Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Abstract

The present invention discloses compounds according to Formula I: Wherein R 1a , R 1b , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , W, X, Y, Z, Cy, and the subscript a are as defined herein. The present invention relates to compounds inhibiting autotaxin (NPP2 or ENPP2), methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of diseases involving fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases by administering the compound of the invention.

1 ) A compound according to Formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1a  is H, halo or C 1-4  alkyl; 
         R 1b  is:
 halo, 
 C 1-4  alkyl (which alkyl is optionally substituted with one or more independently selected halo), or 
 C 1-4  alkoxy (which alkoxy is optionally substituted with one or more independently selected halo); 
 
         X is —S—, —O—, —N═CH—, —CH═N— or —CH═CH—; 
         W is N, or CR 3    
         when W is N, R 2  is:
 H, 
 —CN, 
 halo, 
 C 1-4  alkyl (which alkyl is optionally substituted with one or more independently selected OH, or CN), 
 —C(═O)CH 3 , 
 —C(═O)CF 3 , 
 —C(═O)OCH 3 , 
 —C(═O)NH 2 , 
 —NHC(═O)CH 3 , or 
 
         when W is CR 3 , one of R 2  or R 3  is:
 H, 
 —CN, 
 halo, 
 C 1-4  alkyl (which alkyl is optionally substituted with one or more independently selected OH, or CN), 
 —C(═O)CH 3 , 
 —C(═O)CF 3 , 
 —C(═O)OCH 3 , 
 —C(═O)NH 2 , 
 —NHC(═O)CH 3 , 
 
         and the other is H, or C 1-4  alkyl; 
         R 4  is C 1-4  alkyl; 
         R 5  is C 1-4  alkyl optionally substituted with one or more independently selected CN, OH, halo, or —C(═O)NH 2 ; 
         one of Y and Z is CH and the other is N; 
         R 6  is selected from H, —CH 3  and halo; 
         Cy is:
 C 4-10  cycloalkyl, 
 4-10 membered mono or bicyclic heterocycloalkyl containing one or more heteratoms independently selected from O, N, and S, or 
 4-7 membered heterocycloalkenyl containing 1 double bond, containing one or more heteroatoms independently selected from O, N, and S; 
 
         each R 7  is independently selected from:
 OH, 
 oxo, 
 halo, and 
 C 1-4  alkyl (which alkyl is optionally substituted with one or more independently selected OH, or C 1-4  alkoxy); 
 
         the subscript a is 0, 1 or 2; 
         R 8  is -(L 1 -W 1 ) m -L 2 -G 1 , 
         wherein
 L 1  is absent, or is —O—, —C(═O)—, —NR i , —NR h C(═O)—, or —SO 2 ; 
 W 1  is C 1-4  alkylene; 
 the subscript m is 0, or 1; 
 L 2  is absent, or is —O—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)—C(═O)—, —C(═O)—C(═O)NR a —, —NR b —, —C(═O)NR c —, —NR d C(═O)—, —NR j C(═O)O—, —SO 2 —, —SO 2 NR e — or —NR f SO 2 —; 
 G 1  is
 H, 
 —CN, 
 C 1-4  alkyl (which alkyl is optionally substituted with one or more independently selected —CN, OH, halo or phenyl), 
 C 3-7  cycloalkyl (which cycloalkyl is optionally substituted with —NH 2 ), 
 5-6 membered heterocycloalkenyl containing 1 double bond containing one or more heteratoms independently selected from O, N, and S, (which heterocycloalkenyl is optionally substituted with one or more independently selected R 9  groups), 
 4-10 membered mono, bi or spirocyclic heterocycloalkyl containing one or more heteratoms independently selected from O, N, and S, (which heterocycloalkyl is optionally substituted with one or more independently selected R 9  groups), or 
 5-6 membered heteroaryl containing one or more heteratoms independently selected from O, N, and S, (which heteroaryl is optionally substituted with one or more independently selected R 10  groups), or 
 
 
         each R 9  is oxo, or R 10 ; 
         each R 10  is:
 —OH, 
 halo, 
 —CN, 
 C 1-4  alkyl (which alkyl is optionally substituted with one or more independently selected OH, halo, or phenyl), 
 C 1-4  alkoxy, 
 C 3-7  cycloalkyl, 
 phenyl, 
 —SO 2 CH 3 , 
 —C(═O)C 1-4  alkoxy, 
 —C(═O)C 1-4  alkyl, or 
 —NR g C(═O)C 1-4  alkyl; and 
 
         each R a , R b , R c , R d , R e , R f , R g , R h , R i , and R j  is independently selected from H, and C 1-4  alkyl; 
         or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof; or a biologically active metabolite thereof. 
       
     
     
         2 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein R 1a  is F, Cl, —CH 3  or —C 2 H 5 . 
     
     
         3 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein R 1b  is F, Cl, —CH 3 , —C 2 H 5 , —CF 3 , —OCH 3 , or —OCF 3 . 
     
     
         4 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein Cy is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. 
     
     
         5 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein the subscript a is 1 or 2, and R 7  is OH, oxo, F, Cl, or —CH 3 . 
     
     
         6 ) A compound according to  claim 1 , wherein the compound is according to Formula IVa, IVb, IVc or IVd: 
       
         
           
           
               
               
           
         
       
       wherein Y, Z, R 6 , L 1 , W 1 , L 2 , G 1  and the subscript m are according to  claim 1 . 
     
     
         7 ) A compound according to  claim 1 , wherein the compound is according to Formula Va, Vb, Vc, or Vd: 
       
         
           
           
               
               
           
         
       
       wherein Y, Z, R 6 , W 1 , and G 1  are according to  claim 1 . 
     
     
         8 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein W 1  is —CH 2 —, —CH 2 —CH 2 —, —C(CH 3 )H—, —CH 2 —CH 2 —CH 2 — or —CH 2 —C(CH 3 )H—. 
     
     
         9 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein G 1  is oxetanyl, azetidinyl, tetrahydropyranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one or two independently selected R 9  groups. 
     
     
         10 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 9 , wherein R 9  is R 10  and R 10  is selected from OH, F, Cl, and —CN. 
     
     
         11 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein R 6  is H, —CH 3  or F. 
     
     
         12 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein Y is N and Z is CH. 
     
     
         13 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein the compound is selected from:
 2-((2-ethyl-6-(piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((6-(4-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((6-(4-(2-(azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,   (R)-2-((2-ethyl-6-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   (S)-2-((2-ethyl-6-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)-N-methylacetamide,   2-((2-ethyl-6-(4-(2-morpholino-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(4-(2-(3-fluoroazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)acetoyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   1-(azetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)ethanone,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,   2-(2-((2-ethyl-6-(piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,   2-(2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,   2-(6-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)pyridin-2-yl)-5-fluorobenzonitrile,   2-(2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)pyrimidin-4-yl)-5-fluorobenzonitrile,   2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)pyrimidine-5-carbonitrile,   2-((2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(piperidin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   (R)-2-((2-ethyl-6-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   (S)-2-((2-ethyl-6-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,   2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino) -4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-1-(2-methylpyrrolidin-1-yl)ethanone,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethanone,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N-methylacetamide,   1-(3,3-difluoropyrrolidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanone,   1-(2,5-dimethylpyrrolidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanone,   (R)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,   (S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N-(2-hydroxyethyl)acetamide,   1-(azetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanone,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N-isopropyl-N-methylacetamide,   N-(2-ethyl-6-(4-(oxetan-3-yl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-(2-ethyl-6-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)methyl)oxazolidin-2-one,   5-((4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)methyl)oxazolidin-2-one,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,   2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(2,2,2-trifluoroacetoyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,   1-(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethyl)pyrrolidin-2-one,   (4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone,   N-(2-ethyl-6-(4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)propan-1-ol,   3-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)propan-1-ol,   3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)propanenitrile,   3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)propanamide,   N-(2-ethyl-6-(4-(2-methoxyethyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N-isopropylacetamide,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone,   tert-butyl 2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethylcarbamate,   N-(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethyl)acetamide,   ethyl 2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethylcarbamate,   (S)-tert-butyl 4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate,   (S)-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-2-yl)methanol,   (S)-7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one,   (S)—N-(2-ethyl-6-(3-(methoxymethyl)-4-(methylsulfonyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   (S)-(1-(3-(dimethylamino)propylsulfonyl)-4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-2-yl)methanol,   (S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-2-(hydroxymethyl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone,   (S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-2-(hydroxymethyl)piperazin-1-yl)-1-morpholinoethanone,   (S)-8-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(1H)-one,   (S)-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-1-(methylsulfonyl)piperazin-2-yl)methanol,   (S)-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-1-(methylsulfonyl)piperazin-2-yl)methanol,   (R)-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-1-(methylsulfonyl)piperazin-2-yl)methanol,   3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one,   N-(2-ethyl-6-(4-(ethylsulfonyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-1-(methylsulfonyl)piperazin-2-yl)ethanol,   2-(4-(2-ethyl-3-((4-(4-fluoro-2-methylphenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,   tert-butyl-(1R,4S)-5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-2,5-diazabicyclo[2.2.1]heptane -2-carboxylate,   1-((1R,4S)-5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethanone,   N-(2-ethyl-6-((1S,4R)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-(2-ethyl-6-(3-azaspiro[5.5]undecan-3-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-(2-ethyl-6-morpholinoimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   6-(1,1-Dioxo-thiomorpholin-4-yl)-2-ethyl-imidazo[1,2-b]pyridazin-3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine,   N-(6-(4-(dimethylamino)piperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   tert-butyl 1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-ylcarbamate,   N-(6-(4-aminopiperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)methanesulfonamide,   N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)tetrahydro-2H-pyran-4-carboxamide,   N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)-2-hydroxyacetamide,   N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)-3-methyloxetane-3-carboxamide,   tert-butyl 4-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-ylcarbamoyl)piperidine-1-carboxylate,   N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)piperidine-4-carboxamide,   N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)pyrrolidine-1-carboxamide,   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-ol,   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ol,   N-ethyl-2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-yloxy)acetamide,   (1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)methanol,   (1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-yl)methanol,   1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-b]pyridazin-6-yl)-piperidine-4-carboxylic acid ethyl ester,   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxylic acid,   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-hydroxyethyl)piperidine-4-carboxamide,   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxamide,   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxamide,   [1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-b]pyridazin-6-yl)-piperidin-3-ylmethyl]-carbamic acid tert-butyl ester,   N-(6-(3-(aminomethyl)piperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-yl)methyl)methanesulfonamide,   [1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-b]pyridazin-6-yl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester,   N-(6-(4-(aminomethyl)piperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)methyl)methanesulfonamide,   3-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)methyl)-1,1-dimethylurea,   N-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide,   2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)-N,N-dimethylacetamide,   N-(2-ethyl-6-(4-morpholinopiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-(2-ethyl-6-(3-morpholinopiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-(6-(1,4′-bipiperidin-1′-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   1′-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-1,3′-bipiperidin-4-ol,   N-(2-ethyl-6-(4-phenylpiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-cyclopropyl-1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidine-4-sulfonamide,   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-1,4-diazepan-1-yl)ethanone,   N-(2-ethyl-6-(4-(methylsulfonyl)-1,4-diazepan-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-(2-ethyl-6-(8-oxa-2-azaspiro[4.5]decan-2-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-1-oxa-3,7-diazaspiro[4.4]nonan-2-one,   7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-3-methyl-1-oxa-3,7-diazaspiro[4.4]nonan-2-one,   7-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-3-methyl-1-oxa-3,7-diazaspiro[4.4]nonan-2-one,   7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-2,7-diazaspiro[4.4]nonane-1,3-dione,   tert-butyl 5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate,   N-(2-ethyl-6-(5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   1-(5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethanone,   N-(6-(5-(3-chloropropylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-(6-(5-(3-(dimethylamino)propylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   N-(2-ethyl-6-(5-(3-morpholinopropylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   (S)-1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carbonitrile,   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ol,   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl formate,   N-(2-ethyl-6-(3-thiomorpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   1-(3-((5-chloro-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-one,   tert-butyl 1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamate,   N-(6-(3-aminopyrrolidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   methyl 2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylamino)acetate,   N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)-2-hydroxyacetamide,   N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)methanesulfonamide,   (S)-1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-2-carboxylic acid,   1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidine-3-carboxylic acid methyl ester,   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-hydroxyethyl)pyrrolidine-3-carboxamide,   (1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)(morpholino)methanone,   (1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-2-yl)methanol,   (1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)methanol,   (1-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)methanol,   3-(4-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)piperazin-1-yl)propan-1-ol,   4-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)piperazin-2-one,   N-(2-ethyl-6-(3-morpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   (2-((2-ethyl-6-(3-morpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)methanol,   2-((2-ethyl-6-(3-morpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   {6-[3-(1,1-Dioxo-thiomorpholin-4-yl)-pyrrolidin-1-yl]-2-ethyl-imidazo[1,2-b]pyridazin-3-yl}-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine,   N-(2-ethyl-6-(3-(piperidin-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   1-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)piperidin-4-ol,   (1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)azetidin-3-yl)methanol,   [1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-b]pyridazin-6-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester,   2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)azetidin-3-ylamino)-1-(3-hydroxyazetidin-1-yl)ethanone,   2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)azetidin-3-ylamino)-N,N-dimethylacetamide,   2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)azetidin-3-ylamino)-N-methylacetamide,   N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)azetidin-3-yl)methanesulfonamide,   (1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)azetidin-3-yl)(3-hydroxypyrrolidin-1-yl)methanone,   2-((2-ethyl-6-(4-((2-oxooxazolidin-5-yl)methyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   (S)-2-((2-ethyl-6-(3-(hydroxymethyl)-4-(methylsulfonyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-7-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(3-methyl-2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-7-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(3-methyl-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonan-7-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   tert-butyl 7-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate,   2-((2-ethyl-6-(2,7-diazaspiro[4.4]nonan-2-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((6-(7-acetoyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   methyl (1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)-3-hydroxypyrrolidin-3-yl),   N-((1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)-3-hydroxypyrrolidin-3-yl)methyl)acetamide,   N-((1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)-3-hydroxypyrrolidin-3-yl)methyl)isobutyramide,   2-((2-ethyl-6-(3-hydroxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(3-oxopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(3-(hydroxymethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   (S)-2-((2-ethyl-6-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethylamino)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   (S)-2-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylamino)-N,N-dimethylacetamide,   (R)-2-((2-ethyl-6-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethylamino)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   (R)-2-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylamino)-N,N-dimethylacetamide,   2-((6-(3-((2S,6R)-2,6-dimethylmorpholino)pyrrolidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(3-(4-(hydroxymethyl)piperidin-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((6-(3-(4-acetoylpiperazin-1-yl)pyrrolidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   N-(1-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)piperidin-4-yl)-N-methylacetamide,   2-((2-ethyl-6-(3-(4-hydroxypiperidin-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(3-(4-methoxypiperidin-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-((3S,4S)-3-hydroxy-4-morpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   1-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ol,   (2-((2-ethyl-6-(8-oxa-2-azaspiro[4.5]decan-2-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)methanol,   [1-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-imidazo[1,2-b]pyridazin-6-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester,   2-((6-(3-aminoazetidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethylamino)azetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   N-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)azetidin-3-yl)methanesulfonamide,   2-((2-ethyl-6-(3-(morpholine-4-carbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-((2-ethyl-6-(3-(3-hydroxypyrrolidine-1-carbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,   4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-b]pyridazin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester,   N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,   (3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol,   2-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetonitrile,   3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanamide,   3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanenitrile,   3-(3-((4-(4-fluorophenyl)-5-(2,2,2-trifluoroacetoyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanenitrile,   3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propan-1-ol,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,   2-(2-((2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,   2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,   2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-5-(hydroxymethyl)thiazol-4-yl)-5-fluorobenzonitrile,   2-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,   2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,   2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N-methylacetamide,   2-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)-5-fluorobenzonitrile,   2-(4-(3-((4-(2-cyano-4-fluorophenyl)-5-methylthiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N-methylacetamide,   2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-b]pyridazin -3-yl)(methyl)amino) -4-(4-fluorophenyl)thiazole-5-carbonitrile,   2-(6-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)pyridin-2-yl)-5-fluorobenzonitrile,   2-(4-(2-ethyl-3-((6-(4-fluorophenyl)pyridin-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)pyrimidin-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,   2-(4-(2-ethyl-3-((2-(4-fluorophenyl)pyrimidin-4-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,   2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-6-(4-fluorophenyl)nicotinonitrile,   6-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-2-(4-fluorophenyl)nicotinonitrile,   2-(5-((2-ethyl-6-(piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-1,2,4-thiadiazol-3-yl)-5-fluorobenzonitrile, and 2-(5-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-1,2,4-thiadiazol-3-yl)-5-fluorobenzonitrile.   
     
     
         14 ) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to  claim 1 . 
     
     
         15 ) A pharmaceutical composition according to  claim 14 , comprising a further therapeutic agent. 
     
     
         16 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , for use in medicine. 
     
     
         17 ) A compound or pharmaceutically acceptable salt thereof, according to  claim 1 , for use in the treatment of fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases. 
     
     
         18 ) The use of a compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein said compound is administered in combination with a further therapeutic agent. 
     
     
         19 ) A method for the treatment, or prevention of diseases or conditions selected from fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases, comprising administering an amount of compound according to  claim 1 , sufficient to effect said treatment, or prevention. 
     
     
         20 ) The method according to  claim 19 , wherein the compound, or the pharmaceutical composition, is administered in combination with a further therapeutic agent.