Isoquinoline derivatives as SIK2 inhibitors

A compound of formula (IVa), (IVb) or (IVc), or a salt or solvate thereof:

• wherein X4 is nitrogen;
• m1 and m2 are numbers independently selected from 1, 2, 3 and 4;
• q is a number independently selected from 1, 2 and 3;
• Re is selected from hydrogen, halogen, CN, ═O, (CH2)yOH, C1-6 alkyl, (CH2)yC1-6 alkoxy, (CH2)yC1-6 haloalkyl, (CH2)yC1-6 haloalkoxy, (CH2)yNH2, (CH2)yNHRq, (CH2)yN(Rq)2, (CH2)yNHCO(Rq), (CH2)yCONH2, (CH2)yCONH(Rq), and (CH2)yCON(Rq)2, and where each Rq is independently selected from C1-4 alkyl which is optionally substituted with one or more groups selected from halogen, OH, NH2, NHMe, NMe2, and C1-3 alkoxy;
• and where y is a number between 0 and 3;
• Rx1 and Rx5 are independently selected from hydroxyl, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, 3-10 membered heterocycloalkyl, alkylheterocycloalkyl, C6-11 aryl, alkylaryl, heteroaryl, alkylheteroaryl —C(═O)Rh, —C(═O)ORj, —C(═O)NRjRk, —C(O)C(═O)Rh, —NRjRk, —NRjC(═O)Rh, —NRjC(═O)ORk, —NRjC(═O) NRjRk, —ORj, —SRj, —OC(═O)Rh, —OC(═O)NRjRk, —OC(═O)ORj, —S(═O)2Rh, —S(═O)Rh, —OS(═O)Rh, —OS(═O)2Rh, —OS(═O)2ORj, —S(═O)NRjRk, —OS(═O)2NRjRk, —S(═O)2NRjRk;
• where said C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, 3-10 membered heterocycloalkyl, alkylheterocycloalkyl, C6-11 aryl, alkylaryl, heteroaryl and alkylheteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, ═O, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, NRjRk, C1-6 alkyl, O—C1-6 alkyl, and phenyl;
• and
• Rx2 is selected from hydroxyl, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, C3-6 cycloalkyl, 3-10 membered heterocycloalkyl, alkylheterocycloalkyl, C6-11 aryl, alkylaryl, heteroaryl, alkylheteroaryl-C(═O)Rh, —C(═O)ORj, —C(O)C(═O)Rh, —NRjRk, —NRjC(═O)ORk, —SRj, —OC(═O)Rh, —OC(═O)NRjRk, —OC(═O)ORj, —S(═O)2Rh, —S(═O)Rh, —OS(═O)Rh, —OS(═O)2Rh, —OS(═O)2ORj, —S(═O)NRjRk, —OS(═O)2NRjRk;
• where said C1-6 alkyl, C3-6 cycloalkyl, 3-10 membered heterocycloalkyl, alkylheterocycloalkyl, C6-11 aryl, alkylaryl, heteroaryl and alkylheteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, ═O, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, NRjRk, C1-6 alkyl, O—C1-6 alkyl, and phenyl;
• where each Rh, Rj and Rk are independently selected from hydrogen, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, and C1-6 alkyl wherein said C3-6 cycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl and C1-6 alkyl are optionally substituted with one or more groups selected from halogen, CN, C1-6 alkyl, C1-6 alkoxy, NH2, NH (C1-3 alkyl) and N (C1-3 alkyl)2;
• or Rj and Rk when attached to the same atom and together with the atom to which they are attached combine to provide a 3-7 membered heterocycloalkyl which is optionally substituted by one or more groups selected from halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, ═O and CN;
• or
• a compound selected from:
• Example
• Structure
• E2
• E5
• E6
• E8
• E9
• E10
• E11
• E12
• E13
• E14
• E15
• E16
• E18
• E19
• E21
• E22
• E24
• E27
• E28
• E29
• E44
• E45
• E46
• E47
• E48
• E52
• E55
• E56
• E57
• E58
• E59
• E60
• E61
• E71
• E72
• E73
• E74
• E75
• E76
• E77
• E78
• E79
• E81
• E82
• E83
• E84
• E99
• E100
• E101
• E102
• E104
• E105
• E106
• E107
• E108
• E109
• E110
• E111
• E112
• E113
• E114
• E116
• E118
• E119
• E120
• E134
• E135
• E133
• E136
• Example
• Name
• E2
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(3S)- 3- piperidyl]methyl]isoquinoline-3,5-diamine
• E5
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(2R)- 2- piperidyl]methyl]isoquinoline-3,5-diamine
• E6
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(3R)- pyrrolidin-3- yl]methyl]isoquinoline-3,5-diamine
• E8
• 7-(2-fluoro-6-methyl-phenyl)-N5-(4- piperidylmethyl)isoquinoline-3,5-diamine
• E9
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(3S)- pyrrolidin-3- yl]methyl]isoquinoline-3,5-diamine
• E10
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(3R)- 3- piperidyl]methyl]isoquinoline-3,5-diamine
• E11
• N5-(azetidin-3-ylmethyl)-7-(2-fluoro-6- methyl- phenyl)isoquinoline-3,5-diamine
• E12
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(2R)- pyrrolidin-2- yl]methyl]isoquinoline-3,5-diamine
• E13
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(2S)- pyrrolidin-2- yl]methyl]isoquinoline-3,5-diamine
• E14
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(2S)- 2- piperidyl]methyl]isoquinoline-3,5-diamine
• E15
• 7-(2-fluoro-6-methyl-phenyl)-5-[4- (methylamino)-1- piperidyl]isoquinolin-3-amine
• E16
• 7-(2-fluoro-6-methyl-phenyl)-5-[(3S)-3- (methylamino)pyrrolidin-1-yl]isoquinolin-3-amine
• E18
• 7-(2-fluoro-6-methyl-phenyl)-5-[(3S)-3- (methylamino)-1- piperidyl]isoquinolin-3-amine
• E19
• 7-(2-fluoro-6-methyl-phenyl)-5-[(3R)-3- (methylamino)-1- piperidyl]isoquinolin-3-amine
• E21
• 7-(2-fluoro-6-methyl-phenyl)-5-[(3R)-3-(methylaminomethyl)- 1-piperidyl]isoquinolin-3-amine
• E22
• 7-(2-fluoro-6-methyl-phenyl)-5-[(3S)-3- (methylaminomethyl)- 1-piperidyl]isoquinolin-3-amine
• E24
• 7-(2-fluoro-6-methyl-phenyl)-5-[(3R)-3- (methylamino)pyrrolidin-1-yl]isoquinolin-3-amine
• E27
• 7-(2-fluoro-6-methyl-phenyl)-N3-methyl- N5-(4- piperidyl)isoquinoline-3,5-diamine
• E28
• 7-(2-fluoro-6-methyl-phenyl)-N3- isopropyl-N5-(4- piperidyl)isoquinoline-3,5-diamine
• E29
• 7-(2-fluoro-6-methyl-phenyl)-5-[3- (methylamino)azetidin- 1-yl]isoquinolin-3-amine
• E44
• N-[3-amino-7-(2-fluoro-6-methyl- phenyl)-5- isoquinolyl]piperidine-4-carboxamide
• E45
• N-[3-amino-7-(2-fluoro-6-methyl- phenyl)-5- isoquinolyl]azetidine-3-carboxamide
• E46
• 7-(2-fluoro-6-methyl-phenyl)-5-(4- piperidyloxy)isoquinolin- 3-amine
• E47
• 5-(azetidin-3-yloxy)-7-(2-fluoro-6- methyl-phenyl)isoquinolin- 3-amine
• E48
• 7-(2-fluoro-6-methyl-phenyl)-5-[(3R)- pyrrolidin-3-yl]oxy- isoquinolin-3-amine
• E52
• 3-amino-7-(2-fluoro-6-methyl-phenyl)-N- (4- piperidyl)isoquinoline-5-carboxamide
• E55
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(2S)- 1-methylpyrrolidin- 2-yl]methyl]isoquinoline-3,5-diamine
• E56
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(2R)- 1-methyl-2- piperidyl]methyl]isoquinoline-3,5-diamine
• E57
• 5-[4-(dimethylamino)-1-piperidyl]-7-(2- fluoro-6-methyl- phenyl)isoquinolin-3-amine
• E58
• 5-[(3R)-3-(dimethylamino)pyrrolidin-1- yl]-7-(2-fluoro-6- methyl-phenyl)isoquinolin-3-amine
• E59
• 5-[(3S)-3-(dimethylamino)pyrrolidin-1- yl]-7-(2-fluoro-6- methyl-phenyl)isoquinolin-3-amine
• E60
• 5-[(3R)-3-[(dimethylamino)methyl]-1- piperidyl]-7-(2- fluoro-6-methyl-phenyl)isoquinolin-3-amine
• E61
• 5-[(3S)-3-[(dimethylamino)methyl]-1- piperidyl]-7-(2- fluoro-6-methyl-phenyl)isoquinolin-3-amine
• E71
• 7-(2-fluoro-6-methyl-phenyl)-N5-[(1- methyl-4- piperidyl)methyl]isoquinoline-3,5-diamine
• E72
• 7-(2-fluoro-6-methyl-phenyl)-N5-[(1- methylazetidin-3- yl)methyl]isoquinoline-3,5-diamine
• E73
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(2R)- 1-methylpyrrolidin- 2-yl]methyl]isoquinoline-3,5-diamine
• E74
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(3S)- 1-methylpyrrolidin- 3-yl]methyl]isoquinoline-3,5-diamine
• E75
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(3R)- 1-methylpyrrolidin- 3-yl]methyl]isoquinoline-3,5-diamine
• E76
• 7-(2-fluoro-6-methyl-phenyl)-N5-[(3S)- 1-methyl-3- piperidyl]methyl]isoquinoline-3,5-diamine
• E77
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(3R)- 1-methyl-3- piperidyl]methyl]isoquinoline-3,5-diamine
• E78
• 7-(2-fluoro-6-methyl-phenyl)-N5-[[(2S)- 1-methyl-2- piperidyl]methyl]isoquinoline-3,5-diamine
• E79
• 5-[3-(dimethylamino)azetidin-1-yl]-7-(2- fluoro-6-methyl- phenyl)isoquinolin-3-amine
• E81
• 5-[(3S)-3- [(dimethylamino)methyl]pyrrolidin-1-yl]- 7-(2-fluoro-6-methyl-phenyl)isoquinolin-3-amine
• E82
• 5-[(3S)-3-(dimethylamino)-1-piperidyl]- 7-(2-fluoro-6- methyl-phenyl)isoquinolin-3-amine
• E83
• 5-[(3S)-3-(dimethylamino)-1-piperidyl]- 7-(2-fluoro-6- methyl-phenyl)-N-methyl-isoquinolin-3-amine
• E84
• 5-[(3R)-3-(dimethylamino)-1-piperidyl]- 7-(2-fluoro-6- methyl-phenyl)isoquinolin-3-amine
• E99
• 3-amino-7-(2-fluoro-6-methyl-phenyl)-N- (1-methylpyrrolidin- 3-yl)isoquinoline-5-carboxamide
• E100
• 3-amino-7-(2-fluoro-6-methyl-phenyl)-N- (1-methylazetidin- 3-yl)isoquinoline-5-carboxamide
• E101
• 7-(2-fluoro-6-methyl-phenyl)-5-[(1- methyl-4- piperidyl)oxy]isoquinolin-3-amine
• E102
• 7-(2-fluoro-6-methyl-phenyl)-5-(1- methylazetidin-3 -yl)oxy-isoquinolin-3-amine
• E104
• 1-[3-amino-7-(2-fluoro-6-methyl-phenyl)- 5- isoquinolyl]piperidin-4-ol
• E105
• (3S)-1-[3-amino-7-(2-fluoro-6-methyl- phenyl)-5- isoquinolyl]pyrrolidin-3-ol
• E106
• (3R)-1-[3-amino-7-(2-fluoro-6-methyl- phenyl)-5- isoquinolyl]pyrrolidin-3-ol
• E107
• (3S)-1-[3-amino-7-(2-fluoro-6-methyl- phenyl)-5- isoquinolyl]piperidin-3-ol
• E108
• (3R)-1-[3-amino-7-(2-fluoro-6-methyl- phenyl)-5- isoquinolyl]piperidin-3-ol
• E109
• 4-[[3-amino-7-(2-fluoro-6-methyl- phenyl)-5- isoquinolyl]amino]cyclohexanol
• E110
• 7-(2-fluoro-6-methyl-phenyl)-N5- tetrahydropyran-4-yl- isoquinoline-3,5-diamine
• E111
• N5-cyclohexyl-7-(2-fluoro-6-methyl- phenyl)isoquinoline- 3,5-diamine
• E112
• N-[(3S)-1-[3-amino-7-(2-fluoro-6- methyl-phenyl)-5- isoquinolyl]pyrrolidin-3-yl]acetamide
• E113
• N-[(3R)-1-[3-amino-7-(2-fluoro-6- methyl-phenyl)-5- isoquinolyl]pyrrolidin-3-yl]acetamide
• E114
• N-[1-[3-amino-7-(2-fluoro-6-methyl- phenyl)-5- isoquinolyl]-4-piperidyl]acetamide
• E116
• 3-amino-7-(2-fluoro-6-methyl-phenyl)-N- (1-methyl-4- piperidyl)isoquinoline-5-carboxamide
• E118
• N5-(1-ethyl-4-piperidyl)-8-fluoro-7-(2- fluoro-6-methyl- phenyl)isoquinoline-3,5-diamine
• E119
• 8-fluoro-7-(2-fluoro-6-methyl-phenyl)- N5-(1-methyl-4- piperidyl)isoquinoline-3,5-diamine
• E120
• 8-fluoro-7-(2-fluoro-6-methyl-phenyl)- N5-(4- piperidyl)isoquinoline-3,5-diamine
• E134
• 6-fluoro-7-(2-fluoro-6-methyl-phenyl)- N5-(4- piperidyl)isoquinoline-3,5-diamine
• E135
• 6-fluoro-7-(2-fluoro-6-methyl-phenyl)- N5-(1-methyl-4- piperidyl)isoquinoline-3,5-diamine
• E133
• 3-amino-7-(2-fluoro-6-methyl-phenyl)-5- (4- piperidylamino)isoquinoline-4-carbonitrile
• E136
• N-[3-amino-7-(2-fluoro-6-methyl- phenyl)-5- isoquinolyl]pyrrolidine-3-carboxamide;
• or a salt or solvate of any one thereof.