NOVEL 2,4-DIAMINOTHIAZOLE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to novel 2,4-diaminothiazole derivatives of the general formula (I) Nhich inhibit GSK-3 (glycogen synthase kinase-3), to the use of these compounds as medicaments, to pharmaceutical compositions comprising the compounds and to methods of treatment employing these compounds and compositions. The present compounds may be useful for the treatment of disorders, syndromes, diseases and conditions, Nherein an inhibition of GSK-3 is beneficial, especially IGT (impaired glucose tolerance), type 1 diabetes, type 2 diabetes, obesity, Alzheimer's disease and bipolar disorder.
BACKGROUND OF THE INVENTION
GSK-3 is a protein-serine kinase implicated in the hormonal control of several regulatory proteins. It Nas first discovered by virtue of its ability to phosphorylate and inactivate glycogen synthase, the regulatory enzyme of glycogen synthesis in mammals. Since then a number of other substrates have been identified, implicating the enzyme in the regulation of several physiological processes.
GSK-3 exists in tNo isoforms, termed GSK-3ct and GSK-3(3, Nhich are derived from distinct genes and shoN 85% sequence identity. Unlike many protein kinases, both GSK-3 isoforms are constitutively active in resting cells, and are primarily regulated by inactivation. Thus, it has been shoNn that GSK-3 is inhibited by serine phosphorylation in response to insulin and groNth factors such as IGF-1 and EGF via activation of the MAP kinase cascade or via PI3 kinase dependent activation of protein kinase B.
Compounds that inhibit GSK-3 activity are useful in the treatment of diseases, disorders, syndromes and conditions, Nherein such an inhibition is beneficial, eg in diseases, disorders, syndromes and conditions related to GSK-3, in diseases, disorders, syndromes and conditions related to a dysfunction of GSK-3, in diseases, disorders, syndromes and conditions in Nhich groNth factor induced inhibition of GSK-3 is insufficient, in diseases, disorders, syndromes and conditions in Nhich glycogen synthase is insufficiently activated and in situations Nherein GSK-3 inhibition could counter-regulate unNanted cellular events.
Type 1 diabetes, also knoNn as insulin dependent diabetes mellitus (IDDM), is caused by an autoimmune destruction of insulin producing cells in the pancreas, leading to a lack of insulin. Thus, individuals Nith type 1 diabetes require daily injections of the hormone to sustain life. Current methods of insulin administration, hoNever, cannot reproduce the normal p cell's ability to precisely control blood glucose and other metabolic variables.

Hence, the type 1 diabetic remains susceptible to the long-term and devastating complications of diabetes, such as cardiovascular disease, retinopathy, nephropathy and neuropathy.
Type 2 diabetes, also knoNn as non-insulin dependent diabetes mellitus (NIDDM), is the most common of all metabolic disorders and poses a major health problem NorldNide. Type 2 diabetes results from defects in both insulin secretion and insulin action, but the exact underlying mechanism(s) causing the disease are not knoNn. An elevation of hepatic glucose production contributes significantly to causing fasting hyperglycemia, Nhereas decreased insulin-mediated glucose uptake by mus and fat is a major contributor to postprandial hyperglycemia. Moreover, the metabolic fate of glucose taken up by mus is not normal in people Nith type 2 diabetes. For example mus glycogen synthase activity and glycogen synthesis have been shoNn to be severely impaired in type 2 diabetes. The available treatments do not alloN for a complete normalisation of the metabolic state and most of them are associated Nith side effects. The metabolic derangements created by hyperglycemia, together Nith the strong association betNeen type 2 diabetes, obesity, hypertension and hyperiipidemia, lead to an extensive list of long-term complications, including a high rate of cardiovascular death due to accelerated atherosrosis, as Nell as typical complications of diabetes such as retinopathy, nephropathy and neuropathy.
Thus, there is still a considerable need for novel approaches to treat diabetes.
Recently, it has been found that GSK-3 expression is elevated in mus of people Nith type 2 diabetes and that the GSK-3 expression is inversely correlated Nith both glycogen synthase activity and glucose disposal. Thus, an increased GSK-3 expression may contribute to the impaired glycogen synthase activity and insulin resistance that occurs in type 2 diabetes. Other recent experiments have suggested a role for GSK-3 in attenuating insulin action via its phosphorylation of insulin receptor substrate 1.
Recent studies using lithium salts also support the notion that inhibition of GSK-3 Nould be beneficial in the treatment of diabetes. It has been knoNn for a long time that lithium has a stimulatory effect on glucose metabolism, most prominently on glycogen synthesis. Treatment Nith lithium salts has also been shoNn to alleviate the diabetic state in both type 1 and type 2 diabetic patients. The molecular mechanism for these effects of lithium has until recently been unknoNn. HoNever, it has noN been found that lithium inhibits GSK-3. Although lithium might also have effects on other molecular targets than GSK-3, this finding contributes to explain the molecular effects of lithium and supports that inhibition of GSK-3 leading to activation of glycogen synthase has significant effect on stimulation of glucose metabolism.

In conclusion, GSK-3 inhibitors may be useful for the treatment of metabolic disorders, such as IGT, type 1 diabetes and type 2 diabetes.
GSK-3 is also involved in biological pathNays relating to Alzheimer's disease and GSK-3 inhibitors may be useful in the treatment thereof. Alzheimer's disease is characterized histopathologically by the presence of intraneuronal neurofibrillary tangles and the extracellular deposition of p amyloid in the brain, especially the hippocampus. The neurofibrillary tangles are made up of PHFs (paired helical filaments), the major protein subunit of Nhich is the abnormally phosphorylated and glycosylated microtubule associated protein tau (T). In the tangle bearing neurons in Alzheimer's disease, the normal cytoskeleton is disrupted and replaced Nith PHFs. GSK-3 is one of several kinases that phosphorylates tau in vitro on the abnormal sites characteristic of PHF-tau and has also been demonstrated to do this in living cells. Furthermore, the GSK-3 inhibitor lithium blocks tau hyperphosphorylation in cells. Further evidence for a role of GSK-3 in Alzheimer's disease is provided by ia (i) the association of GSK-3 Nith presenellin 1, (ii) reduced cytotoxicity of (3 amyloid protein in neuronal cells incubated Nith GSK-3 antisense and (iii) 50% increased expression of GSK-3 in postsynaptic supematants of Alzheimer's disease compared to normal brain tissue.
Lithium has been used for decades in the treatment of manic depression (bipolar disorder). The mechanism of action of lithium as a mood-stabilizing agent remains unknoNn, although effects on biological membranes and synaptic neurotransmission have been suggested. HoNever, GSK-3 activity could be implicated in the etiology of bipolar disorder. One mechanism by Nhich lithium and other GSK-3 inhibitors may act to treat bipolar disorder is to increase the survival of neurons subjected to aberrantly high levels of excitation induced by the neurotransmitter glutamate. Glutamate may also be implicated in mediating neurodegen-eration folloNing acute damage, eg in cerebral ischemia, traumatic brain injury and bacterial, viral and prion infection. Excessive glutamate signalling has also been implicated in the chronic neuronal damage seen in diseases such as Huntington's chorea, Parkinson's disease, amyotrophic lateral srosis and multiple srosis. Consequently, GSK-3 inhibitors may be useful in the treatment of these and other neurodegenerative disorders. In connection Nith this it should be noted that lithium has a variety of biological effects that, if mediated through the inhibition of GSK-3, could provide an even broader application of GSK-3 inhibitors.
Furthermore, GSK-3 has been shoNn to phosphorylate the transcription factor NF-AT, Nhich participates in the activation of early immune response genes. Phosphorylation prevents translocation of NF-AT to the nuus and thus blocks early immune responses. Thus, GSK-3 inhibitors may prolong and potentiate the immunostimulatory effect of certain

cytokines and such an effect could be beneficial in the use of cytokines for cancer or immunotherapy.
Different classes of compounds have been disclosed as inhibitors of GSK-3, cf ia NO 98/16528, NO 99/65897, NO 00/21927, NO 01//09106, NO 00/38675, NO 01/44206 and NO 01/44246. These compounds differ structurally from the present compounds.
NO 99/21845 discloses 4-aminothiazole derivatives and their use as inhibitors of cyclin-dependent kinases (CDKs). The compounds are stated to be effective for the treatment of ia cancer. The compounds differ structurally from the present compounds. HoNever, Table I discloses one compound (l(6)), of the folloNing structure:

No CDK inhibition Nas observed for the compound at the tested concentration.
NO 00/75120 discloses diaminothiazoles and their use for inhibiting protein kinases. The compounds are stated to be useful for the treatment of disease conditions associated Nith tumor groNth, cell proliferation or angiogenesis, such as cancer. The compounds differ structurally from the present compounds.
In vieN of the art's interest in GSK-3 inhibitors and the great potential thereof, the identification of potent and specific GSK-3 inhibitors Nould be a highly desirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that the 2,4-diaminothiazole derivatives of the general formula (I) potently and specifically inhibit GSK-3.
The present compounds are accordingly useful in the treatment of a Nide range of disorders, syndromes, diseases and conditions in Nhich an inhibition of GSK-3 is beneficial.
DEFINITIONS
The folloNing is a detailed definition of the terms used to describe the compounds of the invention.
"Halogen" designates an atom selected from the group consisting of F, CI, Br and I.
The term "C1-6-alkyl" in the present context designates a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and the like.

The term "C1-6-alkoxy" in the present context designates a group -O-C1-6-alkyI, Nherein C1-6-alkyl is as defined above. Representative examples include, but are not limited to, meth-oxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy and the like.
The term "C1-6-alkenyl" as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyI, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenylf 4-pentenyl, 3-methyl-2-butenyI, 1-hexenyl, 2-hexenyl, 3-hexenyi, 2,4-hexadienyI, 5-hexenyl and the like.
The term "C2-6-alkynyl" as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyI, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
The term "C3-8-cycloalkyl" as used herein represents a saturated carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term "C1-6-heterocycIyl" as used herein represents a saturated 3 to 8 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulphur. Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azirid-jnyl, tetrahydrofuranyl and the like.
The term "aryl" as used herein represents a carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.
The term "heteroaryl" as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazoIyI, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyi, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl,

benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, di-azepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogen-ated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
"Aryl-C1-6-alkyl", "heteroaryl-C1-6-alkyl" etc. means C1-6-alkyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:

Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
The term "GSK-3" as used herein is intended to mean GSK-3a and/or GSK-p.
The term "treatment' as used herein means the management and care of a patient for the purpose of combating a disease, disorder, syndrome or condition. The term is intended to include the delaying of the progression of the disease, disorder, syndrome or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder, syndrome or condition. The patient to be treated is preferably a mammal, in particular a human being.
DESCRIPTION OF THE INVENTION
The present invention relates to a compound of the general formula (I):

(i) R1 and R2, together Nith the nitrogen atom to Nhich they are attached, form a 5 to 7 mem-bered non-aromatic ring, Nhich ring may optionally contain a double bond, and Nhich ring

may optionally contain a further nitrogen atom, and to Nhich ring is attached tNo groups R4 and R5 Nhich are independently selected from
• hydrogen,
• oxo,
• C1-6-alkyl, C2-6-aIkenyl, C2-6-alkynyl(
Nhich may optionally be substituted Nith one or tNo substituents independently selected from hydroxy, halogen, cyano, nitro, -NR6R7, -C(=0)NR8R7, -OC(=0)NR6R7, -OCH2C(=0)NR6R7, C1-6-alkoxy, -C(=0)OR6, -C(=0)R8, -NHC(=0)R5, -CHF2, -CF3l -OCF3, -OCHF2, -OCH2CF3l -OCF2CHF2l -SCF3, -SR6, -S(=0)R8, -S(=0)2R6, -S(=0)2NH2l
Nherein R6 and R7 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R6 and R7, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
• aryl, C3-8cycloalkyl, heteroaryl, C1-6-heterocyclyl, aryl-C1-6-alkyl, C3-8-cycloalkyl-
C1-6-alkyl, heteroaryl-C1-6-alkyl, C3-8-heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, C1-6-cyclo-
alkyl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, C3-8-heterocyclyl-d_6-alkoxy, -C(=0)-aryl,
-C(=0)-C3-8-cycloalkyl, -C(=0)-heteroaroyl, -C(=0)-C3-8-heterocyclyl, -O-aryl,
-0-C3-8-cycloalkyl, -O-heteroaryl, -O-C1-6-heterocycIyl, -S-aryl, -$-C3-8-cycloalkyl,
-S-heteroaiyl,-S-C3-8-heterocyclyl,
Nherein the ring moieties may optionally be substituted Nith one to three substituents independently selected from hydroxy, halogen, cyano, nitro, -NR8R9, -C(=0)NR8R9, -OC(=0)NR8R9, -OCH2C(=0)NR8R9, C1-6-alkoxy, -C(=0)OR8, -C(=0)R8, -NHC(=0)R8, -CHF2, -CF3, -OCF3l -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2NH2j
Nherein R8 and R9 Nhich may be the same or different independently are selected from hydrogen and d-6-alkyl, or R8 and R9, together Nith the nitrogen atom to Nhich

they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
and R3 is hydrogen,
(ii) or R1 is hydrogen, -C(=0)OR1°, -C(=0)R10, C1-6-alkyl, aryl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkyI, heteroaryl-C1-6-alkyl or C3_8-heterocyclyl-C1_6-alkyl,
Nherein R10 is C1-6-alkyl, C2-6-aIkenyl or C2-8-alkynyl, Nhich may optionally be substituted Nith one or tNo substituents independently selected from
hydroxy, halogen, cyano, nitro, -NR11R12, -C(=0)NR11R12, -OC(=0)NR11R12, -OCH2C(=0)NR11R12, C1-6-alkyl, C2_6-alkenyl, C2-8-alkynyl, C1-6-alkoxy, »C(=0)OR11, -C(=0)R11, -NHC(=0)R11, -CHF2, -CF3, -OCF3f -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR1' -S(=0)R11, -S(=0)2R11 -S(=0)2NH2,
Nherein R11 and R12 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R11 and R12, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
and R2and R3 are connected to form, together Nith A and the nitrogen atom and carbon atom, respectively, to Nhich they are attached, a 5 to 7 membered non-aromatic ring to Nhich ring is attached tNo groups R13 and R14 Nhich are independently selected from
• hydrogen,
• oxo,
• C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl,
Nhich may optionally be substituted Nith one or tNo substituents independently selected from hydroxy, halogen, cyano, nitro, -NR15R16, -C(=0)NR15R19, -OC(=0)NR15R16, -OCH2C(=0)NR15R16, C1-6-alkoxy, -C(=0)OR15, -C(=0)R15,

-NHC(=0)R15, -CHF2, -CF3l -OCF3l -OCHF2l -OCH2CF3l -OCF2CHF2, -SCF3, -SR15, -S(=0)R15, -S(=0)2R15, -S(=0)2NH2,
Nherein R15 and R18 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R15 and R16, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
• aryl, -cycloalkyl, heteroaryl, C3_8-heterocyclyi, aryl-C1-6-alkyl, C3-8-cycloalkyl-
C1-6-alkyl, heteroaryl-C1-6-alkyl, C3-8-heterocycIyl-Ci.8-alkyl, aryl-CC1-6-alkoxy, -cyclo-alkyl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, C3-8-heterocyclyl-C1-6-alkoxy, -C(=0)-aryl, C(=O)-C3-8-cycloalkyl, -C(=0)-heteroaroyl, -C(=0)--heterocyclylI -O-aryl, -O-C1-6-cycloalkyl, -O-heteroaryl, -0-C3-8-heterocyclyl, -S-aryl, -S-C3-8-cycloaikyl, -S-heteroaryl, -S-C1-6-heterocyclyl,
Nherein the ring moieties may optionally be substituted Nith one to three substituents independently selected from
hydroxy, halogen, cyano, nitro, -NR17R18, -C(=0)NR17R18, -OC(=0)NR17R18, -OCH2C(=0)NR17R18, C1-6-alkyl, C2-a-alkenyl, C2-6-alkynyl, C1-C6-alkoxy, -C(=0)OR17, -C(=0)R17, -NHC(=0)R17, -CHF2, -CF3, -OCF3, -OCHF2l -OCH2CF3, -OCF2CHF2, -SCF3, -SR17, -S(=0)R17, -S(=0)2R17, -S(=0)2NH2,
Nherein R17 and R18 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R17 and R18, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
(iii) or R1 and R2 Nhich may be the same or different independently are selected from hydrogen, -C(=0)OR19 -C(=0)R19 and -alkyl,
Nherein R19 is C1-6-alkyl, C2-6-alkenyl or C2-8-alkynyl, Nhich may optionally be substituted Nith one or tNo substituents independently selected from

• hydroxy, halogen, cyano, nitro, -NR20R21, -C(=O)NR20R21, -OC(=O)NR20R21, -OCH2C(=O)NR20R21, C1-C6-alkoxy, -C(=0)OR2°, -C(=0)R20, -NHC(=0)R20, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3l -SR20, -S(=0)R20, -S(=0)2R20, -S(=0)2NH2,
• Nherein R20 and R21 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R20 and R21, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
and R3 is hydrogen,
B is a valence bond, -C(=0)-, -S(=0)- or-S(=0)2-,
Dis
• hydroxy, halogen, cyano, nitro, -NR22R23, -NCR22)OR23, -C(=0)NR22R23,
-OC(=0)NR22R23, -OCH2C(=0)NR22R23, C1-6-alkoxy, -C(=0)OR22, -C(=0)R22,
-NHC(=0)R22, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR22,
-S(=0)R22, -S(=0)2R22, -S(=0)2NH2,
Nherein R22 and R23 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R22 and R23, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
• C1-8-alkyl, C2-6-alkenyl, C2-8-alkynyl,
Nhich may optionally be substituted Nith one or tNo substituents selected from hydroxy, halogen, cyano, nitro, -NR24R25, -C(=0)NR24R25, -OC(=0)NR24R25, -OCH2C(=0)NR24R25, -alkoxy, -C(=0)OR24, -C(=0)R24, -NHC(=0)R24, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR24, -S(=0)R24, -S(=0)2R24, -S(=0)2NH2,

Nherein R24 and R25 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R24 and R25, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
• aryl, -cycloalkyl, heteroaryl, ~heterocyciyl, aryl-C1-6-alkyi, C1-6-cycloaikyl-C1-C6alkyl, heteroaryl-C1-6-alkyl, C1-6-heterocyclyl-C1-6-alkyl, aryl--aikoxy, C1-6-cycloalkyl-C1-6-alkoxy, heteroaryl-C1-C6-alkoxy, C3-8-heterocyclyl-C1-C6-alkoxy, -C(=0)-aryl, -C(=0)-C3-8-cycloalkyl, -C(=0)-heteroaroyI, -C(=0)-C3-8-heterocyclyI, -O-aryl, -O-C1-C6cycloalkyl, -O-heteroaryl, -O-C1-6-heterocyclyl, -S-aryl, -S--cycloalkyl, -S-heteroaryl, -S--heterocycIyl, -NH-aryl, -NH-heteroaryl,
Nherein the ring moieties may optionally be substituted Nith one to three substituents selected from
o hydroxy, halogen, cyano, nitro, -NR26R27, -C(=0)NR28R27, -OC(=0)NR26R27, -OCH2C(=0)NR26R27, -alkoxy, -C(=0)OR28, -C(=0)R26, -NHC(=0)R26I -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR26, -S(=0)R26, -S(=0)2R26, -S(=0)2NH2,
Nherein R26 and R27 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R26 and R27, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
o C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl,
Nhich may optionally be substituted Nith one or tNo substituents selected from hydroxy, halogen, cyano, nitro, -NR^R29, -C(=0)NR28R29, -OC(=0)NR28R29, -OCH2C(=0)NR2aR29, C1-C6-alkoxy, -C(=0)OR28, -C(=0)R28, -NHC(=0)R28, -CHF2| -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR28, -S(=0)R28, -S(=0)2R28, -S(=0)2IMH2,

Nherein R28 and R29 Nhich may be the same or different independently are selected from hydrogen and Chalkyl, or R28 and R29, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
o aryl, C1-6-cycloalkyl, heteroaryl, -heterocyclyl, aryl-C1-6-alkyl, C1-6-cyclo-alkyl-C1-6-alkyl, heteroaryl--alkyl, C3-8-heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, -cycloalkyl-CC1-6-alkoxy, heteroaryl--alkoxy, -hetero-cyclyl-C1-6-aikoxy, -C(=0)-aryl, -C(=0)--cycIoalkylI -C(=0>heteroaroyl, -C(=0)--heterocyclyl, -O-aryl, -0-C3-8-cycloalkyl, -O-heteroaryl, -O-C3-8-heterocyclyl, -S-aryl, -S--cycloalkyl, -S-heteroaryl, -S-C1-6-heterocyclyl,
Nherein the ring moieties may optionally be substituted Nith one to three sub-stituents selected from hydroxy, halogen, cyano, nitro, -NR30R3' -C(=O)NR30R3' -OC(=O)NR30R3' -OCH2C(=O)NR30R31l -alkyl, -alkenyl, C1-6-alkynyl, C1-6-alkoxy, -C(=0)OR30, -C(=0)R30, -NHC(=0)R30, -CHF2, -CF3( -OCF3l -OCHF2, -OCH2CF3, -OCF2CHF2l -SCF3l -SR30, -S(=0)R30, -S(=0)2R30, -S(=0)2NH2,
Nherein R30 and R31 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R30 and R31, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,

as Nell as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention R2and R3 are both hydrogen, and R1 is -C(=0)OR19, Nherein R19is as defined for formula (I). In an embodiment thereof R19 is C1-6-alkyl.
In another embodiment of the invention R3 is hydrogen, and R1 and R2, together Nith the nitrogen atom to Nhich they are attached, form a ring

Nherein R4 and R5 are as defined for formula (I). In an embodiment thereof R4 and R5are independently selected from hydrogen, C1-6-alkyl, phenyl-C1-6-alkyI and oxo. In a further embodiment thereof R4 is hydrogen or C1-6-alkyl, and R5is hydrogen or oxo.
In yet another embodiment of the invention R3 is hydrogen, and R1 and R2, together Nith the nitrogen atom to Nhich they are attached, form a ring

In still another embodiment of the invention R2 and R3, together Nith A and the nitrogen atom and the carbon atom, respectively, to Nhich they are attached, form a ring


In an embodiment thereof R2 and R3, together Nith A and the nitrogen atom and the carbon atom, respectively, to Nhich they are attached, form a ring

In an embodiment thereof R1 is hydrogen, C1-6-alkyl, phenyl-C1-6-alkyl or -C(=0)OR1°, Nherein R10 is as defined in claim 1, and R13 and R14 are independently hydrogen, C1-6-alkyl, phenyl-C1-6-alkyl or oxo. In a further embodiment thereof R1 is hydrogen or -C(=0)0-CC1-8-alkyll and R13 and R14 are hydrogen.
In a further embodiment of the invention R' R2 and R3 are hydrogen.
In still a further embodiment of the invention A is C1-6-alkylene. In an embodiment thereof A is methylene or ethylene. In yet a further embodiment thereof A is ethylene.
In yet a further embodiment of the invention B is -C(=0)-.
In still a further embodiment of the invention D is -cycloalkyl, heteroaryl or aryl, Nhich may optionally be substituted as defined for formula (I).
In an embodiment thereof D is -cycloalkyl, heteroaryl or aryl, Nhich may optionally be substituted as defined for formula (I), but not in the positions adjacent to the point of attachment of D to B.
In another embodiment thereof D is cyclopropyl, thienyl or phenyl, Nhich may optionally be substituted as defined for formula (I).
In still another embodiment thereof D is cyclopropyl.

In yet another embodiment thereof D is thienyl, Nhich is substituted Nith halogen.
In yet a further embodiment thereof D is phenyl, Nhich is optionally substituted Nith
• hydroxy, halogen,
heteroaryl-C1-6-alkoxy, aryl-C1-6-alkoxy, Nherein the ring moieties are optionally substituted as defined for formula (I). In one embodiment thereof D is phenyl Nhich is optionally substituted Nith halogen or benzyloxy, Nherein the ring moiety of benzyloxy is optionally substituted as defined for formula (I). In a further embodiment thereof D is phenyl, Nhich is substituted Nith benzyloxy.
The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included Nithin the scope of the invention.
Furthermore, Nhen a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included Nithin the scope of the invention. LikeNise, molecules having a bond Nith restricted rotation may form geometric isomers. These are also intended to be included Nithin the scope of the present invention.
Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, Nhich the compounds are able to form, are included Nithin the scope of the present invention.
The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as Nell as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulphuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, gly-colic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulphonic, ethanesulphonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulphonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-amino-benzoic, glutamic, benzenesulphonic, p-toluenesulphonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the

pharmaceutical!;/ acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, Nhich is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hy-droxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
Also intended as pharmaceutically acceptable acid addition salts are the hydrates, Nhich the present compounds are able to form.
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherNise separating the salt and solvent.
The compounds of the present invention may form solvates Nith standard loN molecular Neight solvents using methods Nell knoNn to the person skilled in the art. Such solvates are also contemplated as being Nithin the scope of the present invention.
The invention also encompasses prodrugs of the present compounds, Nhich on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs Nill be functional derivatives of the present compounds, Nhich are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
The present compounds are useful for the treatment of hyperglycemia; IGT; Syndrome X; type 1 diabetes; type 2 diabetes; conditions Nith dyslipidemia including diabetic dyslipidemia; and obesity. Furthermore, they may be useful for the treatment of albuminuria; polycystic ovary syndrome, cardiovascular diseases such as cardiac hypertrophy, hypertension and arteriosC1-C6rosis including atherosC1-C6rosis; gastrointestinal disorders; acute pancreatitis; and appetite regulation or energy expenditure disorders.
They may also find use in the treatment of bipolar disorder (manic depressive syndrome), mania, Alzheimer's disease, bipolar disorder, Huntington's chorea, Parkinson's disease, amyotrophic lateral sC1-C6rosis, multiple sC1-C6rosis, leukopenia, anxiety, movement disorder, aggression, psychosis, seizures, panic attacks, hysteria or sleep disorders. Furthermore, they may be useful as contraceptives, cf NO 97/41854, and for the treatment of cancer, hair-loss and neurotraumatic diseases, such as acute stroke, cf NO 00/21927.

Thus, in another aspect the invention relates to the use of a compound of the general formula (]»):

(i) R1 and R2, together Nith the nitrogen atom to Nhich they are attached, form a 5 to 7 mem-bered non-aromatic ring, Nhich ring may optionally contain a double bond, and Nhich ring may optionally contain a further nitrogen atom, and to Nhich ring is attached tNo groups R4 and R5 Nhich are independently selected from
• hydrogen,
• oxot
• -alkyl, C2-6-aIkenyl, -alkynyl,
Nhich may optionally be substituted Nith one or tNo substituents independently selected from hydroxy, halogen, cyano, nitro, -NR6R7, -C(=0)NR6R7, -OC(=0)NR6R7, -OCH2C(=0)NR6R7, C3-8alkoxy, -C(=0)OR6, -C(=0)R6, -NHC(=0)R6, -CHF2, -CF3, -OCF3, -OCHF2l -OCH2CF3, -OCF2CHF2, -SCF3l -SR6, -S(=0)R6, -S(=0)2R6, -S(=0)2NH2,
Nherein R8 and R7 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R6 and R7, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,

• aryl, C3-8-cycloalkyl, heteroaryl, C3-8-heterocyclyl, aryl--alkyl, C3-8-cycIoalkyI--alkyl, heteroaryl--alkyl, C3-8-heterocyclyl--alkyl, aryl--alkoxy, C3-8-cyclo-alkyl--alkoxy, heteroaryl-alkoxy, -heterocyclyl-d-6-aIkoxy, -C(=0)-aryI, -C(=0)--cycloaIkyi, -C(=0)-heteroaroyl, -C(=0)-C3_8-heterocyclyl, -O-aryl, -0--cycioalkyl, -O-heteroaryl, -O-C3-8-heterocyclyl, -S-aryl, -S-C3-8cycloalkyl, -S-heteroaryi-S-C1-6-heterocyclyl,
Nherein the ring moieties may optionally be substituted Nith one to three substituents independently selected from hydroxy, halogen, cyano, nitro, -NR8R9, -C(=0)NR8R9, -OC(=0)NR8R9. -OCH2C(=0)NR8R9, -alkoxy, -C(=0)OR8, -C(=0)R8, -NHC(=0)R8, -CHF2, -CF3( -OCF3) -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SRQ, -S(=0)R8, -S(=0)2R8, -S(=0)2NH2l
Nherein R8 and R9 Nhich may be the same or different independently are selected from hydrogen and -alkyl. or R8 and R9, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
and R3 is hydrogen,
(ii) or R1 is hydrogen, -C(=0)OR10, -C(=0)R10, -alkyl, aryl--alkyl, C3-8-cycloalkyl--alkyl, heteroaryl--alkyl or C3-8heterocyclyl--alkyl,
Nherein R10 is -alkyl, C2-6-alkenyl or C2-6-aikynyl, Nhich may optionally be substituted Nith one or tNo substituents independently selected from
hydroxy, halogen, cyano, nitro, -NR11R12, -C(=0)NR11R12, -OC(=0)NR11R12, -OCH2C(=0)NR11R12, -alkyl, C2-8-alkenyl, -alkynyl, -alkoxy, -C(=0)OR1' -C(=0)Ri1, -NHC(=0)R11, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3l -SR11, -S(=0)R11, -S(=0)2R11, -S(=0)2NH2,
Nherein R11 and R12 Nhich may be the same or different independently are selected from hydrogen and -alkyl, or R11 and R12, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,

and R2and R3 are connected to form, together Nith A and the nitrogen atom and carbon atom, respectively, to Nhich they are attached, a 5 to 7 membered non-aromatic ring to
Nhich ring is attached tNo groups R13 and R14 Nhich are independently selected from
i
• hydrogen,
• oxo,
• -alkyl, C2-6-alkenyl, C2-8-alkynyl,
Nhich may optionally be substituted Nith one or tNo substituents independently selected from hydroxy, halogen, cyano, nltro, -NR15R16, -C(=0)NR15R16, -OC(=0)NR15R16, -OCH2C(=0)NR15R16, -alkoxy, -C(=0)OR15, -C(=0)R15, ~NHC(=0)R15, -CHF2, -CF3l -OCF3, -OCHF2, -OCH2CF3l -OCF2CHF2l -SCF3, -SR15, -S(=0)R15, -S(=0)2R15, -S(=0)2NH2,
Nherein R15 and R16 Nhich may be the same or different independently are selected from hydrogen and d-6-alkyl, or R15 and R16, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
• aryl, -cycloalkyl, heteroaryl, C3_8-heterocyclyl, aryl--alkyl, C3-8-cycloalkyl-
C1-6-alkyl, heteroaryl--alkyl, C3-8-heterocyclyl--alkyl, aryl-C3-8-alkoxy, C3-8cyclo-
alkyl--alkoxy, heteroaryl--alkoxy, C3-8-heterocyclyl--alkoxy, -C(=0)-aryl,
-C(=0)-C3-8-cycloalkyl, -C(=0)-heteroaroyl, -C(=0)--heterocyclyl, -O-aryl,
-0--cycloaIkyl, -O-heteroaryl, -O-C3-8-heterocyclyl, -S-aryl, -S-C1-C6-cycloalkyl,
-S-heteroaryl, -S-C3-8-heterocyclyl,
Nherein the ring moieties may optionally be substituted Nith one to three substituents independently selected from
hydroxy, halogen, cyano. nitro, -NR17R18, -C(=0)NR17R13, -OC(=0)NR17R18, -OCH2C(=0)NR17R18, -alkyl, C1-C6-alkenyl, C1-6-alkynyl, -alkoxy, -C(=0)OR17,

-C(=0)R17. -NHC(=0)R17, -CHF2l -CF3l -OCF3, -OCHF2, -OCH2CF3, ^OCF2CHF2l -SCF3| -SR17, -S(=0)R17, -S(=0)2R17, -S(=0)2NH2|
Nherein R17 and R18 Nhich may be the same or different independently are selected from hydrogen and -alkyl, or R17 and R18f together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
(iii) or R1 and R2 Nhich may be the same or different independently are selected from hydrogen, -C(=0)OR19 -C(=0)R19 and -alkyl,
Nherein R19 is -alkyi, -alkenyl or C2-8-alkynyl, Nhich may optionally be substituted Nith one or tNo substituents independently selected from
• hydroxy, halogen, cyano, nitro, -NR20R21, -C(=O)NR20R21, -OC(=O)NR20R21, -OCH2C(=O)NR20R21) -alkoxy, -C(=0)OR20, -C(=0)R20, -NHC(=0)R20, -CHF2, -CF3| -OCF3, -OCHF2, -OCH2CF3l -OCF2CHF2, -SCF3> -SR20, -S(=0)R20, -S(=0)2R20, -S(=0)2NH2,
• Nherein R20 and R21 Nhich may be the same or different independently are selected from hydrogen and -alkyl, or R20 and R2' together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
and R3 is hydrogen,
B is a valence bond, -C(=0)-, ~S(=0)- or -S(=0)r,
Dis
• hydroxy, halogen, cyano, nitro, -NR^R23, -NCR22)OR23, -C(=0)NR22R23,
-OC(=0)NR22R23, -OCH2C(=0)NR22R23, -alkoxy, -C(=0)OR22, -C(=0)R22,
-NHC1-6R22, -CHF2, -CF3, -OCF3) -OCHF2) -OCH2CF3l -OCF2CHF2) -SCF3, -SR22,
-S(=O)R22, -S(=0)2R22, -S(=0)2NH2,

Nherein R22 and R23 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R22 and R23, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
• C1-6-alkyl, C1-6-alkenyl, C2-8-alkynyl,
Nhich may optionally be substituted Nith one or tNo substituents selected from hydroxy, halogen, cyano, nitro, -NR24R25, -C(=0)NR24R25, -OC(=0)NR24R25, -OCH2C(=0)NR24R25, -alkoxy, -C(=0)OR24, -C(=0)R24, -NHC(=0)R24, -CHF2, -CF3l -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR24, -S(=0)R24, -S(=0)2R24, -S(=0)2NH2,
Nherein R24 and R25 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R24 and R25, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
• aryl, C1-6-cycloalkyl, heteroaryl, C3_8-heterocyciyl, aryl-C1-6-alkyl, C1-6-cycloalkyl-
C1-6-alkyl, heteroaryl-C1-6-alkyl, C3-8-heterocyciyl-C1-6-alkyl, aryl-C1-6-alkoxy,
C3-8-cycloalkyl-C1-C6-alkoxy, heteroaryl-C1-6-alkoxy, C3-8-heterocyclyl-C1-6-alkoxy,
-C(=0)-aryl, -C(=0)-C3-8-cycIoaIkyl, -C(=0)-heteroaroyl, -C(=0)-heterocycIyl,
-O-aryl, -0--cycloalkyl, -O-heteroaryl, -O-C1-6-heterocyclyl, -S-aryi,
-S-C3-8-cydoaikyl, -S-heteroaryl, -S-C1-6-heterocyclyl, -NH-aryl, -NH-heteroaryl,
Nherein the ring moieties may optionally be substituted Nith one to three substituents selected from
o hydroxy, halogen, cyano, nitro, -NR26R27, -C(=0)NR26R27, -OC(=0)NR26R27, -OCH2C(=0)NR26R27, -alkoxy, -C(=0)OR26I -C(=0)R26, -NHC(=0)R26, -CHF2, -CF3] -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3) -SR26, -S(=0)R26, -S(=0)2R26, -S(=0)2NH2,
Nherein R26 and R27 Nhich may be the same or different independently are selected from hydrogen and -alkyl, or R26 and R27, together Nith the nitrogen

atom to Nhich they are attached, form a 3 to 8 membereci cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
o C1-6-alkyl, -alkeny(, -alkynyl,
Nhich may optionally be substituted Nith one or tNo substituents selected from hydroxy, halogen, cyano, nitro, -NR28R29, -C(=0)NR28R29, -OC(=0)NR28R29, -OCH2C(=0)NR28R29, C1-6-alkoxy, -C(=0)OR28, -C(=0)R28( -NHC(=0)R2B, -CHF2, -CF3f -OCF3, -OCHF2l -OCH2CF3l -OCF2CHF2l -SCF3( -SR28, -S(=0)R28, -S(=0)2R28, -S(=0)2NH2,
Nherein R28 and R29 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R28 and R29, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
o aryi, -cycloalkyl, heteroaryl, C3-8-heterocyclyl, aryl-C1-6-alkyl, -cyclo-alkyl-C1-6-alkyl, heteroaryl-C1-C6alkyl, C3-8-heterocyclyl-C1-6-alkyi, aryl--alkoxy, C3-8-cycloalkyi-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, -hetero-cyctyl-C1-6-alkoxy, -C(=0)-aryl, -C(=0)-C3_8-cycloalkyl, -C(=0)-heteroaroyI, -C(=0)--heterocyclyl, -O-aryl, -0-C3-8-cycloalkyl, -O-heteroaryl, -0--heterocyclyl, -S-aryl, -S-C1-6-cycloaikyl, -S-heteroaryl, -S-C1-6-heterocyclyl,
Nherein the ring moieties may optionally be substituted Nith one to three substituents selected from hydroxy, halogen, cyano, nitro, -NR^R31, -C(=O)NR30R3' -OC(=O)NR30R3' -OCH2C(==O)NR30R3' C1-6-alkyl, C2-6-alkenyl, C2-8-alkynylf C1-6-alkoxy, -C(=0)OR30, -C(=0)R30, -NHC(=0)R30, -CHF2l -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR30, -S(=0)R30, -S(=0)2R3°, -S(=0)2NH2|
Nherein R30 and R31 Nhich may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R30 and R31, together Nith the nitrogen atom to Nhich they are attached, form a 3 to 8 membered cyclic ring optionally

containing one or tNo further heteroatoms selected from oxygen, sulphur and nitrogen,
as Nell as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, Nherein an inhibition of GSK-3 is beneficial.
In a further preferred embodiment of the invention the compounds of the general formula (I') are used for the manufacture of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions related to GSK-3.
In a further preferred embodiment of the invention the present compounds of the general formula (I') are used for the manufacture of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, Nherein groNth factor induced inhibition of GSK-3 is insufficient.
In another preferred embodiment of the invention the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, Nherein glycogen metabolism exhibits abnormalities.
In another preferred embodiment of the invention the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, Nherein glycogen synthase is insufficiently activated.
In a further preferred embodiment of the invention the present compounds of the general formula (P) are used for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions involving elevated blood glucose. The compounds are effective in loNering both fasting and postprandial blood glucose.
In still a further preferred embodiment of the invention the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of hyperglycemia.
In yet a further preferred embodiment of the invention the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of IGT.
In another preferred aspect the invention the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes. Such treatment includes ia the delaying of the progression from IGT to type

2 diabetes as Nell as the delaying of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
In a further preferred aspect of the invention the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of type 1 diabetes. Such treatment is normally accompanied by insulin therapy.
Furthermore, the present compounds of the general formula (!') may be used for the preparation of a pharmaceutical composition for the treatment of obesity.
In another aspect of the invention the present compounds of the general formula (!') may be used for the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease.
In another aspect of the invention the present compounds of the general formula (!') may be used for the preparation of a pharmaceutical composition for the treatment of bipolar disorder.
In a further aspect of the invention the present compounds are administered in combination Nith diet and/or exercise.
In yet a further aspect of the invention the present compounds are administered in combination Nith one or more further pharmacologically active substances in any suitable ratios. Such further active agents may be selected from antidiabetic agents, antihyper-lipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated Nith diabetes. Furthermore, they may be administered in combination Nith one or more further pharmacologically active substances selected from agents for the treatment of Alzheimer's disease and agents for the treatment of bipolar disorder. Such combined administration may be in separate preparations or in a single preparation, as appropriate.
Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in NO 98/08871 (Novo NordiskNS), Nhich is incorporated herein by reference as Nell as orally active hypoglycaemic agents.
The orally active hypoglycaemic agents preferably comprise imidazolines, sulpho-nylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, ct-glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the p-cells eg potassium channel openers such as those disclosed in NO 97/26265, NO 99/03861 and NO 00/37474 (Novo NordiskNS), Nhich are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nategiinide, glucagon antagonists such as those disclosed in NO 99/01423 and NO 00/39088 (Novo Nord- jskNS and Agouron Pharmaceuticals, Inc.), Nhich are incorporated herein by reference,

GLP-1 agonists such as those disclosed in NO 00/42026 (Novo NordiskNS and Agouron Pharmaceuticals, Inc.), Nhich is incorporated herein by reference, DPP-IV (dipeptidyl pepti-dase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenosis, glucose uptake modulators, compounds modifying the lipid metabolism such as antilipidemic agents, compounds loNering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists, such as ALRT-268, LG-1268 or LG-1069.
In one embodiment of the invention the present compounds are administered in combination Nith insulin.
In a further embodiment of the invention the present compounds are administered in combination Nith a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, giibencla-mide, glipizide, glimepiride, glicazide orglyburide.
In another embodiment of the invention the present compounds are administered in combination Nith a biguanide eg metformin.
In yet another embodiment of the invention the present compounds are administered in combination Nith a meglitinide eg repaglinide or nateglinide.
In still another embodiment of the invention the present compounds are administered in combination Nith a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 orT 174 or the compounds disclosed in NO 97/41097, NO 97/41119, NO 97/41120, NO 00/41121 and NO 98/45292 (Dr. Reddy's Research Foundation), Nhich are incorporated herein by reference.
In still another embodiment of the invention the present compounds are administered in combination Nith an insulin sensitizer eg such as Gl 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GN-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GN-501516 or the compounds disclosed in NO 99/19313, NO 00/50414, NO 00/63191, NO 00/63192, NO 00/63193 (Dr. Reddy's Research Foundation) and NO 00/23425, NO 00/23415, NO 00/23451, NO 00/23445, NO 00/23417, NO 00/23416, NO 00/63153, NO 00/63196, NO 00/63209, NO 00/63190 and NO 00/63189 (Novo NordiskNS), Nhich are incorporated herein by reference.
In a further embodiment of the invention the present compounds are administered in combination Nith an a-giucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
In another embodiment of the invention the present compounds are administered in combination Nith an agent acting on the ATP-dependent potassium channel of the (3-celIs eg tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.

In still another embodiment of the invention the present compounds are administered in combination Nith an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
In another aspect of the invention, the present compounds are administered in combination Nith more than one of the above-mentioned compounds eg in combination Nith metformin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulphonylurea, metformin and troglitazone; insulin and a sulphonylurea; insulin and metformin; insulin, metformin and a sulphonylurea; insulin and troglitazone; insulin and lovastatin; etc.
Thus, in a further aspect of the invention the present compounds are administered in combination Nith one or more antiobesity agents or appetite regulating agents.
Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano-cortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, adrenergic agonists such as CL-316243, AJ-9677, GN-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or cita-lopram, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, groNth hormone, groNth factors such as prolactin or placental lactogen, groNth hormone releasing compounds, TRH (thyrotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X receptor) modulators, TR p agonists, AGRP (Agouti related protein) inhibitors, H3 histamine antagonists such as those disclosed in NO 00/42023, NO 00/63208 and NO 00/64884 (Novo NordiskNS and Boehringer Ingelheim International GmbH), Nhich are incorporated herein by reference, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.
In one embodiment of the invention the antiobesity agent is leptin.
In another embodiment the antiobesity agent is dexamphetamine or amphetamine.
In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine.
In still another embodiment the antiobesity agent is sibutramine.
In a further embodiment the antiobesity agent is orlistat.

In another embodiment the antiobesity agent is mazindol or phentermine.
In still another embodiment the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.
Furthermore, in another aspect of the invention the present compounds are administered in combination Nith one or more antihypertensive agents. Examples of antihypertensive agents are p-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and a-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
In another aspect of the invention the present compounds are administered in combination Nith one or more agents for the treatment of Alzheimer's disease. Examples of such agents are tacrine, donepezil, haloperidol, olanzapine, quetiapine, risperidone, alprazolam, buspirone, diazepam, lorazepam, amitriptyline, bupropion, desipramine, fluoxetine, fluvoxam-ine, nefazodone, nortriptyline, paroxetine, sertraline and trazodone.
In yet another aspect of the invention the present compounds are administered in combination Nith one or more agents for the treatment of bipolar disorder. Examples of such agents are lithium, valproate, divalproex, carbamazepine, antipsychotic drugs such as haloperidol and perphenazine, antianxiety agents such as lorazepam and clonazepam, antidepressants such as bupropion, fluoxetine, fluvoxamine, paroxetine, sertraline, mirtazepine, phenelzine, tranylcypromine, nefazodone, amitriptyline, desipramine, imipramine, nortriptyline and venlafaxine.
It should be understood that any suitable combination of the compounds according to the invention Nith diet and/or exercise, one or more of the above-mentioned compounds and optionally one or more other pharmacologically active substances are considered to be Nithin the scope of the present invention.
PHARMACEUTICAL COMPOSITIONS
The compounds of the invention may be administered alone or in combination Nith pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated Nith pharmaceutically acceptable carriers or diluents as Nell as any other knoNn adjuvants and excipients in accordance Nith conventional techniques such as those disclosed in Remington:

The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It Nill be appreciated that the preferred route Nill depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, poNders and granules. Nhere appropriate, they can be prepared Nith coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods Nell knoNn in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as Nell as sterile poNders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being Nithin the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, derma! patches, implants etc.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body Neight per day, preferably from about 0.01 to about 50 mg/kg body Neight per day, and more preferred from about 0.05 to about 10 mg/kg body Neight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage Nill depend upon the frequency and mode of administration, the sex, age, Neight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods knoNn to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.

For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. Nhen a compound of the formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) Nith a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound Nith a hydroxy group include the anion of said compound in combination Nith a suitable cation such as sodium or ammonium ion.
For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic Nith sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques knoNn to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or loNer alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or Nater. Similarly, the carrier or diluent may include any sustained release material knoNn in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed Nith a Nax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods knoNn in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and Nhich may include a suitable excipient. These formulations may be in the form of poNder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-Nateror Nater-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in poNder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier Nill vary Nidely but Nill usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

If desired, the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination Nith further pharmacologically active substances such as those described in the foregoing.
The present invention is further illustrated by the folloNing representative examples Nhich are, hoNever, not intended to limit the scope of the invention in any Nay.
EXAMPLES
The compounds used as starting materials are either knoNn compounds or compounds, Nhich can be prepared by methods knoNn per se. NMR spectra Nere recorded on a Bruker 300 MHz instrument. Flash chromatography Nas carried out on Merck silica gel 60 (Art 9385).

HPLC-MS Method A:
Instruments:
Sciex AP1100 single quadropole mass spectrometer, Applied Biosystems 785A UV detector, Sedex 55 evaporative light scattering detector.
Column: YMC ODS-A 120A s - 5'x (50 mm x 3 mm id). Gradient: 5% - 90% acetonitrile C3-8ith 0.05% TFA) during 7.5 min. UV detection at 214 nm.
HPLC-MS Method B:
Column: Naters Xterra MS C-18 X 3 mm id. Linear gradient 10% -100% in 7.5 min, acetonitrile, 0.01% TFA, floN rate 1.0 ml/min. Detection 210 nm (analog output from diode array detector), MS-detection ionisation mode API-ES, scan 100-1000 amu step 0.1 amu.
In the examples and assays the folloNing terms are intended to have the folloNing meanings:
Boc: tert-butyloxycarbonyl
DMF: N,N-dimethylformamide
DMSO: dimethyl sulphoxide
EtOAc: ethyl acetate
HCI: hydrogen chloride
M.p.: melting point
TFA: trifluoroacetic acid
General procedure (A)
The preparation of the compounds of the formula (la) according to this invention Nherein B is -C(=0)- may be illustrated in the scheme beloN and may be achieved using the method described by GeNald K. et al {J. Prakt. Chem., 35,1967, pp 97-104). An isothio-cyanate of formula (III) is reacted together Nith a bromomethylketone of formula (V) to give products of the general formula (la) (step C). Nhen not commercially available, the starting materials of formulae (III) and (V) are prepared using literature procedures, as cited under the individual examples and as illustrated in steps A and B beloN.


Nhen R1 and R2 are both hydrogen the amino group formed should be protected Nith a suitable protecting group, such as Boc, before carrying out step A. After step C the protecting group can be removed in a conventional manner to form the compounds of the formula (la) Nherein R1 and R2 are both hydrogen.

The method described by GeNald K. et al (J. Prakt. Chem., 35,1967, pp 97-104) Nas employed using 2-bromo-1-cyclopropylethanone andN-Boc-isothiocyanatopropylamine. 2-Bromo-1-cyclopropylethanone Nas itself prepared using a slight modification to the

literature procedure described by Calverley M. J. (Tetrahedron, 43, 20,1987, 4609-4619). A temperature of 10-15 °C Nas used throughout the addition of bromine.
The title compound Nas obtained in 32% yield after chromatography using ethyl acetate/heptane (2:1) as eluant.
M.p. 144-146 °C; 1H NMR (300 MHz; DMSO-d6): s0.75 (2H, m, CH2), 0.82 (2H, m, CH2), 1.39 (9H, s, f"Bu), 1.68 (3H, m, CH2 and CH), 2.98 (2H, dd, CH2), 3.23 (2H, dd, CH2), 6.87 (1H, brt, NH), 7.61 (2H, brs, NH2), 8.48 (1H, t, NH).
The folloNing compounds, unless specified otherNise, Nere prepared as described in Example 1 using the appropriate starting materials.

1H NMR (300 MHz; DMSO-d6): 1H NMR (300 MHz; DMSO-d6): 80.75 (2H, m, CH2), 0.82 (2H, m, CH2), 1.40 (9H, s, ("Bu), 1.64 (1H, m, CH), 3.12 (2H, dd, CH2), 3.28 (2H, br, CH2), 6.94 (1H, br t, NH), 7.62 (2H, br s, NH2), 8.49 (1H, t, NH).

1H NMR (300 MHz; DMSO-d6): s1-39 (9H, s, '"Bu), 1.68 (2H, ddd, CH2), 2.98 (2H, dd, CH2), 3.30 (2H, br, CH2), 6.87 (1H, brt, NH), 7.18 (1H, d, Ar-H), 7.32 (1H, brd, Ar-H), 7.85-8.55 (2H, brs, NH2), 8.88 (1H, t, NH); HPLC-MS (ESI): m/z418 [M+H]+; R, = 5.73 min (Method A).


The starting material, 4-isothiocyanatopiperidine-1-carboxylic acid tert-butyl ester, Nas first prepared, from the corresponding amine using di-2-pyridylthionocarbonate, according to the method of Kim, S. and Yi, K. Y. (Tetrahedron Lett., 26 (13), 1985, pp. 1661-1664). The title compound Nas obtained after chromatography using ethyl acetate/heptane (1:1)aseluant.
1H NMR (300 MHz; DMSO-d6): 80.75 (2H, m, CH2), 0.82 (2H, m, CH2), 1-34 (2H, m, CH2), 1.39 (9H, s, ''Bu), 1.62 (1H, m, CH), 1.81 (2H, dd, CH2), 2.88 (2H, m, CH2), 3.73 (1H, br, CH), 3.88 (2H, dd, CH2), 7.64 (2H, br s, NH2), 8.52 (1H, d, NH); HPLC-MS (ESI): m/z367 [M+H]+; Rt = 4.95 min (Method A).

The starting material, 1-(3-benzyloxyphenyl)-2-bromoethanone, Nas first prepared, from the corresponding ketone using copper (II) bromide, according to the method of King, L C. etN (J. Org. Chem., 1964, 29, pp 3459-3461). The title compound Nas obtained after chromatography using ethyl acetate/heptane (1:1) as eluant
1H NMR (300 MHz; DMSO-d6): δ1.34 (2H, m, CH2), 1.39 (9H, s, '"Bu), 1.88 (2H, m, CH2), 2.88 (2H, m, CH2), 3.73 (1H, br, CH), 3.87 (2H, dd, CH2), 5.65 (2H, s, OCH2), 7.07-7.48 (9H, m, Ar-H), 7.70 - 8.50 (2H, br, NH2), 8.62 (1H, br d, NH); HPLC-MS (ESI): m/z 509 [M+H]+; Rt = 7.08 min (Method A).


An intermediate, S-(3-benzyloxybenzoyl)methyl-N-cyano-N- propylcarbamic acid tert-butyl ester isothiourea Nas isolated Nhen the aforementioned method of GeNald K. efN Nas employed.
1H NMR (300 MHz; DMSO-d6): δ1.33 (9H, s, '"Bu), 1.55 (2H, m,CH2), 2.75 (2H, dd, CH2), 2.90 (1H, m, CH), 3.19 (1H, m, CH), 3.70 (2H, AB, dd, SCH2), 5.63 (2H, s, OCH2), 6.71 (1H, t, NH), 7.05 - 7.48 (9H, m, Ar-H), 7,63 (1H, s, NH).

The crude intermediate Nas refiuxed overnight in ethylacetate Nith 2 equivalents of triethylamine. The title compound Nas obtained on cooling and addition of Nater.
1H NMR (300 MHz; DMSO-d6): δ1.41 (9H, s, '"Bu), 1.70 (2H, ddd, CH2), 3.03 (2H, dd, CH2), 3.28 (2H, br, CH2), 5.20 (2H, s, OCH2), 6.85 (1H, br t, NH), 7.08 - 7.48 (9H, m, Ar-H), 7.81 -8.4 (2H, brs, NH2), 8.60 (1H, brt, NH); HPLC-MS (ESI): m/z 483 [M+Hf; R, = 4.23 min (Method B).

The starting material, 1-(3-isothiocyanatopropy!)pyrrolidin-2-one, Nas first prepared, from the corresponding amine, using di-2-pyridylthionocarbonate, according to the method of Kim, S. and Yi, K. Y. (Tetrahedron Lett., 26 (13), 1985, pp. 1661-1664). The product Nas

found to precipitate from the reaction mixture. This was filtered off and stirred in hot ethanol
before warm filtration offered the title compound in 40% yield.
M.p. 224-225 °C; HPLC-MS (ESI): m/z 385 [M+H]+; Rt = 3.31 min (Method B).
Microanalysis for C15H17N402SCI:
Calc: CF 46.81%; H, 4.45%; N, 14.56%;
Found: C, 46.83%; H, 4.46%; N, 14.36%.

The starting material, 1-(3-isothiocyanatopropyl)-4-methyIpiperazine, was first prepared, from the corresponding amine, using di-2-pyridylthionocarbonate, according to the method of Kim, S. and Yi, K. Y. (Tetrahedron Lett., 26 (13), 1985, pp. 1661-1664). The crude product obtained by precipitation from water, was dissolved in ethanol and treated with an excess of HCI gas in diethylether (ca. 2 M) to give the title compound as a hydrochloride salt in 13% yield. M.p. 210-212 °C; HPLC-MS (ESI): m/z 401 [M+H]+; Rt = 1.65 min (Method B).

The reaction was performed according to Example 6, with the ring-opened intermediate first being isolated after addition of water to the reaction mixture. This was dissolved in hot ethanol and treated with 1.2 equivalents of triethlyamine. After 2 hours, reaction was cooled and filtered to furnish the title compound in 32% yield as a white solid. M.p. 184 °C; 1H NMR (300 MHz; DMSO-d6): δ1.73 (2H, ddd, CH2), 1.92 (2H, ddd, CH2), 2.20 (2H, t, CH2), 3.23 (4H, m, 2 x CH2), 3.38 (2H, t, CH2), 5.15 (2H, s, OCH2), 7.08 - 7.48 (9H, m,

Ar-H), 7.81 - 8.4 (2H, br d, NH2), 8.58 (1H, br t, NH); HPLC-MS (ESI): m/z 451 [M+H]+; R, = 3.47 min (Method B).

The reaction and work-up were performed as described in Example 8. The title compound was obtained as a hydrochloride salt.
1H NMR (300 MHz; DMSO-d6): δ2.04 (2H, ddd, CH2), 2.85 (3H, s, CH3), 3.22 (2H, br, CH2), 3.41 (6H, m, 3 x CH2), 3.70 (4H, m, CH2), 5.17 (2H, s, OCH2), 7.08 - 7.48 (9H, m, Ar-H), 7.81 -8.35 (2H, brd, NH2), 8.81 (1H, brt, NH), 11.88 (1H, brs, NH); M.p. 99-100 °C; HPLC-MS (ESI): m/z 466 [M+H]+; R, = 2.30 min (Method B).

The product from Example 1, [3-(4-amino-5-cyclopropanecarbonylthiazol-2-yl-amino)propyl]carbamic acid tert-butyl ester (100 mg; 0.30 mmol), was dissolved in ethanol (5 ml) and treated with a three-fold excess of a solution of HCI gas in diethyl ether (ca. 2M). White solid was filtered off and washed with ether giving the title compound as the hydrochloride salt in 80% yield.
1H NMR (300 MHz; DMSO-d6): δ0.75 (2H, m, CH2), 0.82 (2H, m, CH2), 1.64 (1H, m, CH), 1.88 (2H, ddd, CH2), 2.84 (2H, dd, CH2), 3.34 (2H, dd, CH2), 5.20 - 6.0 (3H, br s, NH3), 8.03 (2H, br s, NH2), 8.75 (1H, t, NH); HPLC-MS (ESI): m/z 241 [M+H]+; R, = 0.43 and 2.68 (Method B).


The title compound was obtained as a hydrochloride salt, starting from [2-(4-amino-5-cyclopropanecarbonylthiazol-2-ylamino)ethyl]carbamic acid tert-butyl ester and using the method described in Example 11.
1H NMR (300 MHz; DMSO-d6): δ0.77 (2H, m, CH2), 0.81 (2H, m, CH2)? 1.66 (1H, m, CH), 3.04 (2Hf dd, CH2)f 3.49 (2Hf ddf CH2), 4.42 (3H, br s, NH3), 8.13 (2H, br s, NH2), 8.75 (1H, t, NH); HPLC-MS (ESI): m/z 227 [M+H]+; Rt = 0.47 min (Method B).

The product from Example 3, 3-[4-amino-5-(5-chlorothiophene-2-carbonyl)thiazol-2-ylamino]propylcarbamic acid tert-butyl ester (51 mg; 0.12 mmol), was dissolved in dichloro-methane (1 ml) and treated with TFA (0.5 ml). After 2 hours at room temperature, solvents were evaporated to afford the title compound as a TFA salt.
1H NMR (300 MHz; DMSO-d6): δ1.86 (2H, ddd, CH2), 2.88 (2H, dd, CH2), 3.40 (2H, br s, CH2), 7.18 (1H, d, Ar-H), 7.33 (1H, df Ar-H), 7.76 (3H, br s, NH3), 8.1 and 8.45 (2H, br, 2 x s, NH2), 8.95 (1H, br t, NH); HPLC-MS (ESI): m/z 317 [M+H]+; Rt = 1.82 min.


The title compound was obtained as a TFA salt, starting from 4-(4-amino-5-cyclo-propanecarbonylthiazol-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester, and using the method described in Example 13. HPLC-MS (ESI): m/z 267 [M+H]+; Rt = 0.65 min.

The title compound was obtained as a TFA salt, starting from 4-[4-amino-5-(3-benzyloxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylicacid tert-butyl ester, and using the method described in Example 13. HPLC-MS (ESI): m/z 409 [M+H]+; Rt = 2.33 min.

The title compound was obtained as a TFA salt, starting from {3-[4-amino-5-(3-benzyloxybenzoyl)thiazol-2-ylamino]propyl}carbamic acid tert-butyl ester, and using the method described in Example 13.
1H NMR (300 MHz; DMSO-d6): δ1.85 (2H, ddd, CH2), 2.83 (2H, dd, CH2)f 3.33 (2H, br, CH2), 5.18 (2H, s, OCH2), 6.58 (3H( br s, NH3), 7.11 - 7.49 (9H, m, Ar-H), 7.95 (2H, br s, NH2), 8.80 (1H, br t, NH); HPLC-MS (ESI): m/z 383 [M+Hf; Rt = 2.30 min.

PHARMACOLOGICAL METHODS
Assay (I)
Inhibition of GSK-3 by a test compound was evaluated using human GSK-3p and a glycogen synthase derived substrate with the following amino acid sequence:
YRRAAVPPSPSLSRHSSPHQS(P04)EDEEE-NH2.
In brief, GSK-3P was incubated with 35 μm substrate and varying concentrations of test compound in a buffer containing 0.1 mM 33P-Iabeled ATP, 10 mM magnesium acetate, 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.1% dithiothreitol and 0.03% Triton-X100 for 60 min at room temperature. The reaction was performed using 96-welI plates. The reaction was terminated by adding 13 μl 2% phosphoric acid to each well, and μl was spotted onto P30 paper which was washed 4 times in 0.5% phosphoric acid to remove non-incorporated 33P-labeled ATP. After drying the radioactivity was counted in a Wallac. Dose-response profiles were generated, and the IC50 value for inhibition of GSK-3 by the test compound was calculated using a four-parameter logistic function.
The following compounds inhibited GSK-3 with an IC50 value lower than 1 μm;
Examples 3, 5, 6, 7, 9 and 10.
From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein for the purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention as defined by the appending claims.

CLAIMS
1. A compound of the generaformula (I):

(i) R1 and R2, together with the nitrogen atom to which they are attached, form a 5 to 7 mem-bered non-aromatic ring, which ring may optionally contain a double bond, and which ring may optionally contain a further nitrogen atom, and to which ring is attached two groups R4 and R5 which are independently selected from

which may optionally be substituted with one or two substituents independently selected from hydroxy, halogen, cyano, nitro, -NR6R7, -C(=0)NR6R7, -OC(=0)NR6R7, -OCH2C(=0)NR6R7, C1-6-alkoxy, -C(=0)OR6, -C(=0)R6, -NHC(=0)R6, -CHF2, -CF3-OCF3-OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3-SR6, -S(=0)R6, -S(=0)2R6, -S(=0)2NH2l
wherein R6 and R7 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R8 and R7, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,

• aryl, C3-8-cycloalkyl, heteroaryl, C3_8-heterocyclyl, aryl-C1-6-alkyl, C3-8-cycloalkyl-
C1-6-alkyl, heteroaryl-C1-6-alkyl, C3-8-heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, C1-6-cycIo-alkyl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, C1-6a-heterocyclyl-C1-6-alkoxy, -C(=0)-aryl, -C(=0)-C3_8-cycIoalkyl, -C(=0)-heteroaroyl, -C(=0)-C3-8-heterocyclyl, -O-aryl, -0-C3-8-cyc!oalkyl, -O-heteroaryl, -O-C1-6-heterocydyl, -S-aryl, -S-C3-8-cycloalkyl, -S-heteroaryl,-S-C3_8-heterocyclyl,
wherein the ring moieties may optionally be substituted with one to three substituents independently selected from hydroxy, halogen, cyano, nitro, -NR8R9, -C(=0)NR8R9, -0C(O)NR8R9, -OCH2C(=0)NR8R9, C1-6-alkoxy, -C(=0)OR8, -C(=0)R8, -NHC(=0)R8, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3| -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2NH2j
wherein R8 and R9 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
and R3 is hydrogen,
[ii) or R1 is hydrogen, -C(=0)OR1°, -C(=0)R1°, C1-6-, aryl-C1-6-alkyl, C1-6-cycloalkyl-C1-6-alkyl, heteroaryl-C1-6-alkyor C3-8-heterocyciyl-C1-6-alkyl,
therein R10 is C1-6-alkyl, C2-6-alkenyor C2-6-alkynyl, which may optionally be substituted with )ne or two substituents independently selected from
hydroxy, halogen, cyano, nitro, -NR11R12, -C(=0)NR11R12, -OC(=0)NR11R12, -OCH2C(=0)NR11R12, C1-6-alkyl, C2-6-alkenyl, C1-6-alkynyl, C1-6-alkoxy, -C(=0)OR11, -C(=0)R11, -NHC(=0)R11, -CHF2, -CF3, -OCF3f -OCHF2) -OCH2CF3, -OCF2CHF2-SCF3, -SR11, -S(=0)R11, -S(=0)2R1, -S(=0)2NH2l
wherein R11 and R12 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R11 and R12, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,

and R2and R3 are connected to form, together with A and the nitrogen atom and carbon atom, respectively, to which they are attached, a 5 to 7 membered non-aromatic ring to which ring is attached two groups R13 and R14 which are independently selected from
• hydrogen,
• oxo,
• C1-6-alkyl, C2-6-aikenyl, C2-6-alkynyl,
which may optionally be substituted with one or two substituents independently selected from hydroxy, halogen, cyano, nitro, -NR15R16, -C(=0)NR15R16, -OC(=0)NR15R16, -OCH2C(=0)NR15R16, C1-6-alkoxy, -C(=0)OR15, -C(=0)R15, -NHC(=0)R15, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2-SCF3, -SR15, -S(=0)R15, -S(=0)2R15, -S(=0)2NH2,
wherein R15 and R16 which may be the same or different independently are selected from hydrogen and -alkyl, or R15 and R16, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
• aryl, C1-6-cycloalkyl, heteroaryl, -heterocyclyl, aryl--alkyl, C3-8-cycloalkyl-
C1-6-alkyl, heteroaryl-C1-6-alkyl, C1-6-heterocyclyl-C1-6-aikyl, aryl-C1-6-alkoxy, C3-8-cyclo-
alkyl-C1-6-alkoxy, heteroaryl--alkoxy, C3-8-heterocyclyl-C1-6-alkoxy, -C(=0)-aryi,
-C(=0)-C3-8-cycloalkyl, -C(=0)-heteroaroyl, -C(=0)-C3-8-heterocyclylI -O-aryl,
-O-C1-6-cycloalkyl, -O-heteroaryl, -0-C3_8-heterocydyl, -S-aryl, -S-C3-8-cycloalkyl,
-S-heteroaryl, -S-C3-8-heterocyclyl,
wherein the ring moieties may optionally be substituted with one to three substituents independently selected from
hydroxy, halogen, cyano, nitro, -NR17R13, -C(=0)NR17R18, -OC(=0)NR17R18, -OCH2C(=0)NR17R18, C1-6-alkyl, alkenyl, C1-6-alkynyl, C1-6-alkoxy, -C(=0)OR17,

-C(=0)R17, -NHC(=0)R17, -CHF2, -CF3-OCF3, -OCHF2, -OCH2CF3-OCF2CHF2, -SCF3, -SR17, -S(=0)R17, -S(=0)2R17, -S(=0)2NH2,
wherein R17 and R18 which may be the same or different independently are selected from hydrogen and -alkyl, or R17 and R18, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
(iii) or R1 and R2 which may be the same or different independently are selected from hydrogen, -C(=0)OR19 -C(=0)R19 and -alkyl,
wherein R19 is -alkyl, -alkenyor -alkynyl, which may optionally be substituted with one or two substituents independently selected from
• hydroxy, halogen, cyano, nitro, -NR20R2, -C(=O)NR20R2, -OC(=O)NR20R21, -OCH2C(=O)NR20R2, -alkoxy, -C(=0)OR20, -C(=0)R20, -NHC(=0)R20, -CHF2, -CF3-OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2-SCF3) -SR20, -S(=0)R2°, -S(=0)2R20, -S(=0)2NH2,
• wherein R20 and R21 which may be the same or different independently are selected from hydrogen and -alkyl, or R20 and R21, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
and R3 is hydrogen,
B is a valence bond, -C(=0)-f -S(=0)- or -S(=0)2-,
D is
• hydroxy, halogen, cyano, nitro, -NR22R23, -N(R22)OR23, -C(=0)NR22R23,
-OC(=0)NR22R23, -OCH2C(=0)NR22R23, -alkoxy, -C(=0)OR22, -C(=0)R22,
-NHC(=0)R22, -CHF2, -CF3-OCF3, -OCHF2-OCH2CF3, -OCF2CHF2, -SCF3, -SR22,
-S(=0)R22, -S(=0)2R22, -S(=0)2NH2,

wherein R22 and R23 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R22 and R23, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
• C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl,
which may optionally be substituted with one or two substituents selected from hydroxy, halogen, cyano, nitro, -NR24R25, -C(=0)NR24R25, -OC(=0)NR24R25. -OCH2C(=0)NR24R25, C1-6-alkoxy, -C(=0)OR24, -C(=0)R24, -NHC(=0)R24, -CHF2, -CF3, -OCF3, OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR24, -S(=0)R24, -S(=0)2R2, -S(=0)2NH2,
wherein R24 and R25 which may be the same or different independently are selected from hydrogen and (^.e-alkyl, or R24 and R25, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
• aryl, C3-8-cycIoalkyl, heteroaryl, C1-6-heterocycIyl, aryl-C1-6-alkyl, C3-8-cycloalkyl-
C1-6-alkyl, heteroaryl-C1-6-alkyl, -heterocyclyl-C1-6-aIkyl, aryl-C1-6-alkoxy,
C3-8-cycloalkyl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, C1-6-heterocyclyl-C1-6-alkoxy,
-C(=0)-aryl, -C(=0)-C3-8-cycIoalkyl, -C(=0)-heteroaroyl, -C(=0)-C3-8-heterocyclyl,
-O-aryl, -0-cycloalkyl, -O-heteroaryl, -O-C1-6-heterocyclyl, -S-aryl,
-S--cydoalkyl, -S-heteroaryl, -S-C3_8-heterocyciyl, -NH-aryl, -NH-heteroaryl,
wherein the ring moieties may optionally be substituted with one to three substituents selected from
o hydroxy, halogen, cyano, nitro, -NR26R27, -C(=0)NR26R27, -OC(=0)NR26R27, -OCH2C(=0)NR26R27, C1-6-alkoxy, -C(=0)OR26, -C(=0)R26, -NHC(=0)R26, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3) -SR26, -S(=0)R26, -S(=0)2R26, -S(=0)2NH2,
wherein R26 and R27 which may be the same or different independently are selected from hydrogen and -alkyl, or R26 and R27, together with the nitrogen

atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
o C1-6-alkyl, C2-6-alkenyl, -aIkynylf
which may optionally be substituted with one or two substituents selected from hydroxy, halogen, cyano, nitro, -NR28R29, -C(=0)NR28R29. -OC(=0)NR28R29, -OCH2C(=0)NR28R29( C1-6-alkoxy, -C(=0)OR28, -C(=0)R28, -NHC(=0)R28, -CHF2, -CF3, -OCF3, -OCHF2 -OCH2CF3, -OCF2CHF2-SCF3| -SR28, -S(=0)R28, -S(=0)2R28, -S(=0)2NH2,
wherein R28 and R29 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R28 and R29, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
o aryl, -cycioalkyl, heteroaryl, C3-8-heterocyclyl, aryl--alkyl, C1-6-cyclo-alkyl-C1-6-alkyl, heteroaryl-C1-6-alkyl, C3-8-heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, C3_8-cydoalkyl-C1_6-alkoxyI heteroaryi-C1-6-alkoxy, C3-8-hetero-cyclyl-C1-6-alkoxy, -C(=0)-aryl, -C(=0)--cycloalkyl, -C(=0)-heteroaroyl, -C(=0)--heterocyclyl, -O-aryl, -0-C1-6-cycloalkyl, -O-heteroaryl, -O-C3-8 heterocyclyl, -S-aryl, -S-C3-8-cycloalkyl, -S-heteroaryl, -S--heterocyclyl,
wherein the ring moieties may optionally be substituted with one to three substituents selected from hydroxy, halogen, cyano, nitro, -NR30R31, -C(=O)NR30R31, -OC(=O)NR30R31, -OCH2C(=O)NR30R31, C1-6-alkyl, C2-6-alkenyI, C1-6-alkynyl, C1-6-alkoxy, -C(=0)OR30, -C(=0)R3°, -NHC(=0)R3°, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3| -SR30, -S(=0)R3°, -S(=0)2R3°, -S(=0)2NH2,
wherein R30 and R31 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R30 and R3, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally

containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
with the proviso that the compound must not be

as welas any opticaor geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof,
2. A compound according to claim 1 wherein R2and R3 are both hydrogen, and R1 is
-C(=0)OR19, wherein R19 is as defined in claim 1.
3. A compound according to claim 2 wherein R19 is C1-6-alkyl.
4. A compound according to claim 1 wherein R3 is hydrogen, and R1 and R2, together with
the nitrogen atom to which they are attached, form a ring

wherein R4 and R5 are as defined in claim 1.
5. A compound according to claim 4 wherein R4 and R5 are independently selected from
hydrogen, C1-6-alkyl, phenyl-C1-6-alkyand oxo.
6. A compound according to claim 5 wherein R4 is hydrogen or C1-6-alkyl, and R5 is hydrogen
or oxo.

7. A compound according to claim 4 wherein R3 is hydrogen, and R1 and R2, together with
the nitrogen atom to which they are attached, form a ring

8. A compound according to claim 1 wherein R2 and R3, together with A and the nitrogen
atom and the carbon atom, respectively, to which they are attached, form a ring

wherein R, R13 and R14 are as defined in claim 1.
9. A compound according to claim 8 wherein R2 and R3, together with A and the nitrogen
atom and the carbon atom, respectively, to which they are attached, form a ring

wherein R, R13 and Ru are as defined in claim 1.
10. A compound according to claim 8 or 9 wherein R1 is hydrogen, C1-6-alkyl, phenyl-
C1-6-alkyor -C(=0)OR1°, wherein R10 is as defined in claim 1, and R13 and R14 are inde
pendently hydrogen, C1-6-alkyl, phenyl-C1-6-alkyor oxo.

11. A compound according to claim 10 wherein R1 is hydrogen or -C(=0)0-C1^-, and R13 and R14 are hydrogen.
12. A compound according to claim 1 wherein R1, R2 and R3 are hydrogen.
13. A compound according to any one of the preceding claims wherein A is C1-6-ene.
14. A compound according to claim 13 wherein A is methylene or ethylene.
15. A compound according to claim 14 wherein A is ethylene.
16. A compound according to any one of the preceding claims wherein B is -C(=0)-.
17. A compound according to any one of the preceding claims wherein D is -cycloalkyl, heteroaryor aryl, which may optionally be substituted as defined in claim 1.
18. A compound according to any one of the preceding claims wherein D is C1-6-cycloalkyl, heteroaryor aryl, which may optionally be substituted as defined in claim 1, but not in the positions adjacent to the point of attachment of D to B.
19. A compound according to claim 17 or 18 wherein D is cyclopropyl, thienyor phenyl, which may optionally be substituted as defined in claim 1.
20. A compound according to claim 17 wherein D is cyclopropyl.
21. A compound according to claim 17 or 18 wherein D is thienyl, which is substituted with halogen.
22. A compound according to claim 17 or 18 wherein D is phenyl, which is optionally substituted with

• hydroxy, halogen,
• heteroaryl-C1-6-alkoxy, aryl-C1-6-alkoxy, wherein the ring moieties are optionally substituted as defined in claim 1.

23. A compound according to claim 22 wherein D is phenywhich is optionally substituted with halogen or benzyloxy, wherein the ring moiety of benzyloxy is optionally substituted as defined in claim 1.
24. A compound according to claim 23 wherein D is phenyl, which is substituted with benzyloxy.
25. Use of a compound according to any one of the claims 1 to 24 as a pharmaceuticacomposition.
26. A pharmaceuticacomposition comprising, as an active ingredient, at least one compound according to any one of the claims 1 to 24 together with one or more pharmaceutically acceptable carriers or excipients.
27. A pharmaceuticacomposition according to claim 26 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to any one of the claims 1 to 24.

wherein
A is a valence bond or C1-6-alkylene,
(i) R1 and R2, together with the nitrogen atom to which they are attached, form a 5 to 7 mem-bered non-aromatic ring, which ring may optionally contain a double bond, and which ring i may optionally contain a further nitrogen atom, and to which ring is attached two groups R4 and R5 which are independently selected from
• hydrogen,

• 0X0,
• -alkyl, C2-6-alkenyl, C2-6-alkynyl,
which may optionally be substituted with one or two substituents independently selected from hydroxy, halogen, cyano, nitro, -NR6R7, -C(=0)NR6R7, -OC(=0)NR6R7, -OCH2C(=0)NR6R7, -alkoxy, -C(=0)OR6, -C(=0)R6, -NHC(=0)R6, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR6, -S(=0)R6, -S(=0)2R6, -S(=0)2NH2,
wherein R6 and R7 which may be the same or different independently are selected from hydrogen and -alkyl. or R6 and R7, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
• aryl, C3-8-cyclo, heteroaryl, C3-8-heterocyclyl, aryl--alkyl, -cycloalkyl-
-alkyl, heteroaryl--alkyl, -heterocyclyl-C1-6-alkyl, aryl--alkoxy, -cyclo-
alkyl--alkoxy, heteroaryl--aikoxy,C3-8-heterocyclyl-C1-6-alkoxy, -C(=0)-aryl,
-C(=0)--cycloaIkyI, -C(=0)-heteroaroyl, -C(=0)-d-8-heterocyclyl, -O-aryl,
-O-C1-6-cycloalkyl, -O-heteroaryl, -O-C3-8-heterocydyl, -S-aryl, -S-C3-8-cycloalkyl,
-S-heteroaryl, -S-C3-8-heterocyclyl,
wherein the ring moieties may optionally be substituted with one to three substituents independently selected from hydroxy, halogen, cyano, nitro, -NR8R9, -C(=0)NR8R9, -OC(=0)NR8R9, -OCH2C(=0)NR8R9, -alkoxy, -C(=0)OR8, -C(=0)R8, -NHC(=0)Rs, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3-SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2NH2,
wherein R8 and R9 which may be the same or different independently are selected from hydrogen and -alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
and R3 is hydrogen,

(ii) or R1 is hydrogen, -C(=0)OR10, -C(=0)R10, C1-6-alkyl, aryl-C1-6-aikyl, -cycloalkyl-C1-6-alkyl, heteroaryi-C1-6-alkyor C3-8-heterocyclyl-C1-6-alkyl,
wherein R10 is C1-6-, C2-6-alkenyor C2-6-alkynyl, which may optionally be substituted with one or two substituents independently selected from
hydroxy, halogen, cyano, nitro, -NR11R12, -C(=0)NR11R12, -OC(=0)NR11R12, -OCH2C(=0)NR11R12, -, C1-6-alkenyl, C2-6alkynyl, C1-6-alkoxy, -C(=0)OR11, -C(=0)R11, -NHC(=0)R11, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR11, -S(=0)R11, -S(=0)2R11, -S(=0)2NH2,
wherein R11 and R12 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R11 and R12, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
and R2and R3 are connected to form, together with A and the nitrogen atom and carbon atom, respectively, to which they are attached, a 5 to 7 membered non-aromatic ring to which ring is attached two groups R13 and R14 which are independently selected from
• hydrogen,
• oxo,
• -alkyl, -alkenyl, -alkynyi,
which may optionally be substituted with one or two substituents independently selected from hydroxy, halogen, cyano, nitro, -NR15R16, -C(=0)NR1SR16I -OC(=0)NR15R16, -OCH2C(=0)NR15R18, C1-6alkoxy, -C(=0)OR15, -C(=0)R15, -NHC(=0)R15, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR16, -S(=0)R1S, -S(=0)2R15, -S(=0)2NH2,
wherein R15 and R16 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R15 and R16, together with the nitrogen atom to which

they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
• aryl, -cyclo, heteroaryl, C3-8-heterocyclyl, aryl-C1-6-alkyl, C1-6-cycIoaikyl-
C1-6-alkylf heteroaryl--alkyl, -heterocyclyl-d-6-alkyl, aryl--alkoxy, -cyclo-
alkyl--alkoxy, heteroaryl--alkoxy, -heterocyclyl--alkoxy, -C(=0)-aryl,
-C(=0)-C3-8-cycloalkylf -C(=0)-heteroaroyl, -C(=0)-C3-8-heterocyclyl, -O-aryl,
-0--cycloalkyl, -O-heteroaryl, -O-d-8-heterocyclyl, -S-aryl, -S-C3-8-cycloalkyl,
-S-heteroaryl, -S--heterocyclyl,
wherein the ring moieties may optionally be substituted with one to three substituents independently selected from
hydroxy, halogen, cyano, nitro, -NR17R18, -C(=0)NR17R18, -OC(=0)NR17R18, -OCH2C(=0)NR17R18, -alkyl, C2-6-alkenyl, C2-6-alkynyl, -alkoxy, -C(=0)OR17, -C(=0)R17, -NHC(=0)R17, -CHF2, -CF3, -OCF3,-OCHF2, -OCH2CF3, -OCF2CHF2,-SCF3, -SR17, -S(=0)R17, -S(=0)2R17, -S(=0)2NH2,
wherein R17 and R18 which may be the same or different independently are selected from hydrogen and -alkyl, or R17 and R18, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
(iii) or R1 and R2 which may be the same or different independently are selected from hydrogen, -C(=0)OR19 -C(=0)R19 and -alkyl,
wherein R19 is -alkyl, -alkeny,or C2-6-alkynyl, which may optionally be substituted with one or two substituents independently selected from
• hydroxy, halogen, cyano, nitro, -NR20R21, -C(=O)NR20R2, -OC(=O)NR20R2,
-OCH2C(=O)NR20R2, d_6-alkoxy, -C(=0)OR2°, -C(=0)R2°, -NHC(=0)R20, -CHF2,
-CF3,-OCF3, -OCHF2, -OCH2CF3) -OCF2CHF2, -SCF3t -SR20, -S(=0)R2°, -S(=0)2R20,
-S(=0)2NH2|

• wherein R20 and R21 which may be the same or different independently are selected
from hydrogen and -alkyl, or R20 and R21, together with the nitrogen atom to which
they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two
further heteroatoms selected from oxygen, sulphur and nitrogen,
and R3 is hydrogen,
B is a valence bond, -C(=0)-, -S(=0)- or -S(=0)2-,
Dis
• hydroxy, halogen, cyano, nitro, -NR22_R23, -NtR22)OR23, -C(=0)NR22R23,
-OC(=0)NR22R23, -OCH2C(=0)NR22R23, C1-6-alkoxy, -C(=0)OR22, -C(=0)R22,
-NHC(=0)R221 -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR22,
-S(=0)R22, -S(=0)2R22, -S(=0)2NH2,
wherein R22 and R23 which may be the same or different independently are selected from hydrogen and -alkyl, or R22 and R23, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
• -alkyl, C2-6-alkenyl, C2-6-alkynyl,
which may optionally be substituted with one or two substituents selected from hydroxy, halogen, cyano, nitro, -NR24R25, -C(=0)NR24R25, -OC(=0)NR24R25, -OCH2C(=0)NR24R25, -alkoxy, -C(=0)OR24, -C(=0)R24, -NHC(=0)R24, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, ^SCF3, -SR24, -S(=0)R24, -S(=0)2R24, -S(=0)2NH2l
wherein R24 and R25 which may be the same or different independently are selected from hydrogen and C1-6-, or R24 and R25, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,

• aryl, C1-6-cycloalkyl, heteroaryl, C3-8-heterocyclyl, aryl-C1-6-alkyl, -cycloaikyl-C1-6-alkyl, heteroaryl-C1-6-alkyl, C1-6-heterocyclyl--aikyi, aryl--alkoxy, -cycloalkyl--alkoxy, heteroaryl-C1-6-alkoxy, C3-8-heterocyclyl--alkoxy, -C(=0)-aryl, -C(=0)--cycloalkylJ -C(=0)-heteroaroyl, -C(=0)--heterocyciyl, -O-aryl, -0--cycloalkyl, -O-heteroaryi, -0-C3-8-heterocyclyl, -S-aryl, -S--cycloalkylf -S-heteroaryl, -S--heterocyclyl, -NH-aryl, -NH-heteroaryl,
wherein the ring moieties may optionally be substituted with one to three substituents selected from
o hydroxy, halogen, cyano, nitre, -NR26R27, -C(=0)NR26R27, -OC(=0)NR26R27, -OCH2C(=0)NR28R27, C1-6-alkoxy, -C(=0)OR26, -C(=0)R26, -NHC(=0)R26, -CHF2,-CF3, -OCF3,-OCHF2, -OCH2CF3) -OCF2CHF2, -SCF3, -SR26, -S(=0)R26, -S(=0)2R26, -S(=0)2NH2,
wherein R26 and R27 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R26 and R27, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
o C1-6-alkyl, C2-6-alkenyI, C2-6-alkynyl,
which may optionally be substituted with one or two substituents selected from hydroxy, halogen, cyano, nitro, -NR28R29, -C(=0)NR28R29, -OC(=0)NR28R29, -OCH2C(=0)NR28R29, C1-6-alkoxy, -C(=0)OR28, -C(=0)R28, -NHC(=0)R28, -CHF2,-CF3> -OCF3J -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR28, -S(=0)R28, -S(=0)2R28, -S(=0)2NH2,
wherein R28 and R29 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R28 and R29, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,

o aryl, C1-6-cycIoalkyl, heteroaryl, C1-6-heterocyclyl, aryl-C1-6-alkyl, -cyclo-alkyl-C1-6-alkyl, heteroaryl-C1-6-alkyl, C3-8-heterocyclyl-C1-6-alkyl, aryl--alkoxy, C3-6-cycloalkyl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, -hetero-cyclyl-C1-6-alkoxy, -C(=0)-aryI, -C(=0)-C3-8-cycloalkyl, -C(=0)-heteroaroyl, -C(=0)-C3-8-heterocyclyl, -O-aryl, -O-C1-6-cycloalkyl, -O-heteroaryl, -O-C3-8-heterocyclyl, -S-aryl, -S--cycloalkyl, -S-heteraaryl, -S-C3-8-heterocyclyl,
wherein the ring moieties may optionally be substituted with one to three sub-stituents selected from hydroxy, halogen, cyano, nitro, -NR30R3, -C(=O)NR30R3, -OC(=O)NR30R3, -OCH2C(=O)NR30R3, C1-6-alkyl, C2-6-alkenyl, alkynyl, C1-6-alkoxy, -C(=0)OR30, -C(=0)R30, -NHC(=0)R30, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR30, -S(=0)R30, -S(=0)2R30, -S(=0)2NH2l
wherein R30 and R31 which may be the same or different independently are selected from hydrogen and C1-6-alkyl, or R30 and R31, together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
as wel,as any optica,or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutica,composition for the treatment of diseases, disorders, syndromes and conditions, wherein an inhibition of GSK-3 is beneficial.
29. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of diseases, disorders, syndromes and conditions related to GSK-3.
30. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of diseases, disorders, syndromes and conditions, wherein growth factor induced inhibition of GSK-3 is insufficient.

31. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of diseases, disorders, syndromes and conditions, wherein glycogen metabolism exhibits abnormalities.
32. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of diseases, disorders, syndromes and conditions, wherein glycogen synthase is insufficiently activated.
33. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of diseases, disorders, syndromes and conditions involving elevated blood glucose.
34. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of hyperglycemia.
35. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of IGT.
36. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of type 2 diabetes.
37. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of type 1 diabetes.
38. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of obesity.
39. Use according to any one of the preceding claims 28 to 38 in combination with one or more further active agents selected from antidiabetic agents, antihyperlipidemic compounds, antiobesity compounds and antihypertensive compounds.
40. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of Alzheimer's disease.

41. Use according to claim 40 in combination with one or more further agents for the treatment of Alzheimer's disease.
42. Use of a compound as defined in claim 28 for the preparation of a pharmaceutica,composition for the treatment of bipolar disorder.
43. Use according to claim 42 in combination with one or more further agents for the treatment of bipolar disorder.
44. A method for the treatment of diseases, disorders, syndromes and conditions, wherein an inhibition of GSK-3 is beneficia,the method comprising administering to a subject in need thereof an effective amount of a compound as defined in claim 28.
45. The method according to claim 44, wherein the effective amount of the compound as defined in claim 28 is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.

46. A compound substantially as herein described and exemplified.
47. A pharmaceutica,composition substantially as herein described and exemplified