Chemical compounds - 643

Abstract

The invention concerns bicyclic compounds of Formula I wherein R 1 , R 2 , L 1 , L 2 , J, Y, k, n, p and r are as defined in the description. The present invention also relates to processes for the preparation of such compounds, pharmaceutical compositions containing them and their use in the treatment of androgen-receptor associated conditions, particularly prostate cancer.

1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents haloC 1-4 alkyl; 
         k represents 0, 1 or 2; 
         n and p independently represent 1 or 2; 
         Y represents N, C, CH or COH; 
            represents a single bond when Y is N, CH or COH; 
            represents a double bond when Y is C, L 1  is a direct bond and J is indolyl or pyrrolopyridinyl; 
         L 1  represents a direct bond, —(CR 3 R 4 ) t —, —(CR 3 R 4 ) v —O—(CR 3 R 4 ) v —, N(R 5 )—(CH 2 ) q , —S—, —S(O)— or —S(O) 2 —; 
         R 3  and R 4 , identically or differently on each occurrence, represent hydrogen or methyl; 
         R 5  represents hydrogen or methyl; 
         q, identically or differently on each occurrence, represents 0, 1, 2, 3 or 4; 
         t represents 1, 2 or 3; 
         v, identically or differently on each occurrence, represents 0, 1 or 2; 
         J represents:
 aryl; 
 C 3-6 cycloalkyl; 
 a monocyclic 4, 5, 6 or 7 membered heterocyclic ring which comprises 1, 2 or 3 heteroatoms independently selected from O, N or S; 
 a 5 or 6 membered monocyclic heteroaryl ring which comprises 1, 2, 3 or 4 heteroatoms independently selected from O, N or S; or 
 a 9 or 10 membered bicyclic heteroaryl ring system which comprises 1, 2, 3, 4 or 5 heteroatoms independently selected from O, N or S; 
 
         L 2  represents a direct bond, —(CR 3 R 4 ) t —, —C(O)N(R 5 )—(CH 2 ) q —, —C(O)N(R 5 )—(CH 2 ) q —S(O) 2 —, —NR 5 C(O)—(CH 2 ) q —, —C(O)—(CH 2 ) q —, —O—(CR 9 R 10 ) q —, —O—(CR 3 R 4 ) q —NR 5 —(CH 2 ) q —, —O—(CR 3 R 4 ) q —C(O)NR 5 —(CH 2 ) q —, —S—, —S(O)— or —S(O) 2 —; 
         R 9  and R 10 , identically or differently on each occurrence, represent hydrogen, methyl, ethyl, isopropyl, cyclopropyl or methoxymethyl; 
         R 2  represents:
 halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carboxy, C 1-6 alkoxy, cyano, oxo, fluoroC 1-6 alkyl, hydroxy, amino, N—C 1-4 alkylamino or N,N-di-C 1-4 alkylamino; 
 aryl, wherein the aryl ring is optionally substituted with 1, 2 or 3 substituents selected from R 6 ; 
 a monocyclic 4, 5, 6 or 7 membered heterocyclic ring which comprises 1, 2 or 3 heteroatoms independently selected from O, N or S and wherein the heterocyclic ring is optionally substituted with 1, 2 or 3 substituents selected from R 6 ; 
 a monocyclic 5 or 6 membered heteroaryl ring which comprises 1, 2, 3 or 4 heteroatoms independently selected from O, N or S and wherein the heteroaryl ring is optionally substituted with 1, 2 or 3 substituents selected from R 6 ; or 
 a 9 or 10 membered bicyclic heteroaryl ring system which comprises 1, 2, 3, 4 or 5 heteroatoms independently selected from O, N or S and wherein the heterocyclic ring is optionally substituted with 1, 2 or 3 substituents selected from R 6 ; 
 
         R 6  represents amino, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkanoyl, C 1-6 alkoxyC 1-6 alkyl, carboxy, cyano, oxo, fluoroC 1-6 alkyl, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkylsulphanyl, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, oxetan-3-ylcarbonyl, N—C 1-4 alkylamino, N,N-di-C 1-4 alkylamino or C(O)NR 7 R 8  wherein R 7  and R 8  independently represent hydrogen or methyl; and 
         r represents 0, 1, 2 or 3. 
       
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  represents trifluoromethyl. 
     
     
         3 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein Y represents N, CH or COH. 
     
     
         4 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein L 1  represents a direct bond or —(CR 3 R 4 ) t —. 
     
     
         5 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein J represents phenyl, pyridinyl, indolyl or pyrrolopyridinyl. 
     
     
         6 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein L 2  represents direct bond, —O—(CR 9 R 10 ) q — or —O—(CR 3 R 4 ) q —C(O)NR 5 —(CH 2 ) q —. 
     
     
         7 . (canceled) 
     
     
         8 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2  represents:
 halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carboxy, C 1-6 alkoxy, cyano, oxo, fluoroC 1-6 alkyl, hydroxy, amino, N—C 1-4 alkylamino or N,N-di-C 1-4 alkylamino; 
 a monocyclic 4, 5, 6 or 7 membered heterocyclic ring which comprises 1, 2 or 3 heteroatoms independently selected from O, N or S and wherein the heterocyclic ring is optionally substituted with 1, 2 or 3 substituents selected from R 6 ; or 
 a monocyclic 5 or 6 membered heteroaryl ring which comprises 1, 2, 3 or 4 heteroatoms independently selected from O, N or S and wherein the heteroaryl ring is optionally substituted with 1, 2 or 3 substituents selected from R 6 . 
 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein n and p both represent 2. 
     
     
         12 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein k represents 0. 
     
     
         13 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein r represents 0 or 1. 
     
     
         14 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 6  represents C 1-6 alkyl, C 2-6 alkanoyl, fluoroC 1-6 alkyl, C 1-6 alkylsulphonyl or oxo. 
     
     
         15 . (canceled) 
     
     
         16 . A compound according to  claim 1  selected from:
 6-[4-(4-fluorobenzyl)piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(1H-indol-3-yl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(3-fluorobenzyl)piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(3-chlorobenzyl)piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 3-(trifluoromethyl)-6-{4-[3-(trifluoromethyl)benzyl]piperazin-1-yl}-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(2,3-difluorobenzyl)piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-{4-[2-(difluoromethyl)-5-fluorobenzyl]piperazin-1-yl}-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(1H-indol-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-{4-[(5-fluoro-1H-indol-3-yl)methyl]piperazin-1-yl}-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 3-({4-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl}methyl)-1H-indole-5-carbonitrile; 
 4-(4-fluorophenyl)-1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol; 
 6-(4-{4-[2-(1-methyl-1H-pyrazol-5-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[2-(1-methyl-1H-pyrazol-5-yl)ethoxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydropyridin-1(2H)-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 N-(2-methoxyethyl)-N-methyl-2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)acetamide; 
 N,N-dimethyl-2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)acetamide; 
 N-(2-hydroxyethyl)-N-methyl-2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)acetamide; 
 N-butyl-N-methyl-2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)acetamide; 
 N-(2-methoxyethyl)-N-methyl-4-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)butanamide; 
 N-(2-hydroxyethyl)-N-methyl-4-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)butanamide; 
 6-(4-{4-[2-(4-pentanoylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(4-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}phenyl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[3-(4-pentanoylpiperazin-1-yl)propoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(4-{3-[4-(methylsulfonyl)piperazin-1-yl]propoxy}phenyl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[3-(4-pentanoylpiperazin-1-yl)propoxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(4-{3-[4-(methylsulfonyl)piperazin-1-yl]propoxy}phenyl)piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[2-(4-pentanoylpiperazin-1-yl)ethoxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(4-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}phenyl)piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-{4-[4-(4,4,4-trifluorobutoxy)phenyl]piperidin-1-yl}-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 4-{4-[2-(1-methyl-1H-pyrazol-5-yl)ethoxy]phenyl}-1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol; 
 1-methyl-4-[2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one; 
 6-(4-{4-[2-(1H-imidazol-1-yl)ethoxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[2-(2-ethyl-1H-imidazol-1-yl)ethoxy]phenyl}piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 3-(trifluoromethyl)-6-[4-(4-{2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]ethoxy}phenyl)piperazin-1-yl]-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[2-(1H-imidazol-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[2-(2-ethyl-1H-imidazol-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-(4-{4-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 3-(trifluoromethyl)-6-[4-(4-{2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]ethoxy}phenyl)piperidin-1-yl]-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}-1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol; 
 1-ethyl-4-[2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one; 
 1-cyclopropyl-4-[2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one; 
 6-(4-{4-[2-(4-acetyl-1,4-diazepan-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 (3R)-1,3-dimethyl-4-[2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one; 
 (3S)-1,3-dimethyl-4-[2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one; 
 6-[4-(4-{2-[(3R)-4-acetyl-3-methylpiperazin-1-yl]ethoxy}phenyl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 6-[4-(4-{2-[(3S)-4-acetyl-3-methylpiperazin-1-yl]ethoxy}phenyl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 (R)-6-(4-{4-[2-(4-acetylpiperazin-1-yl)propoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 (S)-6-(4-{4-[2-(4-acetylpiperazin-1-yl)propoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine; 
 (S)-1-methyl-4-[1-methyl-2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one; 
 (R) 1-methyl-4-[1-methyl-2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . A pharmaceutical composition which comprises a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier. 
     
     
         20 . A method for treating prostate cancer which comprises administering to a warm-blooded animal, such as man, in need thereof a therapeutically effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined in  claim 1 . 
     
     
         21 . A process for the preparation of a compound of Formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, which comprises a process (a), (b), (c), (d), (e) or (f) wherein, unless otherwise defined, the variables are as defined hereinbefore for compounds of Formula (I):
 (a) when Y in Formula (I) is N, CH or COH, reduction of a compound of Formula (II):   
       
         
           
           
               
               
           
         
         (b) when Y in Formula (I) is CH and L 1  is a direct bond, reduction of a compound of Formula (III): 
       
       
         
           
           
               
               
           
         
         (c) when Y in Formula (I) is N and L 1  is —(CH 2 ) t —, reaction of a compound of Formula (IV) with a compound of Formula (V): or 
       
       
         
           
           
               
               
           
         
         (d) when Y in Formula (I) is C,   represents a double bond, L 1  is a direct bond and J is indolyl or pyrrolopyridinyl, reaction of a compound of Formula (VI) with a compound of Formula (VII) wherein X represents CH or N: 
       
       
         
           
           
               
               
           
         
         (e) when R 2  is a monocyclic 4, 5, 6 or 7 membered heterocyclic ring which comprises 1 N atom and optionally comprises 1 or 2 further heteroatoms independently selected from O, N or S and wherein the heterocyclic ring is optionally substituted with 1, 2 or 3 substituents selected from R 6 , L 2  is a direct bond, —(CR 3 R 4 ) t —, —C(O)N(R 5 )—(CH 2 ) q —, —NR 5 C(O)—(CH 2 ) q —, —C(O)—(CH 2 ) q —, —O—(CR 9 R 10 ) q —, —O—(CR 3 R 4 ) q —NR 5 —(CH 2 ) q —, or —O—(CR 3 R 4 ) q —C(O)NR 5 —(CH 2 ) q — and q is 2, 3 or 4, reaction of a compound of Formula (XVIII) with a monocyclic 4, 5, 6 or 7 membered heterocyclic ring which comprises 1 N atom and optionally comprises 1 or 2 further heteroatoms independently selected from O, N or S and wherein the heterocyclic ring is optionally substituted with 1, 2 or 3 substituents selected from R 6 : 
       
       
         
           
           
               
               
           
         
         (f) when R 2  is a monocyclic 4, 5, 6 or 7 membered heterocyclic ring which comprises 1 N atom and optionally comprises 1 or 2 further heteroatoms independently selected from O, N or S and wherein the heterocyclic ring is optionally substituted with 1, 2 or 3 substituents selected from R 6 ; 
         L 2  is —O—(CR 9 R 10 ) q —; and 
         q is 2, 3, or 4; 
         wherein the final occurrence of —CR 9 R 10 — represents —CHR 9a —; and 
         wherein R 9a  represents methyl, ethyl, isopropyl, cyclopropyl or methoxymethyl; 
         reaction of a compound of a compound of Formula (XIX) with a monocyclic 4, 5, 6 or 7 membered heterocyclic ring which comprises 1 N atom and optionally comprises 1 or 2 further heteroatoms independently selected from O, N or S and wherein the heterocyclic ring is optionally substituted with 1, 2 or 3 substituents selected from R 6 : 
       
       
         
           
           
               
               
           
         
         and thereafter, if necessary: 
         (i) converting a compound of Formula (I) into another compound of Formula (I); 
         (ii) removing any protecting groups; 
         (iii) separating a racemic mixture into separate enantiomers; 
         (iv) preparing a pharmaceutically acceptable salt thereof; and/or 
         (v) preparing a crystalline form thereof. 
       
     
     
         22 . 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine or a pharmaceutically acceptable salt thereof, in combination with abiraterone. 
     
     
         23 . A method for treating prostate cancer which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of the 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine or a pharmaceutically acceptable salt thereof in combination with abiraterone. 
     
     
         24 . A pharmaceutical composition which comprises the combination of  claim 22  in association with a pharmaceutically acceptable diluent or carrier. 
     
     
         25 . A kit comprising the combination of  claim 22 . 
     
     
         26 . A kit comprising the combination of  claim 22 , wherein:
 a) the 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine or a pharmaceutically acceptable salt thereof, is in a first unit dosage form;   b) the abiraterone is in a second unit dosage form; and   c) a container means for containing said first and second dosage forms.