baker et al. J. Pharmacol. Exp. Ther. 1997, 281, 761-768). Since the magnitude of the effect of the allosteric modulator on hCHO-A1 cells varies slightly between the minor changes in the number of passages and the difference in cell division, the activity of the test compound and the activity of the reference compound (PD 81,723) were determined in each experiment 25 Is evaluated. The effect of each experimental compound on the cAMP content is expressed as a percentage of the cAMP content under the drug (regulated, 100%).

Chronic Inflammation Pain Model:

[181] Foot injection of chimosan-induced mechanical hyperalgesia can be used as a model of chronic inflammatory pain (Meller et al., Neuropharmacology, 33: 1471-1478, 1994). In this method, typical male Spraque-Dawley or Wistar rats (200-250 g) receive a foot injection of 3 mg / 100 μl chimosan in one hind paw. Wounded inflammation occurs in these hind feet. After inflammatory injury, when mechanical hyperalgesia is considered fully established, the drug is generally administered for 24 hours for efficacy evaluation.

Chronic Neuropathic Pain Model:

Two animal models of chronic neuropathic pain can be used in several related forms of peripheral nerve damage. In the Seltzer model (Seltzer et al., Pain, 43: 205-218, 1990), Spraque-Dawley or Wistar rats (200-250 g) are anesthetized and a small incision is made in the middle of the femur (usually left) to reveal the sciatic nerve. Shall be. The nerve is carefully removed from the connected tissue, surrounded by a point near the peripheral nerve electron at the end of the posterior biceps semitenical nerve that splits into the normal sciatic nerve. The A 7-0 silk suture is infused with 3/8 of the needle and tightly ligated so that 1/3 to 1/2 of the nerve thickness is sustained in the ligation. The muscles and skin are closed with sutures and cuts and the wound is painted with antibiotic powder. The sciatic nerve is revealed but not ligated in the control animal and the wound is closed in the experimental animal.

[183] CCI models (Bennett, GJ and Xie, YK Pain, 33: 87-107, 1988) are anesthetized and small incisions are made at the midpoint of one thigh (usually left) to reveal the sciatic nerve. do. The nerve is removed from the enclosed tissue and four sutures of 4/0 chromic gut are loosely tied around the nerve at approximately 1 mm between each other. Thus the suture barely tightens the nerve surface.

The wound is closed with sutures and cuts as described above. The sciatic nerve is revealed but not ligated in the control animal and the wound is closed in the experimental animal.

[184] In contrast to the Seltzer and CCI models, the Chung model includes ligation of spinal nerves (Kim, S.O. and Chung, J.M. Pain, 50: 355-363, 1992). In this model, Sprague-Dawley or Wistar rats (200-250 g) are anesthetized and placed in the abdominal position and incisions are made on the left side of the spine at the L4-S2 level. Deep anatomy via the paraspinal muscle and muscle separation from the spinal processes at the L4-S2 level will reveal a portion of the sciatic nerve as the sciatic nerve splits to form L4, L5 and L6 spinal cord nerves. The L6 transverse process is carefully removed with a rongeur that allows organ exposure of these spinal nerves. The L5 spinal nerve is isolated and tightly ligated with a 7-0 silk suture. The wound is closed with a single muscle closure thread (6-D silk) and one or two skin closure clips and painted with antibiotic powder. In control animals, L5 nerves are exposed as before but not ligation and the wound is closed as before.

Behavioral Indicators:

[185] In all chronic pain models (inflammation and neuropathy), mechanical hyperalgesia is assessed by using the Analgesy Meter to measure the foot disengagement threshold of both hind paws for increased pressure stimulation. Mechanical allodynia is assessed by measuring the dosing threshold at a mechanical stimulus that does not cause pain by applying von Frey hairs experiments on the surfaces of both hind paws. Fever hyperalgesia is assessed by measuring the incubation latency at thermal stimuli that causes pain applied to the inner hind paw of each. As with all models, mechanical hyperalgesia, allodynia and heat hyperalgesia develop within 1-3 days after surgery and last for at least 50 days. For the trials described herein, drugs can be used pre and post surgery to assess drug efficacy on the onset of hyperalgesia, approximately 14 days after surgery, to determine the capacity for established hyperalgesia conversion.

[186] The percent conduction of hyperalgesia is calculated as follows:

In the pain model described above, all surgeries can be performed under an enfluuran / O ₂ inhalant anesthetic. In all cases the wound is closed after progress and the animal becomes recoverable. With all pain models except the control animals being used several days later, significant mechanical and heat hyperalgesia and allodynia begin at the onset of lesser pain with elevated withdrawal reflexes in which the hind foot contacts pressure or heat stimulation. After surgery, the animal may also exhibit characteristic changes in the affected foot. In most animals, the toes of the infected hind paws retract together and the paws change somewhat on one side, and in some rats the toes also curl and dry. Ligation of rats varies in appearance, but lagging is abnormal. Some rats have been shown to lift the infected hind paws from the bottom of the cage and show unusual stiff stretches of the hind limbs as they retract. Rats tend to be very sensitive to contact and can make sounds. On the other hand, mice in normal healthy conditions are good.

In an example of the invention, the compound of Example 4 exhibits an IC50 value of about 100 nM in a functional experiment by measuring cAMP levels in CHO cells showing human A1-adenosine receptors. Moreover, the compound of Example 4 increases the BMAX value of the [3 H] CCPA agonist to raise the human A1 adenosine receptor by 600% at a 10 μm concentration.

The following examples are intended to illustrate the invention and are not to be construed as limiting thereof. Although no distillation is mentioned, all distillations are carried out under reduced pressure, preferably between approximately 10 mm Hg and 100 mm Hg. The structure of the final product, intermediate and initial material can be identified by standard analytical methods such as microanalysis, melting point (m.p.) and spectroscopic properties such as MS, IR and NMR. Abbreviations are used as such in the art.

Example 1

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

A. (2-amino-4- Methylthiophene -3- days) (4- Chlorophenyl ) Methanone

2,5-dimethyl- [1,4] dithiane-2,5-diol (450 mg, 2.5 mmol) and 3- (in pure EtOH (10 mL), cooled in a solution of water / ice (4 ° C.) To a suspension of 4-chlorophenyl) -3-oxo-propionitrile (900 mg, 5 mmol) TEA (5 mmol, 0.7 mL) is added. After stirring for 10 minutes at RT, the mixture is refluxed for 2 hours. The resulting reddish brown solution is cooled and concentrated, and the residue is dissolved in EtOAc (10 mL). The organic phase is then washed with 1% w / v aqueous HCl (5 mL), saturated solution of NaHCO 3 (5 mL), water (5 mL) and brine (5 mL) is dried over (Na 2 SO 4) and concentrated to give a brown residue. do. The residue is suspended in ethyl ether (15 mL) and the suspension is stirred for 30 minutes and filtered. The filtrate is concentrated, petroleum ether suspended and the suspension is stirred for 30 minutes and filtered. The filtrate was concentrated and the residue was orange solid: mp 148-150 ° C. 1 H NMR (CDCL3) 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); EtOAc-petroleum ether 2 as eluent to give (2-amino-4-methylthiophen-3-yl) (4-chlorophenyl) methanone as IR (KBr) cm ⁻¹ : 3345,1589,1435,1267. Purification by column chromatography using a mixture of -8.

B. 2- [3- (4- Clobenzoyl )-4- Methylthiophene -2 days] Isoindolin -1,3- Dion

The title A compound (755 mg, 3 mmol) is dissolved in acetic acid (20 mL), and then phthalic anhydride (3.6 mmol, 533 mg) is added to the solution and the mixture is heated under reflux for 15 hours. The solvent is distilled off and the residue is dissolved in ethyl acetate (20 mL). The organic solution is washed with saturated NaHCO 3 (5 mL), water (5 mL) and brine (5 mL), dried over (Na 2 SO 4) and concentrated. The residue was stirred for 1 hour with petroleum ether (20 mL) and the solid was brown powder: 1 H NMR (DCCL3) δ: 2.24 (s, 3H), 7.02 (s, 1H), 7.22 (d, J = 7.2 Hz By filtration to give 2- [3-4-chlorobenzoyl) -4-methylthiophen-2-yl] isoindoline-1,3-dione as 2H), 7.62-8.00 (m, 6H). Is collected.

C. 2- [5- Bromo -3- (4- Chlorobenzoyl )-4- Methylthiophene -2 days] Isoindole -1,3- Dion

Solution in Benzene (150 mL) To the title B compound (20 mmol, 7.6 g) is added benzoylperoxide (484 mg, 2 mmol) and the mixture is heated under reflux. In the reflux state, the mixed solution N-bromosuccinimide (20 mmol, 3.56 g) and benzoyl peroxide (484 mg, 2 mmol) are added and the mixture is further refluxed for 6 hours. The solvent is removed under reduced pressure and the residue is dissolved in EtOAc (330 mL). The organic solution is then washed with saturated NaHCO 3 (200 mL), water (50 mL) and brine (50 mL), dried over (Na 2 SO 4) and concentrated to give a brown powder. The powder was suspended in petroleum ether (200 mL) and the mixture was agitated for 30 minutes and the solid was obtained as follows without further purification: mp194-195 ° C. 1 H NMR (CDCl 3) δ: 2.09 (s, 3H ), 7.19 (d, J = 7.4 Hz, 2H), 7.62-7.71 (m, 6H); IR (KBr) cm ⁻¹ : 2- [5-bromo used as 1728,1664,1587,1368,717 -3- (4-chlorobenzoyl) -4-methylthiophen-2-yl] isoindolin-1,3-dione is collected by filtration to provide.

D. 2- [5- Bromo -4- Bromomethyl -3- (4- Chlorobenzoyl ) Thiophen-2-yl] Isoindole -1,3-dione

To a suspension of the title C compound (20 mmol, 9.2 g) in CCl 4 (150 mL) is added benzoylperoxide (242 mg, 1 mmol) and the mixture is heated under reflux. In the reflux state, the mixed solution N-bromosuccinimide (20 mmol, 3.56 g) and benzoyl peroxide (242 mg, 1 mmol) are added and the mixture is further refluxed for 1 hour. After this time, if the reaction is not finished, the mixed solution N-bromosuccinimide (2 mmol, 356 mg) and benzoyl peroxide (242 mg, 1 mmol) is added and the mixture is reflux for another time. The resulting yellow solution is cooled to RT and the precipitated succinimide is removed by filtration and washed with CCl 4 (25 mL). The filtrate is washed with 5% NaHCO 3 solution (50 mL), water (50 mL) and brine (50 mL), dried over (Na 2 SO 4) and concentrated to give a yellow powder. The powder was suspended in petroleum ether (100 mL) and the mixture was stirred for 30 minutes and the solid was yellow solid: mp173-175 ° C. 1 H NMR (CDCl 3) δ: 4.65 (s, 2H), 7.20 (d, J = 6.6 Hz, 2H), 7.66 (d, J = 6.6 Hz, 2H), 7.72-7.71 (m, 4H). IR (KBr) cm ^-1 : 1727, 1658, 1348, 1330, 1084. Collected by filtration to give 5-bromo-4-bromomethyl-3- (4-chlorobenzoyl) thiophen-2-yl] isoindoline-1,3-dione.

E. 2- [5- Bromo -3- (4- Chlorobenzoyl ) -4-((4- Phenylpiperazine -1 day) methyl ) Thiophen-2-yl] Isoindolin -1,3- Dion

Stirred solution in dry DCM (5 mL) To the title D compound (900 mg, 1.6 mmol) TEA (1.1 equiv., 1.76 mmol, 243 mg) is added. The mixture is cooled with an ice / water solution and 4-phenylpiperazine (3 equiv., 5 mmol, 810 mg) is added. The mixture is stirred for 2 hours at RT, diluted with DCM (5 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over (Na 2 SO 4) and as a yellow solid, 2- [5-bromo-3- (4-chlorobenzoyl) -4-((4-phenyl-piperazin-1-yl) methyl) thiophen-2- Isoindolin-1,3-dione: mp186-193 ° C. 1 H NMR (CDCl 3) 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) Concentrated in vacuo to provide a brown residue which was purified by column chromatography (EtOAc-Petroleum ether 4-6 as elution) to give 7.82 (d, J = 6.8 Hz, 1H).

F. 2- [3- (4- Chlorobenzoyl ) -4-((4- Phenylpiperazine -1 day) methyl ) Thiophen-2-yl] Isoindolin -1,3- Dion

The solution title E compound (2 mmol) in DMF (20 mL) containing Et 3 N (0.3 mL, 2 mmol, 1 equiv) is hydrogenated over 120 mg of 10% Pd / c at 60 psi for 3 hours. The catalyst is removed by filtration and the filtrate is concentrated. The residue is dissolved in DCM (20 mL), washed with water (5 mL) and brine (5 mL) and dried over (Na 2 SO 4). The solvent is removed under reduced pressure and the residue is a white solid as 2- [3- (4-chloro-benzoyl) -4-((4-phenylpiperazin-1-yl) methyl) thiophen-2 -Yl] isoindolin-1,3-dione: mp220-222 ° C. 1 H NMR (CDCl 3) 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, 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) to provide column chromatography (EtO-DCM 2-8 as elution). Purified).

G. {2-amino-4-[(4- Phenylpiperazine -1 day) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Me Tanon

The stirred suspension title F compound (0.5 mmol) and 100% hydrazine monohydrate (1.2 equiv, 0.6 mmol, 29 μl) in pure ethanol (10 mL) are heated at reflux for 3 hours. After this time, the result is that the solution remains at RT for 1 hour. The reaction ends after complete solubilization of the initial material. The solvent is distilled off 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 a yellow solid, {2-amino-4-[(4-phenylpiperazin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone: m.p. 1 H NMR (CDCl 3) 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), By column chromatography (EtOAc-DCM / 2-8 as elution) to give 7.23 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H). Purified.

The following compounds are prepared similarly as described in Example 1.

Example 2

{2-amino-4-[(4- Methylpiperazine -1 day) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (MeOH as elution). Yellow oil, 1 H NMR (CDCl 3) δ: 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- [4-((4- Fluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 2: 8 as elution). Yellow solid, mp70-72 ° C. 1 H NMR (CDCl 3) 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- [4-((4- Chlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp148-150 ° C. 1 H NMR (CDCl 3) 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-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 2: 8 as elution). Yellow oil, 1 H NMR (CDCl 3) δ: 2.04 (t, J = 5.4 Hz, 4H), 2.83 (t, J = 5.4 Hz, 4H), 3.10 (s, 2H), 3.75 (s, 2H), 6.80 ( br s, 2H), 6.14 (s, 1H), 6.82 (d, J = 10.2 Hz, 2H), 6.86 (d, J = 10.2Hz, 2H), 7.36 (d, J = 8.4Hz, 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-[(4-p- Tolyl piperazine -1 day) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methane-on

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp73-75 [deg.] C. 1 H NMR (CDCl 3) δ: 2.26 (s, 3H), 2.32 (t, J = 5.6 Hz, 4H), 2.86 (t, J = 5.6 Hz, 4H), 3.12 (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-amino-4-[(4- (pyridin-2-yl) piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 4: 6 as elution). Yellow solid, mp 130-131 ° C. 1 H NMR (CDCl 3) 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 = 6.6Hz, 2H), 7.57 (d, J = 6.6Hz, 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) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 1 as elution). Yellow solid, mp141-143 ° C. 1 H NMR (CDCl 3) δ: 1.95 (t, J = 4.8 Hz, 4H), 2.99 (s, 2H), 3.55 (t, J = 4.8 Hz, 4H), 6.13 (br) 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-[(4- (3,4- Dichlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp 102-104 ° C. 1 H NMR (CDCl 3) 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, 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-[(5-amino-4- (4- Chlorobenzoyl Thiophen-3-yl) methyl ] Piperazin-1-yl} Benzonitrile

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp173-175 ° C. 1 H NMR (CDCl 3) 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- Chlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp197-199 ° C. 1 H NMR (CDCl 3) δ: 2.01 (t, J = 5.2 Hz, 4H), 2.93 (t, J = 5.2 Hz, 4H), 3.00 (s, 2H), 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) cm ⁻¹ : 3356,1587,1512,1430 and 1076.

Example 12

{2-amino-4-[(4- (2- Chlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp115-117 ° C. 1 H NMR (CDCl 3) δ: 2.04 (t, J = 5.2 Hz, 4H), 2.78 (t, J = 5.2 Hz, 4H), 3.10 (s, 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 : 3356,1587,1512,1430 and 1076.

Example 13

{2-amino-4-[(4- (2- Fluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp102-104 <0> C. 1 H NMR (CDCl 3) 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), 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.

Example 14

{2-amino-4-[(4- (3- ( Trifluoromethyl ) Phenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as elution). Yellow solid, mp 167-169 ° C .; 1 H NMR (CDCl 3) δ: 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 : 3346,1578,1522,1424 and 1082.

Example 15

1- {4-[(5-amino-4- (4- Chlorobenzoyl Thiophen-3-yl) methyl ] Piperazin-1-yl} -2- (4-chlorophenyl) Ethanon

The title compound is purified by column chromatography (EtOAc: DCM / 2: 8 as elution). Yellow solid, mp 60-61 ° C .; 1 H NMR (CDCl 3) 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.

Example 16

{2-amino-4-[(4- (4- Chlorobenzoyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp185-186 ° C. 1 H NMR (CDCl 3) 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-[(4- (pyridin-4-yl) piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: MeOH / 7: 3 as elution). Yellow solid, mp86-88 ° C .; 1 H NMR (CDCl 3) 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.

Example 18

{2-amino-4-[(4- ( Benzo [d] [1,3] dioxole -5-day) piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 1 as elution). Yellow solid, mp85-86 ° C .; 1 H NMR (CDCl 3) 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 : 3376,1577,1532,1423 and 1054.

Example 19

{2-amino-4-[(4- (2,3- Dichlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow oil, 1 H NMR (CDCl 3) δ: 2.05 (t, J = 4.4 Hz, 4H), 2.78 (t, J = 4.4 Hz, 4H), 3.01 (s, 2H), 6.07 (brs, 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.

Example 20

{2-amino-4-[(4- (3- Fluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 2: 8 as elution). Yellow solid, mp150-152 ° C. 1 H NMR (CDCl 3) 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 = 7.6Hz, 1H), 7.40 (d, J = 8.2Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H) .IR (KBr) cm ^-1 : 3434, 1577, 1534, 1256, 1077.

Example 21

{2-amino-4-[(4- (3,5- Dichlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp 185-187 ° C. 1 H NMR (CDCl 3) 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 = 8.6Hz, 2H), 7.53 (d, J = 8Hz, 2H) .IR (KBr) cm ^-1 : 2965 , 1587, 1272, 1085 and 1033.

Example 22

{2-amino-4-[(4- (4- ( Trifluoromethyl ) Phenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as elution). Yellow solid, mp 198-200 ° C. 1 H NMR (CDCl 3) 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 = 8.8Hz, 2H), 7.36 (d, J = 8.4Hz, 2H), 7.42 (d, J = 8.4Hz, 2H), 7.54 (d, J = 8.8Hz, 2H) IR (KBr) cm ⁻¹ : 3352, 1568, 1512, 1423 and 1077.

Example 23

2- {4-[(5-amino-4- (4- Chlorobenzoyl Thiophen-3-yl) methyl ] Piperazin-1-yl} -1- (4-chlorophenyl) Ethanon

The title compound is purified by column chromatography (EtOAc: MeOH / 9.5: 0.5 as elution). Yellow solid, mp 77-78 ° C. 1 H NMR (CDCl 3) δ: 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 (brs, 1H ), 6.08 (s, 1H), 7.22 (d, J = 8.4Hz, 2H), 7.35 (d, J = 8.4Hz, 2H), 7.44 (d, J = 8.4Hz, 2H) 7.62 (d, J = 8.4 Hz, 2H) .IR (KBr) cm ^-1 : 3333, 1584, 1512, 1434 and 1074.

Example 24

{2-amino-4-[(4- (2,4- Difluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp 170-172 ° C. 1 H NMR (CDCl 3) δ: 2.04 (t, J = 4.8 Hz, 4H), 2.77 (t, J = 4.8 Hz, 4H), 3.00 (s, 2H), 6.06 (brs, 2H), 6.13 (s, 1H ), 6.80 (m, 3H), 7.35 (d, J = 8.6Hz, 2H), 7.56 (d, J = 8.6Hz, 2H) .IR (KBr) cm ^-1 : 2955, 1592, 1424, 1278, 1092 And 1034.

Example 25

{2-amino-4-[(4- (2,6- Difluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow oil, 1 H NMR (CDCl 3) δ: 1.99 (t, J = 4.8 Hz, 4H), 2.95 (t, J = 4.8 Hz, 4H), 2.98 (s, 2H), 6.08 (brs, 2H), 6.13 ( s, 1H), 6.82 (m, 3H), 7.36 (d, J = 6.6Hz, 2H), 7.58 (d, J = 6.6Hz, 2H) .IR (neat) cm ^-1 : 2988, 1564, 1433, 1256, 1082 and 1047.

Example 26

{2-amino-4-[(4- (3- Chloro -4- Fluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, 161-163 ° C. 1 H NMR (CDCl 3) δ: 2.01 (t, J = 4.6 Hz, 4H), 2.85 (t, J = 4.6 Hz, 4H), 3.00 (s, 2H), 6.07 (brs, 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

{2-amino-4-[(4- Cyclohexylpiperazine -1 day) methyl ] Thiophen-3-yl} (4- Chlorophenyl Methanone

The title compound is purified by column chromatography (EtOAc: MeOH / 1: 1 as elution). Yellow solid, m.p. 120-122 ° C. 1 H NMR (CDCl 3) 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-[(4- (4- Chlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow oil, 1 H NMR (CDCl 3) 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-[(4- (4- Nitrophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp 110-112 ° C .; 1 H NMR (CDCl 3) δ: 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-[(4- Isopropylpiperazine -1 day) methyl ] Thiophen-3-yl} (4- Chlorophenyl Methanone

The title compound is purified by column chromatography (EtOAc: MeOH / 3: 7 as eluent. Yellow oil, 1 H NMR (CDCl 3) δ: 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-yl) piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 2: 8 as elution. Brown solid, mp 178 ° C. 1 H NMR (CDCl 3) 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-[(4- (3,4- Difluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp 143-145 ° C. 1 H NMR (CDCl 3) 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-[(4- Cyclopentylpiperazine -1 day) methyl ] Thiophen-3-yl} (4- Chlorophenyl Methanone

The title compound is purified by column chromatography (EtOAc: MeOH / 6: 4 as eluent. Yellow solid, mp 95-97 ° C. 1 H NMR (CDCl 3) 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- Cycloheptylpiperazine -1 day) methyl ] Thiophen-3-yl} (4- Chlorophenyl Methanone

The title compound is purified by column chromatography (EtOAc: MeOH / 7: 3 as elution. Yellow oil, 1 H NMR (CDCl 3) 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-[(4- (4- Chlorobenzyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 1 as elution). Yellow solid, mp 65-67 ° C .; 1 H NMR (CDCl 3) 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-[(4- Benzylpiperazine -1 day) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (DCM: MeOH / 9.5: 0.5 as elution). Yellow solid, mp 153-155 ° C. 1 H NMR (CDCl 3) 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-{[4- (2- (4- Chlorophenyl ) Ethyl) piperazin-1-yl) methyl ] Thiophen-3-yl} (4-cle Lorophenyl ) Methanone

The title compound is purified by column chromatography (DCM: MeOH / 9.5: 0.5 as elution). Yellow oil, 1 H NMR (CDCl 3) 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-[(4- (4- Fluorobenzyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (MeOH: DCM / 0.5: 9.5 as elution). Yellow oil, mp 230-231 ° C. 1 H NMR (CDCl 3) δ: 1.55 (t, J = 4.6 Hz, 4H), 1.88 (t, J = 4.6 Hz, 4H), 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- Cyclooctylpiperazine -1 day) methyl ] Thiophen-3-yl} (4- Chlorophenyl Methanone

The title compound is purified by column chromatography (DCM: MeOH / 0.5: 9.5 as elution). Yellow oil, 1 H NMR (CDCl 3) 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-{[4- [3- (4- Chlorophenyl ) Propyl] piperazin-1-yl] methyl } Thiophen-3-yl) (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (DCM: MeOH / 9.5: 0.5 as elution). Yellow solid, mp 60-61 ° C .; 1 H NMR (CDCl 3) 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 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-[(4- (2,4- Dichlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp 142-143 ° C. 1 H NMR (CDCl 3) 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-[(4- (2,5- Difluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, mp 62-63 ° C .; 1 H NMR (CDCl 3) 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 = 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-[(4- (2- ( Trifluoromethyl ) Phenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow oil. 1 H NMR (CDCl 3) δ: 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 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-[(4- (4- Chloro -3- ( Trifluoromethyl ) Phenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid. mp 141-143 ° C. 1 H NMR (CDCl 3) 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-[(4- (2,4,6- Trifluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid. mp 153-155 ° C. 1 H NMR (CDCl 3) δ: 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-[(4- (2- Chloro -4- Fluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid. mp 59-61 ° C. 1 H NMR (CDCl 3) 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 (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- Chlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid. mp 161-163 ° C. 1 H NMR (CDCl 3) 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 = 8.8 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H) .IR (KBr) cm ^-1 : 2967, 1577, 1452, 1271, 1110.

Example 48

{2-amino-4-[(4- (3,5- Difluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid. mp 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, 2H), 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-[(4- (2,6- Dichlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid. mp 128-130 ° C. 1 H NMR (CDCl 3) δ: 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 (d, J = 8.6 Hz, 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-[(4- (4- ( Trifluoromethoxy ) Phenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid. mp 151-153 ° C. 1 H NMR (CDCl 3) δ: 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-[(4- (pyridin-3-yl) piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: MeOH / 6: 4 as elution). Yellow solid. mp 101-103 ° C. 1 H NMR (CDCl 3) 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) cm ^-1 : 2958, 1586, 1444, 1270, 1096.

Example 52

{2-amino-4-[(4- (2,5- Dichlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as elution). Yellow solid. mp 78-80 ° C. 1 H NMR (CDCl 3) 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) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as elution). Yellow solid. mp 138 ° C. 1 H NMR (CDCl 3) δ: 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, 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-[(4- (4- Chlorophenyl ) -3- Methylpiperazine -1 day) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid. mp 105 ° C. 1 H NMR (CDCl 3) δ: 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 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-[(4- (4- Trifluoromethyl ) Phenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} [3- ( Trifluoromethyl ) Phenyl ] Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.25: 9.75 as elution). Yellow solid. m.p. 143-145 ° C. 1 H NMR (CDCl 3) δ: 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) methyl ] Thiophen-3-yl} [3- ( Trifluoromethyl ) Phenyl ] Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid. m.p. 100-102 ° C. 1 H NMR (CDCl 3) 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, 1 H).

Example 57

{2-amino-4-[(4- (2,6- Difluorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} [3- (t Refluoromethyl ) Phenyl ] Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as elution). Yellow solid. m.p. 163-165 ° C. 1 H NMR (CDCl 3) δ: 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- ( Spiro [ Benzo [d] [1,3]- Dioxol -2,4'piperidine] -1'- Methyl ) Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (DCM: EtOAc / 1: 9 as elution). Yellow solid. m.p. 209-211 ° C. 1 H NMR (CDCl 3) δ: 2.06 (t, J = 6.0 Hz, 4H), 3.02 (t, J = 6.0 Hz, 4H), 3.52 (s, 2H), 6.02 (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- Tert - Butyl Spiro [ Benzo [d] [1,3]- Dioxol -2,4'piperidine] -1'- Methyl ) Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (DCM: EtOAc / 1: 9 as elution). Yellow solid. m.p. 100-102 ° C. 1 H NMR (CDCl 3) δ: 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- Fluorospiro [ Benzo [d] [1,3]- Dioxol -2,4'-piperidine] -1'- Methyl ) Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (DCM: EtOAc / 9.9: 0.1 as elution). Yellow solid. m.p. 80-81 ° C. 1 H NMR (CDCl 3) δ: 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- Methylspiro [ Benzo [d] [1,3]- Dioxol -2,4'piperidine] -1'- Methyl ) Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (DCM: EtOAc / 7: 3 as elution). Yellow solid. m.p. 184-186 ° C. 1 H NMR (CDCl 3) 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- Methylspiro [ Benzo [d] [1,3]- Dioxol -2,4'-piperidine] -1'- Methyl ) Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (petroleum ether: EtOAc / 2: 8 as elution). White solid. m.p. 119-121 ° C. 1 H NMR (CDCl 3) δ: 1.77 (t, J = 5.2 Hz, 4H), 2.06 (t, J = 5.2 Hz, 4H), 2.23 (s, 3H), 3.02 (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-[(4- (4- Chlorophenylamino ) Piperidin] -1-yl) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as elution). Mass (mass spectrum): 460.48 (M + 1). 1 H NMR (CDCl 3) δ: 1.18 (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) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as elution). Mass (mass spectrum): 476.47 (M + 1). 1 H NMR (CDCl 3) 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-[(4- (4- Chlorophenyl )-[1,4] diazepam-1-yl) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as elution). Mass (mass spectrum): 460.56 (M + 1). 1 H NMR (CDCl 3) 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), 7.12 (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-[(7- (4- Chlorophenyl ) -2,7- Diaza - Spiro [4.4] rain -2 days) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as elution). Mass (mass spectrum): 486.48 (M + 1). 1 H NMR (CDCl 3) δ: 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-c] pyrrole-2-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as elution). Mass (mass spectrum): 472.42 (M + 1). 1 H NMR (CDCl 3) δ: 2.03 (m, 2H), 2.10 (m, 2H), 2.73 (m, 2H), 2.85 (m, 2H), 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-[(5- (4- Chlorophenyl ) -2,5- Diaza Bicyclo [2.2.1] hept -2 days) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (cyclohexane: EtOAc / 8: 2 as elution). Mass (mass spectrum): 458.64 (M + 1). 1 H NMR (CDCl 3) 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-amino-4-[(4- (4- Fluorophenyl Piperazin-1-yl) methyl ] -5- Methylthiophene -3-day} (4- Chlorophenyl ) Methanone

A. 2- [3- (4- Chlorobenzoyl )-4, 5-dimethylthiophene -2 days] Isoindolin -1,3- Dion

Phthalic acid in acetic acid (15 mL) in solution (2-amino-4,5-dimethylthiophen-3-yl) (4-chlorophenyl) methanone (532 mg, 2 mmol) prepared as described in US Pat. No. 6,323,214. Anhydride (360 mg, 2.4 mmol) is added and the mixture is heated to reflux for 15 hours. The solvent is distilled in vacuo and the residue is dissolved in ethyl acetate (20 mL). The organic solution is washed with a saturated aqueous solution of NaHCO 3 (5 mL), water (5 mL), then washed with brine (5 mL) in vacuo, dried over (Na 2 SO 4), filtered and concentrated. The crude product was stirred for 1 hour in petroleum ether (20 mL) and then (2- [3- (4-chlorobenzoyl) -4,5-dimethylthiophen-2-yl] isoindoline as a yellow powder. Filtration while providing -1,3-dione 1 H NMR (CDCl 3) 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- Methylthiophene -2 days] Isoindolin -1,3-dione

To the title A compound (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 hours. After this time, another portion of N-bromosuccinimide (2 mmol, 356 mg) is added and the reflux continues for another 2 hours.

C. 2- [3- (4- Chlorobenzoyl ) -4-((4- (4- Fluorophenyl Piperazin-1-yl) methyl ) -5- Me Tilthiophen-2-yl] Isoindolin -1,3- Dion

To a solution title B compound (900 mg, 0.5 mmol), stirred in dry DMF (5 mL), K 2 CO 3 (0.6 mmol, 83 mg) is added. The mixture is cooled with a solution of ice / water and then 1- (4-fluorophenyl) piperazine (3 equiv, 1.5 mmol) is added. The mixture is stirred at room temperature for 1 hour and the solvent is then removed under reduced pressure and a mixture of DCM (15 mL) and water (5 mL) are added to the residue. The organic phase is washed with brine (5 mL), dried over (Na 2 SO 4), filtered and then 2- [3- (4-chlorobenzoyl) -4-((4- (4-fluorophenyl) piperazin-1- (L) methyl) -5-methylthiophen-2-yl] isoindolin-1,3--dione: mp 110-112 ° C. 1 H NMR (CDCl 3) 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 = 8.6Hz, 1H), 6.64 (d, J = 8.6Hz, 1H), 6.85 (t, J = 8.6Hz, 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) to provide a brown residue which was purified by column chromatography (ethyl acetate: DCM / 1: 9 as a container). Concentrated in vacuo.

D. {2-amino-4-[(4- (4- Fluorophenyl Piperazin-1-yl) methyl ] -5- Methylthiophene -3-day} (4- Chlorophenyl ) Methanone

A stirred suspension of the title C compound (0.5 mmol) and hydrazine monohydrate (0.6 mmol, 29 μl) in pure EtOH (10 mL) is heated to reflux for 3 hours. The result is that the solution remains cooled to RT for 1 hour. The reaction ends after complete solubilization of the initial material. The solvent is evaporated and the residue is partitioned between DCM (10 mL) and water (5 mL). The separated organic phase was washed with brine (2 mL), dried over (Na 2 SO 4), filtered and then {2-amino-4-[(4- (4-fluorophenyl) piperazin-1-yl) Methyl] -5-methylthiophen-3-yl}-(4-chlorophenyl) yellow solid as methanone: mp 70-72 ° C. 1 HNMR (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 (brs, 2H), 6.76 (d, J = 8.6Hz, 1H), 6.83 (t, J = 8.6Hz, 1H), 6.94 (t, J = 8.6Hz, 2H), 7.36 (d, J = 8.4 Hz , 2H), 7.54 (d, J = 8.4 Hz, 2H). Concentrated in vacuo to obtain a residue purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as container).

The following compounds are formulated identically as described in Example 69.

Example 70

{2-amino-5- methyl -4-[(4- Phenylpiperazine -1 day)) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, m.p. 78-80 ° C. 1 H NMR (CDCl 3) 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- ( Trifluoromethyl ) Phenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, m.p. 76-78 ° C. 1 H NMR (CDCl 3) δ: 2.04 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 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-[(4- (4- Chlorophenyl Piperazin-1-yl) methyl ] -5- Methylthiophene -3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, m.p. 83-85 ° C. 1 H NMR (CDCl 3) 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-[(4- (4- Bromophenyl ) Piperazine 1 -Work) methyl ] -5- Methylthiophene -3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, m.p. 73-75 ° C. 1 H NMR (CDCl 3) δ: 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- Iodinephenyl ) Piperazine 1 -Work) methyl ] -5- Methylthiophene -3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, m.p. 72-73 ° C. 1 H NMR (CDCl 3) δ: 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 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H) .

Example 75

{2-amino-5- methyl -4-[(4- (4- Nitrophenyl ) Piperazine 1 -Work) methyl ] Thiophen-3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, m.p. 85-87 ° C. 1 H NMR (CDCl 3) δ: 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-amino-4- (4- Chlorobenzoyl )-2- Methylthiophene -3 days) methyl ] Piperazin-1-yl} Benzonitrile

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, m.p. 76-77 ° C. 1 H NMR (CDCl 3) δ: 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 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H) .

Example 77

{2-amino-4-[(4- Benzylpiperazine -1 day) methyl ) -5- Methylthiophene -3-day} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc as elution). Yellow solid, m.p. 48-50 ° C. 1 H NMR (CDCl 3) δ: 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- Methylthiophene -3-yl} (4-chlorophenyl) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1.5: 8.5 as elution). Yellow solid, m.p. 63-65 ° C. 1 H NMR (CDCl 3) 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-[(4-p- Tolipiperazine -1 day) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, m.p. 77-79 ° C. 1 H NMR (CDCl 3) 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-[(4- (3,4- Dichlorophenyl Piperazin-1-yl) methyl ] -5- Methylthiophene -3- Japanese} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 1: 9 as elution). Yellow solid, m.p. 63-65 ° C. 1 H NMR (CDCl 3) 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, 1H), 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- (3- ( Trifluoromethyl ) Phenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as elution). Yellow solid, m.p. 60-61 ° C. 1 H NMR (CDCl 3) δ: 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-[(4- (3- ( Chlorophenyl Piperazin-1-yl) methyl ] -5- Methylthiophene -3-day} Lorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.75: 9.25 as elution). Yellow solid, m.p. 58-60 ° C. 1 H NMR (CDCl 3) δ: 1.96 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 2.92 (t, J = 4.8 Hz, 4H), 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-amino-4-[(4- (4- Chloro -3- ( Trifluoromethyl ) Phenyl Piperazin-1-yl) methyl ]-5-M Tiltio Pen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: DCM / 0.5: 9.5 as elution). Yellow solid, m.p. 133-135 ° C. 1 H NMR (CDCl 3) 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, J = 2.8 Hz, 1H), 7.29 (t, J = 8 Hz, 1H), 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) methyl ] Thiophen-3-yl} (4-cle Lorope Neil) Methanone

A. Mixed Solution (Z) and (E) 2- (4- Chlorobenzoyl ) -3- Methylhex -2- Ennitrile

Pentane-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) The mixture was heated to reflux in a Dean-Stark system for 18 hours. The solution was cooled to RT, then diluted with EtOAc (50 mL), washed with 5% NaHCO 3 (3 × 20 mL), water (20 mL), brine (20 mL), dried over (Na 2 SO 4) and finally concentrated in vacuo. do. A mixture of the two isomers is obtained as colorless oil by chromatographic purification of the crude residue on silica gel using EtOAc: petroleum ether (0.5: 9.5) as elution.

B. (2-amino-5-ethyl-4- Methylthiophene -3- days) (4- Chlorophenyl ) Methanone

The title A compound (5 mmol), TEA (0.7 mL, 5 mmol) and sulfur (192 mg, 6 mmol) in EtOH (10 mL) are heated at reflux for 2 hours. After cooling at RT, 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 over (Na 2 SO 4) and concentrated in vacuo. The crude residue was taken as EtOAc: petroleum ether (1: 9) to give (2-amino-5-ethyl-4-methylthiophen-3-yl) (4-chlorophenyl) methanone as a yellow oil. Purification by chromatography on silica gel while dissolving. 1 H-NMR (CDCl 3): δ 1.18 (t, 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- Chlorobenzoyl )-4- methyl -5-Ethyl-thiophen-2-yl]- Isoindolin -1,3- Dion

The title B compound (4 mmol) is dissolved in acetic acid (25 mL). Phthalic anhydride (5 mmol, 740 mg) is added to the mixture and the mixture is heated under reflux for 5 hours. The solvent is evaporated in vacuo and the residue is dissolved in DCM (30 mL). The organic solution is washed with water (10 mL), brine (10 mL), dried over (Na 2 SO 4) and concentrated in vacuo. The crude product is first ground in petroleum ether (20 mL) for 1 hour and then as a white solid, 2- [3- (4-chlorobenzoyl) -4-methyl-5-ethyl-thiophen-2-yl] Isoindole-1,3-Dion: mp 115-117 ° C. 1 H-NMR (CDCl 3): 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 - Benzoyl ) -Thiophene-2day]- Isoindole -1,3-dione

To the solution of the title C compound (2 mmol) in CCl 4 (40 ml) was added mixed N-bromosuccinimide (784 mg, 4.4 mmol) and benzoyl peroxide (32 mg) and the mixture was refluxed for 2 hours. The resulting yellow solution is cooled at RT while the succinimide is separated and removed by filtration. The filtrate is concentrated in vacuo and the residue is diluted with DCM (20 mL). The organic solution was washed with 5% NaHCO 3 (10 mL), water (10 mL), brine (10 mL), dried over (Na 2 SO 4) and 2- [5-ethyl-4-bromomethyl-3- (4- as orange oil). Chloro-benzoyl) -thiophen-2-yl] -isoindole-1,3-dione. 1 H-NMR (CDCl 3): 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) Concentrate to give a yellow residue which is purified by column chromatography (EtOAc: Petroleum ether / 2: 8 as eluent).

E. 2- {3- (4- Chlorobenzoyl ) -4- [4- (4- Fluorophenyl ) -Piperazine-1- Methyl -5-Ethyl] -thiophen-2-yl}- Isoindole -1,3- Dion

To the ice / water cooled solution stirred in dry DMF (2.5 ml) title D compound (0.5 mmol) was added TEA (0.12 mL, 1 mmol) and then the appropriate 1- (4-fluorophenyl) piperazine (0.6 mmol) Is also added. The mixture is then stirred at RT for 2 hours. 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 over (Na2SO4). After evaporation in vacuo, the residue was obtained as a white solid as 2- {3- (4-chlorobenzoyl) -4- [4-fluorophenyl) -piperazin-1-ylmethyl-5-ethyl] -thiophene- 2-yl} -isoindole-1,3-dione: mp 122-124 ° C. 1 H-NMR (CDCl 3): δ 1.20 (t, J = 7.6 Hz, 3H), 1.99 (m, 4H), 2.68 (q, J = 7.6 Hz, 2H), 3.02 (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) Purified by column chromatography on silica gel (EtOAc: Petroleum ether / 1.5: 8.5 as eluent) to give 7.72 (m, 2H), 7.84 (m, 2H).

F. {2-amino-4- [4- (4- Fluorophenyl Piperazin-1-yl) methyl ] -5- Ethylthiophene -3-day} (4- Chlorophenyl ) Methanone

A whipped suspension of 100% hydrazine monohydrate (0.3 mmol, 14 μl) and the title E compound (0.25 mmol) in pure EtOH (5 mL) was refluxed for 3 hours. The solvent is evaporated and the residue is partitioned between DCM (10 mL) and water (5 mL). The separated organic phase was washed with brine (2 mL), dried and then {2-amino-4- [4- (4-fluorophenyl) piperazin-1-yl) methyl] -5-ethylthiophene- as a yellow solid. 3-yl} (4-chlorophenyl) methanone: mp 123-125 ° C. 1 H-NMR (CDCl 3): δ 1.21 (t, J = 7.6 Hz, 3H), 1.98 (m, 4H), 2.61 (q, J = 7.6 Hz, 2H), 2.84 (m, 4H), 2.96 (s, 2H), 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 Concentrate in vacuo to afford a residue which is purified by column chromatography (EtOAc: DCM / 8: 2 as elution) to give.

The following compounds are formulated identically as described in Example 84.

Example 85

{2-amino-5-ethyl-4-[(4- Phenylpiperazine -1 day) methyl ] Methylthiophene -3-day} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: Petroleum ether / 0.5: 9.5 as elution). Yellow solid, m.p. 104-106 ° C. 1 H NMR (CDCl 3) 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-[(4- (4- Chlorophenyl Piperazin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The title compound is purified by column chromatography (EtOAc: Petroleum ether / 1.5: 8.5 as eluent). Yellow solid, m.p. 115-117 ° C. 1 H NMR (CDCl 3) 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 J = 9.0 Hz, 2H), 7.19 (d J = 9.0 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H).

Example 87

{2-amino-5- Phenyl -4-[(piperidin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

A. 2- [3- (4- Chlorobenzoyl )-4- methyl -5- Phenylthiophene -2 days] Isoindole -1,3- Dion

Title A compounds are described in Romagnoli et al. in J. Med. Chem. Example 1 described by 2006, 49 (13), 3906-3915 The following procedure is prepared from the title C compound. The product is a brown solid, 2- [3- (4-chlorobenzoyl) -4-methyl-5-phenylthiophen-2-yl] isoindole-1,3-dione, m.p. 223-225 ° C. 1 H NMR (CDCl 3) δ: 2.24 (s, 3H), 7.24 (d, J = 8.4 Hz, 2H), 7.74 (m, 5H), 7.80 (m, 6H) to give column chromatography (eluting as elution) EtOAc: petroleum ether / 1.5: 8.5).

B. 2- [4- Bromomethyl -3- (4- Chlorobenzoyl ) -5- Phenylthiophene -2 days] Isoindole -1,3- Dion

NBS (180 mg, 1 mmol) and benzoyl peroxide (14 mg, 0.06 mmol) are added to the reflux suspension of the title A compound (458 mg, 1 mmol) in CCl 4 (10 ml) and the mixture is refluxed for 1 hour. At this time, the mixed solution N-bromosuccinimide (180 mg, 1 mmol) and benzoyl peroxide (14 mg, 0.06 mmol) were added and the mixture was refluxed for another hour. The yellow solution is then cooled to RT, the succinimide separated under cooling is removed by filtration and the filter cake is washed with CCl 4 (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 give a yellow solid suspended in petroleum ether (10 mL). The mixture is stirred for 30 minutes and the solid is 2- [4-bromomethyl-3- (4-chlorobenzoyl) -5-phenylthiophene- used as such for the next reaction without further purification. 2-yl] isoindole-1,3-dione. m.p. 160-161 ° C. 1 H NMR (CDCl 3) δ: 4.73 (s, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.52 (m, 1H), 7.68 (m, 8H Collected by filtration to provide.

C. 2- [3- (4- Chlorobenzoyl ) -5- Phenyl -4-((piperidin-1-yl) methyl ) Thiophen-2-yl] Iso Indole-1,3- Dion

To a solution title B compound (265 mg, 0.5 mmol), stirred in dry DMF (5 mL), K 2 CO 3 (70 mg, 0.5 mmol) is added. The mixture is cooled with an ice / water solution and then piperidine (4 equivalents, 2 mmol) is added. The mixture is stirred at RT for 2 hours. After this time, the solvent is removed under reduced pressure and the residue is taken up with a mixture of EtOAc (15 mL) and water (5 mL). The organic phase was washed with brine (5 mL), dried over Na 2 SO 4 and 2- [3- (4-chlorobenzoyl) -5-phenyl-4-((piperidin-1-yl) methyl) ti as a yellow solid. Offen-2-yl] isoindole-1,3-dione, mp 187-189 ° C. 1 H NMR (CDCl 3) δ: 1.25 (m, 6 H), 1.65 (m, 4H), 2.98 (s, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.53 (m, 3H), 7.73 ( m, 8H), 7.68 (m, 8H), is concentrated under vacuum to provide a brown residue which is purified by column chromatography (EtOAc as petroleum ether / 1.5: 8.5) as eluent.

D. {2-Amino-5- Phenyl -4-[(piperidin-1-yl) methyl ] Thiophen-3-yl} (4- Chlorophenyl ) Methanone

The whipped suspension of 100% hydrazine monohydrate (1.2 equiv, 0.6 mmol, 29 μl) and the title C compound (0.5 mmol) in pure ethanol (10 ml) was refluxed for 1 hour. 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 {2-amino-5-phenyl-4-[(piperidin-1-yl) methyl] thiophen-3-yl as a yellow solid. } (4-chlorophenyl) methanone, mp 185-187 ° C. 1H NMR (CDCl 3) δ: 1.24 (m, 6H), 1.66 (m, 4H), 2.99 (s, 2H), 5.69 (br s, 2H), 7.33 (m, 7H), 7.65 (d Concentrated under vacuum to obtain a residue which is purified by column chromatography (EtOAc: Petroleum ether / 4: 6 as eluent) to give, J = 8.6 Hz, 2H).

Example 88   (Synthesis example of increasing increase)

{2-amino-4-[(4- (4- Fluorophenyl Piperazin-1-yl) methyl ] -5- Methylthiophene -3-day} Lorope Neil) Methanone

A. (2-amino-4,5-dimethylthiophen-3-yl) (4- Chlorophenyl ) Methanone

A 12 L, three-necked bottom flask with mechanical stirrer and thermometer is a 3- (4-chlorophenyl) -3-oxopropanenitrile (800 g, 4.46 mol), pure EtOH (4 L), sulfur (321 g, 4.46) mol) and ethyl methyl ketone (321 g, 4.46 mol). The morpholine (388 g, 4.46 mol) is added and the reaction mixture thickens and the temperature is raised from 18 ° C to 30 ° C. The reaction mixture is stirred for 1 hour at ambient temperature, heated at reflux overnight, then cooled to ambient temperature and concentrated in vacuo. The residue is combined with a previous batch of crude material from 500 g of reaction. The combined residue is filled with EtOAc (12 L), washed with water (6 L), 10% NaHSO 4 (3 L), brine (2 L), dried over anhydrous NaSO 4 and filtered through Celite. The filtrate is concentrated in vacuo to give a sticky solid. The solid was collected by filtration and washed with hexane and air to produce (2-amino-4,5-dimethylthiophen-3-yl) (4-chlorophenyl) methanone as a tan solid (680 g). To dry.

B. 2- [3- (4- Chlorobenzoyl ) -4,5-dimethylthiophen-2-yl] Isoindolin -1,3- Dion

A 12 L, 3 round bottom flask with mechanical stirrer and thermometer is filled with title A compound (800 g, 3.01 mol), acetic acid (6 L), and phthalic anhydride (535 g, 3.62 mol). The reaction mixture is stirred at reflux overnight, then cooled to ambient temperature and concentrated in vacuo. Methyl-t-butylether (MTBE, 2 L) is added to the residue, as a result of which the slurry is filtered. The solid was washed with MTBE (500 mL) and hexane (1 L), then 2- [3- (4-chlorobenzoyl) -4,5-dimethylthiophen-2-yl] as a tan solid (1050 g). It is dried with air to produce isoindolin-1,3-dione. The 1H NMR spectrum is consistent with the structure.

C. 2- [4- ( Bromomethyl ) -3- (4- Chlorobenzoyl ) -5- Methylthiophene -2 days] Isoindolin -1,3-dione

A three-necked 3 L round bottom flask with mechanical stirrer and thermometer was prepared with the title B compound (150 g, 0.38 mol), N-bromosuccinimide (67 g, 0.38 mol) and acetonitrile (1.5 L). Is filled. The reaction mixture is stirred for 2 hours in reflux and then further treated with N-bromosuccinimide (67 g, 0.38 mol). Heating at reflux lasts more than 2 hours and the reaction mixture is allowed to cool at ambient temperature and concentrated in vacuo. The residue is filled with DCM (600 mL) and washed with water (200 mL), saturated NaHCO 3 (200 mL), water (200 mL) and brine (200 mL), dried over (Na 2 SO 4), filtered and concentrated in vacuo. . The dark brown solid is purified by chromatography (DCM as elution) to yield a tan solid which is stirred in diethyl ether (Et 2 O, 300 mL), then filtered and as off white solid (86 g). It is dried to give 2- [4- (bromomethyl) -3- (4-chlorobenzoyl) -5-methylthiophen-2-yl] isoindoline-1,3-dione. The 1H NMR spectrum is consistent with the structure.

D. 2- [3- (4- Chlorobenzoyl ) -4-((4- (3- Fluorophenyl Piperazin-1-yl) methyl ) -5- Me Tilthiophen-2-yl] Isoindolin -1,3- Dion

A 2 L round bottom flask with a mechanical stirrer is filled with the title C compound (80.7 g, 0.17 mol), CHCl 3 (1.2 L), and triethylamine (3 equiv). The mixture is cooled at ˜5 ° C. in an ice / water solution and then the appropriate 4- (3-fluorophenyl) piperazine (0.9 equiv) is added. The reaction mixture is stirred at 0 ° C. for 5 minutes and then at ambient temperature for 1 hour. The reaction mixture is washed with water (500 mL), saturated NaHCO 3 (500 mL), and brine (500 mL) and then dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. The crude material is purified by chromatography (2% EtOAc in DCM). The elution is concentrated in vacuo and then suspended in Et ₂ O (300 mL) and as 2- [3- (4-chlorobenzoyl) -4-((4- (3-fluorine) as an offwhite solid. Phenyl) piperazin-1-yl) methyl) -5-methylthiophen-2-yl] filtered and dried to give isoindolin-1,3-dione (40 g).

E. {2-amino-4-[(4- (3- Fluorophenyl Piperazin-1-yl) methyl ] -5- Methylthiophene -3-day} (4- Chlorophenyl ) Methanone .

The A 2 L round bottom flask is filled with the title D compound (40 g, 0.07 mol), toluene (0.2 M), and EtOH (0.2 M). Hydrazine hydrate (1.5 equiv, 64% hydrazine) is added in one portion and the mixture is heated to reflux. Upon reaching the reflux temperature, the reaction mixture becomes a purified yellow solution, and a precipitate forms upon continuous heating. The reaction is supervised by TLC and when the reaction is complete (usually ˜5 hours), the reaction mixture is allowed to cool at ambient temperature and concentrated. The residue is filled with Et ₂ O (600 mL) and washed with water (150 mL), saturated NaHCO 3 (150 mL), and brine (150 mL) and dried over (Na 2 SO 4). The solvent is removed in vacuo, whereupon the yellow solid is stirred in ethanol (80 mL) and then {2-amino-4-[(4- (3-fluorophenyl) pipepeas as a yellow solid (24 g). Razin-1-yl) methyl] -5-methylthiophen-3-yl} (4-chlorophenyl) methanone, mp 140-141 ° C. EsI-MS: 444 (M + H) ⁺ . Elemental Analysis: calc C 62.22%, H 5.22%, N 9.46%; Pound C 62.21, H5.27%, 7.09%, N9.48 /%. 1 H NMR (200 MHz, CDCl 3): 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 (51)

Compound of formula (I)

R 1 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl; R 2, R 3 and R 4 are each independently of each other hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy, or substituted alkoxy ; Q is

Is selected from the stages that comprise Wherein R 5 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl, or substituted acyl ego; R6 and R7 are each, independently of one another, hydrogen, C1-C3 alkyl, or C1-C3 substituted alkyl; Also If R 6 and R 7 are attached to the same carbon atom, the bond is alkylene with R 6 and R 7 attached carbon atoms forming a 3- to 7-spirocyclic ring; R8, R9, R10, R11, R12 and R13 are each independently of each other hydrogen, C1-C3 alkyl, or C1-C3 substituted alkyl; X is N or C-H; Also X is C-NR14R15 in that R14 and R15 are each independently of each other hydrogen, C1-C3 alkyl, C1-C3 alkyl, C1-C3 substituted alkyl, aryl, or substituted aryl; Also X is C-R16 in that the bonded R16 and R5 are carbonyl oxygen; Also X is a divalent chemical formula wherein R 16 and R 5 are bonded together with a carbon atom attached to R 16 and R 5 ← Y-CHR17- (CH2) n-CHR18-Y is C-R16 in that it forms 5- to 7-spirocyclic ring, Y is oxygen or sulfur; R 17 and R 18 are each independently of each other hydrogen, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl; n is zero or an integer of 1 or 2; Also X is a divalent chemical formula wherein R 16 and R 5 bonded together with the carbon atoms attached to R 16 and R 5

C-R16 in that it forms a 5-spirocyclic ring; Y is oxygen or sulfur; R 19 and R 20 are each, independently of one another, hydrogen, halogen, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, or C 1 -C 6 alkoxy; Also a compound of formula (I) in that it is a pharmaceutically acceptable salt thereof. The compound according to claim 1, R 1 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; Also a compound in that it is a pharmaceutically acceptable salt thereof. The compound according to claim 2 Q is

In that R 5 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 of each other hydrogen, C1-C3 alkyl, or C1-C3 substituted alkyl; Also If R6 and R7 are attached to the same carbon atom R6 and R7 are attached, the bond is alkylene with R6 and R7 attached carbon atom and forms a 3- to 7-spirocyclic ring; X is N or C-H; Also X is C-NR 14 R 15 in that R 14 and R 15 are each independently of each other hydrogen, C 1 -C 3 alkyl, C 1 -C 3 substituted alkyl, aryl, or substituted aryl; Also X is C-R16 in that the bonded R16 and R5 are carbonyl oxygen; Also X is a combined bivalent chemical formula wherein R 16 and R 5 are bonded together with a carbon atom to which R 16 and R 5 are attached ← Y-CHR17- (CH2) n-CHR18-Y → Which forms a 5- to 7-spirocyclic ring, Wherein Y is oxygen or sulfur; R 17 and R 18 are each independently of each other hydrogen, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl; n is zero or an integer of 1 or 2; Also X is a combined R16 and R5 divalent chemical formula

In that it is C-R16, This, together with the carbon atoms to which R16 and R5 are attached, forms a 5-spirocyclic ring, Wherein Y is oxygen or sulfur; R 19 and R 20 are each independently of each other hydrogen, halogen, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, or C 1 -C 6 alkoxy; Or a pharmaceutically acceptable salt thereof. The compound according to claim 3, X is N; Or a pharmaceutically acceptable salt thereof. Compound of formula (IA) according to claim 4

silver R 1 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; R 2, R 3 and R 4 are each independently of each other hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy, or substituted alkoxy ; R 5 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl, or substituted acyl; R6 and R7 are each, independently of one another, hydrogen, C1-C3 alkyl, or C1-C3 substituted alkyl; Also If R6 and R7 are attached to the same carbon atom, the bond is alkylene with R6 and R7 attached carbon atoms forming a 3- to 7-spirocyclic ring; R8 and R9 are each, independently of one another, hydrogen, C1-C3 alkyl, or C1-C3 substituted alkyl; Also a compound in that it is a pharmaceutically acceptable salt thereof. The compound according to claim 5 R 1 is hydrogen or C 1 -C 3 alkyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 5 R 5 is monocyclic aryl optionally substituted by 1 to 3 substituents selected from the groups constituting halogen, cyano or trifluoromethyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 5 R2 and R4 are hydrogen; Or a pharmaceutically acceptable salt thereof. The compound according to claim 8 R 3 is hydrogen, cyano or trifluoromethyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 5 R2 and R3 are hydrogen; Or a pharmaceutically acceptable salt thereof. The compound according to claim 10 R 4 is halogen, cyano or trifluoromethyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 5 R6, R7, R8, and R9 are each, independently of one another, hydrogen, C1-C3 alkyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 12 R 5 is monocyclic aryl optionally substituted by 1 to 3 substituents selected from the groups constituting halogen, cyano or trifluoromethyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 13 R2 and R4 are hydrogen; Or a pharmaceutically acceptable salt thereof. The compound according to claim 14 R 3 is hydrogen, cyano or trifluoromethyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 15 R 1 is hydrogen or C 1 -C 3 alkyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 13 R2 and R3 are hydrogen; Or a pharmaceutically acceptable salt thereof. The compound according to claim 17 R 4 is halogen, cyano or trifluoromethyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 18 R 1 is hydrogen or C 1 -C 3 alkyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 3 X is a combined R16 and R5 is a divalent chemical formula

In that it is C-R16, This, together with the carbon atoms to which R16 and R5 are attached, forms a 5-spirocyclic ring, Wherein Y is oxygen or sulfur; R 19 and R 20 are each independently of each other hydrogen, halogen, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, or C 1 -C 6 alkoxy; Or a pharmaceutically acceptable salt thereof. The compound of formula (IB) according to claim 20

R 1 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; R2, R3 and R4 are each independently of each other hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy, or substituted alkoxy ; R6, R7, R8 and R9 are each, independently of one another, hydrogen, C1-C3 alkyl, or C1-C3 substituted alkyl; R 19 and R 20 are each, independently of one another, hydrogen, halogen, cyano, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, or C 1 -C 6 alkoxy; Or a pharmaceutically acceptable salt thereof. The compound according to claim 21 R 1 is hydrogen or C 1 -C 3 alkyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 21 R 19 and R 20 are each independently of each other hydrogen, halogen, cyano, trifluoromethyl, or C 1 -C 4 alkyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 21 R2 and R4 are each hydrogen; Or a pharmaceutically acceptable salt thereof. The compound according to claim 24 R 3 is halogen, cyano or trifluoromethyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 21 R2 and R3 are hydrogen; Or a pharmaceutically acceptable salt thereof. The compound according to claim 26 R 4 is halogen, cyano or trifluoromethyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 21 R6, R7, R8 and R9 are hydrogen; Or a pharmaceutically acceptable salt thereof. The compound according to claim 28 R 19 and R 20 are each independently of each other hydrogen, halogen, cyano, trifluoromethyl, or C 1 -C 4 alkyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 29 R2 and R4 are hydrogen; Or a pharmaceutically acceptable salt thereof. The compound according to claim 30 R 3 is halogen, cyano or trifluoromethyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 31 R 1 is hydrogen or C 1 -C 3 alkyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 29 R2 and R3 are hydrogen; Or a pharmaceutically acceptable salt thereof. The compound according to claim 33 R 4 is halogen, cyano or trifluoromethyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 34 R 1 is hydrogen or C 1 -C 3 alkyl; Or a pharmaceutically acceptable salt thereof. The compound according to claim 1 is: {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] [1,3] 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-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-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] [1,3] -dioxol-2,4'-piperidin] -1'-ylmethyl) thiophen-3-yl} (4-chloro Phenyl) methanone; {2-Amino-4- (5-tert-butylspiro [benzo [d] [1,3] -dioxol-2,4'-piperidin] -1'-ylmethyl) thiophen-3-yl } (4-chlorophenyl) methanone; {2-amino-4- (4-fluorospiro [benzo [d] [1,3] -dioxol-2,4'-piperidin] -1'-ylmethyl) thiophen-3-yl} ( 4-chlorophenyl) methanone; {2-amino-4- (4-methylspiro [benzo [d] [1,3] -dioxol-2,4'-piperidin] -1'-ylmethyl) thiophen-3-yl} ( 4-chlorophenyl) methanone; {2-amino-4- (5-methylspiro [benzo [d] [1,3] -dioxol-2,4'-piperidin] -1'-ylmethyl) thiophen-3-yl} ( 4-chlorophenyl) methanone; {2-amino-4- [4-((4-chlorophenylamido) piperidin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-amino-4-[(4- (4-chlorophenyl) methylamido] piperidin-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-amino-4-[(4- (4-chlorophenyl)-[1,4] diazepan-1-yl) methyl] thiophen-3-yl} (4-chlorophenyl) methanone; {2-amino-4-[(7- (4-chlorophenyl) -2,7-diaza-spiro [4.4] non-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) methane On; {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- (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; {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; Is selected from the stages that constitute Or a pharmaceutically acceptable salt thereof. The compound according to claim 1 is: {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; Is selected from the stages that comprise Or a pharmaceutically acceptable salt thereof. A method for the modulation of A1 adenosine receptors in a mammal, the method comprising administering to the mammal in need of a therapeutically effective amount of any one of the compounds of claim 1. A method for treating a disease regulated by an A1 adenosine receptor in a mammal, the method comprising administering to the mammal in need of a therapeutically effective amount of any one of the compounds of claim 1. The method according to claim 39 Wherein the condition is controlled by an A1 adenosine receptor selected from the group consisting of pain, heart disease or disorder, neurological disease or injury, sleep disorder, epilepsy and depression. The method according to claim 40 Method in that the pain is neuropathic pain. The method according to claim 40 A method in that it is a heart disease or disorder selected from the groups comprising deep vein, angina, myocardial infarction and stroke. A pharmaceutical composition comprising an amount of a therapeutically effective compound of any one of claims 1 to 37 in combination with one or more pharmaceutically acceptable carriers. The pharmaceutical composition according to claim 43 Pharmaceutical compositions for the treatment of heart disease or disorders, neuropathic diseases or injuries, sleep disorders, epilepsy and depression. The pharmaceutical composition according to claim 44 Pharmaceutical composition in that the pain is neuropathic pain. The pharmaceutical composition according to claim 43 Pharmaceutical compositions for use as medicaments. The use of the pharmaceutical composition according to claim 43 Use of a pharmaceutical composition for the preparation of a medicament for the treatment of a disease regulated by A1 adenosine receptors. The use of a compound according to any one of claims 1 to 37 Use of compounds for the preparation of pharmaceutical compositions for the treatment of diseases controlled by A1 adenosine receptors. Use according to claim 47 or 48 Use in the sense that it is a disease regulated by A1 adenosine receptor selected from heart disease or disorder, neuropathic disease or injury, sleep disorder, epilepsy and depressive pain, Use according to claim 49 Use in that the pain is neuropathic pain. The compound according to any one of claims 1 to 37 Compound for use as a medicament.