HK1060565B - Spiroheterocyclic nitriles useful as reversible inhibitors of cysteine proteases - Google Patents

Description

Spiroheterocyclic nitriles as reversible inhibitors of cysteine proteases

Information of related application

This application is a continuation-in-part application filed on 8/9/2000 of U.S. application serial No. 09/655,351.

Technical Field

The present invention relates to amidino and guanidino peptide compounds having activity as inhibitors of cysteine proteases. The compounds are reversible inhibitors of the cysteine proteases cathepsin S, K, F, L and B and are therefore useful in the treatment of autoimmune and other diseases. The invention also relates to processes for preparing such compounds and pharmaceutical compositions comprising such compounds.

Background

In a cysteine proteaseIn the papain superfamily of (I), cathepsin S and cathepsin K are members of the papain family. The family of papain is the largest family of cysteine proteases and includes proteases such as cathepsins B, H, K, L, O and S (A.J. Barrett et al, 1996, Perspectives in Drug Discovery and Design, 6, 1). The cysteine proteases have important roles in human biology and diseases including atherosclerosis, emphysema, osteoporosis, chronic inflammation and immune disorders (H.A. Chapman et al, 1997, Ann.R.)_ePhysiol., 59, 63). Cathepsin S plays a key role in the regulation of antigen presentation and Immunity (h.a. chapman, 1998, Current Opinion in Immunology, 10, 93; r.j. riese et al, 1998, j.clin.invest., 101, 2351; r.j. riese et al, 1996, Immunity, 4, 357). Cathepsin S deficient mice have impaired invariant chain degradation leading to reduced antigen presentation and germinal center formation, and reduced sensitivity to collagen-induced arthritis, suggesting therapeutic potential for cathepsin S inhibitors (g.shi et al, 1999, Immunity, 10, 197; t.y.nakagawa et al, 1999, Immunity, 10, 207).

Specificity of the immune response depends on the processing of foreign proteins and the presentation of cell surface antigenic peptides. Antigenic peptides are presented in association with class II MHC, a heterodimeric glycoprotein expressed in certain antigen presenting cells in hematopoietic cell lines, such as B cells, macrophages and dendritic cells. The presentation of antigens to effector cells such as T cells is a fundamental step of non-self-recognition and thus the initiation of an immune response.

Recently, class II MCH heterodimers have been shown to bind intracellularly to a third molecule called the invariant chain. Invariant chains facilitate class II transport to the endosomal compartment and stabilize class II proteins prior to loading with antigen. The invariant chain interacts directly with class II dimers in the antigen binding groove and must therefore be proteolysed (proteolyzed) and removed, otherwise antigen loading and presentation is not possible. Current research suggests that the invariant chain is selectively proteolyzed by cathepsin S, which is separated intracellularly from the class II MCH complex. Cathepsin S degrades the invariant chain into a small peptide called CLIP, which occupies the antigen binding groove. CLIP is released from class II MCH through the interaction of class II MCH with HLA-DM, and MHC class molecules that release class II MCH bind to antigenic peptides. The class II MCH-antigen complex is then transported to the cell surface for presentation to T cells and the initiation of an immune response.

Cathepsin S provides a fundamental step in the generation of an immune response by proteolytic degradation from the invariant chain to CLIP. Thus, by means of cathepsin S, a mechanism is provided for immunomodulation by preventing invariant chain degradation and thereby inhibiting antigen presentation. Control of antigen-specific immune responses has long been desired as an effective and safe treatment for autoimmune diseases. Such diseases include crohn's Disease and arthritis, as well as other T cell mediated Immune responses (c. janeway and p. travers, 1996, immunology, The Immune System in health and Disease, Chapter 12). Furthermore, cathepsin S, which has a broad pH specificity, 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), atherosclerosis (g.k.sukhova et al, 1998, j.clin.invest., 102, 576) and endometriosis (WO 9963115, 1999).

It has been found in a mouse model of pulmonary allergy that cathepsin S inhibitors prevent elevation of IgE titers and infiltration of eosinophils in the lung, suggesting that cathepsin S may be involved in asthma (r.j.riese et al, j.clin.investment, 1998, 101, 2351).

Another semi-light amino acid protease, cathepsin F, has been found in macrophages, which is also associated with antigen processing. It has been postulated that cathepsin F in the exuberant lung macrophages and other potential antigen presenting cells may play a role in respiratory inflammation (g. -p. shi et al, j. exp. med., 2000, 191, 1177).

Another semi-light amino acid protease, cathepsin K, has been found to be highly expressed in osteoclasts and to degrade collagen and other bone matrix proteins. Cathepsin K inhibitors have been shown to inhibit bone resorption in mice. Thus, cathepsin K may play a role in bone resorption in fractured bones, and cathepsin K inhibitors may be useful in the treatment of diseases involving bone resorption, such as osteoporosis (F.Lazner et al, Human Molecular Genetics, 1999, 8, 1839).

The cysteine protease is characterized by having a cysteine residue at the active site which acts as a nucleophile. The active site also contains histidine residues. The imidazole ring on histidine serves as the basis for the generation of thiolates on the cysteine of this active site, while increasing its nucleophilicity. When the substrate is recognized by a protease, the amide bond to be cleaved is directed to the active site where the thiolate attacks the carbonyl carbon to form an acyl-enzyme intermediate and cleaves the amide bond, releasing the amine. Subsequently, the acyl-enzyme material is water-cleaved, allowing the enzyme to be regenerated, while releasing the carboxylic acid, another cleavage product of the substrate.

Inhibitors of cysteine proteases contain functional groups that react reversibly or irreversibly with the active site cysteine. Examples of reactive functional groups that have been described for inhibitors of cysteine proteases (d. rasnick, 1996, Perspectives in Drug Discovery and Design, 6, 47) include peptidyl diazomethanes, epoxides, monofluoroalkanes and acyloxymethanes, which irreversibly alkylate cysteine thiols. Other irreversible inhibitors include Michael receptors such as peptidyl vinyl esters and other carboxylic acid derivatives (s.liu et al, j.med chem., 1992, 35, 1067) and vinyl sulfone (j.t.palmer et al, 1995, j.med chem., 38, 3193).

Reactive functional groups that form reversible complexes with the active site cysteine include peptidyl aldehydes (r.p. hanzlik et al, 1991, biochim. biophysis. acta., 1073, 33), which are non-selective, while inhibiting cysteine and serine proteases and other nucleophiles. Peptidyl nitriles (r.p.hanzlik et al, 1990, biochim.biophysis.acta, 1035, 62) are less reactive than aldehydes and are therefore more selective for more nucleophilic cysteine proteases. A wide variety of reactive ketones have also been reported as reversible inhibitors of cysteine proteases (d.rasnick, 1996, ibid). In addition to reacting with the nucleophilic cysteine at the active site, the reactive ketone also reacts with water to form a hemiketal which can act as a transition state inhibitor.

Examples of cathepsin S inhibitors have been reported. Klaus et al (WO 9640737) describe reversible inhibitors of cysteine proteases including cathepsin S, comprising ethylenediamine. In U.S. patent 5,776,718 to Palmer et al, protease inhibitors are most broadly disclosed which comprise a targeting group linked to an Electron Withdrawing Group (EWG) by a chain of two carbon atoms. The compounds of the present application are structurally distinct and can therefore be excluded from the' 5,776,718 patent, with specific embodiments having unexpectedly greater activity than the closest compounds in the prior art. Other examples of cathepsin S inhibitors have been reported by Altmann et al (WO 9924460, 1999) which describe dipeptide nitriles alleged to have activity as inhibitors of cathepsins B, K, L and S. The WO publication does not disclose any compound having a guanidino or amidino structure at position P3.

Additional peptidyl nitriles have been reported as protease inhibitors. For example, b.a. rowe et al (US5,714,471) describe nitrile and ketone heterocycles as protease inhibitors for the treatment of neurodegenerative diseases. Malcolm et al (WO 9222570) reported peptidyl nitriles as inhibitors of picornaviral proteases. gour-Salin (can.j.chem., 1991, 69, 1288) and t.c.liang (arch.biochim.biophysis., 1987, 252, 626) describe peptidyl nitriles as inhibitors of papain.

Reversible inhibitors offer a more attractive therapy than irreversible inhibitors. Even compounds with high specificity for a particular protease are able to bind non-target enzymes. Irreversible compounds can therefore permanently inactivate non-target enzymes while increasing toxicity. Moreover, any toxic effects caused by inactivation of the target enzyme can be mitigated by the reversible inhibitors, and can be easily remedied by changing or decreasing the dosage. Finally, covalent modification of the enzyme by irreversible inhibitors could potentially generate antibody reactions by acting as haptens.

In light of the above, there is a clear need for compounds that reversibly and selectively inhibit cysteine proteases, such as cathepsin S and cathepsin K, for indications where these proteases exacerbate disease.

Brief description of the invention

It is therefore an object of the present invention to provide novel compounds as shown herein in formulae (Ia) and (Ib) which reversibly inhibit the cysteine proteases cathepsin S, K, F, L and B. It is a further object of the present invention to provide methods of treating diseases and pathological conditions exacerbated by these cysteine proteases, such as but not limited to rheumatoid arthritis, multiple sclerosis, asthma, and osteoporosis. It is a further object of the present invention to provide a process for preparing the above novel compounds.

Detailed description of the invention

The proposed mechanism of action of the cysteine protease inhibitors of the invention is that the inhibitors contain functional groups that react (reversibly or irreversibly) with the active site cysteine. The reactive functional group is attached to a peptide or peptide mimic that is recognized and held by the active site region surrounding the protease. The nature of the reactive functional groups and the remainder of the inhibitor determines its degree of selection and potency for a particular protease.

Given that the active sites are similar among the cysteine proteases, it is expected that a given class of inhibitors may have activity against more than one cysteine protease. It is also contemplated that different compounds of the invention may have different potency against different cysteine proteases due to structural differences between the individual cysteine proteases. Thus, it is also expected that some compounds of the invention will be most effective in treating cysteine protease mediated diseases, where they may be most effective in inhibiting cysteine proteases. The activity of specific compounds disclosed herein against cysteine proteases such as cathepsin S, K, F, L and B can be determined by screening, see section entitled "assessment of biological properties".

Accordingly, a first general aspect of the invention provides compounds of formulae (Ia) and (Ib):

wherein:

het is

Azepane, piperidyl, pyrrolidinyl, azetidinyl, oxepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl, azocycloctyl, oxocyclooctyl, 1, 3-diazacyclooctanyl, 1, 4-diazacyclooctanyl, 1, 5-diazacyclooctanyl, 1, 3-dioxacyclooctyl, 1, 4-dioxacyclooctyl, 1, 5-dioxacyclooctyl, 1, 3-oxazocinyl, 1, 4-oxazocinyl, 1, 5-oxazocinyl, 1, 3-diazepanyl, 1, 4-diazepanyl, 1, 3-dioxacycloheptanyl, 1, 4-diazepanyl, 1, 3-diazepanyl, 1, 4-diazepanyl, 1, 3-oxaazepanyl, 1, 4-oxazepanyl, 1, 2-thiazepanyl-1, 1-dioxide, 1, 2, 8-thiadiazacyclo-ctyl-1, 1-dioxide, 1, 2-thiazepanyl-1, 1-dioxide, 1, 2, 7-thiadiazacycloheptanyl-1, 1-dioxide, tetrahydrothiophenyl, hexahydropyrimidyl, hexahydropyridazinyl, piperazinyl, 1, 4, 5, 6-tetrahydropyrimidinyl, pyrazolidinyl, dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, isoxazolinyl, oxazolidinyl, 1, 2-thiazepanyl-1, 1-dioxide, 1, 2, 6-thiadiazacyclononanyl-1, 1-dioxide, isothiazolidinyl-1, 1-dioxide, imidazolidinyl-2, 4-dione, imidazolidinyl, morpholinyl, dioxanyl, tetrahydropyridinyl, thiomorpholinyl, thiazolidinyl, dihydropyranyl, dithianyl, decahydroquinolinyl, decahydroisoquinolinyl, 1, 2, 3, 4-tetrahydroquinolinyl, indolinyl, octahydroquinolizinyl, indolizinyl, octahydroindolizinyl, octahydroquinazolinyl, decahydroquinoxalinyl, 1, 2, 3, 4-tetrahydroquinazolinyl or 1, 2, 3, 4-tetrahydroquinoxalinyl;

C₆-C₁₀Bridged bicyclic ring of (a), wherein one or more carbon atoms are optionally replaced by a heteroatom selected from N, O and S;

each ring optionally substituted with one or more R₅Substituted;

R₁is a chemical bond, hydrogen, C_1-10Alkyl radical, C_1-10Alkoxy, aryloxy, C_3-8Cycloalkyl radical, C_3-8Cycloalkoxy, aryl, benzyl, tetrahydronaphthyl, indenyl, 2, 3-indanyl, C_1-10Alkylsulfonyl radical C_1-10Alkyl radical, C_3-8Cycloalkyl sulfonyl C_1-10Alkyl, arylsulfonyl C_1-10Alkyl, heterocyclyl selected from: azepanyl, azocyclooctyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl, pyrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzisoxazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl, benzoxazolyl and quinoxalinyl, wherein the heterocyclyl moiety is selected from the heterocyclyloxy, hydroxy or amino groups of those heterocyclyl groups described in this paragraph; wherein R is ₁Optionally substituted by one or more R_aSubstituted;

R_ais a chemical bond, C_1-10Alkyl radical, C_3-8Cycloalkyl radicals, aryl radicalsTetrahydronaphthyl, indenyl, 2, 3-indanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, C_1-10Alkoxy radical, C_1-10Alkanoyl radical, C_1-10Alkanoyloxy, aryloxy, benzyloxy, C_1-10Alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may be independently replaced by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl are mono-or di-substituted,

Or R_aIs C_1-10Alkanoylamino, aroylamino, C in which the sulfur atom may be oxidized to sulfoxide or sulfone_1-10Alkylthio, in which the sulfur atom may be oxidized to the arylthio radical of a sulfoxide or sulfone, in which the nitrogen atom may be independently replaced by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl substituted ureido,

or R_aIs C_1-10Alkoxycarbonylamino, aryloxycarbonylamino, C_1-10Alkyl carbamoyloxy, aryl carbamoyloxy, C_1-10AlkylsulphonylaminosulfaminesRadical, arylsulfonylamino, C_1-10Alkylaminosulfonyl, arylaminosulfonyl, wherein the nitrogen atoms may be independently replaced by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl mono-or disubstituted amino,

Or R_aIs halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_aMay optionally be substituted by one or more R_bFurther substitution;

provided that R is₁And R_aCan not be chemical bonds at the same time;

R_bis C_1-6Saturated or unsaturated, branched or linear carbon chains, optionally partially or fully halogenated, in which one or more carbon atoms are optionally substituted by O, N, S (O)₂Or S, and wherein said chain is optionally independently substituted with 1-2 oxo, -NH₂Or one or more C_1-4Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl;

or R_bIs C_3-6Cycloalkyl, aryl, aryloxy, benzyloxy, halogen, hydroxy, oxy, carboxy, cyano, nitro, mono C_1-5Alkylamino, di-C_1-5Alkylamino, carboxamide, amidino or guanidino;

R₂is hydrogen or C _1-3An alkyl group;

R₃is a chemical bond, hydrogen, C_1-10Alkyl radical, C_2-10Olefin, C_3-8Cycloalkyl, aryl C_1-5Alkyl or aryl, wherein R₃Optionally substituted by one or more R_cSubstituted;

R_cis C_1-10Alkyl radical, C_3-8Cycloalkyl, aryl, 2, 3-indanyl, indenyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [4.1.0 ]]Heptylalkyl, bicyclo [3.1.0]Hexane radical, bicyclo [1.1.1]Pentyl, cubic alkyl, 1, 2, 3, 4-tetrahydronaphthyl, decahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, dihydrobenzofuranyl, octahydrobenzofuranyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, Cquinoxalinyl, C_1-10Alkoxy, aryloxy, C_1-10Alkanoyl, aroyl, C_1-10Alkoxycarbonyl, aryloxycarbonyl, C_1-10Alkanoyloxy, aroyloxy, carbamoyl, wherein the nitrogen atom may be independently replaced by C _1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl are mono-or di-substituted,

or R_cIs C_1-10Alkanoylamino, aroylamino, C in which the sulfur atom may be oxidized to sulfoxide or sulfone_1-10Alkylthio radicals in which the sulfur atom may be replaced by oxygenArylthio radicals, which are converted into sulphoxides or sulphones, in which the nitrogen atom may be replaced independently by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl substituted ureido,

or R _cIs C_1-10Alkoxycarbonylamino, aryloxycarbonylamino, C_1-10Alkyl carbamoyloxy, aryl carbamoyloxy, C_1-10Alkylsulfonylamino, arylsulfonylamino, C_1-10Alkylaminosulfonyl, arylaminosulfonyl, wherein the nitrogen atoms may be independently replaced by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl mono-or disubstituted amino,

or R_cIs halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino or guanidino, R_cMay optionally be substituted by one or more R_dFurther substitution;

R_dis C_1-5Alkyl radical, C_3-6Cycloalkyl, aryl C_1-5Alkyl radical, C_1-5Alkoxy, aryloxy, aryl C_1-5Alkoxy, aroyl, amino, halogen, hydroxy, oxy, carboxy, cyano, nitro, amidino or guanidino;

R₂and R₃Optionally combined with the carbon to which they are attached to form a non-aromatic 5-7 membered cycloalkyl or heterocyclic ring;

Each R₄Independently hydrogen, hydroxy or C_1-3An alkyl group;

R₅is a chemical bond, hydrogen, carbonyl, C_1-10Alkyl radical, C_1-10Alkoxy radical C_1-10Alkyl radical, C_1-10Alkylamino radical C_1-10Alkyl, C in which the sulfur atom may be oxidized to sulfoxide or sulfone_1-10Alkylthio radical C_1-10Alkyl radical, C_1-10Alkoxy, aryloxy, C_3-8Cycloalkyl, aryl, benzyl, tetrahydronaphthyl, indenyl, 2, 3-indanyl, C_3-7Cycloalkyl sulfonyl C_1-5Alkyl, arylsulfonyl C_1-5Alkyl, heterocyclyl, the heterocyclyl being selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl (pyridizinyl), tetrazolyl, triazolyl, pyrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl, benzoxazolyl and quinoxalinyl, wherein the heterocyclyl moiety is selected from the heterocyclyloxy of the heterocyclyl described in this paragraph, C _1-10Alkanoyl, aroyl, C_1-10Alkanoyloxy, benzyloxy, C_1-10Alkoxycarbonyl, aryl C_1-5Alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl, wherein the nitrogen atom may be independently replaced by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl are mono-or di-substituted,

or R₅Is C_1-10Alkanoylamino, aroylamino, C in which the sulfur atom may be oxidized to sulfoxide or sulfone_1-10Alkylthio, in which the sulfur atom may be oxidized to the arylthio radical of a sulfoxide or sulfone, in which the nitrogen atom may be independently replaced by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl substituted ureido,

Or R₅Is C_1-10Alkoxycarbonylamino, aryloxycarbonylamino, C_1-10Alkyl carbamoyloxy, aryl carbamoyloxy, C_1-10Alkylsulfonylamino, arylsulfonylamino, C_1-10Alkylaminosulfonyl, arylaminosulfonyl, wherein the nitrogen atoms may be independently replaced by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl mono-or disubstituted amino,

or R₅Is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R₅May be further optionally substituted by one or more R_eSubstituted;

R_eis C_1-10Alkyl radical, C_1-10Alkoxy radical C_1-10Alkyl radical, C_1-10Alkylamino radical C_1-10Alkyl, in which the sulfur atom can be oxidized to the sulfoxide or sulfone C_1-10Alkylthio radical C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-8Cycloalkyl, aryl, tetrahydronaphthyl, indenyl, 2, 3-indanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, thiopyranyl, tetrahydrothiopyranyl, pyranyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, Cquinoxalinyl, Czocyclodinyl, dihydroindolyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, furyl, thienyl, furyl, thienyl, benzimidazolyl _1-10Alkanoyl, aroyl, C_1-10Alkanoyloxy, aryloxy, benzyloxy, C_1-10Alkoxycarbonyl, aryl C_1-3Alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl, wherein the nitrogen atom may be independently replaced by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl are mono-or di-substituted,

or R_eIs C_1-10Alkanoylamino, aroylamino, C in which the sulfur atom may be oxidized to sulfoxide or sulfone_1-10Alkylthio, in which the sulfur atom may be oxidized to the arylthio group of a sulfoxide or sulfone, in which any nitrogen atom may be independently replaced by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl substituted ureido,

Or R_eIs C_1-10Alkoxycarbonylamino, aryloxycarbonylamino, C_1-10Alkyl carbamoyloxy, aryl carbamoyloxy, C_1-10Alkylsulfonylamino, arylsulfonylamino, C_1-10Alkylaminosulfonyl, arylaminosulfonyl, wherein the nitrogen atoms may be independently replaced by C_1-10Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl mono-or disubstituted amino,

or R_eIs halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_eMay optionally be substituted by one or more R_fFurther substitution;

R_fis C_1-5Alkyl radical, C_3-6Cycloalkyl, tosyl, C_1-5Alkoxy, aryl, aryloxy, benzyloxy, halogen, hydroxy, oxy, carboxy, cyano, nitro, carboxamide, amidino or guanidino;

R₆is that

Hydrogen, hydroxy, nitrile or

C_1-6Saturated or unsaturated, branched or linear carbon chains, optionally partially or fully halogenated, in which one or more carbon atoms are optionally substituted by O, NH, S (O)₂Or S, and wherein said chain is optionally independently substituted with 1-2 oxo, -NH₂One or more C_1-4Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothiophenylThienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl, or quinoxalinyl;

wherein R in formula (Ia) or (Ib)₁And R₆Optionally forming a 4-to 8-membered monocyclic or 7-to 12-membered polycyclic heterocyclic ring system, each ring being aromatic or non-aromatic, wherein each heterocyclic ring is optionally substituted with one or more R₇Substituted;

each R₇And R₈Independently are:

C_1-5alkyl chain, optionally substituted by one or two N, O or S (O)_mOptionally interrupted by 1-2 oxo, amino, hydroxy, halogen, C_1-4Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl or quinoxalinyl,

Aryl, aryloxy, aroyl, furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, C_1-5Alkanoyl radical, C_1-5Alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, C_1-5Alkanoylamino, aroylamino, C_1-5Alkylthio, arylthio C_1-5Alkylsulfonylamino, arylsulfonylamino, C_1-5Alkylaminosulfonyl, arylaminosulfonyl, C_3-6Cycloalkyl and benzyloxy

Each of the foregoing groups is optionally halogenated,

halogen, hydroxy, oxo, carboxy, nitrile, nitro or NH₂C(O)-；

m is 0, 1 or 2;

x is ═ O, ═ S or ═ N-R₆Wherein R is₆Is as defined above, and

a pharmaceutically acceptable derivative thereof.

Another embodiment of the present invention provides compounds of formula (Ia) and formula (Ib) as directly described above, wherein:

het is piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, azepanyl, oxepanyl, tetrahydrofuranyl, oxetanyl, hexahydropyrimidyl, hexahydropyridazinyl, piperazinyl, 1, 4, 5, 6-tetrahydropyrimidinyl, octahydroindolizinyl, octahydroquinolizinyl, decahydroquinolyl, 1, 2, 3, 4-tetrahydroquinolyl, dihydrooxazolyl, 1, 2-thiazeranonyl-1, 1-dioxide, 1, 2, 6-thiadiazacyclononyl-1, 1-dioxide, isothiazolyl-1, 1-dioxide, imidazolidinyl, pyrazolidinyl or a bridged bicyclic ring selected from: azabicyclo [3.2.1] octane, azabicyclo [2.2.1] heptane, azabicyclo [2.2.2] octane, azabicyclo [3.2.2] nonane, azabicyclo [2.1.1] hexane, azabicyclo [3.1.1] heptane, azabicyclo [3.3.2] decane and 2-oxa-or 2-thia-5-azabicyclo [2.2.1] heptane;

Each ring being substituted by one or more R₅Substituted;

R₁is a chemical bond, hydrogen, C_1-7Alkyl radical, C_1-7Alkoxy radical, C_3-7Cycloalkyl, aryloxy, phenyl, benzyl, naphthyl, tetrahydronaphthyl, C_1-7Alkylsulfonyl radical C_1-7Alkyl radical, C_3-7Cycloalkyl sulfonyl C_1-7Alkyl, arylsulfonyl C_1-7Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, isoxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoisoxazolyl, benzoxazolyl or amino; wherein R is₁Optionally is one orPlural R_aSubstituted;

R_ais a chemical bond, C_1-7Alkyl radical, C_3-6Cycloalkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, Czochromyl, thienyl, and the like _1-7Alkoxy radical, C_1-7Alkanoyl radical, C_1-7Alkanoyloxy, aryloxy, benzyloxy, C_1-7Alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl, wherein the nitrogen atom may be independently replaced by C_1-7Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl are mono-or di-substituted, or R_aIs C_1-7Alkanoylamino, aroylamino, C_1-7Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, arylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urethyl, in which any nitrogen atom can be independently replaced by C_1-7Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

Or R_aIs C_1-7Alkoxycarbonylamino, aryloxycarbonylamino, C_1-7Alkyl carbamoyloxy, aryl carbamoyloxy, C_1-7Alkylsulfonylamino, arylsulfonylamino, C_1-7Alkylaminosulfonyl, arylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C_1-7Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, mono-or di-substituted,

or R_aIs halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_aOptionally further substituted by one or more R_bSubstituted;

R_bis C_1-5Alkyl radical, C_3-6Cycloalkyl, aryl, C_1-5Alkoxy, aryloxy, benzyloxy, halogen, hydroxy, oxy, carboxy, cyano, nitro, carboxamide, amidino or guanidino;

R₂is hydrogen or methyl or ethyl;

R₃is a chemical bond, hydrogen, C_1-5Alkyl radical, C_2-5Alkenyl radical, C _3-7Cycloalkyl, aryl C_1-3Alkyl or aryl, wherein R₃Optionally substituted by one or more R_cSubstituted;

R_cis C_1-5Alkyl radical, C_3-7Cycloalkyl, aryl, 2, 3-indanyl, indenyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [4.1.0 ]]Heptylalkyl, bicyclo [3.1.0]Hexane radical, bicyclo [1.1.1]Pentyl, cuboalkyl, 1, 2, 3, 4-tetrahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolylBenzothiazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, C_1-5Alkoxy, aryloxy, C_1-5Alkanoyl, aroyl, C_1-5Alkoxycarbonyl, aryloxycarbonyl, C_1-5Alkanoyloxy, aroyloxy, carbamoyl, wherein the nitrogen atom may be independently replaced by C_1-5Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl are mono-or di-substituted, or R _cIs C_1-5Alkanoylamino, aroylamino, C_1-5Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, arylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently substituted by C_1-5Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_cIs C_1-5Alkoxycarbonylamino, aryloxycarbonylamino, C_1-5Alkylcarbamoyloxy, arylcarbamoyloxy, C_1-5Alkylsulfonylamino, arylsulfonylamino, C_1-5Alkylaminosulfonyl, arylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C_1-5Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl Pyranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, mono-or disubstituted,

or R_cIs halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino or guanidino, R_cOptionally further substituted by one or more R_dSubstituted;

R_dis C_1-5Alkyl radical, C_3-6Cycloalkyl, aryl C_1-4Alkyl radical, C_1-5Alkoxy, aryloxy, aryl C_1-5Alkoxy, aroyl, halogen, hydroxy, oxy or cyano;

R₄is hydrogen or methyl;

R₅is a chemical bond, hydrogen, carbonyl, C_1-8Alkyl radical, C_1-8Alkoxy radical C_1-8Alkyl radical, C_1-8Alkylamino radical C_1-8Alkyl radical, C_1-8Alkylthio radical C_1-8Alkyl in which the sulfur atom may be oxidized to sulfoxide or sulfone, C_1-8Alkoxy, aryloxy, C_3-7Cycloalkyl, aryl, benzyl, tetrahydronaphthyl, 2, 3-indanyl, a heterocyclic group selected from: pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl, pyrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl and quinoxalinyl, heterocyclyloxy, wherein the heterocyclyl moiety is selected from the group consisting of heterocyclyl as described in this paragraph, C _1-7Alkanoyl, aroyl, C_1-7Alkanoyloxy, benzyloxy, C_1-7Alkoxycarbonyl, aryl C_1-4Alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may be independently replaced by C_1-7Alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, mono-or disubstituted,

or R₅Is C_1-7Alkanoylamino, aroylamino, C_1-7Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, arylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-7Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl,

Or R₅Is C_1-7Alkoxycarbonylamino, aryloxycarbonylamino, C_1-7Alkylcarbamoyloxy, arylcarbamoyloxy, C_1-7Alkylsulfonylamino, arylsulfonylamino, C_1-7Alkylaminosulfonyl, arylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C_1-7Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, mono-or di-substituted,

or R₅Is halogen, hydroxy, oxo, carboxy, cyano, nitro or carboxamide, R₅Optionally further substituted by one or more R_eSubstituted;

R_eis C_1-7Alkyl radical, C_1-7Alkoxy radical C_1-7Alkyl radical, C_1-7Alkylamino radical C_1-7Alkyl radical, C_1-7Alkylthio radical C_1-7Alkyl in which the sulfur atom may be oxidized to sulfoxide or sulfone, C_1-7Alkoxy radical, C_3-7Cycloalkyl, aryl, tetrahydronaphthyl, 2, 3-indanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thiopyranyl, tetrahydrothiopyranyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, C _1-5Alkanoyl, aroyl, C_1-5Alkanoyloxy, aryloxy, benzyloxy, C_1-5Alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may be independently replaced by C_1-5Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, mono-or di-substituted,

or R_eIs C_1-5Alkanoylamino, aroylamino, C_1-5Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, arylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-5Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl,

Or R_eIs C_1-5Alkoxycarbonylamino, aryloxycarbonylamino, C_1-5Alkylcarbamoyloxy, arylcarbamoyloxy, C_1-5Alkylsulfonylamino, arylsulfonylamino, C_1-5Alkylaminosulfonyl, arylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C_1-5Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, mono-or di-substituted,

or R_eIs halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_eOptionally further substituted by one or more R_fSubstituted;

R_fis methyl, ethyl, tert-butyl, tosyl, C_1-3Alkoxy, cyclopropyl, cyclohexyl, phenyl, naphthyl, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxy, carboxy, cyano, nitro or carboxamide;

R₆is composed of

Hydrogen, hydroxy, nitrile or

C_1-6Saturated or unsaturated, branched or linear carbon chains, optionally partially or fully halogenated, in which one or more carbon atoms are optionally substituted by O, NH, S (O) ₂Or S, and wherein the carbon chain is optionally independently substituted with 1-2 oxo, -NH₂One or more C_1-4Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinylQuinazolinyl, benzoxazolyl or quinoxalinyl;

r of formula (Ia) or formula (Ib)₁And R₆A 5, 6 or 7 membered aromatic or nonaromatic heterocyclic ring forming a monocyclic ring, which is optionally substituted by R₇Substituted;

or bicyclic having one 5, 6 or 7 membered aromatic or nonaromatic heterocyclic ring fused to a second 5 to 7 membered aromatic or nonaromatic heterocyclic or carbocyclic ring wherein each ring is optionally independently substituted by one or more R₇Substituted;

R₇and R₈Independently is C_1-5Alkyl radical, C_3-6Cycloalkyl, aryl, C_1-5Alkoxy, aryloxy, benzyloxy, each of the foregoing being optionally halogenated, or R_xIs halogen, hydroxy, oxo, carboxy, nitrile, nitro or NH ₂C(O)-；

M is 0, 1 or 2; and is

X is O or S.

In another embodiment of the present invention, there are provided novel compounds of the formulae (Ia) and (Ib) as specified directly above,

wherein:

het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl, octahydroindolizinyl, octahydroquinolizinyl or azabicyclo [3.2.1]Octyl, each ring optionally substituted with one or more R₅Substituted;

R₁is a chemical bond, C_1-5Alkyl radical, C_1-5Oxy radical, C_3-6Cycloalkyl, aryloxy, phenyl, benzyl, naphthyl, C_1-3Alkylsulfonyl radical C_1-3Alkyl radical, C_3-6Cycloalkyl sulfonyl C_1-3Alkyl, arylsulfonyl C_1-3Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, isoxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or amino; wherein R is₁Optionally substituted by one or more R_aSubstituted;

R_ais a chemical bond, C_1-3Alkyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, C _1-3Alkoxy radical, C_1-3Alkanoyl radical, C_1-3Alkanoyl, aryloxy, benzyloxy, C_1-3Alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may be independently replaced by C_1-3Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, mono-or disubstituted,

or R_aIs C_1-3Alkanoylamino, aroylamino, C_1-3Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, arylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently substituted by C_1-3Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, or R_aIs C_1-3Alkoxycarbonylamino, aryloxycarbonylamino, C_1-3Alkylcarbamoyloxy, arylcarbamoyloxy, C_1-3Alkylsulfonylamino, arylsulfonylamino, C_1-3Alkylaminosulfonyl, arylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C_1-3Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl mono-or disubstituted,

Or R_aIs halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_aOptionally further substituted by one or more R_bSubstituted;

R_bis C_1-3Alkyl radical, C_3-6Cycloalkyl, aryl, C_1-3Alkoxy, aryloxy, benzyloxy, halogen, hydroxy, oxy, carboxy, cyano, nitro, carboxamide, amidino or guanidino;

R₂is hydrogen or methyl;

R₃is a chemical bond, hydrogen, C_1-5Alkyl radical, C_2-5Alkenyl radical, C_4-6Cycloalkyl or aryl C_1-2Alkyl radical, wherein R₃Optionally substituted by one or more R_cSubstituted;

R_cis C_1-4Alkyl radical, C_5-6Cycloalkyl, phenyl, naphthyl, 2, 3-indanyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [4.1.0 ]]Heptylalkyl, bicyclo [3.1.0]Hexane radical, bicyclo [1.1.1]Pentyl, cuboalkyl, 1, 2, 3, 4-tetrahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, indolinyl, furyl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, C _1-4Alkoxy, phenoxy, naphthoxy, C_1-3Alkanoyl, benzoyl, C_1-3Alkoxycarbonyl, phenoxycarbonyl, C_1-3Alkanoyl, benzoyloxy, carbamoyl, wherein the nitrogen atom may independently be replaced by C_1-5Alkyl or aryl groups are mono-or di-substituted,

or R_cIs C_1-3Alkanoylamino, benzoylamino, C_1-3Alkylthio radicals in which the sulfur atom may beOxidized to sulfoxide or sulfone, phenylthio in which the sulfur atom can be oxidized to sulfoxide or sulfone, ureido in which any nitrogen atom can be independently substituted by C_1-5Alkyl or aryl, or a substituted alkyl or aryl group,

or R_cIs C_1-3Alkoxycarbonylamino, aryloxycarbonylamino, C_1-3Alkylcarbamoyloxy, arylcarbamoyloxy, C_1-3Alkylsulfonylamino, arylsulfonylamino, C_1-3Alkylaminosulfonyl, arylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C_1-5Alkyl or aryl groups are mono-or di-substituted,

or R_cIs halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino or guanidino, R_cOptionally independently by one or more R_dSubstituted;

R_dis C_1-3Alkyl radical, C_3-6Cycloalkyl, phenyl, benzyl, C_1-3Alkoxy, phenoxy, phenyl C_1-3Alkoxy, benzoyl, halogen, hydroxy, oxy or cyano;

R₄Is hydrogen;

R₅is a chemical bond, hydrogen, carbonyl, C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkylthio radical C_1-6Alkyl in which the sulfur atom may be oxidized to sulfoxide or sulfone, C_1-6Alkoxy, phenoxy, naphthoxy, C_3-6Cycloalkyl, phenyl, naphthyl, benzyl, 2, 3-indanyl, a heterocyclyl selected from: pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl and benzoxazolyl, heterocyclyloxy, heterocyclyl group thereofPart being selected from heterocyclyl as described in this paragraph, C_1-3Alkanoyl, benzoyl, naphthoyl, C_1-4Alkanoyloxy, benzyloxy, C_1-4Alkoxycarbonyl, aryl C_1-2Alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, in which the nitrogen atom may be replaced independently by C_1-3Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl mono-or disubstituted,

Or R₅Is C_1-4Alkanoylamino, aroylamino, C_1-4Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, arylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-3Alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl or benzothiazolyl,

or R₅Is C_1-4Alkoxycarbonylamino, phenoxycarbonylamino, C_1-4Alkylcarbamoyloxy, phenylcarbamoyloxy, C_1-4Alkylsulfonylamino, phenylsulfonylamino, C_1-3Alkylaminosulfonyl, phenylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C_1-4Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, mono-or disubstituted,

or R₅Is halogen, hydroxy, oxo, carboxy, cyano, nitro or carboxamide, R ₅Optionally independently by one or more R_eSubstituted;

R_eis C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-7Cycloalkyl, phenylNaphthyl, 2, 3-indanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, Czochromyl, pyridinyl, pyridinylyl, and the like_1-4Alkanoyl, aroyl, C_1-4Alkanoyloxy, phenoxy, naphthoxy, benzyloxy, C_1-4Alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, in which the nitrogen atom may be replaced independently by C_1-3Alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, or benzothiazolyl, mono-or disubstituted,

or R_eIs C_1-4Alkanoylamino, benzoylamino, C_1-4Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C _1-3Alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl,

or R_eIs C_1-4Alkoxycarbonylamino, phenoxycarbonylamino, C_1-4Alkylcarbamoyloxy, phenylcarbamoyloxy, C_1-4Alkylsulfonylamino, phenylsulfonylamino,

C_1-4alkylaminosulfonyl, phenylaminosulfonyl, amino in which the nitrogen atom may be independently replaced by C_1-3Alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazole(ii) an oxazolyl group or a benzothiazolyl group is mono-or di-substituted,

or R_eIs halogen, hydroxy, oxo, carboxy, cyano, nitro or carboxamide, R_eOptionally independently by one or more R_fSubstituted;

R_fis methyl, ethyl, tert-butyl, tosyl, methoxy, cyclopropyl, phenyl, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxy, carboxy or carboxamide.

R of formula (Ia) or formula (Ib) ₁And R₆Optionally forming a monocyclic 5-or 6-membered aromatic or nonaromatic heterocycle which is optionally substituted by R₇Substituted;

or bicyclic having one 5, 6 or 7 membered aromatic or nonaromatic heterocyclic ring fused to a second 5 to 6 membered aromatic or nonaromatic heterocyclic or carbocyclic ring wherein each ring is optionally independently substituted by one or more R₇Substituted;

R₇and R₈Independently is C_1-4Alkyl radical, C_5-6Cycloalkyl radical, C_1-4Alkoxy, halogen, hydroxy, oxy, carboxy, nitrile, nitro or NH₂C (O) -; and

x is O.

In a further embodiment of the present invention, there are provided novel compounds of the formulae (Ia) and (Ib) as specified directly above,

wherein:

het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepinyl, tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl, each ring optionally substituted with one or more R₅Substituted;

R₁is a chemical bond, C_1-5Alkyl radical, C_1-5Alkoxy radical, C_3-6Cycloalkyl, aryloxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholineA group selected from the group consisting of phenyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or amino; wherein R is ₁Optionally substituted by one or more R_aSubstituted;

R_ais a chemical bond, C_1-3Alkyl, cyclopropyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thienyl, imidazolyl, C_1-3Alkoxy radical, C_1-3Alkanoyl radical, C_1-3Alkanoyl, aryloxy, benzyloxy, C_1-3Alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may be independently replaced by C_1-3Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl mono-or disubstituted, or R_aIs C_1-3Alkanoylamino, aroylamino, C_1-3Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, arylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-3Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,

or R_aIs C_1-3Alkoxycarbonylamino, aryloxycarbonylamino, C_1-3Alkylcarbamoyloxy, arylcarbamoyloxy, C_1-3Alkylsulfonylamino, arylsulfonylamino, C_1-3Alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may independently be replaced by C _1-3Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl mono-or disubstituted,

or R_aIs halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_aOptionally independently by one or more R_bSubstituted;

R_bis methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenoxy, benzyloxy, fluoro, chloro, bromo, iodo, hydroxy, oxy, carboxy, cyano, nitro or carboxamide;

R₂is hydrogen;

R₃is a chemical bond, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_5-6Cycloalkyl, benzyl or naphthylmethyl, wherein R₃Optionally substituted by one or more R_cSubstituted;

R_cis C_1-3Alkyl radical, C_5-6Cycloalkyl, phenyl, naphthyl, 2, 3-indanyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [4.1.0 ]]Heptylalkyl, bicyclo [3.1.0]Hexane radical, bicyclo [1.1.1]Pentyl, cubic alkyl, 1, 2, 3, 4-tetrahydronaphthyl, furyl, tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, C _1-3Alkoxy, phenoxy, naphthoxy, C_1-2Alkanoyl, benzoyl, C_1-7Alkoxycarbonyl, phenoxycarbonyl, C_1-2Alkanoyloxy, benzoyloxy, carbamoyl, wherein the nitrogen atom may independently be replaced by C_1-3Alkyl or aryl groups are mono-or di-substituted,

or R_cIs C_1-2Alkanoylamino, benzoylamino, C_1-2Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-3Alkyl or aryl, or a substituted alkyl or aryl group,

or R_cIs C_1-2Alkoxycarbonylamino, phenoxycarbonylamino, C_1-2Alkylcarbamoyloxy, arylcarbamoyloxy, C_1-2Alkylsulfonylamino, phenylsulfonylamino，C_1-2Alkylaminosulfonyl, phenylaminosulfonyl, amino in which the nitrogen atom may be independently replaced by C_1-3Alkyl or phenyl is mono-or di-substituted,

or R_cIs halogen, hydroxy, oxo, carboxy or cyano, R_cOptionally further substituted by one or more R_dSubstituted;

R_dis methyl, cyclopropyl, cyclohexyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl, fluoro, chloro, oxy or cyano;

R₅Is a chemical bond, hydrogen, carbonyl, C_1-5Alkyl radical, C_1-5Alkoxy radical C_1-5Alkyl radical, C_1-5Alkylamino radical C_1-5Alkyl radical, C_1-5Alkylthio radical C_1-5Alkyl in which the sulfur atom may be oxidized to sulfoxide or sulfone, C_1-5Alkoxy, phenoxy, C_3-6Cycloalkyl, phenyl, naphthyl, benzyl, 2, 3-indanyl, a heterocyclyl selected from: pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl and benzothiazolyl, heterocyclyloxy, wherein the heterocyclyl moiety is selected from heterocyclyl as described in this paragraph, C_1-3Alkanoyl, benzoyl, naphthoyl, C_1-3Alkanoyloxy, benzyloxy, C_1-3Alkoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, in which the nitrogen atom may be independently replaced by C_1-3Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl mono-or disubstituted,

or R₅Is C_1-3Alkanoylamino, aroylamino, C_1-3Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C _1-3An alkyl group, a carboxyl group,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl or benzothiazolyl,

or R₅Is C_1-3Alkoxycarbonylamino, phenoxycarbonylamino, C_1-3Alkylcarbamoyloxy, phenylcarbamoyloxy, C_1-3Alkylsulfonylamino, phenylsulfonylamino, C_1-3Alkylaminosulfonyl, phenylaminosulfonyl, amino in which the nitrogen atom may be independently replaced by C_1-3Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, or R is mono-or disubstituted₅Is halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R₅Optionally further substituted by one or more R_eSubstituted;

R_eis C_1-3Alkyl radical, C_1-3Alkoxy radical, C_3-7Cycloalkyl, phenyl, naphthyl, 2, 3-indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, C _1-3Alkanoyl, aroyl, C_1-3Alkanoyloxy, phenoxy, benzyloxy, C_1-3Alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, in which the nitrogen atom may be replaced independently by C_1-3Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, mono-or disubstituted,

or R_eIs C_1-3Alkanoylamino, benzoylamino, C_1-3Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, ureidoAny one of the nitrogen atoms may be independently substituted by C_1-3Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl,

or R_eIs C_1-3Alkoxycarbonylamino, phenoxycarbonylamino, C_1-3Alkylcarbamoyloxy, phenylcarbamoyloxy, C_1-3Alkylsulfonylamino, phenylsulfonylamino, C_1-3Alkylaminosulfonyl, phenylaminosulfonyl, amino in which the nitrogen atom may be independently replaced by C _1-3Alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, mono-or disubstituted,

or R_eIs halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R_eOptionally further substituted by one or more R_fSubstituted; and

R_fis methyl, phenyl, tosyl, methoxy, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxy, carboxy or carboxamide;

r of formula (Ia) or formula (Ib)₁And R₆Form a bicyclic ring having one 5-or 6-membered aromatic or non-aromatic heterocyclic ring fused to a second 5-to 6-membered heteroaryl, heterocyclic ring or phenyl ring; wherein each ring is optionally independently substituted with one or two R₇And (4) substituting.

In a further embodiment of the present invention, there are provided novel compounds of the formulae (Ia) and (Ib) as specified directly above, wherein:

het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl or tetrahydropyranyl, each ring being substituted by one or more R₅Substituted;

R₁is a chemical bond, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropylA group selected from the group consisting of phenyl, cyclopentyl, cyclohexyl, phenoxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridyl, pyrazinyl, and amino; wherein R is ₁Optionally substituted by one or more R_aSubstituted;

R_ais a bond, methyl, ethyl, cyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thienyl, imidazolyl, methoxy, acetyl, acetoxy, phenoxy, benzyloxy, methoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl, or R is_aAcetylamino, benzoylamino, methylthio, phenylthio wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido wherein any of the nitrogen atoms may be independently substituted by methyl, ethyl or phenyl,

or R_aIs methoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogen atom of the amino group may be independently mono-or disubstituted by methyl or phenyl,

or R_ais fluoro, chloro, bromo, iodo, hydroxy, oxy, carboxy, cyano, nitro or carboxamide, R_aOptionally further substituted by one or more R _bSubstituted;

R_bis methyl, cyclopropyl, phenyl, methoxy, phenoxy, benzyloxy, fluoro, chloro, hydroxy, oxy, carboxy or a carboxamide;

R₃is a chemical bond, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_5-6Cycloalkyl, benzyl or naphthylmethyl, wherein R₃Optionally substituted by one or more R_cSubstituted;

R_cis methyl, ethyl, n-propyl, isopropyl, C_5-6Cycloalkyl, 2, 3-indanyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [4.1.0 ]]Heptylalkyl, bicyclo [3.1.0]Hexane radical, bicyclo [1.1.1]Pentyl, cubic alkyl, 1, 2, 3, 4-tetrahydronaphthyl, thienyl, oxazolyl, thiazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, methoxy, ethoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently mono-or di-substituted by methyl, ethyl or aryl,

or R_cAcetylamino, benzoylamino, methylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, phenylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido, wherein any of the nitrogen atoms may be independently substituted by methyl, ethyl or aryl,

Or R_cIs methoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogen atom of the amino group may be independently mono-or disubstituted by methyl, ethyl or phenyl,

or R_cIs fluorine, chlorine or oxy, R_cOptionally further substituted by one or more R_dSubstituted;

R_dis methyl, cyclopropyl, phenyl, methoxy, fluoro, chloro or oxy;

R₅is a chemical bond, hydrogen, carbonyl, C_1-4Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Alkylamino radical C_1-4Alkyl radical, C_1-4Alkylthio radical C_1-4Alkyl in which the sulfur atom may be oxidized to sulfoxide or sulfone, C_1-4Alkoxy, phenoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, 2, 3-di-n-butylHydrogenated indenyl groups selected from the following heterocyclic groups: pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl and benzothiazolyl, heterocyclyloxy, wherein the heterocyclyl moiety is selected from heterocyclyl as described in this paragraph, C_1-2Alkanoyl, benzoyl, naphthoyl, C _1-2Alkanoyloxy, benzyloxy, C_1-2Alkoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, in which the nitrogen atom may be independently replaced by C_1-2Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl mono-or disubstituted,

or R₅Is C_1-2Alkanoylamino, benzoylamino, C_1-2Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-2Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl,

or R₅Is C_1-2Alkoxycarbonylamino, phenoxycarbonylamino, C_1-2Alkylcarbamoyloxy, phenylcarbamoyloxy, C_1-2Alkylsulfonylamino, phenylsulfonylamino, C_1-2Alkylaminosulfonyl, phenylaminosulfonyl, amino in which the nitrogen atom may be independently replaced by C_1-2Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl mono-or disubstituted,

Or R₅Is fluorine, chlorine, bromine, hydroxyl, oxy, carboxyl or carboxamide, R₅Optionally further substituted by one or more R_eSubstituted;

R_eis C_1-3Alkyl radical，C_1-2Alkoxy radical, C_3-6Cycloalkyl, phenyl, naphthyl, 2, 3-indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, C_1-2Alkanoyl, aroyl, C_1-2Alkanoyloxy, phenoxy, benzyloxy, C_1-2Alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, in which the nitrogen atom may be replaced independently by C_1-2Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl mono-or disubstituted,

or R_eIs C_1-2Alkanoylamino, benzoylamino, C_1-2Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-2Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridyl or pyrimidinyl,

Or R_eIs C_1-2Alkoxycarbonylamino, phenoxycarbonylamino, C_1-2Alkylcarbamoyloxy, phenylcarbamoyloxy, C_1-2Alkylsulfonylamino, phenylsulfonylamino, C_1-2Alkylaminosulfonyl, phenylaminosulfonyl, amino in which the nitrogen atom may be independently replaced by C_1-2Alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl mono-or disubstituted,

or R_eIs fluorine, chlorine, bromine, hydroxyl, oxy, carboxyl or carboxamide, R_eOptionally further substituted by one or more R_fSubstituted;

R_fis methyl, phenyl, tosyl, methoxy, phenoxyBenzyloxy, fluoro, chloro, hydroxy, oxy, carboxy or carboxamide; and

r of formula (Ia) or formula (Ib)₁And R₆Form a bicyclic ring having a 5-to 6-membered aromatic or nonaromatic heterocyclic ring, and condensed with a benzene ring; wherein each ring is optionally independently substituted with one or two R₇And (4) substituting. In a further embodiment of the present invention, there are provided novel compounds of formula (Ia) or formula (Ib) as specified directly above, wherein:

het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl, azepan-4-yl or tetrahydropyran-4-yl, each ring optionally substituted with one or more R ₅Substituted;

R₁is a bond, methyl, ethyl, isopropyl, methoxy, cyclopropyl, cyclohexyl, phenoxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl or amino; wherein R is₁Optionally substituted by one or more R_aSubstituted;

R_ais methyl, phenyl, thienyl, methoxy, acetyl, acetoxy, phenoxy, benzyloxy, methoxycarbonyl, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently mono-or di-substituted by methyl or phenyl,

or R_aAcetylamino, methylthio, phenylthio wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido wherein any of the nitrogen atoms may be independently substituted with methyl or phenyl,

or R_aIs methoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, amino, wherein the nitrogen atom may be independently mono-or disubstituted by methyl or phenyl,

or R_aIs fluorine, chlorine, hydroxyA group, oxy, carboxy, cyano or carboxamide;

R₃Is a bond, methyl, ethyl, n-propyl, propenyl, butenyl, isobutenyl, cyclohexyl, benzyl or naphthylmethyl, wherein R₃Optionally substituted by one or more R_cSubstituted;

R_cis methyl, ethyl, n-propyl, isopropyl, cyclohexyl, cyclopentyl, 2, 3-indanyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [4.1.0 ]]Heptylalkyl, bicyclo [3.1.0]Hexane radical, bicyclo [1.1.1]Pentyl, cubic alkyl, 1, 2, 3, 4-tetrahydronaphthyl, methoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy, methylthio, wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, phenylthio, wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, fluorine, chlorine or oxy;

R₅is a chemical bond, hydrogen, carbonyl, C_1-4Alkyl radical, C_1-2Alkoxy radical C_1-2Alkyl radical, C_1-2Alkylamino radical C_1-2Alkyl radical, C_1-2Alkylthio radical C_1-2Alkyl in which the sulfur atom may be oxidized to sulfoxide or sulfone, C_1-2Alkoxy, phenoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, heterocyclyl selected from: pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl and pyrimidinyl, heterocyclyloxy, wherein the heterocyclyl moiety is selected from the group consisting of heterocyclyl, acetyl, benzoyl, acetoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently mono-or di-substituted by methyl, ethyl or phenyl,

Or R₅Is acetylamino, benzoylamino, methylthio, in which the sulfur atom may be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido, in which any nitrogen atom may be independently substitutedMethyl, ethyl or phenyl, or a salt thereof,

or R₅Is methoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, amino, wherein the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl,

or R₅Is fluorine, chlorine, hydroxy, oxy, carboxy or carboxamide, R₅Optionally further substituted by one or more R_eSubstituted;

R_eis methyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, 2, 3-indanyl, piperidinyl, morpholinyl, indolyl, thienyl, pyridinyl, acetyl, benzoyl, acetoxy, phenoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, wherein the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl,

Or R_eAcetylamino, benzoylamino, methylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, phenylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido, wherein any nitrogen atom may be independently substituted by methyl, ethyl or phenyl,

or R_eIs methoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, the amino group in which the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl,

or R_eIs fluorine, chlorine, hydroxy, oxy, carboxy or carboxamide, R_eOptionally further substituted by one or more R_fSubstituted; and

R_fis methyl, phenyl, tosyl, phenoxy, benzyloxy, fluoro, chloro or oxy;

r of formula (Ia) or formula (Ib)₁And R₆Form a double ring

Wherein W is-S (O)_n-, -O-C (O) -or-N-C (O) -N is 0, 1 or 2, and wherein each ring is optionally independently substituted with one or two R₇And (4) substituting.

In a further embodiment of the present invention, there are provided novel compounds of the formulae (Ia) and (Ib) as specified directly above, wherein:

Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl or tetrahydropyran-4-yl, each ring being independently substituted with one or more R₅Substituted;

R₁is isopropyl, benzyloxy, cyclohexyl, phenyl, 4- (acetylamino) -phenyl, 4- (methylsulfonylamino) -phenyl, 4-methoxyphenyl, 3-phenoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 2-fluoro-4-chlorophenyl, naphthyl, thienylmethyl, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, furyl, thienyl, 5-chlorothienyl, pyridin-4-yl, pyrazinyl, methylamino, ethylamino, dimethylamino, or diethylamino;

R₃is ethyl, n-propyl, propenyl, butenyl, isobutenyl, benzyl or naphthylmethyl, wherein R₃Optionally substituted by one or more R_cSubstituted;

R_cis methyl, cyclohexyl, cyclopentyl, 2, 3-indanyl, 1, 2, 3, 4-tetrahydronaphthyl, methoxy, methylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, fluorine or chlorine;

R₅is a chemical bond and is characterized in that,carbonyl, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, piperidinyl, tetrahydropyranyl, pyrimidinyl, acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl, methylsulfonylamino, phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy, R ₅Optionally further substituted by one or more R_eSubstituted;

R_eis methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, 2, 3-indanyl, thienyl, 5-methylthiophenyl, methoxy, phenoxy, benzyloxy, piperidinyl, pyridinyl, indolyl, 1- (tosyl) -indolyl, carbamoyl, wherein the nitrogen atom may be independently mono-or disubstituted by methyl, phenyl or benzyl,

or R_eIs hydroxy, fluoro, chloro, oxy, dimethylamino or trifluoromethyl; and

n is 2.

In a further embodiment of the present invention there are provided novel compounds of the above formulae (Ia) and (Ib) in their broadest sense wherein:

R₁and R₆Is kept non-annular and is,

het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepinyl, tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl, each ring optionally substituted with one or more R₅Substituted;

R₁is a chemical bond, C_1-5Alkyl radical, C_1-5Alkoxy radical, C_3-6Cycloalkyl, aryloxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, phenyl And oxazolyl or amino; wherein R is₁Optionally substituted by one or more R_aSubstituted;

R_ais a chemical bond, C_1-3Alkyl, cyclopropyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thienyl, imidazolyl, C_1-3Alkoxy radical, C_1-3Alkanoyl radical, C_1-3Alkanoyl, aryloxy, benzyloxy, C_1-3Alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may be independently replaced by C_1-3Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl mono-or disubstituted, or R_aIs C_1-3Alkanoylamino, aroylamino, C_1-3Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, arylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-3Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,

or R_aIs C_1-3Alkoxycarbonylamino, aryloxycarbonylamino, C_1-3Alkylcarbamoyloxy, arylcarbamoyloxy, C_1-3Alkylsulfonylamino, arylsulfonylamino, C_1-3Alkylaminosulfonyl, arylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C _1-3Alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl mono-or disubstituted,

or R_aIs halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_aOptionally further substituted by one or more R_bSubstituted;

R_bis methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenoxy, benzyloxy, fluorine, chlorine, bromineIodine, hydroxy, oxy, carboxy, cyano, nitro or carboxamide;

R₂is hydrogen;

R₃is a chemical bond, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_5-6Cycloalkyl, benzyl or naphthylmethyl, wherein R₃Optionally substituted by one or more R_cSubstituted;

R_cis C_1-3Alkyl radical, C_5-6Cycloalkyl, phenyl, naphthyl, 2, 3-indanyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [4.1.0 ]]Heptylalkyl, bicyclo [3.1.0]Hexane radical, bicyclo [1.1.1]Pentyl, cubic alkyl, 1, 2, 3, 4-tetrahydronaphthyl, furyl, tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, C _1-3Alkoxy, phenoxy, naphthoxy, C_1-2Alkanoyl, benzoyl, C_1-2Alkoxycarbonyl, phenoxycarbonyl, C_1-2Alkanoyloxy, benzoyloxy, carbamoyl, wherein the nitrogen atom may independently be replaced by C_1-3Alkyl or aryl groups are mono-or di-substituted,

or R_cIs C_1-2Alkanoylamino, benzoylamino, C_1-2Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-3Alkyl or aryl, or a substituted alkyl or aryl group,

or R_cIs C_1-2Alkoxycarbonylamino, phenoxycarbonylamino, C_1-2Alkylcarbamoyloxy, arylcarbamoyloxy, C_1-2Alkylsulfonylamino, phenylsulfonylamino, C_1-2Alkylaminosulfonyl, phenylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C_1-3Alkyl or phenyl is mono-or di-substituted,

or R_cIs halogen, hydroxy, oxo, carboxy or cyano, R_cOptionally further substituted by one or more R_dSubstituted;

R_dis methyl, cyclopropyl, cyclohexyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl, fluoro, chloro, oxy or cyano;

R₄Is hydrogen;

R₅is a chemical bond, hydrogen, carbonyl, C_1-5Alkyl radical, C_1-5Alkoxy radical C_1-5Alkyl radical, C_1-5Alkylamino radical C_1-5Alkyl radical, C_1-5Alkylthio radical C_1-5Alkyl in which the sulfur atom may be oxidized to sulfoxide or sulfone, C_1-5Alkoxy, phenoxy, C_3-6Cycloalkyl, phenyl, naphthyl, benzyl, 2, 3-indanyl, a heterocyclyl selected from: pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl and benzothiazolyl, heterocyclyloxy, wherein the heterocyclyl moiety is selected from heterocyclyl as described in this paragraph, C_1-3Alkanoyl, benzoyl, naphthoyl, C_1-3Alkanoyloxy, benzyloxy, C_1-3Alkoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, in which the nitrogen atom may be independently replaced by C_1-3Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl mono-or disubstituted,

or R₅Is C_1-3Alkanoylamino, aroylamino, C_1-3Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C _1-3Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzofuranyl, phenylSubstituted by benzothienyl, benzimidazolyl or benzothiazolyl,

or R₅Is C_1-3Alkoxycarbonylamino, phenoxycarbonylamino, C_1-3Alkylcarbamoyloxy, phenylcarbamoyloxy, C_1-3Alkylsulfonylamino, phenylsulfonylamino, C_1-3Alkylaminosulfonyl, phenylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C_1-3Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, or R is mono-or disubstituted₅Is halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R₅Optionally further substituted by one or more R_eSubstituted;

R_eis C_1-3Alkyl radical, C_1-3Alkoxy radical, C_3-7Cycloalkyl, phenyl, naphthyl, 2, 3-indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, C _1-3Alkanoyl, aroyl, C_1-3Alkanoyloxy, phenoxy, benzyloxy, C_1-3Alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, in which the nitrogen atom may be replaced independently by C_1-3Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, mono-or disubstituted,

or R_eIs C_1-3Alkanoylamino, benzoylamino, C_1-2Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-3Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazoOxazolyl, imidazolyl, pyridyl, pyrimidinyl, benzimidazolyl or benzothiazolyl,

or R_eIs C_1-3Alkoxycarbonylamino, phenoxycarbonylamino, C_1-3Alkylcarbamoyloxy, phenylcarbamoyloxy, C_1-3Alkylsulfonylamino, phenylsulfonylamino, C_1-3Alkylaminosulfonyl, phenylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C _1-3Alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, mono-or disubstituted,

or R_eIs halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R_eOptionally further substituted by one or more R_fSubstituted;

R_fis methyl, phenyl, tosyl, methoxy, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxy, carboxy or carboxamide;

R₆is composed of

Hydroxy, nitrile or

C_1-5A saturated or unsaturated, branched or straight carbon chain, optionally partially or fully halogenated, in which one or more carbon atoms are optionally replaced by O, NH, or S (O)₂Wherein the carbon chain is optionally independently substituted with 1-2 oxo, -NH₂One or more C_1-4Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl or quinoxalinyl; and

X is O.

In a further embodiment of the present invention, there are provided novel compounds of formula (Ia) and (Ib) as directly described above, wherein:

R₁is a bond, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenoxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl or amino; wherein R is₁Optionally independently by one or more R_aSubstituted;

R_ais a bond, methyl, ethyl, cyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thienyl, imidazolyl, methoxy, acetyl, acetoxy, phenoxy, benzyloxy, methoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl, or R is_aAcetylamino, benzoylamino, methylthio, phenylthio wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido wherein any of the nitrogen atoms may be independently substituted by methyl, ethyl or phenyl,

Or R_aIs methoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, amino, wherein the nitrogen atom may be independently mono-or disubstituted by methyl or phenyl,

or R_aIs fluorine, chlorine, bromine, iodine, hydroxyl, oxy, carboxyl, cyano, nitro or carboxamide, R_aOptionally further substituted by one or more R_bSubstituted;

R_bis methyl, cyclopropyl, phenyl, methoxy, phenoxy, benzyloxy, fluoro, chloro, hydroxy, oxy, carboxy orCarboxamides;

R₃is a chemical bond, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_5-6Cycloalkyl, benzyl or naphthylmethyl, wherein R₃Optionally independently by one or more R_cSubstituted;

R_cis methyl, ethyl, n-propyl, isopropyl, C_5-6Cycloalkyl, 2, 3-indanyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [4.1.0 ]]Heptylalkyl, bicyclo [3.1.0]Hexane radical, bicyclo [1.1.1]Pentyl, cubic alkyl, 1, 2, 3, 4-tetrahydronaphthyl, thienyl, oxazolyl, thiazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, methoxy, ethoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently mono-or di-substituted by methyl, ethyl or aryl,

Or R_cAcetylamino, benzoylamino, methylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, phenylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido, wherein any of the nitrogen atoms may be independently substituted by methyl, ethyl or aryl,

or R_cIs methoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, amino, wherein the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl,

or R_cIs fluorine, chlorine or oxy, R_cOptionally further substituted by one or more R_dSubstituted;

R_dis methyl, cyclopropyl, phenyl, methoxy, fluoro, chloro or oxy;

R₅is a chemical bond, hydrogen, carbonylBase, C_1-4Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Alkylamino radical C_1-4Alkyl radical, C_1-4Alkylthio radical C_1-4Alkyl in which the sulfur atom may be oxidized to sulfoxide or sulfone, C_1-4Alkoxy, phenoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, 2, 3-indanyl, a heterocyclic group selected from: pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl and benzothiazolyl, heterocyclyloxy, wherein the heterocyclyl moiety is selected from heterocyclyl as described in this paragraph, C _1-2Alkanoyloxy, benzoyl, naphthoyl, C_1-2Alkanoyloxy, benzyloxy, C_1-2Alkoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, in which the nitrogen atom may be independently replaced by C_1-2Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl mono-or disubstituted,

or R₅Is C_1-2Alkanoylamino, benzoylamino, C_1-2Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C_1-2Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzothiazolyl,

or R₅Is C_1-2Alkoxycarbonylamino, phenoxycarbonylamino, C_1-2Alkylcarbamoyloxy, phenylcarbamoyloxy, C_1-2Alkylsulfonylamino, phenylsulfonylamino, C_1-2Alkylaminosulfonyl, phenylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C _1-2Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl,a pyridyl or pyrimidyl group which is mono-or di-substituted,

or R₅Is fluorine, chlorine, bromine, hydroxyl, oxy, carboxyl or carboxamide, R₅Optionally further substituted by one or more R_eSubstituted;

R_eis C_1-3Alkyl radical, C_1-2Alkoxy radical, C_3-6Cycloalkyl, phenyl, naphthyl, 2, 3-indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, C_1-2Alkanoyl, aroyl, C_1-2Alkanoyloxy, phenoxy, benzyloxy, C_1-2Alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl, in which the nitrogen atom may be replaced independently by C_1-2Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl mono-or disubstituted,

or R_eIs C_1-2Alkanoylamino, benzoylamino, C_1-2Alkylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, urea, in which any nitrogen atom can be independently replaced by C _1-2Alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridyl or pyrimidinyl,

or R_eIs C_1-2Alkoxycarbonylamino, phenoxycarbonylamino, C_1-2Alkylcarbamoyloxy, phenylcarbamoyloxy, C_1-2Alkylsulfonylamino, phenylsulfonylamino, C_1-2Alkylaminosulfonyl, phenylaminosulfonyl, amino, wherein the nitrogen atom may be independently replaced by C_1-2Alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridyl or pyrimidinyl monosubstituted or notThe substitution of the two groups is carried out,

or R_eIs fluorine, chlorine, bromine, hydroxyl, oxy, carboxyl or carboxamide, R_eOptionally further substituted by one or more R_fSubstituted;

R_fis methyl, phenyl, tosyl, methoxy, phenoxy, benzyloxy, fluoro, chloro, hydroxy, oxy, carboxy or carboxamide; and

R₆is composed of

Nitrile or

C_1-5A saturated or unsaturated, branched or linear carbon chain, optionally partially or fully halogenated, in which one or more carbon atoms are optionally replaced by O, NH, or S (O)₂And wherein the carbon chain is optionally independently replaced by oxy, -NH ₂Piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyridinyl, pyrimidinyl, or pyrazinyl.

In a further embodiment of the present invention, there are provided novel compounds of formula (Ia) or formula (Ib) as specified directly above, wherein:

het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl, azepan-4-yl or tetrahydropyran-4-yl, each ring optionally substituted with one or more R₅Substituted;

R₁is a bond, methyl, ethyl, isopropyl, methoxy, cyclopropyl, cyclohexyl, phenoxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl or amino; wherein R is₁Optionally substituted by one or more R_aSubstituted;

R_ais methyl, phenyl, thienyl, methoxy, acetyl, acetoxy, phenoxy, benzyloxy, methoxycarbonyl, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently replaced by methyl orThe phenyl group is mono-or di-substituted,

or R_aAcetylamino, methylthio, phenylthio wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido wherein any of the nitrogen atoms may be independently substituted with methyl or phenyl,

Or R_aIs methoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, amino, wherein the nitrogen atom may be independently mono-or disubstituted by methyl or phenyl,

or R_aIs fluorine, chlorine, hydroxyl, oxy, carboxyl, cyano or carboxamide;

R₃is a bond, methyl, ethyl, n-propyl, propenyl, butenyl, isobutenyl, cyclohexyl, benzyl or naphthylmethyl, wherein R₃Optionally substituted by one or more R_cSubstituted;

R_cis methyl, ethyl, n-propyl, isopropyl, cyclohexyl, cyclopentyl, 2, 3-indanyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [4.1.0 ]]Heptylalkyl, bicyclo [3.1.0]Hexane radical, bicyclo [1.1.1]Pentyl, cubic alkyl, 1, 2, 3, 4-tetrahydronaphthyl, methoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy, methylthio, wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, phenylthio, wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, fluorine, chlorine or oxy; and is

Wherein R will be different ₂And R₃And the configuration of the stereocenter defined by the carbon to which they are attached is defined as L; and is

R₅Is a chemical bond, hydrogen, carbonyl, C_1-4Alkyl radical, C_1-2Alkoxy radical C_1-2Alkyl radical, C_1-2Alkylamino radical C_1-2Alkyl radical, C_1-2Alkylthio radical C_1-2Alkyl radical of whichThe sulfur atom being oxidizable to the sulfoxide or sulfone, C_1-2Alkoxy, phenoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, heterocyclyl selected from: pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl and pyrimidinyl, heterocyclyloxy, wherein the heterocyclyl moiety is selected from the group consisting of heterocyclyl, acetyl, benzoyl, acetoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently mono-or di-substituted by methyl, ethyl or phenyl,

or R₅Acetylamino, benzoylamino, methylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, phenylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido, wherein any nitrogen atom may be independently substituted by methyl, ethyl or phenyl,

or R ₅Is methoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, the amino group in which the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl,

or R₅Is fluorine, chlorine, hydroxy, oxy, carboxy or carboxamide, R₅Optionally further substituted by one or more R_eSubstituted;

R_eis methyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, 2, 3-indanyl, piperidinyl, morpholinyl, indolyl, thienyl, pyridinyl, acetyl, benzoyl, acetoxy, phenoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, wherein the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl,

or R_eIs acetylamino, benzoylamino, methylThio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, phenylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, ureido, in which any nitrogen atom can be independently substituted by methyl, ethyl or phenyl,

Or R_eIs methoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, the amino group in which the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl,

or R_eIs fluorine, chlorine, hydroxy, oxy, carboxy or carboxamide, R_eOptionally further substituted by one or more R_fSubstituted;

R_fis methyl, phenyl, tosyl, phenoxy, benzyloxy, fluoro, chloro or oxy;

R₆is composed of

Nitrile or

C_1-5A saturated or unsaturated, branched or linear carbon chain, optionally partially or fully halogenated, in which one or more carbon atoms are optionally replaced by O, NH, or S (O)₂And wherein the carbon chain is optionally independently substituted with oxy, -NH₂Morpholinyl or piperazinyl.

In a further embodiment of the present invention, there are provided novel compounds of the formulae (Ia) and (Ib) as specified directly above, wherein:

het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl or tetrahydropyran-4-yl, each ring being substituted by one or more R₅Substituted;

R₁Is isopropyl, benzyloxy, cyclohexyl, phenyl, 4- (acetylamino) -phenyl, 4- (methylsulfonylamino) -phenyl, 4-methoxyphenyl, 3-phenoxyphenyl, 4-chlorophenyl, 4-fluorophenyl2-fluorophenyl, 2-fluoro-4-chlorophenyl, naphthyl, thienylmethyl, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, furanyl, thienyl, 5-chlorothienyl, pyridin-4-yl, pyrazinyl, methylamino, ethylamino, dimethylamino, or diethylamino;

R₃is ethyl, n-propyl, propenyl, butenyl, isobutenyl, benzyl or naphthylmethyl, wherein R₃Optionally substituted by one or more R_cSubstituted;

R_cmethyl, cyclohexyl, cyclopentyl, 2, 3-indanyl, 1, 2, 3, 4-tetrahydronaphthyl,

methoxy, methylthio, in which the sulfur atom can be oxidized to the sulfoxide or sulfone, fluorine or chlorine; r₅Is a bond, carbonyl, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, piperidinyl, tetrahydropyranyl, pyrimidinyl, acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl, methylsulfonylamino, phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxy or carboxy, R ₅Optionally further substituted by one or more R_eSubstituted;

R_eis methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, 2, 3-indanyl, thienyl, 5-methylthiophenyl, methoxy, phenoxy, benzyloxy, piperidinyl, pyridinyl, indolyl, 1- (tosyl) -indolyl, carbamoyl, wherein the nitrogen atom may be independently mono-or disubstituted by methyl, phenyl or benzyl,

or R_eIs hydroxy, fluoro, chloro, oxy, dimethylamino or trifluoromethyl; and

R₆is acetyl, C_1-3Alkylaminocarbonyl or C_1-3An alkoxycarbonyl group.

In a further embodiment of the present invention, there are provided novel compounds of the formulae (Ia) and (Ib) as specified directly above, wherein:

het is piperidine 4-yl or pyrrolidin-3-yl;

R₁is morpholin-4-yl, p-fluorophenyl or p-methoxyphenyl;

R₅is methyl, propyl, n-propyl or cyclohexyl; and

R₆is acetyl, ethylaminocarbonyl or ethoxycarbonyl.

The anti-cathepsin K activity of particular compounds disclosed herein can be determined without undue experimentation by one of ordinary skill in the art, with reference to the prior art, the guidance provided throughout the specification, and the screen described in the section entitled "assessment of biological Properties".

The following general aspects of the compounds of formulae (Ia) and (Ib) are assumed to have cathepsin K activity: the broadest embodiments of (Ib) of formula (Ia) are as described above, wherein

Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepinyl, tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl, each ring optionally substituted with one or more R₅Substituted;

R₁is a chemical bond, C_1-4Alkyl radical, C_1-4Alkoxy, cyclopropyl, cyclohexyl, phenoxy, naphthoxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, or amino; wherein R is₁Optionally substituted by one or more R_aSubstituted;

R_ais methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, phenyl, pyrrolidinyl,

piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thienyl, imidazolyl, methoxy, ethoxy, acetyl, acetoxy, phenoxy, naphthoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,

Or R_aAcetylamino, benzoylamino, methylthio wherein the sulfur atom may be oxidized to sulfoxide or sulfone, ethylthio wherein the sulfur atom may be oxidized to sulfoxide or sulfone, phenylthio wherein the sulfur atom may be oxidized to sulfoxide or sulfone, ureido wherein any of the nitrogen atoms may be independently substituted by methyl, ethyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,

or R_aIs methoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino, C_1-2Alkylcarbamoyloxy, phenylcarbamoyloxy, naphthylcarbamoyloxy, C_1-2Alkylsulfonylamino, phenylsulfonylamino, naphthylsulfonylamino, C_1-2Alkylaminosulfonyl, phenylaminosulfonyl, naphthylaminosulfonyl, amino in which the nitrogen atom may be mono-or disubstituted independently by methyl, ethyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,

or R_aIs halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_aOptionally further substituted by one or more R _bSubstituted;

R_bis methyl, ethyl, cyclopropyl, cyclohexyl, phenyl, methoxy, ethoxy, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxy, carboxy, cyano, nitro or carboxamide;

R₂is hydrogen or methyl;

R₃is a bond, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-propyl, propenyl, isobutenyl, cyclohexyl, benzyl or naphthylmethyl, where R is₃Optionally substituted by one or more R_cSubstituted;

R_cis methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, bicyclo [3.1.0]Hexane radical, bicyclo [1.1.1]Pentyl, cubic alkyl, furyl, tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, methoxy, ethoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently mono-or di-substituted by methyl or phenyl,

or R_cIs acetylamino, benzoylamino, methylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, phenylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido, wherein any of the nitrogen atoms may be independently substituted by methyl or phenyl, or R _cIs methoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogen atom of the amino group may be independently mono-or disubstituted by methyl or phenyl,

or R_cIs chlorine, fluorine, hydroxyl, oxy, carboxyl or cyano;

R₂and R₃Optionally forming a ring selected from the group consisting of: cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or tetrahydrothienyl;

R₄is hydrogen;

R₅is a chemical bond, hydrogen, carbonyl, C_1-5Alkyl radical, C_1-5Alkoxy radical C_1-5Alkyl radical, C_1-5Alkylamino radical C_1-5Alkyl radical, C_1-5Alkylthio radical C_1-5Alkyl in which the sulfur atom may be oxidized to sulfoxide or sulfone, C_1-5Alkoxy, phenoxy, naphthoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, a heterocyclic group selected from: pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl and pyrimidinyl, heterocyclyloxy, wherein the heterocyclyl moiety is selected from the group consisting of heterocyclyl, acetyl, benzoyl, acetoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzoyloxy, carbamoyl, wherein the nitrogen atom may be independently mono-or di-substituted by methyl, ethyl or phenyl,

Or R₅Acetylamino, benzoylamino, phenylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido, wherein any of the nitrogen atoms may be independently substituted by methyl, ethyl or phenyl,

or R₅Is methoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, phenylsulfonylamino, phenylaminosulfonyl, amino, wherein the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl,

or R₅Is fluorine, chlorine, hydroxy, oxy, carboxy or carboxamide, R₅Optionally further substituted by one or more R_eSubstituted;

R_eis methyl ethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, 2, 3-dihydroindenyl, piperidinyl, morpholinyl, indolyl, thienyl, pyridinyl, methoxy, ethoxy, acetyl, benzoyl, acetoxy, phenoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, wherein the nitrogen atoms may independently beMono-or di-substituted by methyl, ethyl or phenyl,

or R_eAcetylamino, benzoylamino, methylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, phenylthio, methylthio, wherein the sulfur atom may be oxidized to the sulfoxide or sulfone, ureido, wherein any of the nitrogen atoms may be independently substituted by methyl, ethyl or phenyl,

Or R_eIs methoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, the amino group in which the nitrogen atom may be independently mono-or disubstituted by methyl, ethyl or phenyl,

or R_eIs fluorine, chlorine, hydroxy, oxy, carboxy or carboxamide, R_eOptionally further substituted by one or more R_fSubstituted;

R_fis methyl, phenyl, tosyl, phenoxy, benzyloxy, fluoro, chloro or oxy.

Preferred cathepsin K inhibitors are those specified directly above, wherein:

R₁is a bond, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, benzyloxy, cyclopropyl, cyclohexyl, phenoxy, naphthoxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or amino; wherein R is ₁Optionally substituted by one or more R_aSubstituted;

R_ais methyl, cyclopropyl, phenyl, halogen, hydroxy, oxo, carboxy, cyano, nitro or carboxylic acidAn amine;

R₃is a bond, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-propyl, propenyl, isobutenyl, benzyl or naphthylmethyl, where R₃Optionally substituted by one or more R_cSubstituted;

R_cis methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, furyl, tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, methoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl, carbamoyl, wherein the nitrogen atom may be independently mono-or di-substituted by methyl or phenyl,

or R_cIs acetylamino, benzoylamino, methylthio, methoxycarbonylamino, methylcarbamoyloxy, methylsulfonylamino, methylaminosulfonyl, amino, wherein the nitrogen atom may be independently mono-or di-substituted by methyl,

or R_cIs fluorine or oxy;

R₂and R₃Optionally forming a ring selected from: cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, pyrrolidinyl, or piperidinyl; r ₅Is methyl, ethyl, n-propyl, n-butyl, n-propyl, 2-pentyl, 3-pentyl, phenethyl, phenylpropyl, 2, 2-dimethylpropyl, tert-butyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2, 6-dimethylbenzyl, 2, 5-dimethylbenzyl, 2, 4-dimethylbenzyl, 2, 3-dimethylbenzyl, 3, 4-dimethylbenzyl, 3, 5-dimethylbenzyl, 2, 4, 6-trimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-phenoxybenzyl, 3-phenoxybenzyl, 4-phenoxybenzyl, 2-benzyloxybenzyl, 3-benzyloxybenzyl, 4-benzyloxybenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2, 6-difluorobenzyl, 2, 5-bis (fluorobenzyl)Fluorobenzyl, 2, 4-difluorobenzyl, 2, 3-difluorobenzyl, 3, 4-difluorobenzyl, 3, 5-difluorobenzyl, 2, 4, 6-trifluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, naphthylmethyl, 2, 3-dihydroindenylmethyl, pyridylmethyl, indolylmethyl, thienylmethyl, 5-methylthiomethyl, piperidinyl, piperidinylcarbonyl, pyridylcarbonyl, tetrahydropyranyl, pyrimidinyl, acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, methylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, methylsulfonylamino, phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxy or carboxy.

Most preferred cathepsin K inhibitors are those directly specified above, wherein:

R₁is methoxy, benzyloxy, cyclohexyl, phenoxy, naphthoxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or amino; wherein R is₁Optionally substituted by one or more R_aSubstituted;

R_ais methyl, phenyl, fluoro, chloro, hydroxy, oxy, carboxy or carboxamide;

R₃is a bond, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-propyl, propenyl, isobutenyl or benzyl, where R₃Optionally substituted by one or more R_cSubstituted;

R_cis methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, furyl, tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, methoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl, acetylamino, methylthio, methylsulfonylamino or fluoro;

R₂and R₃Optionally together with the carbon to which it is attached, form a ring selected from: cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrothiopyranyl, or tetrahydrofuranyl;

R₅Is methyl, ethyl, n-propyl, n-butyl, phenethyl, phenylpropyl, tert-butyl, isopropyl, isobutyl, cyclopropyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl-4-fluorobenzyl, 3, 5-difluorobenzyl, 4-trifluoromethylbenzyl, naphthylmethyl, pyridylmethyl, indolylmethyl, thienylmethyl, acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, phenylcarbamoyl, phenylsulfonylamino or fluorine.

Most preferred cathepsin K inhibitors are those directly specified above, wherein:

het is pyrrolidinyl, piperidinyl or tetrahydropyranyl;

R₁is benzyloxy, phenoxy, naphthoxy, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyridinyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, or phenylamino;

R₃is n-propyl, isobutyl, propenyl, isobutenyl or 2, 2-dimethylpropyl;

R₂and R₃Optionally together with the carbon to which it is attached, form a ring selected from: cyclopentyl, cyclohexyl, or cycloheptyl;

R₅Is methyl, ethyl, n-propyl, phenethyl, tert-butyl, isopropyl, isobutyl, cyclohexyl, cyclohexylmethyl, benzyl, 4-fluorobenzyl, naphthylmethyl, acetyl, benzoyl or benzyloxycarbonyl.

Further compounds of the formula (Ia) consisting of the components A, B and C are shown in Table I below. Within the structural limitations of formula (Ia), any and all combinations of moieties a, B and C comprise a compound of the present invention and pharmaceutically acceptable derivatives thereof. These compounds can be synthesized by general protocols, by the methods described in the experimental section of this document, and by analogous methods known to those skilled in the art without undue experimentation. Preferred compounds have desirable activity in inhibiting cathepsin S in cells according to the assay described in Riese, R.J. et al, Immunity, 1996, 4, 357-366 (incorporated herein by reference).

Formula (Ia)

TABLE I

And pharmaceutically acceptable derivatives thereof.

In another embodiment of the present invention, there are provided compounds of formulae (Ia) and (Ib) below, which are synthesized using conventional protocols, procedures described in the experimental section of the present application, and similar procedures well known to those skilled in the art, without undue experimentation. According to the above cited test, the compounds have the desired activity of inhibiting cathepsin S in cells.

{ [1- (3-cyano-1-isobutyl-piperidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 493(M +1)

N- (2-cyano-octahydroquinolizin-2-yl) -3-cyclohexyl-2- (1, 1-dioxy-1H-1 λ -benzo-3-ylamino) -propionamide; MS: 498(M +1)

{ [ 1-3-cyano-1-methyl-piperidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 451(M +1)

{ [1- (2-cyano-octahydroquinolizin-2-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 491(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3-methyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 465(M +1)

{ [1- (4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 545(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexylmethyl ester; MS: 545(M +1)

{ [ -1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclobutyl ester; MS: 503(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid allyl ester; MS: 489(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -4-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 480(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3-cyclohexyl-propylamino ] -morpholin-4-yl-methylene } -carbamic acid ester; MS: 519(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydro-furan-3-ylmethyl ester; MS: 533(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydro-furan-2-ylmethyl ester; MS: 533(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (5, 6-difluoro-3-oxo-2, 3-dihydroisoindol-1-ylideneamino) -propionamide; MS: 458(M +1)

2- (5, 6-difluoro-3-oxo-2, 3-dihydroisoindol-1-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 460(M +1)

2- (6-fluoro-3-oxo-2, 3-dihydroisoindol-1-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 442(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (6-fluoro-3-oxo-2, 3-dihydroisoindol-1-ylideneamino) -propionamide; MS: 440(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester; MS: 465(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester; MS: 463(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2, 2-dimethyl-propyl ester; MS: 519(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester; MS: 437(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid benzyl ester; MS: 539(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid isobutyl ester; MS: 505(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid propyl ester; MS: 491(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid hexyl ester; MS: 533(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid cyclobutylmethyl ester; MS: 517(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3, 3, 3-trifluoro-propyl ester; MS: 545(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester; MS: 507(M +1)

5, 5-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 454(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -4, 4-dimethyl-pentylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 493(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-isopropoxy-ethyl ester; MS: 534(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3-methoxy-butyl ester; MS: 534(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-isobutoxy-ethyl ester; MS: 549(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester; MS: 509(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (6-methoxy-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 468(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (6-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 456(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 456(M +1)

2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 458(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-methoxy-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 468(M +1)

2- (7-methoxy-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 470(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -5-methyl-hexylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 479(M +1)

2- [ (N-benzyl-morpholine-4-iminomethyl) -amino ] -N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide; MS: 495(M +1).

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 438(M +1).

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -pyrrolidin-1-yl-methyl } -carbamic acid ethyl ester; MS: 461(M +1).

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -piperidin-1-yl-methyl } -carbamic acid ethyl ester; MS: 475(M +1).

{ azepan-1-yl- [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 489(M +1).

{ azacyclooctan-1-yl- [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 503(M +1).

1- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -ethoxycarbonylamino-methyl } -piperidine-4-carboxylic acid ethyl ester; MS: 547(M +1).

1- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -ethoxycarbonylamino-methyl } -piperidine-3-carboxylic acid ethyl ester; MS: 547(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (4-pyrrolidin-1-yl-piperidin-1-yl) -methyl ] -carbamic acid ethyl ester; MS: 544(M +1).

{ [1, 4 '] bipiperidinyl-1' -yl- [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 558(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (4-phenyl-piperazin-1-yl) -methyl ] -carbamic acid ethyl ester; MS: 552(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (4-ethyl-piperazin-1-yl) -methyl ] -carbamic acid ethyl ester; MS: 504(M +1).

{ (4-acetyl-piperazin-1-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 518(M +1).

4- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -ethoxycarbonylamino-methyl } -piperazine-1-carboxylic acid ethyl ester; MS: 548(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (3, 3, 5-trimethyl-6-aza-bicyclo [3.2.1] octan-6-yl) -methyl ] -carbamic acid ethyl ester; MS: 543(M +1).

{ (3-acetylamino-pyrrolidin-1-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 518(M +1).

{ (3-acetylamino-pyrrolidin-1-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 518(M +1).

{ (3-azapent-3-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 463(M +1).

{ (1-methoxy-3-azapent-3-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 493(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (3-oxy-piperazin-1-yl) -methyl ] -carbamic acid ethyl ester; MS: 490(M +1).

{ (1, 5-dimethoxy-3-azapent-3-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 523(M +1).

4, 4-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 440(M +1)

{ (4-carbamoyl-piperidin-1-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 518(M +1)

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2-methoxymethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester; MS: 521(M +1)

(4- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -ethoxycarbonylamino-methyl } -piperazin-1-yl) -acetic acid ethyl ester; MS: 562(M +1)

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2, 6-dimethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester; MS: 505(M +1)

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2, 6-dimethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester; MS: 505(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -thiomorpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 493(M +1)

4, 4-dimethyl-2- (6-methyl-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 454(M +1)

2- (6-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 475(M +1)

4, 4-dimethyl-2- (2-oxo-2, 3-dihydro-1H-quinazolin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 439(M +1)

2- (7-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 475(M +1)

5-methyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 440(M +1)

4, 4-dimethyl-2- (1-methyl-2-oxo-1, 2-dihydroquinazolin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 453(M +1)

3-tert-butylsulfanyl-N- (4-cyano-1-propyl-piperidin-4-yl) -2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 472(M +1)

{ [ 2-tert-butylsulfanyl-1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 511(M +1)

3-benzylsulfanyl-N- (4-cyano-1-propyl-piperidin-4-yl) -2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 506(M +1)

{ [ 2-benzylsulfanyl-1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 545(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3-cyclooctyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 494(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3-cycloheptyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 480(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cycloheptyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 519(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cyclooctyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 533(M +1)

{ [1- (4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid isobutyl ester; MS: 491(M +1)

({1- [ 4-cyano-1- (2-morpholin-4-yl-ethyl) -piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester; MS: 604(M +1)

({1- [ 1-2-carbamoyl-ethyl) -4-cyano-piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester; MS: 562(M +1)

[ (1- { 4-cyano-1- [2- (2-methoxy-1-ethoxy) -ethyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate; MS: 593(M +1)

[ (1- { 4-cyano-1- [3- (2-methoxy-1-ethoxy) -propyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate; MS: 607(M +1)

{ [ 2-tert-butoxy-1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 495(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- { [ diethyl-carbamoylimino) -morpholin-4-yl-methyl ] -amino } -propionamide; MS: 504(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2- (3, 3, 5, 5-tetramethyl-cyclohexyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 561(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2- (4, 4-dipropyl-cyclohexyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 589(M +1)

{ [1- (4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 505(M +1)

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 567(M +1)

{ [1- (4-cyano-1-ethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 491(M +1)

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 553(M +1)

4-cyano-4- { 3-cyclohexyl-2- [ (ethoxycarbonylimino-morpholin-4-yl-methyl) -amino ] -propionylamino } -piperidine-1-carboxylic acid benzyl ester; MS: 597(M +1)

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 527(M +1)

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 541(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-benzyl-4-cyano-piperidin-4-yl) -amide; MS: 488(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (5-methyl-thiophen-2-ylmethyl) -piperidin-4-yl ] -amide; MS: 508(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (4-fluoro-benzyl) -piperidin-4-yl ] -amide; MS: 506(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-ethyl-piperidin-4-yl) -amide; MS: 426(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-methyl-piperidin-4-yl) -amide; MS: 412(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-piperidin-4-yl) -amide; MS: 398(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-phenethyl-piperidin-4-yl) -amide; MS: 502(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (2, 2-dimethyl-propyl) -piperidin-4-yl ] -amide; MS: 468(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3-dimethyl-butyl) -piperidin-4-yl ] -amide; MS: 482(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-pentyl-piperidin-4-yl) -amide; MS: 468(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-butyl-4-cyano-piperidin-4-yl) -amide; MS: 454(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yl ] -amide; MS: 494(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl) -amide; MS: 494(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dimethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 494(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dipropyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 550(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4-tert-butyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 522(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (3, 3, 5, 5-tetramethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazine 4-ylamino) -propionamide; MS: 522(M +1)

{ [1- (3-cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester MS: 477(M +1)

2- [ (methanesulfonylimino-morpholin-4-yl-methyl) -amino ] -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide MS: 485(M +1)

{ [1- (3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester MS: 465(M +1)

({1- [ 3-cyano-1- (4, 4-dimethyl-cyclohexyl) -pyrrolidin-3-ylcarbamoyl ] -3, 3-dimethyl-butylamino } -morpholin-4-yl-methylene) -carbamic acid ethyl ester MS: 533(M +1)

{ [1- (3-cyano-1-ethyl-5, 5-dimethyl-pyrrolidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester MS: 479(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (7, 8-difluoro-2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 474(M +1)

{ [1- (4-cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 559(M +1)

3-cyano-3- [4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoylamino ] -azepan-1-carboxylic acid benzyl ester; MS: 546(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (3-cyano-1-propyl-azepan-3-yl) -amide; MS: 454(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-azepan-4-yl) -amide; MS: 454(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid 4-methoxy-cyclohexylmethyl ester; MS: 575(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexyl ester; MS: 531(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -phenyl-methylene } -carbamic acid ethyl ester; MS: 470(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -phenyl-methylene } -carbamic acid ethyl ester; MS: 468(M +1)

2- { [ N- (4-cyano-phenyl) -morpholin-4-iminomethyl ] -amino } -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 508(M +1)

4, 4-dimethyl-2- { [ N- (4-trifluoromethyl-phenyl) -morpholin-4-iminomethyl ] -amino } -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 551(M +1)

The following are preferred compounds of formulae (Ia) and (Ib):

{ [1- (3-cyano-1-isobutyl-piperidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 493(M +1)

{ [1- (4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 545(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexylmethyl ester; MS: 545(M +1)

{ [ -1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclobutyl ester; MS: 503(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid allyl ester; MS: 489(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -4-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 480(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydro-furan-3-ylmethyl ester; MS: 533(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydro-furan-2-ylmethyl ester; MS: 533(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (5, 6-difluoro-3-oxo-2, 3-dihydroisoindol-1-ylideneamino) -propionamide; MS: 458(M +1)

2- (5, 6-difluoro-3-oxo-2, 3-dihydroisoindol-1-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 460(M +1)

2- (6-fluoro-3-oxo-2, 3-dihydroisoindol-1-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 442(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (6-fluoro-3-oxo-2, 3-dihydroisoindol-1-ylideneamino) -propionamide; MS: 440(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester; MS: 465(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester; MS: 463(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2, 2-dimethyl-propyl ester; MS: 519(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester; MS: 437(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid benzyl ester; MS: 539(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid isobutyl ester; MS: 505(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid propyl ester; MS: 491(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid hexyl ester; MS: 533(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid cyclobutylmethyl ester; MS: 517(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3, 3, 3-trifluoro-propyl ester; MS: 545(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester; MS: 507(M +1)

5, 5-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 454(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-isopropoxy-ethyl ester; MS: 534(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3-methoxy-butyl ester; MS: 534(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-isobutoxy-ethyl ester; MS: 549(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester; MS: 509(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (6-methoxy-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 468(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (6-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 456(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 456(M +1)

2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 458(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-methoxy-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 468(M +1)

2- (7-methoxy-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 470(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 438(M +1).

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -pyrrolidin-1-yl-methyl } -carbamic acid ethyl ester; MS: 461(M +1).

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -piperidin-1-yl-methyl } -carbamic acid ethyl ester; MS: 475(M +1).

{ azepan-1-yl- [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 489(M +1).

{ azacyclooctan-1-yl- [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 503(M +1).

1- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -ethoxycarbonylamino-methyl } -piperidine-4-carboxylic acid ethyl ester; MS: 547(M +1).

1- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -ethoxycarbonylamino-methyl } -piperidine-3-carboxylic acid ethyl ester; MS: 547(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (4-phenyl-piperazin-1-yl) -methyl ] -carbamic acid ethyl ester; MS: 552(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (4-ethyl-piperazin-1-yl) -methyl ] -carbamic acid ethyl ester; MS: 504(M +1).

{ (4-acetyl-piperazin-1-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 518(M +1).

4- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -ethoxycarbonylamino-methyl } -piperazine-1-carboxylic acid ethyl ester; MS: 548(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (3, 3, 5-trimethyl-6-aza-bicyclo [3.2.1] octan-6-yl) -methyl ] -carbamic acid ethyl ester; MS: 543(M +1).

{ (3-acetylamino-pyrrolidin-1-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 518(M +1).

{ (3-acetylamino-pyrrolidin-1-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 518(M +1).

{ (3-azapent-3-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 463(M +1).

{ (1-methoxy-3-azapent-3-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 493(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (3-oxy-piperazin-1-yl) -methyl ] -carbamic acid ethyl ester; MS: 490(M +1).

{ (1, 5-dimethoxy-3-azapent-3-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 523(M +1).

4, 4-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 440(M +1)

{ (4-carbamoyl-piperidin-1-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 518(M +1)

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2-methoxymethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester; MS: 521(M +1)

(4- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -ethoxycarbonylamino-methyl } -piperazin-1-yl) -acetic acid ethyl ester; MS: 562(M +1)

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2, 6-dimethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester; MS: 505(M +1)

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2, 6-dimethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester; MS: 505(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -thiomorpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 493(M +1)

4, 4-dimethyl-2- (6-methyl-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 454(M +1)

2- (6-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 475(M +1)

4, 4-dimethyl-2- (2-oxo-2, 3-dihydro-1H-quinazolin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 439(M +1)

2- (7-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 475(M +1)

5-methyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 440(M +1)

4, 4-dimethyl-2- (1-methyl-2-oxo-1, 2-dihydroquinazolin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 453(M +1)

3-tert-butylsulfanyl-N- (4-cyano-1-propyl-piperidin-4-yl) -2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 472(M +1)

3-benzylsulfanyl-N- (4-cyano-1-propyl-piperidin-4-yl) -2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 506(M +1)

{ [ 2-benzylsulfanyl-1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 545(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3-cyclooctyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 494(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3-cycloheptyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 480(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cycloheptyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 519(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cyclooctyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 533(M +1)

{ [1- (4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid isobutyl ester; MS: 491(M +1)

({1- [ 4-cyano-1- (2-morpholin-4-yl-ethyl) -piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester; MS: 604(M +1)

({1- [ 1-2-carbamoyl-ethyl) -4-cyano-piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester; MS: 562(M +1)

[ (1- { 4-cyano-1- [2- (2-methoxy-1-ethoxy) -ethyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate; MS: 593(M +1)

[ (1- { 4-cyano-1- [3- (2-methoxy-1-ethoxy) -propyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate; MS: 607(M +1)

{ [ 2-tert-butoxy-1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 495(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- { [ diethyl-carbamoylimino) -morpholin-4-yl-methyl ] -amino } -propionamide; MS: 504(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2- (3, 3, 5, 5-tetramethyl-cyclohexyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 561(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2- (4, 4-dipropyl-cyclohexyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 589(M +1)

{ [1- (4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 505(M +1)

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 567(M +1)

{ [1- (4-cyano-1-ethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 491(M +1)

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 553(M +1)

4-cyano-4- { 3-cyclohexyl-2- [ (ethoxycarbonylimino-morpholin-4-yl-methyl) -amino ] -propionylamino } -piperidine-1-carboxylic acid benzyl ester; MS: 597(M +1)

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 527(M +1)

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 541(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-benzyl-4-cyano-piperidin-4-yl) -amide; MS: 488(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (5-methyl-thiophen-2-ylmethyl) -piperidin-4-yl ] -amide; MS: 508(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (4-fluoro-benzyl) -piperidin-4-yl ] -amide; MS: 506(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-ethyl-piperidin-4-yl) -amide; MS: 426(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-methyl-piperidin-4-yl) -amide; MS: 412(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-piperidin-4-yl) -amide; MS: 398(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-phenethyl-piperidin-4-yl) -amide; MS: 502(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (2, 2-dimethyl-propyl) -piperidin-4-yl ] -amide; MS: 468(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3-dimethyl-butyl) -piperidin-4-yl ] -amide; MS: 482(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-pentyl-piperidin-4-yl) -amide; MS: 468(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-butyl-4-cyano-piperidin-4-yl) -amide; MS: 454(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yl ] -amide; MS: 494(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl) -amide; MS: 494(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dimethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 494(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dipropyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 550(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4-tert-butyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 522(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (3, 3, 5, 5-tetramethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 522(M +1)

{ [1- (3-cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester MS: 477(M +1).

{ [1- (3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester MS: 465(M +1).

({1- [ 3-cyano-1- (4, 4-dimethyl-cyclohexyl) -pyrrolidin-3-ylcarbamoyl ] -3, 3-dimethyl-butylamino } -morpholin-4-yl-methylene) -carbamic acid ethyl ester MS: 533(M +1).

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (7, 8-difluoro-2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 474(M +1)

{ [1- (4-cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 559(M +1)

3-cyano-3- [4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoylamino ] -azepan-1-carboxylic acid benzyl ester; MS: 546(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (3-cyano-1-propyl-azepan-3-yl) -amide; MS: 454(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-azepan-4-yl) -amide; MS: 454(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid 4-methoxy-cyclohexylmethyl ester; MS: 575(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexyl ester; MS: 531(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -phenyl-methylene } -carbamic acid ethyl ester; MS: 470(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -phenyl-methylene } -carbamic acid ethyl ester; MS: 468(M +1)

More preferred compounds of formula (Ia) and (Ib) are selected from:

{ [1- (4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 545(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexylmethyl ester; MS: 545(M +1)

{ [ -1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclobutyl ester; MS: 503(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid allyl ester; MS: 489(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydro-furan-3 yl methyl ester; MS: 533(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydro-furan-2-ylmethyl ester; MS: 533(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester; MS: 463(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2, 2-dimethyl-propyl ester; MS: 519(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid benzyl ester; MS: 539(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid isobutyl ester; MS: 505(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid propyl ester; MS: 491(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid hexyl ester; MS: 533(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid cyclobutylmethyl ester; MS: 517(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3, 3, 3-trifluoro-propyl ester; MS: 545(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester; MS: 507(M +1)

5, 5-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 454(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-isopropoxy-ethyl ester; MS: 534(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3-methoxy-butyl ester; MS: 534(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-isobutoxy-ethyl ester; MS: 549(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 456(M +1)

2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 458(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-methoxy-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 468(M +1)

2- (7-methoxy-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 470(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 438(M +1).

4, 4-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 440(M +1)

4, 4-dimethyl-2- (2-oxo-2, 3-dihydro-1H-quinazolin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 439(M +1)

2- (7-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 475(M +1)

4, 4-dimethyl-2- (1-methyl-2-oxo-1, 2-dihydroquinazolin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 453(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3-cyclooctyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 494(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3-cycloheptyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 480(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cycloheptyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 519(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cyclooctyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 533(M +1)

({1- [ 1-2-carbamoyl-ethyl) -4-cyano-piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester; MS: 562(M +1)

[ (1- { 4-cyano-1- [2- (2-methoxy-1-ethoxy) -ethyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate; MS: 593(M +1)

[ (1- { 4-cyano-1- [3- (2-methoxy-1-ethoxy) -propyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate; MS: 607(M +1)

{ [1- (4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 505(M +1)

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 567(M +1)

{ [1- (4-cyano-1-ethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 491(M +1)

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 553(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-benzyl-4-cyano-piperidin-4-yl) -amide; MS: 488(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (5-methyl-thiophen-2-ylmethyl) -piperidin-4-yl ] -amide; MS: 508(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (4-fluoro-benzyl) -piperidin-4-yl ] -amide; MS: 506(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-ethyl-piperidin-4-yl) -amide; MS: 426(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-methyl-piperidin-4-yl) -amide; MS: 412(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-phenethyl-piperidin-4-yl) -amide; MS: 502(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (2, 2-dimethyl-propyl) -piperidin-4-yl ] -amide; MS: 468(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3-dimethyl-butyl) -piperidin-4-yl ] -amide; MS: 482(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-pentyl-piperidin-4-yl) -amide; MS: 468(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-butyl-4-cyano-piperidin-4-yl) -amide; MS: 454(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yl ] -amide; MS: 494(M +1)

4, 4-5-methyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl) -amide; MS: 494(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dimethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 494(M +1)

{ [1- (3-cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester MS: 477(M +1).

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (7, 8-difluoro-2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 474(M +1)

{ [1- (4-cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 559(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid 4-methoxy-cyclohexylmethyl ester; MS: 575(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexyl ester; MS: 531(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl } -3, 3-dimethyl-butylamino ] -phenyl-methylene } -carbamic acid ethyl ester; MS: 470(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -phenyl-methylene } -carbamic acid ethyl ester; MS: 468(M +1)

Most preferred compounds of formula (Ia) and (Ib) are selected from:

{ [1- (3-cyano-1-isobutyl-piperidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 493(M +1)

{ [1- (4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 545(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexylmethyl ester; MS: 545(M +1)

{ [ -1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclobutyl ester; MS: 503(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid allyl ester; MS: 489(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -4-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 480(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydro-furan-3 yl methyl ester; MS: 533(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydro-furan-2-ylmethyl ester; MS: 533(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (6-fluoro-3-oxo-2, 3-dihydroisoindol-1-ylideneamino) -propionamide; MS: 440(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester; MS: 463(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2, 2-dimethyl-propyl ester; MS: 519(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid benzyl ester; MS: 539(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid isobutyl ester; MS: 505(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid propyl ester; MS: 491(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid hexyl ester; MS: 533(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid cyclobutylmethyl ester; MS: 517(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3, 3, 3-trifluoro-propyl ester; MS: 545(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester; MS: 507(M +1)

5, 5-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 454(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-isopropoxy-ethyl ester; MS: 534(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3-methoxy-butyl ester; MS: 534(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-isobutoxy-ethyl ester; MS: 549(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 456(M +1)

2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 458(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-methoxy-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide; MS: 468(M +1)

2- (7-methoxy-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 470(M +1)

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 438(M +1).

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -pyrrolidin-1-yl-methyl } -carbamic acid ethyl ester; MS: 461(M +1).

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -piperidin-1-yl-methyl } -carbamic acid ethyl ester; MS: 475(M +1).

{ azepan-1-yl- [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 489(M +1).

{ azacyclooctan-1-yl- [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 503(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (4-phenyl-piperazin-1-yl) -methyl ] -carbamic acid ethyl ester; MS: 552(M +1).

{ (4-acetyl-piperazin-1-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -methyl } -carbamic acid ethyl ester; MS: 518(M +1).

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (3, 3, 5-trimethyl-6-aza-bicyclo [3.2.1] octan-6-yl) -methyl ] -carbamic acid ethyl ester; MS: 543(M +1).

4, 4-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 440(M +1)

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2-methoxymethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester; MS: 521(M +1)

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2, 6-dimethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester; MS: 505(M +1)

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2, 6-dimethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester; MS: 505(M +1)

4, 4-dimethyl-2- (2-oxo-2, 3-dihydro-1H-quinazolin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 439(M +1)

2- (7-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 475(M +1)

5-methyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 440(M +1)

4, 4-dimethyl-2- (1-methyl-2-oxo-1, 2-dihydroquinazolin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide; MS: 453(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3-cyclooctyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 494(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3-cycloheptyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide; MS: 480(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cycloheptyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 519(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cyclooctyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester; MS: 533(M +1)

{ [1- (4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid isobutyl ester; MS: 491(M +1)

({1- [ 4-cyano-1- (2-morpholin-4-yl-ethyl) -piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester; MS: 604(M +1)

({1- [ 1-2-carbamoyl-ethyl) -4-cyano-piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester; MS: 562(M +1)

[ (1- { 4-cyano-1- [2- (2-methoxy-1-ethoxy) -ethyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate; MS: 593(M +1)

[ (1- { 4-cyano-1- [3- (2-methoxy-1-ethoxy) -propyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate; MS: 607(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2- (3, 3, 5, 5-tetramethyl-cyclohexyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 561(M +1)

{ [1- (4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 505(M +1)

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 567(M +1)

{ [1- (4-cyano-1-ethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 491(M +1)

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 553(M +1)

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 541(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-benzyl-4-cyano-piperidin-4-yl) -amide; MS: 488(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (5-methyl-thiophen-2-ylmethyl) -piperidin-4-yl ] -amide; MS: 508(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (4-fluoro-benzyl) -piperidin-4-yl ] -amide; MS: 506(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-ethyl-piperidin-4-yl) -amide; MS: 426(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-methyl-piperidin-4-yl) -amide; MS: 412(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-piperidin-4-yl) -amide; MS: 398(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-phenethyl-piperidin-4-yl) -amide; MS: 502(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (2, 2-dimethyl-propyl) -piperidin-4-yl ] -amide; MS: 468(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3-dimethyl-butyl) -piperidin-4-yl ] -amide; MS: 482(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-pentyl-piperidin-4-yl) -amide; MS: 468(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-butyl-4-cyano-piperidin-4-yl) -amide; MS: 454(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yl ] -amide; MS: 494(M +1)

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl) -amide; MS: 494(M +1)

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dimethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 494(M +1)

{ [1- (3-cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester MS: 477(M +1).

{ [1- (3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester MS: 465(M +1).

({1- [ 3-cyano-1- (4, 4-dimethyl-cyclohexyl) -pyrrolidin-3-ylcarbamoyl ] -3, 3-dimethyl-butylamino } -morpholin-4-yl-methylene) -carbamic acid ethyl ester MS: 533(M +1).

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (7, 8-difluoro-2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide; MS: 474(M +1)

{ [1- (4-cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester; MS: 559(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid 4-methoxy-cyclohexylmethyl ester; MS: 575(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexyl ester; MS: 531(M +1)

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -phenyl-methylene } -carbamic acid ethyl ester; MS: 470(M +1)

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -phenyl-methylene } -carbamic acid ethyl ester; MS: 468(M +1)

Any compound of the present invention containing one or more asymmetric carbon atoms may exist as racemates with racemic mixtures, single enantiomers, mixtures of diastereomers and single diastereomers. All such isomers of these compounds are expressly included in the present invention. Unless otherwise specified, each stereoisomeric carbon may be in the R or S configuration or a combination thereof.

Some compounds of formula (Ia) and (Ib) may exist as more than one tautomer. The present invention includes all such tautomers.

It will be understood by those skilled in the art that all compounds of the present invention should be those that are chemically stable.

The invention includes pharmaceutically acceptable derivatives of the compounds of formula (Ia) and (Ib). "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable acid, salt or ester of a compound of the present invention, or any other compound that, when administered to a patient, is capable of providing (directly or indirectly) a compound of the present invention or a pharmaceutically active metabolite or residue thereof.

In addition, the compounds of the present invention include prodrugs of the compounds of formula (Ia) and (Ib). Prodrugs include those compounds which upon simple transformation yield the compounds of the present invention. Simple chemical transformations include hydrolysis, oxidation and reduction, which occur through enzymatic, metabolic or other actions. In particular, when a prodrug of the present invention is administered to a patient, the prodrug may be converted to compounds of formulae (Ia) and (Ib), thereby producing the desired pharmacological effect.

In order that the invention may be more fully understood, a detailed description is given below. The following abbreviations are used herein:

BOC or t-BOC is tert-butoxycarbonyl;

t-Bu is tert-butyl;

DMF is dimethylformamide;

EtOAc is ethyl acetate;

THF is tetrahydrofuran;

ar is argon;

EDC is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; and

HOBT is 1-hydroxybenzotriazole.

Further, as used herein, alone or in combination with other terms, each term is defined as follows (unless stated to the contrary):

the term "alkyl" refers to a saturated aliphatic group containing 1 to 10 carbon atoms, or to a mono-or polyunsaturated aliphatic hydrocarbon group containing 2 to 12 carbon atoms. The mono-or polyunsaturated aliphatic hydrocarbon radicals contain at least one double or triple bond, respectively. "alkyl" refers to both branched and unbranched alkyl groups. Examples of the "alkyl group" include a straight-chain alkyl group having 1 to 8 carbon atoms and a branched-chain alkyl group having 3 to 8 carbon atoms. Other examples include straight chain alkyl groups having 1 to 6 carbon atoms and lower alkyl groups having branched alkyl groups having 3 to 6 carbon atoms. It is to be understood that the combination of terms employing alkyl prefixes is analogous to the definition of "alkyl" above. For example, the terms "alkoxy", "alkylthio" or "alkylthio" refer to an alkyl group attached to a second group through an oxygen or sulfur atom. "alkanoyl" refers to an alkyl group attached to a carbonyl group (C ═ O). Each alkyl or alkyl analog described herein is to be understood as optionally partially or fully halogenated.

The term "cycloalkyl" is defined as above and refers to cyclic analogs of alkyl groups. Examples of the cycloalkyl group are saturated or unsaturated non-aromatic cycloalkyl groups having 3 to 8 carbon atoms, and other examples include cycloalkyl groups having 3 to 6 carbon atoms. Each cycloalkyl group described herein is to be understood as optionally partially or fully halogenated.

The term "aryl" refers to phenyl and naphthyl.

The term "halo" refers to a halogen group selected from fluoro, chloro, bromo or iodo. Representative halogen groups of the present invention are fluorine, chlorine and bromine.

The term "heteroaryl" refers to a stable 5-to 8-membered (preferably 5-or 6-membered) monocyclic or 8-to 11-membered bicyclic aromatic heterocyclic group. Each heterocycle consists of carbon and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocyclic ring may be attached through any ring-forming atom that forms a stable structure. Examples of "heteroaryl" include groups such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, 2, 3-diazanaphthyl, quinazolinyl, quinoxalinyl, 1, 5-diazanaphthyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenazinyl.

The term "heterocycle" refers to a stable 4-to 8-membered (preferably 5-or 6-membered) monocyclic or 8-to 11-membered bicyclic heterocyclic group which may be saturated or unsaturated and is non-aromatic. Each heterocyclic ring is composed of carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocyclic ring may be attached through any ring atom that forms a stable structure. Examples of "heterocycle" include groups such as pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl, indolinyl, azetidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidyl, hexahydropyridazinyl, 1, 4, 5, 6-tetrahydropyrimidin-2-ylamine, dihydrooxazolyl, 1, 2-thiaazacyclononane-1, 1-dioxide, 1, 2, 6-thiadiazacyclononane-1, 1-dioxide, isothiazolidinyl-1, 1-dioxide and imidazolidinyl-2, 4-dione.

The terms "heterocycle", "heteroaryl" or "aryl" in combination with other moieties shall have the same meaning as given above unless otherwise indicated. For example, "aroyl" refers to phenyl or naphthyl attached to a carbonyl (C ═ O).

Unless otherwise indicated, each aryl or heteroaryl group includes partially or fully hydrogenated derivatives thereof. For example, the quinolyl group may include decahydroquinolyl and tetrahydroquinolyl, and the naphthyl group may include hydrogenated derivatives thereof such as tetrahydronaphthyl. Other partially or fully hydrogenated derivatives of the aryl or heteroaryl compounds described herein will be apparent to those skilled in the art.

The term heterocycle in relation to "Het" should be understood to mean a stable nonaromatic spiroheterocycle, a 4-to 8-membered (preferably 5-or 6-membered) monocyclic, 8-to 11-membered bicyclic heterocyclic group which may be saturated or unsaturated, or C₆-C₁₀Bridged bicyclic rings in which one or more carbon atoms are optionally replaced by heteroatoms. Each heterocyclic ring is composed of carbon atoms and 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur. The heterocyclic ring may be attached through any ring atom that forms a stable structure. Examples of "Het" include the following heterocycles: azepanes as pharmaceutical agentsA group, piperidinyl, pyrrolidinyl, azetidinyl, oxepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl, azocycloctyl, oxocyclooctyl, 1, 3-diazacyclooctanyl, 1, 4-diazacyclooctanyl, 1, 5-diazacyclooctanyl, 1, 3-dioxacyclooctyl, 1, 4-dioxacyclooctyl, 1, 5-dioxacyclooctyl, 1, 3-oxazocinyl, 1, 4-oxazocinyl, 1, 5-oxazocinyl, 1, 3-diazepanyl, 1, 4-diazepanyl, 1, 3-dioxacycloheptyl, 1, 4-dioxacycloheptyl, 1, 3-oxazepanyl, 1, 4-oxazepanyl, 1, 2-thiazepanyl-1, 1-dioxide, 1, 2, 8-thiadiazacyclo-ctyl-1, 1-dioxide, 1, 2-thiazepanyl-1, 1-dioxide, 1, 2, 7-thiadiazacycloheptanyl-1, 1-dioxide, tetrahydrothienyl, hexahydropyrimidyl, hexahydropyridazinyl, piperazinyl, 1, 4, 5, 6-tetrahydropyrimidinyl, pyrazolidinyl, dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, isoxazolinyl, oxazolidinyl, 1, 2-thiazepanyl-1, 1-dioxide, 1, 2, 6-thiadiazacyclononanyl-1, 1-dioxide, isothiazolidinyl-1, 1-dioxide, imidazolidinyl-2, 4-dione, imidazolidinyl, morpholinyl, dioxanyl, tetrahydropyridinyl, thiomorpholinyl, thiazolidinyl, dihydropyranyl, dithianyl, decahydroquinolinyl, decahydroisoquinolinyl, 1, 2, 3, 4-tetrahydro-quinolinyl, indolinyl, octahydroquinolizinyl, indolizinyl, octahydroindolizinyl, octahydroindolinyl, decahydroquinazolinyl, decahydroquinoxalinyl, 1, 2, 3, 4-tetrahydroquinazolinyl or 1, 2, 3, 4-tetrahydroquinoxalinyl, azabicyclo [3.2.1 ]Octane, azabicyclo [2.2.1]Heptane, azabicyclo [2.2.2]Octane, azabicyclo [3.2.2]Nonanes, azabicyclo [2.1.1]Hexane, azabicyclo [3.1.1]Heptane, azabicyclo [3.3.2]Decane and 2-oxa-or 2-thia-5-azabicyclo [2.2.1]Heptane; the heterocyclic ring may be interrupted by one or more R₅And (4) substituting. Substituent R₅The definition of (A) is as above.

As used herein above and throughout the application, "nitrogen" and "sulfur" include any oxidized form of nitrogen and sulfur as well as quaternized forms of any basic nitrogen.

For a more complete understanding of the present invention, the following examples are set forth. These examples are intended to illustrate preferred embodiments of the invention and should not be construed as limiting the scope of the invention in any way.

The following examples are illustrative, and the specific reactants and reaction conditions for a particular compound may be modified, as recognized by one skilled in the art. The starting materials for the following schemes are either commercially available or can be readily prepared from commercially available starting materials by those skilled in the art.

General synthetic methods

The invention also provides processes for preparing the novel compounds of formula (Ia) and (Ib). The compounds of the present invention may be prepared according to the methods described in U.S. patent application Ser. No. 09/655,351, incorporated herein by reference in its entirety, or by methods known to those of ordinary skill in the art.

Key intermediates for the preparation of compounds of (Ia) and (Ib) are the dipeptide nitrile intermediates (III).

The synthesis of intermediates of formula (III) is described in U.S. provisional patent application 60/222,900 and is outlined in schemes I and II below.

Scheme I

As illustrated in scheme I, an amino acid (IV) with an appropriate protecting group R' is reacted with an aminonitrile (V) under appropriate coupling conditions. An example of a suitable protecting group is tert-Butoxycarbonyl (BOC). An example of standard coupling conditions is to combine the starting material with 1-Hydroxybenzotriazole (HOBT) in the presence of a coupling agent such as 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) in a suitable solvent such as DMF or dichloromethane. A base such as N-methylmorpholine may be added. Deprotection then affords the amino acid nitrile III.

The intermediate aminonitrile (V) used in scheme I above can be prepared according to the procedure outlined in scheme II.

Scheme II

In this process, a ketone (VII) having "Het" is reacted with a primary amine or ammonium salt such as ammonium chloride, and a cyanide salt such as potassium cyanide or sodium cyanide in a suitable solvent such as water or a methanol solution of ammonia at room temperature to reflux temperature.

Compounds having formula (Ia/Ib) can be prepared according to methods A-D described in schemes III-VI.

Scheme III (method A)

According to method A, the dipeptide nitrile intermediate (III) or its basic salt (VIII) is reacted in the presence of a suitable coupling agent to give the desired product (Ia/Ib). Suitable reaction conditions are well known to those skilled in the art, and some examples of suitable coupling agents include 2-chloro-1-methylpyridinium iodide (Yong, y.f. et al, j.org.chem.1997, 62, 1540), phosgene or triphosgene (Barton, d.h. et al, j.chem.soc.perkin trans.i, 1982, 2085), alkyl halides (branch, e.and branch, f.c., org.synth, 1955, 3, 440), carbodiimides (pos, m.a. et al, Tetrahedron lett, 1992, 40, 5933), and mercury salts (Su, w., Synthetic comm., 1996, 26, 407, and wigall, k.j.andd richaramon, s.k.j., hetercycolic chem, 1995, 867).

Compounds having formula (Ia) and (Ib) can also be prepared according to method B described in scheme IV, wherein R is alkyl or aryl.

Scheme IV (method B)

According to method B, the dipeptide nitrile intermediate (III) or its basic salt is reacted with IX with or without addition of a base such as triethylamine to give the desired product (Ia/Ib). Suitable reaction conditions are well known to those skilled in the art, and examples of such amine additions can be found in the chemical literature, e.g., Haake, m.and Schummelfeder, b., Synthesis, 1991, 9, 753; dauwe, c.and Buddrus, j., Synthesis 1995, 2, 171; ried, w.and pierhaczek, d., jusus liebig ann. chem.1966, 97, 696 and Dean, w.d.and Papadopoulos, e.p., j.heterocyclic chem., 1982, 19, 1117.

Intermediates IX is either commercially available or can be prepared by methods well known to those skilled in the art, for example as described in Francesconi, i.et.al, j.med.chem.1999, 42, 2260; kurzer, f., Lawson, a., org.synth.1963, 645; and the method described in Gutman, a.d. us 3984410, 1976.

In a similar process, intermediate X having a halogen or other suitable leaving group (X') can be used in place of intermediate IX, as illustrated in method C of scheme V.

Scheme V (method C)

According to method C, the dipeptide nitrile intermediate or its basic salt is reacted with intermediate X with or without the addition of a base such as triethylamine to give the desired product (Ia/Ib). Methods for accomplishing this reaction are well known to those skilled in the art, for example, the chemical literature Dunn, a.d., org.prep.proceed.int., 1998, 30, 709; lindstrom, s, et al, Heterocycles, 1994, 38, 529; katritzky, a.r. and Saczewski, f., Synthesis, 1990, 561; hontz, A.C. and Wagner, E.C., OrgSynth, 1963, IV, 383; methods described in Stephen, e.and Stephen, h., j.chem.soc., 1957, 490.

Has the formula (Ia/Ib) and wherein R ₁Compounds that are amines can also be prepared by method D described in scheme VI.

Scheme VI (method D)

According to method D, the carbodiimide derivative (XI) of (III) is reacted with an amine (R)₁) The reaction yielded the desired guanidine product (Ia/Ib). The conversion of amines to carbodiimides is well known to those skilled in the art, for example, in the documents Pri-Bar, i.and Schwartz, j., j.chem.soc.chem.commun., 1997, 347; a method as described in Hirao, t.and Saegusa, t., j.org.chem., 1975, 40, 298. Nucleophilic reactions of carbodiimides with amines can also be found, for example, in Yoshiizumi, k, et al, chem.pharm.bull, 1997, 45, 2005; thomas, e.w. et al, j.med.chem., 1989, 32, 228; lawson, a.and Tinkler, r.b., j.chem.soc.c, 1971, 1429, etc.

In an improved process D, thiourea XII (via the corresponding amine with isothiocyanate R) may be used₆Formed by reaction of N ═ C ═ S) as starting material, thenThen by reacting with an appropriate desulfurizing agent such as HgCl in an appropriate solvent such as DMF or acetonitrile₂The reaction forms the corresponding carbodiimide (XI).

Wherein R is₁Compounds of formula (Ib) which are amines may be prepared using the general method described in m.haake and b.schummfelder (Synthesis, 1991, 753). According to this process (method E, scheme VII), an intermediate XIII having two leaving groups Z, such as phenoxy, is reacted sequentially with an amine R in a suitable solvent, such as methanol or isopropanol ₁And R₆R8NH to give the desired product. The reaction with the first amine may be carried out at about room temperature, and the reaction with the second amine is preferably carried out at the heated reflux temperature of the solvent. If XIII is reacted with a bifunctional nucleophilic intermediate XIV, where Y is a nucleophilic heteroatom such as N, O or S, a product of formula (Ib) can be obtained, where R is₁And R₆Forming a heterocyclic ring. Intermediate XIII can be prepared by III (R)₄H) with dichlorodiphenyloxymethane which in turn can be prepared by heating diphenyl carbonate with PCl₅To prepare (r.l.webb and c.s.labow, j.het.chem., 1982, 1205).

Scheme VII (method E)

For a more complete understanding of the present invention, the following examples are set forth. These examples are intended to illustrate embodiments of the invention and should not be construed as limiting the scope of the invention in any way.

The following examples are illustrative, and as those skilled in the art will recognize, the particular reagents and reaction conditions for a particular compound may be modified without undue experimentation. The starting materials for the following schemes are either commercially available or can be readily prepared from commercially available starting materials by those skilled in the art.

Synthetic examples

Example 1

2- { [ acetylimino- (4-methoxy-phenyl) -methyl ] -amino } -N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide (method A).

(a) N- (4-methoxy-thiobenzoyl) acetamide

A solution of acetyl chloride (4.69g, 59.8mmol) in acetone (20mL) was added dropwise to a solution of 4-methoxythiobenzamide (5.00g, 29.9mmol) and pyridine (4.76g, 60.1mmol) in acetone (30 mL). The reaction mixture was heated to reflux for 30 minutes and then poured onto ice water. The resulting precipitate was isolated by filtration and dried under vacuum overnight to give a pale yellow/orange solid (4.52g, 72%).¹H NMR(400MHz，CDCl₃)δ2.56(s，3H)，3.87(s，3H)，6.89(dd，J＝6.9，2.0Hz，2H)，7.77(dd，J＝6.9，2.0Hz，2H)。

(b)2- { [ acetylimino- (4-methoxy-phenyl) -methyl ] -amino } -N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide.

2-chloro-N-methylpyridinium iodide (660mg, 2.58mmol) was added to a solution of N- (4-methoxy-thiobenzoyl) acetamide (420mg, 2.01mmol), 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide dihydrochloride (730mg, 2.00mmol), and N, N-diisopropylethylamine (1.05mL, 6.02mmol) in dichloromethane (8.0 mL). The reaction mixture was stirred at room temperature for 2 hours, then diluted with dichloromethane (100mL) and washed with 2X 150mL of saturated sodium bicarbonate. Dried (MgSO4) and concentrated with And (4) organic phase. The resulting residue was chromatographed on 100g of flash silica gel, eluting first with EtOAc and then 9: 1 dichloromethane/methanol, to give the desired product as an off-white solid (377mg, 40%).¹H NMR(400MHz，DMSO-d₆)δ0.70-0.90(m，2H)，1.00-1.30(m，4H)，1.35-1.65(m，8H)，1.72(s，3H)，1.85-2.20(m，6H)，2.48-2.60(m，1H)，3.78(s，3H)，4.20-4.35(m，1H)，6.95-6.99(m，2H)，7.33(d，J＝8.4Hz，1H)，7.72(d，J＝8.4Hz，1H)。MS，m/z 468＝M+1。

Example 2

2- [ (acetylimino-phenyl-methyl) -amino ] -N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide

(a) Thiobenzoylacetamide was prepared according to the procedure of example 1, step a, starting from thiobenzamide.

(b) The title compound was prepared according to the procedure for example 1 step b from thiobenzoylacetamide and 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide dihydrochloride. MS, M/z438 ═ M + 1.

Example 3

2- { [ acetylimino- (4-fluoro-phenyl) -methyl ] -amino } -N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide

(a) N- (4-fluoro-thiobenzoyl) acetamide was prepared from 4-fluorothiobenzamide according to the procedure of example 1, step a.

(b) The title compound was prepared according to the method of example 1 step b from N- (4-fluoro-thiobenzoyl) acetamide and 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide dihydrochloride. MS, M/z 456 ═ M + 1.

Example 4

2- [ (acetylimino-phenyl-methyl) ] -amino ] -N- [ 3-cyano-1- (1-ethyl-propyl) -pyrrolidin-3-yl ] -3-cyclohexyl-propionamide

(a) The title compound was prepared from thiobenzoylacetamide and 2-amino-N- [ 3-cyano-1- (1-ethyl-propyl) -pyrrolidin-3-yl ] -3-cyclohexyl-propionamide dihydrochloride according to the method of example 1, step b, except that the compound was purified by HPLC using a 20 x 250mm C18 reverse phase chromatography column using 20% acetonitrile in water to 90% acetonitrile in water. MS, M/z 480 ═ M + 1.

Example 5

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester (method A)

(a) (morpholine-4-thioformyl) -carbamic acid ethyl ester

Morpholine (7.5mL, 86.0mmol) was added dropwise to a solution of isothiocyanato ethyl formate (10.0mL, 84.8mmol) in tetrahydrofuran (200 mL). The reaction mixture was stirred at room temperature for 2.5 hours, then concentrated and dried in vacuo to give the desired product as a white solid (16.5g, 89%). This material was used without further purification. ¹H NMR(400MHz，CDCl₃)δ1.28(t，J＝7.1Hz，3H)，3.61-3.97(m，8H)，4.16(q，7.1Hz，2H)，7.44(br s，1H)。

(a) { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester

2-chloro-N-methylpyridinium iodide (680mg, 2.66mmol) was added to a solution of (morpholine-4-thiocarbonyl) -carbamic acid ethyl ester (450mg, 2.06mmol), 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide dihydrochloride (745mg, 2.04mmol), and N, N-diisopropylethylamine (1.10mL, 6.3mmol) in dichloromethane (8.0 mL). The reaction was stirred at room temperature for 2.5 hours, then dissolved in 10% citric acid solution and washed with EtOAc. The aqueous phase was basified with saturated sodium carbonate and extracted with EtOAc. Drying (MgSO)₄) And the organic extracts were concentrated to give the desired product as a white solid (250mg, 26%). The material was further purified by HPLC using 20X 250mm C₁₈A reverse phase chromatographic column from 20% acetonitrile in water to 90% acetonitrile in water. MS, M/z 477 ═ M + 1.

Example 6

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester

The title compound was prepared from (morpholine-4-thiocarbonyl) -carbamic acid ethyl ester and 2-amino-N- (-4-cyano-1-propyl-piperidin-4-yl) -3-cyclohexylpropionamide dihydrochloride according to the procedure of example 5, step b, except that the compound was first purified by silica gel chromatography using 9: 1 dichloromethane: methanol as eluent and then by reverse phase HPLC. MS, M/z 505 ═ M + 1.

Example 7

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester

The title compound was prepared according to the procedure for example 5 from (morpholine-4-thiocarbonyl) -carbamic acid ethyl ester and 2-amino-4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) amide dihydrochloride. MS, M/z 460 ═ M + 1.

Example 8

({1- [ 3-cyano-1- (1-ethyl-propyl) -pyrrolidin-3-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid ethyl ester

The title compound was prepared according to the procedure for example 5 step b from (morpholine-4-thiocarbonyl) -carbamic acid ethyl ester and 2-amino-N- [ 3-cyano-1- (1-ethyl-propyl) -pyrrolidin-3-yl ] -3-cyclohexyl-propionamide dihydrochloride. MS, M/z 519 ═ M + 1.

Example 9

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- [ (isopropylcarbamoylimino-phenyl-methyl) -amino ] -propionamide (method B)

(a) Benzimidazole carboxylic acid (Benzimidic acid) methyl ester

Benzimidazole methyl formate saltsThe acid salt (5g, 29.1mmol) was partitioned between saturated sodium carbonate solution (200mL) and diethyl ether (100 mL). Drying (MgSO)₄) And the organic layer was concentrated to give the desired product as a colorless liquid (3.20g, 81%). This material was used without further purification.¹H NMR(400MHz，CDCl₃)δ3.93(s，3H)，7.39-7.46(m，3H)，7.75(d，J＝1.1Hz，2H)。

(a) 1-ethyl-3- (methoxy-phenyl-methylene) -urea

A mixture of pure methyl benzimidazolecarboxylate (750mg, 5.56mmol) and ethyl isocyanate (808mg, 11.3mmol) was stirred at 50 ℃ for 24 h. Excess isocyanate was removed under vacuum to give the desired product as a colorless viscous oil (1.09g, 95%). This material was used without further purification.¹H NMR(400MHz，CDCl₃)δ1.07(t，J＝7.3Hz，3H)，3.25(q，J＝7.3Hz，2H)，3.87(s，3H)，4.97(br s，1H)，7.26-7.40(m，2H)，7.45(d，J＝7.4Hz，1H)，7.69-7.71(m，2H).MS，m/z 207＝M+1。

(a) N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- [ (ethylcarbamoylimino-phenyl-methyl) -amino ] -propionamide

A solution of 1-ethyl-3- (methoxy-phenyl-methylene) -urea (350mg, 1.70mmol), 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide dihydrochloride (512mg, 1.40mmol) and N, N-diisopropylethylamine (352mg, 2.73mmol) in dry methanol (5.0mL) was stirred at room temperature for 60 hours. The reaction mixture was concentrated and the residue obtained was chromatographed on 50g of flash silica gel using dichloromethane to 5% methanol in dichloromethane as eluent. The desired product was thus obtained as a pale yellow solid (280mg, 43%), which was further purified by HPLC using 20X 250mm C ₁₈A reverse phase chromatographic column is prepared from 20% acetonitrile in water to 90% acetonitrile in water. MS, M/z 467 ═ M + 1.

Example 10

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (1, 1-dioxy-1H-1. lambda⁶-benzo [ d ]]Isothiazol-3-ylamino) -propionamide (method C)

Preparation of 3-chloro-benzo [ d ] in 5.5mL of acetonitrile]A suspension of isothiazole-1, 1-dioxide (300mg, 1.49mmol) and 2-amino-N- (-4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexylpropionamide dihydrochloride (500mg, 1.37 mmol). Triethylamine (575. mu.L, 4.10mmol) was added and the reaction mixture was stirred at room temperature for 1 day. The suspension was filtered to remove triethylamine hydrochloride and the filtrate was concentrated. The resulting residue was chromatographed on 50g of flash silica gel with 9: 1 dichloromethane/methanol as eluent to give the desired product as a pale yellow solid (310mg, 49%).¹H NMR(400MHz，CDCl₃)δ0.25-0.45(m，1H)，0.65-0.85(m，2H)，0.95-1.10(m，2H)，1.30-1.60(m，7H)，1.75-1.85(m，2H)，1.85-2.2(m，2H)，2.31(s，3H)，2.35-2.50(m，3H)，2.65-2.80(m，2H)，4.60-4.70(m，1H)，7.35-7.50(m，2H)，7.58(t，J＝7.3，1H)，7.78(d，J＝7.7Hz，1H)，7.81(br s，1H)，8.91(br s，1H)。MS，m/z 458＝M+1。

Example 11

N- (4-cyano-1-propyl-piperidin-4-yl) -3-cyclohexyl-2- (1, 1-dioxy-1H-1. lambda⁶-benzo [ d ]]Isothiazol-3-ylamino) -propionamides

By the process of example 10 from 3-chloro-benzo [ d ]Isothiazole 1, 1-dioxide and 2-amino-N- (-4-cyano-1-propyl-piperidin-4-yl) -3-cyclohexylpropionamide dihydrochloride the title compound was prepared except thatThe compound was further purified by HPLC using 20X 250mm C₁₈Reverse phase chromatography by using 20% acetonitrile in water to acetonitrile. MS, M/z 486 ═ M + 1.

Example 12

2- (1, 1-dioxy-1H-1 lambda)⁶-benzo [ d ]]Isothiazol-3-ylamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propylpiperidin-4-yl) -amide

By the process of example 10 from 3-chloro-benzo [ d]Isothiazole-1, 1-dioxide and 2-amino-4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) amide dihydrochloride the title compound was prepared except that the compound was further purified by HPLC using 20 x 250mm C₁₈Reverse phase chromatography by using 20% acetonitrile in water to acetonitrile. MS, M/z 460 ═ M + 1.

Example 13

N- [ 3-cyano-1- (1-ethyl-propyl) -pyrrolidin-3-yl]-3-cyclohexyl-2- (1, 1-dioxy-1H-1. lambda⁶-benzo [ d ]]Isothiazol-3-ylamino) -propionamides

The process according to example 10, starting from 3-chlorobenzo [ d ]Isothiazol-1, 1-dioxides and 2-amino-N- [ 3-cyano-1- (1-ethyl-propyl) -pyrrolidin-3-yl]Preparation of the title Compound from (E) -3-cyclohexyl-propionamide dihydrochloride, except that the Compound was further purified by HPLC using 20X 250mm C₁₈Reverse phase chromatography using 40% acetonitrile in water to acetonitrile. MS, M/z 500 ═ M + 1.

Example 14

N- (3-cyano-1-cyclohexyl-pyrrolidin-3-yl) -3-cyclohexyl-2- (1, 1-dioxy-1H-1. lambda⁶-benzo [ d ]]Isothiazol-3-ylamino) -propionamides

The process according to example 10, starting from 3-chlorobenzo [ d]Isothiazole-1, 1-dioxide and 2-amino-N- (3-cyano-1-cyclohexyl-pyrrolidin-3-yl) -3-cyclohexyl-propionamide dihydrochloride the title compound was prepared except that the compound was further purified by HPLC using 20X 250mm C₁₈Reverse phase chromatography using 40% acetonitrile in water to acetonitrile. MS, M/z 512 ═ M + 1.

Example 15

N- (4-cyano-methyl-piperidin-4-yl) -3-cyclohexyl-2- (3-oxo-3H-isoindol-1-ylamino) -propionamide

The title compound was prepared from 3-imino-2, 3-dihydroisoindol-1-one and 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide dihydrochloride according to the method of example 10, except that refluxing THF was used as the solvent. The compound was further purified by HPLC using 20X 250mmC ₁₈Reverse phase chromatography using 20% acetonitrile in water to acetonitrile. MS, M/z 422.5 ═ M + 1.

Example 16

4, 4-dimethyl-2- (3-oxo-3H-isoindol-1-ylamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide

The title compound was prepared according to the procedure for example 15 from 3-imino-2, 3-dihydroisoindol-1-one and 2-amino-4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) amide dihydrochloride. MS, M/z424.5 ═ M + 1.

Example 17

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (5, 6-difluoro-3-oxo-3H-isoindol-1-ylamino) propionamide

(a) 2-chloro-4, 5-difluorobenzoic acid methyl ester

2-chloro-4, 5-difluorobenzoic acid (1.93g, 10mmol) was dissolved in 20mL of acetone. Cesium carbonate (5.29g, 15mmol) was added followed by methyl iodide (1.0mL, 15 mmol). The reaction mixture was heated to reflux for 1 hour and then cooled to room temperature. Thereafter, the suspension was diluted with 40mL of diethyl ether. The solid was filtered off and washed with diethyl ether. The filtrate was evaporated in vacuo to give the title compound in quantitative yield as a clear oil.

(b) 2-cyano-4, 5-difluorobenzoic acid methyl ester

The above oil (2.06g, 10mmol) was dissolved in 10mL of N-methylpyrrolidone. Copper (I) cyanide (1.79g, 20mmol) was added. The mixture was heated under nitrogen at 195 ℃ for 1 hour, and after cooling to room temperature, the solution was diluted with 100mL of water. The resulting solid was collected by filtration. The solid was then suspended in a rapidly stirred solution of potassium cyanide (0.5g) in 30mL of water for 1 hour. EtOAc (30mL) was added. The mixture was then filtered through celite. The organic phase was separated and the aqueous phase was extracted with EtOAc (20 mL. times.2). The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was removed under vacuum. The residue was recrystallized from ether and petroleum ether to give the title compound as a yellow solid (1.26g, 64%).

(c)5, 6-difluoro-2, 3-dihydro-3-imino-1H-isoindol-1-ones

The above solid (0.493g, 2.5mmol) was dissolved in 20mL of MeOH. The solution was saturated with ammonia at 0 ℃ and then stirred in a pressure tube at room temperature for 3 days. The solid was collected by filtration and washed with diethyl ether to give the title compound as a yellow solid (0.363g, 80%).

The title compound was prepared according to the procedure for example 15 from 5, 6-difluoro-2, 3-dihydro-3-imino-1H-isoindol-1-one and 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide dihydrochloride. MS, M/z 458.3 ═ M + 1.

Example 18

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide

By the method of example 10 from 4-chloro-benzo [ e ]][1，3]Oxazin-2-ones (from benzo [ e ] in refluxing toluene][1，3]Oxazine-2, 4-diones and PCl₅Prepared) and 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide dihydrochloride. MS, M/z 438 ═ M + 1.

Example 19

N- (4-cyano-1-methyl-piperidin-4-yl) -2- (4-cyano-pyrimidin-2-ylamino) -3-cyclohexyl-propionamide (method C)

2-chloro-4-pyrimidinecarbonitrile (0.3mmol, Daves, g.d.jr., O' Brien, d.e., Cheng, c.c.j.het.chem, 1964, 1, 130) and 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide (0.7mmol) containing N, N-diisopropylethylamine (0.6mmol) were dissolved in acetonitrile (10 mL). The solution was heated to reflux for 17 hours. The volatiles were evaporated and the residue was purified by chromatography (silica gel, eluent EtOAc then MeOH). The methanol fraction was concentrated to a colorless solid, which was purified by chromatography (10% MeOH/EtOAc) to give the title compound as a colorless solid (52%). The material was recrystallized from dichloromethane/petroleum ether.

Example 20

N- (4-cyano-1-methyl-piperidin-4-yl) -2- (4-trifluoromethyl-pyrimidin-2-ylamino) -3-cyclohexyl-propionamide

The title compound was prepared according to the method of example 19 from 2-chloro-4-trifluoromethylpyrimidine and 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide. MS, M/z 439.5 ═ M + 1.

Example 21

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2 [ N-cyano-morpholine-4-iminomethyl (caxboximidyl)) -amino ] -propionamide (method D)

(a)2- (N-cyano-iminomethylene-amino) -N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide

A solution of diphenyl cyanocaminate (455mg, 1.91mmol), 2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide dihydrochloride (680mg, 1.86mmol) and N, N-diisopropylethylamine (482mg, 3.73mmol) in isopropanol (5.0mL) was stirred at room temperature overnight. The reaction mixture was then filtered to give the desired carbodiimide as a white powder (140mg, 22%). This material was used without further purification. 1H NMR (400MHz, CDCl 3). delta.0.80-1.00 (m, 2H), 1.05-1.20(m, 1H), 1.20-1.40(2H), 1.50-1.85(m, 8H), 2.32(s, 3H), 2.40-2.50(m, 2H), 2.55-2.70(m, 4H), 2.85-2.95(m, 2H), 4.10-4.20(m, 1H), 8.77(br s, 1H). MS, M/z 343 ═ M + 1.

(b)2- (N-cyano-aminobenzylidene-amino) -N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide A suspension of 2- (N-cyano-iminomethylene-amino) -N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide (120mg, 0.35mmol) in tetrahydrofuran (1mL) was treated with morpholine (4mL, 45.9 mmol). The reaction mixture was stirred at room temperature for 3 days, then concentrated to dryness. The residue was purified by HPLC using a 20X 250mm C18 reverse phase chromatography column from 20% acetonitrile in water to 90% acetonitrile in water. MS, M/z 430 ═ M + 1.

Example 22

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- { [ (diethyl-carbamoylimino) -morpholin-4-yl-methyl ] -amino } -propionamide (method D)

(a) N, N-diethylcarbamoylthiocyanate

A suspension of sodium thiocyanate (3.30g, 40.7mmol) in dry acetonitrile (25mL) was treated by dropwise addition of a solution of N, N-diethylcarbamoyl chloride (5.0g, 36.9mmol) in dry acetonitrile (15mL) at 80 ℃. The reaction mixture was stirred at 80 ℃ for 50 minutes, cooled to room temperature and then filtered through a fine glass frit. The filtrate was used as a 0.9M solution of N, N-diethylcarbamoylthiocyanate in acetonitrile.

(b) N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (3-diethylamino-carbonyl-thioureido) -propionamide

A solution of 2-amino-N- (-4-cyano-1-propyl-piperidin-4-yl) -3-cyclohexylpropionamide dihydrochloride (560mg, 1.53mmol) and triethylamine (500. mu.L, 3.59mmol) in acetonitrile (4mL) was treated with a solution of N, N-diethylcarbamoylthiocyanate in acetonitrile (3.0mL, 2.7 mmol). The reaction mixture was stirred at room temperature overnight and concentrated by rotary evaporator. The resulting residue was chromatographed (1: 1 ethyl acetate: hexane, then ethyl acetate, finally 1: 9 methanol: dichloromethane as eluent) to give the desired product as a pale yellow solid (340mg, 49%). MS, M/z 451.3 ═ M + 1.

The title compound was prepared by treating a solution of the resulting thiourea (340mg, 0.75mmol) and triethylamine (230 μ L, 1.65mmol) in dry acetonitrile (4mL) with mercury (II) chloride (225mg, 0.83mmol) and morpholine (200 μ L, 2.23 mmol). The reaction mixture was stirred at room temperature for 4 hours and then filtered through a 0.45 μm filter disk. The filtrate was filtered through a silica column (5% methanol/dichloromethane as eluent) and the crude product was further purified by HPLC using a 20X 250mm C18 reverse phase chromatography column from 20% acetonitrile in water to acetonitrile. MS, M/z 504.6 ═ M + 1.

The following examples were prepared in parallel according to method D:

example 23

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -pyrrolidin-1-yl-methyl } -carbamic acid ethyl ester. MS, M/z 461 ═ M + 1.

Example 24

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -piperidin-1-yl-methyl } -carbamic acid ethyl ester. MS, M/z 477 ═ M + 1.

Example 25

{ azepan-1-yl- [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -methylene } -carbamic acid ethyl ester. MS, M/z 490 ═ M + 1.

Example 26

{ azacyclooctan-1-yl- [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -methylene } -carbamic acid ethyl ester. MS, M/z 504 ═ M + 1.

Example 27

1- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -ethoxycarbonylimino-methyl } -piperidine-4-carboxylic acid ethyl ester. MS, M/z 548 ═ M + 1.

Example 28

1- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -ethoxycarbonylimino-methyl } -piperidine-3-carboxylic acid ethyl ester. MS, M/z 548 ═ M + 1.

Example 29

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] - (4-pyrrolidin-1-yl-piperidin-1-yl) -methylene ] -carbamic acid ethyl ester. MS, M/z 545. M + 1.

Example 30

{ [1, 4 '] bipiperidinyl-1' -yl- [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -methylene } -carbamic acid ethyl ester. MS, M/z 559 ═ M + 1.

Example 31

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] - (4-phenyl-piperazin-1-yl) -methylene ] -carbamic acid ethyl ester. MS, M/z 553 ═ M + 1.

Example 32

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] - (4-ethyl-piperazin-1-yl) -methylene ] -carbamic acid ethyl ester. MS, M/z 505 ═ M + 1.

Example 33

{ (4-acetyl-piperazin-1-yl) - [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -methylene } -carbamic acid ethyl ester. MS, M/z 519 ═ M + 1.

Example 34

4- { [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -ethoxycarbonylimino-methyl } -piperazine-1-carboxylic acid ethyl ester. MS, M/z 549 ═ M + 1.

Example 35

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] - (3, 3, 5-trimethyl-6-aza-bicyclo [3.2.1] octan-6-yl) -methylene ] -carbamic acid ethyl ester. MS, M/z 544 ═ M + 1.

Example 36

2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide

To a stirred solution of aluminum trichloride (7.13g, 53.5mmol) in nitromethane (40mL) at 0 deg.C was added isocyanatoethyl formate (3.5g, 26.8 mmol). The reaction was stirred at 0 ℃ for 1 hour and then at room temperature for 48 hours. The reaction mixture was then poured onto crushed ice and filtered to give 2.0g of an orange solid. The solid was dissolved in pyridine (20mL) and heated to reflux for 4 hours. The reaction was diluted with dichloromethane and washed with water. The organic fraction was dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The crude product was purified by flash column chromatography on silica, eluting with 25% EtOAc and hexanes, to give 0.27g of 7-fluoro-4-thioxo-3, 4-dihydrobenzo [ e ] ][1，3]Oxazin-2-one (5.1%). To a solution of the above intermediate (0.135g, 0.685mmol) and 2-amino-5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide (0.251g, 0.685mmol) in dry THF (10mL) was added diisopropylethylamine (0.36mL, 2.06mmol) and 2-chloro-1-methylpyridinium iodide (0.288g, 0.89 mmol). The reaction was stirred at room temperature for 48 hours. The solvent was distilled off and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated. The crude product was first purified by flash column chromatography on silica eluting with 10% MeOH in dichloromethane (0.25g, 79.8%). Final purification by HPLC gave the title compound,¹HNMR and MS were consistent with the desired product; MS: 458(M + 1).

Example 37

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dimethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide

To a solution of 4, 4-dimethylcyclohexanone (4.60g, 36.5mmol) in dry THF (82mL) cooled in a dry ice/acetone bath was added bis (trimethylsilyl) chlorideAlkyl) sodium amide (38mL of 1.0M solution in THF, 38 mmol). The reaction mixture was stirred at-78 ℃ for 30 minutes under argon atmosphere. A solution of 2- (N, N-bis (trifluoromethanesulfonyl) amino) -5-chloropyridine (15g, 37.7mmol) in dry THF (20mL) was introduced via syringe and the resulting solution was warmed to room temperature and stirred overnight. The reaction mixture was washed with half-saturated brine (60mL) and the aqueous phase was extracted with ether. The combined organic extracts were MgSO ₄Dried and concentrated to give a dark brown oil (23 g). Purification by silica gel chromatography with petroleum ether as eluent gave 4, 4-dimethyl-cyclohex-1-enyl trifluoromethanesulfonate as a colorless liquid (5.2g, 56%).¹H NMR(400MHz，CDCl₃)δ0.98(s，6H)，1.53(t，J＝6.5Hz，2H)，1.95-1.99(m，2H)，2.30-2.40(m，2H)，5.65-5.70(m，1H)。

The above trifluoromethanesulfonate (2.26g, 8.75mmol), Cbz dehydroalanine methyl ester (2.10g, 8.93mmol), Pd (OAc)₂A mixture of (160mg, 0.71mmol), and KOAc (3.42g, 34.8mmol) in dry DMF was stirred at room temperature for 24 h. The reaction mixture was diluted with water (400mL) and extracted with EtOAc (2X 150 mL). Drying (MgSO)₄) And the combined organic extracts were concentrated. The resulting residue was purified by column chromatography on silica gel using 1: 20 EtOAc/hexanes followed by 3: 17 EtOAc/hexanes as eluent to give 2-benzyloxycarbonylamino-3- (4, 4-dimethyl-cyclohex-1-enyl) -acrylic acid methyl ester as a yellow oil (1.38g, 46%).¹H NMR(400MHz，CDCl₃)δ0.88(s，6H)，1.34(t，J＝6.4Hz，2H)，1.95-2.00(m，2H)，2.23-2.30(m，2H)，3.74(s，3H)，5.15(s，2H)，5.90-6.10(m，1H)，6.10-6.15(m，1H)，7.0(s，1H)，7.25-7.36(m，5H)。m/z 382.4(MK⁺)。

A suspension of the above acrylate (2.18g, 6.35mmol), Boc anhydride (1.52g, 6.96mmol), and 10% Pd/C (300mg) in MeOH was shaken on a Parr apparatus under 40psi of hydrogen for 17 h. The reaction mixture was filtered through a plug of celite and concentrated to give methyl 2-tert-butoxycarbonylamino-3- (4, 4-dimethyl-cyclohexyl) -propionate as yellow A colored oil (1.87g, 94%).¹HNMR(400MHz，CDCl₃)δ0.85(s，3H)，0.88(s，3H)，1.05-1.20(m，5H)，1.21-1.40(m，2H)，1.44(s，9H)，1.45-1.59(m，m，2H)，1.60-1.78(m，2H)，3.72(broad s，3H)，4.27-4.40(m，1H)，4.82-4.96(m，1H)。

A suspension of the above methyl ester (1.87g, 5.97mmol) and lithium hydroxide monohydrate (1.76g, 41.9mmol) in THF (18mL), MeOH (6mL) and water (6mL) was stirred at room temperature for 4 h. The reaction mixture was acidified with 10% citric acid (aq) and extracted with ether (3 × 100 mL). Drying (MgSO)₄) And the combined organic layers were concentrated to give the corresponding carboxylic acid as a white foam (1.21g, 68%).¹H NMR(400MHz，DMSO-d₆)δ0.83(s，3H)，0.85(s，3H)，0.87-1.10(m，4H)，1.10-1.46(m，3H)，1.35(s，9H)，1.46-1.60(m，4H)，3.88-3.94(m，1H)，7.0(d，8.2Hz，1H)，11.7-12.9(b s，1H)。

Isobutyl chloroformate (0.55mL, 4.24mmol) was added dropwise to a solution of the above carboxylic acid (1.21g, 4.04mmol) and N-methylmorpholine (0.89mL, 8.10mmol) in dry THF, cooled to 0 deg.C. The reaction mixture was stirred at 0 ℃ for 1 hour. A solution of 4-amino-1-propyl-piperidine-4-carbonitrile (780mg, 4.65mmol) in dry THF (5mL) was added, and the reaction mixture was warmed to room temperature and stirred overnight. Volatiles were removed on a rotary evaporator and the resulting residue was dissolved in EtOAc (50mL) and saturated Na₂CO₃(50mL) washed. Drying (MgSO)₄) And the organic phase was concentrated. The crude product was purified by silica gel chromatography using a gradient of dichloromethane to 5% MeOH in dichloromethane as eluent to give [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2- (4, 4-dimethyl-cyclohexyl) -ethyl ]Tert-butyl carbamate, a white foam (1.17g, 65%).¹H NMR(400MHz，CDCl₃)δ0.85(s，3H)，0.88(s，3H)，0.89(t，J＝7.3Hz，3H)，1.05-1.30(m，6H)，1.30-1.40(m，2H)，1.45(s，9H)，1.40-1.60(m，5H)，1.70-1.83(m，1H)，1.87-2.02(m，2H)，2.32-2.54(m，6H)，2.68-2.90(m，2H)，4.00-4.10(m，1H)，4.80-5.00(m，1H)，6.70-6.90(m，1H)；m/z 449.5(M+H)⁺，447.4(M-H)^-。

The above tert-butyl ester (1.17g, 2.6mmol) was dissolved in a solution of HCl in 1, 4-dioxane (10.0mL of a 4.0M solution, 40mmol) and stirred under a flowing argon atmosphere for 10 minutes. The solution was concentrated on a rotary evaporator and dissolved in CHCl₃(50mL) and concentrated again to give amine dihydrochloride as a white powder (1.05g, 95%). M/z 349.5(M + H)⁺。

A suspension of 4-chlorobenzoxazin-2-one (500mg, 2.69mmol), the above amine salt (400mg, 0.95mmol), and polystyrene supported diisopropylamine (2.40g, 8.40mmol) in dry acetonitrile was heated at 50 ℃ for 5 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The resulting residue was purified by chromatography on silica gel using dichloromethane followed by 2.5% MeOH in dichloromethane and finally 10% MeOH in dichloromethane as eluent to give the title compound as a white solid (45mg, 10%).¹HNMR(400MHz，DMSO d₆)δ0.82(t，J＝7.5Hz，3H)，0.83(s，3H)，0.84(s，3H)，1.00-1.20(m，5H)，1.25-1.42(m，5H)，1.48-1.58(m，2H)，1.60-1.70(m，1H)，1.80-1.92(m，2H)，2.10-2.30(m，6H)，2.55-2.68(m，2H)，4.83-4.92(m，1H)，7.29(d，J＝8.3Hz，1H)，7.36(t，J＝7.7Hz，1H)，7.73(t，J＝7.3Hz，1H)，8.36(d，J＝8.1Hz，1H)，8.73(s，1H)，8.98-9.10(m，1H)；m/z＝494.5(M+H)⁺，492.4(M-H)^-。

Example 38

4, 4-dimethyl-2- (1-methyl-2-oxo-1, 2-dihydroquinazolin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide

A mixture of 4-chloro-1, 2-dihydro-2-oxo-quinazoline (1.0g, 5.5mmol), iodomethane (0.86mL, 2.5 equivalents) and potassium carbonate (1.91g, 2.5 equivalents.) in DMF (15mL) was heated at 80 ℃ for 90 minutes and then the solvent was removed under reduced pressure at 80 ℃. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated, and subjected to silica gel column chromatography (eluent: EtOAc) to give N-methyl analogue (0.21g, 19.5%).

A mixture of the above intermediate (100mg, 0.5mmol), 2-amino-4, 4-dimethylpentanoic acid (4-cyano-1-propyl-piperidin-4-yl) amide (151mg, 0.5mmol), Cu (powder, 66mg, 1mmol) and potassium carbonate (285mg, 2mmol) in NMP (3mL) was heated at 150 ℃ for 16 hours. After cooling to room temperature, it was filtered. The filtrate was diluted with water and extracted with dichloromethane. The organic phase was washed with brine, dried (sodium sulfate), concentrated and purified by silica gel chromatography to give the title compound (101mg, 44.6%); MS: 453(M + 1).

Example 39

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2, 2-dimethyl-propyl ester

To a solution of sodium thiocyanate (4.46g, 55mmol) in 50mL acetonitrile was added neopentyl chloroformate (6.15mL, 50 mmol). The mixture was heated at 80 ℃ for 2 hours. After cooling to room temperature, the solids were removed by filtration and the filtrate was used as a 1M stock solution of pivaloyl isothiocyanate.

2-amino-N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-propionamide dihydrochloride (6.33g, 17.32mmol) was suspended in 50mL of dichloromethane. Triethylamine (5.00mL, 35.9mL) was added. To this solution was added the above solution (20mL, 20mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour. Removing the solvent in vacuoAnd (3) preparing. The residue was purified by flash chromatography on silica gel with 5% MeOH in ether (R)_f0.2) to give thiourea (4.76g, 59%) as a yellow oil; MS: m +1 is 466.

The thiourea (4.67g, 10.0mmol) was dissolved in 30mL of THF. Copper sulfate on silica gel (4.00g, 10.0mmol) was added followed by 1mL triethylamine. The mixture was stirred at room temperature for 30 minutes. Morpholine (1.25mL, 20mmol) was added. The reaction mixture was heated to reflux for 2 hours. 4g of copper sulfate on silica gel and 1.25mL of morpholine were again added. The reaction mixture was heated for an additional 2 hours. After cooling to room temperature, the solid was removed by filtration and washed with acetonitrile. The filtrate was concentrated under reduced pressure and then purified by flash chromatography on silica, eluting with a mixture of diethyl ether, dichloromethane and MeOH (2: 1: 0.1) to give a yellow oil. The used material was crystallized from diethyl ether and hexane to give the title compound (1.81g, 35%) as a white solid; m +1 ═ 519.

Example 40

2-amino-4, 4, 5-trimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide dihydrochloride

Lithium diisopropylamide (1.5M solution in cyclohexane/THF/ethylbenzene) (113mL, 169mmol, 1.1 equiv.) was charged to a 1000mL round-bottom flask under argon. Dry THF (150mL) was added and the mixture was cooled to-78 ℃ with a dry ice/acetone bath. 3-methyl-butyric acid ethyl ester (20g, 23mL, 154mmol, 1.0 equiv.) was added dropwise over 10 minutes from syringe, followed by stirring at-78 deg.C for 1 hour. Methyl iodide (10.5mL, 169mmol, 1.1 equiv.) was added dropwise from syringe over 10 minutes and the creamy mixture was stirred at-78 ℃ for 1 hour to give a very viscous mixture. The dry ice bath was removed and replaced with an ice bath at 0 ℃. An additional 150mL of dry THF was added followed by additional LDA (113 mL)169mmol, 1.1 equiv). The resulting mixture was stirred for 10 minutes, and then the flask was again immersed in a dry ice/acetone bath. Stirring was continued for an additional 50 minutes, then methyl iodide (10.5mL, 169mmol, 1.1 equiv.) was added dropwise and the dry ice/acetone bath was removed and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with 3mL of concentrated HCl and 2N HCl was added until the pH was adjusted to < 1. The mixture was taken up in 150mL of water and 500mL of Et ₂And further diluting the O. The layers were separated and washed with 1X 100mL of 2N HCl, 1X 100mL of saturated NaHCO₃And 1X 200mL of brine. The organic layer is passed over Na₂SO₄Drying and then concentration in vacuo gave ethyl 2, 2, 3-trimethylbutyrate as an orange oil mixed with ethylbenzene (36.4g, 22.1g of which was the product according to NMR). The mixture was used without further purification.

A500 mL round bottom flask equipped with a stir bar was rinsed with Ar and charged with 50mL dry THF and 1MLAH of Et₂O solution (87.5mL, 87.5mmol, 0.625 equiv). The solution was cooled to 0 ℃ with an ice bath and the above ethyl ester (22.1g, 140mmol, 1.0 equiv) was added dropwise (about 50% solution in ethylbenzene) at such a rate that the solution did not reflux (50 minutes were required). After addition of ethyl ester, the reaction was stirred at 0 ℃ for 2 hours and then at ambient temperature for 14 hours. The reaction solution was again cooled to 0 ℃ and carefully quenched by addition of EtOAc. 1N NaOH was added until a granular precipitate (7.5mL) formed. The mixture was filtered through a pad of celite and then 3X 100mL of Et₂And O washing. The organics were combined and passed over Na₂SO₄Drying is carried out. The solution was decanted off and concentrated in vacuo to give 2, 2, 3-trimethyl-butanol as a nearly colorless oil (11.7g of alcohol in 15.4g of a mixture with ethylbenzene). The crude product was used without further purification.

A1000 mL round bottom flask was fitted with a stir bar, rinsed with Ar and added 300mL dry CH₂Cl₂And oxalyl chloride (13.2mL, 151mmol, 1.5 equivalents). The solution was cooled to-78 ℃ with a dry ice/acetone bath. Dried DMSO (21.5mL, 302mmol,3.0 equivalents) (vigorous gas evolution). The above alcohol (11.7g, 100mmol, 1.0 equiv) was added dropwise over 10 min (with residual ethylbenzene). The resulting solution was stirred for 90 minutes. Triethylamine (56mL, 403mmol, 4.0 equiv.) was added over 5 minutes and the cooling bath was removed. The resulting creamy white mixture was stirred at room temperature for 1.5 hours. The reaction mixture was carefully diluted with 200mL of water (more gas evolved). The layers were separated and the organic phase was washed with 1X 100mL of 2N HCl and 1X 100mL of brine. The organic phase is passed over Na₂SO₄Dried, decanted and concentrated in vacuo. The crude product was fractionated through a 4 inch VigoReux column at 57-67 deg.C and 15mm Hg to give 2, 2, 3-trimethyl-butyraldehyde (9.1g) as a colorless oil.

A clean and dry 250mL round bottom flask was fitted with a stir bar and rinsed with Ar. Dry THF (40mL) was added followed by a 1.0M solution of KO-t-Bu (32.2mL, 32.2mmol, 1.05 equiv). The solution was cooled to-78 ℃ in a dry ice/acetone bath. Ethylisocyanatoacetate (3.35mL, 30.7mmol, 1.0 equiv.) is added dropwise over 10 minutes. The resulting mixture was stirred for an additional 5 minutes, then 2, 2, 3-trimethyl-butyraldehyde (3.5g, 30.7mmol, 1.0 equiv.) was added via syringe. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by adding 125mLEt ₂O, 20g ice, 2mL AcOH. After the ice had melted, 50mL of water was added, the layers were mixed and separated. The organic layer was saturated with 1X 50mL NaHCO₃Washed and passed over Na₂SO₄And (5) drying. The organic layer was decanted and concentrated. The crude enamide was purified by flash chromatography on silica gel using CH₂Cl₂To 4% MeOH CH₂Cl₂Solution to give 2-formylamino-4, 4, 5-trimethyl-hex-2-enoic acid ethyl ester as a viscous oil (4.54 g); MS: 228(M + 1).

The above ethyl ester (4.54g, 20mmol, 1.0 equiv.) was dissolved in 35mL MeOH in a Parr bottle, then PtO was added₂(1g, 4.4mmol, 0.22 equiv.). The mixture was shaken on a Parr hydrogenation instrument for 4 days, during which MS showed consumption of starting material; MS: 230(M +1), 216 (M of the methyl ester)+1). Carefully decant the liquid and wash the Pt with 3 x 20mL of MeOH, after each wash, taking care not to dry the Pt (if it is allowed to dry, the Pt may catch fire). The MeOH solutions were combined and concentrated to a viscous oil, which was suspended in 25mL of 6N HCl, and the mixture was refluxed for 4 hours, during which 5mL of concentrated HCl was added at the end of the first 3 hours. The mixture was cooled and water and excess HCl were removed on a rotary evaporator at a bath temperature of 70 ℃. After concentration of about 50%, a crystalline solid formed in the form of a flake. The mixture was cooled to 0 ℃ and the precipitate was collected by filtration. The filtrate was again concentrated to about 50% and cooled again to 0 ℃ to give a second crop of crystals. The crystals were combined and dried under high vacuum to give 2-amino-4, 4, 5-trimethyl-hexanoic acid hydrochloride as a near white crystalline solid (2.32 g); MS: 174(M-Cl + 1).

NaOH the above amino acid salt (2.32g, 11.1mmol, 1.0 equiv.) was dissolved in 100mL of 50/50 bis. The solution was cooled to 0 ℃ and Boc anhydride (3.6g, 16.6mmol, 1.5 equiv.) was added. The cooling bath was removed and the reaction was stirred at ambient temperature for 16 hours. Carefully adjust the pH to 2 with concentrated HCl and 3X 100mL of CH₂Cl₂The product is extracted. Combine the organic layers and add Na₂SO₄And (5) drying. The solution was decanted and concentrated using 100mL of hexane as a chaser (chaser) to give a viscous glass which was triturated with 100mL of hexane. After vigorous stirring for 4 hours, the resulting waxy solid was collected by filtration and dried in air to give 2-tert-butoxycarbonylamino-4, 4, 5-trimethyl-hexanoic acid (1.42 g).

The carboxylic acid described above (0.400g, 1.46mmol, 1.0 equiv.) was dissolved in 15mL of THF and cooled to 0 deg.C. N-methylmorpholine (0.338mL, 3.07mmol, 2.1 equiv.) was added, followed by the dropwise addition of isobutyl chloroformate (0.19mL, 1.0 equiv.) over 1 minute. A white precipitate formed immediately. The mixture was stirred for 30 minutes during which time a solution of 4-amino-4-cyano-1-propyl-piperidine (0.257g, 1.54mmol, 1.05 eq.) in 5mL THF was added. The resulting mixture was stirred at room temperature for 16 hours. Volatiles were removed on a rotary evaporator and vigorous shaking with 100mL of water The resulting paste was triturated with stirring to give a fluffy white solid which was collected by filtration. The solid was washed with 100mL of water and dried under vacuum to give the desired product as an almost white powder (0.521 g); MS: 423(M + 1). The Boc protecting group was removed by treating the above solid with 20mL of 4N HCl in dioxane under Ar for 1 hour. The resulting paste was used 40mL Et₂O was diluted and the solid was filtered off under Ar. The resulting paste was used in 1X 25mL Et₂O wash and vacuum dry to give the title compound as the dihydrochloride salt; MS: 323(M + 1).

EXAMPLE 41

2-tert-Butoxycarbonylamino-5, 5-dimethyl-hexanoic acid

N- (benzyloxycarbonyl) - α -phosphonoglycine trimethyl ester (2g, 6.0mmol, 1.0 equiv.) was dissolved in dry THF (20 mL). Tertiary butyraldehyde (0.758mL, 6.0mmol, 1.0 equiv.) and DBU (0.903mL, 6.0mmol, 1.0 equiv.) were added and the reaction mixture was stirred for 16 h. The solution was taken up in 100mL of CH₂Cl₂Diluted and washed with 1X 50mL of water, and 1X 50mL of brine. The organic layer is passed over Na₂SO₄Dried, decanted and concentrated in vacuo to give 2-benzyloxycarbonylamino-5, 5-dimethyl-hex-2-enoic acid methyl ester as a viscous oil (1.73g, 94%) which was used without further purification; MS: 306(M + 1).

The above ester (1.73g, 5.67mmol, 1.0 equiv.) was dissolved in Boc anhydride (1.36g, 6.23mmol, 1.0 equiv.) and MeOH (35mL) in a Parr bottle. Pd-carbon (Degussa type) (0.5g) was added. The mixture was brought to 50psi H₂Shake for 16 hours. The mixture was filtered through celite, then the celite was washed with 3 × 50mL of MeOH. The organic phases were combined and concentrated to give methyl 2-tert-butoxycarbonylamino-5, 5-dimethyl-hexanoate as a very viscous oil without the need for further purificationFurther purifying for use.

The above ester (1.31g, 4.79mmol, 1.0 equiv.) was dissolved in 50mL of MeOH. 1NLiOH (50mL) was added and the mixture was stirred for 16 h. Concentrated HCl was carefully added until the pH was close to 2, during which a bright white solid precipitated. The solid was collected by filtration and washed with 2 × 20mL of water and dried under vacuum to give the title compound (1.05g, 85%); MS: 258 (M-1).

Method of therapeutic application

The mixtures of the invention are useful for inhibiting the activity of cathepsins S, K, F, L and B. In this case, the compounds are useful for blocking disease processes mediated by these cysteine proteases.

The compounds of the invention effectively block the degradation of invariant chain to CLIP by cathepsin S, thus inhibiting antigen presentation and antigen-specific immune responses. Control of antigen-specific immune responses is an attractive approach to the treatment of autoimmune diseases and other undesirable T-cell mediated immune responses. Thus, methods of treating such conditions using the compounds of the present invention are provided. These include autoimmune diseases and other diseases involving an immune response of inappropriate antigen specificity, including but not limited to rheumatoid arthritis, systemic lupus erythematosus, crohn's disease, ulcerative colitis, multiple sclerosis, guillain-barre syndrome, psoriasis, graves' disease, myasthenia gravis, scleroderma, glomerulonephritis, dermatitis including contact and atopic dermatitis, insulin dependent diabetes mellitus and asthma including allergic asthma. The compounds of the invention are also useful in the treatment of other disorders associated with extracellular proteolysis such as Alzheimer's disease and atherosclerosis. The compounds of the invention may also be used to treat other conditions not mentioned in the background of the invention above which are associated with inappropriate autoimmune responses, T-cell mediated immune responses or cathepsin S mediated extracellular proteolysis. Accordingly, the present invention also provides a method of modulating autoimmune disease comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of the present invention.

The compounds of the invention also inhibit cathepsin K. In this case, they can block the inappropriate degradation of collagen and other bone matrix proteases. Thus, methods of treating diseases that play an important role in these processes, such as osteoporosis, are provided. The inhibitory effect on cathepsins F, L and B is also included within the scope of the present invention due to the similarity of the active sites in the above mentioned cysteine proteases.

For therapeutic use, the compounds of the present invention may be administered in any conventional manner and in any conventional dosage form. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, infusion, sublingual, transdermal, oral, topical or inhalation. Preferred modes of administration are oral administration and intravenous administration.

The compounds of the present invention may be administered alone or, in some embodiments, in combination with adjuvants which enhance the stability of the inhibitor, to facilitate the administration of pharmaceutical compositions containing such compounds, to enhance solubility or dispersibility, to increase inhibitory activity, to provide adjunctive therapy, and the like, and in combination with other active ingredients. Advantageously, such combination therapy utilizes lower conventional therapeutic doses, thus avoiding toxicity and adverse side effects that may be incurred with these agents as monotherapeutic agents. The compounds of the present invention may in fact be combined with conventional therapeutic agents or other adjuvants in a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, a pharmaceutical composition comprising such a combination of compounds contains at least about 15%, more preferably at least about 20% of a compound of the present invention (w/w), or a combination thereof. Alternatively, the compounds may be administered separately (sequentially or in parallel). Single administration allows greater dosing flexibility.

As noted above, dosage forms of the compounds of the invention include those of ordinary skill in the artPharmaceutically acceptable carriers and adjuvants well known to the person. Such carriers and auxiliaries include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum albumin, buffer substances, water, salts or electrolytes and also substances based on cellulose. Preferred dosage forms include tablets, capsules, caplets, liquids, solutions, suspensions, emulsions, lozenges, syrups, re-dissolvable powders, granules, suppositories, and transdermal patches. Methods for preparing such dosage forms are known (see, e.g., h.c. ansel and n.g. popovish, Pharmaceutical dosage forms and Drug Delivery Systems, 5^thed, Lea and Febiger (1990)). Dosage levels and requirements are well known in the art and can be selected by one of ordinary skill in the art based on the methods and techniques appropriate for the particular patient. In some embodiments, the dose level ranges from about 10 to 1000mg per dose for a 70kg patient. Up to 5 doses per day may be administered, although one dose per day may be sufficient. For oral administration, up to 2000mg per day may be necessary. One skilled in the art will recognize that lower or higher dosages may be required depending on specific factors. For example, the specific dose and treatment regimen will depend on such factors as the general health of the patient, the severity and course of the patient's condition or the treatment thereof, and the judgment of the treating physician.

Evaluation of biological Properties

Expression and purification of recombinant human cathepsin S

Cloning of human cathepsin S:

the U937 RNA was subjected to reverse transcriptase/polymerase chain reaction with primer A (5 'cacaatgaaacggctggtttg 3') and primer B (5 'ctagatttctgggtaagaggg 3'), which was used to specifically amplify cathepsin S cDNA. The resulting 900bp DNA fragment was subcloned into pGEM-T (Promega) and sequenced to confirm its identity. This configuration is used for all subsequent operations. This is a typical method for cloning known genes and has been established in the art.

From the pGem-T vector (Promega, 2800Woods Hollow R_dMadison, Wis 53711) by digesting with the restriction enzyme SacII, treating with T4 DNA polymerase to obtain blunt ends, and digesting with a second restriction enzyme SalI. This fragment was subcloned into the pFastBacl donor plasmid (GibcoBRL, 8717 grovmont Cr., Gaithersburg, MD 20884) which had been cut with the restriction enzyme BamH1 and blunt-ended, and then cut with the restriction enzyme SalI. DH5a competent cells (GibcoBRL) were transformed with this ligation mixture and plated onto LB plates containing 100ug/ml ampicillin. The resulting colonies were cultured overnight on LB medium containing 50ug/ml ampicillin, plasmid DNA was isolated and the correct insert was confirmed by restriction enzyme digestion. The recombinant pFastBac donor plasmid was transformed into DH10Bac competent cells (GibcoBRL). Large white colonies were picked from LB plates containing 50ug/ml kanamycin, 7ug/ml gentamicin, 10ug/ml tetracycline, 100ug/ml Bluo-gal, and 40ug/ml IPTG. DNA was isolated and used to transfect Sf9 insect cells using CellFECTIN reagent (GibcoBRL). Cells and supernatant were harvested after 72 hours. Viral supernatants were passaged twice and the presence of Cat S was confirmed by PCR on the supernatants.

SF9 cells were infected with recombinant baculovirus at MOI 5 for 48-72 hours. Cells were lysed and incubated at 37 ℃ for 2 hours in pH 4.5 buffer to activate Cat S from the pro-form to the active mature form (Bromme, D)&McGR_ath，M.， Protein Science,1996,5: 789-791.). The presence of Cat S was confirmed by SDS-PAGE and Western blotting with rabbit anti-human Pro-Cat S.

Inhibition of cathepsin S:

human recombinant cathepsin S expressed in baculovirus was used in the buffer at a final concentration of 10 nM. The buffer was 50mM sodium acetate, pH 6.5, 2.5mM EDTA, 2.5mM TCEP. The enzyme was incubated with compound or DMSO at 37 ℃ for 10 minutes. The substrate 7-amino-4-methylcoumarin, CBZ-L-valyl-L-arginine amide (custom synthesis by Molecular Probes) was diluted to 20uM (final concentration of 5M) in water, added to the analyte and incubated at 37 ℃ for 10 min. The activity of the compounds was determined by reading the decrease in fluorescence from 360nm excitation and 460nm emission compared to DMSO control.

The examples listed above were used to evaluate the inhibition of cathepsin S in the above assay. All compounds had an IC of 100 micromolar or less₅₀The value is obtained.

Inhibition of cathepsins K, F, L and B:

The inhibitory activity of particular compounds of the present invention against these enzymes may be determined without undue experimentation using art-recognized methods provided in the following references, which are incorporated herein by reference:

cathepsin B and L are tested in the following references:

1.Methods in Enzymology，Vol.244，Proteolytic Enzymes：Serine andCysteine Peptidases，Alan J.Barrett，ed.

cathepsin K assays are described in the following references:

2.Bromme，D.，Okamoto，K.，Wang，B.B.，and Biroc，S.(1996)J.Biol.Chem.271，2126-2132.

cathepsin F was tested in the following references:

3.Wang，B.，Shi，G.P.，Yao，P.M.，Li，Z.，Chapman，H.A.，and Bromme，D.(1998)J.Biol.Chem.273，32000-32008.

4.Santamaria，I.，Velasco，G.，Pendas，A.M.，Paz，A.，and Lopez-Otin，C(1999)J.Biol.Chem.274，13800-13809.

in the above assay, preferred compounds for evaluating the inhibition of cathepsin K, F, L and B have an IC of 100 micromolar or less₅₀The value is obtained.

Claims (11)

1. A compound of formula (Ia):

wherein, for the moiety of formula (Ia),

independently selected from the group consisting of A1-A57 in the table below;

independently selected from the group consisting of B1-B12, B20-B40, B42-B49 in the table below;

independently selected from the group consisting of C1-C48 in the table below;

or a pharmaceutically acceptable salt thereof.

2. A compound selected from the group consisting of:

{ [1- (3-cyano-1-isobutyl-piperidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [ 1-3-cyano-1-methyl-piperidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3-methyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexylmethyl ester;

{ [ -1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclobutyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid allyl ester;

n- (4-cyano-1-propyl-piperidin-4-yl) -4-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3-cyclohexyl-propylamino ] -morpholin-4-yl-methylene } -carbamate;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydrofuran-3 ylmethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydrofuran-2-ylmethyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2, 2-dimethyl-propyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid isobutyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid propyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid hexyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid cyclobutylmethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3, 3, 3-trifluoro-propyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester;

5, 5-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -4, 4-dimethyl-pentylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester;

n- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (6-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide;

n- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide;

2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -5-methyl-hexylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester;

n- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide;

4, 4-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2-methoxymethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester;

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2, 6-dimethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester;

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2, 6-dimethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester;

4, 4-dimethyl-2- (6-methyl-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

2- (6-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2, 3-dihydro-1H-quinazolin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

2- (7-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

5-methyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (1-methyl-2-oxo-1, 2-dihydroquinazolin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3-cyclooctyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3-cycloheptyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cycloheptyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cyclooctyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester;

{ [1- (4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid isobutyl ester;

({1- [ 4-cyano-1- (2-morpholin-4-yl-ethyl) -piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester;

({1- [ 1-2-carbamoyl-ethyl) -4-cyano-piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester;

[ (1- { 4-cyano-1- [2- (2-methoxy-ethoxy) -ethyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate;

[ (1- { 4-cyano-1- [3- (2-methoxy-ethoxy) -propyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate;

{ [ 2-tert-butoxy-1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2- (3, 3, 5, 5-tetramethyl-cyclohexyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2- (4, 4-dipropyl-cyclohexyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-ethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

4-cyano-4- { 3-cyclohexyl-2- [ (ethoxycarbonylimino-morpholin-4-yl-methyl) -amino ] -propionylamino } -piperidine-1-carboxylic acid benzyl ester;

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-benzyl-4-cyano-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (4-fluoro-benzyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-ethyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-methyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-phenethyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (2, 2-dimethyl-propyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3-dimethyl-butyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-pentyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-butyl-4-cyano-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl) -amide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dimethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dipropyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3- (4-tert-butyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (3, 3, 5, 5-tetramethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

{ [1- (3-cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

2- [ (methylsulfonylimino-morpholin-4-yl-methyl) -amino ] -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

{ [1- (3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

({1- [ 3-cyano-1- (4, 4-dimethyl-cyclohexyl) -pyrrolidin-3-ylcarbamoyl ] -3, 3-dimethyl-butylamino } -morpholin-4-yl-methylene) -carbamic acid ethyl ester;

{ [1- (3-cyano-1-ethyl-5, 5-dimethyl-pyrrolidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

n- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (7, 8-difluoro-2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

{ [1- (4-cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

3-cyano-3- [4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoylamino ] -azepan-1-carboxylic acid benzyl ester;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (3-cyano-1-propyl-azepan-3-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-azepan-4-yl) -amide;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid 4-methoxy-cyclohexylmethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -phenyl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -phenyl-methylene } -carbamic acid ethyl ester;

2- { [ N- (4-cyano-phenyl) -morpholin-4-iminomethyl ] -amino } -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- { [ N- (4-trifluoromethyl-phenyl) -morpholin-4-iminomethyl ] -amino } -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide

Or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 selected from

{ [1- (3-cyano-1-isobutyl-piperidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexylmethyl ester;

{ [ -1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclobutyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid allyl ester;

n- (4-cyano-1-propyl-piperidin-4-yl) -4-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydrofuran-3 ylmethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydrofuran-2-ylmethyl ester;

N- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (6-fluoro-3-oxo-2, 3-dihydroisoindol-1-ylideneamino) -propionamide;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2, 2-dimethyl-propyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid isobutyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid propyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid hexyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid cyclobutylmethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3, 3, 3-trifluoro-propyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester;

5, 5-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester;

n- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (6-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide;

n- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide;

2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

n- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide;

4, 4-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2-methoxymethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester;

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2, 6-dimethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester;

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] - (2, 6-dimethyl-morpholin-4-yl) -methyl ] -carbamic acid ethyl ester;

4, 4-dimethyl-2- (6-methyl-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

2- (6-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2, 3-dihydro-1H-quinazolin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

2- (7-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

5-methyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (1-methyl-2-oxo-1, 2-dihydroquinazolin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3-cyclooctyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3-cycloheptyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cycloheptyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cyclooctyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester;

{ [1- (4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid isobutyl ester;

({1- [ 4-cyano-1- (2-morpholin-4-yl-ethyl) -piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester;

({1- [ 1-2-carbamoyl-ethyl) -4-cyano-piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester;

[ (1- { 4-cyano-1- [2- (2-methoxy-ethoxy) -ethyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate;

[ (1- { 4-cyano-1- [3- (2-methoxy-ethoxy) -propyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate;

{ [ 2-tert-butoxy-1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2- (3, 3, 5, 5-tetramethyl-cyclohexyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2- (4, 4-dipropyl-cyclohexyl) -ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-ethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

4-cyano-4- { 3-cyclohexyl-2- [ (ethoxycarbonylimino-morpholin-4-yl-methyl) -amino ] -propionylamino } -piperidine-1-carboxylic acid benzyl ester;

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-benzyl-4-cyano-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (4-fluoro-benzyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-ethyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-methyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-phenethyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (2, 2-dimethyl-propyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3-dimethyl-butyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-pentyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-butyl-4-cyano-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl) -amide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dimethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dipropyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4-tert-butyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3- (3, 3, 5, 5-tetramethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

{ [1- (3-cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

({1- [ 3-cyano-1- (4, 4-dimethyl-cyclohexyl) -pyrrolidin-3-ylcarbamoyl ] -3, 3-dimethyl-butylamino } -morpholin-4-yl-methylene) -carbamic acid ethyl ester;

n- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (7, 8-difluoro-2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

{ [1- (4-cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

3-cyano-3- [4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoylamino ] -azepan-1-carboxylic acid benzyl ester;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (3-cyano-1-propyl-azepan-3-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-azepan-4-yl) -amide;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid 4-methoxy-cyclohexylmethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -phenyl-methylene } -carbamic acid ethyl ester; or

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -phenyl-methylene } -carbamic acid ethyl ester.

4. The compound of claim 3 selected from the group consisting of:

{ [1- (4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexylmethyl ester;

{ [ -1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclobutyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid allyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydrofuran-3 ylmethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid tetrahydrofuran-2-ylmethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid methyl ester;

[ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2, 2-dimethyl-propyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid isobutyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid propyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid hexyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid cyclobutylmethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 3, 3, 3-trifluoro-propyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid 2-methoxy-ethyl ester;

5, 5-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

n- (4-cyano-1-methyl-piperidin-4-yl) -4-cyclohexyl-2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -butyramide;

2- (7-fluoro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -5, 5-dimethyl-hexanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

n- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide;

4, 4-dimethyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2, 3-dihydro-1H-quinazolin-4-ylideneamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

2- (7-chloro-2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -4, 4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (1-methyl-2-oxo-1, 2-dihydroquinazolin-4-ylamino) -pentanoic acid (4-cyano-1-propyl-piperidin-4-yl) -amide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3-cyclooctyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide;

n- (4-cyano-1-propyl-piperidin-4-yl) -3-cycloheptyl-2- (2-oxo-2, 3-dihydrobenzo [ e ] [1, 3] oxazin-4-ylideneamino) -propionamide;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cycloheptyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -2-cyclooctyl-ethylimino ] -morpholin-4-yl-methyl } -carbamic acid ethyl ester;

({1- [ 1-2-carbamoyl-ethyl) -4-cyano-piperidin-4-ylcarbamoyl ] -2-cyclohexyl-ethylamino } -morpholin-4-yl-methylene) -carbamic acid isobutyl ester;

[ (1- { 4-cyano-1- [2- (2-methoxy-ethoxy) -ethyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate;

[ (1- { 4-cyano-1- [3- (2-methoxy-ethoxy) -propyl ] -piperidin-4-ylcarbamoyl } -2-cyclohexyl-ethylamino) -morpholin-4-yl-methylene ] -isobutyl carbamate;

{ [1- (4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-ethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (1-benzyl-4-cyano-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-benzyl-4-cyano-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (4-fluoro-benzyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-ethyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-methyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-phenethyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (2, 2-dimethyl-propyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3-dimethyl-butyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-pentyl-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (1-butyl-4-cyano-piperidin-4-yl) -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid [ 4-cyano-1- (3, 3, 3-trifluoro-propyl) -piperidin-4-yl ] -amide;

4, 4-dimethyl-2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -pentanoic acid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl) -amide;

N- (4-cyano-1-propyl-piperidin-4-yl) -3- (4, 4-dimethyl-cyclohexyl) -2- (2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

{ [1- (3-cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

n- (4-cyano-1-methyl-piperidin-4-yl) -3-cyclohexyl-2- (7, 8-difluoro-2-oxo-2H-benzo [ e ] [1, 3] oxazin-4-ylamino) -propionamide;

{ [1- (4-cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid ethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid 4-methoxy-cyclohexylmethyl ester;

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -morpholin-4-yl-methylene } -carbamic acid cyclohexyl ester;

{ [1- (4-cyano-1-propyl-piperidin-4-ylcarbamoyl) -3, 3-dimethyl-butylamino ] -phenyl-methylene } -carbamic acid ethyl ester; or

{ [1- (4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -2-cyclohexyl-ethylamino ] -phenyl-methylene } -carbamic acid ethyl ester.

5. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1 or 2, said pharmaceutical composition being associated with cathepsin S inhibitory activity.

6. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for modulating autoimmune diseases, said use being associated with cathepsin S inhibitory activity.

7. The use of claim 6, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis, Guillain-Barre syndrome, psoriasis, Graves' disease, myasthenia gravis, scleroderma, glomerulonephritis, dermatitis, endometriosis or insulin-dependent diabetes.

8. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of alzheimer' S disease, said use being associated with cathepsin S inhibitory activity.

9. Use of a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of atherosclerosis, said use being associated with cathepsin S inhibitory activity.

10. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of osteoporosis, said use being associated with cathepsin S inhibitory activity.

11. Use of a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of asthma, said use being associated with cathepsin S inhibitory activity.