Fused thiazole derivatives as kinase inhibitors
View Patent ↗A series of 5,6-dihydro-1,3-benzothiazol-7(4H)-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, being selective inhibitors of PD kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
1. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein
—X— represents a group of formula (a), (b), (c), (d), (e), (f), (g) or (h):
R 1 and R 2 independently represent hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl-(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
R 1 and R 2 , when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or
R 1 and R 2 , when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
R 3 and R 4 independently represent hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, biaryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C 1-6 )alkyl, heteroaryl-aryl(C 1-6 )alkyl or aryl-heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
R 3 and R 4 , when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or
R 3 and R 4 , when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents; and
R 5 and R 6 independently represent hydrogen or C 1-6 alkyl,
together with a pharmaceutically acceptable carrier.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein,
—X— represents a group of formula (a), (b), (c), (d), (e), (f), (g) or (h):
R 1 and R 2 independently represent hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-4 alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl-(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally, substituted by one or more substituents; or
R 1 and R 2 , when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or
R 1 and R 2 , when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;
R 3 and R 4 independently represent hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 1-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, biaryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )allyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C 1-6 )alkyl, heteroaryl-aryl(C 1-6 )alkyl or aryl-heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
R 3 and R 4 , when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or
R 3 , and R 4 , when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C 5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents; and
R 5 and R 6 independently represent hydrogen or C 1-6 alkyl;
provided the compound is not:
2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-dimethyl-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-(morpholin-4-yl)-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one; and
7,7-dimethyl-2-(morpholin-4-yl)-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one.
3. A compound of formula (IIA), or a pharmaceutically acceptable salt thereof:
wherein
—X 1 — represents a group of formula (a) or (e):
R 6 represents hydrogen or C 1-6 alkyl;
R 11 represents hydrogen or optionally substituted C 2-6 alkyl; and
R 12 represents C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
R 11 and R 12 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; and
R 13 represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, biaryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C 1-6 )alkyl, heteroaryl-aryl(C 1-6 )alkyl or aryl-heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
4. The compound of formula (IIB), or a pharmaceutically acceptable salt thereof:
wherein
—X 1 — represents a group of formula (a) or (e):
R 6 represents hydrogen or C 1-6 alkyl;
R 21 represents hydrogen or optionally substituted C 1-6 alkyl; and
R 22 represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
R 21 and R 22 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; and
R 23 represents C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, biaryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C 1-6 )alkyl, heteroaryl-aryl(C 1-6 )alkyl or aryl-heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
5. The compound as claimed in claim 4 wherein R 23 represents C 1-6 alkyl, aryl(C 1-6 )alkyl, biaryl-(C 1-6 )alkyl, heteroaryl(C 1-6 )alkyl or heteroaryl-aryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
6. The compound as claimed in claim 5 wherein R 23 represents substituted or unsubstituted indolylmethyl.
7. A compound of formula (IIC), or a pharmaceutically acceptable salt thereof:
wherein
—X 2 — represents a group of formula (b), (c), (d), (f), (g) or (h):
R 5 and R 6 independently represent hydrogen or C 1-6 alkyl;
R 13 represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, biaryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkylcarbonyl, heteroaryl, heteroaryl(C 1-6 )alkyl, heteroaryl-aryl(C 1-6 )alkyl or aryl-heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
R 21 represents hydrogen or optionally substituted C 1-6 alkyl; and
R 22 represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-4 alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
R 21 and R 22 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents.
8. The compound as claimed in claim 4 , or a pharmaceutically acceptable salt thereof,
wherein
R 23 represents
and R 33 represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.
9. The compound as claimed in claim 4 , or a pharmaceutically acceptable salt thereof:
wherein
R 23 represents
W represents CH or N; and
R 43 represents hydrogen, halogen, cyano, C 1-6 alkyl, hydroxy(C 1-6 )alkyl, trifluoromethyl, aryl(C 1-6 )alkyl, hydroxy, C 1-6 alkoxy, trifluoromethoxy, aryloxy, aryl(C 1-6 )alkoxy, C 1-6 alkylthio, arylsulphonyl, C 1-6 alkylsulphonyloxy, amino, C 2-6 alkylcarbonylamino, C 1-6 alkylsulphonylamino, C 2-6 alkylcarbonyl or aminocarbonyl.
10. The compound as claimed in claim 9 wherein W represents CH.
11. The compound as claimed in claim 9 wherein R 43 represents hydrogen.
12. The compound as claimed in claim 2 that is
2-(Morpholin-4-yl)-4H-spiro[1,3-benzothiazole-5,1′-cyclopentan]-7(6H)-one;
5-Isopropyl-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5-(4-Chlorophenyl)-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-(Morpholin-4-yl)-5-phenyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-(Morpholin-4-yl)-4H-spiro[1,3-benzothiazole-5,1′-cyclohexan]-7(6H)-one;
5-(4-Methoxyphenyl)-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-(Morpholin-4-yl)-5-propyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5-Methyl-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
6,6-Dimethyl-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5-[4-(Methylthio)phenyl]-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7-(4H)-one;
5-(2-Furyl)-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
6-Methyl-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[(3R)-3-(1H-Indol-3-ylmethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[3-(2-naphthylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[3-(1-naphthylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2,3-(2-phenethyl)morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[(3S)-3-Benzylmorpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(4aS,9aR)-2,3,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-4(4aH)-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[3-(4-Chlorobenzyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[3-(5-methyl-1H-indol-3-ylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{3-[4-(morpholin-4-yl)benzyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-(2,3-Dihydro-4H-1,4-benzoxazin-4-yl)-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[3-(1H-indol-3-ylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-(1H-indol-3-ylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{3-[(1-methyl-1H-indol-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(1-Acetyl-1H-indol-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-(2-phenylmorpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[3-(4-Bromobenzyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[3-(2,3-Dihydro-1H-indol-1-ylmethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[3-(1H-indol-1-ylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-(trans-2,6-dimethylmorpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[3-(Anilinomethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{3-[(N-methyl-N-phenylamino)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[3-(3,4-Dihydroquinolin-1(2H)-ylmethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[3-(3,4-Dihydroisoquinolin-2(1H)-ylmethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
(7E,Z)-5,5-Dimethyl-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one oxime;
7Z)-5,5-Dimethyl-2-(morpholin-4-O-5,6-dihydro-1,3-benzothiazol-7(4H)-one oxime;
(7E,Z)-2-(Morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one oxime;
(7E,Z)-5,5-Dimethyl-2-[(3S)-3-(1H-indol-3-ylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one oxime;
(7E,Z)-6-Methyl-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one oxime;
(7E,Z)-6,6-Dimethyl-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one oxime;
7,7-Dimethyl-2-[(3S)-3-(1H-indol-3-ylmethyl)morpholin-4-yl]-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
6-Methyl-2-(morpholin-4-yl)-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
6,6-Dimethyl-2-(morpholin-4-yl)-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
5,5-Dimethyl-2-(morpholin-4-yl)-4,5,6,7-tetrahydro-1,3-benzothiazol-7-ol;
5,5-Dimethyl-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazole-7(4H)-thione;
2-[(3S)-3-(3-Bromobenzyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[(3S)-3-(Biphenyl-3-ylmethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one:
5,5-Dimethyl-2-[(3S)-3-(3-(pyridin-3-yl)benzyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-(3-thienyl)benzyl morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-(3-(pyridin-4-yl)benzyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-(3-(pyrimidin-5-yl)benzyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[(3S)-3-(3-Bromobenzyl)morpholin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
2-[(3S)-3-(Biphenyl-3-ylmethyl)morpholin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
7,7-Dimethyl-2-[(3S)-3-(3-(pyridin-3-yl)benzyl)morpholin-4-yl]-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
5,5-Dimethyl-2-[3-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
7,7-Dimethyl-2-[(3R)-3-(1H-indol-3-ylmethyl)morpholin-4-yl]-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
7,7-Dimethyl-2-[3-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)morpholin-4-yl]-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
5,5-Dimethyl-2-{(3R)-3-[(phenylthio)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(41-1)-one;
5,5-Dimethyl-2-[3-(phenoxymethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
7,7-Dimethyl-2-(morpholin-4-yl)-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepine-4-thione;
7,7-Dimethyl-2-[(3S)-3-(1H-indol-3-ylmethyl)morpholin-4-yl]-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepine-4-thione;
5,5-Dimethyl-2-[3-[(pyridin-3-ylamino)methyl]morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[3-(piperidin-1-ylcarbonyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[3-(3,4-Dihydroquinolin-1(2H)-ylcarbonyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[3-(1-Benzothien-3-ylmethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[3-(Biphenyl-4-ylmethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[3-(4-(pyridin-3-yl)benzyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[3-(5-methyl-1H-indol-3-yl)methyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazole-7(4H)-thione;
5,5-Dimethyl-2-[3-(1-naphthylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazole-7(4H)-thione;
2-[3-(1-Benzothien-3-ylmethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazole-7(4H)-thione;
N-{[4-(5,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)morpholin-3-yl]methyl}benzenesulfonamide;
2-[3-(1-Benzothien-2-ylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
7,7-Dimethyl-2-[3-(isoquinolin-4-ylmethyl)morpholin-4-yl]-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
7,7-Dimethyl-2-[3-(quinolin-5-ylmethyl)morpholin-4-yl]-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
7,7-Dimethyl-2-[3-(quinolin-8-ylmethyl)morpholin-4-yl]-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
5,5-Dimethyl-2-[3-(quinolin-8-ylmethyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-(3-(pyrroldin-1-yl)benzyl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{3-[(6-Bromopyridin-2-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one:
5,5-Dimethyl-2-{3-[(6-phenylpyridin-2-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one:
5,5-Dimethyl-2-{(3S)-3-[2(2′-methylbiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[3′-methoxybiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[2′-(trifluoromethyl)biphenyl-3-yl]methyl morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2{(3S)-3-[(2′-Chlorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[3-(1-naphthyl)benzyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[3-(2-naphthyl)benzyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(3′-Chlorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[(3′-fluorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[(2′-fluorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(2′,6′-Difluorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(3′,4′-Dichlorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-{[4′-(methylthio)biphenyl-3-yl]methyl}morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[(3S)-3-[3-(1-Benzofuran-2-yl)benzyl]morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[3-(1-Benzothien-2-yl)benzyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[(3′-methylbiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[(2′-methoxybiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[3-(thien-2-yl)benzyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-[(3′-ethoxybiphenyl-3-yl)methyl]morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[3-(4-methylthien-2-yl)benzyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[3-(5-Acetylthien-2-yl)benzyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[3-(1-Benzothien-3-yl)benzyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[3(4′-methylbiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(3′-Acetylbiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(4′-Acetylbiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[3(2′-Bromobiphenyl-3-yl]methyl)morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(3′-Bromobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(4′-Bromobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[(3S)-3-{[3′,5′-Bis(trifluoromethyl)biphenyl-3-yl]methyl}morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(4′-Chlorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(2′,5′-Dichlorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(3′,5′-Difluorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(3′,4′-Dimethoxybiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(2′,3′-Dimethylbiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(3′,5′-Dimethylbiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[(2′,5′-Dimethylbiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[(4′-fluoro-3′-methylbiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[(4′-fluorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[(4′-methoxybiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[3-(1,3-benzodioxol-5-yl)benzyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[4′-phenoxybiphenyl-3-yl)methyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-{[3′-(trifluoromethyl)biphenyl-3-yl]methyl}morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[3′,4′-Difluorobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
N-(3′-{[(3S)-4-(5,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)morpholin-3-yl]methyl}biphenyl-3-yl)acetamide;
2-{(3S)-3-[(3′-Aminobiphenyl-3-yl)methyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
3′-{[(3S)-4-(5,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)morpholin-3-yl]methyl}biphenyl-4-carbonitrile;
5,5-Dimethyl-2-[(3S)-3-{[3′-(hydroxymethyl)biphenyl-3-yl]methyl}morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-{[2′-(hydroxymethyl)biphenyl-3-yl]methyl}morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-{[3′-(trifluoromethoxy)biphenyl-3-yl]methyl}morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[3-(6-methoxypyridin-3-yl)benzyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
N-(3′-{[(3S)-4-(5,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)morpholin-3-yl]methyl}biphenyl-3-yl)methanesulfonamide;
2-{(3S)-3-[3-(3,5-Dimethylisoxazol-4-yl)benzyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-{3-[1-(phenylsulfonyl)-1H-indol-3-yl]benzyl}morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[3-(6-Chloropyridin-3-yl)benzyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
3′-{[(3S)-4-(5,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)morpholin-3-yl]methyl}biphenyl-4-carboxamide;
5,5-dimethyl-2-{(3S)-3-[3-(3-fluoropyridin-4-yl)benzyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-{(3S)-3-[3-(1-Benzyl-1H-pyrazol-4-yl)benzyl]morpholin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{(3S)-3-[3-(1-methyl-1H-pyrazol-4-yl)benzyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
7,7-Dimethyl-2-(morpholin-4-yl)-4,6,7,8-tetrahydro-5H-[1,3]thiazolo[5,4-b]azepin-5-one;
2-[(3S)-3-{[5-(Benzyloxy)-1H-indol-3-yl]methyl}morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-{[5-(hydroxy)-1H-indol-3-yl]methyl}morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
7,7-Dimethyl-2-{(3S)-3-[(5-hydroxy-1H-indol-3-yl)methyl]morpholin-4-yl}-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one;
3-{[(3S)-4-(5,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-Amorpholin-3-yl]methyl}-1H-indol-5-yl methanesulfonate;
2-[3-(3,4-Dihydroisoquinolin-2(1H)-ylcarbonyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[3-(3,4-Dihydroquinoxalin-1(2H)-ylcarbonyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{3-[(6-methyl-3,4-dihydroquinolin-1(2H)-yl)carbonyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-{3-[(6-methoxy-3,4-dihydroquinolin-1(2H)-ylcarbonyl]morpholin-4-yl}-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
5,5-Dimethyl-2-[(3S)-3-(3-phenylprop-2-yn-1-yl)morpholin-4-yl]-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[(3S)-3-(1H-Benzotriazol-1-ylmethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[(3S)-3-(1H-Benzimidazol-1-ylmethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
2-[2-(Aminomethyl)morpholin-4-yl]-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one;
N-(1-Benzothien-3-ylmethyl)-2-[4-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)morpholin-2-yl]acetamide;
N-{[4-(5,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)morpholin-2-yl]methyl}-1-benzofuran-2-carboxamide;
N-{[4-(5,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)morpholin-2-yl]methyl}benzenesulfonamide; or
(7E)-5,5-Dimethyl-2-(morpholin-4-yl)-5,6-dihydro-1,3-benzothiazol-7(4H)-one hydrazone.
13. The pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.
14. The compound as claimed in claim 10 wherein R 43 represents hydrogen.
15. The pharmaceutical composition comprising a compound according to claim 3 and a pharmaceutically acceptable carrier.
16. The pharmaceutical composition comprising a compound according to claim 4 and a pharmaceutically acceptable carrier.