Classifications

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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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  • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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  • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
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  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
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  • A61K31/4164—1,3-Diazoles
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  • A61K31/4192—1,2,3-Triazoles
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  • A61K31/4196—1,2,4-Triazoles
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  • A61K31/42—Oxazoles
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  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D495/14—Ortho-condensed systems

Definitions

• the invention relates to pharmaceutical compositions comprising casein kinase 1 delta (CK15) inhibitors and to the use of said inhibitors in the treatment of neurodegenerative disorders such as Alzheimer's disease.
• CK15 casein kinase 1 delta
• Alzheimer's disease also known as senile dementia of the Alzheimer type (SDAT), primary degenerative dementia of the Alzheimer's type (PDDAT), or Alzheimer's
• SDAT senile dementia of the Alzheimer type
• PDAT primary degenerative dementia of the Alzheimer's type
• Alzheimer's is the most common form of dementia. Most often, Alzheimer's disease is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.
• Alzheimer's disease is a neurodegenerative disease characterised by the presence of senile plaques and neurofibrillary tangles in the brain.
• the degree of dementia at death correlates better with neurofibrillary tangle numbers than with senile plaques counts.
• the presence of neurofibrillary tangles in neurons results in the death of those neurons, implying that prevention of tangle formation is an important therapeutic goal.
• the principal protein that forms the neurofibrillary tangle is the microtubule-associated protein, tau, which assembles into filaments that have the appearance of twisting about each other in pairs and are referred to as paired helical filaments (PHF).
• PHF paired helical filaments
• tauopathies are frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, corticobasal degeneration, and multisystem atrophy (MSA).
• FTDP-17 progressive supranuclear palsy
• MSA multisystem atrophy
• this hyperphosphorylated tau is often referred to as PHF- tau because it is derived from the PHF.
• Tau is a phosphoprotein, the function of phosphorylation remaining to be unequivocally established.
• increased phosphorylation of tau on multiple serine and threonine residues reduces the ability of tau to promote microtubule assembly and to stabilise assembled microtubules, effects that have been demonstrated both in vitro and in cells.
• Many studies have shown that PHF-tau from AD brain is more heavily phosphorylated on serine and threonine than tau from control brain.
• CK15 As a potential tau kinase is of particular interest since it has been reported that CK15 protein is increased more than 30- fold in the hippocampus of Alzheimer brain compared to equivalent controls (Ghoshal, N. ei a/ (1999) Am. J. Pathol 155, 1 163-1 172) while its mRN A content is increased 24-fold (Yasojima, K. et a/ (2000) Brain Res 865, 1 16-120) and CK1 has also been shown to be tightly associated with PHF (Kuret, J.ei a/ (1997) J. Neurochem 69, 2506-2515).
• CK15 has also been reported to phosphorylate tau at two epitopes detecting using phospho- specific monoclonal antibodies to tau, and exogenous expression of CK15 in non- neuronal cells reduces binding of tau to microtubules (Li, G. et al (2004) J. Biol. Chem. 279, 15938-15945).
• CK1 activity is stimulated by amyloid beta-peptide ( ⁇ ), a component of the senile neuritic plaques that, together with tangles, characterise Alzheimer brain (Chauhan, A. et al (1993) Brain Res. 629, 47-52).
• CK15 inhibitors which may be of potential therapeutic benefit in the treatment of neurodegenerative diseases, such as tauopathies including
• Alzheimer's disease frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, corticobasal degeneration, and multisystem atrophy (MSA).
• FTDP-17 frontotemporal dementia with Parkinsonism linked to chromosome 17
• PSP progressive supranuclear palsy
• MSA multisystem atrophy
• a pharmaceutical composition comprising a compound of formula (IA) or a pharmaceutically acceptable salt or solvate thereof:
• Het A represents a 4 or 5 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings;
• X and Y independently represent a bond, -C(R 7a )(R 8a )-, (CH 2 ) 2 , -0-, -S-, -CH 2 -0-, -(CH 2 ) 2 - 0-, NR 6a , -N(R 6a )-C(R 7a )(R 8a )-, -N(R 6a )-(CH 2 ) 2 -, -N(R 6a )-(CH 2 ) 3 -, -CH 2 -N(R 6a )-(CH 2 ) 2 -, -CH 2 -N(R 6a )-(CH 2
• R 5a represents hydrogen, C 1-6 alkyl or cyano
• R 6a represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, -CH 2 -C 3-8 cycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-aryl, -CO-aryl, -CO-heteroaryl or -C(R 7a )(R 8a )- heteroaryl, wherein said aryl groups of R 6a may be optionally substituted by one or more halogen or C 1-6 alkoxy groups;
• R 7a and R 8a independently represent hydrogen or C 1-6 alkyl
• R 1a and R 2a independently represent aryl, C 3-8 cycloalkyl, monocyclic or bicyclic
• R 1a and R 2a may be substituted by one or more (e.g. 1 , 2 or 3) R 4a groups;
• R 4a represents halogen, Ci -6 alkyl, Ci -6 alkenyl, Ci -6 alkynyl, C 3-8 cycloalkyl, haloCi -6 alkyl, hydroxyl, d -6 alkoxy, -0-Ci -6 alkenyl, haloCi -6 alkoxy, -COOH, -CO-Ci -6 alkyl, -COO-Ci -6 alkyl, -CONH 2 , -CH 2 -CONH 2 , -NH-Ci -6 alkyl, -NH-C 2-6 alkenyl, -NH-CO-Ci -6 alkyl, -CO- NH-Ci-6 alkyl, -0-CH 2 -CO-NH-Ci -6 alkyl, -CH 2 -CH 2 -CO-NH-Ci -6 alkyl, -S-Ci -6 alkyl, -SO-d.
• n an integer from 0 to 3;
• the compound is other than compound number 38, 138, 212, 243, 378, 415, 441 , 480, 577, 579, 580, 587-589, 593, 598, 600, 629, 636, 678, 684, 747, 760, 802, 861 , 871 , 873, 879, 883, 897-899, 904-905, 907, 909, 915, 917-919, 922-923, 925, 929-930, 938-939, 961.
• the compound of formula (IA) is selected from any of compounds: 1 , 4-17, 19-25, 36-37, 39-40, 42, 44-45, 52, 61 , 71 -76, 80-83, 86-91 , 93-97, 102-107, 1 10- 1 12, 1 14, 1 17-122, 139-143, 149-151 , 153, 158-160, 163-170, 174-177, 185-197, 200, 202-203, 208-209, 21 1 , 213-221 , 223-224, 226, 228-229, 232, 234, 237-240, 256, 261- 264, 267-268, 270, 272, 275-283, 296, 304, 313, 319, 321-323, 326-328, 332, 334-335, 342-345, 350, 356, 361-365, 367-369, 372, 377, 379, 383, 393, 398, 403, 406, 412-413, 416-423, 431-432
• the compound of formula (IA) is selected from any of
• the compound of formula (IA) is selected from any of compounds:
• the compound of formula (IA) is selected from any of compounds:
• the compound of formula (IA) is selected from any of compounds: 10, 25, 42, 45, 223, 240, 281 -282, 321 , 439, 465, 506, 512, 61 1-614, 619, 623-624, 633, 639, 654, 656, 670, 672, 676-677, 683, 697, 717, 736, 761 , 765-766, 768, 809-810, 820, 842, 851 , 856, 859-860, 863, 931 , 947-948, 967, 970, 982, 984, 989, 991-992, 1000 and 1002 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compounds of this embodiment were tested in the CK15 inhibition assay as described herein and exhibited inhibition of greater than
• the compound of formula (IA) is selected from any of compounds: 10, 42, 45, 240, 654, 656, 766, 856, 859, 863, 931 , 947-948 and 967 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compounds of this embodiment were tested in the CK15 inhibition assay as described herein and exhibited inhibition of greater than 50%.
• the compound of formula (IA) is selected from any of compounds: 10, 654, 856, 859, 931 and 947 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compounds of this embodiment were tested in the CK15 inhibition assay as described herein and exhibited inhibition of greater than 90%.
• composition comprising a compound of formula (IB) or a pharmaceutically acceptable salt or solvate thereof:
• Het B represents a 5 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is fused to one or more (e.g. 1 -3) further rings to form a polycyclic ring system comprising up to 4 rings;
• R 5b represents hydrogen, C 1-6 alkyl or cyano
• R 6b represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, COOH, -COOC 1-6 alkyl, C 3-8 cycloalkyl, -CH 2 -C 3- 8 cycloalkyl, aryl, heteroaryl, -Ci -6 alkylene-aryl, -CO-aryl, -O-CO- heteroaryl, -CO-heteroaryl or -C(R )(R )-heteroaryl, wherein said aryl groups of R may be optionally substituted by one or more halogen or Ci -6 alkoxy groups;
• R 7b and R 8b independently represent hydrogen or Ci -6 alkyl
• R 1b represents aryl, C 3 - 8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1b may be substituted by one or more (e.g. 1 , 2 or 3) R 4b groups;
• R 4b represents halogen, Ci -6 alkyl, Ci -6 alkenyl, Ci -6 alkynyl, C 3- 8 cycloalkyl, haloCi -6 alkyl, hydroxyl, C 1-6 alkoxy, -0-C 1-6 alkenyl, haloC 1-6 alkoxy, -COOH, -CO-C 1-6 alkyl, -COO-C 1-6 alkyl, -CONH 2 , -CH 2 -CONH 2 , -NH-C 1-6 alkyl, -NH-C 2-6 alkenyl, -NH-CO-C 1-6 alkyl, -CO- NH-C 1-6 alkyl, -0-CH 2 -CO-NH-C 1-6 alkyl, -CH 2 -CH 2 -CO-NH-C 1-6 alkyl, -S-C 1-6 alkyl, -SO-d.
• n an integer from 0 to 3;
• the compound is other than compound number 54, 373, 458, 496, 585, 590, 594, 596-597, 601 -602, 649, 703, 778, 877, 891 , 910, 912, 926 and 962-963.
• the compound of formula (IB) is selected from any of compounds 2-3, 26-28, 30-33, 35, 47-48, 51 , 57-60, 63-64, 78, 84, 1 13, 123, 127-129, 145, 155-157, 171- 173, 204, 206-207, 210, 225, 227, 233, 235-236, 241 -242, 244, 249, 269, 285, 288, 303, 307-312, 314-316, 320, 324-325, 333, 336, 351 , 357-360, 374-375, 384-391 , 396, 399- 402, 404-405, 407-41 1 , 414, 424-425, 427-428, 437, 448, 456-457, 482, 484-485, 489- 491 , 495, 497-498, 505, 507, 516, 519, 524, 526, 553, 559-560, 568, 570,
• the compound of formula (IB) is selected from any of
• the compound of formula (IB) is selected from any of compounds:
• the compound of formula (IB) is selected from any of compounds:
• a pharmaceutical composition comprising a compound of formula (IC) or a pharmaceutically acceptable salt or solvate thereof:
• Het C represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings;
• R 5c represents hydrogen, Ci -6 alkyl or cyano
• R 6c represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, -CH 2 -C 3-8 cycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-aryl, -CO-aryl, -CO-heteroaryl or -C(R 7c )(R 8c )- heteroaryl, wherein said aryl groups of R 6c may be optionally substituted by one or more halogen or C 1-6 alkoxy groups;
• R 7c and R 8c independently represent hydrogen or C 1-6 alkyl
• R 1c and R 2c independently represent aryl, C 3-8 cycloalkyl, monocyclic or bicyclic
• R 1c and R 2c may be substituted by one or more (e.g. 1 , 2 or 3) R 4c groups;
• R 4c represents halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl, hydroxyl, Ci -6 alkoxy, -0-Ci -6 alkenyl, haloCi -6 alkoxy, -COOH, -CO-Ci -6 alkyl, -COO-Ci -6 alkyl, -CONH 2 , -CH 2 -CONH 2 , -NH-C 1-6 alkyl, -NH-C 2-6 alkenyl, -NH-CO-C 1-6 alkyl, -CO- NH-C1-6 alkyl, -0-CH 2 -CO-NH-Ci -6 alkyl, -CH 2 -CH 2 -CO-NH-Ci -6 alkyl, -S-Ci -6 alkyl, -SO-d.
• p represents an integer from 0 to 3;
• the compound is other than compound number 161 , 648, 658, 680, 726, 824, 867, 880, 892, 896, 901 , 903, 906, 928 and 944.
• Het C represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to one further ring to form a bicyclic ring system.
• Het C represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to a phenyl ring to form a bicyclic ring system.
• Het C represents a 6 membered heterocyclic ring system containing 1 or 2 nitrogen atoms, wherein said ring system is optionally fused to a phenyl ring to form a bicyclic ring system.
• Het C represents pyridinyl, pyrimidinyl or quinazolinyl. In a yet further embodiment, Het C represents quinazolinyl.
• X c and Y c independently represent a bond or NR 6c . In a further embodiment, X c and Y c independently represent a bond or NH. In a yet further embodiment, one of X c and Y c represents a bond and the other represents a bond or NH. In a yet further embodiment, one of X c and Y c represents a bond and the other represents NH.
• R 1c and R 2c independently represent aryl, bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1c and R 2c may be substituted by one or more (e.g. 1 , 2 or 3) R 4c groups.
• R 1c and R 2c independently represent aryl, bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1c and R 2c may be substituted by one or more (e.g. 1 , 2 or 3) R 4c groups.
• R 1c and R 2c independently represent aryl, bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1c and R 2c may be substituted by one or more (e.g. 1 , 2 or 3) R 4c groups.
• R 1c and R 2c independently represent aryl, bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring
• R 1c and R 2c independently represent aryl (e.g. phenyl), bicyclic heterocyclyl (e.g. benzodioxinyl), monocyclic heteroaryl (e.g. pyridinyl, pyrazolyl or thiophenyl) or bicyclic heteroaryl ring system (e.g. benzoxazolyl), wherein R 1c and R 2c may be substituted by one or more (e.g. 1 , 2 or 3) R 4c groups.
• R 1c and R 2c independently represent aryl (e.g. phenyl), bicyclic heterocyclyl (e.g. benzodioxinyl), monocyclic heteroaryl (e.g.
• R 1c and R 2c may be substituted by one or more (e.g. 1 ) R 4c groups selected from hydroxyl, C 1-6 alkoxy (e.g. methoxy) or -CONH 2 .
• R 1c and R 2c independently represent aryl (e.g. phenyl) or monocyclic heteroaryl (e.g. pyridinyl, pyrazolyl or thiophenyl) wherein R 1c and R 2c may be substituted by one or more (e.g. 1 ) R 4c groups selected from hydroxyl, Ci -6 alkoxy (e.g. methoxy) or -CONH 2 .
• R 1c and R 2c independently represent unsubstituted aryl (e.g. phenyl) or unsubstituted monocyclic heteroaryl (e.g. pyridinyl or pyrazolyl).
• one of R 1c and R 2c represents unsubstituted aryl (e.g. phenyl) and the other represents unsubstituted monocyclic heteroaryl (e.g. pyridinyl or pyrazolyl).
• p represents an integer from 0 to 2. In one embodiment, p represents 0. In an alternative embodiment, p represents 1 . In an alternative embodiment, p represents 2.
• the compound of formula (IC) is selected from any of compounds: 43, 46, 49, 147, 152, 154, 178-181 , 183-184, 294-295, 305, 329, 339-341 , 366, 370-371 , 376, 435, 455, 459, 462, 486, 520, 539-543, 546-549, 556-557, 567, 631 -632, 640-642, 645, 657, 661 , 668, 671 , 674, 681 , 700-702, 727, 735, 755, 817-818, 823, 826, 845 or 865-866, 868, 870, 888-890, 894, 946, 949-951 , 953, 957, 973, 977, 981 , 983, 985-986, 993 and 995 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compound of formula (IC) is selected from any of compounds:
• the compound of formula (IC) is selected from any of compounds:
• the compound of formula (IC) is selected from any of compounds: 567, 631 , 640, 661 , 668, 700, 727, 823, 868, 870, 888-890, 894, 946, 949-951 , 953, 957, 973, 977, 981 , 983, 985-986, 993 and 995 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compounds of this embodiment were tested in the CK15 inhibition assay as described herein and exhibited inhibition of greater than 5%.
• the compound of formula (IC) is selected from any of compounds:
• the compound of formula (IC) is selected from any of compounds:
• the compound of formula (IC) is selected from any of compounds:
• a pharmaceutical composition comprising a compound of formula (ID) or a pharmaceutically acceptable salt or solvate thereof:
• Het D represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is fused to one or more (e.g. 1 -3) further rings to form a polycyclic ring system comprising up to 4 rings;
• R 5d represents hydrogen, C 1-6 alkyl or cyano
• R 6d represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, -CH 2 -C 3-8 cycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-aryl, -CO-aryl, -CO-heteroaryl or -C(R 7d )(R 8d )- heteroaryl, wherein said aryl groups of R 6d may be optionally substituted by one or more halogen or C 1-6 alkoxy groups;
• R 7d and R 8d independently represent hydrogen or C 1-6 alkyl
• R 1d represents aryl, C 3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1d may be substituted by one or more (e.g. 1 , 2 or 3) R 4d groups;
• R 4d represents halogen, Ci -6 alkyl, Ci -6 alkenyl, Ci -6 alkynyl, C 3-8 cycloalkyl, haloCi -6 alkyl, hydroxyl, C 1-6 alkoxy, -0-C 1-6 alkenyl, haloC 1-6 alkoxy, -COOH, -CO-C 1-6 alkyl, -COO-C 1-6 alkyl, -CONH 2 , -CH 2 -CONH 2 , -NH-Ci -6 alkyl, -NH-C 2-6 alkenyl, -NH-CO-Ci -6 alkyl, -CO- NH-Ci-6 alkyl, -0-CH 2 -CO-NH-Ci -6 alkyl, -CH 2 -CH 2 -CO-NH-Ci -6 alkyl, -S-Ci -6 alkyl, -SO-d.
• q represents an integer from 0 to 3;
• the compound is other than compound number 273, 286, 467, 533, 544, 571 , 591 , 662, 783, 795, 806, 884, 887, 895, 902, 908, 921 , 932, 934, 942, 959-960 and 1001.
• the compound of formula (ID) is selected from any of compounds: 29, 34, 41 , 65-70, 92, 109, 1 16, 126, 130-137, 162, 182, 231 , 246, 252-255, 258, 274, 290-293, 297-298, 317-318, 330-331 , 347-349, 352, 450-454, 483, 536-538, 545, 550, 564-565, 572, 620, 637, 655, 663, 675, 682, 686, 691 , 696, 706, 71 1 , 724, 728-729, 737, 744-745, 748, 752, 774-776, 781 , 797-799, 832, 834, 954, 958, 964-965, 971 , 974-976, 978-980, 994 and 997-998 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compound of formula (ID) is selected from any of
• the compound of formula (ID) is selected from any of compounds:
• the compound of formula (ID) is selected from any of compounds: 663, 675, 682, 696, 706, 737, 748, 797, 832, 834, 954, 958, 964-965, 971 , 974-976, 978- 980, 994 and 997-998 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compounds of this embodiment were tested in the CK15 inhibition assay as described herein and exhibited inhibition of greater than 5%.
• the compound of formula (ID) is selected from any of compounds: 682, 954, 964, 978-979 and 997 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compounds of this embodiment were tested in the CK15 inhibition assay as described herein and exhibited inhibition of greater than 50%.
• a pharmaceutical composition comprising a compound of formula (IE) or a pharmaceutically acceptable salt or solvate thereof:
• Het E represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S;
• R 5e represents hydrogen, Ci -6 alkyl or cyano
• R 6e represents hydrogen, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 alkylamino, cyano, C 3- 8 cycloalkyi, - CH 2 -C 3 -8 cycloalkyi, aryl, heteroaryl, -Ci -6 alkylene-aryl, -Ci -6 alkylene-heteroaryl, -NH-CO- aryl, -CO-aryl, -CO-heteroaryl or -C(R 7e )(R 8e )-heteroaryl, wherein said aryl groups of R 6e may be optionally substituted by one or more halogen or Ci -6 alkoxy groups;
• R 7e and R 8e independently represent hydrogen or Ci -6 alkyl
• R 1e represents aryl, C 3 - 8 cycloalkyi, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1d may be substituted by one or more (e.g. 1 , 2 or 3) R 4e groups;
• R 4e represents halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyi, haloC 1-6 alkyl, hydroxyl, C 1-6 alkoxy, -0-C 1-6 alkenyl, haloC 1-6 alkoxy, -COOH, -CO-C 1-6 alkyl, -COO-C 1-6 alkyl, -CONH 2 , -S0 2 NH 2 , -CH 2 -CONH 2 , -NH-C 1-6 alkyl, -NH-C 2-6 alkenyl, -NH-CO-C 1-6 alkyl, -CO-NH-C 1-6 alkyl, -NH-NH 2 , -0-CH 2 -CO-NH-C 1-6 alkyl, -CH 2 -CH 2 -CO-NH-C 1-6 alkyl, -S-C 1-6 alkyl, -SO-C 1-6
• r represents an integer from 0 to 3;
• the compound of formula (IE) is selected from any of compounds: 18, 50, 55-56, 62, 77, 85, 108, 1 15, 144, 146, 148, 198-199, 201 , 222, 230, 245, 247,
• the compound of formula (IE) is selected from any of
• the compound of formula (IE) is selected from any of compounds:
• the compound of formula (IE) is selected from any of compounds: 583, 646, 660, 723, 730, 780, 822, 830, 885-886, 941 , 966 and 988 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compounds of this embodiment were tested in the CK15 inhibition assay as described herein and exhibited inhibition of greater than 5%.
• a pharmaceutical composition comprising a compound of formula (IF) or a pharmaceutically acceptable salt or solvate thereof:
• Het F represents a heterocyclic ring system containing 1 to 3 heteroatoms selected from
• ring system O, N or S, wherein said ring system is fused to one or more (e.g. 1 -3) further rings to form a polycyclic ring system comprising up to 4 rings;
• R 1 represents halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl, hydroxyl, C 1-6 alkoxy, -0-C 1-6 alkenyl, haloC 1-6 alkoxy, -COOH, -CO-C 1-6 alkyl, -COO-C 1-6 alkyl, -CONH 2 , -CH 2 -CONH 2 , -NH-Ci -6 alkyl, -NH-C 2-6 alkenyl, -NH-CO-Ci -6 alkyl, -CO-
• s represents an integer from 1 to 3;
• the compound of formula (IF) is selected from any of compounds: 53, 79, 124-125, 205, 289, 299, 301 -302, 353-355, 397, 500 and 51 1 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compound of formula (IF) is selected from any of
• the compound of formula (IF) is Compound 205 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• a pharmaceutical composition comprising a compound of formula (IG) or a pharmaceutically acceptable salt or solvate thereof:
• R 5g represents hydrogen, Ci -6 alkyl or cyano
• R 6g represents hydrogen, Ci -6 alkyl, Ci -6 alkoxy, cyano, C 3- 8 cycloalkyl, -CH 2 -C 3- 8 cycloalkyl, aryl, heteroaryl, -Ci -6 alkylene-aryl, -CO-aryl, -CO-heteroaryl or -C(R 7g )(R 8g )- heteroaryl, wherein said aryl groups of R 69 may be optionally substituted by one or more halogen or Ci -6 alkoxy groups;
• R 7g and R 89 independently represent hydrogen or Ci -6 alkyl
• R 19 represents aryl, C 3 - 8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1g may be substituted by one or more (e.g. 1 , 2 or 3) R 49 groups;
• R 49 represents halogen, Ci -6 alkyl, Ci -6 alkenyl, Ci -6 alkynyl, C 3- 8 cycloalkyl, haloCi -6 alkyl, hydroxyl, C 1-6 alkoxy, -0-C 1-6 alkenyl, haloC 1-6 alkoxy, -COOH, -CO-C 1-6 alkyl, -COO-C 1-6 alkyl, -CONH 2 , -CH 2 -CONH 2 , -NH-C 1-6 alkyl, -NH-C 2-6 alkenyl, -NH-CO-C 1-6 alkyl, -CO- NH-C 1-6 alkyl, -0-CH 2 -CO-NH-C 1-6 alkyl, -CH 2 -CH 2 -CO-NH-C 1-6 alkyl, -S-C 1-6 alkyl, -SO-d.
• t represents an integer from 0 to 3;
• the compound of formula (IG) is selected from any of compounds: 98-101 , 248, 257, 259-260, 266, 271 , 380, 394, 449, 461 , 464, 477, 502-504, 523, 530, 535, 574, 673, 713, 779, 788, 825, 881-882, 935, 956, 968, 972 and 996 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compound of formula (IG) is selected from any of
• the compound of formula (IG) is compound 825 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compound of formula (IG) is selected from any of compounds: 825, 881-882, 935, 956, 968, 972 and 996 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• the compounds of this embodiment were tested in the CK15 inhibition assay as described herein and exhibited inhibition of greater than 5%.
• the compound of formula (IG) is Compound 972 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• a pharmaceutical composition comprising a compound of formula (IH) or a pharmaceutically acceptable salt or solvate thereof:
• Het H1 and Het H2 independently represent a 5 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S;
• R 5h represents hydrogen, C 1-6 alkyl or cyano
• R 6h represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, -CH 2 -C 3-8 cycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-aryl, -CO-aryl, -CO-heteroaryl or -C(R 7h )(R 8h )- heteroaryl, wherein said aryl groups of R 6h may be optionally substituted by one or more halogen or Ci -6 alkoxy groups;
• R 7h and R 8h independently represent hydrogen or Ci -6 alkyl
• R 1h and R 2h independently represent halogen, Ci -6 alkyl, Ci -6 alkenyl, Ci -6 alkynyl, C 3- 8 cycloalkyl, haloCi -6 alkyl, hydroxyl, Ci -6 alkoxy, -0-Ci -6 alkenyl, haloCi -6 alkoxy, -COOH, - CO-Ci-6 alkyl, -COO-Ci -6 alkyl, -CONH 2 , -CH 2 -CONH 2 , -NH-Ci -6 alkyl, -NH-C 2-6 alkenyl, - NH-CO-Ci-6 alkyl, -CO-NH-Ci -6 alkyl, -0-CH 2 -CO-NH-Ci -6 alkyl, -CH 2 -CH 2 -CO-NH-Ci -6 alkyl, -S-d -6 alkyl, -SO-Ci -6 alkyl
• u and v independently represent an integer from 0 to 3;
• the compound of formula (IH) is selected from any of compounds: 395, 433, 689 and 786 as described herein or a pharmaceutically acceptable salt or solvate thereof.
• salts are intended to indicate salts which are not harmful to the patient.
• Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts and pharmaceutically acceptable akaline addition salts.
• Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
• suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
• compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
• metal salts include lithium, sodium, potassium, magnesium salts and the like.
• ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
• alkaline salts include, for example, sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, ethylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N- dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, piperidine, piperazine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.
• bases such as, for example, methylamine, ethylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N- dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, piperidine, piperazine, picoline, dicyclohexylamine, morpholine, benzylamine,
• the compounds of formulae (IA)-(IH) can be in racemic forms, as well as in the form of pure enantiomers or non racemic (scalemic) mixture of enantiomers, including when the compounds of formulae (IA)-(IH) have more than one stereogenic centre.
• the compounds of formulae (IA)-(IH) have unsaturated carbon carbon double bonds, both the cis (Z) and trans (E) isomers and their mixtures belong to the invention.
• halogen means a fluorine, chlorine, bromine or iodine atom.
• C 1-6 alkyl means any linear, branched hydrocarbon groups having
• halod-ealkyl mean a Ci- 6 alkyl group substituted by one or more halogen atoms as herein defined.
• C 1-6 alkylene means a saturated divalent hydrocarbon chain having the specified number of member atoms.
• C 1-6 alkylene refers to a bond or an alkylene group having from 1 to 6 member atoms.
• Alkylene groups may be straight or branched. Representative branched alkylene groups have one or two branches.
• Alkylene includes methylene, ethylene, propylene (n-propylene and isopropylene) and butylene (n- butylene, isobutylene, and t-butylene).
• C 2- 6 alkenyl means any linear, branched hydrocarbon groups of 2 to 6 carbon atoms, or cyclic hydrocarbon group having 3 to 6 carbon atoms having at least one double bond. Representative examples of such alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
• C 2- 6 alkynyl means any linear, or branched hydrocarbon groups of
• alkynyl groups include ethynyl, propargyl and butynyl.
• references herein to 'C 1-6 alkoxy' means an -0-C 1-6 alkyl group wherein C 1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.
• references herein to 'C 3-8 cycloalkyl' means a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
• References herein to 'aryl' means a C 6- 12 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, indyl or naphthyl and the like.
• heteroatom means a nitrogen, sulphur, or oxygen atom.
• heterocyclyl means a saturated or unsaturated non-aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heterocyclyl groups containing more than one heteroatom may contain different heteroatoms. Heterocyclyl groups may be optionally substituted with one or more substituents as defined herein. Heterocyclyl groups are monocyclic ring systems or fused bicyclic or polycyclic ring systems or bicyclic structures known as heterocyclic "spiro" ring systems. In certain embodiments, heterocyclyl is saturated. In other embodiments, heterocyclyl is unsaturated and non-aromatic.
• Non-limiting examples of monocyclic heterocyclyl ring systems include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3- oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, and azetidinyl.
• heteroaryl means an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined herein. Heteroaryl groups are monocyclic ring systems or are fused bicyclic or polycyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 member atoms. Bicyclic heteroaryl rings have from 7 to 1 1 member atoms.
• Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocyclyl ring are attached forming a fused bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl ring are attached forming a fused bicyclic ring system.
• Non- limiting examples of heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, furopyridinyl
• Representative compounds of the invention include compounds 1-1002 as set forth below:
• composition comprising any one of the compounds of formulae (IA)-(IH) for use in the treatment of a neurodegenerative disorder, such as tauopathies.
• compositions of the invention may comprise, in addition to one of the above substances, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
• a pharmaceutically acceptable excipient e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.
• Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form.
• a tablet may include a solid carrier such as gelatin or an adjuvant.
• Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animaL or vegetable oils, mineral oil or synthetic oil.
• Physiological saline solution dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
• the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
• a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
• isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
• Preservatives, stabilisers, buffers, antioxidants and/or other additives may be incLuded, as required.
• the compounds of formulae (IA)-(IH) are believed to be casein kinase 1 delta (CK15) inhibitors.
• Certain compounds of formulae (IA)-(IH) have inhibitory activity of greater than 5%, in particular greater than 10%, more particularly greater than 25%, yet more particularly greater than 50%, especially greater than 75%, such as greater than 90%.
• Such compounds may be useful in the treatment in neurodegenerative disorders such as tauopathies.
• Tauopathies are conditions which are characterised by neurofibrillary tangles or aggregates of the tau protein.
• Tauopathies are a recognised class of conditions known to those skilled in the art and include Alzheimer's disease, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, corticobasal degeneration, multisystem atrophy (MSA), neurobasal degeneration with iron accumulation, type 1 (Hallervorden-Spatz), argyrophilic grain dementia, Down's syndrome, diffuse neurofibrillary tangles with calcification, dementia pugilistica, Gerstmann-Straussler-Scheinker disease, myotonic dystrophy, Niemann-Pick disease type C, progressive subcortical gliosis, prion protein cerebral amyloid angiopathy, tangle only dementia, postencephalitic parkinsonism, subacute sclerosing panencephalitis, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis/parkinsonism- dementia complex, non-
• the intracellular tau deposits are usually neuronal or glial and are filamentous and generally in a hyperphosphorylated state as compared to the level of phosphorylation in tau from control human brain.
• this hyperphosphorylated tau is often referred to a paired helical filament tau (PHF) tau because it is derived from the PHF.
• the tauopathy comprises Alzheimer's disease.
• a method of treating a neurodegenerative disorder, such as tauopathies which comprises administering a therapeutically effective amount of a compound of formulae (IA)-(IH).
• the compounds of the invention may be tested for inhibition of casein kinase 1 delta (CK15) in accordance with the assay protocols described in US 2010/0152157, EP 1 ,636,375 or Hanger et al (2007) J. Biol. Chem. 282, 23645-23654.
• the assay was conducted in accordance with the following protocol :
• Base Reaction buffer 20 mM Hepes (pH 7.5), 10 mM MgCI 2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na 3 V0 4 , 2 mM DTT, 1 % DMSO
• Recombinant human full-length construct GST-tagged, expressed in insect cells.

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