FUSED DIHYDROINDAZOLE DERIVATIVES HAVING MULTIMODAL ACTIVITY AGAINST PAIN

Title:

FUSED DIHYDROINDAZOLE DERIVATIVES HAVING MULTIMODAL ACTIVITY AGAINST PAIN

Document Type and Number:

WIPO Patent Application WO/2020/016315

Kind Code:

Abstract:

The present invention relates to fused dihydroindazole derivatives having pharmacological activity towards the α2δ subunit, in particular the α2δ subunit, of the voltage-gated calcium channel. It also relates to compounds having dual pharmacological activity towards both the α2δ subunit, in particular the α2δ subunit, of the voltage-gated calcium channel and the δ1 receptor. The present invention also relates to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

Inventors:

DÍAZ-FERNÁNDEZ JOSÉ-LUÍS (ES)
GARRIGA-SANAHUJA LOURDES (ES)
GARCIA-LOPEZ MONICA (ES)
RODRIGUEZ-ESCRICH SERGI (ES)
ALMANSA-ROSALES CARMEN (ES)

Application Number:

PCT/EP2019/069277

Publication Date:

January 23, 2020

Filing Date:

July 17, 2019

Export Citation:

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Assignee:

ESTEVE PHARMACEUTICALS SA (ES)

International Classes:

C07D495/04; A61K31/4162; A61P29/00

Domestic Patent References:

WO2017016669A1	2017-02-02
WO2017178510A1	2017-10-19
WO2018100041A1	2018-06-07
WO2017198339A1	2017-11-23

Other References:

DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 24 April 2007 (2007-04-24), XP002784351, Database accession no. 932299-37-1
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 25 April 2007 (2007-04-25), XP002784352, Database accession no. 932485-28-4
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 26 April 2007 (2007-04-26), XP002784353, Database accession no. 932537-28-5
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 22 June 2008 (2008-06-22), XP002784354, Database accession no. 1029748-76-2
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 1 July 2008 (2008-07-01), XP002784355, Database accession no. 1031991-99-7
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 25 April 2007 (2007-04-25), XP002784356, Database accession no. 932485-75-1
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GOLDBERG DSMCGEE SJ, BMC PUBLIC HEALTH, vol. 11, 2011, pages 770
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CHIEN CCPASTERNAK GW, NEUROSCI. LETT., vol. 190, 1995, pages 137 - 9
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MAO J, GOLD MSBACKONJA M., J. PAIN, vol. 12, 2011, pages 157 - 166
KROGSGAARD-LARSEN ET AL.: "Textbook of Drug design and Discovery", April 2002, TAYLOR & FRANCIS

Attorney, Agent or Firm:

CARRASCOSA, Maria-Jose (ES)

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Claims:

CLAIMS:

1 . A compound of formula (I):

wherein

Ri is selected from hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted alkyl-heterocyclyl;

R2 IS selected from substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl- heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, and [CH2]n-C(0)-R5; wherein when the cycloalkyl group is substituted, the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl; substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, -OR₅, -C(O), -C(0)Rs, -NO₂, -CN, - NR₅C(0)-[CH₂]_n-NR₅ R_5”, -C(0)NR₅-[CH₂]_n-NR_5'R_5'', -NR₅C(0)R₅·, -C(0)NR₅R₅·, and -NR₅[CH₂]_n-NR_5'R_5”; when the heterocyclyl group is substituted, the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted alkyl-heterocyclyl, -ORs, -C(O), -C(0)Rs, -NO2, -CN, -NR₅C(0)- [CH₂]_n-NR₅ R_5”, -C(0)NR₅-[CH₂]_n-NR_5'R_5”, -NR₅C(0)R₅·, -C(0)NR₅R₅·, and - NR₅[CH₂]_n-NR_5'R_5”; when the aryl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, OR5, NO2, NR5R5', alkyl-aryl, CN, -NR₅C(0)-[CH₂]_n-NR_5'R_5”, -C(0)NR₅-[CH₂]_n-NR_5'R_5”, -

NR₅C(0)R5', -C(0)NR₅R5', -NR₅[CH2]n-NR_5'R5”, substituted or unsubstituted alkyl-heterocyclyl, and substituted or unsubstituted heterocyclyl wherein said heterocyclyl is not piperidine; wherein

R5, R5' or R_5” are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH₂]_n-NR”R’”; wherein

R’, R” and R’” are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted alkyl-heterocyclyl;

R₃ and R_3' are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted haloalkyl; wherein n is 0, 1 or 2;

R₆ is selected from hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; group A is a diamine selected from:

wherein a and b are independently selected from 0, 1 and 2;

R_? and R_7' are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; alternatively, in group A’, R₇ and R_7' taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclyl group; Rs and Rs· are hydrogen; and m is 1 , 2, 3 or 4;

X is selected from a bond, -[C(R4R4')] -, -[C(R4R4')] C(0)[C(R4”R4 )]q-> and -0-, wherein R₄, R_4', R_4” and R₄ are independently selected from hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; p is 0, 1 , 2 or 3; and q is 0, 1 , 2 or 3; and

W is selected from S and O; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

2. Compound according to claim 1 wherein R₂ is as represented in formula (G)

O^’)

3. Compound according to claim 1 or 2 wherein W is -S.

4. Compound according to any one of claims 1 to 3 wherein group is selected from:

5. Compound according to claim 4 wherein group

6. Compound according to claim 5 wherein a and b are independently selected from 1 and 2.

7. Compound according to any one of claims 1 to 6, wherein said compound is selected from:

[1 ] (1 -(4-ethoxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-ethylpiperazin- 1-yl)methanone;

[2] (4-ethylpiperazin-1 -yl)(1 -phenyl-4, 5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)methanone;

[3] (4-ethylpiperazin-1-yl)(2-methyl-4,5-dihydro-2H-thieno[2,3-g]indazol-3- yl)methanone;

[4] (1 -(2,4-difluorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- ethylpiperazin-1 -yl)methanone;

[5] (4-ethylpiperazin-1 -yl)(1 -(6-methoxypyridin-3-yl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[6] (4-ethylpiperazin-1 -yl)(1 -(3-fluorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol- 3-yl)methanone;

[7] (4-methylpiperazin-1 -yl)(1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3-g]indazol-3- yl)methanone;

[8] (1 -(3-aminophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-ethylpiperazin- 1-yl)methanone;

[9] (4-ethylpiperazin-1 -yl)(1 -(3-methoxyphenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[10] (1 -(2-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- ethylpiperazin-1 -yl)methanone;

[11 ] (4-ethylpiperazin-1 -yl)(1 -(3-(4-((methylamino)methyl)-1 H-1 ,2,3-triazol- 1-yl)phenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone; [12] (4-ethylpiperazin-1 -yl)(1 -(3-nitrophenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[13] (4-ethylpiperazin-1 -yl)(1 -(3-hydroxyphenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[14] N-(3-(3-(4-ethylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1 -yl)phenyl)acetamide;

[15] (1 -benzyl-4, 5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin- 1 -yl)methanone;

[16] (1 -(2-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[17] (1 -(2,4-dichlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[18] (4-methylpiperazin-1 -yl)(1 -(2-(trifluoromethyl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[19] (1 -(2-methoxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[20] (1 -(6-methoxypyridin-3-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone

[21 ] (1 -cyclohexyl-4, 5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[22] (1 -(2-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-(2- isopropoxyethyl)piperazin-1 -yl)methanone;

[23] (1 -(2-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- isobutylpiperazin-1 -yl)methanone;

[24] (1 -(2-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- (cyclopropylmethyl)piperazin-1 -yl)methanone;

[25] (1 -(2,4-dichlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- ethylpiperazin-1 -yl)methanone;

[26] (1 -(3,5-dichloropyridin-4-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[27] (4-methylpiperazin-1 -yl)(1 -(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[28] (1 -(4-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[29] (1 -(2-fluorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[30] (1 -(4-methoxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[31 ] (1 -(4-ethoxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[32] (1 -(2,6-dichlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[33] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(6-methoxypyridin-3-yl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone; [34] (1 -(2,3-dichlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[35] (1 -(2,5-dichlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[36] (1 -(6-oxaspiro[4.5]decan-9-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1 -yl)methanone;

[37] 1 -(2-chlorophenyl)-N-(1 -methylpiperidin-4-yl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carboxamide;

[38] (1 -(3,5-dichlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[39] (1 -(4-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- isobutylpiperazin-1 -yl)methanone;

[40] (1 -(4-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- ethylpiperazin-1 -yl)methanone;

[41 ] (1 -(5-chloropyridin-2-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[42] (1 -(4-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- (cyclopropylmethyl)piperazin-1 -yl)methanone;

[43] (1 -(5-chloropyridin-2-yl)-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[44] (1 -isopropyl-4, 5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[45] (1 -(3-chloro-4-fluorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1 -yl)methanone;

[46] (1 -(4-chloro-2-methoxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1 -yl)methanone;

[47] (1 -(2,2-dimethylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[48] (4-methylpiperazin-1 -yl)(1 -(1 -methylpiperidin-4-yl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[49] (1 -(2,4-difluorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[50] 1 -(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1 -yl)piperidin-1 -yl)ethanone;

[51 ] (1 -(2,4-dichlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-

(dimethylamino)piperidin-1 -yl)methanone;

[52] (4-(dimethylamino)piperidin-1 -yl)(1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3- g]indazol-3-yl)methanone;

[53] (1 -(isoquinolin-6-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[54] (1 -(2-bromophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[55] (1 -(3-(5-methyl-1 ,3,4-oxadiazol-2-yl)phenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone; [56] (1 -(2-(benzyloxy)phenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[57] (1 -(2-chloro-4-methoxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1-yl)methanone;

[58] (1 -(3-bromophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[59] (1 -(4-bromophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[60] (1 -(2-(3-(methylamino)-1 -phenylpropoxy)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[61 ] (1 -(4-chloro-2-hydroxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1-yl)methanone;

[62] (1 -(2-chloro-4-hydroxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1-yl)methanone;

[63] (4-methylpiperazin-1 -yl)(1 -(4-nitrophenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[64] (1 -(4-aminophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[65] (1 -(4-(hydroxymethyl)phenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1-yl)methanone;

[66] (1 -(3-(hydroxymethyl)phenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1-yl)methanone;

[67] (1 -(4-bromophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methyl- 1 ,4-diazepan-1-yl)methanone;

[68] (1 -(4-bromophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(3- methylimidazolidin-1-yl)methanone;

[69] (1 -(1 -benzylpiperidin-4-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[70] 1 -(4-(3-(4-isobutylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1 -yl)piperidin-1 -yl)ethanone;

[71] 1-(4-(3-(4-isopentylpiperazine-1-carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1 -yl)piperidin-1 -yl)ethanone;

[72] (1 -(1 -benzylpiperidin-4-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- ethylpiperazin-1 -yl)methanone;

[73] (1 -(5-chloropyridin-2-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- (cyclopropylmethyl)piperazin-1-yl)methanone;

[74] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(tetrahydro-2H-pyran-4-yl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[75] 1 -(4-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)piperidin-1 -yl)ethanone;

[76] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(4-(hydroxymethyl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[77] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(3-(hydroxymethyl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone; [78] N-(4-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)acetamide;

[79] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(tetrahydrofuran-3-yl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[80] (1 -(6-oxaspiro[4.5]decan-9-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-(cyclopropylmethyl)piperazin-1-yl)methanone;

[81 ] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(5-fluoropyridin-2-yl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[82] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(2,2-dimethyltetrahydro-2H- pyran-4-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[83] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(3,4-dichlorophenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[84] (3,7-dimethyl-3,7,11-triazaspiro[5.6]dodecan-11-yl)(1 -phenyl-4, 5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[85] (4-isopentylpiperazin-1 -yl)(1 -(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[86] (1 -(4-(hydroxymethyl)phenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-isopentylpiperazin-1-yl)methanone;

[87] (4-methylpiperazin-1 -yl)(1 -(6-(trifluoromethyl)pyridin-2-yl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)methanone;

[88] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(6-(trifluoromethyl)pyridin-2-yl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[89] (4-isopentylpiperazin-1 -yl)(1 -(6-(trifluoromethyl)pyridin-2-yl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[90] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(3-nitrophenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[91 ] (4-methylpiperazin-1 -yl)(1 -(3-nitrophenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[92] N-(4-(3-(4-isopentylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1-yl)phenyl)acetamide;

[93] N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1-yl)phenyl)acetamide;

[94] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(4-nitrophenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[95] (1 -(3-aminophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[96] N-(3-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1-yl)phenyl)acetamide;

[97] (1 -(3-aminophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- (cyclopropylmethyl)piperazin-1-yl)methanone;

[98] N-(3-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)acetamide;

[99] N-methyl-4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)benzamide; [100] 4-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)benzonitrile;

[101 ] 4-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)benzamide;

[102] N-(4-(3-(4,6-dimethyl-1 ,4-diazepane-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)phenyl)acetamide;

[103] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -((tetrahydro-2H-pyran-4- yl)methyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[104] 3-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)benzonitrile;

[105] 2-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)benzonitrile;

[106] (S)-(3-(dimethylamino)piperidin-1 -yl)(1 -phenyl-4, 5-dihydro- 1 H- thieno[2,3-g]indazol-3-yl)methanone;

[107] 6-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1 -yl)picolinonitrile;

[108] 6-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)picolinonitrile;

[109] (1 -(4-aminophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- isopentylpiperazin-1 -yl)methanone;

[1 10] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(3,4-difluorophenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[1 1 1 ] (S)-N-(4-(3-(3-aminopiperidine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1 -yl)phenyl)acetamide;

[1 12] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -((2,2-dimethyltetrahydro-2H- pyran-4-yl)methyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[1 13] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(6-(trifluoromethyl)pyridin-3-yl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[1 14] N-(4-(3-((3R,4S)-3-(dimethylamino)-4-phenylpyrrolidine-1 -carbonyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)phenyl)acetamide;

[1 15] 3-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1 -yl)benzonitrile;

[1 16] 3-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)-5-fluorobenzamide;

[1 17] (4-methylpiperazin-1 -yl)(1 -(piperidin-4-yl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[1 18] (4-isobutylpiperazin-1 -yl)(1 -(pi pe ri d i n-4-y I )-4 , 5-d i hy d ro- 1 H-thieno[2,3- g]indazol-3-yl)methanone;

[1 19] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -(piperidin-4-yl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[120] (4-isopentylpiperazin-1 -yl)(1 -(piperidin-4-yl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[121 ] (4-methylpiperazin-1 -yl)(1 -(1 -phenethylpiperidin-4-yl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone; [122] (4-ethylpiperazin-1 -yl)(1 -(1 -phenethylpiperidin-4-yl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[123] (4-aminopiperidin-1 -yl)(1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3-g]indazol-3- yl)methanone;

[124] (1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(piperazin-1 - yl)methanone;

[125] (1 -(3-fluorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(piperazin- 1-yl)methanone;

[126] (1 -(2-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(piperazin- 1-yl)methanone;

[127] (1 -(6-methoxypyridin-3-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(piperazin-1 -yl)methanone;

[128] (1 -(4-ethoxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(piperazin-1 -yl)methanone;

[129] 1 -(2-chlorophenyl)-N-(piperidin-4-yl)-4,5-dihydro-1 H-thieno[2,3- g]indazole-3-carboxamide;

[130] (4-aminopiperidin-1 -yl)(1 -(2,4-dichlorophenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[131] (4-(methylamino)piperidin-1 -yl)(1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3- g]indazol-3-yl)methanone;

[132] (1 -(2,4-dichlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- (methylamino)piperidin-1-yl)methanone;

[133] (S)-(3-aminopiperidin-1 -yl)(1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3- g]indazol-3-yl)methanone;

[134] N-(2-aminoethyl)-1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3-g]indazole-3- carboxamide;

[135] N-(2-(dimethylamino)ethyl)-1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3- g]indazole-3-carboxamide;

[136] N-methyl-N-(2-(methylamino)ethyl)-1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3- g]indazole-3-carboxamide;

[137] N-(2-(methylamino)ethyl)-1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3- g]indazole-3-carboxamide;

[138] N-(2-aminoethyl)-N-methyl-1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3- g]indazole-3-carboxamide;

[139] N-benzyl-N-(2-(methylamino)ethyl)-1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3- g]indazole-3-carboxamide;

[140] (4-ethylpiperazin-1 -yl)(1 -phenyl-4, 5-dihydro-1 H-furo[2,3-g]indazol-3- yl)methanone;

[141] (1 -(4-amino-2-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1-yl)methanone;

[142] (1 -(4-amino-2-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-(cyclopropylmethyl)piperazin-1-yl)methanone;

[143] (1 -(4-amino-2-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-isopentylpiperazin-1-yl)methanone; [144] N-(3-chloro-4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)acetamide;

[145] N-(3-chloro-4-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1 -yl)phenyl)acetamide;

[146] N-(3-chloro-4-(3-(4-isopentylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)acetamide;

[147] N-(3-methyl-4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)acetamide;

[148] N-acetyl-N-(4-(3-(4-isopentylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)acetamide;

[149] N-acetyl-N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)acetamide;

[150] 1 -methyl-N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)phenyl)-1 H-pyrazole-3-carboxamide;

[151 ] N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1-yl)phenyl)-2-morpholinoacetamide;

[152] N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1-yl)phenyl)benzo[d]thiazole-2-carboxamide;

[153] N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1-yl)phenyl)benzamide;

[154] 4-chloro-N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)benzamide;

[155] 2-methyl-N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)-1 ,2,3,4-tetrahydroisoquinoline-3- carboxamide;

[156] 2-(benzylamino)-N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-1 -yl)phenyl)acetamide;

[157] 2-(benzyl(methyl)amino)-N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1 -yl)phenyl)acetamide;

[158] 2-(dimethylamino)-N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1 -yl)phenyl)acetamide;

[159] N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1 -yl)phenyl)-2-(piperidin-1 -yl)acetamide;

[160] 2-(benzylamino)-N-(4-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)phenyl)acetamide;

[161] 2-(4-methylpiperazin-1 -yl)-N-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1 -yl)phenyl)acetamide;

[162] 2-(1 H-imidazol-1-yl)-N-(4-(3-(4-methylpiperazine-1-carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1 -yl)phenyl)acetamide;

[163] N-methyl-N-(2-(methylamino)ethyl)-4-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)benzamide;

[164] N-(2-(benzyl(methyl)amino)ethyl)-N-methyl-4-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)benzamide;

[165] N-(2-(benzyl(methyl)amino)ethyl)-4-(3-(4-methylpiperazine-1 -carbonyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)benzamide; [166] N-(2-(dibenzylamino)ethyl)-4-(3-(4-methylpiperazine-1 -carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1 -yl)benzamide;

[167] (4-ethylpiperazin-1 -yl)(1 -(4-(2-morpholinoethoxy)phenyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)methanone;

[168] (4-methylpiperazin-1 -yl)(1 -(4-(2-morpholinoethoxy)phenyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)methanone;

[169] (1 -(4-(methyl(2-(methylamino)ethyl)amino)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[170] N-ethyl-N-((1 -phenethylpiperidin-3-yl)methyl)-1 -phenyl-4, 5-dihydro-1 H- thieno[2,3-g]indazole-3-carboxamide;

[171] (3-(methyl(phenethyl)amino)piperidin-1 -yl)(1 -phenyl-4, 5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[172] N-methyl-N-((1 -phenethylpiperidin-3-yl)methyl)-1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3-g]indazole-3-carboxamide;

[173] N-(4-(7-bromo-3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)acetamide;

[174] (4-methylpiperazin-1 -yl)(1 -(2-morpholinoethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[175] (4-ethylpiperazin-1 -yl)(1 -(2-morpholinoethyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[176] ((4-methylpiperazin-1 -yl)(1 -(2-(piperidin-1 -yl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[177] (4-ethylpiperazin-1 -yl)(1 -(2-(piperidin-1 -yl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone;

[178] 1 -(4,6-dimethyl-1 ,4-diazepan-1 -yl)-2-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)ethanone;

[179] 6-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)isobenzofuran-1 (3H)-one;

[180] (1 -(benzo[c][1 ,2,5]oxadiazol-5-yl)-4,5-dihydro-1 H-thieno[2,3-g]indazol- 3-yl)(4-(cyclopropylmethyl)piperazin-1-yl)methanone;

[181] (1 -(4-(Methylamino)phenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone;

[182] 3-(3-(4-(cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)-5-fluorobenzonitrile; and

[183] 3-(3-(4-(2-Methoxyethyl)piperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)benzonitrile.

8. Process for the preparation of a compound of formula (I) according to claim 1 : wherein R1, R₂, R₃, R_3', R₆, W, X, n and A have the same meaning as indicated in any one of claims 1 to 7, said process comprising treating a compound of formula (VII)

with a compound of formula (V):

wherein

Ri, R₂, R₃, R_3', R₆, W, X, n and A have the same meaning as indicated in any one of claims 1 to 7; and Z is selected from O-alkyl, OH, Cl, N(OMe)Me and H.

9. Process according to claim 8, wherein Z is OH or Cl.

10. Process for the preparation of a compound of formula (I) according to claim 1 :

wherein Ri, R₂, R3, R3', R₆, W, X, n and A have the same meaning as indicated in any one of claims 1 to 7, said process comprising: a) treating a compound of formula (VII)

with a compound of formula (VIII):

wherein

Ri, R₂, R₃, R_3', R₆, W, X, n and A have the same meaning as indicated in any one of claims 1 to 9; and Z is OH or O-alkyl; and b) treating the compound obtained in step a) with a compound of formula XI

R₂ G

(XI) wherein R₂ have the same meaning as indicated in any one of claims 1 to 9; and G is B(OH)₂ or a leaving group.

1 1 . Use of a compound selected from

wherein R₂ and R₆ have the same meaning as indicated in any one of claims 1 to 7 and Z is O-alkyl, OH, H or Cl for the manufacture of a compound according to claim 1 .

12. A pharmaceutical composition which comprises a compound of formula (I) as defined in any of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

13. A compound as defined in any of claims 1 to 7 or a pharmaceutical salt thereof for use in therapy.

14. A compound as defined in any of claims 1 to 7 or a pharmaceutical salt thereof for use in the treatment or prophylaxis of pain, specially medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia.

Description:

FUSED DIHYDROINDAZOLE DERIVATIVES HAVING MULTIMODAL ACTIVITY AGAINST PAIN

FIELD OF THE INVENTION

The present invention relates to compounds having pharmacological activity towards the a ₂d subunit of the voltage-gated calcium channel. In particular, the present invention also relates to compounds having dual pharmacological activity towards both the a ₂d subunit of the voltage-gated calcium channel, and the sigma-1 (s1 ) receptor. More particularly, the present invention relates to fused dihydroindazole derivatives having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

BACKGROUND OF THE INVENTION

The adequate management of pain constitutes an important challenge, since currently available treatments provide in many cases only modest improvements, leaving many patients unrelieved (Turk DC, Wilson HD, Cahana A. Lancet, 201 1 , 377, 2226-2235). Pain affects a big portion of the population with an estimated prevalence of 20 % and its incidence, particularly in the case of chronic pain, is increasing due to the population ageing. Additionally, pain is clearly related to comorbidities, such as depression, anxiety and insomnia, which leads to important productivity losses and socio- economical burden (Goldberg DS, McGee SJ, BMC Public Health, 201 1 , 11, 770). Existing pain therapies include non-steroidal anti-inflammatory drugs (NSAIDs), opioid agonists, calcium channel blockers and antidepressants, but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of secondary effects that preclude their use, especially in chronic settings.

Voltage-gated calcium channels (VGCC) are required for many key functions in the body. Different subtypes of voltage-gated calcium channels have been described (Zamponi et a I . , Pharmacol Rev. 2015, 67, 821 -70). The VGCC are assembled through interactions of different subunits, namely oti (Ca _voti), b (Ca _vp) a ₂d (Ca _va ₂3) and g (Ca _vy). The o i subunits are the key porous forming units of the channel complex, being responsible for the Ca ²⁺ conduction and generation of Ca ²⁺ influx. The a ₂d, b, and g subunits are auxiliary, although very important for the regulation of the channel, since they increase the expression of the oti subunits in the plasma membrane as well as modulate their function, resulting in functional diversity in different cell types. Based on their physiological and pharmacological properties, VGCC can be subdivided into low voltage-activated T-type (Ca _v3.1 , Ca _v3.2, and Ca _v3.3), and high voltage-activated L- (Ca _v1 .1 through Ca _v1 .4), N-(Ca _v2.2), P/Q-(Ca _v2.1 ), and R-(Ca _v2.3) types, depending on the channel forming Cava subunits. All of these five subclasses are found in the central and peripheral nervous systems. Regulation of intracellular calcium through activation of these VGCC plays obligatory roles in: 1 ) neurotransmitter release, 2) membrane depolarization and hyperpolarization, 3) enzyme activation and inactivation, and 4) gene regulation (Perret and Luo, Neurotherapeutics. 2009, 6, 679-92; Zamponi et al., 2015 supra ; Neumaier et al., Prog Neurobiol. 2015, 129, 1 -36). A large body of data has clearly indicated that VGCC are implicated in mediating various disease states including pain processing. Drugs interacting with the different calcium channel subtypes and subunits have been developed. Current therapeutic agents include drugs targeting L-type Ca _v1 .2 calcium channels, particularly 1 ,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca _v3) channels are the target of ethosuximide, widely used in absence epilepsy. Ziconotide, a peptide blocker of N-type (Ca _v2.2) calcium channels, has been approved as a treatment of intractable pain (Perret and Luo, 2009, supra, Vink and Alewood, Br J Pharmacol. 2012, 167, 970-89).

The Ca _v1 and Ca _v2 subfamilies contain an auxiliary a d subunit, which is the therapeutic target of the gabapentinoid drugs of value in certain epilepsies and chronic neuropathic pain. To date, there are four known a d subunits, each encoded by a unique gene and all possessing splice variants. Each a d protein is encoded by a single messenger RNA and is posttranslationally cleaved and then linked by disulfide bonds. Four genes encoding a2d subunits have now been cloned. a ₂d-1 was initially cloned from skeletal muscle and shows a fairly ubiquitous distribution. The a ₂d-2 and a ₂d-3 subunits were subsequently cloned from brain. The most recently identified subunit, a ₂d-4, is largely nonneuronal. The human a ₂d-4 protein sequence shares 30, 32 and 61 % identity with the human a ₂d-1 , a ₂d-2 and a ₂d-3 subunits, respectively. The gene structure of all a ₂d subunits is similar. All a ₂d subunits show several splice variants (Davies et al., Trends Pharmacol Sci. 2007, 28, 220-8.; Dolphin AC, Nat Rev Neurosci. 2012, 13, 542-55, Biochim Biophys Acta. 2013, 1828, 1541 -9). The Ca _vot ₂5-1 subunit may play an important role in neuropathic pain development (Perret and Luo, 2009, supra ; Vink and Alewood, 2012, supra). Biochemical data have indicated a significant Ca _vot ₂5-1 , but not Ca _vot ₂5-2, subunit upregulation in the spinal dorsal horn, and DRG (dorsal root ganglia) after nerve injury that correlates with neuropathic pain development. In addition, blocking axonal transport of injury-induced DRG Ca _vot ₂5-1 subunit to the central presynaptic terminals diminishes tactile allodynia in nerve injured animals, suggesting that elevated DRG Ca _vot ₂5-1 subunit contributes to neuropathic allodynia.

The Ca _vot ₂5-1 subunit (and the Ca _vot ₂5-2, but not Ca _vot ₂5-3 and Ca _vot ₂5-4, subunits) is the binding site for gabapentin which has anti-allodynic/ hyperalgesic properties in patients and animal models. Because injury-induced Ca _vot ₂5-1 expression correlates with neuropathic pain development and maintenance, and various calcium channels are known to contribute to spinal synaptic neurotransmission and DRG neuron excitability, injury-induced Ca _vot ₂5-1 subunit upregulation may contribute to the initiation and maintenance of neuropathic pain by altering the properties and/or distribution of VGCC in the subpopulation of DRG neurons and their central terminals, therefore modulating excitability and/or synaptic neuroplasticity in the dorsal horn. Intrathecal antisense oligonucleotides against the Ca _vot ₂5-1 subunit can block nerve injury-induced Ca _vot ₂5-1 upregulation and prevent the onset of allodynia and reserve established allodynia.

As mentioned above, the 0, ₂6 subunits of VGCC form the binding site for gabapentin and pregabalin, which are structural derivatives of the inhibitory neurotransmitter GABA although they do not bind to GABAA, GABAB, or benzodiazepine receptors, or alter GABA regulation in animal brain preparations. The binding of gabapentin and pregabalin to the Ca _vot ₂5 subunit results in a reduction in the calcium-dependent release of multiple neurotransmitters, leading to efficacy and tolerability for neuropathic pain management. Gabapentinoids may also reduce excitability by inhibiting synaptogenesis (Perret and Luo, 2009, supra, Vink and Alewood, 2012, supra, Zamponi et al., 2015, supra).

The sigma-1 (s1 ) receptor was discovered 40 years ago and initially assigned to a new subtype of the opioid family. This receptor is expressed both in the endoplasmic reticulum and in the plasma membrane and plays an important role in the regulation of intracellular calcium concentration. A signaling pathway associated with the activation of the s1 receptor has not been described, although it is believed that it has an amplification function of activation of intracellular cascades. In this sense, the s1 receptor regulates and modulates the activity of numerous voltage-dependent ion channels, including Ca2+-, K+-, Na+, CI-, SK, and NMDA channels and the IP3 receptor.

It is also known that the s1 receptor is linked to analgesia, since s1 receptor agonists counteract opioid receptor mediated analgesia, while s1 receptor antagonists, such as haloperidol, potentiated it (Chien CC, Pasternak GW. Neurosci. Lett. 1995, 190, 137- 9).

Many additional preclinical evidences have indicated a clear role of the s1 receptor in the treatment of pain (Zamanillo D, Romero L, Merlos M, Vela JM. Eur. J. Pharmacol, 2013, 716, 78-93). The development of the s1 receptor knockout mice, which show no obvious phenotype and perceive normally sensory stimuli, was a key milestone in this endeavour. In physiological conditions the responses of the s1 receptor knockout mice to mechanical and thermal stimuli were found to be undistinguishable from WT ones but they were shown to possess a much higher resistance to develop pain behaviours than WT mice when hypersensitivity entered into play. Hence, in the s1 receptor knockout mice, capsaicin did not induce mechanical hypersensitivity, both phases of formalin-induced pain were reduced, and cold and mechanical hypersensitivity were strongly attenuated after partial sciatic nerve ligation or after treatment with paclitaxel, which are models of neuropathic pain. Many of these actions were confirmed by the use of s1 receptor antagonists and led to the advancement of one compound, S1 RA, into clinical trials for the treatment of different pain states. Compound S1 RA exerted a substantial reduction of neuropathic pain and anhedonic state following nerve injury (i.e., neuropathic pain conditions) and, as demonstrated in an operant self- administration model, the nerve-injured mice, but not sham-operated mice, acquired the operant responding to obtain it (presumably to get pain relief), indicating that s1 receptor antagonism relieves neuropathic pain and also address some of the comorbidities (i.e., anhedonia, a core symptom in depression) related to pain states (Romero et al. BrJ Pharmacol. 2012, 166, 2289-306). Polypharmacology is a phenomenon in which a drug binds multiple rather than a single target with significant affinity. The effect of polypharmacology on therapy can be positive (effective therapy) and/or negative (side effects). Positive and/or negative effects can be caused by binding to the same or different subsets of targets; binding to some targets may have no effect. Multi-component drugs or multi-targeting drugs can overcome toxicity and other side effects associated with high doses of single drugs by countering biological compensation, allowing reduced dosage of each compound or accessing context-specific multitarget mechanisms. Because multitarget mechanisms require their targets to be available for coordinated action, one would expect synergies to occur in a narrower range of cellular phenotypes given differential expression of the drug targets than would the activities of single agents. In fact, it has been experimentally demonstrated that synergistic drug combinations are generally more specific to particular cellular contexts than are single agent activities, such selectivity is achieved through differential expression of the drugs’ targets in cell types associated with therapeutic, but not toxic, effects (Lehar et al., Nat Biotechnol. 2009, 27, 659-666).

In the case of chronic pain, which is a multifactorial disease, multi-targeting drugs may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive pain. Because they actually make use of biological complexity, multi-targeting (or multi-component drugs) approaches are among the most promising avenues toward treating multifactorial diseases such as pain (Gilron et al., Lancet Neurol. 2013, 12, 1084-95). In fact, positive synergistic interaction for several compounds, including analgesics, has been described (Schroder et al., J Pharmacol Exp Ther. 201 1 , 337, 312-20. Erratum in: J Pharmacol Exp Ther. 2012, 342, 232; Zhang et al., Cell Death Dis. 2014, 5:e1 138; Gilron et al., 2013, supra).

Given the significant differences in pharmacokinetics, metabolisms and bioavailability, reformulation of drug combinations (multi-component drugs) is challenging. Further, two drugs that are generally safe when dosed individually cannot be assumed to be safe in combination. In addition to the possibility of adverse drug-drug interactions, if the theory of network pharmacology indicates that an effect on phenotype may derive from hitting multiple targets, then that combined phenotypic perturbation may be efficacious or deleterious. The major challenge to both drug combination strategies is the regulatory requirement for each individual drug to be shown to be safe as an individual agent and in combination (Hopkins et al, Nat Chem Biol. 2008, 4, 682-90). An alternative strategy for multitarget therapy is to design a single compound with selective polypharmacology (multi-targeting drug). It has been shown that many approved drugs act on multiple targets. Dosing with a single compound may have advantages over a drug combination in terms of equitable pharmacokinetics and biodistribution. Indeed, troughs in drug exposure due to incompatible pharmacokinetics between components of a combination therapy may create a low-dose window of opportunity where a reduced selection pressure can lead to drug resistance. In terms of drug registration, approval of a single compound acting on multiple targets faces significantly lower regulatory barriers than approval of a combination of new drugs (Hopkins, 2008, supra).

Thus, the present application, also relates to the advantages of having dual activity, for the a ₂d-1 subunit of voltage-gated calcium channels and the s1 receptor, in the same molecule to treat chronic pain.

Pain is multimodal in nature, since in nearly all pain states several mediators, signaling pathways and molecular mechanisms are implicated. Consequently, monomodal therapies can be complemented with a dual mechanism of action to provide complete pain relief. Currently, combining existing therapies is a common clinical practice and many efforts are directed to assess the best combination of available drugs in clinical studies (Mao J, Gold MS, Backonja M. J. Pain, 201 1 , 12, 157-166).

Accordingly, there is still a need to find compounds that have an alternative or improved pharmacological activity in the treatment of pain, being both effective and showing the desired selectivity, and having good“drugability” properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion.

The inventors have found a serie of compounds that show a primary pharmacological activity towards the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel, and compounds that show dual pharmacological activity towards both the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel and the s1 receptor resulting in an innovative, effective, complementary and alternative solution for the treatment of pain.

In view of the existing results of the currently available therapies and clinical practices, the present invention offers a solution by developing compounds binding to a single target or by combining in a single compound binding to two different targets relevant for the treatment of pain. This was mainly achieved by providing the compounds according to the invention that bind to the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel, or both to the s1 receptor and to the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel. SUMMARY OF THE INVENTION

The inventors have found a series of compounds, encompassed by formula (I), that show pharmacological activity towards the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel. Also, the inventors have found that some of these compounds have a dual pharmacological activity towards both the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel and the s1 receptor, thus solving the above problem of identifying alternative or improved pain treatments by offering such compounds.

The main object of the invention is directed to a compound having binding capacicy to the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel. This compound can be used in the treatment of pain.

Another object of the invention is directed to a compound having a dual activity binding to the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel and the sΐ receptor. This compound can be used in the treatment of pain.

The invention is directed in a main aspect to a compound of formula (I),

wherein Ri, R ₂, R ₃, R _3', R ₆, X, A, n and W are as defined below in the detailed description. A further aspect of the invention refers to the processes for preparation of compounds of formula (I).

A still further aspect of the invention refers to the use of intermediate compounds for the preparation of a compound of formula (I).

It is also an aspect of the invention a pharmaceutical composition comprising a compound of formula (I).

Finally, it is an aspect of the invention a compound of formula (I) for use in therapy and more particularly for the treatment of pain and pain related conditions.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a family of compounds, in particular, to fused dihydroindazole derivatives which show primary pharmacological activity towards the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel. The invention also refers to compounds having a dual pharmacological activity towards both the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel and the s1 receptor and to their use in the treatment of pain and related disorders. The applicant has surprisingly found that the problem of providing a new effective and alternative solution for treating pain and pain related disorders can be solved by using an analgesic approach using binding to the a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel or a multimodal analgesic approach combining two activities in a single drug (i.e., dual ligands which are bifunctional and bind to s1 receptor and to a ₂d subunit, in particular the a ₂d-1 subunit, of the voltage-gated calcium channel).

As described above, the s1 receptor as well as the a2d1 subunit modulate intracellular calcium concentration and the activity of voltage-dependent calcium channels. There is also a robust clinical and pre-clinical evidence linking both targets with the treatment of chronic neuropathic pain. Thus, the present invention, also relates to the advantages of having dual activity, for the a ₂d-1 subunit of voltage-gated calcium channels and the s1 receptor, in the same molecule to treat pain, i.e. binding to two different targets relevant for the treatment of pain. A dual compound that possess binding to both the s1 receptor and to the a ₂d subunit of the voltage-gated calcium channel shows a highly valuable therapeutic potential by achieving an outstanding analgesia.

A further advantage of using designed multiple ligands is a lower risk of drug-drug interactions compared to cocktails or multi-component drugs, thus involving simpler pharmacokinetics and less variability among patients. Additionally, this approach may improve patient compliance and broaden the therapeutic application in relation to monomechanistic drugs, by addressing more complex aetiologies.

In a first aspect, the present invention is directed to a compound of formula (I):

wherein Ri is selected from hydrogen, halogen, substituted or unsubstituted Ci- ₆ alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted alkyl-heterocyclyl; R _{2 IS} selected from substituted or unsubstituted C _2-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl- heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; and [Chhln -C(0)-Rs; wherein when the cycloalkyl group is substituted, the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl; substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, -OR ₅, -C(O), -C(0)Rs, -NO ₂, -CN, - NR ₅C(0)-[CH ₂]n-NR _5'R _5”, -C(0)NR ₅-[CH ₂]n-NR _5'R _5”, -NR ₅C(0)R ₅·, -C(0)NR ₅R ₅·, and -NR ₅[CH ₂]n-NR _5'R _5”; when the heterocyclyl group is substituted, the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted alkyl-heterocyclyl, -ORs, -C(O), -C(0)Rs, -NO2, -CN, -NR ₅C(0)- [CH ₂] _n-NR ₅ R _5”, -C(0)NR ₅-[CH ₂] _n-NR _5'R _5”, -NR ₅C(0)R ₅·, -C(0)NR ₅R ₅·, and - NR ₅[CH ₂] _n-NR ₅ R _5”, when the aryl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, OR5, N0 ₂, NR5R5', alkyl-aryl, CN, -NR ₅C(0)-[CH ₂] _n-NR ₅ R _5”, -C(0)NR ₅-[CH ₂] _n-NR ₅ R _5”, -

NR ₅C(0)R5', -C(0)NR ₅R5', -NR ₅[CH ₂]n-NR5'R5”, substituted or unsubstituted alkyl-heterocyclyl, and substituted or unsubstituted heterocyclyl wherein said heterocyclyl is not piperidine; more particularly, said heterocyclyl is an aromatic heterocycyl; wherein

R5, R5' or R _5” are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH ₂] _n-NR”R’”; wherein

R’, R” and R’” are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, and substituted or unsubstituted C _2-6 alkynyl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted alkyl- heterocyclyl;

R3 and R3' are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted haloalkyl; wherein n is 0, 1 or 2; R ₆ is selected from hydrogen, halogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl;group A is a diamine selected from

wherein a and b are independently selected from 0, 1 and 2;

R _? and R _7' are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; alternatively, in group A’, R ₇ and R ₇· taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclyl group; Rs and Rs· are hydrogen; and m is 1 , 2, 3 or 4; preferably m is 2;

X is selected from a bond, -[C(R4R4')] -, -[C(R4R4')] C(0)[C(R4”R4 )]q-> and -0-, wherein

R ₄, R _4', R _4” and R _4” are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; p is 0, 1 , 2 or 3; and q is 0, 1 , 2 or 3; and

The compounds of the invention represented by the above described formula (I) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds. The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.

In another embodiment, these compounds according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt or solvate thereof.

For the sake of clarity the expression“a compound according to formula (I), wherein wherein Ri, R ₂, R ₃, R _3', R ₆, X, A, n and W are as defined herein in the detailed description” would (just like the expression“a compound of formula (I) as defined in any one of claims 1 to 7 found in the claims) refer to“a compound according to formula (I)”, wherein the definitions of the respective substituents R ₁ etc. (also from the cited claims) are applied.

For clarity purposes, all groups and definitions described in the present description and referring to compounds of formula (I), also apply to all intermediates of synthesis.

In the context of this invention, alkyl is understood as meaning a straight or branched hydrocarbon chain radical containing no unsaturation, and which is attached to the rest of the molecule by a single bond. It may be unsubstituted or substituted once or several times. It encompasses e.g. -CH ₃ and -CH ₂-CH ₃. In these radicals, Ci- ₂-alkyl represents C1 - or C2-alkyl, Ci-3-alkyl represents C1 -, C2- or C3-alkyl, Ci- ₄-alkyl represents C1 -, C2-, C3- or C4-alkyl, Ci-s-alkyl represents C1 -, C2-, C3-, C4-, or C5-alkyl and Ci- ₆-alkyl represents C1 -, C2-, C3-, C4-, C5- or C6-alkyl. Examples of alkyl radicals include among others methyl, ethyl, propyl, methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1 ,1 -dimethylethyl, pentyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1 -methylpentyl. If substituted by cycloalkyl, it corresponds to a“cycloalkylalkyl” radical, such as cyclopropylmethyl. If substituted by aryl, it corresponds to an "arylalkyl" radical, such as benzyl, benzhydryl or phenethyl. If substituted by heterocyclyl, it corresponds to a “heterocyclylalkyl” radical. Preferably alkyl is understood in the context of this invention Ci- ₆-alkyl like methyl, ethyl, propyl, butyl, pentyl, or hexyl; and more preferably is Ci _-4-alkyl like methyl, ethyl, propyl or butyl.

Alkenyl is understood as meaning straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one unsaturation, and which is attached to the rest of the molecule by a single bond. It may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -CH=CH-CH ₃. The alkenyl radicals are preferably vinyl (ethenyl), allyl (2-propenyl). Preferably in the context of this invention alkenyl is C2-6-alkenyl like ethylene, propylene, butylene, pentylene, or hexylene; or is C2- ₄-alkenyl, like ethylene, propylene, or butylenes.

Alkynyl is understood as meaning a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one carbon-carbon triple bond, and which is attached to the rest of the molecule by a single bond. It may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -C^C-CHs (1 - propynyl). Preferably alkynyl in the context of this invention is C2-6-alkynyl like ethyne, propyne, butyene, pentyne, or hexyne; or is C2- ₄-alkynyl like ethyne, propyne or butyene.

In connection with alkyl (also in aryl-alkyl, alkyl-heterocyclyl or alkyl-cycloalkyl, alkyl- aryl), alkenyl, alkynyl and O-alkyl - unless defined otherwise - the term substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical on a carbon atom by halogen, -OR’, -SR’, -SOR’, -SO2R’, -OR’, -CN, -COR’, -COOR’, -NR’R”, -CONR’R”, haloalkyl, haloalkoxy or -OC1-6 alkyl wherein each of the R’ and R” groups is independently selected from the group consisting of hydrogen, OH, NO2, NH2, SH, CN, halogen, -COH, -COalkyl, -COOH and C1-6 alkyl. In a particular embodiment of the invention, the alkyl, alkenyl or alkynyl as defined in Ri-Rir if substituted, is substituted with one or more substituent/s selected from -OR’, halogen, -CN, haloalkyl, haloalkoxy and -NR’R”; wherein R, R’ and R” are independently selected from hydrogen, unsubstituted Ci- ₆ alkyl, unsubstituted C2-6 alkenyl, and unsubstituted C2-6 alkynyl;

More than one replacement on the same molecule and also on the same carbon atom is possible with the same or different substituents. This includes for example 3 hydrogens being replaced on the same C atom, as in the case of CF ₃, or at different places of the same molecule, as in the case of e.g. -CH(OH)-CH=CH-CHCl2.

In the context of this invention haloalkyl is understood as meaning an alkyl being substituted once or several times by a halogen (selected from F, Cl, Br, I). It encompasses e.g. -CH2CI, -CH2F, -CHC , -CHF2, -CCI3, -CF3 and -CH2-CHCI2. Preferably haloalkyl is understood in the context of this invention as halogen- substituted Ci-4-alkyl representing halogen substituted C1-, C2-, C3- or C4-alkyl. The halogen-substituted alkyl radicals are thus preferably methyl, ethyl, propyl, and butyl. Preferred examples include -CH ₂CI, -CH ₂F, -CH ₂-CH ₂F, -CH ₂-CHF ₂, -CHCb, -CHF ₂, and -CF3.

In the context of this invention haloalkoxy is understood as meaning an -O-alkyl being substituted once or several times by a halogen (selected from F, Cl, Br, I). It encompasses e.g. -OCH2CI, -OCH2F, -OCHC , -OCHF2, -OCCI3, -OCF3 and - OCH2-CHCI2. Preferably haloalkoxy is understood in the context of this invention as halogen-substituted -OCi-4-alkyl representing halogen substituted C1-, C2-, C3- or C4- alkoxy. The halogen-substituted O-alkyl radicals are thus preferably O-methyl, O-ethyl, O-propyl, and O-butyl. Preferred examples include -OCH2CI, -OCH2F, -OCHCb, - OCHF2, and -OCF3.

In the context of this invention cycloalkyl is understood as meaning saturated and unsaturated (but not aromatic) cyclic hydrocarbons (without a heteroatom in the ring), which can be unsubstituted or once or several times substituted. Preferred cycloalkyls are C3-4-cycloalkyl representing C3- or C4-cycloalkyl, C3-5-cycloalkyl representing C3-, C4- or C5-cycloalkyl, C3-6-cycloalkyl representing C3-, C4-, C5- or C6-cycloalkyl, C3-7- cycloalkyl representing C3-, C4-, C5-, C6- or C7-cycloalkyl, C3-8-cycloalkyl representing C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C4-5-cycloalkyl representing C4- or C5- cycloalkyl, C _4-6-cycloalkyl representing C4-, C5- or C6-cycloalkyl, C _4-7-cycloalkyl representing C4-, C5-, C6- or C7-cycloalkyl, C5-6-cycloalkyl representing C5- or C6- cycloalkyl and Cs-7-cycloalkyl representing C5-, C6- or C7-cycloalkyl. Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl. Preferably in the context of this invention cycloalkyl is C3-8-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or is C3-7-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or is C3-6-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclopentyl or cyclohexyl.

Aryl is understood as meaning 6 to 18 membered mono or polycyclic ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, 9H- fluorenyl or anthracenyl radicals, which can be unsubstituted or once or several times substituted. Most preferably aryl is understood in the context of this invention as phenyl, naphthyl or anthracenyl, more preferably the aryl is phenyl.

A heterocyclyl radical or group (also called heterocyclyl hereinafter) is understood as meaning 5 to 18 membered mono or polycyclic heterocyclic ring systems, with at least one saturated or unsaturated ring which contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. A heterocyclic group can also be substituted once or several times.

Examples include non-aromatic heterocyclyls such as tetrahyd ropy ran, oxazepane, morpholine, piperidine, pyrrolidine as well as heteroaryls such as furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, thiazole, benzothiazole, indole, benzotriazole, carbazole and quinazoline.

Subgroups inside the heterocyclyls as understood herein include heteroaryls and non- aromatic heterocyclyls.

the heteroaryl (being equivalent to heteroaromatic radicals or aromatic heterocyclyls) is an aromatic 5 to 18 membered mono or polycyclic heterocyclic ring system of one or more rings of which at least one aromatic ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a 5 to 18 membered mono or polycyclic aromatic heterocyclic ring system of one or two rings of which at least one aromatic ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably it is selected from furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzothiazole, indole, benzotriazole, carbazole, quinazoline, thiazole, imidazole, pyrazole, oxazole, thiophene and benzimidazole;

the non-aromatic heterocyclyl is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or more rings of which at least one ring - with this (or these) ring(s) then not being aromatic - contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably it is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two rings of which one or both rings - with this one or two rings then not being aromatic - contain/s one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably it is selected from oxazepam, pyrrolidine, piperidine, piperazine, tetrahyd ropy ran, morpholine, indoline, oxopyrrolidine, benzodioxane, especially is piperazine, benzodioxane, morpholine, tetrahydropyran, piperidine, oxopyrrolidine and pyrrolidine.

Preferably, in the context of this invention heterocyclyl is defined as a 5 to 18 membered mono or polycyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. Preferably it is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur in the ring. More preferably, it is a 5 to 10 membered mono or bicyclic heterocyclyl ring system containing one nitrogen atom and optionally a second heteroatom selected from nitrogen and oxygen. In another preferred embodiment of the invention, said heterocyclyl is a substituted mono or bicyclic heterocyclyl ring system. Preferred examples of heterocyclyls include oxazepam, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, tetrahydroisoquinoline, phthalazine, benzo-1 ,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline, especially is pyridine, piperazine, pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine, tetrahydropyran, pyrazole, imidazole, piperidine, thiophene, indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole, oxopyrrolidine, pyrimidine, oxazepane and pyrrolidine. In the context of this invention oxopyrrolidine is understood as meaning pyrrolidin-2-one.

In connection with aromatic heterocyclyls (heteroaryls), non-aromatic heterocyclyls, aryls and cycloalkyls, when a ring system falls within two or more of the above cycle definitions simultaneously, then the ring system is defined first as an aromatic heterocyclyl (heteroaryl) if at least one aromatic ring contains a heteroatom. If no aromatic ring contains a heteroatom, then the ring system is defined as a non-aromatic heterocyclyl if at least one non-aromatic ring contains a heteroatom. If no non-aromatic ring contains a heteroatom, then the ring system is defined as an aryl if it contains at least one aryl cycle. If no aryl is present, then the ring system is defined as a cycloalkyl if at least one non-aromatic cyclic hydrocarbon is present.

In the context of this invention alkyl-aryl or aryl-alkyl is understood as meaning an aryl group (see above) being connected to another atom through a Ci- ₆-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably aryl-alkyl is understood as meaning an aryl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups.

In the context of this invention alkyl-heterocyclyl or heterocyclyl-alkyl is understood as meaning an heterocyclyl group (see above) being connected to another atom through a Ci- ₆-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkyl-heterocyclyl is understood as meaning an heterocyclyl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups. In the context of this invention alkyl-cycloalkyl or cycloalkyl-alkyl is understood as meaning an cycloalkyl group (see above) being connected to another atom through a Ci- ₆-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkyl-cycloalkyl is understood as meaning a cycloalkyl group (see above) being connected to another atom through 1 to 4 (-Chh) groups.

Preferably, the aryl is a monocyclic aryl. More preferably the aryl is a 6 or 7 membered monocyclic aryl. Even more preferably the aryl is a 6 membered monocyclic aryl, preferably phenyl.

Preferably, the heteroaryl is a monocyclic heteroaryl. More preferably the heteroaryl is a 5, 6 or 7 membered monocyclic heteroaryl. Even more preferably the heteroaryl is a 5 or 6 membered monocyclic heteroaryl.

Preferably, the non-aromatic heterocyclyl is a monocyclic non-aromatic heterocyclyl. More preferably the non-aromatic heterocyclyl is a 4, 5, 6 or 7 membered monocyclic non-aromatic heterocyclyl. Even more preferably the non-aromatic heterocyclyl is a 5 or 6 membered monocyclic non-aromatic heterocyclyl. In another preferred embodiment, said non-aromatic heterocyclyl is a bicyclic non-aromatic heterocyclyl.

Preferably, the cycloalkyl is a monocyclic cycloalkyl. More preferably the cycloalkyl is a 3, 4, 5, 6, 7 or 8 membered monocyclic cycloalkyl. Even more preferably the cycloalkyl is a 3, 4, 5 or 6 membered monocyclic cycloalkyl.

A ring system is a system consisting of at least one ring of connected atoms but including also systems in which two or more rings of connected atoms are joined with “joined” meaning that the respective rings are sharing one (like a spiro structure), two or more atoms being a member or members of both joined rings.

The term“leaving group” means a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI-, Br-, and I-, and sulfonate esters, such as tosylate (TsO-), mesylate, nosylate or triflate. The term“salt” is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes via ionic interactions. The definition particularly includes physiologically acceptable salts, this term must be understood as equivalent to “pharmacologically acceptable salts”.

The term“physiologically acceptable salt” means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially lacking toxicity caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.

These physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals. The salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH ₄, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.

Physiologically acceptable salts can also be formed with anions or acids and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals. By this it is understood in particular, in the context of this invention, the salt formed with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.

The compounds of the invention may be present in crystalline form or in the form of free compounds like a free base or acid. Any compound that is a solvate of a compound according to the invention like a compound according to formula (I) defined above is understood to be also covered by the scope of the invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. The term “solvate” according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non- covalent binding another molecule (most likely a polar solvent). Especially preferred examples include hydrates and alcoholates, like methanolates or ethanolates.

Any compound that is a prodrug of a compound according to the invention like a compound according to formula (I) defined above is understood to be also covered by the scope of the invention. The term “prodrug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al.“Textbook of Drug design and Discovery” Taylor & Francis (April 2002).

Any compound that is a N-oxide of a compound according to the invention like a compound according to formula (I) defined above is understood to be also covered by the scope of the invention.

Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon or of a nitrogen by ¹⁵N-enriched nitrogen are within the scope of this invention.

The compounds of formula (I) as well as their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable pure form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts. This applies also to its solvates or prodrugs.

All the groups above mentioned that can be substituted or unsubstituted may be substituted at one or more available positions by one or more suitable groups such as OR’, =0, SR’, SOR’, S0 ₂R’, OS0 ₂R’, OSOSR’, N0 ₂, NHR’, N(R’) ₂, =N-R’, N(R’)COR’, N(COR’) ₂, N(R’)S0 ₂R’, N(R’)C(=NR’)N(R’)R’, N ₃, CN, halogen, COR’, COOR’, OCOR’, OCOOR’, OCONHR’, OCON(R’) ₂, CONHR’, CON(R’) ₂, CON(R’)OR’, CON(R’)S0 ₂R’, PO(OR’) ₂, PO(OR’)R’, PO(OR’)(N(R’)R’), C _M2 alkyl, C _3-io cycloalkyl, C _2-i2 alkenyl, C _2-i2 alkynyl, aryl, and heterocyclic group, wherein each of the R’ groups is independently selected from the group consisting of hydrogen, OH, N0 _2, NH ₂, SH, CN, halogen, COH, COalkyl, COOH , C _M2 alkyl, C _3-io cycloalkyl, C _2-i2 alkenyl, C _2-i2 alkynyl, aryl and heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list. In a particular embodiment of the invention, the compound according to the invention of formula (I) is a compound wherein R ₂ is located as represented in formula (G)

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a particular embodiment of the invention, the compound of formula (I) or (I’) according to the invention is a compound wherein

R ₂ is selected from substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted aryl, preferably phenyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, and [Chhj _n- C(0)-R5; wherein when the cycloalkyl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl; substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, -OR5, -C(O), -C(0)R5, -NO2, -CN, - NR ₅C(0)-[CH ₂] _n-NR _5'R _5”, -C(0)NR ₅-[CH ₂] _n-NR _5'R _5”, -NR ₅C(0)R ₅·, -C(0)NR ₅R ₅·, and -NR ₅[CH ₂] _n-NR _5'R _5”; when the heterocyclyl group is substituted the substituents are selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl- aryl, substituted or unsubstituted alkyl-heterocyclyl, -OR5, -C(O), -C(0)Rs, -NO2, -CN, -NR ₅C(0)-[CH ₂] _n-NR _5'R _5”, -C(0)NR ₅-[CH ₂] _n-NR _5'R _5”, -NR ₅C(0)R ₅·, - C(0)NR ₅R _5', and -NR ₅[CH ₂] _n-NR _5'R _5”; when the aryl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, OR5, NO2, NR5R5', alkyl-aryl, CN, -NR ₅C(0)-[CH ₂] _n-NR _5'R _5”, -C(0)NR ₅-[CH ₂] _n-NR _5'R _5”, -

NR ₅C(0)R5', -C(0)NR ₅R5', -NR ₅[CH2]n-NR _5'R5”, substituted or unsubstituted alkyl-heterocyclyl, and substituted or unsubstituted heterocyclyl wherein said heterocyclyl is not piperidine; more particularly, said heterocyclyl is an aromatic heterocycyl; wherein

R5, R5' or R _5” are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH2] _n-NR”R’”; wherein

R’, R” and R’” are independently selected from hydrogen, halogen, substituted or unsubstituted Ci- ₆ alkyl, substituted or unsubstituted C2- ₆ alkenyl, and substituted or unsubstituted C2- ₆ alkynyl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted alkyl-heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a more particular embodiment of the invention, the compound according to the invention of formula (I) or (I’) is a compound wherein

R2 IS selected from substituted or unsubstituted C2- ₆ alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, and [Chhl _n -C(0)-Rs; wherein when the cycloalkyl group is substituted the substituents are selected from the group consisting of halogen and substituted or unsubstituted C1-6 alkyl, preferably substituted or unsubstituted C1- ₃ alkyl; when the heterocyclyl group is substituted the substituents are selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, preferably substituted or unsubstituted C1- ₃ alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-aryl, preferably Ci- 3 alkyl-phenyl, substituted or unsubstituted alkyl-heterocyclyl, -OR ₅, -C(O), - C(0)R ₅, -NO2, and -CN; when the aryl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-3 alkyl, OR5, NO2, NR5R5', C1-3 alkyl-aryl, CN, -NR ₅C(0)- [CH ₂]n-NR ₅ R _5”, -C(0)NR ₅-[CH ₂]n-NR _5'R _5”, -NR ₅C(0)R ₅·, -C(0)NR ₅R _5', NR ₅[CH2]n-NR _5'R5”, substituted or unsubstituted alkyl-heterocyclyl, and substituted or unsubstituted heterocyclyl wherein said heterocyclyl is not piperidine, preferably said heterocyclyl is an aromatic heterocyclyl; wherein

R ₅, R _5' or R _5” are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, preferably unsubstituted C _1-3 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl- alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, preferably C _1-3 alkyl-phenyl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH ₂] _n-NR”R’”; wherein

R’, R” and R’” are independently selected from hydrogen, halogen, substituted or unsubstituted C _1-6 alkyl, preferably unsubstituted C _1-3 alkyl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted alkyl-heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment the compound of the invention according to formula (I) is a compound, wherein in R ₅, Rs and Rs- as defined in any of the embodiments of the present invention, the C _1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or

the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1 ,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole, and quinazoline; and/or

the aryl is selected from phenyl, naphtyl, and anthracenyl; preferably is napthyl and phenyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment the compound of the invention according to formula (I) is a compound, wherein in R’, R” and R’” as defined in any of the embodiments of the present invention, the C alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or

In another particular embodiment of the invention, the compound according to the invention of formula (I) or (G) is a compound wherein group

is selected from: optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the invention, the compound according to the invention of formula (I) or (G) is a compound wherein group

wherein a and b are independently selected from 1 and 2; preferably a and b are 1 ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a more particular embodiment of the invention, the compound according to the invention of formula (I) or (G) is a compound wherein in group

Ri is selected from hydrogen, halogen, substituted or unsubstituted Ci- ₆ alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl;

R ₃ and R _3' are independently selected from hydrogen, halogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; wherein n is 0, 1 or 2;

R _? and R _7' are independently selected from hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; alternatively, R ₇ and R _7' taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclyl, preferably a substituted or unsubstituted N-containing heterocyclyl group; a and b are independently selected from 1 and 2; preferably, a and b are 1 ; and

X is selected from a bond and -[C(R4R4')] _P-, wherein

R ₄ and R _4' are independently selected from hydrogen and substituted or unsubstituted C _1-6 alkyl; and p is 0, 1 , 2 or 3; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention, the compound according to the invention of formula (I) or (I’) is a compound wherein in group

Ri is selected from hydrogen, substituted or unsubstituted Ci- ₆ alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl;

R _? and R _7' are hydrogen;

X is selected from a bond and -[C(R4R4')] _P-, wherein

R ₄ and R _4' are independently selected from hydrogen and substituted or unsubstituted C _1-6 alkyl; and p is 0, 1 , 2 or 3; n is 0; and a and b are 1 ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a particular embodiment of the invention, the compound according to the invention of formula (I) or (G) is a compound wherein W is selected from S and O, preferably W is -S; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the invention, the compound according to the invention of formula (I) or (G) is a compound wherein

R ₆ is selected from hydrogen, halogen, substituted or unsubstituted Ci- ₆ alkyl, substituted or unsubstituted C _2-6 alkenyl, and substituted or unsubstituted C _2-6 alkynyl; preferably Re is selected from hydrogen, halogen and substituted or unsubstituted C _1-6 alkyl, more preferably, R ₆ is hydrogen or halogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another particular embodiment of the invention, the compound according to the invention of formula (I) or (G) is a compound wherein

X is selected from a bond, -[C(R4R4')] _P- and -O- , wherein

R ₄ and R _4' are independently selected from hydrogen and substituted or unsubstituted C _1-6 alkyl; preferably R ₄ and R _4', are hydrogen and p is 0, 1 , 2 or 3; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a preferred embodiment, the compound according to the invention of formula (I) or (G) is a compound wherein

Ri is selected from hydrogen, halogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; preferably C1-3 alkyl-cycloalkyl, substituted or unsubstituted aryl; preferably phenyl, substituted or unsubstituted alkyl-aryl, preferably C1-3 alkyl-phenyl, and substituted or unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred embodiment, the compound according to the invention of formula (I) is a compound wherein

R ₁ is selected from hydrogen, substituted or unsubstituted C _1-6 alkyl, preferably substituted or unsubstituted C1-3 alkyl; substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; preferably C1-3 alkyl-cycloalkyl, preferably C1-3 alkyl-cyclopropyl; substituted or unsubstituted aryl; preferably phenyl, substituted or unsubstituted alkyl-aryl, preferably C1-3 alkyl-phenyl and substituted or unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment, the aryl as defined in R1 , if substituted, is substituted with one or more substituent/s selected from C1-6 alkyl and -O Rn , wherein

R11 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl. In a more preferred embodiment, Rn is unsubstituted C1-6 alkyl, preferably C1-3 alkyl, more preferably methyl. In a particular embodiment, the C _1-6 alkyl as defined in R ₁, if substituted, is substituted with one or more substituent/s selected from unsubstituted C _1-6 alkyl, preferably unsubstituted C _1-3 alkyl, more preferably methyl, or unsubstituted C _2-6 alkenyl and unsubstituted C _2-6 alkynyl.

In a more particular embodiment of the invention, the compound according to the invention of formula (I) is a compound wherein

-X-R ₁ is substituted or unsubstituted C _1-6 alkyl-Ri, preferably unsubstituted C _1-3 alkyl- R ₁, wherein

R ₁ is selected from hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl; preferably, R ₁ is selected from hydrogen, substituted or unsubstituted C _1-3 alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted alkyl-cycloalkyl; preferably C _1-3 alkyl -cyclopropyl, substituted or unsubstituted aryl; preferably phenyl, and substituted or unsubstituted alkyl-aryl, preferably C _1-3 alkyl-phenyl;

R ₄ and R _4' are hydrogen; and p is 0, 1 or 2;

In a preferred embodiment, the compound according to the invention of formula (I) is a compound wherein

R ₃ and R _3' are independently selected from hydrogen, halogen, and substituted or unsubstituted C _1-6 alkyl, preferably unsubstituted C _1-3 alkyl; wherein n is 0 or 1 ; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein

R ₂ is selected from substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl- heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, and [Chhln -C(0)-R5; wherein when the cycloalkyl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, preferably C1-3 alkyl, substituted or unsubstituted heterocyclyl; substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, -OR5, -C(O), -C(0)R5, -NO2, -CN, -NR ₅C(0)-[CH ₂] _n-NR _5'R _5”, -C(0)NR ₅-[CH ₂] _n-NR _5'R _5”, -NR ₅C(0)R ₅·, - C(0)NR ₅R _5', and -NR ₅[CH ₂] _n-NR _5'R _5”; when the heterocyclyl group is substituted the substituents are selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl- aryl, preferably alkyl-phenyl, substituted or unsubstituted alkyl-heterocyclyl, - ORs, -C(O), -C(0)R ₅, -NO2, -CN, -NR ₅C(0)-[CH ₂] _n-NR _5'R _5”, -C(0)NR ₅-[CH ₂] _n- NR5 R5”, -NR ₅C(0)R _5', -C(0)NR ₅R _5', and -NR ₅[CH ₂] _n-NR _5'R _5”, when the aryl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, OR ₅, NO2, NR ₅R _5', alkyl-aryl, CN, -NR ₅C(0)-[CH ₂]n-NR _5'R _5”, -C(0)NR ₅-[CH ₂]n-NR _5'R _5”, -

NR ₅C(0)R5', -C(0)NR ₅R5', -NR ₅[CH ₂]n-NR _5'R5”, substituted or unsubstituted alkyl-heterocyclyl, and substituted or unsubstituted heterocyclyl, wherein said heterocyclyl is not piperidine, more preferably said heterocyclyl is an aromatic heterocyclyl; wherein

R ₅, R _5' or R _5” are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH ₂] _n-NR”R’”; wherein R’, R” and R’” are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, and substituted or unsubstituted C _2-6 alkynyl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted alkyl- heterocyclyl; and/or

R3 and R3' are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted alkyl-aryl; preferably C1- ₃ alkyl-aryl and substituted or unsubstituted haloalkyl; wherein n is 0, 1 or 2; and/or

Re is selected from hydrogen, halogen and substituted or unsubstituted C1-6 alkyl; and/or group A is a diamine selected from wherein a and b are independently selected from 0, 1 and 2; and

R _? and R _7' are independently selected from hydrogen, halogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; alternatively, in group A’, R ₇ and R _7' taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclyl group, preferably a N-containing heterocyclyl group; and/or

X is selected from a bond, -[C(R4R4')] -, -[C(R4R4')] C(0)[C(R4”R4 )]q- _> and -0-, wherein

R ₄, R _4', R _4” and R _4” are independently selected from hydrogen, halogen, and substituted or unsubstituted C _1-6 alkyl; and p is 0, 1 , 2 or 3; q is 0, 1 , 2 or 3; and/or

W is selected from S and O; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein R ₂ is as represented in formula (G)

R ₂ is selected from substituted or unsubstituted C _2-6 alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl- heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; and [CH ₂]n -C(0)-Rs; wherein when the cycloalkyl group is substituted the substituents are selected from the group consisting of halogen and substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-3 alkyl; when the heterocyclyl group is substituted the substituents are selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1- ₃ alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-aryl, preferably alkyl-phenyl, substituted or unsubstituted alkyl-heterocyclyl, -OR5, -C(O), -C(0)Rs, -NO2, and

-CN; when the aryl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-3 alkyl, OR5, NO2, NR5R5', C1-3 alkyl-aryl, CN, -NR ₅C(0)- [CH ₂]n-NR ₅ R _5”, -C(0)NR ₅-[CH ₂]n-NR _5'R _5”, -NR ₅C(0)R ₅·, -C(0)NR ₅R ₅·, -

NR ₅[CH2]n-NR _5'R5”, substituted or unsubstituted alkyl-heterocyclyl, and substituted or unsubstituted heterocyclyl wherein said heterocyclyl is not piperidine, preferably said heterocyclyl is an aromatic heterocyclyl; wherein R ₅, R _5' or R _5” are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH2] _n-NR”R’”; wherein

R’, R” and R’” are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl; substituted or unsubstituted alkyl- aryl, and substituted or unsubstituted alkyl-heterocyclyl; and/or R3 and R3' are independently selected from hydrogen, halogen, and substituted or unsubstituted C1-6 alkyl; wherein n is 0, 1 or 2;

Re is selected from hydrogen, halogen and substituted or unsubstituted C1-6 alkyl; and/or group A is a diamine selected from

wherein a and b are independently selected from 0, 1 and 2; and

R _? and R _7' are independently selected from hydrogen, halogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; alternatively, in group A, R ₇ and R _7' taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclyl group, preferably a N-containing heterocyclyl group; and/or

X is selected from a bond, -[C(R4R4')] -, -[C(R4R4')] C(0)[C(R4”R4 )]q- _> and -0-, wherein R ₄, R _4', R _4” and R ₄- are independently selected from hydrogen, halogen, and substituted or unsubstituted C _1-6 alkyl; and p is 0, 1 , 2 or 3; q is 0, 1 , 2 or 3; and/or W is selected from S and O; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein R ₂ is as represented in formula (G)

O ^’) wherein

R ₂ is selected from substituted or unsubstituted C _2-6 alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl- heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, and [CH ₂] _n-C(0)-R5; wherein when the cycloalkyl group is substituted the substituents are selected from the group consisting of halogen and substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-3 alkyl; when the heterocyclyl group is substituted the substituents are selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1- ₃ alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-aryl, preferably alkyl-phenyl, substituted or unsubstituted alkyl-heterocyclyl, -OR5, -C(O), -C(0)Rs, -NO2, and -CN; when the aryl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-3 alkyl, OR5, NO2, NR5R5', C1-3 alkyl-aryl, CN, -NR ₅C(0)- [CH ₂]n-NR ₅ R _5”, -C(0)NR ₅-[CH ₂]n-NR _5'R _5”, -NR ₅C(0)R ₅·, -C(0)NR ₅R ₅·, -

R ₃ and R _3' are independently selected from hydrogen, halogen, and substituted or unsubstituted C _1-6 alkyl; wherein n is 0, 1 or 2;

Re is selected from hydrogen, halogen and substituted or unsubstituted C _1-6 alkyl; and group A is a diamine selected from

wherein a and b are independently selected from 0, 1 and 2; and

X is selected from a bond, -[C(R4R4')] -, -[C(R4R4')] C(0)[C(R4”R4 )]q- _> and -0-, wherein

R ₄, R _4', R _4” and R _4” are independently selected from hydrogen, halogen, and substituted or unsubstituted C _1-6 alkyl; and p is 0, 1 , 2 or 3; q is 0, 1 , 2 or 3; and

In another preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein R ₂ is as represented in formula (G)

O ^’)

Ri is selected from substituted or unsubstituted C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl; and

R ₂ is selected from substituted or unsubstituted C _2-6 alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl and [Chhl _n -C(0)-Rs; wherein when the aryl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-3 alkyl, OR5, NO2, NR5R5', C1-3 alkyl-aryl, CN, -NR ₅C(0)-[CH2] _n- NR ₅ R _5”, -C(0)NR ₅-[CH ₂] _n-NR _5'R _5”, -NR ₅C(0)R ₅·, -C(0)NR ₅R ₅·, -NR ₅[CH ₂] _n-NR _5'R _5”, substituted or unsubstituted alkyl-heterocyclyl, and substituted or unsubstituted heterocyclyl wherein said heterocyclyl is an aromatic heterocyclyl; wherein R ₅, R _5' or R _5” are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’ and [CH2] _n-NR”R’”; wherein

wherein a and b are independently 1 ; and

R _? and R7' are independently hydrogen; and n is 0 and X is a bond, and

W is S; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention, the compound according to formula (I) is a compound, wherein in R ₄, R ₄·, R ₄- and R ₄ as defined in any of the embodiments of the present invention, the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or

the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or

the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention, the compound according to formula (I) is a compound, wherein in R ₆ as defined in any of the embodiments of the present invention, the C _1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or

the C _2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or

the C _2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R ₃ and R ₃ as defined in any of the embodiments of the present invention, the C _1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl;

and/or the C _2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or

the C _2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; and/or

the haloalkyl is selected from -CH2CI, -CH2F, -CHCb, -CHF2, -CCI3, -CF3, and -CH2-CHCI2; and/or

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R ₇ and R ₇ as defined in any of the embodiments of the present invention, the C _1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or

the C _2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or

the C _2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; and/or

the haloalkyl is selected from -CH ₂CI, -CH ₂F, -CHC , -CHF ₂, -CCI ₃, -CF ₃ and -CH2-CHCI2; and/or

the aryl is selected from phenyl, naphtyl, or anthracenyl; preferably is napthyl and phenyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in Ri as defined in any of the embodiments of the present invention, the C _1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or

the C _2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or

the C _2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; and/or

the haloalkyl is selected from -CH ₂CI, -CH ₂F, -CHCI ₂, -CHF ₂, -CCI ₃, -CF ₃ and -CH2-CHCI2; more preferably the haloalkyl is -CHF2 or -CF3; and/or

the cycloalkyl is C _3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C _3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C _3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably the cycloalkyl is cyclopropyl; and/or

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R ₅, Rs· and Rs- as defined in any of the embodiments of the present invention, the alkyl is preferably selected from C alkyl; more preferably, the Ci- ₆ alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2- methylpropyl; and/or the C _2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or

the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne;

and/or

-C(0)0R ₃ or -S(0) ₂0R _3' are preferably -C(0)0H and -S(0) ₂0H; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the compound according to the invention of formula (I) the halogen is fluorine, bromine or chlorine. optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred further embodiment, the compound of formula (I) is selected from:

[1 ] (1 -(4-ethoxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- ethylpiperazin-1 -yl)methanone;

[2] (4-ethylpiperazin-1 -yl)(1 -phenyl-4, 5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)methanone;

[3] (4-ethylpiperazin-1-yl)(2-methyl-4,5-dihydro-2H-thieno[2,3-g ]indazol-3- yl)methanone;

[4] (1 -(2,4-difluorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- ethylpiperazin-1 -yl)methanone;

[5] (4-ethylpiperazin-1 -yl)(1 -(6-methoxypyridin-3-yl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[6] (4-ethylpiperazin-1 -yl)(1 -(3-fluorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol- 3-yl)methanone;

[7] (4-methylpiperazin-1 -yl)(1 -phenyl-4, 5-dihydro- 1 H-thieno[2,3-g]indazol-3- yl)methanone; [8] (1 -(3-aminophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-ethylpiperazin- 1 -yl)methanone;

[9] (4-ethylpiperazin-1 -yl)(1 -(3-methoxyphenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;

[10] (1 -(2-chlorophenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- ethylpiperazin-1 -yl)methanone;

[1 1 ] (4-ethylpiperazin-1 -yl)(1 -(3-(4-((methylamino)methyl)-1 H-1 ,2,3-triazol- 1 -yl)phenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[12] (4-ethylpiperazin-1 -yl)(1 -(3-nitrophenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)methanone;