Novel 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use

Abstract

The present invention relates to compound of Formula I or pharmaceutically acceptable enantiomers, salts or solvates thereof. The invention further relates to the use of the compounds of Formula I as TDO2 inhibitors. The invention also relates to the use of the compounds of Formula I for the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity. The invention also relates to a process for manufacturing compounds of Formula I.

1 . A method of treating a patient having a cancer associated with tryptophan 2,3-dioxygenase (TDO), and said method comprising delivering a compound according to Formula I or a pharmaceutically acceptable salt or solvate thereof to the patient, where a compound of Formula I is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable enantiomer or salt thereof wherein:
 X 1  and X 2  represent each independently H, halogen or haloalkyl; 
 M and Q represent each independently H, halogen, hydroxyl, or C1-C6 alkyl optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, CONR 1 R 2 , or NR 1 COR 2  wherein R 1  and R 2  represent each independently a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, or alkylheteroaryl; 
 A represents:
 heteroaryl, optionally substituted with halogen, hydroxyl, nitro, amido, carboxy, amino, cyano, haloalkoxy, haloalkyl, or alkyl; 
 heterocyclyl; optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COW, CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me; 
 C1-C3 alkyl-heterocyclyl; wherein both the C1-C3 alkyl and the heterocyclyl are optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 , CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me; 
 cycloalkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 , CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me; or 
 C1-C3 alkyl-cycloalkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 , CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me. 
 
 
     
     
         2 . The method according to  claim 1 , wherein said cancer associated with TDO2 is colon cancer, leukemia, lymphoma, breast cancer, liver cancer, lung cancer, or skin cancer. 
     
     
         3 . The method according to  claim 1 , wherein the compound has Formula Ia: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable enantiomer or salt thereof, wherein:
 X 1  and X 2  represent each independently H, halogen or haloalkyl; 
 M and Q represent each independently H, halogen, hydroxyl, or C1-C6 alkyl optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, CONR 1 R 2 , or NR 1 COR 2 , wherein R 1  and R 2  represent each independently a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, or alkylheteroaryl; 
 n represents an integer equal to 0, 1, 2 or 3; 
 m 1  and m 2  represent each independently an integer equal to 1 or 2; 
 Y 1  and Y 2  represent each independently CR 7 , N, O, or SO 2 , wherein R 7  represents H or hydroxyl; 
 R 3  represents H or alkyl; 
 R 4 , R 4′ , R 5  and R 5′  represent each independently H, hydroxyl, alkyl, alkoxy, or haloalkyl or R 4  and R 4′  form together an oxo moiety or R 5  and R 5′  form together an oxo moiety; 
 R 6  is absent or represents H or alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, COR 1 , COOR 1 , CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl or amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me. 
 
       
     
     
         4 . The method according to  claim 1 , the compound having Formula Ia-1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable enantiomer or salt thereof, wherein: 
         X 1  and X 2  represent each independently H or F; 
         M and Q represent each independently H or C1-C6 alkyl optionally substituted by one or more halogen; 
         Y 2  represents N or CH; 
         R 4 , R 4′ , R 5  and R 5′  represent each independently H, hydroxyl, alkyl, alkoxy, or haloalkyl, or R 4  and R 4′  form together an oxo moiety, or R 5  and R 5′  form together an oxo moiety; 
         R 6  represents H, or alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, COOR 1 , COR 1 , CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl or amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me. 
       
     
     
         5 . The method according to  claim 1 , the compound having Formula Ia-2: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable enantiomer or salt thereof, wherein:
 X 1  and X 2  represent each independently H or F; 
 M and Q represent each independently H or C1-C6 alkyl optionally substituted one or more halogen; 
 Y 2  represents N or CH; 
 R 4 , R 4′ , R 4 ″, R 4′″ , R 5 , R 5′ , R 5 ″ and R 5′″  represent each independently H, hydroxyl, alkyl, alkoxy, or haloalkyl, or R 4  and R 4′  form together an oxo moiety, or R 4 ″ and R 4′″  form together an oxo moiety, or R 5  and R 5′  form together an oxo moiety, or R 5 ″ and R 5′″  form together an oxo moiety; 
 R 6  represents
 H; 
 alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; 
 cycloalkyl; 
 halogen; 
 hydroxyl; 
 oxo; 
 COR 1  or SO 2 R 1 , wherein R 1  represents a group selected from C1-C6 alkyl or cycloalkyl, wherein R 1  groups are optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me. 
 
 
       
     
     
         6 . The method according to  claim 1 , the compound having Formula Ia-3: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable enantiomer or salt thereof, wherein:
 X 1  and X 2  represent each independently H or F; 
 M and Q represent each independently H or C1-C6 alkyl optionally substituted one or more halogen; 
 Y 2  represents N or CH; 
 R 6  represents
 H; 
 alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; 
 cycloalkyl; or 
 COR 1  or SO 2 R 1 , wherein R 1  represents a group selected from C1-C6 alkyl, cycloalkyl, alkene, amino, wherein R 1  groups are optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me. 
 
 
     
     
         7 . The method according to  claim 1 , the compound having Formula Ic: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable enantiomer or salt thereof, wherein:
 X 1  and X 2  represent each independently H, halogen or haloalkyl; 
 M and Q represent each independently H, halogen, hydroxyl, or C1-C6 alkyl optionally substituted one or more substituents selected from the group comprising halogen, hydroxyl, CONR 1 R 1 , or NR 1 COR 2 , wherein R 1  and R 2  represent each independently a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, or alkylheteroaryl; 
 Y 3 , Y 4 , Y 5  represent each independently N or CH; and at least one of Y 3 , Y 4 , Y 5  represents N; 
 R 9  is absent or represents H, halogen, or amino. 
 
     
     
         8 . The method according to  claim 1 , the compound selected from the group consisting of:
 3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)azetidin-2-one,   3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   1-(3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone,   3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxamide,   3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)-N-methylazetidine-1-carboxamide,   3-(1-(azetidin-3-ylmethyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   1-(2-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)ethyl)imidazolidin-2-one,   6-fluoro-3-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indole,   4-(2-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)ethyl)morpholine,   6-fluoro-3-(1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indole,   1-(4-(2-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)ethanone,   6-fluoro-3-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indole,   1-(2-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)ethyl)pyrrolidin-2-one,   6-fluoro-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole,   5,6-difluoro-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-((1-(2-fluoroethyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indole,   2-(4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethanol,   1,1,1-trifluoro-3-(4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)propan-2-ol,   2-(4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)acetic acid,   4-(4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)-4-oxobutanoic acid,   1-(4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethanone,   3-(1-((1-cyclopropylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   6-fluoro-3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indole,   3-(3,5-dimethyl-1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   6-fluoro-3-(3-methyl-1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(5-methyl-1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indole,   4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-pyran-4-ol,   4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide,   (1S,3S)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide,   (1R,3R)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide,   (1S,3S)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)-N-methylcyclobutanecarboxamide,   (1R,3R)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)-N-methylcyclobutanecarboxamide,   (1S,3S)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylic acid,   (1R,3R)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylic acid,   (1R,4R)-4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclohexanecarboxamide   (1R,4R)-4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclohexanol,   (1R,4R)-4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclohexanol,   6-fluoro-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   2-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanol,   4-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-oxobutanoic acid,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-methoxypropan-1-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propan-1-one,   2-(dimethylamino)-1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-hydroxyethanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methoxyethanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methylpropan-1-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one,   cyclopropyl(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,   4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylpiperidine-1-carboxamide,   6-fluoro-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   1-(4-(4-(1H-indol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-3-methyl-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,   6-fluoro-3-(1-(1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   3-(1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   3-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   6-fluoro-3-(1-(1-(isopropylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-2-one,   4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)-1-methylpiperidin-2-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-(methylsulfonyl)butan-1-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-hydroxypropan-1-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-(methylsulfonyl)propan-1-one,   6-fluoro-3-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-(pyridazin-3-yl)-1H-pyrazol-4-yl)-1H-indole,   3-(1-(6-chloropyridazin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   6-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)pyridazin-3-amine,   6-fluoro-3-(1-(pyridazin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   or a pharmaceutically acceptable enantiomer or salt thereof.   
     
     
         9 . The method according to  claim 1 , wherein the compound of formula I is in a composition which further comprises at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. 
     
     
         10 . The method according to  claim 1 , wherein the enantiomer of compound of formula I is in a composition which further comprises at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. 
     
     
         11 . The method according to  claim 1 , wherein the salt of compound of formula I is in a composition which further comprises at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. 
     
     
         12 . A method of treating a patient having neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, or obesity, and said method comprising delivering a compound according to Formula I or a pharmaceutically acceptable salt or solvate thereof to the patient, where a compound of Formula I is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable enantiomer or salt thereof wherein:
 X 1  and X 2  represent each independently H, halogen or haloalkyl; 
 M and Q represent each independently H, halogen, hydroxyl, or C1-C6 alkyl optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, CONR 1 R 2 , or NR 1 COR 2  wherein R 1  and R 2  represent each independently a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, or alkylheteroaryl; 
 A represents:
 heteroaryl, optionally substituted with halogen, hydroxyl, nitro, amido, carboxy, amino, cyano, haloalkoxy, haloalkyl, or alkyl; 
 heterocyclyl; optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 , CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me; 
 C1-C3 alkyl-heterocyclyl; wherein both the C1-C3 alkyl and the heterocyclyl are optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 , CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me; 
 cycloalkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 , CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me; or 
 C1-C3 alkyl-cycloalkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 , CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me. 
 
 
     
     
         13 . The method according to  claim 12 , wherein the compound has Formula Ia: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable enantiomer or salt thereof, wherein:
 X 1  and X 2  represent each independently H, halogen or haloalkyl; 
 M and Q represent each independently H, halogen, hydroxyl, or C1-C6 alkyl optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, CONR 1 R 2 , or NR 1 COR 2 , wherein R 1  and R 2  represent each independently a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, or alkylheteroaryl; 
 n represents an integer equal to 0, 1, 2 or 3; 
 m 1  and m 2  represent each independently an integer equal to 1 or 2; 
 Y 1  and Y 2  represent each independently CR 7 , N, O, or SO 2 , wherein R 7  represents H or hydroxyl; 
 R 3  represents H or alkyl; 
 R 4 , R 4′ , R 5  and R 5′  represent each independently H, hydroxyl, alkyl, alkoxy, or haloalkyl or R 4  and R 4′  form together an oxo moiety or R 5  and R 5′  form together an oxo moiety; 
 R 6  is absent or represents H or alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, COW, COOR 1 , CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl or amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me. 
 
       
     
     
         14 . The method according to  claim 12 , the compound having Formula Ia-1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable enantiomer or salt thereof, wherein: 
         X 1  and X 2  represent each independently H or F; 
         M and Q represent each independently H or C1-C6 alkyl optionally substituted by one or more halogen; 
         Y 2  represents N or CH; 
         R 4 , R 4′ , R 5  and R 5′  represent each independently H, hydroxyl, alkyl, alkoxy, or haloalkyl, or R 4  and R 4′  form together an oxo moiety, or R 5  and R 5′  form together an oxo moiety; 
         R 6  represents H or alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, COOR 1 , COW, CONR 1 R 2 , NR 1 COR 2 , NR 1 R 2 , SO 2 R 1 , SO 2 NR 1 R 2 , NR 1 SO 2 R 2 , or SOR 1 , wherein R 1  and R 2  represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl or amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me. 
       
     
     
         15 . The method according to  claim 12 , the compound having Formula Ia-2: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable enantiomer or salt thereof, wherein:
 X 1  and X 2  represent each independently H or F; 
 M and Q represent each independently H or C1-C6 alkyl optionally substituted one or more halogen; 
 Y 2  represents N or CH; 
 R 4 , R 4′ , R 4 ″, R 4′″ , R 5 , R 5′ , R 5 ″ and R 5′″  represent each independently H, hydroxyl, alkyl, alkoxy, or haloalkyl, or R 4  and R 4′  form together an oxo moiety, or R 4 ″ and R 4′″  form together an oxo moiety, or R 5  and R 5′  form together an oxo moiety, or R 5 ″ and R 5′″  form together an oxo moiety; 
 R 6  represents
 H; 
 alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; 
 cycloalkyl; 
 halogen; 
 hydroxyl; 
 oxo; 
 COR 1  or SO 2 R 1 , wherein R 1  represents a group selected from C1-C6 alkyl or cycloalkyl, wherein R 1  groups are optionally substituted by one or more groups selected from halogen,-hydroxyl, alkoxy, COOH, amino, or SO 2 Me. 
 
 
       
     
     
         16 . The method according to  claim 12 , the compound having Formula Ia-3: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable enantiomer or salt thereof, wherein:
 X 1  and X 2  represent each independently H or F; 
 M and Q represent each independently H or C1-C6 alkyl optionally substituted one or more halogen; 
 Y 2  represents N or CH; 
 R 6  represents
 H; 
 alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; 
 cycloalkyl; or 
 COR 1  or SO 2 R 1 , wherein R 1  represents a group selected from C1-C6 alkyl, cycloalkyl, alkene, amino, wherein R 1  groups are optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, or SO 2 Me. 
 
 
     
     
         17 . The method according to  claim 12 , the compound having Formula Ic: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable enantiomer or salt thereof, wherein:
 X 1  and X 2  represent each independently H, halogen or haloalkyl; 
 M and Q represent each independently H, halogen, hydroxyl, or C1-C6 alkyl optionally substituted one or more substituents selected from the group comprising halogen, hydroxyl, CONR 1 R 1 , or NR 1 COR 2 , wherein R 1  and R 2  represent each independently a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, or alkylheteroaryl; 
 Y 3 , Y 4 , Y 5  represent each independently N or CH; and at least one of Y 3 , Y 4 , Y 5  represents N; 
 R 9  is absent or represents H, halogen, or amino. 
 
     
     
         18 . The method according to  claim 12 , the compound selected from the group consisting of:
 3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)azetidin-2-one,   3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   1-(3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone,   3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxamide,   3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)-N-methylazetidine-1-carboxamide,   3-(1-(azetidin-3-ylmethyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   1-(2-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)ethyl)imidazolidin-2-one,   6-fluoro-3-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indole,   4-(2-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)ethyl)morpholine,   6-fluoro-3-(1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indole,   1-(4-(2-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)ethanone,   6-fluoro-3-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indole,   1-(2-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)ethyl)pyrrolidin-2-one,   6-fluoro-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole,   5,6-difluoro-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-((1-(2-fluoroethyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indole,   2-(4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethanol,   1,1,1-trifluoro-3-(4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)propan-2-ol,   2-(4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)acetic acid,   4-(4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)-4-oxobutanoic acid,   1-(4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethanone,   3-(1-((1-cyclopropylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   6-fluoro-3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indole,   3-(3,5-dimethyl-1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   6-fluoro-3-(3-methyl-1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(5-methyl-1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indole,   4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-pyran-4-ol,   4-((4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide,   (1S,3S)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide,   (1R,3R)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide,   (1S,3S)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)-N-methylcyclobutanecarboxamide,   (1R,3R)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)-N-methylcyclobutanecarboxamide,   (1S,3S)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylic acid,   (1R,3R)-3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylic acid,   (1R,4R)-4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclohexanecarboxamide   (1R,4R)-4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclohexanol,   (1R,4R)-4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclohexanol,   6-fluoro-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   2-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanol,   4-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-oxobutanoic acid,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-methoxypropan-1-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propan-1-one,   2-(dimethylamino)-1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-hydroxyethanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methoxyethanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-methylpropan-1-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one,   cyclopropyl(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,   4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylpiperidine-1-carboxamide,   6-fluoro-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   1-(4-(4-(1H-indol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-3-methyl-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)ethanone,   6-fluoro-3-(1-(1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   3-(1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   3-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   6-fluoro-3-(1-(1-(isopropylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-2-one,   4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)-1-methylpiperidin-2-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-(methylsulfonyl)butan-1-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-hydroxypropan-1-one,   1-(4-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-(methylsulfonyl)propan-1-one,   6-fluoro-3-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-(pyridazin-3-yl)-1H-pyrazol-4-yl)-1H-indole,   3-(1-(6-chloropyridazin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1H-indole,   6-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)pyridazin-3-amine,   6-fluoro-3-(1-(pyridazin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)-1H-indole,   6-fluoro-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1H-indole,   or a pharmaceutically acceptable enantiomer or salt thereof.