MXPA04000906A

MXPA04000906A - Novel 2,4-diaminothiazole derivatives.

Info

Publication number: MXPA04000906A
Application number: MXPA04000906A
Authority: MX
Inventors: Falck Hansen Bo
Original assignee: Novo Nordisk As
Priority date: 2001-08-03
Filing date: 2002-07-22
Publication date: 2004-11-22
Also published as: EP1417188A1; HUP0401403A3; JP2004538315A; CA2455753A1; WO2003011843A1; HUP0401403A2

Abstract

Novel 2,4-diaminothiazole derivatives of the general formula (I) which inhibit GSK-3 (glycogen synthase kinase-3), use of these compounds as medicaments, pharmaceutical compositions comprising the compounds and methods of treatment employing these compounds and compositions. The present compounds may be useful for the treatment of disorders, syndromes, diseases and conditions, wherein an inhibition of GSK-3 (glycogen synthase kinase-3) is beneficial, especially IGT (impaired glucose tolerance), type 1 diabetes, type 2 diabetes, obesity, Alzheimer's disease and bipolar disorder.

Description

NEW 2, 4-DIAMINOTIAZOLE DERIVATIVES FIELD OF THE INVENTION The present invention relates to the novel 2,4-diaminothiazole derivatives of the general formula (I) which 'inhibit GSK-3 (glycogen synthase kinase-3), for the use of these compounds as medicaments, to the pharmaceutical compositions comprising the compounds and to the methods of treatment employing these compounds and the compositions. The present compounds can be useful for the treatment of disorders, syndromes, diseases and conditions, where an inhibition of GSK-3, especially IGT (impaired tolerance against glucose), type 1 diabetes, type 2 diabetes, obesity, is beneficial. Alzheimer's disease and bipolar disorder. BACKGROUND OF THE INVENTION GSK-3 is a protein-serine kinase involved in the hormonal control of several regulatory proteins. That was 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, involving the enzyme in the regulation of several physiological processes. GSK-3 exists in two isoforms, called GSK-3oc and EF: 156569 GSK-3p, which are derived from different genes and show 85% sequential activity. Contrary to many protein kinases, both isoforms of GS-3 are constitutively active in resting cells, and are mainly regulated by inactivation. Thus, it has been shown that GSK-3 is inhibited by phosphorylation of serine in response to insulin and growth factors such as IGF-1 and EGF via activation of the MA.P or kinase cascade. via PI3 kinase dependent activation of protein kinase B. Compounds that inhibit the activity of GSK-3 are useful in the treatment, diseases, disorders, syndromes and conditions, wherein such inhibition is beneficial, for example, 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 which the inhibition of GSK-3 induced by the factor of growth, is insufficient, in diseases, in disorders, syndromes and conditions in which the glycogen synthase is insufficiently activated and in situations where the inhibition of GSK-3 could contra-reg ular unwanted cellular events. Type 1 diabetes, also known as insulin-dependent diabetes mellitus (IDD), is caused by a autoimmune destruction of insulin-producing cells in the pancreas, leading to a lack of insulin. In this way, individuals with type I diabetes require daily injections of the hormone to sustain life. Current methods of insulin administration, however, can not reproduce the ability of normal β cells to accurately control blood glucose and other metabolic variables. Hence, type 1 diabetes remains susceptible to the long-term and devastating complications of diabetes, such as cardiovascular disease, retinopathy, nephropathy, and neuropathy. Type 2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDD), is the most common of all metabolic disorders and imposes a major health problem worldwide. Type 2 diabetes results from defects in insulin secretion and the action of insulin, but it or the exact underlying mechanisms that cause the disease are unknown. Elevated hepatic glucose production significantly contributes to fasting hyperglycemia, while decreased insulin-mediated glucose uptake by muscle and fat is a major contributor to postprandial hyperglycemia. In addition, the metabolic fate of the glucose collected by the muscle is not normal in people with type 2 diabetes. For example, muscle glycogen synthase activity and glycogen synthesis have been shown to be severely impaired in type 2 diabetes. Available treatments do not allow a complete normalization of the metabolic state and most of them are associated with side effects. The metabolic derangements created by hyperglycemia, together with the strong association between type 2 diabetes, obesity, hypertension and hyperlipidemia, lead to an extensive list of long-term complications, including a high rate of cardiovascular death due to accelerated atherosclerosis. , as well as typical complications of diabetes, such as retinopathy, nephropathy and neuropathy. Thus, there is still a considerable need for novel methods to treat diabetes. Recently, it has been found that the expression of GSK-3 is elevated in the muscle of people with type 2 diabetes and that the expression of GSK-3 is inversely correlated with glycogen synthase activity and glucose waste. Thus, an increased expression of GSK-3 may contribute to the impaired activity of glycogen synthase, and the insulin resistance that occurs in type 2 diabetes. Other recent experiments have suggested a role for GSK-3 in the attenuation of the action of insulin via its phosphorylation of substrate 1 of the insulin receptor. Recent studies using lithium salts also support the notion that inhibition of GSK-3 might be beneficial in the treatment of diabetes. It has been known for a long time that lithium has a stimulating effect on glucose metabolism, more predominantly on synthesis in glycogen. The treatment with lithium salts has also been shown to alleviate the diabetic state in diabetic patients type 1 and type 2. The molecular mechanism for these effects of lithium has been recently unknown. However, it has now found that lithium inhibits GSK-3. Although lithium may also have an effect on other molecular targets than GSK-3, this finding helps to explain the molecular effects of lithium and supports that the inhibition of GSK-3 leading to the activation of glycogen synthase, has significant effects on the 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 the biological pathways related to Alzheimer's disease, and GSK-3 inhibitors may be useful in the treatment thereof. Alzheimer's disease is characterized histopathologically due to the presence of neurofibrillary and intraneuronal tangles and the extracellular deposition of β-amyloid in the brain, especially the hippocampus. The neurofibrillary tangles are made up of PHF (paired helical filaments). The major protein subunit of which is the microtubule-associated protein, abnormally phosphorylated and glycosylated, (x). In neurons that have tangles in Alzheimer's disease, the normal cytoskeleton is disturbed and replaced with PSF. GSK-3 is one of several kinases that phosphorylate tau in vitro over normal sites, characteristic of PHF-tau, and has also been shown to do this in living cells. In addition, the lithium inhibitor of GSK-3 blocks the hyperphosphorylation of tau in cells. Additional evidence for a role of GSK-3 in Alzheimer's disease is provided for example by (i) the association of GSK-3 with presenelin 1, (ii) reduced cytotoxicity of the β-amyloid protein in neuronal cells incubated with GSK- 3 antisense, and (iii) increased 50% GSK-3 expression in post-synaptic supernatants 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 stabilizing agent of humor remains unknown, although effects on biological membranes and synaptic neurotransmission have been suggested. However, the activity of GSK-3 could be implicated in the etiology of bipolar disorder. One mechanism by which lithium and other GSK-3 inhibitors can 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 can also be involved in the mediation of neurodegeneration after acute damage, for example, in cerebral ischemia, traumatic brain damage and bacterial, viral and prion infections. Excessive glutamate signaling has also been implicated in the chronic neuronal damage observed in diseases such as Huntington's chorea, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Consequently, GSK-3 inhibitors may be useful in the treatment of these and other neurodegenerative disorders. In connection with this, it should be noted that lithium has a variety of biological effects which, if mediated through the inhibition of GSK-3, could provide an even wider application of the GSK-3 inhibitors. In addition, it has been shown that GSK-3 phosphorylates the transcription factor NF-AT, which participates in the activation of the genes of the early immune response. Phosphorylation prevents the translocation of NF-AT to the nucleus, and thus blocks early immune responses. Thus, inhibitors of GKS-3 can 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 described as inhibitors of GSK-3, see for example WO 98/16528, WO 99/65897, WO 00/21927, WO 01/09106, WO 00/38675, WO 01/44206 and WO 01/44246 These compounds differ structurally from the present compounds. WO 99/21845 describes the 4-aminothiazole derivatives and their use as inhibitors of cyclin-dependent kinases (CDKs). It is stated that the compounds are effective for the treatment of, for example, cancer. The compounds differ structurally from the present compounds. However, Table I describes a compound (1 (6)), of the following structure: No inhibition of CDK was observed for the compound at the tested concentration. WO 00/75120 describes the diaminothiazoles and their use to inhibit protein kinases. It is stated that the compounds are useful for the treatment of disease conditions associated with the development of tumors, cell proliferation or angiogenesis such as cancer. The compounds differ structurally from the present compounds. In view of the interest of the technique in GSK-3 inhibitors and the great potential thereof, the identification of potent and specific GSK-3 inhibitors could be a highly desirable contribution to the art. The present invention provides such a contribution to the art, which is 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 consequently useful in the treatment of a wide range of disorders, syndromes, diseases and conditions in which an inhibition of GSK-3 is beneficial. DEFINITIONS The following 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 fluorine, chlorine, bromine and iodine. The term "alkyl of 1 to 6 carbon atoms" in the present context designates a saturated, branched or linear 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, ter-pentyl, n-hexyl, isohexyl and the like. 6 carbon atoms "in the present context, designates a group -0- (alkyl of 1 to 6 carbon atoms) wherein the alkyl of 1 to 6 carbon atoms is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, h-hexoxy, isohexoxy and the like. "C2-C6 alkenyl" as used herein, represents a branched or linear 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-butenyl, 3-butenyl, 2-methyl-1-prop enyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like. The term "alkynyl of 2 to 6 carbon atoms" as used herein, represents a linear or branched 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, ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl, 3-butinyl, β -pentinyl, 2-pentynyl, 3-pentynyl, 4-pentynyl , 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like. The term "cycloalkyl of 3 to 8 carbon atoms" 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 "heterocyclyl of 3 to 8 carbon atoms" as used herein, represents a saturated ring of 3 to 8 members containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, 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 Similar . It is intended that the aryl also include the partially hydrogenated derivatives of the carbocyclic aromatic systems listed above. Non-limiting examples of such partially hydrogenated derivatives are 1, 2, 3, 4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like. The term "heteroarx" as used herein, is intended to include heterocyclic aromatic ring systems having one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1. 2,4-triazolyl, 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-thiadiazolyl, 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 pterindinyl, carbazolyl, azepinyl, di-azepinyl, acridinyl and the like. It is intended that heteroarxlo also includes partially hydrogenated derivatives of the Heterocyclic systems listed above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like. "Aryl- (alkyl of 1 to 6 carbon atoms)", "heteroaryl- (alkyl of 1 to 6 carbon atoms), etc., means alkyl of 1 to 6 carbon atoms as defined above, substituted with an aryl or heteroaryl as defined above, for example: Some of the previously defined terms may appear more than once in the structural formulas, and after each occurrence each term will be defined independently of each other. The term "GSK-3" as used herein is intended to mean GSK-3a and GSK-3p. 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 delay in the progression of the disease, the disorder, the syndrome or condition, the 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, preferably a human being. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula (I): wherein A is a valence or alkylene bond of 1 to 6 carbon atoms, (i) R1 and R2, together with the nitrogen atom to which they are bound, form a non-aromatic ring of 5 to 7 members, whose ring can optionally containing a double bond, and whose ring may optionally contain an additional nitrogen atom, and to which ring are linked two groups R4 and R5 which are independently selected from: • hydrogen, • oxo, • alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkinyl of 2 to 6 carbon atoms, which may optionally be substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR6R7, -C (= 0) NR6R7, - OC (= 0) NR6R7, -OCH2C (= 0) NR6R7, alkoxy of 1 to 6 atoms carbon, -C (= 0) OR6, -C (= 0) Rs, -NHC (= 0) Rs, -CHF2, -CF2, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2 / -SCF3, -SR6, -S (= 0) R6, -S (= 0) 2R6, -S (= 0) 2H2, wherein R6 and R7 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms carbon, or R6 and R7, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 at 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms) ), heteroaryl- (alkyl of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (alkoxy of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkoxy of 1 to 6 carbon atoms) bond), heteroaryl- (alkoxy of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -0- ( cycloalkyl of 3 to 8 carbon atoms), -O- heteroaryl, -0- (heterocyclyl of 3 to 8 carbon atoms), S-aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- (heterocyclyl of 3 to 8 carbon atoms) ), wherein the ring portions may be optionally substituted with one to three substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR8R9, -C (= 0) NR8RS, -0C (= 0) NR8R9, 0C¾C (= 0) NR8R9, alkoxy of 1 to 6 carbon atoms, C (= 0) 0R8, -C (= 0) R8, -NHC (= 0) R8, -CHF2, -CF3, -0CF3, 0CHF2, -OCH2CF3, -OCF2CF3, -SCF3, -SR8, -S (= 0) R8, -S (= 0) 2R8, -S (= 0) 2N¾, wherein R8 and R9 which may be the same or different independently select hydrogen and alkyl of 1 to 6 carbon atoms, and R8 and R9 together with the nitrogen atom to which they are attached, form a cyclic ring of 3 to 8 members optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, and R3 is hydrogen, (ii) or R1 is hydrogen, -C (= 0) 0R10, -C (= 0) 0R10, alkyl of 1 to 6 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (C 3 -C 8 cycloalkyl) - (C 1-6 -alkyl), heteroaryl- (C 1-6 -alkyl) or (heterocyclyl with 3 to 8 C atoms) carbon) - (alkyl of 1 to 6 carbon atoms), wherein 10 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -R ^ R12, -C (= 0) NRi: LR12, -0C (= 0) NR1: LR12, -0CH2C (= 0) NR ^ R12 , alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R21, -C (= 0 ) R1: L, - HC (= 0) R11, - CHF2, -CF3, -0CF3, -OCHF2, -0CH2CF3, -0CF2CHF2, -SCF3 / - SR11, -S (= 0) R ", -S (= 0) 2R11, -S (= 0) 2NH2, wherein R11 and R12 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 atoms carbon, or R11 and R12, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, and R2 and R3 are connected to form, together with A and the nitrogen atom and the carbon atom, respectively, to which they are linked, a non-aromatic ring of 5 to 7 members to whose ring two groups R13 and R14 are linked which are independently selected from • hydrogen, • oxo, • alkyl of 1 to 6 carbon atoms, alkenyl of 2 carbon atoms, alkynyl of 2 to 6 carbon atoms, which may optionally be substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR15R1S, -C (= 0) NR15R1S, -0C (= 0) NR15R16, -0CH2C (= 0) NR15R16, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R15, -C (= 0) R15, -NHC (= 0) R15, -CHF2, -FC3, -0CF3, -0CHF2, -0C¾CF3, -0CF2CHF2, -SCF3, -SR15, -S (= 0) R15, -S (= 0) 2R15, -S (= 0) 2NH2, wherein R15 and R16 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R15 and R16, together with the nitrogen atom to which they are attached , form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl - (alqu ilo of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (alkoxy of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) carbon) - (alkoxy of 1 to 6 carbon atoms), heteroaryl- (alkoxy of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) -alkoxy of 1 to 5 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -O- (cycloalkyl of 3 to 8 carbon atoms), -0-heteroaryl, - O- (C 3 -C 8 heterocyclyl), S-aryl, S- (C 3 -C 8 cycloalkyl), -S-heteroaryl, -S- (C 3 -C 8 heterocyclyl), in wherein the ring portions may be optionally substituted with one to three substituents independently selected from idroxyl, halogen, cyano, nitro, -NR17R18, -C (= 0) NR17R18, -0C (= 0) NR17R18, -OCH2C (= 0) NR17R: L8, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to S carbon atoms, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R17, -C (= 0) R17, - HC (= 0) R17, -CHF2, -CF3, -0CF3, -0CHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR17, -S (= 0) R17, -S (= 0) 2R17, -S (= 0) 2NH 2, wherein R17 and R18 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R17 and R18, together with the nitrogen atom to which they are attached, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, (iii) or R1 and R2 which may be the same or different are independently selected from hydrogen, -C (= 0) OR19, C (= 0) R19 and alkyl of 1 to 6 carbon atoms, wherein R19 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, which they may be optionally substituted with one or two substituents independently selected from • hydroxyl, halogen, cyano, nitro, -NR20R21, -C (= 0) NR20R21, -OC (= O) NR20R2: i, -OCH2C (= O) NR20R21, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR2 °, -C (= 0) R20, -NHC (= 0) R20, -CHF2, - CF3, -0CF3, -OCHFz, -OCH2CF3í -OCF2CHF2 , -SCF3í -SR20, -S (= 0) R20, -S (= 0) 2R20, -S (= 0) 2 ¾, • wherein R20 and R21 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R20 and R21, together with on the nitrogen atom to which they are bonded, they form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, and R3 is hydrogen, B is a valence bond, -C (= 0) -, -S (= 0) - or -S (= 0) 2- hydroxyl, halogen, cyano, nitro, -MR, -N (R22) OR, -C (= 0) NR22R23, -0C (= 0) NR22R23, -OCH2C (= 0) NR2R23, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R22, -C (= 0) R22, - HC (= 0) R22, -CHF2, -CF3, -0CF3, -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 are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms , or R22 and R23, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, alkyl of 1 to 6 carbon atoms. carbon, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents selected from hydroxyl, halogen, cyano, nitro, -NR24R25, -C (= 0) R24R25 , -0C (= 0) NR24R25, 0CH2C (= 0) NR24R25, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR24, -C (= 0) R24, -NHC (= 0) R24, - CHF2, -CF3, -0CF3, -0CHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR24, -S (= 0) R24, S (= 0) 2R24, -S (= 0) 2N¾, wherein R24 and R25 which may be the same or different are independently selected from hydrogen and alkyl from 1 to 6 carbon atoms, or R24 and R25, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, • aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - ( 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (alkoxy of 1 to 6 carbon atoms), (C 3 -C 8 cycloalkyl) - (C 1-6 -alkoxy), heteroaryl- (C 1-6 -alkoxy), (C 3 -C 8 -heterocyclyl) ) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (hetero cyclyl of 3 to 8 carbon atoms), -0-aryl, -0- (cycloalkyl of 3 to 8 carbon atoms), -0-heteroaryl, -0- (heterocyclyl of 3 to 8 carbon atoms), S- aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- (heterocyclyl of 3 to 8 carbon atoms), H-aryl, NH-heteroaryl, wherein the ring portions may be optionally substituted with one to three substituents selected from hydroxyl, halogen, cyano, nitro, -NR26R27, -C (= 0) NR26R27, -0C (= 0) R26R27, -OCH2C (= 0) NR26R27, alkoxy of 1 to 6 atoms of carbon, -C (= 0) ORS, -C (= 0) R2S, -NHC (= 0) R2e, -CHF2, -CF3, -OCF3 -OCHF2, -0CH2CF3, -OCF2CHF2, -SCF3, -SR26, -S (= 0) R26, -S (= 0) 2R2S, -S (= 0) 2NH2, wherein R26 and R27 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms , or R26 and R27, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, alkyl of 1 to 6 carbon atoms. carbon, alkenyl of 2 to 6 carbon atoms, alkinyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents selected from hydroxyl, halogen, cyano, nitro, -NR28R29, -C (= 0) NR28R29, -0C (= 0) NR28R29, 0CH2C (= 0) NR28R29, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR28, -C (= 0) R28, -NHC (= 0) R28, -CHF2, -CF3, -0CF3f -0CHF2 , -OCH2CF3, -OCF2CHF2, -SCF3, -SR28, -S (= 0) R28, S (= 0) 2R28, -S (= 0) 2N¾, wherein R28 and R29 which may be the same or different are selected independently of hydrogen and alkyl from 1 to 6 carbon atoms, or R28 and R29, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkyl of 1) to 6 carbon atoms), heteroaryl- (alkyl of 1 to 5 carbon atoms), (eterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (alkoxy of 1 to 6) carbon atoms), (C 3 -C 8 cycloalkyl) - (C 1-6 -alkoxy), heteroaryl- (C 1-6 -alkoxy), (C 3 -C 8 -heterocyclyl) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C ( = 0) - (heterocyclic or from 3 to 8 carbon atoms), -0-aryl, -0- (cycloalkyl of 3 to 8 carbon atoms), -0-heteroaryl, -0- (heterocyclyl of 3 to 8 carbon atoms), S- aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- (heterocyclyl of 3 to 8 carbon atoms), wherein the ring portions can be optionally substituted with one to three substituents selected from hydroxyl, halogen, cyano, nitro, - NR30R31, -C (= O) NR30R31, -0C (= 0) NR30R31, -0CH2C (= 0) NR30R31, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms carbon, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR30, -C (= 0) R30, -NHC (= 0) R30, -CHF2, -CF3, -0CF3, -0CHF2, -0CH2CF3, OCF2CHF2, -SCF3, -SR30, -S (= 0) R30, -S (= 0) 2R30, -S (= 0) 2NH2, wherein R30 and R31 which can be same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R30 and R31, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, with the proviso that the compounds should not be as well as any optical or geometric isomer or tautomeric form thereof, including mixtures thereof or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, R2 and R3 are both hydrogen, and R1 is ~ C (= 0) 0R19, wherein R19 is as defined for the formula (I). In one embodiment thereof R19 is alkyl of 1 to 6 carbon atoms. In yet another embodiment of the invention, R3 is hydrogen, and R1 and R2, together with the nitrogen atom to which they are bonded, form a ring Where R4 and R5 are as defined for formula (I). In one embodiment thereof, R4 and R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, phenyl- (alkyl of 1 to 6 carbon atoms) and oxo. In a further embodiment thereof, R 4 is hydrogen or alkyl of 1 to 6 carbon atoms, and R 5 is hydrogen or oxo. In yet another embodiment of the invention, R3 is hydrogen and R1 and R2, together with the nitrogen atom to which they are attached, form a ring In yet another embodiment of the invention, R2 and R3, together with A and the nitrogen atom and the carbon atom, respectively, to which they are bonded, form a ring R13-} - -R > 4 _ R'H- -f-RH wherein R1, R13 and R1 are as defined for formula (I). In an embodiment thereof R2 and R3, together with A and the nitrogen atom and the carbon atom, respectively, to which they are bonded, form a ring wherein R1, R13 and R14 are as defined for formula (I). In one embodiment thereof, R1 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl- (alkyl of 1 to 6 carbon atoms) or -C (= 0) OR10, wherein R10 is as defined in claim 1, and R13 and R14 are independently hydrogen, alkyl of 1 to 6 carbon atoms, phenyl- (alkyl of 1 to 6 carbon atoms) or oxo. In a further embodiment thereof, R1 is hydrogen or -C (= 0) 0- (alkyl of 1 to 6 carbon atoms), and R13 and R14 are hydrogen. In a further embodiment of the invention, R1, R2 and R3 are hydrogen. In yet another embodiment of the invention A is alkylene of 1 to 6 carbon atoms. In one embodiment of the present, A is methylene or ethylene. In another embodiment of the same, A is ethylene. In still another embodiment of the invention B is -C (= 0) -. In still another embodiment of the invention, D is cycloalkyl of 3 to 8 carbon atoms, heteroaryl or aryl, which may be optionally substituted as defined for formula (I). In one embodiment thereof, D is cycloalkyl of 3 to 8 carbon atoms, heteoaryl or aryl, which may be optionally substituted as defined for formula (I), but not at positions adjacent to the point of attachment of D to B. In yet another embodiment thereof, D is cyclopropyl, thienyl or phenyl, which may be optionally substituted as defined for formula (I). In yet another embodiment thereof, D is cyclopropyl. In yet another embodiment thereof, D is thienyl, which is substituted with halogen. In yet another embodiment thereof, D is phenyl, which is optionally substituted with • hydroxyl, nalinogen, heteroaryl- (alkoxy of 1 to 6 carbon atoms), aryl- (alkoxy of 1 to 6 carbon atoms), wherein the ring portions are optionally substituted as defined for formula (I). In one embodiment thereof, D is phenyl which is optionally substituted with halogen or benzyloxy, wherein the ring portion of the benzyloxy is optionally substituted as defined for formula (I). In a further embodiment thereof, D is phenyl, which is replaced with benzyloxy. The compounds of the present invention can have one or more asymmetric centers and it is intended that any optical isomers, either separate, pure or partially purified optical isomers or racemic mixtures thereof, be included within the scope of the invention. In addition, when a double bond or a complete or partially saturated ring system is present in the molecule, geometric isomers can be formed. It is intended that any geometric isomers, either separate, pure or partially purified geometric isomers or mixtures thereof, are included within the scope of the invention. Similarly, molecules that have a bond with restricted rotation can form geometric isomers. It is intended that they also be included within the scope of the present invention. In addition, some of the compounds of the present invention may exist in different tautomeric forms, and any tautomeric forms, which the compounds are capable of forming, are intended to be included within the scope of the present invention. The present invention also encompasses the pharmaceutically acceptable salts of the present compounds. Such salts include the acid addition salts pharmaceutically acceptable, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. The acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of unsuitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene-salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic and the like. Additional examples of the pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated by reference herein. Examples of metal salts include the salts of lithium, sodium, potassium, magnesium and the like. Examples of the ammonium and alkylated ammonium salts include the ammonium, methylammonium, dimethylammonium, trimethylammonium salts, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium and the like. Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds are capable of forming. The acid addition salts can be obtained as the direct products of the synthesis of the compound. In an alternative, the free base can be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporation of the solvent, or otherwise separating the salt and the solvent. The compounds of the present invention can form solvates with standard low molecular weight solvents using methods well known to those skilled in the art. Such solvates are also contemplated within the scope of the present invention. The invention also encompasses the prodrugs of the present compounds, which undergo chemical conversion in the administration, by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo to 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 Produgs", ed. H. Bundgaard, Elsevier, 1985. The invention also encompasses the active metabolites of the present compounds. The present compounds are useful for the treatment of hyperglycemia; IGT; Syndrome X; Diabetes type 1; type 2 diabetes; conditions with dyslipidemia including diabetic dyslipidemia; and obesity. In addition, these may be useful for the treatment of albuminuria; polycystic ovary syndrome, cardiovascular diseases such as cardiac hypertrophy, hypertension and atherosclerosis including atherosclerosis; gastrointestinal disorders; and regulation of appetite or disorders of energy expenditure. These can 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 sclerosis, multiple sclerosis, leukopenia, anxiety, movement disorder, aggression, psychosis, stroke, panic attacks, hysteria or sleep disorders. In addition, these may be useful as contraceptives, see WO 97/41854, and for the treatment of cancer, hair area and neurotraumatic diseases, such as acute stroke, see WO 00/21917. Thus, in still another aspect, the invention is refers to the use of a compound of the general formula (I '): where "A is a valence or alkylene bond of 1 to 6 carbon atoms, (i) R1 and R2, together with the nitrogen atom to which they are bound, form a non-aromatic ring of 5 to 7 members, whose ring it may optionally contain a double bond, and whose ring may optionally contain an additional nitrogen atom, and to which ring are linked two groups R4 and R5 which are independently selected from: • hydrogen, • oxo, • alkyl of 1 to 6 carbon atoms , alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, which may optionally be substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR6R7, -C (= 0) NR6R7 , - OC (= 0) NR6R7, -OCH2C (= 0) NR6R7, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR6, -C (= 0) R6, -NHC (= 0) R6, -CHF2, -CF2 / - 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 they are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R6 and R7, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) carbon) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (C 1-6 -alkoxy), (C 3-8 -cycloalkyl) - (C 1-6 -alkoxy), heteroaryl- (C 1-6 -alkoxy), (heterocyclyl) of 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 ato carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -0- (cycloalkyl of 3 to 8 carbon atoms) , -0-heteroaryl, -O- (heterocyclyl of 3 to 8 carbon atoms), S-aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- (heterocyclyl of 3) to 8 carbon atoms), wherein the ring portions may be optionally substituted with one to three substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR8R9, -C (= 0) NR8Rs, -0C (= 0) NR8R9, 0CH2C (= 0) NR8R9, alkoxy of 1 to 6 carbon atoms, - C (= 0) 0R8, -C (= 0) R8, -NHC (= 0) R8, -CHF2, -CF3, -0CF3, 0CHF2, -OCH2CF3, - OCF2CF3i - -SCF3, -SR8, -S (= 0) R8, -S (= 0) 2R8, -S (= 0) 2NH2, wherein R8 and R9 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, and R8 and R9 together with the nitrogen atom to which they are attached, form a cyclic ring of 3 to 8 members optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, and R3 is hydrogen, (ii) or R1 is hydrogen, -C (= 0) OR10, -C (= 0) 0R10, alkyl of 1 to 6 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (C 3 -C 8 cycloalkyl) - (C 1-6 alkyl) , heteroaryl- (alkyl of 1 to 6 carbon atoms) or (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), wherein R10 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR- ^ R12, -C (= 0) NR1: LR12, -0C (= 0) NR11R12, -0CH2C (= 0) NR1: LR12, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R1: L, -C (= 0) R11 , - HC (= 0) R11, - CHF2, -CF3, -0CF3, -0CHF2, -OCH2CF3, -0CF2CHF2, -SCF3, -SR11, -S ^ OR11, -S (= 0) 2R ^, -S (= 0) 2N¾, where R11 and R12 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R11 and R12, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, which optionally contain one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, and R2 and R3 are connected to form, together with A and the nitrogen atom and the carbon atom, respectively, to which they are bound, a ring not Aromatic of 5 to 7 members to whose ring are linked two groups R13 and R14 which are independently selected from • hydrogen, • oxo, • alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, which can optionally be substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR15R16, -C (= 0) NR15R16, -0C (= 0) NR15R1S, -0CH2C (= 0) NR15R1S, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R1S, -C (= 0) Rls, -NHC (= 0) R15, -CHF2, -CF3, -0CF3, - OCHF2, -OCH2CF3, - OCF2CHF2, -SCF3, -SR15, -S (= 0) R15, -S (= 0) 2R15, -S (= 0) 2N¾, wherein R15 and R1S which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R15 and R1S, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl - (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl) of 1 to 6 carbon atoms), (heterocyclyl) of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (alkoxy of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkoxy of 1 to 6) carbon atoms), heteroaryl- (alkoxy of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl) from 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -O-aryl, -0- (cycloalkyl of 3 to 8) carbon atoms), -0- heteroaryl, -O- (heterocyclyl of 3 to 8 carbon atoms), S-aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- ( heterocyclyl of 3 to 8 carbon atoms), wherein the ring portions may be optionally substituted with one to three substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR17R18, -C (= 0) R17R18, -OC ( = 0) NR17R18, -0CH2C (= 0) NR17R18, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, - C (= 0) 0R17, -C (= 0) R17, -NHC (= 0) R17, - CHF2, -CF3, -0CF3, -OCHF2, -0CH2CF3, -0CF2CHF2, -SCF3, -SR17, -S ( = 0) R17, -S (= 0) 2R17, -S (= 0) 2NH2, wherein R17 and R18 which may be the same or different are independently selected from hydrogen and alkyl from 1 to 6 carbon atoms, or R17 and R18, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, ( iii) or R1 and R2 which may be the same or different independently selected from hydrogen, -C (= 0) OR, C (= 0) R19 and alkyl of 1 to 6 carbon atoms, wherein R19 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents independently selected from • hydroxyl, halogen, cyano, nitro, -NR20R21, -C (= 0) NR20R21, -OC (= O) NR20R21 , -0CH2C (= 0) NR20R21, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R20, -C (= 0) R20, -NHC (= 0) R20, -CHF2, - CF3, -0CF3 / -0CHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR20, -S (= 0) R20, -S (= 0) 2R2 °, -S (= 0) 2 H2, • where R20 and R21 which can be the same or different ones are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R20 and R21, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen or, and R3 is hydrogen, B is a valence bond, -C (= 0) -, -S (= 0) - or -S (= 0) 2-D is • hydroxyl, halogen, cyano, nitro, - NR22R23, -N (R22) 0R23, - C (= 0) NR22R23, -0C (= 0) R22R23, -0C¾C (= 0) NR22R23, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R22, -C (= 0) R22, -NHC (= 0) R22, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -S22, -S (= 0) R22, -S (= 0) 2R22, -S (= 0) 2H2, wherein R22 and R23 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R22 and R23, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, alkyl of 1 to 6 carbon atoms. carbon, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents selected from hydroxyl, halogen, cyano, nitro, -NR24R25, -C (= 0) NR24R2E , -0C (= 0) NR2R25, 0CH2C (= 0) NR24R2S, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R24, -C (= 0) R24, - HC (= 0) R24, - CHF2, -CF3, -0CF3, -0CHF2, -OCH2CF3, -OCF2CHF2, ~ SCF3, -SR24, -S (= 0) R24, -S (= 0) 2R24, -S (= 0) 2NH2, wherein R24 and R25 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R24 and R25, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, which optionally contain one od the additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkyl of 1) to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (eterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (alkoxy of 1 to 6) carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkoxy of 1 to 6 carbon atoms), heteroaryl- (alkoxy of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -O- (cycloalkyl of 3 to 8 carbon atoms), -O-heteroaryl, - O- (C 3 -C 8 heterocyclyl), S-aryl, S- (C 3 -C 8 cycloalkyl), -S-heteroaryl, -S- (C 3 -C 8 heterocyclyl), H -aryl, H-heteroaryl, wherein the ring portions may be optionally substituted with one to three substituents selected from hydroxyl, halogen, cyano, nitro, -NR26R27, -C (= 0) R26R27, -0C (= 0) NR26R27 , -0CH2C (= 0) NR26R27, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R2S, -C (= 0) R25, -NHC (= 0) R26, -CHF2, - CP3, -OCF3i -0CHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR26, -S (= 0) R26, -S (= 0) 2R26, -S (= 0) 2NH2, wherein R26 and R27 which can be the same or different ones are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R26 and R27, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents selected from hydroxyl, halogen, cyano, nitro, -R28R29, -C (= 0) R28R29, -0C (= 0) R28R29, -0CH2C (= 0) NR28R29, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR28, -C (= 0) R28, - HC (= 0) R28, -CHF2, -CF3, -0CF3, -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 are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R28 and R29, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected of oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkyl of 1) to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (alkoxy of 1 to 6) carbon atoms), (C 3 -C 8 cycloalkyl) - (C 1-6 -alkoxy), heteroaryl- (C 1-6 -alkoxy), (C 3 -C 8 -heterocyclyl) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C ( = 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -O- (cycloalkyl of 3 to 8 carbon atoms), -0-heteroaryl, -O- (heterocyclyl of 3 to 8 carbon atoms) carbon), S-aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- (heterocyclyl of 3 to 8 carbon atoms), wherein the ring portions may be optionally substituted with one to three substituents selected from hydroxyl, halogen, cyano, nitro, NR30R31, -C (= O) NR30R31, -0C (= 0) NR30R31, - 0CH2C (= 0) R30R31, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR30, -C (= 0) R30, -NHC (= 0) R30, -CHF2, -CF3, -0CF3, -OCHF2, -OCH2CF3, OCF2CHF2, -SCF3, -SR30, -S (= 0) R30, -S (= 0) 2R30, -S (= 0) 2NH2, wherein R30 and R31 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R30 and R31, together with the atom of nitrogen to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, as well 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, wherein an inhibition of GSK-3 is beneficial. In a further preferred embodiment of the invention, the compounds of the formula (α ') 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 (? ') Are used for the manufacture of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, where the inhibition driven by the growth factor, of GSK-3, is insufficient. In a further preferred embodiment of the invention, the compounds of the formula (α ') are used for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, wherein the glycogen metabolism shows abnormalities. In a further preferred embodiment of the invention, the compounds of the general formula (α ') are used for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, wherein the glycogen synthase is insufficiently activated. In a further preferred embodiment of the invention, the compounds of the formula (α ') are used for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, which involve elevated blood glucose. The compounds are effective in lowering fasting and postprandial blood glucose. In still another preferred embodiment of the invention, the present compounds of the general formula (η ') are used for the preparation of a pharmaceutical composition for the treatment of hyperglycemia.

In still another preferred embodiment of the invention, the present compounds of the general formula (η ') are used for the preparation of a pharmaceutical composition for the treatment of IGT. In still another preferred embodiment of the invention, the present compounds of the formula (γ ') are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes. Such treatment includes for example, the delay of the IGT progression to type 2 diabetes, as well as the delay of progression from type 2 diabetes that does not require insulin, to type 2 diabetes that requires insulin. In a further preferred aspect of the invention, the present compounds of the general formula (α ') are used for the preparation of a pharmaceutical composition for the treatment of type 1 diabetes. Such treatment is usually accompanied by insulin therapy. In addition, the present compounds of the general formula (? ') Can be used for the preparation of a pharmaceutical composition for the treatment of obesity. In still another aspect of the invention, the present compounds of the general formula (? '), Can be used for the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease. In still another aspect of the invention, the present compounds of the general formula I can 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 with diet and / or exercise. In still another aspect of the invention, the present compounds are administered in combination with one or more other additional, pharmacologically active substances, in any suitable proportions. Such additional active agents can be selected from antidiabetic agents, antihyperlipidemic agents, anti-obesity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes. In addition, these can be administered in combination with one or more additional 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 simple preparation, as appropriate. Suitable antidiabetics comprise insulin, GLP-1 (glucagon-like peptide-1) derivatives such as those described in O 98/08871 (Novo Nordisk A / S), which is incorporated by reference herein, as well as orally active hypoglycemic agents. Orally active hypoglycemic agents preferably comprise imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolindiones, thiazolidinediones, insulin sensitizers, a-glucosidase inhibitors, agents that act on the ATP-dependent potassium channel of the β-cells, for example, the potassium channel openers such as described in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A / S), which are incorporated by reference herein, or mitiglinide, or a potassium channel blocker, such as BTS -67582, nateglinide, glucagon antagonists such as those described in WO 99/01423 and WO 00/39088 (Novo Nordisk A / S and Agouron Pharmaceuticals, Inc.), which are incorporated by reference herein, GLP agonists -1 such as those described in WO 00/42026 (Novo Nordisk A / S and Agouron Pharmaceuticals, Inc.), which is incorporated by reference herein, inhibitors of DPP-IV (dipeptidyl-peptidase-IV), inhibitors of PTPase (tyrosine protein a-phosphatase), inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, compounds that modify the metabolism of lipids such as antilipidemic agents, compounds that decrease food intake, agonists of PPAR (peroxisome proliferator activated receptor) and RXR (retinoid X receptor), such as ALRT-268, LG-1268 and LG-1069. In one embodiment of the invention, the present compounds are administered in combination with insulin. In a further embodiment of the invention, the present compounds are administered in combination with a sulfonylurea for example tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glycazide or glyburide. In still another embodiment of the invention, the present compounds are administered in combination with a biguanide for example metformin. In still another embodiment of the invention, the present compounds are administered in combination with meglitinide for example, repaglinide or nateglinide. In still another embodiment of the invention, the present compounds are administered in combination with an insulin sensitizer of triazolidinedione, for example troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-Oll / Cl-1037 or T174 or the compounds described in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Eddy's Research Foundation), which are incorporated by reference herein. In still another embodiment of the invention, the present compounds are administered in combination with an insulin sensitizer, for example such as GI 262570, ??? 440, MCC-555, JTT-501, AR-H039242, KRP-297, GW -409544, CRE-16336, AR-HO49020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds described in WO 99/19313, O 00/50414, O 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196. , WO 00/63209, WO 00/63190 and WO 00/63169 (Novo Nordisk A / S), which are incorporated by reference herein. In a further embodiment of the invention, the present compounds are administered in combination with the α-glucosidase inhibitor for example, voglibose, emiglitate, miglitol or acarbose. In yet another embodiment of the invention, the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the β cells for example tolbutamide, glibenclamide, glipizide, glycoside, BTS-67582 or repaglinide. In yet another embodiment of the invention, the present compounds are administered in combination with an antilipidemic agent, for example, cholestyramide, colestipol, clcfibrate, genfibrozil, lovastatin, pravastatin, sinvastatin, probucol or dextrothyroxine. In still another aspect of the invention, the present compounds are administered in combination with more than one of the aforementioned compounds, for example in combination with metformin and a sulfonylurea such glyburide; a sulfonylurea and acarbose, nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; 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 with one or more anti-obesity agents or appetite regulating agents. Such agents may be selected from the group consisting of agonists of CART (transcript regulated by ***e amphetamine), NPY (neuropeptide Y) antagonists, MC4 agonists (melanocortin 4), MC3 agonists (melanocortin 3), orexin antagonists, TNF agonists (tumor necrosis factor), CFR agonists (corticotropin release factor) CRF BP agonists (corticotropin releasing factor binding protein), urocortin agonists, β3 adrenergic agonists such as CL-316243, AJ -9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH agonists (melanocyte stimulation hormone), MCH agonists (melanocyte concentration hormone), CCK antagonists (cholecystokinin), serotonin reuptake inhibitors such as fluoxetine, seroxat or citalopram, serotonin reuptake inhibitors and of norepinephrine, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin or placental lactogen, growth hormone releasing compounds, agonists of TRH (thyrotropin releasing hormone), modulators of UCP 2 or 3 (decoupling protein 2 or 3), leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, PPAR modulators (activated receptor by the peroxisome proliferator), modulators of RXR (retinoid X receptor), TR ß agonists, AGRP inhibitors (protein na related to Agouti), histamine H3 antagonists such as those described in WO 00/42023, WO 00/63208 and WO 00/64884 (Novo Nordisk A / S and Boehringer Ingelheim International GmbH), which are incorporated by reference herein , opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor. In one embodiment of the invention, the anti-obesity agent is leptin.

In yet another embodiment, the anti-obesity agent is dexamfetamine or amphetamine. In yet another embodiment, the anti-obesity agent is fenfluramine or dexfenfluramine. In another additional embodiment, the anti-obesity agent is sibutramine. In a further embodiment, the anti-obesity agent is orlistat. In a further embodiment, the anti-obesity agent is mazindol or phentermine. In another additional embodiment, the anti-obesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam. In addition, in another aspect of the invention the present compounds are administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, tenolol, timolol, pindol, propranolol and metoprolol, inhibitors of ACE (angiotensin converting enzyme) such as benazeprit, captopril, enalapril, fosinopril, quinapril and ramipril, blockers of the calcium channels such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and oc-blockers such as doxazosin, urapidil, prazosin and tetrazosin. Additional reference can be made to Remington: The Science and Pratice of Pharmacy, 19th. Edition, Gennaro, Ed., Mack Publishing Co. , Easton, PA, 1995. In still another aspect of the invention, the present compounds are administered in combination with 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, fluoxeline, fluvoxamine, nefazodone, nortriptyline, paroxetine, sertraline and trazodone. In still another aspect of the invention, the present compounds are administered in combination with 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, anti-anxiety agents such as lorazepam and clonazepam, antidepressants such as bupropion, fluvoxamine, paroxetine, sertraline, mirtazepine, phenelzine, tranylcypromine, nefazodone, amitriptyline. , desipramine, imipramine, nortriptyline and venlafaxine. It should be understood that any combination of the compounds according to the invention are, with diet and / or exercise, one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances, are considered within the scope of the invention. scope of the present invention. PHARMACEUTICAL COMPOSITIONS The compounds of the invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients., in single or multiple doses. The pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients, according to conventional techniques such as those described in Remington: The Science and Practice of Pharmacy, 19a. Editing, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions can be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical route (including buccal and sublingual). ), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal), with the oral route being the preferred route. It will be appreciated that the preferred route will 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, pills, powders and granules. Where appropriate, these can be prepared with coatings such as enteric coatings or can be formulated to provide controlled release of the active ingredient, such as sustained release or prolonged release, according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs. Pharmaceutical compositions for parenteral administration include injectable, sterile, aqueous and non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions, before use. Depot injectable formulations are also contemplated within the scope of the present invention. Other suitable forms of administration include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, etc. A simple oral dose is in the range of from about 0.001 to about 100 mg / kg of body weight per day, preferably from about 0.01 to about 50 mg / kg of body weight per day, and more preferably from about 0.05 to about mg / kg of body weight per day, administered in one or more doses, such as 1 to 3 doses. The exact dosage will depend on the frequency and mode of administration, sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases that will be treated, and other obvious factors for those skilled in the art. The formulations can be conveniently presented in the unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times a day such as 1 to 3 times a day, may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferably of about 0.5 mg to approximately 200 mg. For parenteral routes, such as intravenous, intramuscular, and similar administration, doses of the order of about half the dose used for oral administration are typically employed. The compounds of this invention are generally used as the free substance or as a pharmaceutically acceptable salt thereof. An example is a salt by acid addition of a compound having the utility of a free base. When 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) with a chemical equivalent of a pharmaceutically acceptable acid, by example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxyl group include the anion of said compound in combination with a suitable cation such as the sodium or ammonium ion. For parenteral administration, solutions of the new compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may also be employed. Such aqueous solutions should be adequately buffered if necessary, the liquid diluent first made isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, aqueous solution sterile and various organic solvents. Examples of solid carriers are lactose, alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by the combination of the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then easily administered in a variety of dosage forms suitable for the administration routes described. The formulations can be conveniently presented in unit dosage form by methods known in the pharmacy art. 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 which may include a suitable excipient. These compositions can be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as a liquid emulsion, oil in water or water in oil. If a solid carrier is used for oral administration, the preparation may be in the form of tablets, placed in a hard gelatin capsule in powder or pellet form, or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely, but will 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 gelatin capsule or sterile injectable liquid, such as a suspension or aqueous or non-aqueous liquid solution. A typical tablet, which can be prepared by conventional tablet forming techniques, may contain: Core: Active compound (as free compound or salt thereof) 5.0 mg (European Pharmacopoeia) 67.8 mg Cellulose, microcrystalline (Avicel) 31.4 mg Amberlite® IRP88 * 1.0 mg Magnesium Stearate (European Pharmacopoeia) as long as it is sufficient Coating: Hydroxypropylmethylcellulose approx. 9 mg Mywacett 9-40 T ** approx. 0.9 mg * Polacryllin potassium NF, tablet disintegrator, Rohm and Haas. ** Acylated monoglyceride used as a plasticizer for coating the film If desired, the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with additional, pharmacologically active substances, such as those described above. The present invention is further illustrated by the following representative examples which, however, are not intended to limit the scope of the invention in any way. EXAMPLES The compounds used as starting materials are either known compounds or compounds which can be prepared by methods known per se. The NMR spectra were recorded on a Bruker instrument at 300 MHz. Flash chromatography was carried out on 60 Merck silica gel (Art 9385).

HPLC-MS (high performance liquid chromatography - mass spectrum) Method A: Instruments: Sciex API 100 single quadrupole mass spectrometer, Applied Biosystems 785A UV detector, Sedex 55 evaporative light scattering detector, Column: YMC ODS-A 120 Á s - 5 μ (50 miti x 3 mm id).

Gradient: 5% - 90% acetonitrile (with 0.05% trifluoroacetic acid) for 7.5 min. UV detection at 214 nm.

HPLC-MS Method B: Column: Waters Xterra MS C-18 x 3 mm internal diameter. Linear gradient of 10% - 100% in 7.5 minutes, acetonitrile, 0.01% TFA, flow rate 1.0 ml / minute. Detection at 210 nm (analog output of the diode array detector), MS detection ionization mode, API-ES, scanning 100-1000 amu gradually 0.1 amu. In the examples and tests the following terms are intended to have the following meanings: Boc: tert-butyloxycarbonyl DMF: N, -dimethylformamide DMSO: dimethyl sulfoxide EtOAc: ethyl acetate HCl hydrogen chloride P.f. : melting point TFA: trifluoroacetic acid General Procedure (A) The preparation of the compounds of the formula (Ia) according to this invention wherein B is -C (= 0) - can be illustrated in the following reaction scheme, and can be achieved using the method described by Gewald K. et al (J. Prakt. Che., 35, 1967, pp. 97-104). An isothiocyanate of the formula (III) is reacted together with a bromomethyl ketone of the formula (V) to give the products of the general formula (la) (Step C). When they are not commercially available, the initial materials of formula (III) and (V) are prepared using literature procedures, as cited under the individual examples and as illustrated in steps? and B following. Step A: When R1 and R2 are both hydrogen, the amino group formed must be protected with a suitable protecting group, such as Boc, before carrying out the step? After step C, the protecting group can be removed in a conventional manner to form the compounds of the formula (Ia) wherein R1 and R2 are both hydrogen. EXAMPLE 1 [3- (4-Amino-5-cyclopropancarbonylthiazol-2-ylamino) propyl] carbamic acid tert-butyl ester H3C The method described by Gewald K. et al (J. Prakt. Chem., ,1967, pp. 97-104) was employed using 2-bromo-l-cyclopropyletanone and N-Boc-isothiocyanatopropylamine. The 2-bromo-l-cyclopropyletanone was prepared by itself 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 was used throughout the addition of the bromine. The title compound was obtained in 32% yield after chromatography using ethyl acetate / heptane (2: 1) as eluent. P.f. 144-146 ° C; NMR ½ (300 MHz; D SO-d5): d 0.75 (2H, m, CH2), 0.82 (2H, m, CH2), 1.39 (9H, s, t-Bu), 1.68 (3H, m, CH2 and CH), 2.98 (2H, dd, CH2), 3.23 (2H, dd, CH2), 6.87 (1 H, broad t, H), 7.61 (2H, broad s, NH2), 8.48 (1 H, t, NH ). The following compounds, unless otherwise specified, were prepared as described in Example 1 using the appropriate starting materials. EXAMPLE 2 [2- (4-Amino-5-cyclopropancarbonylthiazol-2-ylamino) ethyl] carbamic acid tert-butyl ester NMR ½ (300 MHz, DMSO-d 6): 2 H NMR (300 MHz, DMSO-d 6): d 0.75 (2H, m, CH 2), 0.82 (2H, m, CH 2), 1.40 (9H, s, t-Bu ), 1.64 (1H, m, CH), 3.12 (2H, dd, CH2), 3.28 (2H, broad, CH2), 6.94 (1 H, broad t, NH), 7.62 (2H, broad s, NH2), 8.49 (1 H, t, NH).

EXAMPLE 3 3- [4-Amino-5- (5-chlorothiophen-2-carbonyl) thiazol-2-ylamino] propylcarbamic acid tert-butyl ester NMR ¾ (300 MHz; D SO-d6): 6 1.39 (9H, s, t-Bu), 1.68 (2H, ddd, CH2), 2.98 (2H, ddf CH2), 3.30 (2H, broad, CH2), 6.87 (1H, broad t, NH), 7.18 (1H, d, Ar-H), 7.32 (1H, broad d, Ar-H), 7.85-8.55 (2H, broad s, NH2), 8.88 (1H, t , NH); HPLC-MS (ESI): m / z 418 [M + H] +; Rt = 5.73 minutes (Method A). Example 4 4- (4-Amino-5-cyclopropanecarbonylazol-2-ylamino) piperidine-l-carboxylic acid tert-butyl ester The starting material, tert-butyl ester of 4-isothiocyanatopyperidine-l-carboxylic acid, was first prepared, from the corresponding amine using the di-2-pyridylthiocarbonate, according to the Method of Kim, S. and Yi, K.Y. (Tetrahedron Lett., 26 (13), 1985, pp. 1661-1664).

The title compound was obtained after chromatography using ethyl acetate / heptane (1: 1) as eluent. NMR ¾ (300 MHz, DMSO-d6): d 0.75 (2H, m, CH2), 0.82 (2H, m, CH2), 1.34 (2H, m, CH2), 1.39 (9H, s, t-Bu), 1.62 (1H, m, CH), 1.81 (2H, dd, CH2), 2.88 (2H, m, CH2), 3.73 (1H, broad, CH), 3.88 (2H, dd, CH2), 7.64 (2H, s broad, NH2), 8.52 (1H, d, NH); HPLC-MS (ESI): m / z 367 [M + H] +; Rt = 4.95 minutes (Method A). Example 5 4- [4-Amino-5- (3-benzyloxybenzoyl) thiazol-2-ylamino] piperidine-l-carboxylic acid tert-butyl ester H The starting material, 1- (3-benzyloxyphenyl) -2-bromoethanone, was first prepared, from the corresponding ketone using copper (II) bromide, according to the method of King, LC et al (J. Org. Chem. ., 1964.29, pp 3459-3461). The title compound was obtained after chromatography using ethyl acetate / heptane (1: 1) as eluent. NMR ¾ (300 MHz, DMSO-d6): d 1.34 (2H, m, CH2), 1.39 (9H, s, t-Bu), 1.88 (2H, m, CH2), 2.88 (2H, m, CH2), 3.73 (1H, broad, CH), 3.87 (2H, dd, CH2), 5.65 (2H, s, OCH2), 7.07-7.48 (9H, m, Ar-H), 7.70-8.50 (2H, broad, NH2), 8.62 (1H, broad d, NH); HPLC-MS (ESI): m / z 509 [M + H] +; Rt = 7.08 minutes (Method A). Example 6: Tert-butyl ester of the acid. { 3- [4-amino-5- (3-benzyloxybenzoyl) thiazol-2-ylamino] propyl} carbamic An intermediate, the isothiourea of the S- (3-benzyloxybenzoyl) methyl- '-cyano-N "-propylcarbamic acid tert-butyl ester was isolated when the above-mentioned method was employed by Gewald K. et al., XH NMR (300 MHz; DMSO-d6): d 1.33 (9H, s, t-Bu), 1.55 (2H, m, CH2), 2.75 (2H, dd, CH2), 2.90 (1H, m, CH), 3.19 (1H, m , CH), 3.70 (2H, ABr 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 was refluxed overnight in ethyl acetate with 2 equivalents of triethylamine. The title compound was obtained with cooling and addition of water.

NMR a? (300 MHz, DMSO-d6): d 1.41 (9H, s, t-Bu), 1-70 (2H, ddd, CH2), 3.03 (2H, dd, CH2), 3.28 (2H, broad, CH2), 5.20 (2H, s, OCH2), 6.85 (1H, broad t, NH), 7.08-7.48 (9H,, Ar-H), 7.81-8.4 (2H, broad s, NH2), 8.60 (1 H, broad t , NH); HPLC-MS (ESI): m / z 483 [M + H] +; Rt = 4.23 minutes (Method B). Example 7 l-. { 3- [4-amino-5- (5-chlorothiophen-2-carbonyl) thiazol-2-ylamino] propyl} pyrrolidin-2-one The starting material, 1- (3-isothiocyanatopropyl) pyrrolidin-2-one, was first prepared, from the corresponding amine, using di-2-pyridylthiocarbonate, according to the Method of Kim, S. and Yi, KY (Tetrahedron Lett., 26 (13), 1985, pp. 1661-1664). It was found that the product precipitated from the reaction mixture. This was filtered and stirred in hot ethanol before hot filtration afforded the title compound in 40% yield. P.f. 224-225 ° C; HPLC-MS (ESI): m / z 385 [M + H] +; Rt = 3.31 minutes (Method B). Microanalysis for Ci5Hi7 402SCl: Calculated: C, 46.81%; H, 4.45%; N, 14.56%; Found: C, 46.83%; H, 4.46%; N, 14.36%. Example 8 { -amino-2- [3- (4-methyl-piperazin-1-yl) -propylamino] -thiazol-5-yl} - (5-chlorothiophen-2-yl) -metanone The starting material, 1- (3-isothiocyanotropyl) -4-methylpiperazine, was first prepared, from the corresponding amine, using di-2-pyridylthiocarbonate, according to the Method of Kim, S. and Yi, KY (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 gaseous HC1 in diethyl ether (approximately 2 M) to give the title compound as a hydrochloride salt in a yield of 13%. P.f. 210-212 ° C; HPLC-MS (ESI): m / z 401 [M + H] +; Rt = 1.65 minutes (Method B). Example 9 { 4-amino-2- [3- (4-methyl-piperazin-1-yl) -propylamino] -thiazol-5-yl} - (5-chlorothiophen-2-yl) -metanone The reaction was carried out according to Example 6, with the ring-opened intermediate being first isolated after the addition of water to the reaction mixture. This was dissolved in hot ethanol and treated with 1.2 equivalents of triethylamine. After 2 hours, the reaction was cooled and filtered to provide the title compound in 32% yield as a white solid. P.f. 184 ° C; RN ½ (300 MHz, DMSO-d6): d 1.73 (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, 0CH2), 7.08-7.48 (9H, m, Ar-H), 7.81-8. 4 (2H, broad d, NH2), 8.58 (1 H, broad t, NH); HPLC-MS (ESI): m / z 451 [M + H] +; Rt = 3.47 minutes (Method B). Example 10 { 4-amino-2- [3- (4-methyl-piperazin-1-yl) -propylamino] -thiazol-5-yl} -3- (benzyloxyphenyl) methanone The reaction and the treatment were performed as described in Example 8. The title compound was obtained as a hydrochloride salt. NMR ¾ (300 MHz; DMSO-d6): d 2.04 (2H, ddd, CH2), 2.85 (3H, s, CH3), 3.22 (2H, broad, 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, broad d, NH2), 8.81 (1 H, broad t, NH), 11.88 (1 H, broad s, NH); P.f. 99-100 ° C HPLC-MS (ESI): m / z 466 [M + H] +; Rt = 2.30 minutes (Method B). Example 11 [4-amino-2- (3-aminopropylamino) thiazol-5 'yl] cyclopropylmetanone The product of Example 1, [3- (4-amino-5-cyclopropancarbonylthiazol-2-ylamino) propyl] carbamic acid tert-butyl ester (100 mg, 0.30 ml), was dissolved in 5 ml of ethanol and treated with a triple excess of a solution of HCl gas in diethyl ether (approximately 2M). The white solid was filtered and washed with ether to give the title compound as the hydrochloride salt in 80% yield. NMR ½ (300 Hz, DMSO-d6): d 0.75 (2H, m, CH2), 0.82 (2H, m, CH2), 1.64 (1 H, m, CH), 1.88 (2H, ddd, CH2), 2.84 (2H, dd, CH2), 3.34 (2H, dd, CH2), 5.20-6.0 (3H, broad s, NH3), 8.03 (2H, broad s, NH2), 8.75 (1H, t, NH); HPLC-MS (ESI): m / z 241 [M + H] +; Rt = 0.43 and 2.68 (Method B). Example 12 [4-amino-2- (2-aminoethylamino) thiazol-5-yl] cyclopropylmetanone H The title compound was obtained as a salt of Hydrochloride, starting from the butyl ester of [2- (4-amino-5-cyclopropanecarbonylazothia-2-ylamino) ethyl] carbamic acid and using the method described in Example 11. XH NMR (300 MHz; DMSO-d6) : d 0.77 (2H, m, CH2), 0.81 (2H, m, CH2), 1.66 (1H, m, CH), 3.04 (2H, dd, CH2), 3.49 (2H, dd, CH2), 4.42 (3H , broad s, NH3), 8.13 (2H, broad s, NH2), 8.75 (1H, t, NH); HPLC-M3 (ESI): m / z 227 [M + H] +; Rt = 0.47 minutes (Method B). Example 13 [4-amino-2- (3-aminopropylamino) thiazol-5-yl] - (5-chlorothiophen-2-yl) methanone The Example product, of the 3-, 3- [4-amino-5- (5-chlorothiophen-2-carbonyl) thiazol-2-ylamino] propylcarbamic acid tert-butyl ester (51 mg, 0.12 mmol), was dissolved in 1 ml of dichloromethane and treated with 0.5 ml of TFA. After 2 hours at room temperature, the solvents were evaporated to provide the title compound as a TFA salt. NMR? (300 MHz, DMSO-d6): d 1.86 (2H, ddd, CH2), 2.88 (2H, dd, CH2) r 3.40 (2H, broad s, CH2), 7.18 (1H, d, Ar-H), 7.33 (1 H, d, Ar-H), 7.76 (3 H, broad s, NH 3), 8.1 and 8.45 (2 H, broad, 2 x s, NH 2), 8.95 (1 H, broad t, NH); HPLC-S (ESI): m / z 317 [M + H] +; Rt = 1.82 minutes. Example 14 [4-amino-2- (piperidin-4-ylamino) thiazol-5-yl] cyclopropylmetanone H The title compound was obtained as a TFA salt, starting from the (4-amino-5-cyclo-propanecarbonylthiazol-2-ylamino) piperidine-1 carboxylic acid tert-butyl ester, using the Method described in Example 13 HPLC-MS (ESI): m / z 267 [M + H] +; Rt = 0.65 minutes. Example 15 [4-amino-2- (piperidin-4-ylamino) -thiazol-5-yl] - (3- H The title compound was obtained as a TFA salt, starting from the 4- [4-] -butyl ester of the acid. amino-5- (3-benzyloxybenzoyl) thiazol-2-ylamino] piperidine-1-carboxylic acid, and using the Method described in Example HPLC-MS (ESI): m / z 409 [M + H] +; Rt = 2.33 minutes. Example 16 [4-amino-2- (3-aminopropylamino) thiazol-5-yl] - (3-'-benzyloxyphenyl) methanone The title compound was obtained as a TFA salt, starting from the tert-butyl ester of the acid. { 3- [4-amino-5- (3-benzyloxybenzoyl) thiazol-2-ylamino] propyl} The reaction was carried out using the method described in Example 13. NMR ½ (300 MHz, DMSO-d6): d 51.85 (2H, ddd, CH2), 2.83 (2H, dd, CH2), 3.33 (2H, broad, CH2) , 5.18 (2H, s, OCH2), 6.58 (3H, broad s, NH3), 7.11-7.49 (9H, m, Ar-H), 7.95 (2H, broad s, NH2), 8.80 (1 H, broad t , NH); HPLC-MS (ESI): m / z 383 [M + H] +; Rt = 2.30 minutes. The following compounds are also within the scope of the present invention: [4-amino-2- (1-ethyl-l, 2,5,6- [4-amino-2- (1-tetrahydro-pyridin-3-ylamino) -benzylpiperidin-4-yl-thiazol-5-yl] ] phenyl-methanone amino) thiazol-5-yl] - (5-NH2 \ chlorothiophen-2-yl) methanone HH [4-amino-2 - (l-benzylpiperidin-4- tert-butyl ester of ylamino) -thiazol-5-yl] - (3-acid. {3 - [4-amino-5 ~ (3, 4 -benzyloxyphenyl) methanone difluorobenzoyl) iazol-2-ylamino] propyl} carbamic Terbutyl ester of (3-L-. {3- [4-amino-5- (3. {4-amino-5- [3- (2-chlorothiazol-4-hydroxybenzoyl) -thiazole-2-} il-methoxy) benzoyl] thiazol-2-ylamino] propyl} pyrrolidin-ylamino} propyl) -carbamic 2 -one N-. { 3- [4-amino-5- (3-l-. {3- [4-amino-5- (5-benzyloxybenzoyl) thiazole-2-chlorothiophen-2-carbonyl) -ylamino] propyl} acetamide thiazol-2-ylamino] ropil} pyrrolidine PHARMACOLOGICAL METHODS Assay (I) Inhibition of GSK-3 by a test compound was evaluated using human GSK-3P and a substrate derived from glycogen synthase, with the following amino acid sequence: YRRAAVPPSPSLSRHSSPHQS (P04) EDEEE-N¾. In summary, GSK-3P was incubated with the 35 μ? of the substrate and varying the concentrations of the test compound in a buffer containing 0.1 mM of ATP labeled with 33P, 10 mM magnesium acetate, 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 0.1% dithiothreitol and 0.03% Triton- X100 for 60 minutes at room temperature. The reaction was performed using 96-well plates. The reaction was terminated by the addition of 13 μ? of 2% phosphoric acid to each well, and 10 μ? on P30 paper that was washed 4 times in 0.5% phosphoric acid to remove ATP labeled with unincorporated 33P. After drying the radioactivity was counted in an allac apparatus. The dose-response profiles were generated, and the IC 50 value for the 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 of less than 1 μ ?: Examples 3, 5, 6, 7, 9 and 10. From the foregoing, it will be appreciated that, although the specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit of the invention. spirit and scope of the invention as defined by the appended claims. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims

Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the general formula (I) characterized in that A is a valence or alkylene bond of 1 to 6 carbon atoms, (i) R1 and R2, together with the nitrogen atom to which they are bonded, form a non-aromatic ring of 5 to 7 members, whose ring can optionally containing a double bond, and whose ring may optionally contain an additional nitrogen atom, and to which ring are linked two groups R4 and R5 which are independently selected from: • hydrogen, • oxo, • alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkinyl of 2 to 6 carbon atoms, which may optionally be substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR6R7, -C (= 0) NR6R7, -
OC (= 0) NR6R7, -OCH2C (= 0) NReR7, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR6, -C (= 0) R6, -NHC (= 0) R6, -CHF2 , -CF3 / -OCF3, -OCHF2, -OCH2CF3i -OCF2CHF2 (-SCF3, -SR6, -S (= 0) R6, -S (= 0) 2R6, -S (= 0) 2NH2, where Rs and R7 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R6 and R7, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, which optionally contain one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (C 3 -C 8 cycloalkyl) - (C 1 -C 6 -alkyl), heteroaryl- (C 1-6 -alkyl), (C 3 -C 8 -heterocyclyl) - (C 1 -C 6 -alkyl) to 6 carbon atoms), aryl- (C 1 -C 6 -alkoxy), (3-cycloalkyl) to 8 carbon atoms) - (C 1 -C 6 -alkoxy), heteroaryl- (C 1-6 -alkoxy), (C 3 -C 8 -heterocyclyl) -alkoxy of 1 to 6 carbon atoms ), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -
O- (C 3 -C 8 cycloalkyl), -0- heteroaryl, -0- (C 3 -C 8 heterocyclyl), S-aryl, S- (C 3 -C 8 cycloalkyl), - S-heteroaryl, -S- (heterocyclyl of 3 to 8 carbon atoms), wherein the ring portions may be optionally substituted with one to three substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR8R9, -C ( = 0) NR8R9, -0C (= 0) NR8R9, 0CH2C (= 0) NR8R9, alkoxy of 1 to 6 carbon atoms, C (= 0) 0R8, -C (= 0) R8, -NHC (= 0) Ra, -CHF2, -CF3, -0CF3, 0CHF2, -0C¾CF3, -OCF2CHF2, -SCF3, -SR8, -S (= 0) R8, -S (= 0) 2R8, -S (= 0) 2NH2í where R8 and R9 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, and Rs and R9 together with the nitrogen atom to which they are attached form a cyclic ring of 3 to 8 members which optionally contain one or two additional heteroatoms selected from oxygen, sulfur and nitroge no, and R3 is hydrogen, (ii) or R1 is hydrogen, -C (= 0) 0R10, -C (= 0) 0R10, alkyl of 1 to 6 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms) carbon), (cycloalkyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6) carbon atoms) or (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), wherein R 1 C is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl from 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR1: LR12, -C (= 0) NR1: LR12, -OC ^ C NR ^ R12, -OCH2C (= 0) NR1: LR12, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR11, -C (= 0) R1: L, -NHC (= 0) R11, - CHF2, -CF3 , -0CF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR11, -S ^ OjR11, -S ^ O R11, -S (= 0) 2 H2, wherein R11 and R12 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R11 and R12, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, and R2 and R3 are connected to form, together with A and the nitrogen atom and the carbon atom, respectively, to which they are bonded, a non-aromatic ring of 5-7 members to which ring binds two groups R13 and R14 that are independently selected from • hydrogen, • oxo, • alkyl of 1 to 6 carbon atoms, alkenyl of 2 carbon atoms, alkynyl of 2 to 6 carbon atoms, which may optionally be substituted with one or two substituents independently selected from hydroxyl, halogen, cyano , nitro, -NR15R16, -C (= 0) R15R16, -0C (= 0) NR15R16, -0CH2C (= 0) R15R16, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R15, -C ( = 0) R15, -NHC (= 0) R15, -CHF2, - CF3, -0CF3, -OCHF2, -OCH2CF3, - OCF2CHF2, -SCF3í -SR15, -S (= 0) R15, -S (= 0) 2R15, -S (= 0) 2H2, wherein R15 and R16 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R15 and Rie, together with the nitrogen atom at which are linked form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms. carbon, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (alkoxy of 1) to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkoxy of 1 to 6 carbon atoms), heteroaryl- (alkoxy of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -O- (cycloalkyl of 3 to 8 carbon atoms), -0-heteroaryl, - O- (C 3 -C 8 heterocyclyl), S-aryl, S- (C 3 -C 8 cycloalkyl), -S-heteroaryl, -S- (C 3 -C 8 heterocyclyl), in wherein the ring portions may be optionally substituted with one to three substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR17R18, -C (= 0) NR17R18, -OC (= 0) NR17R18, -0CH2C (= 0) NR17R18, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R17, -C (= 0) R17, -NHC (= 0) R17, -CHF2, -CF3, -0CF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR17, -S (= 0) R17, -S (= 0) 2R17, -S (= 0) 2N¾, wherein R17 and R18 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R17 and R18, together with the
Nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, (iii) or R1 and R2 which may be the same or different are selected independently of hydrogen, -C (= 0) 0R19, C (= 0) R19 and alkyl of 1 to 6 carbon atoms, wherein R19 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents independently selected from • hydroxyl, halogen, cyano, nitro, -NR20R21, -C (= 0) R20R21, -0C (= O) NR20R21, -0CH2C (= O) R20R21, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R2 °, -C (= 0) R °, -NHC (= 0) R20, -CHF2,-CF3, - 0CF3, -OCHF2, -0C¾CF3, -0CF2CHF2, -SCF3, -SR20, -S (= 0) R20, -S (= 0) 2R20, -S (= 0) 2NH2, • where R20 and R21 can be the same or different ones are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R20 and R21, together with the nitrogen atom to which they are attached, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen , and R3 is hydrogen, a valence bond, -C (= 0) -7 -S (= 0) - or -S (= 0) 2- hydroxyl, halogen, cyano, nitro, -NR22 23, -N (R22) OR23, -C (= 0) NR22R23, -0C (= 0) NR22R23, -OCH2C (= 0) NR22R23, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR22, -C (= 0) R22, -NHC (= 0) R22, -CHF2, -CF3, -0CF3, -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 are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R22 and R23, together with the nitrogen atom to which they are attached, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents selected from hydroxyl, halogen, cyano, nitro, - NR24R25, -C (= 0) NR24R25, -0C (= 0) NR24R25, 0CH2C (= 0) NR24R25, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR24, -C (= 0) R24, -NHC (= 0) R24, -CHF2, -CF3, -0CF3, -0CHF2i -OCH2CF3, -OCF2CHF2, -SCF3, -SR24, -S (= 0) R24, - S (= 0) 2R24, -S (= 0) 2NH2, where R24 and R25 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R24 and R2S, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected of oxygen, sulfur and nitrogen, • aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 atoms) carbon) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (C 1-6 -alkoxy), (C 3-8 -cycloalkyl) - (C 1-6 -alkoxy), heteroaryl- (C 1-6 -alkoxy), (heterocyclyl of 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -0- (cycloalkyl of 3 to 8 carbon atoms), -0-heteroaryl, - 0- (heterocyclyl of 3 to 8 carbon atoms), S-aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- (heterocyclyl of 3 to 8 carbon atoms), H -Aryl, NH-heteroaryl, wherein the ring portions may be optionally substituted with one to three substituents selected from hydroxyl, halogen, cyano, nitro, -NR26R27, -C (= 0) R26R27, -0C (= 0) NR2SR27, -0CH2C (= 0) NR26R27, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR26, -C (= 0) R26, -NHC (= 0) R26, -CHF2, -CF3, -0CF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR26, -S (= 0) R26, -S (= 0) 2R26, -S (= 0) 2H2, wherein R2S and R27 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R26 and R27, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents selected from hydroxyl, halogen, cyano, nitro, ~ NR28R29, -C (= 0) NR28R29, -0C (= 0) NR28R29, 0CH2C (= 0) NR28R29, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR28, -C (= 0) ) R28, -NHC (= 0) R28, -CHF2, -CF3, -0CF3, -0CHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -SR28, -S (= 0) R28, S (= 0) 2R28, -S (= 0) 2NH2, where R28 and RS that can be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R28 and R29, together with the nitrogen atom to which they are attached, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected of oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) carbon) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl - (C 1 -C 6 -alkoxy), (C 3 -C 8 -cycloalkyl) - (C 1-6 -alkoxy), heteroaryl- (C 1-6 -alkoxy), (heterocyclyl) 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 át carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -O- (cycloalkyl of 3 to 8 carbon atoms) , -0-heteroaryl, -0- (heterocyclyl of 3 to 8 carbon atoms), S-aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- (heterocyclyl of 3 to 8 carbon atoms), wherein the ring portions may be optionally substituted with one to three substituents selected from hydroxyl, halogen, cyano, nitro, NR30R31, -C (= 0) NR30R31, -OC (= 0) NR30R31, -0CH2C (= 0) NR30R31, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms , alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R30, -C (= 0) R30, -NHC (= 0) R30, -CHF2, -CF3, - 0CF3, -OCHF2, -OCH2CF3, OCF2CHF2, -SCF3r -SR30, -S (= 0) R30, -S (= 0) 2R30, -S (= 0) 2NH2, wherein R30 and R31 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R30 and R31, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, with the proviso that the compounds should not be H as well as any optical or geometric isomer or tautomeric form thereof, including mixtures thereof or a pharmaceutically acceptable salt thereof. 2. A compound in accordance with claim 1, characterized in that R2 and R9 are both hydrogen, and R1 is -C (= 0) OR19, wherein R13 is as defined in accordance with claim 1. 3. A compound according to claim 2, characterized by R19 is alkyl of 1 to 6 carbon atoms. 4. A compound according to claim 1, characterized in that R3 is hydrogen, and R1 and R2, together with the nitrogen atom to which they are bound, form a ring wherein R 4 and R 5 are as defined according to claim 1. 5. A compound according to claim 4, characterized in that R 4 and R 5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, phenyl- ( alkyl of 1 to 6 carbon atoms) and oxo.
6. A compound according to claim 5, characterized in that R4 is hydrogen, alkyl of 1 to 6 carbon atoms and R5 is hydrogen or oxo.
7. A compound according to claim 4, characterized in that R3 is hydrogen, and R1 and R2, together with the nitrogen atom to which they are bound, form a ring
8. A compound according to claim 1, characterized in that R2 and R3, together with A and the nitrogen atom and the carbon atom, respectively, to which they are bonded, form a ring wherein R1, R13 and R14 are as defined according to claim 1.
9. A compound according to claim 8, characterized in that R2 and R3, together with A and the nitrogen atom and the carbon atom, respectively to which they are linked, form a ring wherein R, R and R are as defined in accordance with claim 1.
10. A compound according to claim 8 6 9, characterized in that R1 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl- (alkyl of 1 to 6 carbon atoms) or -C (= 0) OR10, wherein R10 is as defined in accordance with claim 1, and R13 and R14 are independently hydrogen, alkyl of 1 to 6 carbon atoms, phenyl- (C1-C6 alkoxy) or oxo.
11. A compound according to claim 10, characterized in that R1 is hydrogen or -C (= 0) 0- (alkyl of 1 to 6 carbon atoms) and R13 and R14 is hydrogen.
12. A compound according to claim 1, characterized in that R1, R2 and R3 are hydrogen.
13. A compound according to any of the preceding claims, characterized in that A is alkylene of 1 to 6 carbon atoms. 1 . A compound according to claim 13, characterized in that? It is methylene or ethylene. 15. A compound according to claim 14, characterized in that A is ethylene. 16. A compound according to any of the preceding claims, characterized in that B is -C (= 0) -. 17. A compound in accordance with any of the preceding claims, characterized in that D is cycloalkyl of 3 to 8 carbon atoms, heteroaryl or aryl, which may be optionally substituted as defined according to claim 1. 18. A compound according to any of the preceding claims, characterized because D is cycloalkyl, of 3 to 8 carbon atoms, heteroaryl or aryl, which may be optionally substituted as defined according to claim 1, but not at the positions adjacent to the point of attachment of D to B. 19. A compound according to claim 17 or 18, characterized in that D is cyclopropyl, thienyl or phenyl, which may be optionally substituted as defined according to claim 1. 20. A compound according to claim 17, characterized in that D is cyclopropyl. 21. A compound according to claim 17 or 18, characterized in that D is thienyl, which is substituted by halogen. 22. A compound according to claim 17 or 18, characterized in that D is phenyl, which is optionally substituted with • hydroxyl, halogen, • heteroaryl- (C 1-6 alkoxy), aryl- (C 1-6 alkoxy), wherein the ring portions are optionally substituted as defined according to claim 1. 23. A compound according to claim 22, characterized in that D is phenyl the which is optionally substituted with halogen or benzyloxy, wherein the ring portion of the benzyloxy is optionally substituted as defined according to claim 1. 24. A compound according to claim 23, characterized in that D is phenyl, which is replaced with benzyloxy. 25. The use of a compound according to any of claims 1 to 24, as a pharmaceutical composition. 26. A pharmaceutical composition, characterized in that it comprises as an active ingredient, at least one compound according to any of claims 1 to 24, together with one or more pharmaceutically acceptable carriers or excipients. 27. A pharmaceutical composition according to claim 26, in unit dosage form, characterized in that it comprises 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 of claims 1 to 24. 28. The use of a compound of the general formula where A is a valence or alkylene bond of 1 to 6 carbon atoms, (i) R1 and R2, together with the nitrogen atom to which they are bound, form a non-aromatic ring of 5 to 7 members, whose ring can optionally containing a double bond, and whose ring may optionally contain an additional nitrogen atom, and to which ring are linked two groups R4 and R5 which are independently selected from: • hydrogen, • oxo, • alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkinyl of 2 to 6 carbon atoms, which may optionally be substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -NRSR7, -C (= 0) NR6R7, - OC (= 0) NR6R7, -OCH2C (= 0) NR6R7, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR6, -C (= 0) R6, -NHC (= 0) R6, - CHF2, -CF2, - 0CF3, -OCHF2, -OCH2CF2, -OCF2CHF2, -SCF3, -SR6, -S (= 0) R6, -S (= 0) 2R6, -S (= 0) 2NH2, wherein R6 and R7 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R6 and R7, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (3-cycloalkyl) to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms) carbon), aryl- (C 1-6 -alkoxy), (C 3-8 -cycloalkyl) - (C 1-6 -alkoxy), heteroaryl- (C 1-6 -alkoxy) ), (heterocyclyl of 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -0- (cycloalkyl of 3 to 8 carbon atoms), -0-heteroaryl, - 0- (heterocyclyl of 3 to 8 atoms of carbon), S-aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- (heterocyclyl of 3 to 8 carbon atoms), wherein the ring portions may be optionally substituted with one to three substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR8R9, -C (= 0) NR8R9, -0C (= 0) NR8R9, 0CH2C (= 0) NR8R9, alkoxy of 1 to 6 carbon atoms, - C (= 0) 0R8, -C (= 0) R8, - HC (= 0) R8, -CHF2, -CF3, -0CF3, 0CHF2, -OCH2CF3 / -OCF2CF3, - -SCF3, -SR8, - S (= 0) R8, -S (= 0) 2R8, -S (= 0) 2H2, wherein R8 and R9 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms , and R8 and R9 together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, and R3 is hydrogen, (ii) or R1 is hydrogen, -C (= 0) 0R10, -C (= 0) 0R10, alkyl of 1 to 6 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) carbon) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms) or (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), wherein R is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR1: LR12, - C (= 0) NR1: LR12, -0C (= 0) NR1: LR12, -OCH2C (= 0) NRI: LR12, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -C ^ C OR11, -C (= 0) R1: L, - HC (= 0) R11, - CHF2, -CF3, -0CF3, -OCHF2, -OCH2CF3, -0CF2CHF2, -SCF3, -SR11, -S ^ OJR11, -S (= 0) 2Rxr -S (= 0) 2NH2, wherein R11 and R12 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R11 and R12, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and n itrogen, and R2 and R3 are connected to form, together with A and the nitrogen atom and the carbon atom, respectively, to which they are bound, a non-aromatic ring of 5-7 members to whose ring two R13 groups are linked. and R14 which are independently selected from • hydrogen, • oxo, • alkyl of 1 to S carbon atoms, alkenyl of 2 carbon atoms, alkynyl of 2 to 6 carbon atoms, which may optionally be substituted with one or two substituents independently selected from hydroxyl, halogen, cyano, nitro, -R15R16, -C (= 0) NR15R16, -OC (= 0) NR15R16 (-OCH2C (= 0) NR15R1S, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R15, -C (= 0) R15, - NHC (= 0) R15, -CHF2, -FC3, -0CF3, -0CHF2, -OCH2CF3, -0CF2CHF2, -SCF3, -SR15, -S (= 0) R15, -S (= 0) 2R15, -S ( = 0) 2NH2, wherein R15 and R16 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, 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 additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl) from 1 to 6 carbon atoms), (C 3 -C 8 cycloalkyl) - (C 1-6 -alkyl), heteroaryl- (C 1-6 -alkyl), (C 3 -C 8 -heterocyclyl) - (alkyl of 1 to S carbon atoms), aryl- (alkoxy of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkoxy of 1 to 6 carbon atoms), heteroaryl- (alkoxy of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (C 3 -C 8 cycloalkyl), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -O- (3-cycloalkyl) to 8 carbon atoms), -0-heteroaryl, -0- (heterocyclyl of 3 to 8 carbon atoms), S-aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S - (heterocyclyl of 3 to 8 carbon atoms), wherein the ring portions may be optionally substituted with one to three substituents independently selected from hydroxyl, halogen, cyano, nitro, -NR17R18, -C (= 0) R1R18, - OC (= 0) NR17R18, -0CH2C (= 0) NR17R18, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , -C (= 0) 0R17, -C (= 0) R17, -NHC (= 0) R17, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S CF3, -SR17, -S (= 0) R17, -S (= 0) 2R17, -S (= 0) 2NH2, wherein R17 and R18 which may be the same or different are independently selected from hydrogen and alkyl from 1 to 6 carbon atoms, or R17 and R18, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, which contain optionally one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, (iii) or R1 and R2 which may be the same or different are independently selected from hydrogen, -C (= 0) 0R19, C (= 0) R19 and alkyl of 1 to 6 carbon atoms, wherein R19 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to S carbon atoms, which may be optionally substituted with one or two substituents independently selected from · hydroxyl, halogen, cyano , nitro, -NR20R21, -C (= O) NR20R21, -OC (= O) NR20R21, -OCH2C (= O) NR20R21, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR20, -C ( = 0) R20, -NHC (= 0) R20, -CHF2, - CF3, -0CF3 / -OCHF2, -OCH2CF3, -OCF2CHF2 / -SCF3 / -SR20, -S (= 0) R20, -S (= 0 ) 2R20, -S (= 0) 2NH2, wherein R20 and R21 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R20 and R21, together with the nitrogen atom at which are linked, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, and R3 is hydrogen, B is a valence bond, -C (= 0) -, -S (= 0) - or -S (= 0) 2- D is · hydroxyl, halogen, cyano, nitro, -NR22R23, -N (R22) OR23, - C (= 0) N 22R23, -OC (= 0) NR2R, -OCH2C (= 0) NR R, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR22, -C (= 0) R22, - HC (= 0) R22, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3 -OCF2CHF2, -SCF3, -SR22, -S (= 0) R22, -S (= 0) 2R22, -S ( = 0) 2NH2í • wherein R22 and R23 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, 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 additional heteroatoms selected from oxygen, sulfur and nitrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms , which may be optionally substituted with one or two substituents selected from hydroxyl, halogen, cyano, nitro, -NR2R25, -C (= 0) NR2R25, -OC (= 0) NR24R25, 0CH2C (= 0) NR4R25, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R24, -C (= 0) R24, -NHC (= 0) R24, -CHF2, -CF3, -0CF3, -0CHF2, -OC H2CF3, -OCF2CHF2, -SCF3, -SR24, -S (= 0) R24, S (= 0) 2R24, -S (= 0) 2N¾, wherein R24 and R2S which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R24 and R25, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered cyclic ring, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, • aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- ( alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- (alkoxy of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkoxy of 1 to 6 carbon atoms) ), heteroaryl- (alkoxy of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0 ) - (C3-C8-cycloalkyl), -C (= 0) -heteroaryl, -C (= 0) - (C3-C8-heterocyclyl), -0-aryl, -O- (cycloalkyl) 3 to 8 carbon atoms), -0-heteroaryl , -O- (heterocyclyl of 3 to 8 carbon atoms), S-aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- (heterocyclyl of 3 to 8 carbon atoms) , NH-aryl, NH-heteroaryl, wherein the ring portions may be optionally substituted with one to three substituents selected from hydroxyl, halogen, cyano, nitro, -NR26R27, -C (= 0) NR26R27, -0C (= 0) NR26R27, -OCH2C (= 0) NR25R27, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R2S, -C (= 0) R2e, -NHC (= 0) R26, -CHF2, -CF3, -0CF3, -0CHF2, -0CH2CF3, -0CF2CHF2, -SCF3, -SR26, -S (= 0) R25, -S (= 0) 2R26, -S (= 0) 2N¾, wherein R26 and R27 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R26 and R27, together with the nitrogen atom to which they are bound form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 atoms carbon, alkynyl of 2 to 6 carbon atoms, which may be optionally substituted with one or two substituents selected from hydroxyl, halogen, cyano, nitro, -NR8R29, -C (= 0) R28R29, -OC (= 0) NR28R29, 0CH2C (= 0) NR8R29, alkoxy of 1 to 6 carbon atoms, -C (= 0) OR28, -C (= 0 ) R28, -NHC (= 0) R28, -CHF2, -CF3, -0CF3, -0CHF2, -0C¾CF3, -OCF2CHF2, -SCF3, -SR28, -S (= 0) R28, S (= 0) 2R28, -S (= 0) 2NH2, wherein R28 and R29 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R28 and R29, together with the nitrogen atom to which they are attached , they form a 3- to 8-membered cyclic ring, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, aryl, cycloalkyl of 3 to 8 carbon atoms, heteroaryl, heterocyclyl of 3 to 8 carbon atoms, aryl- (alkyl of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), heteroaryl- (alkyl of 1 to 6 carbon atoms), (eterocyclyl of 3 to 8 carbon atoms) - (alkyl of 1 to 6 carbon atoms), aryl- ( alkoxy of 1 to 6 carbon atoms), (cycloalkyl of 3 to 8 carbon atoms) - (alkoxy of 1 to 6 carbon atoms), heteroaryl- (alkoxy of 1 to 6 carbon atoms), (heterocyclyl of 3 to 8 carbon atoms) -alkoxy of 1 to 6 carbon atoms), -C (= 0) -aryl, -C (= 0) - (cycloalkyl of 3 to 8 carbon atoms), -C (= 0) -heteroaryl, -C (= 0) - (heterocyclyl of 3 to 8 carbon atoms), -0-aryl, -0- (cycloalkyl of 3 to 8 carbon atoms), -0-heteroaryl, - 0- (heterocyclyl of 3 to 8 carbon atoms), S-aryl, S- (cycloalkyl of 3 to 8 carbon atoms), -S-heteroaryl, -S- (heterocyclyl of 3 to 8 carbon atoms), in wherein the ring portions may be optionally substituted with one to three substituents selected from hydroxyl, halogen, cyano, nitro, R30R31, -C (= O) NR30R31, -OC (= O) NR30R31, -OCH2C (= 0) NR30R31, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to S atoms carbon, alkoxy of 1 to 6 carbon atoms, -C (= 0) 0R30, -C (= 0) R30, -NHC (= 0) R30, -CHF2, -CF3, -0CF3, -0CHF2, -0C¾CF3 , OCF2CHF2í -SCF3, -SR30, -S (= 0) R3 °, -S (= 0) 2R30, -S (= 0) 2NH2, wherein R30 and R31 which may be the same or different are independently selected from hydrogen and alkyl of 1 to 6 carbon atoms, or R30 and R31, together with the nitrogen atom to which they are bonded, form a cyclic ring of 3 to 8 members, optionally containing one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, as well as any optical or geometric isomer or tautomeric form thereof, including mixtures thereof or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of diseases, disorders , syndromes and conditions, where an inhibition of GSK-3 is beneficial. 29. The use of a compound according to claim 28, for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions related to GSK-3. 30. The use of a compound according to claim 28, for the preparation of a composition Pharmaceutical for the treatment of diseases, disorders, syndromes and conditions, where the inhibition of GSK-3 induced by the growth factor is insufficient. 31. The use of a compound according to claim 28, for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, wherein the metabolism of glycogen shows abnormalities. 32. The use of a compound according to claim 28, for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, wherein the glycogen synthase is insufficiently activated. 33. The use of a compound according to claim 28, for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, which involves elevated blood glucose. 34. The use of a compound according to claim 28, for the preparation of a pharmaceutical composition for the treatment of hyperglycemia. 35. The use of a compound according to claim 28, for the preparation of a pharmaceutical composition for the treatment of IGT. 36. The use of a compound in accordance with claim 28, for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes. 37. The use of a compound according to claim 28, for the preparation of a pharmaceutical composition for the treatment of type 1 diabetes. The use of a compound according to claim 28, for the preparation of a pharmaceutical composition for the treatment of obesity. 39. The use of a compound according to any of the preceding claims 28 to 38, in combination with one or more additional active agents selected from antidiabetic agents, antihyperlipidemic compounds, antiobesity compounds and antihypertensive compounds. 40. The use of a compound according to claim 28, for the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease. 41. The use according to claim 40, in combination with one or more additional agents, for the treatment of Alzheimer's disease. 42. The use of a compound according to claim 28, for the preparation of a pharmaceutical composition for the treatment of bipolar disorder. 43. The use according to claim 42, in combination with one or more additional agents for the treatment of bipolar disorder. 44. The use of the compound according to claim 28, for the preparation of a medicament for the treatment of diseases, disorders, syndromes and conditions where the inhibition of GSK-3 is beneficial. 45. The use according to claim 44, wherein the effective amount of the compound as defined according to claim 28, is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 to about 1000 mg and especially and preferably from about 0.5 mg to about 500 mg per day.