MXPA01008713A - Compounds useful as reversible inhibitors of cathepsin s - Google Patents
Compounds useful as reversible inhibitors of cathepsin sInfo
- Publication number
- MXPA01008713A MXPA01008713A MXPA/A/2001/008713A MXPA01008713A MXPA01008713A MX PA01008713 A MXPA01008713 A MX PA01008713A MX PA01008713 A MXPA01008713 A MX PA01008713A MX PA01008713 A MXPA01008713 A MX PA01008713A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- group
- aryl
- alkoxy
- substituted
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract 19
- 230000002401 inhibitory effect Effects 0.000 title abstract 2
- 230000002441 reversible Effects 0.000 title abstract 2
- 102000005600 Cathepsins Human genes 0.000 title 1
- 108010084457 Cathepsins Proteins 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims 466
- 125000001072 heteroaryl group Chemical group 0.000 claims 250
- 125000000623 heterocyclic group Chemical group 0.000 claims 229
- 125000003118 aryl group Chemical group 0.000 claims 228
- 125000001544 thienyl group Chemical group 0.000 claims 214
- 125000002541 furyl group Chemical group 0.000 claims 210
- 125000004076 pyridyl group Chemical group 0.000 claims 209
- -1 aryisulfonylamino Chemical group 0.000 claims 206
- 125000002883 imidazolyl group Chemical group 0.000 claims 202
- 125000000335 thiazolyl group Chemical group 0.000 claims 198
- 125000000168 pyrrolyl group Chemical group 0.000 claims 197
- 125000001041 indolyl group Chemical group 0.000 claims 192
- 125000002971 oxazolyl group Chemical group 0.000 claims 192
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims 181
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 179
- 125000004193 piperazinyl group Chemical group 0.000 claims 178
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims 176
- 125000002757 morpholinyl group Chemical group 0.000 claims 176
- 125000003386 piperidinyl group Chemical group 0.000 claims 176
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims 175
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims 174
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 174
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims 172
- 125000003545 alkoxy group Chemical group 0.000 claims 166
- 229910052757 nitrogen Inorganic materials 0.000 claims 166
- 150000002829 nitrogen Chemical group 0.000 claims 160
- 229910052717 sulfur Inorganic materials 0.000 claims 153
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 152
- 150000003457 sulfones Chemical class 0.000 claims 143
- 125000003831 tetrazolyl group Chemical group 0.000 claims 142
- 229910052736 halogen Inorganic materials 0.000 claims 137
- 150000002367 halogens Chemical group 0.000 claims 135
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 130
- 125000003373 pyrazinyl group Chemical group 0.000 claims 120
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 120
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims 114
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims 114
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims 114
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims 113
- 125000001425 triazolyl group Chemical group 0.000 claims 110
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 101
- 125000004434 sulfur atoms Chemical group 0.000 claims 96
- 125000004043 oxo group Chemical group O=* 0.000 claims 86
- 150000003462 sulfoxides Chemical class 0.000 claims 86
- 125000002098 pyridazinyl group Chemical group 0.000 claims 80
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims 78
- 125000004104 aryloxy group Chemical group 0.000 claims 76
- 125000000842 isoxazolyl group Chemical group 0.000 claims 76
- 125000001786 isothiazolyl group Chemical group 0.000 claims 75
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims 74
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims 74
- 125000001589 carboacyl group Chemical group 0.000 claims 73
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 72
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims 70
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 claims 69
- 125000001113 thiadiazolyl group Chemical group 0.000 claims 69
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 67
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 66
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims 65
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims 62
- 125000001624 naphthyl group Chemical group 0.000 claims 62
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 61
- 125000005239 aroylamino group Chemical group 0.000 claims 59
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 claims 56
- 125000005110 aryl thio group Chemical group 0.000 claims 54
- 125000004093 cyano group Chemical group *C#N 0.000 claims 54
- 125000005141 aryl amino sulfonyl group Chemical group 0.000 claims 52
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 51
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims 50
- 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 claims 49
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 47
- 125000005333 aroyloxy group Chemical group 0.000 claims 47
- 150000003463 sulfur Chemical compound 0.000 claims 46
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 41
- 125000000753 cycloalkyl group Chemical group 0.000 claims 36
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 35
- 125000003710 aryl alkyl group Chemical group 0.000 claims 32
- 125000003435 aroyl group Chemical group 0.000 claims 28
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims 27
- 125000003277 amino group Chemical compound 0.000 claims 27
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims 26
- 229910052739 hydrogen Inorganic materials 0.000 claims 26
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims 24
- 125000004414 alkyl thio group Chemical group 0.000 claims 21
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 20
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims 19
- 125000005236 alkanoylamino group Chemical group 0.000 claims 19
- 125000005466 alkylenyl group Chemical compound 0.000 claims 19
- 125000004423 acyloxy group Chemical group 0.000 claims 17
- YZYQQJHFYIVWPS-UHFFFAOYSA-N 3,4,5,6-tetradehydrothiopyran Chemical group [CH]1SC#CC#C1 YZYQQJHFYIVWPS-UHFFFAOYSA-N 0.000 claims 12
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims 9
- 229910052760 oxygen Inorganic materials 0.000 claims 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 7
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims 6
- 125000003342 alkenyl group Chemical group 0.000 claims 6
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims 6
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims 6
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims 6
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims 6
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 6
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims 6
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 claims 6
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims 6
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims 6
- 125000004306 triazinyl group Chemical group 0.000 claims 6
- 125000004429 atoms Chemical group 0.000 claims 5
- 229910019567 Re Re Inorganic materials 0.000 claims 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 4
- 125000002837 carbocyclic group Chemical group 0.000 claims 4
- 125000006626 methoxycarbonylamino group Chemical group 0.000 claims 4
- 125000002950 monocyclic group Chemical group 0.000 claims 4
- 239000011593 sulfur Substances 0.000 claims 4
- KJFMBFZCATUALV-UHFFFAOYSA-N Phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 claims 3
- 125000003282 alkyl amino group Chemical group 0.000 claims 3
- 125000001769 aryl amino group Chemical group 0.000 claims 3
- 229910052799 carbon Inorganic materials 0.000 claims 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical compound 0.000 claims 2
- 229910003813 NRa Inorganic materials 0.000 claims 2
- 241000822135 Ula Species 0.000 claims 2
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims 2
- 125000005842 heteroatoms Chemical group 0.000 claims 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-O 1,3-benzoxazol-3-ium Chemical compound C1=CC=C2OC=[NH+]C2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-O 0.000 claims 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical group C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims 1
- HPZZTKGICNGATO-UHFFFAOYSA-N 6-chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-1H-quinazolin-2-one Chemical group FC(F)(F)CN1C(=O)NC2=CC=C(Cl)C=C2C1(CC)C1=CC=C(F)C=C1 HPZZTKGICNGATO-UHFFFAOYSA-N 0.000 claims 1
- JYZIHLWOWKMNNX-UHFFFAOYSA-N Benzimidazole Chemical group C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 claims 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N Benzoxazole Chemical group C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical group C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 1
- NRCPVGIMMWPWGT-UHFFFAOYSA-N N,N''-sulfonyldiurea Chemical compound NC(=O)NS(=O)(=O)NC(N)=O NRCPVGIMMWPWGT-UHFFFAOYSA-N 0.000 claims 1
- DHHVAGZRUROJKS-UHFFFAOYSA-N Phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 claims 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 125000001188 haloalkyl group Chemical compound 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims 1
- 150000002460 imidazoles Chemical group 0.000 claims 1
- 125000006525 methoxy ethyl amino group Chemical group [H]N(*)C([H])([H])C([H])([H])OC([H])([H])[H] 0.000 claims 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 125000001174 sulfone group Chemical group 0.000 claims 1
- 125000000472 sulfonyl group Chemical compound *S(*)(=O)=O 0.000 claims 1
- 206010003816 Autoimmune disease Diseases 0.000 abstract 1
- 102100015379 CTSS Human genes 0.000 abstract 1
- 108090000613 Cathepsin S Proteins 0.000 abstract 1
Abstract
Disclosed are novel cathepsin S reversible inhibitory compounds of formulas (I),(Ia) and (II),(IIa) as defined herein. The compou nds are useful for treating autoimmune diseases. Also disclosed are processes for making such novel compounds.
Description
USEFUL COMPOUNDS AS REVERSIBLE INHIBITORS OF CATEPSIN S
TECHNICAL FIELD OF THE INVENTION This invention relates to inhibitors of peptidyl-cysteine proteases. The compounds are reversible inhibitors of the cysteine protease, cathepsin S, and are therefore useful in the treatment of autoimmune diseases. The invention also relates to processes for preparing said compounds and to pharmaceutical compositions comprising them.
BACKGROUND OF THE INVENTION Cathepsin S is a member of the papain family, within the papain superfamily between cysteine proteases. The papain family is the largest group of cysteine proteases and includes proteases such as cathepsins B, H, K, L, O, and S. (AJ Barret et al., 1996, Perspectives in Drug Discovery and Design, 6, 1) . Cysteine proteases have important roles in human biology and in diseases including atherosclerosis, emphysema, osteoporosis, chronic inflammation and immune disorders (H. A. Chapman et al., 1997, Ann. Rev. Physiol., 59,
REF: 131566 63). Cathepsin S plays a key role in the regulation of antigen presentation and in immunity (HA Chapman, 1998, Current Opinion in Immunology, 10, 93, RJ Riese et al, 1998, J. Clin. Invest., 101, 2351; RJ Riese et al., 1996, immunity, 4, 357). The specificity of the immune response is based on the treatment of an alien protein and the presentation of an antigenic peptide on the surface of the cells. The antigenic peptide is presented in a state attached to the MHC of Class II, which is a heterodimeric glycoprotein expressed in certain antigen-presenting cells of hematopoietic lineage, such as B cells, macrophages and dendritic cells. The presentation of an antigen to effector cells, such as T cells, is a fundamental operation in the recognition of a non-autonomous response and therefore the initiation of the immune response. Recently, it was shown that heterodimers with MHC of Class II are associated intracellularly with a third molecule, designated as invariant chain. The invariant chain facilitates the transport of Class II to the endosomal compartment and stabilizes the Class II protein before loading it with an antigen. The invariant chain interacts directly with Class II dimers in the antigen binding slot and therefore must be proteolyzed and eliminated, otherwise the antigen can not be loaded or presented. Current research suggests that the invariant chain is selectively proteolyzed by cathepsin S, which is compartmentalized with MHC Class II complexes within the cell. Cathepsin S degrades to the invariant chain to form a small peptide, called CLIP, which occupies the antigen binding slot. CLIP is released from Class II MHC by the MHC interaction of Class II with HLA-DM, which is a MHC-like molecule, thereby releasing Class II MHC to associate with antigenic peptides. . Then the complexes between the Class II MHC and the antigen are transported to the surface of a cell for presentation to T cells and the initiation of the immune response. Cathepsin S, by proteolytic degradation of the invariant chain to form CLIP, provides a fundamental operation in the generation of an immune response. It follows that the inhibition of the presentation of an antigen by preventing the degradation of the invariant chain by cathepsin S could provide a mechanism for immune regulation. It has long been desirable to control specific immune responses to antigens as a useful and safe therapy for autoimmune diseases. These diseases include Crohn's disease and arthritis, as well as other immune responses mediated by T cells (C. Janeway and P. Travers, 1996, Immunobiology, The Immune System in Health and Disease, chapter 12). In addition, cathepsin S, which has a broad specificity for pH values, has been implicated in a variety of other diseases involving extracellular proteolysis, such as Alzheimer's disease (U. Muller-Ladner et al., 1996, Perspectives in Drug Discovery and Design, 6, 87) and atherosclerosis (GK Sukhova et al., 1998, J. Clin. Invest., 102, 576). Cysteine proteases are characterized by having a cysteine residue in the active site, which serves as a nucleophile. The active site also contains a histidine residue. The imidazole ring in histidine serves as a base to generate a thiolate anion in the active site cysteine, increasing its nucleophilicity. When a substrate is recognized by the protease, the amide bond to be dissociated is directed to the active site, where the thiolate attacks the carbonyl carbon forming an intermediate acyl-enzyme compound and dissociates the amide, thereby an amine is released. Subsequently, the water dissociates the acyl-enzyme species by regenerating the enzyme and releasing the other dissociation product from the substrate, a carboxylic acid. A proposed mechanism of action of the cysteine protease inhibitors of this invention is that the inhibitors contain a functionality that can react (reversibly or irreversibly) with the active site of cysteine. The reactive functionality is fixed to a peptide or a peptide mimetic, which can be recognized and accommodated by the region of the protease surrounding the active site. The nature of both the reactive functionality and the remaining portion of the inhibitor determines the degree of selectivity and potency towards a particular protease. Examples of reactive functionalities that have been described (D. Rasnick, 1996, Perspectives in Drug Discovery and Design, 6, 47) in inhibitors of cysteine proteases, include peptidyl diazomethanes, epoxides, monofluoroalkanes and acyloxymethanes, which irreversibly alkylate thiol of cysteine. Other irreversible inhibitors include Michael acceptor compounds such as vinyl peptidyl esters and other carboxylic acid derivatives (S. Liu et al., J. Med. Chem., 1992, 35, 1067) and vinyl sulphones (JT Palmer et al. 1995, J. Med. Chem., 38, 3.193). Reactive functionalities that form reversible complexes with the active site of cysteine include peptidyl aldehydes (RP Hanzlik et al., 1991, Biochim, Biophys, Acta, 1073, 33), which are non-selective, inhibiting both the cysteine and the protease proteases. serine as well as other nucleophiles. Peptidyl nitriles (R.P. Hanzlik et al., 1990, Biochim Biophys. Acta., 1035, 62) are less reactive than aldehydes and therefore more selective for the more nucleophilic cysteine proteases. It has also been reported that various reactive ketones are reversible inhibitors of cysteine proteases (D. Rasnick, 1996, ibid). In addition to reacting with the active site nucleophilic cysteine, the reactive ketones can react with water, forming a semicetal that can act as a transition state inhibitor Examples of cathepsin S inhibitors have been reported previously. J.T. Palmer (US Patent 5,776,718, 1998) described reversible peptidyl sulphones as inhibitors of cysteine proteases, including cathepsin SJL Klaus et al. (International patent application WO 9640737, 1996) described reversible inhibitors of cysteine proteases including cathepsin S, which contain an ethylenediamine. Additional peptidyl nitriles or peptidyl- (keto-heterocycles) have been reported either as protease inhibitors or as possessors of other utilities. For example, both nitriles and keto-heterocycles have been described by B.A. Rowe et al. (US 5,714,471, 1998) as protease inhibitors that are useful in the treatment of neurodegenerative diseases. Peptidyl nitriles have been reported by B. Malcolm et al. (WO 9222570, 1992) as inhibitors of a picornavirus protease. H. Saika et al. (WO 9512611, 1995) report peptidyl nitriles between compounds that have an endothelin receptor antagonist activity. B. J. Gour-Salin (Can. J. Chem., 1991, 69, 1288) and T.C. Liang (Arch. Biochim, Biophys., 1987, 252, 626) described peptidylnitriles as inhibitors of papain. D.W. Woolley et al (J. Org. Chem., 1963, 28, 2012) described a peptidyl-nitrile as an intermediate chemical compound. Peptidyl- (keto-heterocycles) having protease inhibitory or other activities that have been reported include the serine protease inhibitors described by R.D. Tung et al. (WO 9817679, 1998). Certain factor Xa inhibitors have been described by C.K. Marlowe et al. (WO 9640744, 1996). Certain peptidyl keto-heterocycles useful in the treatment of thrombin-related diseases have been described by M. Costanzo et al. (WO 9640742, 1996). A reversible inhibitor presents a more attractive therapy than irreversible inhibitors. Even compounds with high specificity for a particular protease can bind to enzymes that are not targets. An irreversible compound could therefore permanently deactivate a non-target enzyme, increasing the likelihood of occurrence of toxicity. In addition, any toxic effects that result from deactivation of the target enzyme would be mitigated by reversible inhibitors, and could be easily remedied by improved or reduced dosing. Finally, a covalent modification of an enzyme by an irreversible inhibitor could potentially generate an antibody response acting as a hapten. In view of the foregoing, there is a manifest need for compounds that reversibly and selectively inhibit cathepsin S, said inhibitors would be useful in therapy for specific immune responses for certain antigens as well as for indications in which cathepsin S exacerbates a disease through extracellular activity.
BRIEF DESCRIPTION OF THE INVENTION The aforementioned works support the principle that the inhibition of cathepsin S and the subsequent inhibition of the presentation of antigens would be beneficial in the treatment of various morbid states of disease. Therefore, an object of this invention is to provide novel compounds that inhibit the presentation of antigens by virtue of a reversible inhibition of the cysteine protease, cathepsin S. A further object of the invention is to provide methods for treating diseases and pathological conditions involving immune disorders such as rheumatoid arthritis. Still a further object of the invention is to provide processes for the preparation of the new compounds mentioned above.
DETAILED DESCRIPTION OF THE INVENTION The invention provides new compounds of the formula (I):
(I) wherein A is -C (Y) - or -SO- Y is O, S or NRa wherein Ra is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylamino and arylamino; Ri is alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or amino wherein R ± is optionally substituted with one or more Rb; Rb is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono- or di -substituted alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone , ureido wherein either nitrogen atom may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino, wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R2 is H or alkyl; Rs is H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R3 is optionally substituted with one or more groups of the formula Rd; Rd is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino, alk laminosulfonilo, arylaminosulfonyl, amino wherein the atom nitrogen can be independently mono- or di-substituted with alkyl, aryl, h Eterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Ra may also be optionally substituted with one or more Re; Re is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R 4 is H or alkyl; R5 is H, alkyl or cycloalkyl; R6 is H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R6 is optionally substituted with one or more groups of the formula Rf; Rf is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkanoyl, aroyl, arylalkoxy, heteroarylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylalkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, ami non wherein the nitrogen atom may be independently mono or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may be further optionally substituted by one or more Rg; Rg is selected from the group consisting of alkyl, cycloalkyl, aryl optionally substituted with halogen, Cl-5 or alkoxy Cl-5, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in that the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl; alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in the
That the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl;
Alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyl loxy, alkylsulfonylamino, aryisulfonylamino, alkylsulphonyl, arylaminosulfonyl, amino in which the nitrogen atom can be
To be independently mono- or disubstituted with alkyl, aryl, heterocyclyl or heteroaryl; halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
or R5 together with Rβ forms a carbocyclic ring of 3 to 6 members, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of alkyl, aryl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, carbamoyl in which the nitrogen atom may be optionally mono- or disubstituted with a group selected from alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl or heteroaryl; halogen, hydroxy, carboxy and cyano; R7 is R8-C (Z) -; wherein Z is O, S, or NRX in which Rx is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, and hydroxy; R8 is an annular system of 5-8 membered monocyclic or 8-11 membered bicyclic heteroaryl, each of the monocyclic or bicyclic ring systems having 1-4 of the same or different heteroatoms selected from the group consisting of N, O and S wherein any of the above Re may optionally be substituted with one or more RD; R3 is selected from the group consisting of alkyl, cycloalkyl. aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, alkanoyl, aroyl, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylalkylthio in which the sulfur atom it may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl; alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulphonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl; halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, R may also be optionally substituted with one or more Rk;
Rk is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl,
Aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or disubstituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino,
Alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the
The nitrogen may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, arylalkylcarbonylaminoalkyl, alkylcarbamoyloxy, arylcarbamoyl loxy, alkylsulfonylamino, aryisulphonylamino, to which laminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can
To be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; X is 0, S or N-OH; and its pharmaceutically acceptable derivatives; with the proviso that when R6 is alkyl, the alkyl must be substituted with Rf in which Rf is not to be hydroxy, sulfhydryl or halogen. Preferred compounds of the formula (I) are those in which: Ra is selected from the group consisting of H, alkyl and aryl; Ri is Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomofolinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, C?-8-carbonyl alkoxy, aryloxycarbonyl, C 8 -oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetra zolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroyl amino , alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the atoms of nitrogen may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrim dinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyloxy, arylcarbamoyl loxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl. , quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-8 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R3 is H, C? -8 alkyl, C3-7 cycloalkyl or aryl in which R is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, alkanoyl, aroyl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with C? _8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazole yl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8 -amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl , thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-arylcarbamoyloxy, alkylsulfonylamino , aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl. pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl. benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rd may also be optionally substituted with one or more Re: Re is selected from the group consisting of Cl-8 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, Cl-8 alkoxy, aryloxy, arylalkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R5 is H or alkyl; R6 is H, C? _8 alkyl, C3-7 cycloalkyl or aryl in which R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl purinyl, quinolinyl, isoquinolinyl quinazolinyl, quinoxalinyl, carbazolyl phenothiazinyl and phenoxazinyl, alkoxy Cl-8 aryloxy, aryl-alkoxy Cl-8, heteroaryl-alkoxy Cl-8 alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8- oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazole lilo, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl -8-amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl- alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl , Thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl , phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, a: "il xy-arbonylamino, alkyl Cl-8-carbamoyloxy, arylcarbamoyl loxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di- -substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl , oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pi Ridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl optionally substituted by halogen, Cl-3 alkyl or Cl-3 alkoxy; heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl;
heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl , benzothiazolyl,
Benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, arylalkoxy Cl-8, alkoxy, alkoxy Cl-8-carbonyl,
Aryloxycarbonyl, Cl-8-oxy, aroyloxy, carbamoyl alkanoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of
A group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, Cl-8-amino alkanoyl,
Arylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which
Any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,
piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
Tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl -8- carbamoi loxi, arylcarbamoyloxy,
Alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl and arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with alkyl, aryl, heterocyclyl
selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl,
Oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,
Benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rh is selected from the group consisting of alkyl Cl-8, aryl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, aryl-alkoxy Cl-8-carbonyl, carbamoyl in which the nitrogen atom may be optionally mono- or di- substituted with a group selected from alkyl Cl-8, cycloalkyl C3-7, aryl, aryl-alkyl Cl-8, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of a group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, carboxy and cyano; Rs is a heteroaryl ring selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl. , indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, triazolyl, tetrazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl and phenazinyl, wherein any of the above R8 may optionally be substituted with one or more Rj; R is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinium, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl , isothiazolyl, oxadiazolyl, triazolyl, t etrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylalkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyl loxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfoyl, arylaminosulfonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, ind olyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, R, may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl , benzothiazolyl,
Benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl,
Alkanoyloxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
Isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoylamino, aroylamino, alkylthio in which the sulfur atom can
to be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be substituted
Independently with alkyl, heterocyclyl aryl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from
The group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl,
Pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl,
-quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, arylalkoxycarbonylaminoalkyl, alkyl Cl-8-10 carbamoyl loxi, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- is substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of
consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,
Pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; X is 0 or S. More preferred compounds of the formula (I) are those in which: Y is 0 or S; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl or amino in which Ri is optionally substituted with one or more Rb;
Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5, aryloxy, alkoxy Cl -5-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl , benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl The sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be oxidized. be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyl loxi, arylcarbamoyloxy, alkyl Cl- 5-sulfonylamino, arylsulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom ede independently being mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl and pyridinyl, alkoxy Cl-5, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; or Cl-3 alkyl;
Rs is H, Cl-5 alkyl, C3-7 cycloalkyl or aryl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, alkanoyl
Cl-5, aroyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy-alkanoyl, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl , benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone , arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted and with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl , tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyl loxi, arylcarbamoyloxy, alkyl Cl -5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of a of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro , amidino and guanidino; R 4 is H or Cl 3 alkyl; R is H or Cl-8 alkyl;
R6 is H, Cl-5 alkyl, C3-7 cycloalkyl or aryl wherein Rs is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, arylalkoxyCl-5, heteroaryl-Cl-5-alkoxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy-alkanoyl, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-alkyl 5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl
Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, heterocyclyl aryl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl , benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclic clile selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl optionally substituted with halogen, methyl or methoxy; heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and
-quinoxalinyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently
mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl
Selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,
Benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the 5 sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be
being independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or
Heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,
Benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl
Cl-5-carbamoyloxy, Loxi arilcarbamoí, alkyl Cl-5- sulfonylamino, ariisulfonilamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by Cl-5 , aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinils or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl , pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rh is selected from the group consisting of Cl-5 alkyl, aryl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-5-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with a group selected from Cl-5, C3-7 cycloalkyl, aryl, aryl- Cl-5, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, carboxy and cyano; Ri is alkoxy, aryloxy or hydroxy; R8 is a ring heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl , indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, and phenazinyl, wherein any of the foregoing R8 can be optionally substituted with one or more Rj; Rj is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl; aryl-Cl-8 alkyl, Cl-8 alkoxy, aryloxy, aryl-Cl-8 alkoxy, Cl-8-alkoxycarbonyl, aryloxycarbonyl, Cl-8-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl. , quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the atom of sulfur can be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxyazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyl loxi, arylcarbamoyl loxy, alkylsulfonylamino, aryisulphonylamino, to which laminosulfonyl, arylaminosulfonyl, amino in which the The nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imid azolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl. , quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, arylalkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidini it, piperidinyl, morpholinyl, thiomorpholinyl,
Piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
Tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl,
quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoylamino, aroylamino, Cl-8 alkyl-alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or
Sulfone, arylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with 5-Cl-8 alkyl, aryl, heterocyclyl selected from the group consists of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of
furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
Indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and
phenoxazinyl, Cl-8 alkoxy-carbonylamino, aryloxycarbonylamino, aryl Cl-8 alkoxy carbo i lamino, ari lalcoxi carbonylaminoalkyl Cl-8 alkyl Cl-8-carbamoí Loxi, Loxi arilcarbamoí, alkyl Cl-8 alkylsulfonylamino,
ariisulfonilamino, Cl-8- alkyl aminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl , thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino. Even more preferred compounds of the formula (I) are those in which: Y is 0;
Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl-, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl , oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl or amino wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; Cl-5 alkoxy, aryloxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy, alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the Sulfur atom can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl or aryl; alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl , indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy and cyano; R2 is H or methyl; Rs is H, Cl-5 alkyl, C3-7 cycloalkyl or phenyl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aroyl, alkoxy Cl- 5-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-aminos aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the Sulfur may be oxidized to a sulfoxide or a sulfide ureido in which any of the nitrogen atoms may be independently substituted with alkyl Cl-5, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected among the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5 carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also optionally be substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, aryl-Cl-5 alkyl, Cl-5 alkoxy, aryloxy, aryl-Cl-3 alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; R 4 is H or methyl; R5 is H or Cl-5 alkyl; R6 is H, Cl-5 alkyl, C3-7 cycloalkyl, phenyl or naphthyl in which R5 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, arylalkoxy
Cl-5, pyridyl-alkoxy Cl-5, thienyl-alkoxy Cl-5, furanyl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the Nitrogen may independently be mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which either of the nitrogen atoms can est ar independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl , benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzyl imidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rq; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl optionally substituted with halogen, methyl or methoxy; naphthyl optionally substituted by halogen, methyl or methoxy; heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl , Cl-5 alkoxy,
Aryloxy, aryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with C 1 + 5 alkyl,
Aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienil, benzimidazolyl, benzothiazolium, benzoxazolyl, quinolinyl and isoquinolini J.o, alkanoyl Cl-5-amino, aroylamino, alkyl < The sulfur atom may be oxidized to a sulphoxide or sulfur, wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the Nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, orpholinyl JD and piperazinyl or heteroaryl selected
Among the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl,
benzoxazolyl, quinolinyl, isoquinolinyl, Cl-5-alkoxycarbonylamino, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, alkyl ClJ-5-sulfonylamino, aryisulfonylamino, alkyl Cl-
-aminosulfonyl, arylaminosulfonyl, apino in which the nitrogen atom can independently be mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of
Pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazole, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of alkyl Cl-5, phenyl, naphthyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, aryl-alkoxy Cl-3-carbonyl, carbamoyl in which the nitrogen atom may be optionally mono- or disubstituted with a group selected from Cl-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, arylalkyl Cl-3, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, time, pyrrolyl, oxazolium, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolium, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, carboxy and cyano;
Z is O or S; Re is a heteroaryl ring selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothieni , indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazoliniyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazoliol, acridinyl and phenazinyl, wherein any of the above R8 may be optionally substituted. with one or more groups of the formula R ^; R-, is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl 'and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolium, quinolinyl and isoquinolinyl, aryl-C1-5alkyl, alkoxy Cl- 5, aryloxy, aryl-alkoxy Cl-5, alkoxy-Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-fxi, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl -5, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperaziryl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl , benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in that any of the nitrogen atoms I can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazoli thiazolyl, imidazolyl, tetrazolyl, pyridimyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl-C-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl] -5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino! and guanidino, R-, may also be optionally substituted with one or more Rt; Rμ is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, tetrazolyl and pyridinyl, Cl-3 alkoxy, aryloxy, alkylalkoxy Cl-3, alkoxy aryloxycarbonyl, alkanoyl Cl-3-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently
mono- or di-substituted with Cj-3 alkyl, aryl, heterocyclyl selected from the group consisting of morpholinyl 'and piperazinyl or heteroaryl selected from the group consisting of furanyl,
Thienyl, pyrrolyl, oxazolyl, t-azole, imidazolyl, tetrazolyl and pyridinyl, alkanoyl Cl-3-amino, aroylamino, alkyl Cl-3-thio in which the sulfur atom is oxidized to sulfoxide or sulfoia,
arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfothia, ureido in which any of the atoms! of nitrogen may be independently substituted with Cl-3 alkyl, phenyl,
Naphthyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl and pyridinyl, alkoxy Cl-3-carbonylamino,
-aryloxycarbonylamino, aryl-alkoxy Cl-3-carbonylamino, benzyloxycarbonylami-non-alkyl Cl-5, alkyl Cl-3-carbamoyl-l-xxi, arylcarbamoyloxy, alkyl Cl-3-sulfonylamino, aryisulfonylamino, alkyl Cl-3- aminosulfonyl, arylaminosulfonyl, Amino acid in which the nitrogen atom can independently be mono- or di-substituted alkyl Cl-3, aryl, heterocyclyl selected from the group consisting of
Piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolylpyridinyl, indoliflo,
Benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinoliniio, halogen, hydroxy, oxo, carboxy, cyano and nitro; And X is O. Even more preferred compounds of formula (I) are those in which: Ri is Cl-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl , piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazole, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, or amino, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of | alkyl Cl-3, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolium, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothieniio, benzimidazolyl, benzothiazolyl, benzoxazolium, quinolinyl and isoquinolinyl, alkoxy Cl-3, phenoxy, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in the that the nitrogen atom may independently be unsubstituted or substituted with Cl-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl , benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl | and isoquinolinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in | that any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, phenyl or naphthyl; Cl-5-carbonylamino alkoxy, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, alko
Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in! wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, aryl, Cl-3 alkoxy, phenoxy, halogen, hydroxy, dxo, carboxy and cyano: R2 is H; R3 is Cl-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of i Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, quinolinylq and isoquinolinyl, alkoxy Cl-5, phenoxy, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom may independently be mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl.
heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl. thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, phenylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-3 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, alkoxy Cl-5-carbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyl loxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl -3, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrid Inyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Ra may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, aryl-Cl-3 alkyl, Cl-5 alkoxy, phenoxy, aryl-Cl-3 alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; wherein the configuration in the stereo center defined by R and R3 and the carbon to which they are attached is L; R4 is H; R5 is H or Cl-3 alkyl; Rd is H, Cl-5 alkyl, C3-6 cycloalkyl or phenyl wherein R5 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl- 3, pyridyl-alkoxy Cl-5, thienyl-alkoxy Cl-5, furanyl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be be independently mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl alkanoyl Cl-5-amino, aroylamino, alkyl Cl Wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, aryl-alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or phenyl; Cl-5-carbonylamino alkoxy, Cl-5-sulfonylamino, aryisulphonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl optionally substituted with halogen, methyl or methoxy; heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl , alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or aryl; Cl-5-amino alkanoyl, aroylamino, Cl-5-thio alkyl wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or aryl; Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or aryl, halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-5 alkyl, phenyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, aryl-Cl-3 halogen alkyl, hydroxy, carboxy and cyano; where Z is 0; Re is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, wherein any of the above R8 may be optionally substituted with one or more Rj; Rj is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, aryl - Cl-3 alkyl, Cl-3 alkoxy, aryloxy, aryl-Cl-3 alkoxy, Cl-3-alkoxycarbonyl, aryloxycarbonyl, Cl-3-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono - or di-substituted with Cl-3 alkyl, phenyl, naphthyl, piperidinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl or isoquinolinyl; Cl-3-amino alkanoyl, aroylamino, Cl-3 alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-3 alkyl, phenyl, naphthyl, piperidinyl , morpholinyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl or isoquinolinyl; alkoxy Cl-3-carbonylamino, aryloxycarbonylamino, alkyl Cl-3-carbamoyl loxi, arylcarbamoyloxy, alkyl Cl-3-sulfonylamino, aryisulfonylamino, alkyl Cl-3-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, naphthyl, piperidinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl or isoquinolinyl; halogen, hydroxy, oxo, carboxy, cyano and nitro, R may also be optionally substituted with one or more Rk:
Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, morpholinyl, furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen may independently be mono- or disubstituted with Cl-3 alkyl, phenyl, furanyl, thienyl, pyrrolyl,
Oxazolyl, thiazolyl, imidazolyl or pyridinyl; acetylamino, benzoylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the atoms of
The nitrogen may be independently substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl or pyridinyl; Arylalkoxy Cl-3-carbonylamino,
-benzyloxycarbonylamino-Cl-5 amino, wherein the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkenyl, phenyl, naphthyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,
Imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl or isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro. Still more preferred compounds of formula (I) are those in which: Ri is Cl-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, or amino, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl and benzothiazolyl; alkanoyl Cl-5-amino, aroylamino, alkyl Cl-3-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-3 alkyl or phenyl; alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected among the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more R, 'Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, Cl-3 alkoxy, halogen and hydroxy; R3 is Cl-5 alkyl, C5-6 cycloalkyl or phenyl in which Rj is optionally substituted with one or more Rd, "Rd is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, 4-morpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, alkoxy Cl-5, phenoxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroylloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl; Cl-5-amino alkanoyl, Cl-3 alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido wherein any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl; Cl-5-carbonylamino alkoxy, Cl-5-sulfonylamino, aryisulphonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, benzyl, Cl-5 alkoxy, phenoxy, benzyloxy, aroyl, halogen, hydroxy, oxo, carboxy and cyano; R6 is H, C1-5 alkyl or phenyl in which RP is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl, Cl-3 alkoxy, thienyl- Cl-3 alkoxy, furanyl-Cl-3 alkoxy, Cl-3-alkoxycarbonyl, phenoxyxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl -3 or phenyl; alkanoyl Cl-5-amino, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or phenyl; Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rq; Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with halogen, methyl or methoxy; heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridinyl, Cl-3 alkoxy, aryloxy, benzyloxy, Cl-5-carbonyl alkoxy, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl wherein the nitrogen atom may be be independently mono- or di-substituted with Cl-5 alkyl or phenyl; Cl-5-amino alkanoyl, aroylamino, Cl-5-thio alkyl wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with C1-6alkyl 5 or phenyl; alkoxy Cl-5-carbonylamino, alkyl Cl-5-carbamoyl loxi, arylcarbamoyloxy, alkyl Cl-3-sulfonylamino, aryisulfonylamino, alkyl Cl-3-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di- -substituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-alkoxycarbonyl, phenoxyxycarbonyl, benzyloxy, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with Cl-5 alkyl, phenyl, benzyl, halogen, hydroxy, carboxy and cyano; Rs is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyridyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, wherein any of the above R8 may be optionally substituted with one or more Rj; Rj is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, benzyl, Cl-3 alkoxy, phenoxy, benzyloxy, Cl-alkoxy. -3-carbonyl, acetyloxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl or pyridinyl; acetylamino, benzoylamino, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with methyl, phenyl, thiazolyl, imidazolyl or pyridinyl; Cl-3-carbonylamino alkoxy, Cl-3-carbamsyl loxy alkyl, arylcarbamoyloxy, Cl-3-sulfonylamino alkyl, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl or pyridinyl halogen, hydroxy, carboxy, cyano and nitro, Rj may also be optionally substituted with one or more Rk;
Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, pyridinyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom can be independently mono - or di-substituted with methyl, phenyl, furanyl or thienyl; acetylamino, benzoylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or sulfone, ureido in which any of the nitrogen atoms can be independently substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl and thiazolyl , benzyloxycarbonylamino, benzyloxycarbonylamino-Cl-5 alkyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and pyridinyl, halogen , hydroxy, carboxy, cyano and nitro. Even much more preferred compounds of the formula (I) are those in which:
Ri is C5-6 cycloalkyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, pyranyl, thiopyranyl or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, Cl-3 alkoxy, Cl-3 alkoxy -carbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; alkanoyl
Cl-5-amino, aroylamino, ureido in which any of the nitrogen atoms can be independently substituted with Cl-3 alkyl or phenyl; alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, Cl-3 alkoxy, halogen and hydroxy;
Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, Cl-5-alkoxycarbonyloxy , benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino alkanoyl, Cl-3 alkylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, Cl-3-carbonylamino alkoxy, Cl-3-sulfonylamino alkyl, amino in which the atom of nitrogen may independently be mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-3 alkyl, phenyl, benzyl, Cl-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen, hydroxy, oxo, carboxy and cyano; R5 is H or methyl; Re is Cl-5 alkyl or phenyl, wherein Rs is optionally substituted by one or more groups of the formula Rf, Rf is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, Cl-5-amino alkanoyl, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom it may be oxidized to a sulphoxide or a sulfone, Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with halogen or methyl; Cl-3 alkoxy, aryloxy, benzyloxy, Cl-3-carbonyl alkoxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino, aroylamino, amino alkanoyl wherein the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-alkoxycarbonyl, benzyloxy and carboxy; Rs is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyridyl, benzimidazolyl, benzothiazolyl and benzoxazolyl, wherein any of the above Rs may be optionally substituted with one or more Rj; R is selected from the group consisting of methyl, cyclohexyl, phenyl, furanyl, thienyl, benzyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with methyl, phenyl, furanyl or thienyl; acetylamino, benzoylamino, ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; methoxycarbonylamino, alkyl Cl-3-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl, phenyl, furanyl or thienyl; halogen, hydroxy, carboxy and cyano, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of methyl, phenyl, furanyl, thienyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; acetylamino, benzoylamino, ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; benzyloxycarbonylamino, benzyloxycarbonylamino-Cl-3 alkyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl, phenyl, furanyl or thienyl; halogen, hydroxy, carboxy, cyano and nitro. Even more preferred compounds of the formula (I) are those in which: A is -. { O) - or -S02 ~; Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl or amino, wherein Ri is optionally substituted with one or more Rt;
Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, Cl-3 alkoxy, alkoxy
Cl-3-carbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino alkanoyl, aroylamino, Cl-5-sulfonylamino alkyl, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more R :; Rc is selected from the group consisting of Cl-3 alkoxy, halogen and hydroxy; R3 is C1-5 alkyl or C5-6 cycloalkyl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, thienyl, imidazolyl, pyridinyl, indolyl, Cl-4 alkoxy, Cl-5-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl, halogen and hydroxy; Rf is selected from the group consisting of C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy, benzyloxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulphone, methoxycarbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with halogen or methyl; methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; halogen, hydroxy and carboxy; R9 is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more Rj; R is selected from the group consisting of methyl, phenyl, furanyl, thienyl, benzyl, methoxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; acetylamino, benzoylamino, ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; methoxycarbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; halogen, hydroxy, carboxy and cyano, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of methyl, phenyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; benzyloxycarbonylamino, benzyloxycarbonylamino-Cl-5 alkyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl, phenyl, furanyl or thienyl; halogen, hydroxy, carboxy, cyano and nitro.
Preferred penultimate grade compounds of formula (I) are those in which Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl or thiopyranyl, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy and carboxy, R ^ may also be optionally substituted with one or more R =; Rc is selected from the group consisting of methoxy, halogen and hydroxy;
Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, Cl-4 alkoxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano,
Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, methoxy, halogen and hydroxy; R5 is H; Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, thienyl, indolyl, methoxy, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with halogen; methoxy, phenoxy, benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy; Re is a heteroaryl ring selected from the group consisting of oxazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the foregoing
Re may optionally be substituted with one or more R3;
R is selected from the group consisting of methyl, phenyl, benzyl, methoxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; methoxycarbonylamino, halogen, hydroxy and carboxy,
R-, can also be optionally substituted with one or more Rk; Rk is selected from the group consisting of methyl, phenyl, methoxy, methoxycarbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl, benzyloxycarbonylamino, amino in which the nitrogen atom can be be independently mono- or di-substituted with methyl or phenyl; halogen, hydroxy and carboxy. Preferred compounds of the last formula of formula (I) are those in which: Ri is phenyl or 4-morpholinyl, wherein R] is optionally substituted with one or more Rb;
Rb is selected from the group consisting of benzimidazolyl, methoxy and dimethylamino, Rb may also be optionally substituted with a halogen atom; R3 is Cl-5 alkyl wherein R3 is optionally substituted with one or more Rd; Rd is - selected from the group consisting of C3-6 cycloalkyl and phenyl, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl and halogen, Re is Cl-5 alkyl optionally substituted with one or more Rf; Rt- is selected from the group consisting of C5-6 cycloalkyl, phenyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, and halogen, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, methoxy, methoxycarbonyl, halogen and hydroxy; Rs is a heteroaryl ring selected from the group consisting of oxazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more Rj;
Rj is selected from the group consisting of phenyl, methoxycarbonyl, carbamoyl in which the nitrogen atom can be independently mono- or disubstituted with methyl or phenyl; methoxycarbonylamino and halogen, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of phenyl, methoxycarbonyl, carbamoyl, benzyloxycarbonylamino and halogen. In another embodiment of the invention new compounds of the formula (la) are provided:
(a) wherein A is -C (Y) - or -S02- Y is 0, S or NRa wherein Ra is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylamino and arylamino; Ri is alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or amino wherein Ri is optionally substituted with one or more Rb;
Rb is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyl loxy, alkylsulfonylamino, aryisulphonylamino, to which laminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rb it may also be optionally substituted with one or more Rc;
Rc is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with alkyl , aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rs is H or alkyl; Rs is H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R3 is optionally substituted with one or more groups of the formula Rd; Rd is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyl loxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen may independently be mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R 4 is H or alkyl; R5 is H, alkyl or cycloalkyl; Re is H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R6 is optionally substituted with one or more groups of the formula Rf, - Rf is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl , alkoxy, aryloxy, alkanoyl, aroyl, arylalkoxy, heteroarylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or disubstituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, arylalkylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonyl mino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkyl aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of alkyl, cycloalkyl, aryl optionally substituted with halogen, Cl-5 alkyl or Cl-5 alkoxy, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in the that the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl; alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl; alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulphonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with alkyl, aryl, heterocyclyl or heteroaryl; halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; or R5 together with R6 forms a carbocyclic ring of 3 to 6 members, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of alkyl, aryl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with a group selected from alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl or heteroaryl; halogen, hydroxy, carboxy and cyano; R7 is Re-C (Z) -; wherein Z is 0, S, or NRi in which Ri is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy and hydroxy; R8 is an annular system of 5-8 membered monocyclic or 8-11 membered monocyclic heteroaryl, each monocyclic or bicyclic ring system having 1-4 of the same or different heteroatoms selected from the group consisting of N, O and S wherein any of the above Re may optionally be substituted with one or more R; Rj is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, alkanoyl, aroyl, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylalkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkenyl, aryl, heterocyclyl or heteroaryl; alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl; halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or disubstituted with alkyl , aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in the that any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, arylalkoxycarbonylaminoalkyl, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulphonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom may be be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, wherein Rk may also be optionally substituted with Rx; Ri is selected from the group consisting of alkyl, cycloalkyl, aryl and benzyl; X is 0, S or N-OH; and its pharmaceutically acceptable derivatives; with the following conditions: when R6 is alkyl, the alkyl must be substituted with Rf in which Rf does not have to be hydroxy, sulfhydryl or halogen; And when Ri is alkyl Cl then Rb can not be carbamoyl, alkanoylamino, aroylamino, ureido, alkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aryisulfonylamino, amino, amidino or guanidino in which each of said Rb is linked to Ri through its nitrogen.
Preferred compounds of the formula (la) are those in which Ra is selected from the group consisting of
H, alkyl and aryl; Ri is Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl in which the The nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetr azolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroyl amino , alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the atoms of nitrogen may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrim idinilo, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino , alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected among the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazsyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benz oxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, apridin and guanidino, Rb may also be optionally substituted with one or more Rc;
Rc is selected from the group consisting of Cl-8 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rs is H, Cl-8 alkyl, C3-7 cycloalkyl or aryl wherein R3 is optionally substituted with one or more Rg; Rd is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, alkanoyl, aroyl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazole yl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8 -amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl , thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-arylcarbamoyloxy, alkylsulfonylamino , aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, Enzyothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, R may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-8 alkyl, C 3-6 cycloalkyl, aryl, arylalkyl, Cl-8 alkoxy, aryloxy, arylalkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R5 is H or alkyl; R6 is H, Cl-8 alkyl, C3-7 cycloalkyl or aryl wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, aryl-alkoxy Cl-8, heteroaryl-alkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, is otiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl -8-amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl- alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxa zolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl , pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl optionally substituted by halogen, Cl-3 alkyl or Cl-3 alkoxy; heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,
Benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, aryl-alkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl- 8-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl,
Aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of
furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and
Phenoxazinyl, Cl-8-amino alkanoyl, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a
Sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
Isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl,
-benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-10 carbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl and arylaminosulfonyl, amino in which the The nitrogen may independently be mono- or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of
consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,
Pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
Rh is selected from the group consisting of alkyl Cl-8, aryl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, aryl-alkoxy Cl-8-carbonyl, carbamoyl in which the nitrogen atom may be optionally mono- or di- substituted with a group selected from alkyl Cl-8, cycloalkyl C3-7, aryl, aryl-alkyl Cl-8, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of a group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, carboxy and cyano: R8 is a heteroaryl ring cited between the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, tetrazolyl, purinyl, quinolizinyl , quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl and phenazinyl, wherein any of the above R8 may be optionally substituted with one or more Rj; Rj is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylalkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the The nitrogen atom can independently be mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, R-, can also be optionally substituted with one or more R i .;
Rk is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
Triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl,
Quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in which
The nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,
Piperazinyl and indolinyl, heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, 10 arilalcoxicarbonilamino, arilalcoxicarbonilaminoalquilo, C 1-8- alkyl arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino, alkylaminosulfonyl, arylaminosulfonyl,
Amino in which the nitrogen atom can be independently mono- or disubstituted with alkenyl, aryl, heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,
piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
Tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy , cyano, nitro, amidino and guanidino, wherein Rk may also be optionally substituted with Ri; Ri is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl and benzyl; and X is O or S. More preferred compounds of the formula (la) are those in which: Y is O or S; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5, aryloxy , Cl-5-carbonyl alkoxy, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group it consists of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl- 5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzo xazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl and pyridinyl, alkoxy Cl-5, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R2 is H or Cl-3 alkyl; R3 is H, Cl-5 alkyl, C3-7 cycloalkyl or aryl, wherein R is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5, aryloxy, alkanoyl Cl-5, aroyl, alkoxy Cl-5- carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently being mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5 thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, or wherein any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylane, aryloxycarbonylamino , alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl. amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group which consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo , carboxy, cyano, nitro, amidino and guanidino, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro , amidino and guanidino; R is H or Cl-3 alkyl; R5 is H or C1-8 alkyl; R6 is H, Cl-5 alkyl, C3-7 cycloalkyl or aryl wherein Re is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, heteroaryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrslidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl , quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl Cl-5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazslinyl and quinoxalinyl, alkoxy Cl-5-carbonyl lamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl optionally substituted with halogen, methyl or methoxy; heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5, aryloxy, arylalkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently being mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, 5-piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl , oxazolyl, thiazolyl, imidazolyl, triazolyl,
Tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and
Quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a
Sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with C5-alkenyl, aryl, heterocyclyl selected from the group consisting of
pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, 5 triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl , benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl,
Quinazolinyl and quinoxalinyl 10, alkoxy Cl -5- carbonylamino, aryloxycarbonylamino, Cl-5 alkyl-arylcarbamoyloxy, alkyl Cl-5- sulfonylamino, ariisulfonilamino, alkyl Cl-5-aminosulphonyl,
Arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkenyl Cl-5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,
tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
Rh is selected from the group consisting of Cl-5 alkyl, aryl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-5-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with a group selected from Cl-5, C3-7 cycloalkyl, aryl, aryl- Cl-5, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, mdolilo, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, carboxy and cyano;
Ri is alkoxy, aryloxy or hydroxy; Re is a ring heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl , indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, and phenazinyl, wherein any of the foregoing R8 can be optionally substituted with one or more Rj; Rj is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazole, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl; aryl-alkyl Cl-8, alkoxy Cl-8, aryloxy, aryl-alkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or disubstituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, aryl-alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which either of the nitrogen atoms may be independently substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morfo linyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyl loxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can independently be mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rj may also be optionally substituted with one or more Rk; Rt is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,
Benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, aryl-15 alkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl- 8-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl,
Aryl, heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl,
Oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and
Phenoxazinyl, alkanoylamino, aroylamino, alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or
A sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl oxazolyl. thiazolyl, imidazolyl, isoxazolyl,
Isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl benzofuranyl, benzothienyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl. purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8-carbonylamino, aryloxycarbonylamino, arylalkoxy Cl-8-10 carbonylamino, arylalkoxycarbonylaminoC 1-8 alkyl, alkyl Cl-8-carbamoyl loxi, arylcarbamoyloxy , alkyl Cl-8-sulfonylamino, aryisulfonylamino, alkyl Cl-8-aminosulfonyl, arylaminosulfonyl, amino in
Wherein the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl,
Thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
Triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo , carboxy, cyano, nitro, amidino and guanidino, wherein Rk may also be optionally substituted with even more preferred Recombines of the formula (la) are those in which: Y is 0; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, or amino in which Ri is optionally substituted with one or more Rb;
Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; Cl-5 alkoxy, aryloxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy, alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl. pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl or aryl; Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, Rb may also be optionally substituted with one or more Rc;
Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy and cyano; R2 is H or methyl; Rs is H, Cl-5 alkyl, C3-7 cycloalkyl or phenyl, wherein R3 is optionally substituted with one or more Ra; Ra is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aroyl, alkoxy Cl- 5-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino , aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the Sulfur may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5 -carbamoy loxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl , heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, aryl-Cl-5 alkyl, Cl-5 alkoxy, aryloxy, aryl-Cl-3 alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; R 4 is H or methyl; R5 is H or Cl-5 alkyl; R6 is H, Cl-5 alkyl, C3-7 cycloalkyl, phenyl or naphthyl in which R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, pyridyl-alkoxy Cl-5, thienyl-alkoxy Cl-5, furanyl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy , carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, Morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, aryl-Cl-5- alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl Cl-5, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzyl midazolilo, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoí Loxi arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, ariisulfonilamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in the nitrogen atom may be independently mono or di-substituted by Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, R may be further optionally substituted by one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl optionally substituted with halogen, methyl or methoxy; naphthyl optionally substituted with halogen, methyl or methoxy heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, aryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl , benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl , Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-10-sulphonylamino, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono - or di-substituted with Cl-5 alkyl, aryl, heterocyclyl
1 selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,
Imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano;
Rh is selected from the group consisting of Cl-5 alkyl, phenyl, naphthyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or disubstituted with a group selected from alkyl Cl-5, cycloalkyl C3-6, phenyl, naphthyl, arylalkyl Cl-3, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, carboxy and cyano; Z is 0 or S; R8 is a heteroaryl ring selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl , indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl and phenazinyl, wherein any of the above R8 may be optionally substituted with one or more groups of the formula R; R j is selected from the group consisting of Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, arylalkyl Cl-5 , Cl-5 alkoxy, aryloxy, aryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl , benzoxazolyl, quinolinyl and isoquinolinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sul oxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in that any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl . heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, wherein Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, Cl-3 alkoxy, aryloxy, aryl-alkoxy Cl-3, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl- 3-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, aryl, heterocyclyl selected from the group consisting of morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl and pyridinyl, Cl-3-amino alkanoyl, aroylamino, alkyl Cl-3-thio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-3 alkyl, phenyl, naphthyl, heteroaryl selected Among the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl and pyridinyl, alkoxy Cl-3-carbonylamino, aryloxycarbonylamino, aryl-alkoxy Cl-3-carbonylamino, benzyloxycarbonylamino-alkyl Cl-5, alkyl Cl- 3-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-3-sulfonylamino, aryisulfonylamino, alkyl Cl-3-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, wherein Rk may also be optionally substituted with Ri; Ri is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl and phenyl. Still more preferred compounds of the formula (la) are those in which Ri is Cl-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, or amino, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, phenoxy, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl-5 oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkenyl Cl-5, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the sulfur may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl Cl-5, phenyl or naphthyl; Cl-5-carbonylamino alkoxy, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di- substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl , benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, aryl, Cl-3 alkoxy, phenoxy, halogen, hydroxy, oxo, carboxy and cyano; R2 is H; R3 is Cl-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl. phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, quinolinyl and isoquinolinyl, Cl-5 alkoxy, phenoxy, aroyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, alkanoyl
Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently ono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazsyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-3-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, phenylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-3 alkyl, phenyl or heteroaryl selected from the group which consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, alkoxy Cl-5-carbonylamino, alkyl Cl-5-carbamoyl loxi, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, arisulfonyl ino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, aryl-Cl-3 alkyl, Cl-5 alkoxy, phenoxy, aryl-Cl-3 alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; in that the configuration in the stereo center defined by R2 and R3 and the carbon to which these are attached is L; R4 is H; R5 is H or Cl-3 alkyl; Re is H, Cl-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl- 3, pyridyl 1-alkoxy Cl-5, thienyl-alkoxy Cl-5, furanyl-alkoxy Cl-5, alkoxy Cl-5-carbonyls aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can independently being mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroyl amino, alkyl Cl-3-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, aryl-alkyl Cl-3-thio in the that the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or phenyl; Cl-5-carbonylamino alkoxy, Cl-5-sulfonylamino, aryisulphonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl optionally substituted with halogen, methyl or methoxy; heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl , alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or aryl; Cl-5-amino alkanoyl, aroylamino, Cl-5-thio alkyl in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl or aryl; Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or aryl; halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-5 alkyl. phenyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, aryl-alkyl Cl-3 halogen hydroxy, carboxy and cyano; where Z is O; Rs is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl. pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, wherein any of the above R8 may be optionally substituted with one or more Rj; Rj is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl. benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, arylalkyl Cl-3, alkoxy Cl-3, aryloxy, aryl-alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl-3-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently being mono- or di-substituted with Cl-3 alkyl, phenyl, naphthyl, piperidinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; Cl-3-amino alkanoyl; aroylamino, alkyl Cl-3-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-3 a thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-3 alkyl, phenyl, naphthyl, piperidinyl, morpholinyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; alkoxy Cl-3-carbonylamino, aryloxycarbonylamino, alkyl Cl-3-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-3-sulfonylamino, aryisulfonylamino, alkyl Cl-3-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, naphthyl, piperidinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; halogen, hydroxy, oxo, carboxy, cyano and nitro, R3 may also be optionally substituted with one or more Rt; Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, Cl-3 alkoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy , benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl or pyridinyl; acetylamino, benzoylamino, methylthio in which the sulfur atom can be oxidized to a sulfoxide or sulfone, ureido in which any of the nitrogen atoms can be independently substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl , imidazolyl or pyridinyl; aryl-alkoxy Cl-3- carbonyl lamino, benzyloxycarbonylaminoalkyl Cl-5, methylcarbamoyl loxy, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl , furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl or isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, wherein Rk can also be optionally substituted with Ri; Ri is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl and phenyl. Still even more preferred compounds of the formula (la) are those in which: Ri is Cl-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and Thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, or amino, wherein Ri is optionally substituted with one or more Rb;
Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl-5 oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl , benzothienyl, benzimidazolyl and benzothiazolyl; alkanoyl Cl-5-amino, aroylamino alkyl ,, Cl-3 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone , ureido wherein either nitrogen atom may be independently substituted with Cl-3 alkyl or phenyl, alkyl Cl-5-sulfonylamino, ariisulfonilamino, amino wherein the nitrogen atom may be independently mono or di-substituted with alkyl Cl-3, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, Cl-3 alkoxy, halogen and hydroxy; Cl-5 cycloalkyl, C5-6 cycloalkyl or phenyl in which optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, 4-morpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-5 alkoxy, phenoxy, aroyl, alkoxy Cl-5-carboni it, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by Cl-5 or phenyl; Cl-5-amino alkanoyl, Cl-3 alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido wherein any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl; Cl-5-carbonylamino alkoxy, Cl-5-sulfonylamino, aryisulphonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, benzyl, Cl-5 alkoxy, phenoxy, benzyloxy, aroyl, halogen, hydroxy, oxo, carboxy and cyano; Re is H, Cl-5 alkenyl or phenyl wherein Re is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl. naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl, Cl-3-thienyl-alkoxy Cl-3 alkoxy, furanyl-Cl-3 alkoxy, Cl-3-alkoxycarbonyl, phenoxycarbonyl , alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; alkanoyl Cl-5-amino, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or phenyl; alkoxy Cl-3-carbonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by Cl-5 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; R ?, is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with halogen, methyl or methoxy; heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridinyl, Cl-3 alkoxy, aryloxy, benzyloxy, Cl-5-alkoxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl wherein the nitrogen atom may be be independently mono- or di-substituted with Cl-5 alkyl or phenyl; Cl-5-amino alkanoyl, aroylamino, Cl-5-thio alkyl wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with C1-6alkyl 5 or phenyl; alkoxy Cl-5-carbonylamino, alkyl Cl-5-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-3-sulfonylamino, aryisulfonylamino, alkyl Cl-3-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di- -substituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano; R is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-alkoxycarbonyl, phenoxyxycarbonyl, benzyloxy, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with Cl-5 alkyl, phenyl, benzyl, halogen, hydroxy, carboxy and cyano; Re is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, wherein any of the foregoing Rs may optionally be substituted with one or more R3; R3 is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, benzyl, Cl-3 alkoxy, phenoxy, benzyloxy, Cl-3-alkoxy, acetyloxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and pyridinyl; acetylamino, benzoylamino, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with methyl, phenyl, thiazolyl, imidazolyl and pyridinyl; alkoxy Cl-3-carbonylamino, alkyl Cl-3-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-3-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and pyridinyl; halogen, hydroxy, carboxy, cyano and nitro, Rj may also be optionally substituted with one or more R; Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, pyridinyl, Cl-3 alkoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl. wherein the nitrogen atom can be independently mono- or disubstituted with methyl, phenyl, furanyl, thienyl; acetylamino, benzoylamino, methylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl and thiazolyl , benzyloxycarbonylamino, benzyloxycarbonylamino-Cl-5 alkyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and pyridinyl, halogen , hydroxy, carboxy, cyano and nitro, wherein Rk may also be optionally substituted with Ri; Ri is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl and phenyl. Even much more preferred compounds of the formula (la) are those in which: Ri is cycloalkyl CS-6, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, pyranyl, thiopyranyl or amino in which Rx is optionally substituted with one or more Rb;
Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, Cl-3 alkoxy, Cl-3 alkoxy -carbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino, aroylamino, ureido alkanoyl wherein any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl; alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, Cl-3 alkoxy, halogen and hydroxy; Ra is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, Cl-5-alkoxycarbonyl , alkanoyl Cl-5-oxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino alkanoyl, Cl-3 alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, Cl-3-carbonylamino alkoxy, Cl-3-sulfonylamino alkyl, amino in which the atom of nitrogen may independently be mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-3 alkyl, phenyl, benzyl, Cl-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen, hydroxy, oxo, carboxy and cyano; Rs is H or methyl; Re is Cl-5 alkyl or phenyl, wherein R6 is optionally substituted by one or more groups of the formula Rf, Rf is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, Cl-5-amino alkanoyl, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom it may be oxidized to a sulphoxide or a sulfone, Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with halogen or methyl; Cl-3 alkoxy, aryloxy, benzyloxy, Cl-3-carbonyl alkoxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino, aroylamino, amino alkanoyl wherein the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano;
Rn is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-alkoxycarbonyl, benzyloxy and carboxy; R8 is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, benzimidazolyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more R3; Rj- is selected from the group consisting of Cl-5 alkyl, cyclohexyl, phenyl, piperidinyl, furanyl, thienyl, pyridinyl, benzyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may be be independently mono- or di-substituted with methyl, phenyl, furanyl, thienyl; acetylamino, benzoylamino, ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; methoxycarbonylamino, Cl-3-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl, phenyl, furanyl or thienyl; halogen, hydroxy, carboxy and cyano, R3 may also be optionally substituted with one or more Ri;
Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, piperidinyl, piperazinyl, furanyl, thienyl, Cl-3 alkoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may be be independently mono- or disubstituted with methyl or phenyl; acetylamino, benzoylamino, ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; benzyloxycarbonylamino, benzyloxycarbonylamino Cl-5 alkyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, furanyl, or thienyl; halogen, hydroxy, carboxy, cyano and nitro, wherein Rk may also be optionally substituted with Ri; Ri is selected from the group consisting of methyl, C3-6 cycloalkyl and phenyl. Still even more preferred compounds of the formula (la) are those in which: A is -C (0) - or -S02-;
Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl or amino, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, Cl-3 alkoxy, Cl-3 alkoxy -carbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino alkanoyl, aroylamino, Cl-5-sulfonylamino alkyl, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkoxy, halogen and hydroxy; R3 is C1-5 alkyl or C5-6 cycloalkyl, wherein Rs is optionally substituted with one or more Rd; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, thienyl, imidazolyl, pyridinyl, indolyl, Cl-4 alkoxy, Cl-5-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl, halogen and hydroxy; Rf is selected from the group consisting of C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy, benzyloxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulphone, methoxycarbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy, carboxy and cyano,
Rt- may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of phenylmethyl optionally substituted with halogen or methyl; methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; halogen, hydroxy and carboxy; R8 is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more R3; R- is selected from the group consisting of Cl-5 alkyl, phenyl, furanyl, thienyl, piperidinyl, pyridinyl, benzyl, methoxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- di-substituted with methyl or phenyl; acetylamino, benzoylamino, ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; methoxycarbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; halogen, hydroxy, carboxy and cyano, R-, can also be optionally substituted with one or more Rt; and Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, piperidinyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; benzyloxycarbonylamino, benzyloxycarbonylamino-Cl-5 alkyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, furanyl and thienyl; halogen, hydroxy, carboxy, cyano and nitro, wherein Rk may also be optionally substituted with R1; Ri is selected from the group consisting of methyl and phenyl. Preferred compounds in the penultimate degree of the formula (la) are those in which: Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl or thiopyranyl, wherein Ri is optionally substituted with one or more Rb;
Rb is selected from the group consisting of pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy and carboxy, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of methoxy, halogen and hydroxy: Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, Cl-4 alkoxy, Cl-3-amino alkanoyl, methylthio in which the Sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, methoxy, halogen and hydroxy; R5 is H; Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, thienyl, indolyl, methoxy, methylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with halogen; methoxy, phenoxy, benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy; Ro is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more R3; Rj is selected from the group consisting of Cl-5 alkyl, phenyl, piperidinyl, pyridinyl, benzyl, methoxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; methoxycarbonylamino, halogen, hydroxy and carboxy, Rp may also be optionally substituted with one or more Rμ; Ri is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, piperidyl, methoxy, methoxycarbonyl, carbamoyl wherein the nitrogen atom can be independently mono- or disubstituted with methyl or phenyl; benzyloxycarbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; halogen, hydroxy and carboxy. Preferred ultimate grade compounds of formula (la) are those in which: Ri is phenyl or 4-morpholinyl, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of benzimidazolyl, methoxy and dimethylamino, Rb may also be optionally substituted with a halogen atom; Rs is Cl-5 alkyl wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of C3-6 cycloalkyl and phenyl, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl and halogen: R5 is Cl-5 alkyl optionally substituted with one or more Rf, "Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, methylthio in which the atom of sulfur may be oxidized to a sulfoxide or a sulfone, and halogen, R; - may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, methoxy, methoxycarbonyl, halogen and hydroxy; a heteroaryl ring selected from the group consisting of oxazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the foregoing Rt may be optionally substituted with one or more R3; R3 is selected from the group consisting of Cl-5 alkyl phenyl, pyridinyl, piperidinyl, methoxycarbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; methoxycarbonylamino and halogen, R3 can optionally also be I replaced you with one or more Ry; Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, methoxycarbonyl, carbamoyl, benzyloxycarbonylamino and halogen.
The invention also provides new compounds of the formula (II):
(II) wherein A is -C (Y) - or -S02- Y is 0, S or NRa wherein Ra is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylamino and arylamino; Ri is alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or amino wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di- -substituted with alkenyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone , ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkyl aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rb may also be optionally substituted with one or more Rc;
Rc is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with alkyl , aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R2 is H or alkyl; R3 is H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylsulphonyl, arylaminosulfonyl, amino in which the atom of nitrogen can be independently mono- or di-substituted with alkyl, aryl , heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rd may also be optionally substituted with one or more Re: Re is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R 4 is H or alkyl; R? is H or alkyl-Re is H, alkyl, cycloalkyl, aryl, heterocyclyl, aryl, heteroaryl or cyano, wherein Ro is optionally substituted with one or more Rf; Rf is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, heteroarylalkoxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamyl, arylcarbamoyl or, alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylalkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido wherein any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulphonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the Nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf can also be optionally substituted with one or more Rg;
Rg is selected from the group consisting of alkyl, cycloalkyl, aryl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in the that the nitrogen atom may independently be mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone , arylthio in which the sulfur atom can
is oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl,
Alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be
To be independently mono- or disubstituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
or R5 together with R6 forms a carbocyclic ring of 3 to 6 members, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of alkyl, aryl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with a group selected from alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl , heteroaryl, halogen, hydroxy, carboxy and cyano; X is 0, S or N-OH; with the proviso that when Y is O and R6 is arylalkyl or heteroarylalkyl then Ri can not be alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or arylcycloalkyl.
Preferred compounds of the formula (II) are those in which: Y is 0, S or NR a in which Ra is H, alkyl or aryl; Ri is Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl, phenoxazinyl, and amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of alkyl Cl-8, cycloalkylene C3-7, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorphslinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl. , quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl, alkoxy Cl-8, aryloxy, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the Nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl , imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridinyl dazinilo, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, Enzyothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino, guanidino; Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-8 alkyl, C3-6 cycloalkyl, aryl, Cl-8 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R is H, Cl-8 alkyl, C3-7 cycloalkyl, aryl wherein R3 is optionally substituted with one or more Rd; R is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl , benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, alkanoyl, aroyl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl in wherein the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or xadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino , aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyrid ynyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of it consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl. pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo carboxy, cyano, nitro, amidino, guanidino, Rd may be further optionally substituted with one or more Re-Re is selected from the group consisting of Cl-8 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, Cl-8 alkoxy, aryloxy, arylalkoxy, aroyl, amino, halogen, hydroxy, oxo , carboxy, cyano, nitro, amidino and guanidino; Re is H, Cl-8 alkyl, C3-7 cycloalkyl, aryl or cyano, wherein R5 is optionally substituted with one or more
Rf; Rf is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-88 aryloxy, aryl-alkoxy Cl-8, heteroaryl-alkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxa zolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl -8-amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl- alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazoli it, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulphonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group which consists of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl , piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl. ,
Benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, arylalkoxy Cl-8, alkoxy Cl-8-carbonyl,
Aryloxycarbonyl, Cl-8-oxy, aroyloxy, carbamoyl alkanoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of
A group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, Cl-8-amino alkanoyl,
Arylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which
Any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,
Piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
Triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino,
Arylisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl
selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl,
Oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,
Isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
Rh is selected from the group consisting of alkyl Cl-8, aryl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, aryl-alkoxy Cl-8-carbonyl, carbamoyl in which the nitrogen atom may be optionally mono- or di- substituted with a group selected from alkyl Cl-8, cycloalkyl C3-7, aryl, aryl-alkyl Cl-8, heterocyclyl selected from the group consisting of pyrridinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolidyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl , purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, carboxy and cyano; and X is 0 or S. More preferred compounds of formula (II) are those in which: Y is 0 or S; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl or amino; wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected among the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl , benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl C l-5-amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido wherein any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5 -carbamoy loxi, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the atom or nitrogen may independently be mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R2 is H or Cl-3 alkyl; R5 is H, Cl-5 alkyl, C3-7 cycloalkyl, aryl wherein R3 is optionally substituted with one or more Rd. Rd is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl.; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, alkanoyl Cl-5, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl -5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group group consisting of furanyl, thienyl, pyrrolyl, oxazolyl. thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl. quinazolinyl and quinoxalinyl, Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom may be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl , thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino,
Rd may also be optionally substituted Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, aroyl, amino, halogen, hydroxy, oxo , carboxy, cyano, nitro, amidino and guanidino; R4 is H or Cl-3 alkyl, R5 is H or Cl-8 alkyl, Re is H, Cl-5 alkyl, C3-7 cycloalkyl, aryl or cyano, wherein R is optionally substituted with one or more
Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, aryl-alkoxy Cl-5, heteroaryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl , imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, aryl , heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl , indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carba moyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl , piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di- substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the
The group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl. thienyl, pyrrolyl, oxazolyl,
Thiazolyl, imidazolyl. Triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl,
isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which
The sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl,
Oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzstienyl, benzimidazolyl, benzothiazolyl,
Quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5- carba or loxi, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl
Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group
which consists of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl , benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
Rh is selected from the group consisting of Cl-5 alkyl, aryl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-5-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with a group selected from C1-5 alkyl, C3-7 cycloalkyl, aryl, arylC1-5 alkyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of a group consisting of furanyl, thienyl, pyrslyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, carboxy and cyano. Even more preferred compounds of the formula (II) are those in which: Y is 0; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, thiomorphslinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl; or amino in which Ri is optionally substituted with one or more Rb;
Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected between the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl , quinolinyl and isoquinolinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfonyl, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl or aryl, Cl-5-alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamo Iloxy, arylcarbamoyloxy, alkyl Cl-5-sulfsnilamins, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consists of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl , halogen, hydroxy, oxo, carboxy, cyano and nitro, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy and cyano; Rs is H or methyl; Rs is H, Cl-5 alkyl, C3-7 cycloalkyl or phenyl wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl , oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently ono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, Cl-5-amino alkanoyl, aroylamino, Cl-5-thio alkyl wherein the sulfur atom may be oxidized to a sulphoxide or a sulfonyl, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyl loxi, arylcarbamoyloxy, aikyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylamine sulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naph tyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, aryl-Cl-5 alkyl, Cl-5 alkoxy, aryloxy, aryl-Cl-3 alkoxy, amino aroyl, halogen, hydroxy, oxo , carboxy and cyano; R 4 is H or methyl; R5 is H or Cl-5 alkyl; R6 is H, C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl or cyano, wherein Rfe is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl. triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-5 heteroaryl-alkoxy Cl-5, alkoxy Cl -5-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl , morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl. quinolinyl and isoquinolinyl, alkanoyl Cl-5-aroylamino, alkyl Cl-5-alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, aryl-Cl-5-alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl Cl-5, aryl , heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, Cl-5 alkyl-arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, ariisulfonilamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, to where the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl optionally substituted with one or more groups selected from halogen, methyl or methoxy naphthyl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of 5-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
Triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl
And quinoxalinyl, Cl-5 alkoxy, aryloxy, aryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently
mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of
furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amine, aroylamino, alkyl Cl-5-thio in which the atom Sulfur may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in the
That any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or
Heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,
benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5- carbamoyl loxi, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl
Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected between the group consisting of furanyl, thienyl. pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl. benzothienyl. benzimidazolyl benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-5 alkyl, phenyl, naphthyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may optionally be mono- or di-substituted with a group selected from C1-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, arylalkyl Cl-3, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, carboxy and cyano; and X is 0. Still more preferred compounds of the formula (II) are those in which: Y is 0; Ri is Cl-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl or amino, wherein Ri is optionally substituted with one or more Rt >;
Rb is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, phenoxy, alkoxy Cl-3-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl , oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, phenyl or naphthyl; Cl-5-carbonylamino alkoxy, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di- substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl , benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, aryl, Cl-3 alkoxy, phenoxy, halogen, hydroxy, oxo, carboxy and cyano; R2 is H; R3 is Cl-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, phenoxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy , carbamoyl in which the nitrogen atom can independently be mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroyl amino, alkyl Cl-3-thio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, phenylthio that the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-3 alkyl, phenyl or heteroaryl selected from Among the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, alkoxy Cl-5-carbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in the that the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, aryl-Cl-3 alkyl, Cl-5 alkoxy, phenoxy, aryl-alkoxy Cl-3 aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; R4 is H; R6 is H, Cl-5 alkyl, C3-6 cycloalkyl, phenyl or cyano, wherein Re is optionally substituted with one or more Rf; R t- is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-3, heteroaryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl Cl-5 or phenyl, Cl-5-alkoxycarbonylamino, Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may be also more optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl optionally substituted by one or more groups selected from halogen or methyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl, Cl-5-oxy, aroylloxy, carbamoyl alkanoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or aryl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in that the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be substituted independently with Cl-5 or aryl alkyl, Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the The nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or aryl, halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-5 alkyl, phenyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or disubstituted with Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl or aryl-Cl-3 alkyl; halogen, hydroxy, carboxy and cyano. Still even more preferred compounds of formula (II) are those in which:
Ri is Cl-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl or amino, wherein Ri is optionally substituted with one or more
Rh r R b is selected from the group consisting of Cl-3 alkyl, C 5-6 cycloalkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; hetersaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl -5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl and benzothiazolyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-3 alkyl or phenyl, Cl-5-sulfonylamino, aryisulfonylamino, amino in wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, heterocyclyl phenyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more R :; R is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, Cl-3 alkoxy, halogen and hydroxy; R3 is Cl-5 alkyl, C5-6 cycloalkyl or phenyl in which R3 is optionally substituted with one or more Rd;
Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, 4-morpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-5 alkoxy, phenoxy, aroyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy-alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, Cl-alkanoyl 5-amino, alkyl Cl-3-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl Cl-3 or phenyl, alkoxy Cl-5-carbonylamino, alkyl Cl-5-sulfsylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, benzyl, Cl-5 alkoxy, phenoxy, benzyloxy, aroyl, halogen, hydroxy, oxo, carboxy and cyano; R5 is H or Cl-3 alkyl; R5 is H, Cl-5 alkyl, phenyl or cyano, wherein Re is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl-Cl-3 alkoxy, thienyl -alkoxy C103, furanyl-alkoxy Cl-3, alkoxy Cl-3-carbonyl, phenoxyxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-alkyl 3 or phenyl, Cl-5-amino alkanoyl, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl or phenyl, Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with one or more groups selected from the group consisting of halogen and methyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridinyl, alkoxy Cl-3. aryloxy, benzyloxy, Cl-5-alkoxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, Cl-5 alkanoyl amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or phenyl, alkoxy Cl-5- carbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-3-sulfonylamino alkyl, aryisulfonylamino, Cl-3-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with alkyl Cl-3 or phenyl, halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-alkoxycarbonyl, phenoxyxycarbonyl, benzyloxy, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with a group selected from the group consisting of group consisting of Cl-5 alkyl, phenyl and benzyl, halogen, hydroxy, carboxy and cyano. Even more preferred compounds of the formula (II) are those in which: Ri is C5-6 cycloalkyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl or amino, in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl. furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, alkoxy Cl-3, alkoxy Cl-3-carbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl -3 or phenyl; Cl-5-amino, aroylamino, ureido alkanoyl wherein any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl; alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rb can also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, Cl-3 alkoxy, halogen and hydroxy; R3 is Cl-5 alkyl, C5-6 cycloalkyl or phenyl, wherein R3 is optionally substituted with one or more groups of the formula Rd; Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, Cl-5-alkoxycarbonyl , alkanoyl Cl-5-oxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino alkanoyl, Cl-3 alkylthio in the that the sulfur atom may be oxidized to a sulphoxide or a sulfone, Cl-3-carbonylamino alkoxy, Cl-3-sulfonylamino alkyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-alkyl 3 or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-3 alkyl, phenyl, benzyl, Cl-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen, hydroxy, oxo, carboxy and cyano; in that the configuration in the stereo center defined by R2 and R3 and the carbon to which they are attached is defined as L; R5 is H or methyl; R6 is Cl-5 alkyl, phenyl or cyano wherein R6 is optionally substituted with one or more groups of the formula Rf; Rf is selected from the group consisting of methylC3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl-alkoxy Cl-3, thienyl-alkoxy Cl-3, furanyl-alkoxy Cl-3, Cl-5-amino alkanoyl, aroylamino, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, Cl-3- alkoxy carbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, halogen hydroxy, oxo, carboxy and cyano, Rf can also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl phenyl optionally substituted with one or more groups selected from halogen or methyl, Cl-3 alkoxy, aryloxy, benzyloxy, Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen may independently be mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino, aroylamino, alkanoyl, amino wherein the nitrogen atom may be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-carbonyl alkoxy, benzyloxy and carboxy. Much more preferred compounds of the formula (II) are those in which Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl or amino in which Ri is optionally substituted with one or more
Rb; Rb is selected from the group consisting of Cl-3 alkyl, CS-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, Cl-3 alkoxy, Cl-3-carbonyl alkoxy , carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino alkanoyl, aroylamino, Cl-5-sulfonylamino alkyl, aryisulfonylamino, amino in which the atom of nitrogen may independently be mono- or di-substituted with Cl-3 alkyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkoxy, halogen and hydroxy, R3 is Cl-5 alkyl or C5-6 cycloalkyl wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, Cl-4 alkoxy, Cl-5-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl, halogen and hydroxy; R6 is C1-5 alkyl or phenyl, wherein Re is optionally substituted with one or more Rf; Rf is selected from the group consisting of C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy, benzyloxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, methoxycarbonylamino, amino in which the nitrogen atom may independently be mono- or di-substituted with Cl-3 alkyl, halogen, hydroxy, carboxy and cyano,
Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with one or more groups selected from halogen or methyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy and carboxy; Rh is selected from the group consisting of vinyl, phenyl, methoxycarbonyl, benzyloxycarbonyl and carboxy. Preferred penultimate grade compounds of formula (II) are those in which Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl or thiopyranyl, wherein Ri is optionally substituted with one or more Rb;
Rb is selected from the group consisting of pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, halogen, hydroxy and carboxy, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of methoxy, halogen and hydroxy; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, Cl-4 alkoxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re-Re is selected from the group consisting of methyl, phenyl, methoxy, halogen and hydroxy;
Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, thienyl, indolyl, methoxy, benzyloxy, methylthio in which the sulfur atom may be oxidized to a sulphoxid or a sulfone, benzylthio in which the atom Sulfur may be oxidized to a sulfoxide or a sulfone, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; R? it is selected from the group consisting of methyl, phenyl optionally substituted with halogen, methoxy, phenoxy, benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy; Rh is vinyl or phenyl. Preferred ultimate grade compounds of formula (II) are those in which: Ri is phenyl, naphthyl or 4-morpholinyl wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of benzimidazolyl, methoxy and dimethylamino, Rb may further be optionally substituted with Rc wherein Rc is a halogen atom; Rs is Cl-5 alkyl wherein Rs is optionally substituted with one or more Rd; Rd is selected from the group consisting of C3-6 cycloalkyl, phenyl or naphthyl, Rd may also be optionally substituted with one or Re is selected from the group consisting of methyl and halogen, Rf is selected from the group consisting of cycloalkyl CS-6, phenyl, naphthyl, indolyl, benzyloxy, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen and carboxy, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, methoxy, methoxycarbonyl, halogen and hydroxy. In another embodiment of the invention, compounds of the formula (lia] are provided
J la) wherein A is -C (Y) - or -S02- Y is O, S or NRa wherein Ra is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylamino and arylamino; Ri is alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or amino wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di- -substituted with alkenyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone , ureido wherein any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxy carbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom may be be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with alkenyl , aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rs is H or alkyl; Rs is H, C2-8 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoylsi, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the atom of nitrogen can be independently mono- or di-substituted with alkyl, aryl, tercyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rd may also be optionally substituted with one or more Re-Re is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, alkoxy , aryloxy, arylalkoxy, alkanoyl, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R 4 is H or alkyl; R5 is H or alkyl; R6 is H, alkyl, cycloalkyl, aryl, heterocyclyl, aryl, heteroaryl or cyano, wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, heteroarylalkoxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylalkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be substituted independently with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkyl aminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg;
Rg is selected from the group consisting of alkyl, cycloalkyl, aryl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in the that the nitrogen atom can be independently mono- or di-substituted with alkenyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino , aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; or R5 and R6 together with the carbon to which they are attached form a carbocyclic ring of 3 to 6 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of alkyl, aryl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with a group selected from alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl , heteroaryl, halogen, hydroxy, carboxy and cyano; X is 0, S or N-OH; and their pharmaceutically acceptable salts, esters or tautomers with the following conditions: when Y is 0 and R5 is arylalkyl or heteroarylalkyl then Ri can not be alkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, arylalkyl or arylcycloalkyl; when R5 is H then R6 can not be H; and when Ri is alkyl Cl then Rb can not be carbamoyl, alkanoylamino, aroylamino, ureido, alkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aryisulfonylamino, amino, amidino or guanidino in which each of said Rb is linked to said Ri through its atom of nitrogen. Preferred compounds of the formula (lia) are those in which: Y is 0, S or NR a in which Ra is H, alkyl or aryl; Ri is Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl, phenoxazinyl, and amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl, alkoxy Cl-8, aryloxy, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl , purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the atoms of nitr Oxygen can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl , pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl , alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, to which laminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group c pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl ester, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl. imidazolyl, pyrazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino, guanidino; Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-8 alkyl, C3-6 cycloalkyl, aryl, Cl-8 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R3 is H, C2-8 alkyl, C3-7 cycloalkyl, aryl wherein R3 is optionally substituted with one or more Rd;
Rd is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, alkanoyl, aroyl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkenyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group which consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino , aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkenyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, py idinilo, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, nzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino, guanidino, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-8 alkyl, C 3-6 cycloalkyl, aryl, arylalkyl, Cl-8 alkoxy, aryloxy, arylalkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Re is H, Cl-8 alkyl, C3-7 cycloalkyl, aryl or cyano, wherein Re is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, aryl-alkoxy Cl-8, heteroaryl-alkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl. imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, Cl-8-amino alkanoyl, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group a group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl or, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rt- may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl , piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, indolyl, isoindolyl, benzofuranyl. benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and
Phenoxazinyl, alkoxy Cl-8, aryloxy, arylalkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently
mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl
selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl. , benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl,
-quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, Cl-8-amino alkanoyl, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which
The sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected
between the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl,
Thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, f notiazinyl and phenoxazinyl, alkoxy carbonylamino,
Aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom may be
Independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl 'and indolinyl,
Or a heteroaryl selected from the furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl group
Thiadiazolyl, pyridinyl. pyridazinyl, pyrimidinyl, pyrazinyl. indolyl, isoindolyl. benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, cfuinoxalinyl, carbazolyl, f notiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino: or Rc and Rs together with the carbon at that these are bound to form a carbocyclic ring of 3 to 6 carbon atoms, the cacylcyclic ring optionally being substituted with one or more Rh; Rb is selected from the group consisting of alkyl Cl-8, aryl < "> alkoxy Cl-8-carbonyl, aryloxycarbonyl, aryl-alkoxy Cl-8-carbonyl, carbamoyl in which the nitrogen atom may be optionally mono- or di-substituted with a group selected from alsuyl Cl-8, C3-7 cycloalkyl, aryl, aryl-Cl-8 alkyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, iomorf linyl, piperazinyl, and oligoalkylidene; The group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl. , isoindolyl, benzofuranyl, benzothi nyl, benzimidazolyl, benzothiazolyl, purinyl, suinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, carboxy, and cyano; and X is 0 or S. Most preferred compounds of the formula (Ha) are those in which: Y is 0 or S; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, qnol inyl, isoquinolinyl, quinazolinyl and quinoxalinyl or amino; in which qwe Ri is ricion9 Ircent substituted * "* with one more R'-;
p «or selected from the group q'-UB consists of alsuyl Cl-5, cycloalkyl C3-" 7, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, pinrf ni i and 1? 1"i or Ti rfnl i ni 1 ninora7Í ni l n o indolinllo; heteroaryl selected from the
< T "*" U ri rrpo rnirsl-a Ho fnrsp-i 1 n f i o n a n d i n n a n a n a n d i n n a n a n d n a n a n d n a n a n d n a n a n d n a n a n a n d n a n a n a n d n a n a n a n a n a n d n a n a n a n a n a n a n a n a n a n a n a n a n a n a n y thiazolyl. imidazolyl, triazolyl, pyrazinyl, indolyl, benzofuran, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5, aryloxy, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroylloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomethyl, piperazinyl and
T "f-" * ~ Q Q!
^ ru or its consists of fur ^ niA, thienyl, pirrclilo f. r zi * -t -., ~] - ~ \ r + - -í '- * T? 1 n i mi Ha ^ ^ l i l o * - * ~ -? -2 r7r ^ -] i r tetrazolyl, pyridinyl, pyrimidinyl, ov ipolipilo * i socuinolinyl-cuipßzoliril /
£ »1 r1" 11 1 P1 - "-G"! Orí P> 1 A "1" "! ID O "l a + - may be oxidized to a sulphoxide or a sulfone, arylthio in the dream the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indclinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl , pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, ischolinolinyl, quinazolinyl and quincxalinylc, alkoxy CJ-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyl loxi, arylcarbamoyloxy, alkyl Cl-5-sulfonylamins, aryisulfonylamino , alkyl Cl-5- CL n J-4.J. \ "'ji CU i-_L GL4.ll.j- 4.4.W.-i_J-' J.4.-iJ.W f £ 3. in J - J- A t-Ii fc -L than the nitr atom The oxygen can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, ben? ofuranyl, benzctienylc, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carbxy, cyano, nitro, amidino and guanidino,
P-c may also be optionally substituted with one or more R; P- is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 akoxy, aryloxy, halogen, hydroxy, oxo, carbcxy, cyan, nitro, amidino and cjuanidino; p. Q C. u -. -. i I i i i r 1 1 -3 • R-- is H, C2-5 alkyl, C3-7 cycloalkyl, aryl in the "QQ? a O" p.-i selection, between the graph A consisted of the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, alkanoyl Cl-5, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbcnilc, alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl -5, aryl, heterocyclyl selected from the tmr ° ^ u consists of pyrrolidinyl, piperidinyl, morpholinyl, tICIJ rfc 1 piperazinyl and indolinyl o terraryl ° sLl cited between the r ^ pr ^ ^ G? O f ~ * They will have i 1 r. - i an i 1 i rrnl i 1 n
^ az ^ lyl, thiazolyl, imidazolyl, triazolyl, l -i -K- -i rl j -n -i] n i i i i i i i i i n
. i -f n r a n T o,? -n > "l t -? 1 * -? /" • > you? n 1 i n -í I * i? to 7 ^ 1? n -! 1
alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen may be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently being mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morphelinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl , oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino , R may also be optionally substituted with one or more Re; R is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro , amidino and guanidino; R 4 is H or Cl 3 alkyl; R5 is H or C1-8 alkyl; F,? is H, alsuyl Cl-5, cycloalkyl C3-7, aryl or cyano, wherein R? is optionally substituted with one or more p ..
Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, aryl-alkoxy Cl-5, heteroaryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alsuyl Cl-5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl , imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, aryl , heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl , quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyl loxi, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alsuyl Cl-5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl. oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, cyano carboxy, nitro, amidino and guanidino, Rf it may also be optionally substituted with one or more Ra; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl , piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and
-quinoxalinyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently
mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl
Selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,
Benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the 5 sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio that the sulfur atom can be oxidized to a sulphoxide or sulfone, ureido in which any of the nitrogen atoms can
is independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl,
Or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,
benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamine, alkyl Cl-5-25 carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5 aminosulfonyl , arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy , oxo, carboxy, cyano, nitro, amidino and guanidino; or R5 and R6 together with the carbon to which they are attached form a carbocyclic ring of 3 to 6 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rb is selected from the group consisting of Cl-5 alkyl, aryl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-5-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with a group selected from allyl Cl-5, C3-7 cycloalkyl, aryl, aryl-Cl-5 alkyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, carboxy and cyano.
Even more preferred compounds of the formula (Ha) are those in which: Y is 0; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl; or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, alkoxy Cl-5- carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl- 5-amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the Sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl or aryl, C1-5-alkoxycarbonylamino, aryloxycarbonylamino} alkyl Cl-5-carbamoyl loxi, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl , benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy and cyano; R2 is H or methyl; R3 is H, C2-5 alkyl, C3-7 cycloalkyl or phenyl in which R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl , oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, Carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, Cl-5-amino alkanoyl, aroylamino, Cl-5-thio alkyl wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of a group consisting of piperidinyl, morpholinyl and piperazyrylyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, aryl-Cl-5 alkyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-3, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; Ri is H or methyl; Rs is H or Cl-5 alkyl; Re is H, Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl or cyano, wherein R6 is optionally substituted with one or more Rt-;
Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, aryl-alkoxy Cl-5, heteroaryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the sulfur atom may be A sulphonide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, aryl-alkyl
Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consists of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino , aryloxycarbonylamino, alkyl Cl-5-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from The group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl optionally substituted with one or more groups selected from halogen, methyl or methoxy, naphthyl optionally substituted with one or more groups selected from halogen, methyl or methoxy , heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, aryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-5, aryl, heterocyclyl selected from the
The group consisting of picperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,
Indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized
to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted
with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, 5-oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino,
-aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be
To be independently mono- or disubstituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl
Selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, or R5 and Re together with the carbon to which these are attached form a carbocyclic ring of 3 to 6 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of Cl-5 alkyl, phenyl, naphthyl, Cl-5- carbonyl alkoxy, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or disubstituted with a group selected from C1-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, arylC1-3 alkyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolito, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, carboxy and cyano; and X is 0.
Even more preferred compounds of the formula (Ha) are those in which: Y is 0; R 1 is Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl or amino, wherein Ri is optionally substituted with one or more Rb , 'Rb is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, phenoxy, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl-5 oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selected Named between the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, phenyl or naphthyl; Cl-5-carbonylamino alkoxy, Cl-5-carbamoyl-loxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di- -substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, msrpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, aryl, Cl-3 alkoxy, phenoxy, halogen, hydroxy, oxo, carboxy and cyano; R 2 is H; R3 is C2-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, phenoxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy , carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroyl amino, alkyl Cl-3-thio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, phenylthio that the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-3 alkyl, phenyl or heteroaryl selected from Among the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, alkoxy Cl-5-carbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in the that the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Ra may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, aryl-Cl-3 alkyl, Cl-5 alkoxy, phenoxy, aryl-Cl-3 alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; R4 is H; R6 is H, C1-5 alkyl, C3-6 cycloalkyl, phenyl or cyano, wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-3, heteroaryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur can be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl or phenyl, Cl-5-carbonylamino alkoxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl , heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rf can also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl optionally substituted with one or more groups selected from halogen or methyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 or aryl alkyl, Cl-5-amino alkanoyl, aroylamino, Cl-5-alkyl in that the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently replaced; with C1-5 or aryl alkyl, Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyl loxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl or aryl, halogen, hydroxy, oxo, carboxy and cyano; or R5 and Rs together with the carbon to which they are attached form a carbocyclic ring of 3 to 6 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of Cl-5 alkyl, phenyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl or aryl-Cl-3 alkyl; halogen, hydroxy, carboxy and cyano.
Still even more preferred compounds of the formula (Ha) are those in which: Ri is Cl-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and Thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl or amino, wherein Ri is optionally substituted with one or more
Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl -5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl and benzothiazolyl alkanoyl Cl-5-amino, aroylamino, alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl, Cl-5-sulphonylamino, aryisulphonylamino, amino at that the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl , indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc:
Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, Cl-3 alkoxy, halogen and hydroxy; R3 is C2-5 alkyl, C5-6 cycloalkyl or phenyl in which R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, 4-morpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-5 alkoxy, phenoxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, Cl-alkanoyl 5-amino, alkyl Cl-3-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl Cl-3 or phenyl, alkoxy Cl-5-carbonylamino, Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Rei-Re is selected a among the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, benzyl, Cl-5 alkoxy, phenoxy, benzyloxy, aroyl, halogen, hydroxy, oxo, carboxy and cyano; R5 is H or Cl-3 alkyl; Re is H, Cl-5 alkyl, phenyl or cyano, wherein Rd is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl-Cl-3 alkoxy, thienyl. -alkoxy Cl-3, furanyl-alkoxy Cl-3, alkoxy Cl-3-carbonyl, phenoxyxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-3 or phenyl, Cl-5-amino alkanoyl, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl or phenyl, Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with one or more groups selected from the group consisting of halogen and methyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridinyl, Cl-3 alkoxy, aryloxy, benzyloxy, Cl-5-alkoxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl wherein the nitrogen atom may be independently being mono- or di-substituted with Cl-5 alkyl or phenyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in that any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or phenyl, Cl-5-carbonylamino alkoxy, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-3-sulfonylamino alkyl, aryisulfonylamino, Cl-3- alkyl aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano; or Rs and R together with the carbon to which they are attached form a carbocyclic ring of 3 to 5 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-alkoxycarbonyl, phenoxyxycarbonyl, benzyloxy, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with a group selected from group consisting of Cl-5 alkyl, phenyl and benzyl, halogen, hydroxy, carboxy and cyano.
Even more preferred compounds of the formula (Ha) are those in which: Ri is C5-6 cycloalkyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl or amino, in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, Cl-3 alkoxy, Cl-3-carbonyl alkoxy , carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino, aroylamino, ureido alkanoyl wherein any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl; alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rb can also be optionally substituted with one or more Rc;
Rc is selected from the group consisting of Cl-3 alkyl, Cl-3 alkoxy, halogen and hydroxy; R is C2-5 alkyl, C5-6 cycloalkyl or phenyl, wherein R3 is optionally substituted with one or more groups of the formula Rd; Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl,
4-piperidinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, alkoxy Cl-3, alkoxy Cl-5-carbonyl, alkanoyl Cl-5-oxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino alkanoyl, Cl-3 alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, Cl-3-carbonylamino alkoxy, alkyl Cl-3-sulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd can also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-3 alkyl, phenyl, benzyl, Cl-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen, hydroxy, oxo, carboxy and cyano; in that the configuration in the stereo center defined by R2 and R3 and the carbon to which they are attached is defined as L; R5 is H or methyl; R6 is Cl-5 alkyl, phenyl or cyano wherein Re is optionally substituted with one or more groups of the formula Rf; Rf is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl-alkoxy Cl-3, thienyl-alkoxy Cl -3, furanyl-alkoxy Cl-3, alkanoyl Cl-5-amino, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rf can be in addition optionally substituted with one or more Rg;
Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with one or more groups selected from halogen or methyl, Cl-3 alkoxy, aryloxy, benzyloxy, Cl-3-alkoxycarbonyl, carbamoyl wherein the atom of nitrogen may independently be mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino alkanoyl, aroylamino, amino wherein the nitrogen atom may be independently mono- or disubstituted with Cl-3 alkyl or phenyl , halogen, hydroxy, oxo, carboxy and cyano; or Rs and Re together with the carbon to which they are attached form a carbocyclic ring of 3 to 5 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh, * Rh is selected from the group consisting of Cl- 3, phenyl, Cl-3-alkoxycarbonyl, benzyloxy and carboxy.
Much more preferred compounds of the formula (Ha) are those in which: Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl or amino in which Ri is optionally substituted with one or more
Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, Cl-3 alkoxy, Cl-3-carbonyl alkoxy , carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino alkanoyl, aroylamino, Cl-5-sulfonylamino alkyl, aryisulfonylamino, amino in which the atom of nitrogen may independently be mono- or di-substituted with Cl-3 alkyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkoxy, halogen and hydroxy, R3 is C2-5 alkyl or C5-6 cycloalkyl wherein R3 is optionally substituted with one or more Rd, "Rd is selected from the group that consists of methyl, C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, Cl-4 alkoxy, Cl-5-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone , halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl, halogen and hydroxy; Rd is Cl-5 alkyl or phenyl, wherein Re is optionally substituted with one or more Rf; Rf is selected from the group consisting of C 3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy, benzyloxy, alkanoyl Cl-3-aminos methylthio in which the sulfur atom may be oxidized a sulfoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulphone, methoxycarbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with C1-3 alkyl , halogen, hydroxy, carboxy and cyano,
Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with one or more groups selected from halogen or methyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy and carboxy; or R5 and R6 together with the carbon to which they are attached form a carbocyclic ring of 3 to 5 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of vinyl, phenyl, methoxycarbonyl, benzyloxycarbonyl and carboxy.
Preferred compounds in the penultimate degree of the formula (Ha) are those in which: Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl or thiopyranyl, wherein Ri is optionally substituted with one or more Rb, 'Rb is selected from the group consisting of pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, halogen, hydroxy and carboxy, Rb it may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of methoxy, halogen and hydroxy; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, Cl-4 alkoxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, methoxy, halogen and hydroxy;
R t- is selected from the group consisting of C 5-6 cycloalkyl, phenyl, naphthyl, thienyl, indolyl, methoxy, benzyloxy, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the Sulfur atom may be oxidized to a sulfoxide or a sulfone, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg;
Rg is selected from the group consisting of methyl, phenyl optionally substituted with halogen, methoxy, phenoxy, benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy; or R5 and Rβ together with the carbon to which they are attached form a carbocyclic ring of 3 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is vinyl or phenyl.
Preferred compounds of the formula (Ha) are those in which: Ri is phenyl, naphthyl or 4-morpholinyl wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of benzimidazolyl, methoxy and dimethylamino, Rt, it may further be optionally substituted with Rc wherein Rc is a halogen atom; R3 is C2-5 alkyl wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of C3-6 cycloalkyl, phenyl or naphthyl, Rd may also be optionally substituted with one or more Re;
Re is selected from the group consisting of methyl and halogen, Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, indolyl, benzyloxy, methylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen and carboxy, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, methoxy, methoxycarbonyl, halogen and hydroxy and R5 and R6 together with the carbon to which these are attached form a carbocyclic ring of 3 carbon atoms, the carbocyclic ring being substituted with one or more Rh. The following are representative compounds according to the invention: N- (4-morpholinocarbonyl) -L-leucine (lS-cyano-3-phenyl-propyl) amide; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-homophenylalanine; (1- S-cyano-3-phenyl-propyl) amide of N- (5-dimethylamino-naphth-1-ylsulfonyl) -L-leucine;
(1- S-cyano-3-phenyl-propyl) -N-methyl-amide of N- (4-morpholino-carbonyl) -L-leucine; [IR, S- (benzthiazol-2-ylcarbonyl) -3-phenyl-propyl] amide of N- (-morpholino-carbonyl) -L-leucine; [IR, S- (thiazol-2-ylcarbonyl) -3-phenyl-propyl] amide of N- (4-morpholino-carbonyl) -L-leucine; [IR, S- [1- (3-N-benzyl) imidazol-2-ylcarbonyl] -3-phenyl-propyl] -amide of N- (4-morpholinocarbonyl) -L-leucine; [IR, S- [1- (2-imidazolyl-carbonyl) -3-propyl] amide of N- (4-morpholino-carbonyl) -L-leucine; (cyano-methyl) amide of N- (4-morpholino-carbonyl) -L-leucine; [1- S-cyano-5- ((benzyloxycarbonyl) amino) -pentyl] amide of N- (4-morpholino-carbonyl) -L-leucine; (lR-cyano-3-phenyl-propyl-amide) of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-5-amino-pentyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (p-ethoxy) phenylalanine; [1- S-cyano-4- (benzyloxycarbonylamino) butyl] amide of N- (4-morpholino-carbonyl) -L-leucine;
[1- (Benzothiazol-2-ylcarbonyl) -5- [(benzyloxycarbonyl) amino] -pentyl] amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (1-naphthyl-sulfonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (4-methyl) leucine; (1-R-cyano-2-benzyloxy-ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3-propyl) amide of N- (methanesulfonyl) -D- (0-benzyl) serine; (1-R-cyano-3-phenyl-propyl) amide of N- (5-dimethylamino-naphth-1-ylsulfonyl) -D-leucine; (N- (4-morpholino-carbonyl) -L- (4-methyl) leucine (LR-cyano-2-benzyloxy-ethyl) amide; (lR-cyano-3- (phenyl-propyl) amide of N- ((4-dimethylamino-phenyl) sulfonyl) -L-leucine; [1- (benzothiazol-2-ylcarbonyl) -3-phenyl-propyl] amide N- (t-butoxycarbonyl) -L-leucine; N- (5-dimethylamino-naphth-1-ylsusfonyl) -L-leucine [1- (benzothiazol-2-ylcarbonyl) -3-phenyl-propyl] amide; 1- (Benzothiazol-2-ylcarbonyl) -3-phenyl-propyl] -amide of N- (4-methoxy-phenylsulfonyl) -L-leucine; [IR, S- (benzoxazol-2-ylcarbonyl) -3-phenyl-propyl] ] N- (4-morpholino-carbonyl) -L-leucine amide;
(LR-cyano-2R-benzyloxy-propyl) amide of N- (4-morpholinocarbonyl) -L-leucine; [IR, S- [4-phenyl-thiazol-2-yl) -carbonyl] -3-phenylpropyl] -amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -D-leucine; [[1- [(6-phenyl-carbamoyl) benzothiazol-2-ylcarbonyl] -3-phenyl-propyl]] amide of N- (4-morpholinocarbonyl) -L-leucine; [1- (benzothiazol-2-ylcarbonyl) -3-phenyl-propyl]] amide of N- (methyl-sulfonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (p-phenyl) phenylalanine; [IR, S- [(5-phenyl-thiazol-2-yl) carbonyl] -3-phenylpropyl] -amide of N- (4-morpholino-carbonyl) -L-leucine; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (benzyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (2-chloro-phenyl) methyloxy-ethyl) amide; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-phenyl-glycine; [1- (benzothiazol-2-ylcarbonyl) -2-benzyloxy-ethyl] amide of N- (4-morpholino-carbonyl) -L-leucine; [[6- (carbomethoxy) benzoxazol-2-ylcarbonyl] -3-phenyl-propyl] amide N- (4-morpholino-carbonyl) -L-leucine;
(1-R-cyano-2-benzyloxy-ethyl) amide of N- (5-dimethylamino-naphth-1-ylsulfonyl) -L- (4-methyl) leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (-morpholinocarbonyl) -L-cyclohexyl-alanine; [IR, S- [(4- (4-benzyloxycarbonylamino) phenyl-thiazol-2-yl) carbonyl] -3-phenyl-propyl] -amide of N- (4-morpholinocarbonyl) -L-leucine; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-methoxy-phenyl) ethyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L- (4-methyl) leucine; LR-cyano-2- (benzyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (benzylsulfonyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (benzyl-sulfinyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- ((4-methoxy-phenyl) methyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- ((4-methyl-phenyl) methyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (4-chloro-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-chloro-phenyl) methyloxy-ethyl) amide; (N- (5-dimethylamino-naphth-1-ylsulfonyl) -L-leucine (LR-cyano-2-benzyloxyethyl) amide;
(lS- ((2-phenyl-oxazol-5-yl) carbonyl) -3-phenyl-propyl-amide of N- (4-morpholino-carbonyl) -L-leucine; (lS-cyano-3-phenyl-propyl) N- (4-morpholinocarbonyl) -L- (p-phenyl-carbonyl) phenylalanine amide; N- (4-morpholino-carbonyl) (1-R-cyano-2- (2-methyl-phenyl) methyloxy-ethyl) amide ) -L-leucine; N- (4-morpholino-carbonyl) -L-leucine; (1-R-cyano-2- (3-methyl-phenyl) methyloxy-ethyl) amide; N- (4-morpholino-carbonyl) -L-leucine; (IR, S- ((5-phenyl-oxazol-2-yl) carbonyl) -3-phenyl-propyl) methyl- (methyl-phenyl) methyloxy-ethyl) amide; N- (4-morpholino-carbonyl) -L-leucine amide: N- (4-morpholinocarbonyl) -L-cyclohexyl-alanine (lR-cyano-2-benzyloxyethyl) amide; phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-nor-leucine; (lR-cyano-2-benzyloxyethyl) amide of N- (benzyloxycarbonyl) -L- (0-t-butyl) serine; (N- (4-morpholino-carbonyl) -L-leucine (1- (benzothiazol-2-ylcarbonyl) -3-phenyl-propyl] - (S-oxazol-2-ylcarbonyl) -3-phenyl-propyl) amide] amide N- (4-morpholino-carbonyl) -L- (4-methyl) leucine; (1-R-cyano-2-benzyloxy-ethyl) amide of N- (5-dimethylamino-naphth-1-yl sulphonyl) -L-cyclohexyl-alanine;
(N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-carboxy-methoxy-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (4-carbomethoxy-phenyl) methyloxy-ethyl) amide; Í- (Pyrid-2-ylcarbonyl) -3-phenyl-propyl-amide of N- (4-morpholino-carbonyl) -L-leucine; [IR, S- [(4-2-benzyloxy-amino) phenyl-thiazol-2-yl) carbonyl] -3-phenyl-propyl] -amide of N- (4-morpholino-carbonyl) -L-leucine; (N- (4-morpholinocarbonyl) -L- (O-t-butyl) serine (lR-cyano-2-benzyloxyethyl) amide; (1-R-cyano-2-hydroxy-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3- (carbo-t-butoxy) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (LR-cyano-2-benzyloxyethyl) amide of N- (cyclohexylcarbonyl) -L-leucine; (1- S-cyano-3- (carbo-t-butoxy) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; dicyanomethyl-amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (-morpholinocarbonyl) -L- (2-naphthyl) alanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholino-carbonyl) -L- (O-benzyl) glutamate;
(1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-homo-tyrosine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-nor-valine; (1- S-cyano-3-phenyl-propyl) amide of N- (-morpholinocarbonyl) -L- (2-chloro-phenyl) alanine; (lR-cyano-2-benzyloxy-ethyl) amide of N-benzoyl-1-L-leucine;
(1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (4,5-dehydro) leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (O-methyl) tyrosine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-iso-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholino-carbonyl) -L- (4-nitro-phenyl) alanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (4-fluoro-phenyl) alanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-tyrosine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (1-naphthyl) alanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-methionine; (1- S-cyano-2- (1-benzyl-4-imidazolyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine;
(1- S-cyano-2- (l-benzyl-4-imidazolyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (carbobenzyloxy) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenyl-alanine; (1- S-cyano-2- (carbobenzyloxy) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-1-phenyl-methyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-1-phenyl-methyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (4-benzyloxy-phenyl) ethyl) amide of N- (4-orpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (4-benzyloxy-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- cyano-cyclopropyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- cyano-cyclopropyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (4-phenyl-phenyl) ethyl) amide of N- (-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (4-phenyl-phenyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-2- (4-benzoyl-1-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine;
(1- S-cyano-2- (4-benzoyl-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (1-naphthyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2- (1-naphthyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-2- (2-naphthyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2- (2-naphthyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (N- (4-morpholinocarbonyl) -L-phenylalanine lS-cyano-2- (2-chloro-phenyl) ethyl) amide; (1- S-cyano-2- (2-chloro-phenyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-2- (4-chloro-phenyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2- (4-chloro-phenyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-2- (3,4-dichloro-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (3,4-dichloro-phenyl) ethyl) amide of N- (4-orpholino-carbonyl) -L-leucine; (1- S-cyano-but-3-ynyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine;
(1- S-cyano-but-3-ynyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-propyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (4- (2,6-dichloromethyloxy) pheny1) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2S-methyl-butyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-pentyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-pentyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2, 2-dimethyl-propyl) amide of N- (-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2, 2-dimethyl-propyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3-methyl-butyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-3-methyl-butyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (4-nitro-phenyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2- (4-nitro-phenyl-ethyl) -amide of N- (4-morpholinocarbonyl) -L-leucine;
(1- S-cyano-butyl) N- (4-morpholino-carbonyl) -L-phenylalanine amide; (1- S-cyano-butyl) N- (4-morpholino-carbonyl) -L-leucine amide; (LR-cyano-2R-benzyloxy-propyl) -amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-ethyl) amide of N- (-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3- (carbobenzyloxy) propyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-3- (carbobenzyloxy) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (N- (4-morpholino-carbonyl) -L-phenylalanine lS-cyano-2- (3-benzimidazolyl) ethyl) amide; (1- S-cyano-2- (3-benzimidazolyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; N- (4-morpholino-carbonyl) -L-phenylalanine (1-cyano-l-methyl-ethyl) amide; N- (4-morpholino-carbonyl) -L-leucine (1-cyano-l-methyl-ethyl) amide; (1- S-cyano-2- (4-hydroxy-phenyl) ethyl) amide of N- (4-orpholino-carbonyl) -L-phenylalanine;
(1- S-cyano-2- (4-hydroxy-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (ÍS, 3-dicyano-propyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (ÍS, 3-dicyano-propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (4-hydroxy-3-iodo-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (4-hydroxy-3-iodo-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (ÍS, 2-dicyano-ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (ÍS, 2-dicyano-ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1-R-cyano-2-benzyloxy-ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (2-thienyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2- (2-thienyl) ethyl) amide of N- (-morpholino-carbonyl) -L-leucine; (1- S-cyano-3- (methyl-sulfonyl) propyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-3- (methyl-sulfonyl) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine;
(1- S-cyano-2-phenyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2-phenyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3- (4-hydroxy-phenyl) propyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-3- (4-hydroxy-phenyl) propyl) amide of N- (4-orpholino-carbonyl) -L-leucine; (1- S-cyano-2-cyclohexyl-ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2-cyclohexyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (N- (4-morpholinocarbonyl) -L-phenylalanine lS-cyano-2- (3-chloro-phenyl) ethyl) amide; and (1- S-cyano-2- (3-chloro-phenyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine.
Preferred compounds of the invention include: (1- S-cyano-3-phenyl-propyl) amide of N- (5-dimethylamino-naphth-1-ylsulfonyl) -L-leucine; (lR-cyano-3-phenyl-propyl-amide) of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (1-naphthyl-sulfonyl) -L-leucine;
(1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (4-methyl) leucine; (LR-cyano-2-benzyloxy-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (N- (4-morpholinocarbonyl) -L- (4-methyl) leucine (LR-cyano-2-benzyloxyethyl) amide; (1- S-cyano-3- (phenyl-propyl) amide of N- ((4-dimethylamino-phenyl) sulfonyl) -L-leucine; (1-R-cyano-2R-benzyloxy-propyl) amide of N- (4-morpholino) -carbonyl) -L-leucine; (1-R-cyano-2- (benzyl-sulfanyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (lR-cyano-2- (2-chloro- N- (4-morpholino-carbonyl) -L-leucine; (lR-cyano-2-benzyloxy-ethyl) -amide of N- (5-dimethylamino-naphth-1-ylsulfonyl) -L - (4-methyl) leucine; (1-R-cyano-2- (3-methoxy-phenyl) methyloxy-ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (lR-cyano-2- ( N- (4-morpholino-carbonyl) -L- (4-methyl) leucine benzyl-sulfanyl) ethyl) amide; (N- (4-morpholino-) (1-R-cyano-2- (benzyl-sulfonyl) ethyl) amide) carbonyl) -L-leucine; (1-R-cyano-2- (benzyl-sulfinyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine;
(N- (4-morpholino-carbonyl) -L-leucine IR-cyano-2- ((4-methoxy-phenyl) methyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- ((4-methyl-phenyl) methyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (4-chloro-phenyl) ethyloxyethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-chloro-phenyl) methyloxy-ethyl) amide; (1-R-cyano-2-benzyloxy-ethyl) amide of N- (5-dimethylamino-naphth-1-ylsulfonyl) -L- (4-methyl) leucine; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (2-methyl-phenyl) methyloxy-ethyl) amide; (N- (4-Orpholino-carbonyl) -L-leucine lR-cyano-2- (3-methyl-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (4-methyl-phenyl) methyloxy-ethyl) amide; (N- (5-dimethylamino-naphth-1-ylsulfonyl) -L-cyclohexylalanine (LR-cyano-2-benzyloxyethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-carbomethoxy-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (4-carbomethoxy-phenyl) methyloxy-ethyl) amide; (1-R-cyano-2-hydroxy-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine;
(1- S-cyano-3- (carbo-t-butoxy) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (LR-cyano-2-benzyloxyethyl) amide of N- (cyclohexylcarbonyl) -L-leucine; (1- S-cyano-3- (carbo-t-butoxy) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholino-carbonyl) -L-homophenylalanine; (cyano-methyl) amide of N- (4-morpholino-carbonyl) -L-leucine; [1- S-cyano-5- ((benzyloxycarbonyl) amino) -pentyl] amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-5-amino-pentyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholino-carbonyl) -L- (p-ethoxy) phenylalanine; [1- S-cyano-4- (benzyloxycarbonylamino) butyl] amide of N- (4-morpholino-carbonyl) -L-leucine; [IR, S- (benzothiazol-2-ylcarbonyl) -3-phenyl-propyl] amide of N- (-morpholino-carbonyl) -L-leucine;
[IR, S- (benzoxazol-2-ylcarbonyl) -3-phenyl-propyl] amide of N- (-morpholino-carbonyl) -L-leucine; [1- (Benzothiazol-2-ylcarbonyl) -5- [(benzyloxycarbonyl) amino] -pentyl] amide of N- (4-morpholino-carbonyl) -L-leucine; [[6- (carbomethoxy) benzoxazol-2-ylcarbonyl] -3-phenylpropyl] amide N- (4-morpholino-carbonyl) -L-leucine; [[1- [(6-phenyl-carbamoyl) benzothiazol-2-ylcarbonyl] -3-phenyl-propyl]] amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (p-phenyl) phenylalanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-phenyl-glycine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-cyclohexyl-alanine; (1- S- ((2-phenyl-oxazol-5-yl) carbonyl) -3-phenyl-propyl-amide of N- (4-morpholino-carbonyl) -L-leucine; (lS-cyano-3-phenyl-propyl) N- (4-morpholino-carbonyl) -L- (p-phenyl-carbonyl) phenylalanine amide: (lR, S- ((5-phenyl-oxazol-2-yl) carbonyl) -3-phenylpropyl) amide N- (4-morpholino-carbonyl) -L-leucine; N- (4-orpholino-carbonyl) -L-leucine; (S- (oxazsl-2-ylcarbonyl) -3-phenyl-propyl) -amide;
(LR-cyano-2-benzyloxy-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-nor-leucine; [1- (Benzothiazol-2-ylcarbonyl) -3-phenyl-propyl] amide of N- (4-morpholino-carbonyl) -L- (4-methyl) leucine; Í- (Pyrid-2-ylcarbonyl) -3-phenyl-propyl-amide of N- (4-morpholino-carbonyl) -L-leucine; (NR-cyano-2-benzyloxyethyl) amide of N- (benzyloxycarbonyl) -L- (0-t-butyl) serine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (2-naphthyl) alanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (O-benzyl) glutamate; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-homo-tyrosine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-nor-valine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholino-carbonyl) -L- (2-chloro-phenyl) alanine; (lR-cyano-2-benzyloxy-ethyl) amide of N-benzoyl 1-L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (4,5-dehydro) leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholino-carbonyl) -L- (O-methyl) tyrosine;
(1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-iso-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (-morpholinocarbonyl) -L- (4-nitro-phenyl) alanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (4-fluoro-phenyl) alanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-tyrosine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholino-carbonyl) -L- (1-naphthyl) alanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-methionine; (1- S-cyano-2- (1-benzyl-4-imidazolyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (l-benzyl-4-imidazolyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (carbobenzyloxy) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenyl-alanine; (1- S-cyano-1-phenyl-methyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-1-phenyl-methyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-2- (4-benzyloxy-phenyl) ethyl) amide of N- (4-orpholino-carbonyl) -L-phenylalanine;
(1- S-cyano-2- (4-benzyloxy-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; N- (4-morpholino-carbonyl) -L-phenylalanine (1-cyano-cyclopropyl) amide, N- (4-morpholino-carbonyl) -L-leucine (1-cyano-cyclopropyl) amide; (1- S-cyano-2- (4-phenyl-phenyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2- (4-phenyl-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (4-benzoyl-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (4-benzoyl-1-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (1-naphthyl) ethyl) amide of N- (-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2- (1-naphthyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-2- (2-naphthyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (2-naphthyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (N- (4-morpholinocarbonyl) -L-phenylalanine lS-cyano-2- (2-chloro-phenyl) ethyl) amide;
(1- S-cyano-2- (2-chloro-phenyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-2- (4-chloro-phenyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2- (4-chloro-phenyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-2- (3,4-dichloro-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (3,4-dichloro-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-but-3-ynyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-but-3-ynyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (lS-cyano-propyl) -methine N- (-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (4- (2,6-dichloromethyloxy) phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-2- (4- (2,6-dichloromethyloxy) phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2S-methyl-butyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-pentyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine;
(1- S-cyano-pentyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2, 2-dimethyl-propyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2, 2-dimethyl-propyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3-methyl-butyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-3-methyl-butyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (4-nitro-phenyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2- (4-nitro-phenyl-ethyl) -amide of N- (4-morpholinocarbonyl) -L-leucine; N- (4-morpholino-carbonyl) -L-phenylalanine (lS-cyano-butyl) amide; N- (-morpholino-carbonyl) (lS-cyano-butyl) amide -L-leucine; N- (4-morpholino-carbonyl) -L-phenylalanine (1- S-cyano-ethyl) amide of N- (4-morpholino-carbonyl) (LR-cyano-2R-benzyloxy-propyl) amide -L-phenylalanine; (1- S-cyano-ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine;
(1- S-cyano-3- (carbobenzyloxy) propyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-3- (carbobenzyloxy) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (N- (4-morpholino-carbonyl) -L-phenylalanine lS-cyano-2- (3-benzimidazolyl) ethyl) amide; (1- S-cyano-2- (3-benzimidazolyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; N- (4-morpholino-carbonyl) -L-phenylalanine (1-cyano-l-methyl-ethyl) amide; N- (4-morpholino-carbonyl) -L-leucine (1-cyano-l-methyl-ethyl) amide; (N- (4-morpholino-carbonyl) -L-phenylalanine lS-cyano-2- (-hydroxy-phenyl) ethyl) amide; (1- S-cyano-2- (4-hydroxy-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (ÍS, 3-dicyano-propyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (ÍS, 3-dicyano-propyl) amide of N- (-morpholino-carbonyl) -L-leucine; (1- S-cyano-2- (4-hydroxy-3-iodo-phenyl) ethyl) N- (4-orpholino-carbonyl) -L-phenylalanine amide; (1- S-cyano-2- (4-hydroxy-3-iodo-phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine;
(ÍS, 2-dicyano-ethyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (ÍS, 2-dicyano-ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (N- (4-morpholinocarbonyl) -L-phenylalanine (LR-cyano-2-benzyloxy-ethyl) amide; (1- S-cyano-2- (2-thienyl) ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2- (2-thienyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3- (methyl-sulfonyl) propyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-3- (methyl-sulfonyl) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2-phenyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine; (1- S-cyano-2-phenyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (1- S-cyano-3- (4-hydroxy-phenyl) propyl) amide of N- (4-morpholino-carbonyl) -L-phenylalanine; (1- S-cyano-3- (4-hydroxy-phenyl) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-2-cyclohexyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-phenylalanine;
(1- S-cyano-2-cyclohexyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (N- (4-morpholinocarbonyl) -L-phenylalanine lS-cyano-2- (3-chloro-phenyl) ethyl) amide; and (1- S-cyano-2- (3-chloro-phenyl) ethyl) amide of N- (-morpholino-carbonyl) -L-leucine.
More preferred compounds of the invention include: (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholino-carbonyl) -L- (4-methyl) leucine; (LR-cyano-2-benzyloxy-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (N- (4-morpholinocarbonyl) -L- (4-methyl) leucine (LR-cyano-2-benzyloxyethyl) amide; (LR-cyano-2R-benzyloxy-propyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (benzyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (2-chloro-phenyl) ethyloxyethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (4-chloro-phenyl) methyloxy-ethyl) amide; (1-R-cyano-2- (3-methoxy-phenyl) methyloxy-ethyl) amide of N- (4-orpholino-carbonyl) -L-leucine;
(N- (4-morpholino-carbonyl) -L- (4-methyl) leucine; LR-cyano-2- (benzyl-sulfanyl) ethyl) amide; (1-R-cyano-2- (benzyl-sulfonyl) ethyl) amide of N- (4-orpholino-carbonyl) -L-leucine; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (benzyl-sulfinyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- ((4-methoxy-phenyl) methyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-chloro-phenyl) methyloxy-ethyl) amide; (1-R-cyano-2-benzyloxy-ethyl) amide of N- (5-dimethylamino-naphth-1-ylsulfonyl) -L- (4-methyl) leucine; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (2-methyl-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-methyl-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (4-methyl-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-carbomethoxy-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (4-carbomethoxy-phenyl) methyloxy-ethyl) amide; (1- S-cyano-3- (carbo-t-butoxy) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine;
(1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-leucine; [N- (-morpholino-carbonyl) -L-leucine-IS- (benzothiazol-2-ylcarbonyl) -3-phenyl-propyl] amide; [1- S-cyano-5- ((benzyloxycarbonyl) amino) -pentyl] amide of N- (4-morpholino-carbonyl) -L-leucine; [IR, S- (benzoxazol-2-ylcarbonyl) -3-phenyl-propyl] amide of N- (4-morpholino-carbonyl) -L-leucine; [[1- [(6-phenyl-carbamoyl) -benzothiazol-2-ylcarbonyl] -3-phenyl-propyl]] -amide of N- (4-morpholino-carbonyl) -L-leucine; [[6- (carbomethoxy) benzoxazol-2-ylcarbonyl] -3-phenylpropyl] amide N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholino-carbonyl) -L-cyclohexyl-alanine; (N- (4-morpholinocarbonyl) -L-cyclohexyl-alanine (LR-cyano-2-benzyloxyethyl) amide; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-nor-leucine; N- (4-morpholino-carbonyl) -L-leucine (1RS- ((5-phenyl-oxazol-2-yl) carbonyl) -3- phenylpropyl) amide; (N- (4-morpholino-carbonyl) -L-leucine; S- (oxazol-2-ylcarbonyl) -3-phenyl-propyl) -amide; [1- (Benzothiazol-2-ylcarbonyl) -3-phenyl-propyl] amide of N- (4-morpholino-carbonyl) -L- (4-methyl) leucine;
(1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (2-naphthyl) alanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (2-chloro-phenyl) alanine; (lR-cyano-2-benzyloxy-ethyl) amide of N-benzoyl 1-L-leucine;
(1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (O-methyl) tyrosine; (1- S-cyano-1-phenyl-methyl) amide of N- (4-morpholinocarbonyl) -L-leucine; N- (4-morpholinocarbonyl) -L-leucine (1-cyano-cyclopropyl) amide: N- (-morpholinocarbonyl) -L- (2- S-cyano-2- (2-chloro-phenyl) ethyl) amide leucine; (1- S-cyano-2- (4- (2,6-dichloro-methyl-oxy) -phenyl) -ethyl) -amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3- (carbobenzyloxy) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (ÍS, 3-dicyano-propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (ÍS, 2-dicyano-ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3- (methyl-sulfonyl) propyl) amide of N- (4-orpholino-carbonyl) -L-leucine; (1- S-cyano-3- (4-hydroxy-phenyl) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; and (1- S-cyano-2-cyclohexyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine. Any compounds of this invention which contain one or more asymmetric carbon atoms can be present in the form of racemates and racemic mixtures, individual enantiomers, mixtures of diastereomers as well as individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be in the R or S configuration, or in a combination of configurations. Some of the compounds of formulas (I), (a) and formulas (II), (Ha) can exist in more than one tautomeric form. The invention includes all said tautomers. It should be understood by one of ordinary skill in the art that all compounds of the invention are those that are chemically stable. The invention includes pharmaceutically acceptable derivatives of compounds of formulas (I), (a) and formulas (II), (Ha). A "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester of a compound of this invention or any other compound which, after its administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, a pharmacologically active metabolite or a pharmacologically active residue thereof. It should be understood that a pharmacologically active metabolite means any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the invention. In addition, the compounds of this invention include prodrugs of compounds of formulas (I), (a) and formulas (II), (Ha). Prodrugs include those compounds which, after a simple chemical transformation, are modified to produce the compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug of this invention is administered to a patient, the prodrug can be transformed into a compound of the formulas (I), (a) or of the formulas (II), (Ha), thereby conferring the desired effect pharmacological, In order that the invention described herein can be more fully understood, the following detailed description is set forth. As used in the present context, the following abbreviations are used: BOC or t-BOC is tertiary-carbonyl butoxy; t-Bu is tertiary butyl; DMF is dimethyl formamide; EtOAc is ethyl acetate; THF is tetrahydrofuran; Ar is argon; TFA is trifluoroacetic acid; EDC is 1- (3-dimethylamino-propyl) -3-ethyl-carbodiimide hydrochloride; HOBT is 1-hydroxy-benzotriazole. Also, as used in the present context, each of the following terms, used alone or in conjunction with other terms, is defined as follows (except where noted to the contrary): The term "alkyl" refers to a saturated aliphatic radical containing from one to ten carbon atoms or a mono- or poly-unsaturated aliphatic hydrocarbyl radical containing from two to twelve carbon atoms, containing at least one double or triple bond, respectively. "Alkyl" refers to both branched and unbranched alkyl groups. Preferred alkyl groups are straight chain alkyl groups containing from one to eight carbon atoms and branched alkyl groups containing from three to eight carbon atoms. More preferred alkyl groups are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms. It should be understood that any combination term using a prefix "ale" or "alkyl" refers to analogous compounds according to the above definition of "alkyl". For example, terms such as "alkoxy", "alkylthio" refer to alkyl groups linked to a second group through an oxygen or sulfur atom. "Alkanoyl" refers to an alkyl group bonded to a carbonyl group (C = 0). The term "cycloalguyl" refers to the cyclic analogue of an alkyl group, as defined above. Preferred cycloalkyl groups are saturated cycloalkyl groups containing from three to eight carbon atoms, and more preferably from three to six carbon atoms. The term "aryl" refers to phenyl and naphthyl. "Aroyl" refers to an aryl group bonded to a carbonyl group (C = 0). The term "halo" refers to a halogen radical selected from fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term "heteroaryl" refers to a 5- to 8-membered (but preferably 5-membered or 6-membered) monocyclic aromatic heterocycle radical or 8-11-membered bicyclic heterocycle. Each heterocycle consists of carbon atoms and from 1 to 4. heteroatoms selected from the group consisting of hydrogen, oxygen and sulfur As used in the present context, "nitrogen" and "sulfur" include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen. bonded by any atom of the cycle, which results in the creation of a stable structure Preferred heteroaryl radicals include, for example, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl , thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, b Enzyothiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl. quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl.
The term "heterocycle" refers to a 5- to 8-membered (but preferably 5-membered or 6-membered) monocyclic or 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated, and which is not aromatic. Each heterocycle consists of carbon atoms and 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As used in the present context, "nitrogen" and "sulfur" include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen. The heterocycle can be linked by any atom of the cycle, which results in the creation of a stable structure. Preferred heterocyclic radicals include, for example, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl.
GENERAL SYNTHESIS METHODS The invention also provides methods for preparing the present new compounds. The compounds of the invention can be prepared by the methods described below. Classical reactions of peptide coupling, protection and deprotection are used in this synthesis (see, for example, the work of M. Bodanszky, The Practice of Peptide Synthesis, Springer, 1984). The compounds of the invention having the formulas (II) or (Ha) (nitriles) can be prepared by Method A (Reaction Scheme I).
Reaction Scheme I (Method A)
X = OR '^ X = OH (¡V)
According to Method A, an appropriate amino acid carrying the radical R5 is reacted with ammonia under standard coupling conditions. An example of said protecting group is the t-butoxycarbonyl group (Boc). An example of classical coupling conditions would be to combine the starting materials in the presence of a coupling reagent such as 1- (3-dimethylamino-propyl) -3-ethyl-carbodiimide (EDC) with 1-hydroxy-benzotriazole (HOBT). ), in an appropriate solvent such as DMF or methylene chloride. A base such as N-methyl-morpholine can be added. This is followed by a deprotection to give the amino acid amide III. An amino acid ester that carries the radicals R? and R3 is then reacted with an acid chloride bearing the Ri radical in the presence of an appropriate base such as N, N-diisopropyl-ethyl-amine. Conversion to the carboxylic acid provides compound IV. A classical coupling of the peptides III and IV, followed by a dehydration of the amide provides the desired nitrile II or Ha. An example of suitable dehydration conditions is the use of cyanuric chloride in DMF. In a variant (Method B) illustrated in Reaction Scheme II, an amino acid amide bearing the radical Re is coupled to an amino-protected amino acid carrying the radicals R 2 and R 3. An appropriate protecting group and appropriate coupling conditions could be as described above. The deprotection is followed by the reaction with an acid chloride carrying the radical Ri. The conversion of the amide to the nitrile as above provides the compounds II or Ha.
Reaction Scheme II (Method B)
NH2
c
X = CONH2"X = CN (II)
The compounds of the invention having the formulas (I) or (la) (ketones) can be prepared by Methods C (Reaction Scheme III) or D (Reaction Scheme IV) which are described below.
Reaction Spoke III (Method C)
oxidatiop (
* oxidation oxidation
According to method C, an appropriately protected amino acid (eg, protected with Boc) is coupled with N, O-dimethyl-hydroxyl amine under standard coupling conditions, such as with the use of carbonyldiimidazole (CDl) in a di solvent. such as DMF to give the corresponding amide. This is reduced to form the aldehyde V with an appropriate reducing agent such as LiAlH4 in an appropriate solvent such as THF. The aldehyde (V) is reacted with the anion of a heterocycle Rs, which is generated by reacting R8 with a strong base such as n-BuLi in a solvent such as THF at a temperature of about -30 ° C to -100 ° C, and preferably at around -78 ° C. This is followed by a removal of the protective group that provides the alcohol (VI). This is coupled with (IV), prepared as described in Reaction Scheme I, under classical coupling conditions such as by use of EDC and HOBT in DMF in the presence of a base such as N-methyl-morpholine to provide the compound (VII). Oxidation of the compound (VII) with, for example, the reagent from Dess Martin (1,1, 1-triacetoxy-l, 1-dihydro-l, 2-benzoyodoxol-3 (lH) -one) in methylene chloride and t-BuOH, provides the desired ketone of formulas (I) or (la).
Reaction Scheme IV (Method D)
(IV) (
In Method D, an appropriately protected amino acid N-methoxy-N-methyl-amide (which is prepared as described in Reaction Scheme III) is subjected to treatment with the anion of an Rs heterocycle, which is generated by reacting R8 with a strong base such as n-BuLi in an appropriate solvent such as THF at a temperature of about -30 ° C to -100 ° C and preferably at about -78 ° C. Deprotection of the resulting ketone provides the compound (HIV). This is coupled to the compound (IV), which is prepared as described in Reaction Scheme I, under classical coupling conditions such as the use of EDC and HOBT within DMF in the presence of a base such as N -methylmorpholine, to provide the desired ketone of the formulas (I) or (la). The compounds of the invention in which A is a bond (formulas I, la and II, Ha) could be prepared in a manner analogous to the above Reaction Schemes using RiX, wherein X = Br, Cl or I instead of a acyl halide (R? C (O) Cl) in Reaction Schemes I and II, or by using R? NHC (R2) (R3) C02H in place of compound (IV) in Reaction Schemes III and IV. The intermediate compounds used in Reaction Schemes I-IV are either commercially available or are readily prepared by methods known to those skilled in the art. A method (Method E) which is useful for preparing substituted oxazoles, which can be used as Rp in Reaction Schemes III and IV (Methods C and D) is illustrated below in Reaction Scheme V.
Reaction Scheme V (Method E)
(I) (X) (Xf) (XII) (XIII)
* Acid = Acid
An N-protected amino acid, for example an amino acid (IX) protected with t-Boc, is coupled with N, 0-dimethyl-hydroxylamine using an appropriate coupling agent such as carbonyl-diimidazole (CDl), within an appropriate solvent such as CH2C12, THF or DMF, at about 0 ° C, to provide the compound (X). The protecting group of N is then removed, for example the t-Boc group can be removed by treatment with an appropriate acid, such as trifluoroacetic acid, in an appropriate solvent, such as CH 2 C 2. The resulting amine is coupled to the desired carboxylic acid using appropriate coupling conditions, such as the use of EDC with HOBT in an appropriate solvent such as DMF, in the presence of a base such as N-methyl-morpholine to provide a diamide (XI). The N-methoxy-methyl-amide is then treated with an appropriate reducing agent such as LiAlH4 in an appropriate solvent, such as THF, to provide an aldehyde (XII). Cyclodehydration (see, for example, the citation of P. ipf and S. Lim, J. Amer. Chem. Soc, 1995, 117, 558) of (XII) with triphenylphosphine and hexachloromethane in an appropriate solvent , such as acetonitrile in the presence of an appropriate base, such as Et3N, provides the desired oxazole (XIII). The desired disubstituted thiazoles, which can be used as R8 in Reaction Schemes III and IV
(Methods C and D) can be prepared by the Method of
Hantzsch, in which a thioamide is condensed with an alpha-halocarbonyl compound. This method is known to those skilled in the art and is well documented in the chemical literature (for example, in the citations of J. Metzger and EJ Vincent, The Chemistry of Heterocyclic Compounds, Vol. 34, 1979; of AR Katrizky et al., J. Org. Chem. 1995, 60, 5,638, and of R. Flaig and H. Hatmann, Heterocycles, 1997, 45, 875).
METHODS OF THERAPEUTIC USE The compounds of this invention effectively block the degradation of the invariant chain to form a CLIP by cathepsin S and therefore inhibit the presentation of antigens and antigen-specific immune responses. The control of antigen-specific immune responses is an attractive means of treating autoimmune diseases and other undesirable T cell-mediated immune responses. Treatment methods using the compounds of this invention for such conditions are therefore provided. These include autoimmune diseases including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis, Guillain-Barre syndrome, psoriasis, Grave's disease, myasthenia gravis, scleroderma, glomerulonephritis, atopic dermatitis and insulin-dependent diabetes mellitus. The compounds of the invention can also be used to treat other disorders associated with extracellular proteolysis, such as Alzheimer's disease. The compounds of the invention can also be used to treat other disorders associated with inappropriate autoimmune responses, T-cell mediated immune responses or cathepsin S-mediated extracellular proteolysis, unrelated to those enumerated above or discussed in the Background of the invention. Therefore, the invention also provides methods of modulating an autoimmune disease, comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound according to the invention. For therapeutic use, the compounds of the invention can be administered in any conventional dosage form and in any conventional manner. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, infusion, sublingual, transdermal, oral, topical or inhalation routes. Preferred modes of administration are those using the oral and intravenous routes. The compounds of this invention can be administered alone or in combination with adjuvants that enhance the stability of the inhibitors, facilitate the administration of pharmaceutical compositions containing them in certain embodiments, provide an increased solution or dispersion, increase an inhibitory activity, provide a therapy with adjuncts and the like, including other active ingredients. Advantageously, said combination therapies use lower dosages of conventional therapeutic compounds, thus avoiding the possible toxicity and the possible unfavorable side effects, which are incurred when these agents are used as monotherapies. The compounds of the invention can be physically combined with conventional therapeutic compounds and other adjuvants to form a single pharmaceutical composition. Advantageously, the compounds can then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising said combinations of compounds contain at least about 15%, but more preferably at least about 20%, of a compound of the formulas (I), (a), (II) or (Ha) ) (p / p = weight / weight) or a combination of these. Alternatively, the compounds can be administered separately (either in series or in parallel). A separate dosage allows greater flexibility in the dosage addition regime. As it mentioned above, dosage forms of the compounds of this invention include pharmaceutically acceptable carriers and adjuvants, known to those of ordinary skill in the art. These vehicles and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, buffering substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include those of tablets, capsules, caplets (= capsules-tablets), liquids, solutions, suspensions, emulsions, rhombic pills, syrups, reconstitutable powders, granules, suppositories and transdermal patches. Methods for preparing such dosage forms are known (see, for example, the appointment of HC Ansel and NG Popovish, Pharmaceu tral Dosage Forms and Drug Deli very Sys tems (pharmaceutical dosage forms and drug delivery systems), 5th edition , Lea and Febiger (1990)). Dosage levels and dosage requirements are well recognized in the art sector and can be selected by those with ordinary experience in the art sector from available methods and techniques that are appropriate for a particular patient. In some embodiments, the dosage levels range from about 10 to 1,000 mg / dose for a patient weighing 70 kg. Although one dose per day may be sufficient, up to 5 doses per day can be administered. For oral doses, up to 2,000 mg / day may be required. As an expert professional will appreciate, lower or higher doses may be required depending on particular factors. For example, specific dosing regimens in a treatment will depend on factors such as the general health profile of the patient, the severity and course of the patient's disorder or willingness to do so, and the judgment of the treating physician.
EXAMPLES OF SYNTHESIS
EXAMPLE 1 Morpholine-carboxylic acid 1- (S) - (1- (S) -cyano-3-phenyl-propyl-carbamoyl) -3-methylbutyl] -amide
As outlined generally in Reaction Scheme I (Method A), n-Boc-L-homophenylalanine (0.50 g, 1.79 mmol) was dissolved in 20 ml of DMF, which was cooled with a bath of ice and water. 1-Hydroxy-benzotriazole (HOBT) (0.29 g, 2.14 mmol) and EDC were added
(0.41 g, 2.00 mmol) followed by stirring during
min. Ammonium hydroxide (0.5 ml) was added and stirring was continued overnight (16 h). The reaction mixture was diluted with 50 ml of methylene chloride to give a white precipitate. The mixture was filtered and the filtrate was washed with brine (100 ml) followed by a saturated bicarbonate
(100 ml). The organic layer was dried over MgSO 4, filtered and concentrated by rotary evaporation to give the corresponding amide (0.45 g, 90%) which was used without further purification. The p-toluene sulfonate salt of benzyl-L-leucine (8.00 g, 20.3 mmol) was dissolved in 20 ml of DMF followed by the addition of N, N-diisopropyl-ethyl-amide (10.61 ml. ,
60.9 mmol) and by stirring under Ar for 15 min. 4-Morpholino-carbonyl chloride (4.55 g, 30.4 mmol) was added and the stirring was continued overnight
(16 h). The solution was diluted with 500 ml of EtOAc and washed with 3 times 500 ml of water. The organic layer was dried over MgSO4, filtered and concentrated by rotary evaporation to give 8.01 g of the crude product. The product was purified by flash chromatography (Si02, with a mixture of 40% EtOAc and hexane) resulting in a thick oil. This oil (18 g, 553.8 mmol) was dissolved in ethanol (500 ml). Pd (OH) 2 (642 mg) was added, followed by cyclohexene
(100 ml). The mixture was refluxed for 45 min, at which time TLC (thin layer chromatography) indicated the consumption of the benzyl ester. The reaction mixture was cooled and filtered through diatomaceous earth and evaporated to dryness to give 1 N- (4-morpholino-carbonyl) -L-leucine as a very thick oil.
(13 g, 99%) that was used without any further purification. The N-Boc-L-homophenyl-alanine-amide (from the first paragraph) (114 mg, 0.41 mmol) was dissolved in 10 ml of CH 2 Cl and 10 ml of trifluoroacetic acid (TFA) was added. Stirring was continued for 30 min, at which time the reaction mixture was evaporated to dryness to give the salt with TFA of the L-homo-phenyl-alanine amide. The N- (4-morpholino-carbonyl) -L-leucine (100 mg, 0.41 mmol) from the previous treatment was dissolved in 10 ml of DMF and cooled by an ice-water bath. HOBT (72 mg, 0.53 mmol) and EDC (102 mg, 0.53 mmol) were added and the mixture was stirred at 0 ° C for 15 min. To the cold solution was added the TFA salt of the amide salt of L-homo-phenyl-alanine as a solution in 5 ml of DMF, followed by the addition of N-methyl-morpholine (94 μl, 0.86 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature overnight (16 h). The reaction mixture was diluted with 50 ml of CH 2 Cl to give a white precipitate. The mixture was filtered and the solid material was washed with an additional 50 ml of CH2C12. The filtered materials were combined and washed with a saturated bicarbonate (100 ml), 1 N HCl (100 ml) and brine (2 x 100 ml). The organic layer was dried over MgSO4 and concentrated by rotary evaporation to give an oily residue. The residue was chromatographed (with SiO 2 in a mixture of 5% MeOH in
CH2Cl2) to give a white solid (130 mg, 78%). This amide (150 mg, 0.37 mmol) (material from more than one reaction) was dissolved in 2 ml of DMF and cooled to 0 ° C with an ice-water bath. To the solution was added cyanuric chloride (46 mg, 0.37 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for the next hour. A white precipitate formed in the course of the reaction. The reaction mixture was diluted with 100 mL of EtOAc and washed with 100 mL of water (3x). The organic layer was dried over MgSO 4, filtered and concentrated by rotary evaporation to give the crude residue.
The residue was purified by chromatography (SiO_, 40% hexane in EtOAc) to give the title compound as a white hard vitreous material (120 mg, 84%). XH NMR (270 MHz, CDCl 3): d 8.00-7.87 (1H, m), 7.35-7.13 (3H, m), 7.12-7.05 (2H, m), 5.10-5.02 (1H, m), 4.80-4.60 (1H, m), 4.45-4.20 (1H, m), 3.75-3.50 (4H, m), 3.45-3.30 (4H, m), 2.80-2, 60 (2H, m), 2.10-1.90 (2H, m), 1.70-1.45 (3H, m), 1.05-0.90 (6H, m)
EXAMPLE 2 2- (S) - (4-Dimethylamino-benzene-sul-onyl-amino) -methyl-pentanoic acid (1- (S) -cyano-3-phenyl-propyl) -amide
NH40H (4 mL) was added to a previously mixed solution (over 15 min) of N- (t-butoxycarbonyl) -L-homo-phenylalanine (4.00 g, 14.3 mmol), EDC (3.24 g, 11.2 mmol) and HOBT (2.32 g, 17.2 mmol) in DMF (20 ml) at room temperature. After 16 h the reaction mixture was diluted with CHiCl; and filtered, washed consecutively with 10% aqueous HCl, with saturated NaHCOs, with H 2 O (3 times), with brine, dried over Na 2 SO 4 and concentrated to give the N- (t-butoxycarbonyl) -amide of L- homophenyl-alanine (3.10 g, 78%) as a white solid. TFA (2.5 ml) was added to a solution of N- (t-butoxycarbonyl) -amide of L-homophenyl-alanine (1.00 g, 3.59 mmol) in CH2Cl2 (10 ml) at room temperature. After being stirred for 0.5 h, the reaction mixture was concentrated to give a colorless oil. As described in general terms by the Scheme of
Reaction II, Method B, the oil was dissolved in CH2CI
(10 ml) and in N, N-diisopropyl-ethyl-amine (1.90 g, 14.4 mmol) and added to a pre-mixed solution.
(15 min) of N- (t-butoxycarbonyl) -L-leucine (913 mg, 3.95 mmol), EDC (826 mg, 4.30 mmol), HOBT (581 mg, 4.30 mmol) in CH2C12 ( 10 ml) at room temperature. After stirring for 16 h, the reaction was quenched by the addition of H20, diluted with EtOAc, washed consecutively with 10% aqueous HCl, with saturated NaHCO3, with H20, with brine, dried over Na2SO4 and concentrated to give 1.3 g of a white solid. The crude solid was triturated with a mixture of 5% EtOAc and hexane to give the N- [N- (t-butoxycarbonyl) -L-leucinyl] -amide of L-homophenyl-alanine (1.1 g, 78%) as a solid of white color. TFA (2.5 mL) was added to a solution of the N- [N- (t-butoxycarbonyl) -L-leucinyl] -amide of L-homophenyl-alanine (500 g, 1.28 mmol) in CH2C12 (10 mL). ml) at room temperature. After stirring for 0.5 h, the reaction mixture was concentrated to give a colorless oil which was diluted with CH2C12 (2.5 mL). Diisopropyl-ethyl-amine (588 mg, 4.55 mmol) and p-Me NCeH S02Cl [repaired by the reaction of p-Me2NC6H4S0Na + (1.0 g, 4.48 mmol) with thionyl chloride were added at room temperature. and pyridine (1 ml) at 55 ° C for 2 h, followed by cooling, dilution with toluene and concentration to give p-Me2NC5H4S02Cl]. After stirring for 16 h, the reaction was quenched by the addition of H20, diluted with EtOAc, washed consecutively with 10% aqueous HCl with saturated NaHCO3, with H2O (3 times), with brine, dried Na2SO4 and concentrated to give a yellow solid (408 mg). The crude residue was fractionated by flash chromatography (mixtures of 25-100% EtOAc and hexane) to give 1 N- [N - ((4-dimethylamino-phenyl) sulfonyl) -leucinyl] -amide of L-homophenylalanine ( 90 mg, 15%) as a white solid. A certain amount of the title compound (60 mg, 10%) was likewise isolated from this reaction. Cyanuric chloride (33 mg, 0.18 mmol) was added to a solution of the N- [N- ((-dimethylamino-phenyl) sulfonyl) -L-leucinyl] -amide of L-homophenyl-alanine (80 mg, , 18 mmol) in DMF (2 ml) at 0 ° C. After stirring for 2 h, the reaction was quenched by the addition of saturated NaHCO 3, filtered, diluted with EtOAc, washed consecutively with H 0 (5 times), brine, dried over Na 2 S 4, and concentrated to give a yellow foam. The crude residue was fractionated by preparative HPLC (high performance liquid chromatography) (with a mixture of 65% AcCN, H20 and 0.1% TFA) to give the title compound (47 mg, 57%) as a white solid, m.p. 46-48 ° C. XH NMR (400 MHz, CDC13): d 7.74 (2H, d, J = 9), 7.37-7.34 (2H, m), 7.30-7.26 (2H, m), 7 , 23-7.21 (3H, m), 6.79 (1H, d, J = 8.5), 4.91 (1H, broad s), 4.70 (1H, ddd, J = 8, 8 , 8), 3.68-3.73 (1H, m), 3.06 (3H, s), 2.84-2.76 (2H, m), 2.16-2.09 (2H, m ), 1.63-1.56 (2H, m), 1.42-1.37 (1H, m), 0.88 (3H, d, J = 6), 9.71 (3H, d, J = 6).
EXAMPLE 3 2- (2- (S) -. {4-Methyl-2- (S) - [(morpholino-4-carbonyl) amino] -pentanoylamino} -4-phenylbutyryl acid phenyl-amide ) benzothiazole-6-carboxylic acid
As described in general terms in Method C, the N- (t-Boc) -L-homophenylalanine (10.0 g, 35.8 mmol) was dissolved in 50 ml of DMF. The solution was cooled to 0 ° C with an ice bath and water. To the reaction solution was added carbonyl-diimidazole (6.4 g, 39.4 mmol), followed by N-methyl-morpholine (3.9 g, 39.4 mmol). The reaction mixture was stirred for 1 h, at which time N, O-dimethyl-hydroxylamine hydrochloride (3.8 g, 39.4 mmol) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. The reaction solution was poured into 200 ml of 1 N HCl and extracted with 200 ml of EtOAc. The organic layer was washed with 2 x 100 ml of 1 N HCl, 100 ml of saturated sodium bicarbonate, 2 x 100 ml of water and 2 x 100 ml of brine. The organic layer was dried over Na 2 SO, decanted and concentrated by rotary evaporation to give the desired amide as a thick oil (11.1 g, 96% crude material) which was used without any further purification. The amide (3.7 g, 11.5 mmol), dissolved in 20 ml of THF, was added dropwise over the course of 20 min. a suspension of LiAlH4 (0.53 g, 13.9 mmol) in 60 mL of THF, which was cooled to 0 ° C in an ice-water bath. The mixture was stirred for 15 min, then quenched with 10 ml of a saturated solution of sodium bicarbonate, diluted with 200 ml of water and extracted with 3 x 100 ml of EtOAc. The organic layers were combined and washed with 100 ml of 1 N HCl and 2 x 100 ml of brine. The organic layer was dried over Na 2 SO 4, filtered over a pad of diatomaceous earth and concentrated by rotary evaporation. The residue was purified by flash chromatography (SiO2, mixtures of 5% i-PrOH in CH2C12) to give the desired aldehyde as an oily solid (2.4 g, 79%). To a dried flask of 100 ml capacity were added 6- (phenyl-carbamoyl-1) benzothiazole (0.58 g, 2.3 mmol) and THF (12 ml). The reaction mixture was cooled to -78 ° C with a dry ice bath and acetone. N-BuLi (2.5 M in hexanes) (1.8 ml, 4.5 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred for 20 min to give a suspension. A solution of the above aldehyde (200 mg, 0.75 mmol) in 3 ml of dry THF was added all at once through a syringe. The temperature was gradually increased to -40 ° C and the reaction mixture was stirred for 3 h at which time the TLC showed consumption of the aldehyde. The reaction was quenched at -78 ° C by the addition of a saturated solution of NH 4 Cl and the product was extracted with 50 ml of EtOAc. The organic layer was dried over MgSO, filtered and concentrated to give a residue which was purified by chromatography (SiO2, 2% MeOH in CHCl2) to give the desired alcohol as a solid material (194 mg, 50%) . The N- (4-morpholino-carbonyl) -L-leucine (26.4 mg, 0.11 mmol) prepared as described in example 1, was dissolved in 2 ml of DMF. The solution was cooled to 0 ° C with an ice-water bath and HOBT (19 mg, 0.14 mmol) and EDC (27 mg, 0.14 mmol) were added and then the solution was stirred for 20 min. The salt with TFA of the N-deprotected alcohol from the above (prepared by stirring the above alcohol protected with N-Boc in methylene chloride with TFA at room temperature for 30 min and evaporation to dryness) (57 mg, 0.11 mmol of the precursor with N-Boc) was added to the reaction mixture as a solution in 1 ml of DMF, followed by the addition of N-methyl-morpholine (35 μl, 0.32 mmol). The reaction mixture was stirred for 3 h, diluted with EtOAc and washed with 10 ml of 1 N HCl and 10 ml of saturated bicarbonate in 2 x 100 ml of brine. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography (SiO 2, 2% MeOH in CH 2 Cl 2) to give the desired coupled product as a white solid (57 mg, 82%).
To the above product (50.4 mg, 0.08 mmol) were added Dess-Martin periodinane (133 mg, 0.31 mmol), 10 ml of CH2C12 and 4 ml of t-BuOH. The reaction mixture was allowed to stir overnight at room temperature. This was then diluted with 20 ml of CH2C12, washed with 20 ml of a saturated solution of Na2S2? 3 and 20 ml of a NaHCO solution, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated . The residue was purified by chromatography (SiO 2, 2% MeOH in CH 2 Cl) to give the title compound as a white solid (30 mg, 60%). aH NMR (270 MHz, CDC1A: d 8.77-8.70 (1H, m), 8.57-8.52 (1H, m), 8.28-8.20 (1H, m), 8, 15-8.07 (1H, m), 7.78-7.68 (2H, m), 7.45-7.35 (2H, m), 7.29-7.05 (7H, m), 5.75-5.65 (1H, m), 5.00-4.92 (1H, m),
4.54-4.41 (1H, m), 3.74-3.58 (4H, m), 3.40-3.24 (4H, m),
2.78-2.62 (2H, m), 2.51-2.32 (1H, m), 2.21-2.02 (1H, m),
1.90-1.40 (3H, m), 1.00-80.80 (6H, m).
EXAMPLE 4 { 1- (S) - [1- (S) - (benzothiazole-2-carbonyl) -3-phenyl-propylcarbamoyl] -3-methyl-butyl} - morpholine-4-carboxylic acid amide
The THF dried (1.5 ml), under Ar, was cooled to -78 ° C with a dry ice bath and acetone. To the reaction flask was added n-BuLi (2.0 M in hexanes) (698 μl, 1.40 mmol), followed by the dropwise addition of freshly distilled benzothiazole (180 mg, 1.40 mmol) as a a solution in 0.5 ml of dry THF. The reaction mixture was stirred for 15 min to give a suspension. A solution of N- (t-butoxycarbonyl) - (N '-methyl-N' -methoxy) -L-amide of ho-ofenylalanine (300 mg, 0.930 mmol) (prepared as a whole) was added all at once through a syringe. it has been described in Example 3) in 1 ml of dry THF. The reaction mixture was stirred for 5 min, at which time the TLC showed the consumption of the amide. The reaction was quenched by the addition of water and the product was extracted with 50 ml of EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a residue which was purified by preparative TLC (with CH2C12) to give the desired ketone as a clear, colorless oil. The N- (4-morpholino-carbonyl) -L-leucine (82 mg, 0.34 mmol) (prepared as described in Example 1) was dissolved in 2 ml of DMF. The solution was cooled to 0 ° C with an ice bath and water and HOBT (60 mg, 0.44 mmol) and EDC (83 mg, 0.44 mmol) were added and the solution was stirred for 20 min. The salt with TFA of the ketone deprotected in N from the above (prepared by stirring the above alcohol protected with N-Boc in methylene chloride with TFA at room temperature for 30 min. And evaporation to dryness) (133 mg, 0.34 mmol of the precursor with N-Boc) was added to the reaction as a solution in 1 ml of DMF, followed by the addition of N-methyl-morpholine (77 μl, 0.70 mmol). The reaction mixture was stirred for 3 h, diluted with EtOAc and washed with 100 ml of 1 N HCl and 100 ml of saturated bicarbonate as well as 2 x 100 ml of brine. The organic layer was dried over MgSO 4, filtered and concentrated. The residue was purified by chromatography (SiO2, 50% EtOAc in hexane) to give the title compound as a white solid material (40 mg, 23%) which was shown to be a 1-by-1 mixture of two epimers. ? E NMR (270 MHz, CDC13): d 8.15-8.08 (1H, m), 7.98-7.88 (1H, m), 7.60-7.40 (2H, m), 7.25-7.07 (5H, m), 7.02-6.92 (1H,), 5.90-5.75 (1H, m), 4.98-4.90 (1H, m) , 4.50-4.35 (1H, m), 3.66-3.57 (4H, m), 3.40-3.30 (4H, m), 3.40-3.30 (4H, m), 2.80-2.70 (2H, m), 2.50-2.35 (1H,), 2.25-2.10 (1H,), 1.80-1.40 (3H, m), 1, 00-0, 88 (6H,).
EXAMPLE 5 { 1- (S) - [1- (S) - (2,4-diphenyl-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -3-methyl-butyl} - morpholine-4-carboxylic acid amide
As outlined generally in Reaction Scheme IV (Method D), the 2,4-diphenyl-oxazole (361 mg, 1.63 mmol) in 15 ml of dry THF was cooled to -78 ° C and added n-butyl-lithium (1.16 ml of a solution 1, 4 M, 1.63 mmol). After stirring for 1 h at -78 ° C, a solution of the N- [N- (t-butoxycarbonyl) -L-leucinyl] -amide free base of L-homophenylalanine (prepared as above) was added dropwise. described in Example 3) in 5 ml of dry THF. The temperature of the reaction mixture was allowed to rise to -20 ° C and was maintained for 2 h, after which time the reaction mixture was quenched with 100 ml of NH 4 Cl (10% aqueous) and extracted with 3 ml. x 100 ml EtOAc. The combined extracts were washed with 2 x 100 ml of brine, dried with Na 2 SO 4, filtered and concentrated. The resulting residue was purified by chromatography (Florisil, mixtures of 15% -20% hexane in EtOAc) to give 190 mg (72%) of the [1- (2, -diphenyl-oxazole-5-carbonyl-tert-butyl ester. -3-phenyl-propyl] carbamic acid. The N- [(4-morpholinyl) carbonyl] -leucine (100 mg, 0.35 mmol) (prepared as described in Example 1, was dissolved in 10 ml of DMF and cooled to 0 ° C. solution was added EDC (77 mg, 0.4 mmol) and HOBT (54 mg, 0.4 mmol) and the reaction mixture was stirred for 1 h. In a separate flask, the tert-butyl ester was dissolved. of [1- (2, 4-diphenyl-oxazole-5-carbonyl) -3-phenyl-propyl] carbamic acid (158 mg, 0.31 mmol) in 4 mL of CH2C12 and 2 mL of TFA was added. After stirring for 1 h, the solvents were evaporated, the residue was dissolved in 5 ml of DMF and N-methyl-morpholine (406 mg, 0.4 mmol) was added.The resulting solution was added to the previously prepared solution of the derivative. of leucine activated at 0 ° C. The reaction mixture was stirred at room temperature for 3 h, cooled to 0 ° C., and quenched with 100 ml of a 10% solution of citric acid in water. It was extracted with 3 x 100 ml of EtOAc The combined organic extracts were washed with 2 x 100 ml of saturated bicarbonate and 1 x 100 ml of brine. The organic layer was dried over Na S0, filtered and concentrated to give a residue which was purified by chromatography (Florisil, mixtures of 30% -50% EtOAc in hexane) to give the title compound as a solid color material. white (90 mg, 84%), mp 83-5 ° C, MS (ES) 609 (M +). The following compounds were also prepared using the procedure described in Example 5:
. { 1- (S) - [1- (S) - (2,4-diphenyl-oxazole-5-carbonyl) -3- phenyl-propyl-carbamoyl] -3,3-dimethyl-butyl} Morpholine-4-carboxylic acid amide, m.p. 95-7 ° C, MS (ES) 623 (M +). . { 2-Cyclohexyl-1- (S) - (1 - [(S) - (2, -diphenyl-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -ethyl} -amide of morpholine- 4-carboxylic acid, mp 93-5 ° C, MS (ES) 649 (M +) { 1- (S) - [(2,4-diphenyl-oxazol-5-yl) -2-oxo-ethyl- carbamoyl] -3-methyl-butyl.} - morpholine-4-carboxylic acid amide, mp 155-7 ° C, MS (ES) 505 (M +) {2-cyclohexyl-l- (S) - [2- (2, -dipheni-1-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -ethyl.} - morpholine-4-carboxylic acid amide, mp 122-3 ° C, MS (ES) ) 545 (M +) { L- (S) - [2- (2, -diphenyl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -3,3-dimethyl-butyl. -amino-4-carboxylic acid amide, mp 97-9 ° C, MS (ES) 519 (M +). (1- (S) -. {1- (S) - [2- (3-benzyloxy- phenyl) -oxazole-5-carbonyl] -3-phenyl-propyl-carbamoyl-1.} - 3-methyl-butyl) -amide of morpholine-4-carboxylic acid, mp 61-3 ° C, MS (ES) 639 (M +).
. { 2-cyclohexyl-1- (S) - [1- (R, S} - (4-isobutyl-2-pyridin-2-yl-oxazole-5-carbonyl) -3-phenyl-propylcarbamoyl] -ethyl} - morpholine-4-carboxylic acid amide, mp 93-5 ° C MS (ES '649.
EXAMPLE 6 2- (4-Isobutyl-oxazol-2-yl) pyridine (Method E)
The N- (t-butoxy) -L-leucine (10 g, 43 mmol) was dissolved in 200 ml of CH2C12. The solution was cooled to 0 ° C with an ice and water bath. Carbonyldiimidazole (7.7 g, 47.5 mmol) was added and the reaction mixture was stirred for 1 h. The N, O-dimethyl-hydroxylamine hydrochloride (4.64 g, 47.8 mmol) was added at 0 ° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h. The reaction solution was poured into 200 ml of an ice-cooled solution of 5% citric acid. The organic layer was separated, washed with 2 x 100 ml of 1 N HCl, 1 x 100 ml of saturated NaHCO 3 and 2 x 100 ml of brine. The organic layer was dried over Na 2 SO 4, filtered and concentrated by rotary evaporation to give the [1- (N-methoxy-N-methyl-carbamoyl) -3-methylbutyl] carbamic acid tert-butyl ester as a thick oil ( 7.39 g, 59% crude) which was used without further purification. The ester tere. -butyl from the previous treatment (1 g, 3.47 mmol) was dissolved in 10 mL of CH2C12 and 5 mL of trifluoroacetic acid was added. The reaction mixture was stirred for 1 h. The solvents were evaporated and the residue was taken up in 2 x 10 ml of CH 2 Cl 2 and evaporated to give an oil. In a separately placed flask picolinic acid (470 mg, 3.82 mmol) was dissolved in 10 ml of DMF and the resulting solution was cooled to 0 ° C. EDC (787 mg, 4.1 mmol) and HOBT (554 mg, 411 mmol) were added and the reaction mixture was stirred at 0 ° C for 1 h. In a separately placed flask, the above-prepared free amine was dissolved in 5 ml of DMF and 1.5 ml of N-methyl-morpholine was added. The solution was added to the reaction mixture at 0 ° C. The reaction mixture was allowed to stir at room temperature for 16 h, after which time it was poured into a mixture of ice and 5% citric acid (100 ml) and extracted with 4 x 30 ml EtOAc. The combined EtOAc extracts were washed with 3 x 100 mL of brine, 2 x 100 mL of NaHCO, 1 x 100 mL of brine, dried with NaSO4, and evaporated to give an oil, which was dried under vacuum to provide 990 mg (100%) of [1- (N-methoxy-N-methyl-carbamoyl) -3-methylbutyl] -amide of pyridine-2-carboxylic acid. This amide was used without further purification. The amide from the previous treatment
(4.7 g, 14.7 mmol) was dissolved in 50 mL of THF and added to a suspension of LiAlH4 (558 mg, 4.7 mmol) in 50 mL of THF at -78 ° C. The reaction mixture was allowed to warm to 0 ° C and was maintained for 15 min, after which time it was cooled to -78 ° C and cannulated into an ice-cooled solution of KHS04 (8.16 g, 60 ml). mmol) in 200 ml of H20. The resulting mixture was extracted with 5 x 100 ml EtOAc. The combined extracts were washed with 2 x 100 ml of saturated NaHCO 3 and 1 x 100 ml of brine.were dried with Na2SO4 and vaporated to an oily residue which was chromatographed with rapid resolution through Si02 (with a gradient of mixtures from 25% EtOAc and hexane to 35% EtOAc and hexane) to give 2.8 g ( 86%) of the pyridine-2-carboxylic acid (1-formyl-3-methyl-butyl) -amide as a colorless oil that solidified upon standing. Hexachloroethane (445 mg, 1.87 mmol) was dissolved in 5 mL of CH3CN. A solution of pyridine-2-carboxylic acid (1-formyl-3-methyl-butyl) amide (137.5 mg, 0.625 mmol) in 2 ml of CN CH was added, followed by triethylamine (375 mg, 3.75 mmol) and triphenylphosphine (491 mg, 1.87 mmol). The resulting mixture was stirred for 1/2 h, poured into brine and extracted with 2 x 25 mL EtOAc. The combined extracts were washed with 1 x 50 ml of brine, dried with Na 2 SO 4 and evaporated to give 665 mg of a tan solid material, which was chromatographed with rapid resolution through Si02 (gradient of mixtures from 20% to 35% hexane and EtOAc) to give 100 mg (76%) of the title compound as an amber oil, MS (ES) 203 (M +).
EVALUATION OF BIOLOGICAL PROPERTIES
Expression and purification of recombinant human cathepsin S
Cloning of human cathepsin S:
The U937 RNA was subjected to a reverse transcriptase polymerase chain reaction with primer A (5 'cacaatgaaacggctggtttg 3') and primer B (5 'ctagatttctgggtaagaggg 3') designed to specifically amplify the cathepsin S cDNA. The resulting DNA fragment of 900 bp (base pairs) was subcloned into pGEM-T (Promega) and sequenced to confirm its identity. This artificial structure was used for all subsequent manipulations. This procedure is typical for the cloning of known genes and is enshrined in its field. The human Pre-Pro-Cat S was removed from the pGem-T vector (Promega, 2800 Woods Hollow Rd. Madison, Wl 53711) by digestion with the restriction enzyme Sacll, followed by treatment with DNA polymerase of
T4 to generate a blunt end, and for a second digestion with the Sali restriction enzyme. This material was subcloned into the donor plasmid pFastBací
(GibcoBRL, 8717 Grovemont Cr., Gaithersburg, MD 20884) that had been cut with the restriction enzyme BamHl and terminated in blunt ends and then cut with the SalI restriction enzyme. The ligation mixture was used to transform DH5a competent cells (GibcoBRL) and seeded onto LB plates containing 100 μg / ml ampicillin. Colonies were grown in overnight cultures of LB media containing 50 μg / ml ampicillin, plasmid DNA was isolated and the correct insert confirmed by restriction enzyme digestion. The recombinant pFastBac donor plasmid was transformed into competent DHlOBac cells (GibcoBRL). Large white colonies were harvested from LB plates containing 50 μg / ml kanamycin, 7 μg / ml gentamicin, 10 μg / ml tetracycline, 100 μg / ml Bluo-gal and 40 μg / ml IPTG. The DNA was isolated and used to transfect Sf9 insect cells using the CellFECTIN reagent (GibcoBRL). The cells and the supernatant were harvested after 72 hours. The viral supernatant was passed twice and the presence of Cat S was confirmed by a PCR of the supernatant. SF9 cells were infected with recombinant baculovirus with an MOI of 5 for 48-72 hours. The cell pellet was lysed and incubated in a buffer at pH 4.5 at J37 ° C for 2 hours to activate Cat S from the pro form to the active mature form (Bromme, D &McGrath, M., Protein Science, 1996, 5: 789-791). The presence of Cat S was confirmed by SDS-PAGE and Western blotting using anti-human rabbit proCat S.
Inhibition of Cathepsin S Recombinant human cathepsin S expressed in Baculovirus at a final concentration of 10 nM in a buffer is used. The buffer is 50 mM sodium acetate, pH 6.5, 2.5 mM EDTA, 2.5 mM MTCEP. The enzyme is incubated with either compound or with DMSO for 10 min at 37 ° C. The substrate 7-amino-4-methyl-coumarin, CBZ-L-valyl-L-valyl-L-arginine-amide (synthesis by charge by Molecular Probes (molecular probes)) is diluted to 20 μm in water (with the final concentration of 5 μm), is added to the analysis system and incubated for an additional 10 minutes at 37 ° C. The activity of the compound is measured by a decreased fluorescence compared to a DMSO control when read at excitation at 360 nm and emission at 460 nm. The compounds of the Examples enumerated above were evaluated for the inhibition of cathepsin S in the above analysis system. All of them had an ICEO value of 100 micromolar or less. The following prophetic compounds can be prepared according to the procedure outlined in Reaction Scheme IV (Method D), and Specific Example 5.
. { 1- [2- (4-Isobutyl-2-pyridin-2-yl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -3-methyl-butyl} - morpholine-4-carboxylic acid amide; . { 1- [2- (4-Cyclohexylmethyl-2-pyridin-2-yl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -3-methyl-butyl} - morpholine-4-carboxylic acid amide; . { 1- [2- (4-Cyclohexylmethyl-2-pyridin-3-yl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -3-methyl-butyl} - morpholine-4-carboxylic acid amide; . { 2-cyclohexyl-l- [2- (4-cyclohexylmethyl-2-pyridin-3-yl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl-1] -ethyl} Morpholine-4-carboxylic acid amide; . { 2-cyclohexyl-l- [2- (4-isobutyl-2-pyridin-3-yl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -ethyl} - morpholine-4-carboxylic acid amide; . { 1- [2- (4-Isobutyl-2-pyridin-3-yl-oxazol-5-yl) -2 -oxo-ethyl-carbamoyl] -3-methyl-butyl} - morpholine-carboxylic acid amide; . { 1- [1- (4-Isobutyl-2-pyridin-3-yl-oxazole-S-carbonyl) -3-phenyl-propyl-carbamoyl-1] -3-methyl-butyl} - morpholine - carboxylic acid amide,. { 1- [1- (4-Isobutyl-2-pyridin-3-yl-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -3,3-dimethyl-butyl} - morpholine-4-carboxylic acid amide;
. { 1- [1- (4-Isobutyl-2-pyridin-4-yl-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -3,3-dimethyl-butyl] -amide of morpholine-4- carboxylic; . { 2-Cyclohexyl-l- [1- (4-isobutyl-2-pyridin-4-yl-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -ethyl} - morpholine-4-carboxylic acid amide; . { 2-cyclohexyl-l- [1- (4-cyclohexylmethyl-2-pyridin-4-yloxazole-5-carbonyl) -3-phenyl-propylcarbamoyl] -ethyl} - morpholine-4-carboxylic acid amide; (2-cyclohexyl-l- { 1- [4-isobutyl-2- (1-methyl-piperidin-4-yl) -oxazole-5-carbonyl] -3-phenyl-propylcarbamoyl} -ethyl) - Morpholine-4-carboxylic acid amide; (1- (1- [4-isobutyl-2- (l-methyl-piperidin-4-yl) -oxazole-5-carbonyl] -3-phenyl-propyl-carbamoyl}. -3,3-dimethyl-butyl ) - morpholine-4-carboxylic acid amide: (1- {1- [4-isobutyl-2- (l-pyrimidin-2-yl-piperidin-4-yl) -oxazole-5-carbonyl] -3 morpholine-4-carboxylic acid-phenyl-propylcarbamoyl-1, -3,3-dimethyl-butyl) -amide: (1- {2- [4-isobuty1-2- (l-pyrimidin-2-yl- piperidin-4-yl) -oxazol-5-yl] -2-oxo-ethyl-carbamoyl-1, -3,3-dimethyl-butyl) -amide of morpholine-4-carboxylic acid; - [4-cyclohexylmethyl-2- (l-pyrimidin-2-yl-piperidin-4-yl) -oxazol-5-yl] -2-oxo-ethyl-carbamoyl] -3-methyl-butyl) -amide of morpholine-4-carboxylic acid;
. { 1- [2- (4-Cyclohexylmethyl-2-piperidin-3-yl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -3-methyl-butyl} - morpholine-4-carboxylic acid amide; . { 1- [2- (4-Isobutyl-2-piperidin-3-yl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -3-methyl-butyl} - morpholine-4-carboxylic acid amide; (1-. {2- [4-isobuty1-2- (l-methyl-piperidin-3-yl) -oxazol-5-yl] -2-oxo-ethyl-carbamoyl} -3-methyl-butyl ) - morpholine-4-carboxylic acid (l-. {2- 2- [4-isobutyl-2- (l-methyl-piperidin-3-yl) -oxazol-5-yl] -2-oxo-ethyl- carbamoyl.} - 3, 3-dimethyl-butyl) -amide of morpholine-4-carboxylic acid; (1- {2- [4-Isobutyl-2- (1-methyl-piperidin-2-yl) -oxazol-5-yl] -2-oxo-ethyl-carbamoyl} -3,3-dimethyl -butyl) -amino-4-carboxylic acid amide; (1- { 1- [4-Isobutyl-2- (l-methyl-piperidin-2-yl) -oxazole-5-carbonyl] -3-phenyl-propyl-carbamoyl-1.} -3-methyl-butyl ) - morpholine-4-carboxylic acid amide; . { 1- [-isobutyl-2-pheny1-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -3-methyl-butyl} - morpholine-4-carboxylic acid amide; . { 1- [1- (-dimethylaminomethyl-2-phenyl-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -3-methyl-butyl} - morpholine-4-carboxylic acid amide;
. { 1- [2- (-dimethylaminomethyl] -2-phenyl-oxazol-5-yl} -2-oxo-ethyl-carbamoyl] -3-methyl-butyl} -amide of morpholine-4-carboxylic acid; {2-cyclohexyl-l- [2- (4-dimethylaminomethyl-2-phenyl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -ethyl} -amide of morpholine-4-carboxylic acid; {. 1- [2- (4-Dimethylaminomethyl-2-phenyl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -3,3-dimethyl-butyl} -amide of morpholine-4 -carboxylic acid; {. 1- [1- (4-dimethylaminomethyl-2-phenyl-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -3,3-dimethyl-butyl} -amide morpholine-4-carboxylic acid; {. 1- [1- (-hydroxymethi1-2-phenyl-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -3,3-dimethyl-butyl} -amide of morpholine-4-carboxylic acid (3, 3-dimethyl-l-. {2- 2- [4- (4-methyl-piperazin-1-ylmethyl) -2-phenyl-oxazol-5-yl] -2- oxo-ethyl-carbamoyl) -butyl) -amino-4-carboxylic acid (3, 3-dimethyl-l-. {2- [4- (4-methyl-piperazin-1-ylmethyl) - 2-pyridin-4-yl-oxazo l-5-yl] -2-oxo-ethyl-carbamoyl} -butyl) -amino-4-carboxylic acid amide; (3-methyl-l- { 1- [4- (4-methyl-piperazin-1-ylmethyl) -2-pyridin-4-yl-oxazole-5-carbonyl] -3-phenyl-propyl-carbamoyl} - butyl) - morpholine-4-carboxylic acid amide;
benzyl ester of acid. { 1- [4-isobutyl-5- (2-. {4-methyl-2- [(morpholino-4-carbonyl) -amino] -pentanoylamino] -acetyl) -oxazol-2-yl] -3- methylbutyl} -carbamic; . { 2-cyclohexyl-l- [1- (4-isobutyl-2-pyrimidin-4-yl-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -ethyl} - morpholine-4-carboxylic acid amide; . { 2-cyclohexyl-l- [3-phenyl-1- (4-phenyl-2-pyridin-4-yl-thiazole-5-carbonyl) -propyl-carbamoyl] -ethyl} - morpholine-4-carboxylic acid amide; Y . { 2-Cyclohexyl-l- [2-oxo-2- (2-pyridin-4-yl-4-p-tolyl-thiazol-5-yl) -ethyl-carbamoyl] -ethyl} - morpholine-carboxylic acid amide. The preferred prophetic compounds have the stereochemistry S in their asymmetric carbons.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.
Claims (49)
- 8. The compound according to claim 7, characterized in that: A is -C (0) - or -S02-; Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl or amino, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, Cl-3 alkoxy, Cl-3 alkoxy -carbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino alkanoyl, aroylamino, Cl-5-sulfonylamino alkyl, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkoxy, halogen and hydroxy; R is Cl-5 alkyl or C5-6 cycloalkyl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, thienyl, imidazolyl, pyridinyl, indolyl, Cl-4 alkoxy, Cl-5-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re-Re is selected from the group consisting of methyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl , halogen and hydroxy; Rf is selected from the group consisting of C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy, benzyloxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulphone, methoxycarbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with halogen or methyl; methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; halogen, hydroxy and carboxy; R8 is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more Rj; R j is selected from the group consisting of methyl, phenyl, furanyl, thienyl, benzyl, methoxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; acetylamino, benzoylamino, ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; methoxycarbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; halogen, hydroxy, carboxy and cyano, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of methyl, phenyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; benzyloxycarbonylamino, benzyloxycarbonylamino-Cl-5 alkyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl, phenyl, furanyl or thienyl; halogen, hydroxy, carboxy, cyano and nitro. 9. The compound according to claim 8, characterized in that: Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl or thiopyranyl, wherein Ri is optionally substituted with one or more Rt >;; Rb is selected from the group consisting of pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbo amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy and carboxy, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of methoxy, halogen and hydroxy; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phe Cl-4 alkoxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re-Re is selected from the group consisting of methyl, phe methoxy, halogen and hydroxy; Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, thienyl, indolyl, methoxy, methylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with halogen; methoxy, phenoxy, benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy; R8 is a heteroaryl ring selected from the group consisting of oxazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more Rj; R j is selected from the group consisting of methyl, phenyl, benzyl, methoxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; methoxycarbonylamino, halogen, hydroxy and carboxy, R3 may also be optionally substituted Rk is selected from the group consisting of methyl, phenyl, methoxy, methoxycarbonyl, carbamoyl in which the nitrogen atom can be independently mono- or disubstituted with methyl or phenyl , benzyloxycarbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; halogen, hydroxy and carboxy. 10. The compound according to claim 9, characterized in that: Ri is phenyl or 4-morpholinyl, wherein Rx is optionally substituted with one or more Rb; Rb is selected from the group consisting of benzimidazolyl, methoxy and dimethylamino, Rb may also be optionally substituted with a halogen atom; R3 is alkyl Cl-5 wherein R3 is optionally substituted with one or more R; Rd is selected from the group consisting of C3-6 cycloalkyl and phenyl, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl and halogen, R6 is Cl-5 alkyl optionally substituted with one or more Rf; Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, and halogen, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, methoxy, methoxycarbonyl, halogen and hydroxy; R8 is a heteroaryl ring selected from the group consisting of oxazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more Rj; Rj is selected from the group consisting of phenyl, methoxycarbonyl, carbamoyl in which the nitrogen atom can be independently mono- or disubstituted with methyl or phenyl; methoxycarbonylamino and halogen, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of phenyl, methoxycarbonyl, carbamoyl, benzyloxycarbonylamino and halogen. 11. A compound of the ula (la): of the ula (la): gives; characterized in that A is -C (Y) - or -S02- Y is 0, S or NRa wherein Ra is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylamino and arylamino; Ri is alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or amino wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di- -substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with alkyl , aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R2 is H or alkyl; R3 is H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R3 is optionally substituted with one or more groups of the formula Rd; Rd is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, het erocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R 4 is H or alkyl; R5 is H, alkyl or cycloalkyl; R6 is H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein Re is optionally substituted with one or more groups of the formula Rf; Rf is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkanoyl, aroyl, arylalkoxy, heteroarylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylalkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, ami not in which the nitrogen atom can be independently mono- or di-substituted with alkyl, heterocyclyl or heteroaryl aryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf can also be optionally substituted with one or more Rg; Rg is selected from the group consisting of alkyl, cycloalkyl, aryl optionally substituted by halogen, Cl-5 alkoxy or Cl-5 alkoxy, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in the that the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl; alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl; alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl; halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; or R5 together with R6 forms a carbocyclic ring of 3 to 6 members, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of alkyl, aryl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with a group selected from alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl or heteroaryl; halogen, hydroxy, carboxy and cyano; R7 is R8-C (Z) -; wherein Z is O, S, or NRX in which Rx is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, and hydroxy; Rs is a 5- to 8-membered monocyclic or 8-membered bicyclic heteroaryl ring system, each having monocyclic or bicyclic ring systems 1-4 of the same or different heteroatoms selected from the group consisting of N, O and S wherein any of the above R8 may optionally be substituted with one or more R; Rj is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, alkanoyl, aroyl, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylalkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl; alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl; halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, R3 may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted. with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido wherein any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, arylalkoxycarbonylaminoalkyl, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, wherein Rk may also be optionally substituted with Ri; Ri is selected from the group consisting of alkyl, cycloalkyl, aryl and benzyl; X is 0, S or N-OH; and its pharmaceutically acceptable derivatives; with the following conditions: when R6 is alkyl, the alkyl must be substituted with Rf in which Rf is not to be hydroxy, sulfhydryl or halogen; And when Ri is alkyl Cl then Rb can not be carbamoyl, alkanoylamino, aroylamino, ureido, alkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aryisulphonylamino, amino, amidino or guanidino in which each of said Rb is linked to Ri through its nitrogen. The compound according to claim 11, characterized in that: Ra is selected from the group consisting of H, alkyl and aryl; Ri is Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomylpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl in which the The nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetr azolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroyl amino , alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the atoms of nitrogen may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pirim idinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxyalzolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino , alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkenyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected among the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benz oxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-8 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R3 is H, Cl-8 alkyl, C3-7 cycloalkyl or aryl wherein R3 is optionally substituted with one or more Rg; Rd is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, alkanoyl, aroyl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazo lilo, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8 -amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl , thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl , pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rd may also be optionally substituted Re is selected from the group consisting of alkyl Cl-8, cycloalkyl C3-6, aryl, arylalkyl, alkoxy Cl-8, aryloxy, arylalkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R5 is H or alkyl; Re is H, Cl-8 alkyl, C3-7 cycloalkyl or aryl wherein R5 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanils, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, aryl-alkoxy Cl-8, heteroaryl-alkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, is otiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl -8-amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl- alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxa zolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl optionally substituted by halogen, Cl-3 alkyl or Cl-3 alkoxy; heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, arylalkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, 10 thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, 15 benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, Aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which Any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, Tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, Quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyloxy, arylcarbamoyloxy, Alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl and arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with alkyl, aryl, Heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rh is selected from the group consisting of alkyl Cl-8, aryl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, aryl-alkoxy Cl-8-carbonyl, carbamoyl in which the nitrogen atom may be optionally mono- or di- substituted with a group selected from alkyl Cl-8, cycloalkyl C3-7, aryl, aryl-alkyl Cl-8, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of a group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, carboxy and cyano; R8 is a heteroaryl ring selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl , indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, tetrazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazsyl, acridinyl and phenazinyl, wherein any of the above R8 may be optionally substituted with one or more Rj; Rj is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylalkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom may be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di- -substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, 10 thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, 15 thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, Isoquinolinyl, quinazolinyl, quinoxalinyl, carbazsyl, phenothiazinyl and phenoxazinyl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a Sulfone, arylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from furanyl, thienyl, 10-pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, Isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and Phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, arylalkoxycarbonylaminoalkyl, C 1-8 alkylcarbamoyloxy, arylcarbamoyloxy, Alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with alkyl, aryl, heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from group consisting of furanyl, thienyl, pyrrolyl, Oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, Benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and Phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, wherein Rk may also be optionally substituted with R?; Ri is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl and benzyl; Y X is 0 or S. 13. The compound according to claim 12, characterized in that: Y is 0 or S; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5, aryloxy, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl , piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl , quinazolinyl and quinoxalinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl , benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, arylsulfonilamins, alkyl Cl-5-aminosulfonyl , arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazoli it, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rb may be also optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl and pyridinyl, alkoxy Cl-5, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R2 is H or Cl-3 alkyl; R3 is H, Cl-5 alkyl, C3-7 cycloalkyl or aryl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, Cl-5 alkanoyl, aroyl, Cl-5-carbonyl alkoxy, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl , pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, iso quinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected between group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl- 5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, a l-Cl-5-aminosulfonyl, arylaminosulfonyl. amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group which consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo , carboxy, cyano, nitro, amidino and guanidino, Rd may also be optionally substituted with one or more Re-Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, Cl-5 alkoxy , aryloxy, arylalkoxy Cl-5, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R is H or Cl-3 alkyl; R5 is H or C1-8 alkyl; R6 is H, Cl-5 alkyl, C3-7 cycloalkyl or aryl wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, heteroaryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl , thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl , isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5 carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl optionally substituted with halogen, methyl or methoxy; heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, Benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5, aryloxy, arylalkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, Aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, 20 piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, Tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the atom sulfur may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a Sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with C5-alkenyl, aryl, heterocyclyl selected from the group consisting of Pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, Triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, 25-quinazolinyl and quinoxalinyl, Cl-5-alkoxycarbonylamino, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently being mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rh is selected from the group consisting of Cl-5 alkyl, aryl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-5-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with a group selected from alkyl Cl-5, cycloalkyl C3-7, aryl, aryl-alkyl Cl-5, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group which consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, carboxy and cyano; Rx is alkoxy, aryloxy or hydroxy; Re is a heteroaryl ring selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl. , indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl and phenazinyl, wherein any of the above Rs may be optionally substituted with one or more Rj; Rj is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl; aryl-Cl-8 alkyl, Cl-8 alkoxy, aryloxy, aryl-Cl-8 alkoxy, Cl-8-alkoxycarbonyl, aryloxycarbonyl, Cl-8-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or disubstituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, aryl-alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which either of the nitrogen atoms may be independently substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morfo linyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindole, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-8-carbamoyl loxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can independently be mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomylpholinyl, piperazinyl, indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and 5-phenoxazinyl, alkoxy Cl-8, aryloxy, arylalkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently 10 mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group that 15 consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, Pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, Quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoylamino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-8 alkyl, aryl, heterocyclyl selected 10 between the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl oxazolyl. 15 thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl benzofuranyl, Benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl. purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8-carbonylamino, 25-aryloxycarbonylamino, arylalkoxy Cl-8-carbonylamino, arylacloxycarboni lamino-C 1-8 alkyl, alkyl Cl-8-carbamoyl loxi, arylcarbamoyloxy, alkyl Cl-8-sulfonylamino, aryisulfonylamino, alkyl 5-Cl-8-aminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom can be independently mono- or disubstituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group Which comprises pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, Imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, Benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, Carboxy, cyano, nitro, amidino and guanidino, wherein Rk may also be optionally substituted with Rx; The compound according to claim 13, characterized in that: Y is 0; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; Cl-5 alkoxy, aryloxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy, alkanoyl, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl. pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl or aryl; alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, -morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy and cyano; R2 is H or methyl; R3 is H, Cl-5 alkyl, C3-7 cycloalkyl or phenyl, wherein R is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aroyl, alkoxy Cl- 5-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino , aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the Sulfur may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl- 5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rd can also be optionally substituted with one or more Rei-Re is selected from the group that co Cl-5 alkyl group, C3-6 cycloalkyl, aryl, aryl-Cl-5 alkyl, Cl-5 alkoxy, aryloxy, aryl-Cl-3 alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; R 4 is H or methyl; R5 is H or Cl-5 alkyl; R 5 is H, Cl-5 alkyl, C 3-7 cycloalkyl, phenyl or naphthyl in which Rβ is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, pyridyl-alkoxy Cl-5, thienyl-alkoxy Cl-5, furanyl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy , carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroy lamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-5 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl Cl-5, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino , alkyl Cl-5-arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, arilsulfsnilamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom pued and independently being mono- or di-substituted with Cl-5 alkenyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl , imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carbsxi and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl optionally substituted with halogen, methyl or methoxy; naphthyl optionally substituted with halogen, methyl or methoxy heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, Imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, 15-quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, aryl-alkoxy Cl-5, alkoxy Cl-5- carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroylloxy, carbamoyl in which the nitrogen atom may be 20 independently mono- or di-substituted with Cl-5 alkenyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of 25 consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl 5 and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in that the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a Sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with C5-alkenyl, aryl, heterocyclyl selected from the group consisting of Piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, Benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulphonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-5 alkyl, phenyl, naphthyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl in which the nitrogen atom may be optionally mono- or disubstituted with a group selected from alkyl Cl-5, cycloalkyl C3-6, phenyl, naphthyl, arylalkyl Cl-3, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, carboxy and cyano; Z is 0 or S; Rs is a heteroaryl ring selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl. , indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl and phenazinyl, wherein any of the above R8 may be optionally substituted with one or more groups of the formula Rj; R j is selected from the group consisting of Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, arylalkyl Cl-5, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl , aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl , heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5- thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-5-t io in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylamine sulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl . heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, wherein Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, Cl-3 alkoxy, aryloxy, aryl-alkoxy Cl-3, alkoxy Cl-3- carbonyl, aryloxycarbonyl, alkanoyl Cl- 3- oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, aryl, heterocyclyl selected from the group consisting of morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl and pyridinyl, Cl-3-amino alkanoyl, aroylamino, alkyl Cl-3-thio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with C1-3 alkyl, phenyl, naphthyl , heteroaryl Selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, and pyridinyl, alkoxy Cl-3-carbonylamino, aryloxycarbonylamino, aryl-alkoxy Cl-3- 15 carbonylamino, benzyloxycarbonylamino-alkyl Cl-5, alkyl Cl-3-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-3-sulfsylamino, aryisulfonylamino, alkyl Cl-3-aminosulfonyl, arylaminosulfonyl, Amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, 25 morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, wherein Rk may also be optionally substituted with Ri; Ri is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl and phenyl. 15. The compound according to claim 14, characterized in that: Ri is Cl-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, or amino, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, phenoxy, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl-5 oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl , indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the Sulfur atom can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl , phenyl or naphthyl; Cl-5-carbonylamino alkoxy, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di- substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl , benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, aryl, Cl-3 alkoxy, phenoxy, halogen, hydroxy, oxo, carboxy and cyano; R2 is H; R3 is Cl-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R is optionally substituted with one or more Rd; R is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl. phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, quinolinyl and isoquinolinyl, Cl-5 alkoxy, phenoxy, aroyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, Carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroyl amino, alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, phenylthio in the that the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-3 alkyl, phenyl or heteroaryl selected in The group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, alkoxy Cl-5-carbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in the that the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, aryl-Cl-3 alkyl, Cl-5 alkoxy, phenoxy, aryl-Cl-3 alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; in that the configuration in the stereo center defined by R2 and R3 and the carbon to which these are attached is L; R4 is H; R5 is H or Cl-3 alkyl; Re is H, Cl-5 alkyl, C 3-6 cycloalkyl or phenyl, wherein Rβ is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl- 3, pyridyl-alkoxy Cl-5, thienyl-alkoxy Cl-5, furanyl-alkoxy Cl-5, alkoxy Cl-5-carbonyls aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl Wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, aryl-alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or phenyl; Cl-5-carbonylamino alkoxy, Cl-5-sulfonylamino, aryisulphonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl optionally substituted with halogen, methyl or methoxy; heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, Pyridinyl, pyrimidinyl, pyrazinyl and indolyl, Cl-5 alkoxy, aryloxy, aryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the The nitrogen may be independently mono- or di-substituted with Cl-5 alkyl or aryl; alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or A sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl 25 Cl-5 or aryl; Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl or aryl; halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-5 alkyl. phenyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, aryl-alkyl Cl-3 halogen hydroxy, carboxy and cyano; where Z is 0; R8 is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl. pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, wherein any of the foregoing R8 may be optionally substituted with one or more Rj; Rj is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl. benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, arylalkyl Cl-3, alkoxy Cl-3, aryloxy, aryl-alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl-3-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently being mono- or di-substituted with Cl-3 alkyl, phenyl, naphthyl, piperidinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; Cl-3-amino alkanoyl; aroylamino, alkyl Cl-3-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-3 a thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-3 alkyl, phenyl, naphthyl, piperidinyl, morpholinyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; Cl-3-carbonylamino alkoxy, aryloxycarbonylamino, Cl-3-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-3-sulfonylamino alkyl, aryisulfonylamino, Cl-3-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, naphthyl, piperidinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; halogen, hydroxy, oxo, carboxy, cyano and nitro, R3 may also be optionally substituted with one or more Rk .; R is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, C1-3 alkoxy, phenoxy, benzyloxy, 5-methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, Thiazolyl, imidazolyl or pyridinyl; acetylamino, benzoylamino, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms Can be independently substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl or pyridinyl; aryl-alkoxy Cl-3-carboni lamino, benzyloxycarboni lamino-20 Cl-5 alkyl, methylcarbamoyl loxy, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, furanyl, Thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl or isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, wherein Rk may also be optionally substituted with Ri; Ri is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl and phenyl. 16. The compound according to claim 15, characterized in that: Ri is Cl-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, or amino, wherein Ri is optionally substituted with one or more Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl-5 oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl , benzothienyl, benzimidazolyl and benzothiazolyl; Cl-5-amino alkanoyl, aroylamino. alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the atoms of Nitrogen may be independently substituted with Cl-3 alkenyl or phenyl, Cl-5-sulfonylamino, aryisulfonylamino, amino wherein the nitrogen atom may be independently mono- or di-substituted with Cl-3 alkenyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl; halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Re 'Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, Cl-3 alkoxy, halogen and hydroxy; R is Cl-5 alkyl, C5-6 cycloalkyl or phenyl in which R is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, 4-morpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-5 alkoxy, phenoxy, aroyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy, alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkenyl or phenyl; Cl-5-amino alkanoyl, Cl-3 alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl; Cl-5-carbonylamino alkoxy, Cl-5-sulfonylamino, aryisulphonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re-Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, benzyl, Cl-5 alkoxy, phenoxy, benzyloxy, aroyl, halogen, hydroxy, oxo, carboxy and cyano; Re is H, Cl-5 alkyl or phenyl wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl. naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl, Cl-3-thienyl-alkoxy Cl-3 alkoxy, furanyl-Cl-3 alkoxy, Cl-3-alkoxycarbonyl, phenoxycarbonyl , alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; alkanoyl Cl-5-amino, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or phenyl; Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with halogen, methyl or methoxy; heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridinyl, Cl-3 alkoxy, aryloxy, benzyloxy, Cl-5- carbonyl alkoxy, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl wherein the nitrogen atom may be be independently mono- or di-substituted with Cl-5 alkyl or phenyl; Cl-5-amino alkanoyl, aroylamino, Cl-5-thio alkyl in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with C1-6alkyl 5 or phenyl; Cl-5-carbonylamino alkoxy, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-3-sulfonylamino alkyl, aryisulfonylamino, Cl-3-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di- substituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-alkoxycarbonyl, phenoxyxycarbonyl, benzyloxy, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with Cl-5 alkyl, phenyl, benzyl, halogen, hydroxy, carboxy and cyano; R8 is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl and isoquinolinyl, wherein any of the above R8 may optionally be substituted with one or more Rj; Rj is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, benzyl, Cl-3 alkoxy, phenoxy, benzyloxy, Cl-3-alkoxy, acetyloxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and pyridinyl; acetylamino, benzoylamino, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with methyl, phenyl, thiazolyl, imidazolyl and pyridinyl; alkoxy Cl-3-carbonylamino, alkyl Cl-3-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-3-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and pyridinyl; halogen, hydroxy, carboxy, cyano and nitro, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, pyridinyl, Cl-3 alkoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl. wherein the nitrogen atom can be independently mono- or disubstituted with methyl, phenyl, furanyl, thienyl; acetylamino, benzoylamino, methylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with methyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl and thiazolyl , benzyloxycarbonylamino, benzyloxycarbonylamino-alkenyl Cl-5, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and pyridinyl, halogen , hydroxy, carboxy, cyano and nitro, wherein Rk may also be optionally substituted with Ri, - Ri is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl and phenyl. 17. The compound according to claim 16, characterized in that: Ri is cycloalkyl CS-6, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, pyranyl, thiopyranyl or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, Cl-3 alkoxy, alkoxy Cl -3-carbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino, aroylamino, ureido alkanoyl wherein any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl; alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, Cl-3 alkoxy, halogen and hydroxy; Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, alkoxy Cl-3, alkoxy Cl-5-carbonyl, alkanoyl Cl-5-oxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino alkanoyl, Cl-3 alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, Cl-3-carbonylamino alkoxy, Cl-3-sulfonylamino alkyl, amino in which the atom of nitrogen may independently be mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-3 alkyl, phenyl, benzyl, Cl-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen, hydroxy, oxo, carboxy and cyano; R5 is H or methyl; Re is Cl-5 alkyl or phenyl, wherein Rβ is optionally substituted by one or more groups of the formula Rf, Rf is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, Cl-5-amino alkanoyl, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom it may be oxidized to a sulfoxide or a sulfone, Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with halogen or methyl; Cl-3 alkoxy, aryloxy, benzyloxy, Cl-3-carbonyl alkoxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino, aroylamino, amino alkanoyl wherein the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl or phenyl; halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-alkoxycarbonyl, benzyloxy and carboxy; Re is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, benzimidazolyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more Rj; Rj is selected from the group consisting of Cl-5 alkyl, cyclohexyl, phenyl, piperidinyl, furanyl, thienyl, pyridinyl, benzyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may be independently mono- or di-substituted with methyl, phenyl, furanyl, thienyl; acetylamino, benzoylamino, ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; methoxycarbonylamino, Cl-3-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl, phenyl, furanyl or thienyl; halogen, hydroxy, carboxy and cyano, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, piperidinyl, piperazinyl, furanyl, thienyl, Cl-3 alkoxy, phenoxy, benzyloxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may be be independently mono- or disubstituted with methyl or phenyl; acetylamino, benzoylamino, ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; benzyloxycarbonylamino, benzyloxycarbonylamino Cl-5 alkyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, furanyl, or thienyl; halogen, hydroxy, carboxy, cyano and nitro, wherein Rk may also be optionally substituted with Ri, - Ri is selected from the group consisting of methyl, C3-6 cycloalkyl and phenyl. 18. The compound according to claim 17, characterized in that: A is -C (0) - or -S02-; Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl or amino, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, Cl-3 alkoxy, Cl-3 alkoxy -carbonyl, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino alkanoyl, aroylamino, Cl-5-sulfonylamino alkyl, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkoxy, halogen and hydroxy; R3 is C1-5 alkyl or C5-6 cycloalkyl, wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, thienyl, imidazolyl, pyridinyl, indolyl, Cl-4 alkoxy, Cl-5-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl, halogen and hydroxy; Rf is selected from the group consisting of C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy, benzyloxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulphone, methoxycarbonylamino, amino in which the nitrogen atom may independently be mono- or di-substituted with C1-3alkyl; halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of phenylmethyl optionally substituted with halogen or methyl; methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; halogen, hydroxy and carboxy; Re is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the above Re may be optionally substituted with one or more R-,; R3 is selected from the group consisting of Cl-5 alkyl, phenyl, furanyl, thienyl, piperidinyl, pyridinyl, benzyl, methoxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di- substituted with methyl or phenyl; acetylamino, benzoylamino, ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; methoxycarbonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; halogen, hydroxy, carboxy and cyano, R3 may also be optionally substituted with one or more Ry; and Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, piperidinyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; ureido in which any of the nitrogen atoms can be independently substituted with methyl or phenyl; benzyloxycarbonylamino, benzyloxycarbonylamino-Cl-5 alkyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, furanyl and thienyl; halogen, hydroxy, carboxy, cyano and nitro, wherein Rk may also be optionally substituted with Ri, - Ri is selected from the group consisting of methyl and phenyl. The compound according to claim 18, characterized in that: Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl or thiopyranyl, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl; halogen, hydroxy and carboxy, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of methoxy, halogen and hydroxy: Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, Cl-4 alkoxy, Cl-3-amino alkanoyl, methylthio in which the Sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, methoxy, halogen and hydroxy; Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, thienyl, indolyl, methoxy, methylthis in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano, Rt- may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with halogen; methoxy, phenoxy, benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy; R8 is a heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more Rj; Rj is selected from the group consisting of Cl-5 alkyl, phenyl, piperidinyl, pyridinyl, benzyl, methoxy, methoxycarbonyl, acetyloxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; methoxycarbonylamino, halogen, hydroxy and carboxy, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, piperidinyl, methoxy, methoxycarbonyl, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; benzyloxycarbonylamino, amino in which the nitrogen atom can independently be mono- or di-substituted with methyl or phenyl; halogen, hydroxy and carboxy. The compound according to claim 19, characterized in that: Ri is phenyl or 4-morpholinyl, wherein Ri is optionally substituted with one or more R; Rb is selected from the group consisting of benzimidazolyl, methoxy and dimethylamino, Rb may also be optionally substituted with a halogen atom; R3 is Cl-5 alkyl wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of C3-6 cycloalkyl and phenyl, Rd may also be optionally substituted with one or more ReI- Re is selected from the group consisting of methyl and halogen: R6 is Cl-5 alkyl optionally substituted with one or more Rf; Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, and halogen, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, methoxy, methoxycarbonyl, halogen and hydroxy; Rs is a heteroaryl ring selected from the group consisting of oxazolyl, pyridyl, benzothiazolyl and benzoxazolyl, wherein any of the above R8 may be optionally substituted with one or more Rj; Rj is selected from the group consisting of Cl-5 alkyl, phenyl, pyridinyl, piperidinyl, methoxycarbonyl, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with methyl or phenyl; methoxycarbonylamino and halogen, Rj may also be optionally substituted with one or more Rk; Rk is selected from the group consisting of methyl, C5-6 cycloalkyl, phenyl, methoxycarbonyl, carbamoyl, benzyloxycarbonylamino and halogen. 21. A compound of the formula (II): (H) characterized in that A is -C (Y) - or -S02- Y is 0, S or NRa wherein Ra is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylamino and arylamino; Ri is alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or amino wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di- -substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ur in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with alkyl , aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; or alkyl; R is H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R3 is optionally substituted with one or more Rd; R is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxid or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, to which laminosulfonyl, arylaminosulfonyl, amino in which the atom of nitrogen can be independently mono- or di-substituted with alkyl, aryl, tercyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, R may also be optionally substituted with one or more Re Re is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R 4 is H or alkyl; R5 is H or alkylene-Re is H, alkyl, cycloalkyl, aryl, heterocyclyl, aryl, heteroaryl or cyano, wherein Re is optionally substituted with one or more Rf; Rf is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, v-aryloxy, arylalkoxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, heteroarylalkoxy, carbamoyl wherein the nitrogen atom may be independently being mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the Sulfur may be oxidized to a sulphoxide or a sulfone, arylalkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alky laminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf can also be optionally substituted with one or more Rg; Rg is selected from the group consisting of alkyl, cycloalkyl, aryl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in the that the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, Ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, Alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulphonylamino, alkylaminosulphonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy , cyano, nitro, amidino and guanidino; or R together with R6 forms a carbocyclic ring of 3 to 6 members, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of alkyl, aryl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with a group selected from alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl , heteroaryl, halogen, hydroxy, carboxy and cyano; X is O, S or N-OH; its pharmaceutically acceptable derivatives; with the proviso that when Y is O and R6 is arylalkyl or heteroarylalkyl then Ri can not be alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or arylcycloalkyl. 22. The compound according to claim 21, characterized in that: Y is 0, S or NRa wherein Ra is H, alkyl or aryl; Ri is Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl, phenoxazinyl, and amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl. , quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl, alkoxy Cl-8, aryloxy, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroylamino, alkyl Cl-8-thio wherein the sulfur may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected between the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroar ilo selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulphonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkenyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro , amidino, guanidino; Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-8 alkyl, C3-6 cycloalkyl, aryl, Cl-8 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R3 is H, Cl-8 alkyl, C3-7 cycloalkyl, aryl wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl , benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, alkanoyl, aroyl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl in wherein the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl-Cl-8- amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl , thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pi ridinilo, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of it consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl. pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo carboxy, cyano, nitro, amidino, guanidino, Ra may be in addition optionally substituted with one or more Re; Re is selected from the group consisting of Cl-8 alkyl, C 3-6 cycloalkyl, aryl, arylalkyl, Cl-8 alkoxy, aryloxy, arylalkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Re is H, Cl-8 alkyl, C3-7 cycloalkyl, aryl or cyano, wherein Re is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-88 aryloxy, aryl-alkoxy Cl-8, heteroaryl-alkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxaz olilo, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl -8-amino, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl- alkyl Cl-8-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl or, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulphonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group which consists of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolimyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, p iridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rt may also be optionally substituted with one or more Ry; Ry is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl , piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrslyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl. , Benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, arylalkoxy Cl-8, alkoxy Cl-8-carbonyl, Aryloxycarbonyl, Cl-8-oxy, aroyloxy, carbamoyl alkanoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of A group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, Thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, Cl-8-amino alkanoyl, Arylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which Any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 20 piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, Triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, Arylisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl 15 selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, Oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, Isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R is selected from the group consisting of alkyl Cl-8, aryl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, aryl-alkoxy Cl-8-carbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with a group selected from alkyl Cl-8, cycloalkyl C3-7, aryl, aryl-alkyl Cl-8, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, carboxy and cyano; and X is 0 or S. 23. The compound according to claim 22, characterized in that: Y is 0 or S; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl or amino; wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected among the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl , benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl C l-5-amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido wherein any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5 -carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the atom or nitrogen may independently be mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R2 is H or Cl-3 alkyl; R3 is H, Cl-5 alkyl, cycloalkyl 0.3-1, aryl wherein R3 is optionally substituted with one or more Rd. Rd is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl.; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, alkanoyl Cl-5, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl -5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido wherein any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group which consists of furanyl, thienyl, pyrrolyl, oxazolyl. thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl. quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amine in which the nitrogen atom can be independently being mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, R may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro , amidino and guanidino; R4 is H or alkenyl Cl-3, R5 is H or Cl-8 alkyl, R6 is H, Cl-5 alkyl, C3-7 cycloalkyl, aryl or cyano, wherein R6 is optionally substituted with one or more Rf / Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, aryl-alkoxy Cl-5, heteroaryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl , imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, aryl , heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl , indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carba moyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl , piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di- substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the The group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl. thienyl, pyrrolyl, oxazolyl, Thiazolyl, imidazolyl. Triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, 20 isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which The sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, Oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, Quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamm, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group 25 which consists of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rn is selected from the group consisting of Cl-5 alkyl, aryl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-5-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with a group selected from C1-5 alkyl, C3-7 cycloalkyl, aryl, arylC1-5 alkyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of a group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, carboxy and cyano. 24. The compound according to claim 23, characterized in that: Y is 0; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl; or amino in which Ri is optionally substituted with one or more Rb; RD is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected between the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl , quinolinyl and isoquinolinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl or aryl, C1-5-alkoxycarbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamo loxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consists of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl , halogen, hydroxy, oxo, carboxy, cyano and nitro, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy and cyano; R is H or methyl; Rs is H, Cl-5 alkyl, C3-7 cycloalkyl or phenyl wherein R3 is optionally substituted with one or more Ra; Rd is selected from the group consisting of alkyl Cl-3, C3-6cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl , oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, Cl-5-amino alkanoyl, aroylamino, Cl-5-thio alkyl in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, lamino ariloxicarboní, alkyl Cl-5-arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, na ftilo, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Ra may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, aryl-Cl-5 alkyl, Cl-5 alkoxy, aryloxy, aryl-alkoxy Cl-3, aroyl amino, halogen, hydroxy, oxo , carboxy and cyano; R 4 is H or methyl; Rs is H or Cl-5 alkyl; RG is H, Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl or cyano, wherein Re is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl. triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-5 heteroaryl- alkoxy Cl-5 alkoxy Cl -5-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl , morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl. quinolinyl and isoquinolinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, aryl , heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl , alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, a where the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; P.g is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl optionally substituted with one or more groups selected from halogen, methyl or methoxy. naphthyl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, Triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl And quinoxalinyl, Cl-5 alkoxy, aryloxy, aryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently 20 mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of 25 furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, Cl-5-alkanoyl 5-amino, aroylamino, alkyl Cl-5-thio in which the atom Sulfur may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in the That any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or Heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, 20 benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5- carbamoyl loxi, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl 25 Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected between! the group consisting of furanyl, thienyl. pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl. benzothienyl. benzimidazolyl benáothiazolyl, quinolinyl and isoquinolinyl, Halogen, hydroxy, oxo, carboxy and cyano; ii Rh is selected from the group consisting of alkyl Cl-5, phenyl, naphthyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, aryl-alkoxy Cl-3-carbonyl, carbamoyl, in which the nitrogen atom may optionally be mono- or di-substituted with a group selected from alkyl Cl-5, cycloalkyloxy C3-6, phenyl, naphthyl, arylalkyl Cl-3, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected among the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, carboxy and cyano; and X is 0. 25. The compound according to claim 24, characterized in that: Y is O; Ri is alkyl Cl-5, cycloalkyl; C3-6, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, pip ^ razinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, mdolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl or amino, wherein Ri is optionally substituted with one or more R; RD is selected from the group consisting of C1-3alkyl, cycloalkyl (C3-6, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, phenoxy, Cl-3-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy, aryloxy, carbamoyl alkanoyl wherein the nitrogen atom can be independently mono- or di-substituted with selected Cl-5 alkyl, phenyl or heteroaryl I Among the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in that the sulfur atom may be oxidized to a sailf oxide or a sulfone, wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, in which any one of the nitrogen atoms may be oxidized. be independently substituted with Cl-5 alkyl, phenyl or naphthyl; alkoxy Cl-5-carbonylamino, alkyl Cl-5-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, RD may optionally be substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, aryl, Cl-3 alkoxy, phenoxy, halogen, hydroxy, oxo, carboxy and cyano; ? \ e ?? , Rs is Cl-5 alkyl, C3-6 cycloalkyl or phenyl, wherein Rs is optionally substituted with one or more Ra; Ra is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, phenoxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy , carbamoyl in which the nitrogen atom can be independently ono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, phenylthio in that the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-3 alkyl, phenyl or heteroaryl selected The group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, alkoxy Cl-5-carbonylamino, alkyl Cl-5-carbamoyl loxi, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl , oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Ra can also be optionally substituted with one or Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl , naphthyl, aryl-Cl-3 alkyl, Cl-5 alkoxy, phenoxy, aryl-alkoxy Cl-3 aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; R4 is H; Re is H, Cl-5 alkyl, C3-6 cycloalkyl, phenyl or cyano, wherein Re is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-3, heteroaryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur can be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted v with Cl-5 alkyl or phenyl, Cl-5-carbonylamino alkoxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rf pu ede be further optionally substituted with one or more Rg; Ry is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl optionally substituted with one or more groups selected from halogen or methyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piporidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl, Cl-5-oxy, aroylloxy, carbamoyl alkanoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or aryl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in that the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be substituted independently with alkyl Cl-5 or aryl, Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can independently be mono- or di-substituted with Cl-5 alkyl or aryl, halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-5 alkyl, phenyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl or aryl-Cl-3 alkyl; halogen, hydroxy, carboxy and cyano. 26. The compound according to claim 25, characterized in that: Ri is Cl-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl or amino, wherein Ri is optionally substituted with one or more Rb; RD is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl -5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl and benzothiazolyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-3 alkyl or phenyl, Cl-5-sulfonylamino, aryisulfonylamino, amino in wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, heterocyclyl phenyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, Cl-3 alkoxy, halogen and hydroxy; Cl-5 cycloalkyl, C5-6 cycloalkyl or phenyl in which optionally substituted with one or more Rd; R is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, 4-morpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-5 alkoxy, phenoxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, Cl-alkanoyl 5-amino, alkyl Cl-3-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl Cl-3 or phenyl, alkoxy Cl-5-carbonylamino, Cl-5-sulfonylamino alkyl, arylsulfonylamine, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, benzyl, Cl-5 alkoxy, phenoxy, benzyloxy, aroyl, halogen, hydroxy, oxo, carboxy and cyano; R5 is H or Cl-3 alkyl; Re is H, Cl-5 alkyl, phenyl or cyano, wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl-Cl-3 alkoxy, thienyl -alkoxy C103, furanyl-alkoxy Cl-3, alkoxy Cl-3-carbonyl, phenoxyxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-alkyl 3 or phenyl, Cl-5-amino alkanoyl, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulphoxide or sulfone, ureido wherein any one of the nitrogen atoms can be independently substituted with Cl-5 alkyl or phenyl, Cl-3-carbonylamino alkoxy, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkenyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be s optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with one or more groups selected from the group consisting of halogen and methyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridinyl, alkoxy Cl-3. aryloxy, benzyloxy, Cl-5-alkoxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, Cl-5 alkanoyl amino, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or phenyl, alkoxy Cl-5- carbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-3-sulfonylamino alkyl, aryisulfonylamino, Cl-3-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with alkyl Cl-3 or phenyl, halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-alkoxycarbonyl, phenoxyxycarbonyl, benzyloxy, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with a group selected from group consisting of Cl-5 alkyl, phenyl and benzyl, halogen, hydroxy, carboxy and cyano. 27. The compound according to claim 26, characterized in that: Ri is C5-6 cycloalkyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl or amino, wherein Rx is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl. furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, alkoxy Cl-3, alkoxy Cl-3-carbonyl, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl Cl -3 or phenyl; Cl-5-amino, aroylamino, ureido alkanoyl wherein any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl; alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rb can also be optionally substituted with one or more Rc; Rc is selected from the group consisting of alkyl Cl-3, alkoxy Cl-3, halogen and hydroxy; Rs is Cl-5 alkyl, C5-6 cycloalkyl or phenyl, wherein R is optionally substituted with one or more groups of the formula Rd, 'Rd is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl , phenyl, naphthyl, 4-piperidinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, alkoxy Cl-3, alkoxy Cl-5-carbonyl, alkanoyl Cl-5-oxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino alkanoyl, Cl-3 alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, Cl-3-carbonylamino alkoxy, alkyl Cl-3-sulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd can also be optionally substituted with one or Re is selected from the group consisting of Cl-3 alkyl, phenyl, benzyl, Cl-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen, hydroxy, oxo, carboxy and cyano; in that the configuration in the stereo center defined by R2 and R3 and the carbon to which they are attached is defined as L; R5 is H or methyl; R6 is Cl-5 alkyl, phenyl or cyano wherein R6 is optionally substituted with one or more groups of the formula Rf; Rf is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl-alkoxy Cl-3, thienyl-alkoxy Cl -3, furanyl-alkoxy Cl-3, alkanoyl Cl-5-amino, aroylamino, methylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, halogen hydroxy, oxo, carboxy and cyano, Rf can also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl phenyl optionally substituted with one or more groups selected from halogen or methyl, Cl-3 alkoxy, aryloxy, benzyloxy, Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen may independently be mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino, aroylamino, alkanoyl, amino wherein the nitrogen atom may be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-carbonyl alkoxy, benzyloxy and carboxy. 28. The compound according to claim 27, characterized in that: Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl or amino in which Ri is optionally substituted with one or more Rb; R is selected from the group consisting of Cl-3 alkyl, CS-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, Cl-3 alkoxy, Cl-3-carbonyl alkoxy , carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino alkanoyl, aroylamino, Cl-5-sulfonylamino alkyl, aryisulfonylamino, amino in which the atom of nitrogen may independently be mono- or di-substituted with Cl-3 alkyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkoxy, halogen and hydroxy, R3 is Cl-5 alkyl or C5-6 cycloalkyl wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, Cl-4 alkoxy, Cl-5-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more ReI- Re is selected from the group consisting of methyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy , benzoyl, halogen and hydroxy; R6 is Cl-5 alkyl or phenyl, wherein Re is optionally substituted with one or more Rf, - Rf is selected from the group consisting of C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy, benzyloxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulphone, methoxycarbonylamino, amino in which the nitrogen atom may be independently mono- or di-substituted with alkenyl Cl-3, halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with one or more groups selected from halogen or methyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy and carboxy; Rh is selected from the group consisting of vinyl, phenyl, methoxycarbonyl, benzyloxycarbonyl and carboxy. 29. The compound according to claim 28, characterized in that: Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl or thiopyranyl, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, halogen, hydroxy and carboxy, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of methoxy, halogen and hydroxy; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, Cl-4 alkoxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, methoxy, halogen and hydroxy; R5 is H; Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, thienyl, indolyl, methoxy, benzyloxy, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the atom Sulfur may be oxidized to a sulfoxide or a sulfone, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with halogen, methoxy, phenoxy, benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy; Rh is vinyl or phenyl. 30. The compound according to claim 29, characterized in that: Ri is phenyl, naphthyl or 4-morpholinyl wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of benzimidazolyl, methoxy and dimethylamino, Rb may further be optionally substituted with Rc wherein Rc is a halogen atom; R is Cl-5 alkyl wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of C3-6 cycloalkyl, phenyl or naphthyl, R may also be optionally substituted by one or Re is selected from the group consisting of methyl and halogen, Rf is selected from the group consisting of cycloalkyl CS-6, phenyl, naphthyl, indolyl, benzyloxy, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen and carboxy, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, methoxy, methoxycarbonyl, halogen and hydroxy. 31. A compound of the formula (Ha): (Ha) characterized in that A is -C (Y) - or -S02- Y is 0, S or NRa wherein Ra is selected from the group consisting of H, alkyl , aryl, alkoxy, aryloxy, alkylamino and arylamino; Ri is alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or amino wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di- -substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone , ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxy carbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with alkyl , aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; or alkyl; R3 is H, C2-8 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein Rs is optionally substituted with one or more Rd; Rd is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, het erocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R 4 is H or alkyl; R5 is H or alkyl; R6 is H, alkyl, cycloalkyl, aryl, heterocyclyl, aryl, heteroaryl or cyano, wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, heteroarylalkoxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom it may be oxidized to a sulfoxide or a sulfone, arylalkylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl , alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylamino minosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf can also be optionally substituted with one or more Rg; Rg is selected from the group consisting of alkyl, cycloalkyl, aryl optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl in the that the nitrogen atom may independently be mono- or di-substituted with alkenyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino , aryisulfonylamino, alkylaminosulfonyl, arylaminosulf onyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; or R5 and Re together with the carbon to which these are attached form a carbocyclic ring of 3 to 6 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of alkyl, aryl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with a group selected from alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl , heteroaryl, halogen, hydroxy, carboxy and cyano; X is O, S or N-OH; and their pharmaceutically acceptable salts, esters or tautomers with the following conditions: when Y is 0 and R5 is arylalkyl or heteroarylalkyl then Ri can not be alkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, arylalkyl or arylcycloalkyl; when R5 is H then Re can not be H; and when Ri is alkyl Cl then Rb can not be carbamoyl, alkanoylamino, aroylamino, ureido, alkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aryisulfonylamino, amino, amidino or guanidino in which each of said Rb is linked to said Ri through its atom of nitrogen. 32. The compound according to claim 31, characterized in that: Y is 0, S or NRa wherein Ra is H, alkyl or aryl; Ri is Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl, phenoxazinyl, and amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl. , quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl, alkoxy Cl-8, aryloxy, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroylamino, alkyl Cl-8-thio wherein the sulfur may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected between the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl or phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono - or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl. imidazolyl, pyrazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino, guanidino; Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-8 alkyl, C3-6 cycloalkyl, aryl, Cl-8 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R3 is H, C2-8 alkyl, C3-7 cycloalkyl, aryl wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, alkanoyl, aroyl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroylloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group which consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino , aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, py idinilo, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino, alkylaminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino, guanidino, Rd may also be optionally substituted with one or more Re-Re is selected from the group consisting of Cl-8 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, Cl-8 alkoxy, aryloxy, arylalkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R6 is H, C1-8 alkyl, C3-7 cycloalkyl, aryl or cyano, wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, aryl-alkoxy Cl-8, heteroaryl-alkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, heterocyclyl aryls selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl. imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, Cl-8-amino alkanoyl, aroylamino, alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-8-thio in which the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, ariisulfonilamino, alk laminosulfonilo, arylaminosulfonyl, amino in which the át The nitrogen atom can independently be mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl , oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl , carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-8 alkyl, C3-7 cycloalkyl, aryl Optionally substituted with one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, Piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, Triazolyl, tetrazolyl, thiadiazolyl, pyridinyl pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl. benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, 20-quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxy Cl-8, aryloxy, arylalkoxy Cl-8, alkoxy Cl-8-carbonyl, aryloxycarbonyl, alkanoyl Cl-8-oxy, Aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-8, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, Isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, 15-benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkanoyl Cl-8-amino, aroylamino, alkyl Cl-8-thio in which the The sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be 25 is independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl , pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, Pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, Quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, aryisulphonylamino, alkylaminosulfonyl, Arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of Pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl. pyridazinyl, pyrimidinyl, pyrazinyl. indolyl, isoindolyl. benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; or Rs and R6 together with the carbon to which these are attached form a carbocyclic ring of 3 to 6 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of alkyl Cl-8, aryl, alkoxy Cl-8-carbonyl, aryloxycarbonyl, aryl-alkoxy Cl-8-carbonyl, carbamoyl in which the nitrogen atom may be optionally mono- or di- substituted with a group selected from alkyl Cl-8, cycloalkyl C3-7, aryl, aryl-alkyl Cl-8, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, carboxy, and cyano; and X is O or S. 33. The compound according to claim 32, characterized in that: Y is O or S; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl or amino; wherein Ri is optionally substituted with one or more R; Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy-alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-8 alkyl, aryl, heterocyclyl selected between the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, Cl-5-thio alkyl in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido wherein any of the nitrogen atoms can be independently substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofu ranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group which consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy , cyano, nitro, amidino and guanidino, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R2 is H or Cl-3 alkyl; R3 is H, C2-5 alkyl, C3-7 cycloalkyl, aryl wherein R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, alkanoyl Cl-5, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl -5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido wherein any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group which consists of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfo nyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo , carboxy, cyano, nitro, amidino and guanidino, Rd can also be optionally substituted Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-5, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; R 4 is H or Cl 3 alkyl; R5 is H or C1-8 alkyl; R6 is H, Cl-5 alkyl, C3-7 cycloalkyl, aryl or cyano, wherein R is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, aryl-alkoxy Cl-5, heteroaryl-Cl-5-alkoxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy-alkanoyl, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-alkyl 5, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl , pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consists of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl between the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl. oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy cyano, nitro, amidino and guanidino, Rf it may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, aryl optionally substituted by one or more groups selected from halogen, methyl 5 or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of 10 furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, 15 benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl-5, aryloxy, arylalkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, Aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, Piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and Quinoxalinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a Sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl Cl-5, aryl, heterocyclyl selected from the group consisting of 20 pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, Triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl 5 and quinoxalinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl - 5-sulfonylamino, aryisulfonylamino, alkyl Cl-5 aminosulfonyl, arylaminosulfonyl, Amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, 15 morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, Pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, 25 carboxy, cyano, nitro, amidino and guanidino; or R5 and R together with the carbon to which these are attached form a carbocyclic ring of 3 to 6 carbon atoms, the carbocyclic ring being optionally substituted with one or more R ^ ,; Rh is selected from the group consisting of Cl-5 alkyl, aryl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-5-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with a group selected from C1-5 alkyl, C3-7 cycloalkyl, aryl, arylC1-5 alkyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, carboxy and cyano.
- 34. The compound according to claim 33, characterized in that: Y is O; Ri is Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl; or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, alkoxy Cl-5- carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl or aryl, C1-5-alkoxycarbonylamino , aryloxycarbonylamino} alkyl Cl-5-carbamoyl loxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, arylsulfonyl lamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl, aryl , heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, Cl-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy and cyano; R2 is H or methyl; R is H, C2-5 alkyl, C3-7 cycloalkyl or phenyl in which R3 is optionally substituted with one or more Rd; Rd is selected from the group consisting of alkyl Cl-3, C3-6cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl , oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amine, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino , alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naft ilo, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C3-6 cycloalkyl, aryl, aryl-Cl-5 alkyl, Cl-5 alkoxy, aryloxy, arylalkoxy Cl-3, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; R 4 is H or methyl; R5 is H or Cl-5 alkyl; R is H, Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl or cyano, wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, alkoxy Cl -5, aryloxy, aryl-alkoxy Cl-5, heteroaryl-Cl-5-alkoxy, Cl-5-alkoxycarbonyl, aryloxycarbonyl, Cl-5-oxy-alkanoyl, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-alkyl 5, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, aryl-alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono - or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl , indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen no, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-5 alkyl, C3-7 cycloalkyl, phenyl optionally substituted with one or more groups selected from halogen, methyl or methoxy, naphthyl optionally substituted with one or more groups selected from halogen, methyl or methoxy , heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl 10 and quinoxalinyl, Cl-5 alkoxy, aryloxy, aryl-alkoxy Cl-5, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently 15 mono- or di-substituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of 20 furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio in which the atom Sulfur can be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl , aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or Heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, 15 benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5-carbonylamino, aryloxycarbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, alkyl Cl-5-aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl, aryl, heterocyclyl selected from the group 25 which consists of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, or Rs and Rβ together with the carbon to which they are attached form a carbocyclic ring of 3 to 6 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of Cl-5 alkyl, phenyl, naphthyl, Cl-5- carbonyl alkoxy, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or disubstituted with a group selected from C1-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, arylC1-3 alkyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolito, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, carboxy and cyano; and X is 0. 35. The compound according to claim 34, characterized in that: Y is 0; R 1 is Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl or amino, wherein Ri is optionally substituted with one or more Rb , - Rb is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl , thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, phenoxy, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl-5- oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selection Among the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkanoyl Cl-5-amino, aroylamino, alkyl Cl-5-thio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-5 alkyl, phenyl or naphthyl; Cl-5-carbonylamino alkoxy, Cl-5-carbamoyl-loxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or di- -substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, aryl, Cl-3 alkoxy, phenoxy, halogen, hydroxy, oxo, carboxy and cyano; R2 is H; R is C 2-5 alkyl, C 3-6 cycloalkyl or phenyl, wherein R 3 is optionally substituted with one or more R; Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, phenoxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy , carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroyl amino, alkyl Cl-3-thio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, phenylthio that the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-3 alkyl, phenyl or heteroaryl selected in The group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, alkoxy Cl-5-carbonylamino, alkyl Cl-5-carbamoyloxy, arylcarbamoyloxy, alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in the that the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, aryl-Cl-3 alkyl, Cl-5 alkoxy, phenoxy, aryl-Cl-3 alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano; R4 is H; R6 is H, C1-5 alkyl, C3-6 cycloalkyl, phenyl or cyano, wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-3, heteroaryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, Cl-5-amino alkanoyl, aroyl amino, alkyl Cl-3-thio wherein the sulfur atom may be oxidized to a sulphoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, aryl-alkyl Cl-3-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the atom Nitrogen may be independently substituted with Cl-5 alkyl or phenyl, Cl-5-carbonylamino alkoxy, Cl-5-sulfonylamino, aryisulfonylamino, amino wherein the nitrogen atom may be independently mono- or di-substituted with alkyl Cl-5, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl optionally substituted with one or more groups selected from halogen or methyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl, alkoxy Cl-5, aryloxy, aryl-alkoxy Cl-3, alkoxy Cl-5-carbonyl, aryloxycarbonyl, Cl-5-oxy, aroyloxy, carbamoyl alkanoyl wherein the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or aryl, Cl-5-amino alkanoyl, aroylamino, Cl-5- alkyl thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be substituted independently preferably with Cl-5 or aryl alkyl, Cl-5-carbonylamino alkoxy, aryloxycarbonylamino, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-5-sulfonylamino alkyl, aryisulfonylamino, Cl-5-aminosulfonyl alkyl, arylaminosulfonyl, amino in which the Nitrogen atom can be independently mono- or disubstituted with Cl-5 alkyl or aryl, halogen, hydroxy, oxo, carboxy and cyano; or R5 and Rβ together with the carbon to which these are attached form a carbocyclic ring of 3 to 6 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of Cl-5 alkyl, phenyl, Cl-5-alkoxycarbonyl, aryloxycarbonyl, aryl-Cl-3-alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be optionally mono- or di- substituted with Cl-5 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl or aryl-Cl-3 alkyl; halogen, hydroxy, carboxy and cyano. 36. The compound according to claim 35, characterized in that: Ri is Cl-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl or amino, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, alkoxy Cl-3, alkoxy Cl-3-carbonyl, aryloxycarbonyl, alkanoyl Cl -5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl and benzothiazolyl alkanoyl Cl-5-amino, aroylamino, alkyl Cl-3-thio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, arylthio in which the sulfur atom can be oxidized to a sulfoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl, Cl-5-sulphonylamino, aryisulphonylamino, amino at that the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl , indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, R may also be optionally substituted with one or more Rc: Rc is selected from the group consisting of Cl-3 alkyl , C5-6 cycloalkyl, Cl-3 alkoxy, halogen and hydroxy; R is C2-5 alkyl, C5-6 cycloalkyl or phenyl in which R is optionally substituted with one or more Rd; Rd is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, 4-morpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-5 alkoxy, phenoxy, aroyl, alkoxy Cl-5-carbonyl, aryloxycarbonyl, Cl-5-oxy alkanoyl, aroylloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-5 alkyl or phenyl, Cl-alkanoyl 5-amino, alkyl Cl-3-thio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, ureido in which any of the nitrogen atoms may be independently substituted with alkyl Cl-3 or phenyl, alkoxy Cl-5-carbonylamino, Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-5 alkyl, C5-6 cycloalkyl, phenyl, benzyl, Cl-5 alkoxy, phenoxy, benzyloxy, aroyl, halogen, hydroxy, oxo, carboxy and cyano; R5 is H or Cl-3 alkyl; R6 is H, Cl-5 alkyl, phenyl or cyano, wherein R is optionally substituted with one or more Rf; Rf is selected from the group consisting of Cl-3 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl-Cl-3 alkoxy, thienyl. -alkoxy Cl-3, furanyl-alkoxy Cl-3, alkoxy Cl-3-carbonyl, phenoxyxycarbonyl, alkanoyl Cl-5-oxy, aroyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl-3 or phenyl, Cl-5-amino alkanoyl, aroylamino, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone , ureido in which any of the nitrogen atoms can be independently substituted with Cl-5 alkyl or phenyl, Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom can be independently mono- or di-substituted with alkyl Cl -5 or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be s optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with one or more groups selected from the group consisting of halogen and methyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridinyl, Cl-3 alkoxy, aryloxy, benzyloxy, Cl-5-alkoxycarbonyl, Cl-5-oxy alkanoyl, aroyloxy, carbamoyl wherein the nitrogen atom may be independently being mono- or di-substituted with Cl-5 alkyl or phenyl, Cl-5-amino alkanoyl, aroylamino, alkyl Cl-5-thio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, ureido in that any of the nitrogen atoms may be independently substituted with Cl-5 alkyl or phenyl, Cl-5-carbonylamino alkoxy, Cl-5-carbamoyloxy alkyl, arylcarbamoyloxy, Cl-3-sulfonylamino alkyl, aryisulfonylamino, Cl-3- alkyl aminosulfonyl, arylaminosulfonyl, amino in which the nitrogen atom can be independently mono- or disubstituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano; or R5 and R6 together with the carbon to which they are attached form a carbocyclic ring of 3 to 5 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-alkoxycarbonyl, phenoxyxycarbonyl, benzyloxy, carbamoyl wherein the nitrogen atom may be optionally mono- or di-substituted with a group selected from group consisting of Cl-5 alkyl, phenyl and benzyl, halogen, hydroxy, carboxy and cyano. 37. The compound according to claim 36, characterized in that: Ri is C5-6 cycloalkyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl or amino, wherein Ri is optionally substituted with one or more Rb; R is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, Cl-3 alkoxy, Cl-3-alkoxycarbonyl , carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl; Cl-5-amino, aroylamino, ureido alkanoyl wherein any of the nitrogen atoms may be independently substituted with Cl-3 alkyl or phenyl; alkyl Cl-5-sulfonylamino, aryisulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rb can also be optionally substituted with one or more Rc; Rc is selected from the group consisting of Cl-3 alkyl, Cl-3 alkoxy, halogen and hydroxy; R is C2-5 alkyl, C5-6 cycloalkyl or phenyl, wherein R3 is optionally substituted with one or more groups of the formula Rd; Rd is selected from the group consisting of Cl-3 alkyl, C
- 3-6 cycloalkyl, phenyl, naphthyl,
- 4-piperidinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, alkoxy Cl-3, alkoxy Cl-
- 5-carbonyl, alkanoyl Cl-5-oxy, benzoyloxy, carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino alkanoyl, Cl-3 alkylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, Cl-3-carbonylamino alkoxy, alkyl Cl-3-sulfonylamino, amino in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rd can also be optionally substituted with one or more Re; Re is selected from the group consisting of Cl-3 alkyl, phenyl, benzyl, Cl-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen, hydroxy, oxo, carboxy and cyano; in that the configuration in the stereo center defined by R2 and R3 and the carbon to which they are attached is defined as L; Rs is H or methyl; R6 is Cl-5 alkyl, phenyl or cyano wherein R6 is optionally substituted with one or more groups of the formula Rf, - Rf is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, Cl-3 alkoxy, benzyloxy, pyridyl-alkoxy Cl-3, thienyl-alkoxy Cl-3, furanyl-alkoxy Cl-3, alkanoyl Cl-5-amino, aroylamino, methylthio in the that the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, Cl-3-carbonylamino alkoxy, amino in which the nitrogen atom may be independently mono- or di-substituted with Cl-5 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of Cl-3 alkyl, phenyl optionally substituted with one or more groups selected from halogen or methyl, Cl-3 alkoxy, aryloxy, benzyloxy, Cl-3-alkoxycarbonyl, carbamoyl wherein the atom of nitrogen may independently be mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino alkanoyl, aroylamino, amino wherein the nitrogen atom may be independently mono- or disubstituted with Cl-3 alkyl or phenyl , halogen, hydroxy, oxo, carboxy and cyano; or R5 and Rβ together with the carbon to which they are attached form a carbocyclic ring of 3 to 5 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of Cl-3 alkyl, phenyl, Cl-3-carbonyl alkoxy, benzyloxy and carboxy. 38. The compound according to claim 37, characterized in that: Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl or amino in which Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of Cl-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, Cl-3 alkoxy, Cl-3-carbonyl alkoxy , carbamoyl in which the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, Cl-5-amino alkanoyl, aroylamino, Cl-5-sulfonylamino alkyl, aryisulfonylamino, amino in which the atom of nitrogen may independently be mono- or di-substituted with Cl-3 alkyl, halogen, hydroxy, oxo, carboxy and cyano, Rb may also be optionally substituted with one or more Rc; R c is selected from the group consisting of Cl-3 alkoxy, halogen and hydroxy, R is C 2-5 alkyl or C 5-6 cycloalkyl wherein R 3 is optionally substituted with one or more R; Rd is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, Cl-4 alkoxy, Cl-5-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more ReI- Re is selected from the group consisting of methyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy , benzoyl, halogen and hydroxy; R6 is Cl-5 alkyl or phenyl, wherein R6 is optionally substituted with one or more Rf; Rf is selected from the group consisting of C 3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy, benzyloxy, C 1-3 -alkynyl methylthio alkanoyl wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, methoxycarbonylamino, amino in which the nitrogen atom may be independently mono- or di-substituted with Cl-3 alkyl, halogen, hydroxy , carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with one or more groups selected from halogen or methyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl or phenyl, halogen, hydroxy and carboxy; or Rs and R6 together with the carbon to which they are attached form a carbocyclic ring of 3 to 5 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is selected from the group consisting of vinyl, phenyl, methoxycarbonyl, benzyloxycarbonyl and carboxy. 39. The compound according to claim 38, characterized in that: Ri is cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl or thiopyranyl, wherein Ri is optionally substituted with one or more Rb; Rb is selected from the group consisting of pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbonyl, amino wherein the nitrogen atom can be independently mono- or di-substituted with Cl-3 alkyl, halogen, hydroxy and carboxy, Rb may also be optionally substituted with one or more Rc; Rc is selected from the group consisting of methoxy, halogen and hydroxy; R is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, Cl-4 alkoxy, Cl-3-amino alkanoyl, methylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen, hydroxy, oxo, carboxy and cyano, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl, phenyl, methoxy, halogen and hydroxy; Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, thienyl, indolyl, methoxy, benzyloxy, methylthio in which the sulfur atom may be oxidized to a sulphoxide or a sulfone, benzylthio in which the atom Sulfur may be oxidized to a sulfoxide or a sulfone, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, phenyl optionally substituted with halogen, methoxy, phenoxy, benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy; or R5 and Re together with the carbon to which these are attached form a carbocyclic ring of 3 carbon atoms, the carbocyclic ring being optionally substituted with one or more Rh; Rh is vinyl or phenyl. 40. The compound according to claim 39, characterized in that: Ri is phenyl, naphtyl or 4-morpholinyl wherein Ri is optionally substituted with one or more Rb; R b is selected from the group consisting of benzimidazolyl, methoxy and dimethylamino, R b may also be optionally substituted with R c wherein R c is a halogen atom; R3 is C2-5 alkyl wherein R3 is optionally substituted with one or more Rc; Rd is selected from the group consisting of C3-6 cycloalkyl, phenyl or naphthyl, Rd may also be optionally substituted with one or more Re; Re is selected from the group consisting of methyl and halogen, Rf is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, indolyl, benzyloxy, methylthio wherein the sulfur atom may be oxidized to a sulfoxide or a sulfone, benzylthio in which the sulfur atom may be oxidized to a sulfoxide or a sulfone, halogen and carboxy, Rf may also be optionally substituted with one or more Rg; Rg is selected from the group consisting of methyl, methoxy, methoxycarbonyl, halogen and hydroxy and Rb and Rβ together with the carbon to which these are attached form a carbocyclic ring of 3 carbon atoms, the carbocyclic ring being substituted with one or more Rh. 41. A method for preparing a compound of the formula (I), wherein A is -C (0) -, X is O, R7 is R8 -C (O) - and R2, R3, R6 and R8 are as defined in claim 1, characterized in that it comprises: a) coupling a protected amino acid with N, 0-dimethylhydroxyamine under coupling conditions in a solvent to give the corresponding amide below: wherein R "is an amino protecting group, R 'is NMe (OMe) and R6 is as defined in claim 1; b) reducing the compound produced in step a) with a reducing agent within the an appropriate solvent to form a compound of the formula (V): (V); d) reacting an R8 heterocycle according to claim 1, with n-BuLi to form a corresponding heterocyclic anion in an appropriate solvent at a temperature of about -30 to -100 ° C; reacting the R8 anion of heterocycle with a compound of the formula V; e) removing the protecting group R "from the compound produced in step d) and subsequently coupling with a compound of the formula (IV) under coupling conditions to produce a compound of the formula (VII): (Vile) f) oxidizing compound VII from step e) to produce a compound of formula (I). 42. A method for preparing a compound of the formula (II) wherein A is -C (0) -, X is O, and R2, R3, R4, Rs and R are as defined in claim 21; characterized in that it comprises: a) coupling under coupling conditions an amino acid protected with a protecting group R 'with a compound of the amide type possessing R6: b) removing the protecting group R 'from the compound produced in step a); c) reacting the compound produced from step b) with an acid chloride according to the following formula: wherein X 'is CONH2 and Ri is as defined in claim 21; and d) dehydrating the amide compound produced in step c) with a dehydrating agent under appropriate dehydration conditions to produce the nitrile type compound of the formula (II). 43. A compound selected from the group consisting of: (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (LR-cyano-2-benzyloxy-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine; (N- (4-morpholino-carbonyl) -L- (4-methyl) leucine (LR-cyano-2-benzyloxy-ethyl) amide; (1-R-cyano-2R-benzyloxy-propyl) amide of N- (-morpholinocarbonyl) -L-leucine; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (benzyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (2-chloro-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (4-chloro-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-methoxy-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L- (4-methyl) leucine; LR-cyano-2- (benzyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (benzyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (benzyl-sulfinyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- ((4-methoxy-phenyl) methyl-sulfanyl) ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-chloro-phenyl) methyloxy-ethyl) amide; (1-R-cyano-2-benzyloxy-ethyl) amide of N- (5-dimethylamino-naphth-1-ylsulfonyl) -L- (4-methyl) leucine; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (2-methyl-phenyl) methyloxy-ethyl) amide; (N- (4-Orpholino-carbonyl) -L-leucine lR-cyano-2- (3-methyl-phenyl) methyloxy-ethyl) amide; (N- (4-Orpholino-carbonyl) -L-leucine lR-cyano-2- (4-methyl-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine lR-cyano-2- (3-carbomethoxy-phenyl) methyloxy-ethyl) amide; (N- (4-morpholino-carbonyl) -L-leucine IR-cyano-2- (-carbomethoxy-phenyl) methyloxy-ethyl) amide; (1- S-cyano-3- (carbo-t-butoxy) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-leucine; [N- (-morpholino-carbonyl) -L-leucine-IS- (benzothiazol-2-ylcarbonyl) -3-phenyl-propyl] amide; [1- S-cyano-5- ((benzyloxycarbonyl) amino) -pentyl] amide of N- (4-morpholino-carbonyl) -L-leucine; [IR, S- (benzoxazol-2-ylcarbonyl) -3-phenyl-propyl] amide of N- (-morpholino-carbonyl) -L-leucine; [1- [(
- 6-Phenyl-carbamoyl) benzothiazol-2-ylcarbonyl] -3-phenyl-propyl]] -amide of N- (4-morpholino-carbonyl) -L-leucine; [[6- (carbomethoxy) benzoxazol-2-ylcarbonyl] -3-phenylpropyl] amide N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-mor folino-carbonyl) -L-cyclohexyl-alanine; (N- (4-morpholinocarbonyl) -L-cyclohexyl-alanine (LR-cyano-2-benzyloxyethyl) amide; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L-nor-leucine; (1- (4-morpholinocarbonyl) -L-leucine; (N- (4-morpholino-carbonyl) -L-leucine; S- (oxazol-2-ylcarbonyl) -3-phenyl-propyl) -amide; [1- (Benzothiazol-2-ylcarbonyl) -3-phenyl-propyl] amide of N- (4-morpholino-carbonyl) -L- (4-methyl) leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (2-naphthyl) alanine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (2-chloro-phenyl) alanine; (lR-cyano-2-benzyloxy-ethyl) amide of N-benzoyl 1-L-leucine; (1- S-cyano-3-phenyl-propyl) amide of N- (4-morpholinocarbonyl) -L- (O-methyl) tyrosine; (1- S-cyano-1-phenyl-methyl) amide of N- (4-morpholinocarbonyl) -L-leucine; N- (4-morpholinocarbonyl) -L-leucine (1-cyano-cyclopropyl) amide: (1- S-cyano-2- (2-chloro-phenyl) ethyl) amide of N- (4-morpholinocarbonyl) -L -leucine; (1- S-cyano-2- (4- (2,6-dichloromethoxy) phenyl) ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3- (carbobenzyloxy) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (ÍS, 3-dicyano-propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (ÍS, 2-dicyano-ethyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3- (methyl-sulfonyl) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; (1- S-cyano-3- (4-hydroxy-phenyl) propyl) amide of N- (4-morpholino-carbonyl) -L-leucine; and (1- S-cyano-2-cyclohexyl-ethyl) amide of N- (4-morpholinocarbonyl) -L-leucine. 44. A compound selected from the group consisting of: (l- (S) - [l- (S) - (2,4-di-phenyl-1-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl] -3-methyl-butyl.} - morpholine-4-carboxylic acid amide; {. L- (S) - [l- (S) - (2,4-di-phenyl-oxa-zol-5-carbonyl) 3-phenyl-propyl-carbamoyl-1] -3,3-dimethyl-butyl.} - morpholine-4-carboxylic acid amide;. {2-cyclohexyl-1 - (S) - (1 - [( S) - (2, 4-diphenyl-oxazole-5-carbonyl) -3-phenyl-propyl-carbamoyl-1] -ethyl.} - morpholine-4-carboxylic acid amide;. {L- (S) - [(2,4-diphenyl-oxazol-5-yl) -2-oxo-yl-carbamoyl] -3-methyl-butyl} -amide of morpholine-4-carboxylic acid;. {2-cyclohexyl; -l- (S) - [2- (2, 4-di-phenyl-1-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -ethyl} -amide of morpholine-4-carboxylic acid; . {l- (S) - [2- (2, 4-diphenyl-oxazol-5-yl) -2-oxo-ethyl-carbamoyl] -3,3-dimethyl-butyl} -amide of morpholine 4-carboxylic acid; (1- (S) -. {1- (S) - [2- (3-benzyloxy-phenyl) -oxazole-5-carbonyl] -3-phenyl l-propyl-carbamoyl} -3-methylbutyl) -amide of morpholine-4-carboxylic acid; . { 2-C-Clohexyl-1- (S) - [I- (R, S) - (-isobutyl-2-pyridin-2-yl-oxazole-5-carbonyl) -3-phenyl-propylcarbamoyl-1] -ethyl } - morpholine-4-carboxylic acid amide; and its pharmaceutically acceptable derivatives. 45. A pharmaceutical composition characterized in that it comprises a pharmaceutically effective amount of a compound according to claims 1, 11, 21, 31 or 43. 46. The use of a compound in accordance with subdivisions 1, 11, 21, 31 or 43 for the manufacture of a drug to modulate an autoimmune disease. 47. The use according to claim 46, characterized in that the autoimmune disease is selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis, Guillain-Barre syndrome, psoriasis, Grave's disease, myasthenia gravis, scleroderma, glomerulonephritis, atopic dermatitis and insulin-dependent diabetes mellitus. 48. The use of a compound according to claims 1, 11, 21, 31 or 43 for the manufacture of a medicament for Alzheimer's. 49. The use of a compound according to claims 1, 11, 21, 31 or 43 for the manufacture of a medicament for treating atherosclerosis.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/122,570 | 1999-03-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01008713A true MXPA01008713A (en) | 2002-05-09 |
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