KINASE INHIBITORS FIELD OF THE INVENTION

The present invention relates to new kinase inhibitors, more specifically AGC kinases inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease.

BACKGROUND OF THE INVENTION

AGC-family protein kinases are named after their family members protein kinase A (PKA), protein kinase G (PKG), and protein kinase C (PKC).

One AGC-kinase family of interest is Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK), which is believed to be an effector of Ras-related small GTPase Rho. The Rho family consists of at least 10 members of small GTP binding proteins, including RhoA, B, C, D, E,

F, G, Rad , Rac2, Cdc42 and TC10. Two isoforms of ROCK are known: α (ROCKII) and β

(ROCKI). ROCKI shows highest expression levels in non-neuronal tissues, such as heart, lung and skeletal muscles; whereas ROCKII is preferentially expressed in brain (hippocampus, cortex and cerebellum).

The Rho/Rho-kinase mediated pathway plays an important role in the signal transduction pathway of many agonists such as angiotensin II, 5-HT, NA, thrombin, endothelin-1 , urotensin II, platelet- derived growth factor and ATP/ADP. Activation of ROCK leads to phosphorylation of various proteins: MLCP, MLC, LIMKs, CRMP2 and others. One of the main substrates is the myosin light chain MLC. Activation of MLC, together with the ROCK-induced inactivation of the MLCPhosphatase, leads to stimulation of actin-myosin interactions and subsequent cell contraction and stress fiber formation. ROCK also induces activation of LIMs resulting in an increase of actin filaments. Finally, ROCK activates the ERM protein complex and other proteins involved in cytoskeletal regulation. ROCK associates with and activates the IKK complex. ROCK inhibitors prevent the degradation of the IKK complex and subsequent NF-κB activation induced by MPS and TNF. As a consequence, ROCK inhibitors decrease NF-κB transcription stimulated by pro-inflammatory mediators. NF-κB is a ubiquitously expressed family of transcription factors controlling the expression of numerous genes involved in immunity and inflammation. Therefore ROCK inhibitors provide a useful therapy to treat auto-immune and inflammatory diseases.

In conclusion, ROCKs play an important role in various cellular functions: such as smooth muscle contraction, actin cytoskeleton organization, platelet activation, downregulation of myosin phosphatase cell adhesion, -migration, -proliferation and -survival, thrombin-induced responses of aortic smooth muscle cells, hypertrophy of cardiomyocytes, bronchial smooth muscle contraction, smooth muscle contraction and cytoskeletal reorganization of non- muscle cells, activation of volume- regulated anion channels, neurite retraction, neutrophil chemotaxis, wound healing and cell transformation and gene expression.

More specifically, ROCK has been implicated in various diseases and disorders including hypertension, cerebral vasospasm, coronary vasospasm, bronchial asthma, preterm labor, erectile dysfunction, glaucoma, vascular smooth muscle cell proliferation, myocardial hypertrophy, malignoma, ischemia/reperfusion-induced injury, endothelial dysfunction, Crohn's Disease and colitis, neurite outgrowth, Raynaud's Disease, angina, Alzheimer's disease, benign prostatic hyperplasia and atherosclerosis.

Accordingly, the development of inhibitors of ROCK would be useful as therapeutic agents for the treatment of disorders implicated in the ROCK pathway. Accordingly, there is a great need to develop inhibitors of ROCK that are useful in treating various diseases or conditions associated with ROCK activation, particularly given the inadequate treatments currently available for the majority of these disorders.

SUMMARY OF THE INVENTION

We have surprisingly found that the compounds described herein act as inhibitors of AGC-kinases and in particular of ROCK. These compounds and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of a variety of disorders, including allergic disorders such as asthma, cardiovascular diseases, vascular diseases, eye diseases, renal diseases, erectile dysfunction, inflammatory diseases, proliferative disorders; neurological disorders and diseases of the central nervous system (CNS), osteoporosis, renal diseases and AIDS. Viewed from a first aspect, the invention provides a compound of Formula I or Il or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof,

wherein: q is an integer selected from 0, 1 or 2, s is an integer selected from 1 or 2,

R ¹ is a group selected from aminoalkyl, alkylaminoalkyl, cycloalkyl, cycloalkylalkyl, aminocycloalkyl, aminocycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aminoheterocyclyl, aminoheterocyclylalkyl, each group being optionally substituted by one or more substituents selected from amino, hydroxyl, aryl, arylalkyl, alkyl, aminoalkyl, alkylamino, heteroaryl, heteroarylalkyl, halogen, haloalkyl, haloalkoxy, alkoxy, cycloalkyl, heterocyclyl,

R ² is selected from hydrogen or alkyl, said alkyl being optionally substituted with one or more substituents selected from amino, aryl, arylalkyl, alkyl, aminoalkyl, alkylamino, heteroaryl, heteroarylalkyl, halogen, haloalkyl, haloalkoxy, heterocyclyl, alkoxy, cycloalkyl,

Y is -C(R ³ )R ⁶ - or -NR ³ -, wherein R ³ is hydrogen or a group selected from alkyl, alkylcarbonyl, aryl, arylalkyl, haloarylalkyl, amino, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, each group being optionally substituted by one or more substituents selected from alkyl, aryl, halo, haloalkyl, haloalkoxy, amino, alkoxy, heteroaryl, heterocyclyl, cycloalkyl,

R ⁴ is selected from hydrogen, alkyl, alkoxy, cyano, nitro, halogen, R ⁵ is hydrogen ,

R ⁶ is selected from hydrogen or alkyl,

L in Formula I is -CR ⁹ R ¹⁰ - and L in Formula Il is selected from -CR ⁹ R ¹⁰ - Or -SO ₂ -,

R ⁷ is hydrogen or a group selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, or aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, or fused to said aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, or R ⁷ is -(C(R ⁹ )R ¹⁰ ) _p -C(=A)-N(R ¹¹ )R ¹² , wherein p is 0 or 1 , A is an oxygen or sulfur atom;

R ⁸ is hydrogen or a group selected from alkyl, aryl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, or R ⁷ and R ⁸ are fused together and form an alkylene or alkyleneaminoalkylene optionally substituted with one or more substituent selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino,

R ⁹ and R ¹⁰ are each independently selected from hydrogen or alkyl,

R ¹¹ and R ¹² are each independently hydrogen or a group selected from alkyl, alkenyl, alkenyl, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylsulfonylaminoalkyl, alkylsulfonylamino, alkylcarbonyl, formylamino, formylaminoalkyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkoxyl, alkoxyalkyl, cyanoalkyl, aryloxyaralkyl, aralkylheteroaryl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroarylarylalkyl, or fused to said cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,

heteroarylalkyl, or heteroarylarylalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituent selected from halo, oxo, hydroxyl, nitro, cyano, or a group selected from alkyl, alkoxy, amino, alkylamino, haloalkyl, haloalkoxy, alkenylaminooxy, alkylsulfonyl, sulfo, alkylsulfonylamino, alkylaminosulfonyl, alkylcarbonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylthio, arylalkenylaminooxy, arylalkylaminooxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, aryloxy, aryloxyaralkyl, arylamino, arylaminosulfonyl, arylcarbonyl, arylcarbonylamino, haloaryl, heteroaryl, heteroarylalkenylaminooxy, heteroarylalkyl, heteroarylaralkyl, heteroarylcarbonylamino, heteroarylalkylaminooxy, hydroxyalkyl, or fused to the cycloalkyl, aryl, heterocyclyl substituent or heteroaryl may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each of said group being optionally substituted by one or more further substituent selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, nitro, oxo, or sulfonyl, or R ¹¹ and R ¹² may together with the common nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring, said ring being optionally fused with one or more aryl, heteroaryl, cycloalkyl, or heterocyclyl ring, said ring or fused ring being optionally substituted with one or more substituent selected from halo, alkenylaminooxy, alkoxy, alkyl, alkylamino, alkylaminosulfonyl, alkylcarbonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylsulfonyl, alkylsulfonylamino, alkylthio, amino, aralkyl, aryl, arylalkenylaminooxy, arylamino, arylaminosulfonyl, arylcarbonyl, arylcarbonylamino, aryloxy, cyano, cycloalkyl, haloalkoxy, haloalkyl, haloaryl, heteroaryl, heteroarylcarbonyl, heteroarylalkenylaminooxy, heteroarylalkyl, heteroarylcarbonylamino, heterocyclyl, hydroxyalkyl, nitro, oxo, sulfonyl, or fused to the cycloalkyl, aryl, heterocyclyl or heteroaryl substituent may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each of said substituent being optionally substituted by one or more further substituent selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkyloxycarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, nitro, oxo, or sulfonyl, with the proviso that when L is SO ₂ in formula II, R ⁷ is not hydrogen or alkyl.

Viewed from a further aspect, the invention provides a pharmaceutical and/or veterinary composition comprising a compound of the invention.

Viewed from a still further aspect, the invention provides a compound of the invention for use in human or veterinary medicine.

Viewed from a still further aspect, the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of at least one disease and/or

disorder selected from the group comprising eye diseases; erectile dysfunction; cardiovascular diseases; vascular diseases; proliferative diseases; inflammatory diseases; neurological diseases and disease of the central nervous system (CNS); bronchial asthma; osteoporosis; renal diseases; and AIDS. Viewed from a still further aspect, the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of eyes diseases including macular degeneration, retinopathy and glaucoma, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.

Viewed from a still further aspect, the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of inflammatory diseases, such as contact dermatitis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.

Viewed from a still further aspect, the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of cardiovascular and vascular diseases: including but not limited to acute stroke, congestive heart failure, cardiovascular ischemia, heart disease, cardiac remodeling, angina, coronary vasospasm, cerebral vasospasm, restenosis, hypertension, (pulmonary) hypertension, arteriosclerosis, thrombosis (including deep thrombosis); pulmonary vasoconstriction, and platelet related diseases, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith and/or alleviating complications and/or symptoms associated therewith.

Viewed from a still further aspect, the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention, treatment and/or management of neurological and CNS disorders: including but not limited to stroke, multiple sclerosis, brain or spinal cord injury, inflammatory and demyelinating diseases such as Alzheimer ^' s disease, MS and neuropathic pain, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.

Viewed from a still further aspect, the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of proliferative diseases including but not limited to cancer of the brain (gliomas), breast, colon, intestine, skin, head and neck, kidney, lung, liver, ovarian, pancreatic, prostate or thyroid; leukemia; sarcoma; lymphoma; melanoma; and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.

Viewed from a still further aspect, the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of erectile dysfunction, bronchial asthma, osteoporosis, renal diseases and AIDS, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.

Viewed from a still further aspect, the invention provides the use of a compound of the invention, or a composition comprising such a compound, for inhibiting the activity of at least one kinase, in vitro or in vivo.

Viewed from a still further aspect, the invention provides the use of a compound of the invention, or a composition comprising such a compound, for inhibiting the activity of at least one ROCK kinase, for example ROCKII and/or ROCKI isoforms.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Unless a context dictates otherwise, asterisks are used herein to indicate the point at which a mono- or bivalent radical depicted is connected to the structure to which it relates and of which the radical forms part.

Undefined (racemic) asymmetric centers that may be present in the compounds of Formula I or Il are interchangeably indicated by drawing a wavy bonds or a straight bond in order to visualize the undefined steric character of the bond.

In an embodiment, the present invention provides a compound of Formula I or Il having one of the Formula III, IV, V, Vl, VII, VIII, IX, or X,

IX X wherein r is an integer selected from 1 , 2, 3, 4 or 5, p is an integer selected from 0, 1 or 2,

m is an integer selected from 0 or 1 ,

R ¹³ and R ¹⁴ are each independently selected from hydrogen, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, alkoxy, amino, aminoalkyl, alkylaminoalkyl, R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, haloalkyl,

R ¹⁷ is selected from hydrogen, hydroxyl, amino, aryl, arylalkyl, alkyl, aminoalkyl, alkylamino, heteroaryl, heteroarylalkyl, halogen, haloalkyl, haloalkoxy, alkoxy, cycloalkyl, heterocyclyl,

X and Z are each independently selected from -C(R ¹⁸ )R ¹⁹ - or -NR ¹⁸ -, wherein R ¹⁸ is hydrogen or a group selected from alkyl, alkylcarbonyl, aryl, arylalkyl, haloarylalkyl, amino, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, each group being optionally substituted by one or more substituents selected from alkyl, aryl, halo, haloalkyl, haloalkoxy, amino, alkoxy, heteroaryl, heterocyclyl, cycloalkyl, and R ¹⁹ is selected from hydrogen or alkyl, wherein R ² is selected from hydrogen or alkyl, said alkyl being optionally substituted with one or more substituents selected from amino, aryl, arylalkyl, alkyl, aminoalkyl, alkylamino, heteroaryl, heteroarylalkyl, halogen, haloalkyl, haloalkoxy, heterocyclyl, alkoxy, cycloalkyl,

R ³ is hydrogen or a group selected from alkyl, alkylcarbonyl, aryl, arylalkyl, haloarylalkyl, amino, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, each group being optionally substituted by one or more substituents selected from alkyl, aryl, halo, haloalkyl, haloalkoxy, amino, alkoxy, heteroaryl, heterocyclyl, cycloalkyl,

R ⁴ is selected from hydrogen, alkyl, alkoxy, cyano, nitro, halogen,

R ⁵ is hydrogen ,

R ⁶ is selected from hydrogen or alkyl, L in Formula III, IV, is -CR ⁹ R ¹⁰ - and L in Formula V, Vl, VII, VIII, IX, or X is selected from -CR ⁹ R ¹⁰ - or -SO ₂ -,

R ⁷ is hydrogen or a group selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, or aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, or fused to said aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, or R ⁷ is -(C(R ⁹ )R ¹⁰ ) _p -C(=A)-N(R ¹¹ )R ¹² , wherein p is 0 or 1 , A is an oxygen or sulfur atom;

R ⁸ is hydrogen or a group selected from alkyl, aryl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, or R ⁷ and R ⁸ are fused together and form an alkylene or alkyleneaminoalkylene optionally substituted with one or more substituent selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino,

R ⁹ and R ¹⁰ are each independently selected from hydrogen or alkyl,

R ¹¹ and R ¹² are each independently hydrogen or a group selected from alkyl, alkenyl, alkenyl, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylsulfonylaminoalkyl, alkylsulfonylamino, alkylcarbonyl, formylamino, formylaminoalkyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkoxyl, alkoxyalkyl, cyanoalkyl, aryloxyaralkyl, aralkylheteroaryl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroarylarylalkyl, or fused to said cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or heteroarylarylalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituent selected from halo, oxo, hydroxyl, nitro, cyano, or a group selected from alkyl, alkoxy, amino, alkylamino, haloalkyl, haloalkoxy, alkenylaminooxy, alkylsulfonyl, sulfo, alkylsulfonylamino, alkylaminosulfonyl, alkylcarbonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylthio, arylalkenylaminooxy, arylalkylaminooxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, aryloxy, aryloxyaralkyl, arylamino, arylaminosulfonyl, arylcarbonyl, arylcarbonylamino, haloaryl, heteroaryl, heteroarylalkenylaminooxy, heteroarylalkyl, heteroarylaralkyl, heteroarylcarbonylamino, heteroarylalkylaminooxy, hydroxyalkyl, or fused to the cycloalkyl, aryl, heterocyclyl substituent or heteroaryl may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each of said group being optionally substituted by one or more further substituent selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, nitro, oxo, or sulfonyl, or R ¹¹ and R ¹² may together with the common nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring, said ring being optionally fused with one or more aryl, heteroaryl, cycloalkyl, or heterocyclyl ring, said ring or fused ring being optionally substituted with one or more substituent selected from halo, alkenylaminooxy, alkoxy, alkyl, alkylamino, alkylaminosulfonyl, alkylcarbonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylsulfonyl, alkylsulfonylamino, alkylthio, amino, aralkyl, aryl, arylalkenylaminooxy, arylamino, arylaminosulfonyl, arylcarbonyl,

arylcarbonylamino, aryloxy, cyano, cycloalkyl, haloalkoxy, haloalkyl, haloaryl, heteroaryl, heteroarylcarbonyl, heteroarylalkenylaminooxy, heteroarylalkyl, heteroarylcarbonylamino, heterocyclyl, hydroxyalkyl, nitro, oxo, sulfonyl, or fused to the cycloalkyl, aryl, heterocyclyl or heteroaryl substituent may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each of said substituent being optionally substituted by one or more further substituent selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkyloxycarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, nitro, oxo, or sulfonyl, or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof, with the proviso that when L is SO ₂ in formula V, Vl, VII, VIII, IX, or X, R ⁷ is not hydrogen or alkyl.

In an embodiment, heterocyclyl is preferably selected from piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1- pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, , phthalazinyl, oxetanyl, thietanyl, 3-dioxolanyl, 1 ,4-dioxanyl, 2,5- dioximidazolidinyl, 2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, 6H-1 ,2,5-thiadiazinyl, 2H-1 ,5,2-dithiazinyl, 2H-oxocinyl, 1 H-pyrrolizinyl, tetrahydro-1 ,1-dioxothienyl, N- formylpiperazinyl, and morpholinyl, preferably, aryl is selected from phenyl, biphenylyl, biphenylenyl, tetralinyl, azulenyl, naphthyl, indenyl, anthryl, or pyrenyl, and preferably heteroaryl is selected from pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1 ,2-a]pyridinyl, benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl.

In an embodiment, the present invention provides a compound of Formula I or Il having one of the Formula III, IV, V, Vl, VII, VIII, IX, or X, r is an integer selected from 1 , 2, 3, 4 or 5, preferably 1 , 2 or 3, more preferably 1 or 2, p is an integer selected from 0, 1 or 2, preferably, 0 or 1 , m is an integer selected from 0 or 1 ,

R ¹³ and R ¹⁴ are each independently selected from hydrogen, hydroxyl, cyano, nitro, Ci _-6 alkyl, C ₂ . ₆ alkenyl, C ₂ - ₆ alkynyl, C ₆ -ioaryl, C ₆ -ioarylCi. ₄ alkyl, heterocyclyl, heterocyclyld-βalkyl, heteroaryl, heteroarylCi- ₄ alkyl, C ₃ . ₆ cycloalkyl, halo, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, Ci- ₆ alkoxy, amino, aminoCi_ ₆ alkyl, Ci. ₆ alkylaminoCi. ₆ alkyl, preferably R ¹³ and R ¹⁴ are each independently selected from hydrogen, hydroxyl, cyano, nitro, Ci_ ₆ alkyl, C ₆ -ioaryl, C ₆ -ioarylCi. ₄ alkyl, heterocyclyl, heterocyclyld-βalkyl, heteroaryl, heteroarylCi_ ₄ alkyl, C ₃ . ₆ cycloalkyl, C ₃ . ₆ cycloalkylCi. ₄ alkyl, halo, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, Ci_ ₆ alkoxy, amino, aminoCi_ ₆ alkyl, Ci. ₆ alkylaminoCi_ ₆ alkyl, more preferably, R ¹³ and R ¹⁴ are each independently selected from hydrogen, hydroxyl, cyano, nitro, Ci_ ₆ alkyl, C ₆ -ioaryl, halo, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, Ci_ ₆ alkoxy, amino, aminoCi. ₆ alkyl, Ci. ₆ alkylaminoCi. ₆ alkyl,

R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, d- ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . i _O aryl, C ₆ -ioarylCi_ ₄ alkyl, C ₃ . ₆ cycloalkyl, Cs-ecycloalkylCi-βalkyl, heteroaryl, heteroarylCi_ ₆ alkyl, heterocyclyl, heterocyclyld-βalkyl, haloCi_ ₆ alkyl, preferably R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, Ci_ ₆ alkyl, C ₆ -ioaryl, C ₆ -ioarylCi_ ₄ alkyl, C ₃ . ₆ cycloalkyl, Cs-ecycloalkylCi-βalkyl, heteroaryl, heteroarylCi_ ₆ alkyl, heterocyclyl, heterocyclylCi-βalkyl, haloCi_ ₆ alkyl, more preferably R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, Ci_ ₆ alkyl, C ₆ -ioaryl, C ₆ -ioarylCi_ ₄ alkyl, C ₃ . ₆ cycloalkyl, Cs-ecycloalkylCi-βalkyl, haloCi_ ₆ alkyl, yet more preferably R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, Ci_ ₆ alkyl, haloCi_ ₆ alkyl,

R ¹⁷ is selected from hydrogen, hydroxyl, amino, C ₆ -ioaryl, C ₆ -ioarylCi_ ₄ alkyl, d- ₆ alkyl, aminoCi. ₆ alkyl, Ci_ ₆ alkylamino, heteroaryl, heteroarylCi_ ₆ alkyl, halogen, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, Ci- ₆ alkoxy, C ₃ . ₆ cycloalkyl, heterocyclyl, preferably R ¹⁷ is selected from hydrogen, hydroxyl, amino, C ₆ - i _O aryl, C ₆ -ioarylCi_ ₄ alkyl, Ci_ ₆ alkyl, aminoCi_ ₆ alkyl, Ci_ ₆ alkylamino, halogen, haloCi_ ₆ alkyl, haloCi. ₆ alkoxy, Ci_ ₆ alkoxy, C ₃ . ₆ cycloalkyl, heterocyclyl, more preferably R ¹⁷ is selected from hydrogen, amino, C ₆ -ioarylCi_ ₄ alkyl, Ci_ ₆ alkyl, aminoCi_ ₆ alkyl, Ci_ ₆ alkylamino, halogen, haloCi_ ₆ alkyl, haloCi. ₆ alkoxy, Ci_ ₆ alkoxy,

X and Z are each independently selected from -C(R ¹⁸ )R ¹⁹ - or -NR ¹⁸ -, wherein R ¹⁸ is hydrogen or a group selected from d- ₆ alkyl, d- ₆ alkylcarbonyl, C ₆ -ioaryl, C ₆ -ioaryld- ₆ alkyl, haloC ₆ -ioarylCi. ₆ alkyl, amino, aminod. ₆ alkyl, C ₃ . ₆ cycloalkyl, Cs-ecycloalkyld-βalkyl, heterocyclyl, heterocyclyld-βalkyl, heteroaryl, heteroaryld_ ₆ alkyl, each group being optionally substituted by one or more substituents selected from d_ ₆ alkyl, C ₆ -ioaryl, halo, halod_ ₆ alkyl, halod_ ₆ alkoxy, amino, d_ ₆ alkoxy, heteroaryl, heterocyclyl, C ₃ . ₆ cycloalkyl, and R ¹⁹ is selected from hydrogen or d_ ₆ alkyl, preferably R ¹⁸ is hydrogen or a group selected from d_ ₆ alkyl, C ₆ -ioaryl, C ₆ -ioaryld- ₆ alkyl, haloC ₆ -ioaryld- ₆ alkyl, amino, aminod_ ₆ alkyl, C ₃ . ₆ cycloalkyl, Cs-ecycloalkyld-βalkyl, heterocyclyl, heterocyclyld-βalkyl, heteroaryl, heteroaryld_ ₆ alkyl, preferably R ¹⁸ is hydrogen or a group selected from d_ ₆ alkyl, aryl, arylCi- ₆ alkyl, haloaryld_ ₆ alkyl, amino, aminod_ ₆ alkyl, wherein R ² is selected from hydrogen or d_ ₆ alkyl, said d_ ₆ alkyl being optionally substituted with one or more substituents selected from amino, C ₆ -ioaryl, C ₆ -ioarylCi_ ₄ alkyl, d_ ₆ alkyl, aminod_ ₆ alkyl, Ci_ ₆ alkylamino, heteroaryl, heteroaryld_ ₆ alkyl, halogen, halod_ ₆ alkyl, halod_ ₆ alkoxy, heterocyclyl,

Ci- ₆ alkoxy, C ₃ . ₆ cycloalkyl, preferably R ² is selected from hydrogen or Ci_ ₆ alkyl, said Ci_ ₆ alkyl being optionally substituted with one or more substituents selected from amino, Ci _-6 alkyl, aminoCi_ ₆ alkyl, Ci_ ₆ alkylamino, halogen, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, more preferably R ² is selected from hydrogen or Ci_ ₆ alkyl, R ³ is hydrogen or a group selected from C-|. ₆ alkyl, C-|. ₆ alkylcarbonyl, C ₆ -ioaryl, C ₆ -ioarylC-|. ₄ alkyl, haloC ₆ -ioarylCi. ₄ alkyl, amino, aminoCi_ ₆ alkyl, C ₃ . ₆ cycloalkyl, C ₃ . ₆ cycloalkyld- ₄ alkyl, heterocyclyl, heterocyclylCi_ ₄ alkyl, heteroaryl, heteroarylCi_ ₄ alkyl, each group being optionally substituted by one or more substituents selected from Ci_ ₆ alkyl, C ₆ -ioaryl, halo, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, amino, Ci- ₆ alkoxy, heteroaryl, heterocyclyl, C ₃ . ₆ cycloalkyl, preferably R ³ is hydrogen or a group selected from Ci- ₆ alkyl, Ci_ ₆ alkylcarbonyl, C ₆ -ioaryl, C ₆ -ioarylCi. ₄ alkyl, haloC ₆ -ioarylCi_ ₄ alkyl, amino, aminoC-i- ₆ alkyl, C ₃ . ₆ cycloalkyl, d-ecycloalkyld^alkyl, each group being optionally substituted by one or more substituents selected from Ci_ ₆ alkyl, C ₆ -ioaryl, halo, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, preferably R ³ is hydrogen or a group selected from C-|. ₆ alkyl, C-|. ₆ alkylcarbonyl, C ₆ -ioaryl, C ₆ -ioarylC-|. ₄ alkyl, haloC ₆ - ₁₀ arylC"i- ₄ alkyl, amino, aminoC-|. ₆ alkyl, each group being optionally substituted by one or more substituents selected from C-|. ₆ alkyl, C ₆ -ioaryl, halo, haloC-|. ₆ alkyl, haloC-|. ₆ alkoxy,,

R ⁴ is selected from hydrogen, C-|. ₆ alkyl, C-|. ₆ alkoxy, cyano, nitro, halogen, preferably R ⁴ is selected from hydrogen, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, more preferably R ⁴ is hydrogen,

R ⁵ is hydrogen,

R ⁶ is selected from hydrogen or C-|. ₆ alkyl, L in Formula III or IV is -CR ⁹ R ¹⁰ - and L in Formula V, Vl, VII, VIII, IX, or X is selected from - CR ⁹ R ¹⁰ - or -SO ₂ -,

R ⁷ is hydrogen or a group selected from Ci_ ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, hydroxyCi_ ₆ alkyl, Ci- ₆ alkoxy, Ci. ₆ alkoxyCi. ₆ alkyl, hydroxyl, Ci_ ₆ alkyloxycarbonyl, carboxyl, aminoCi_ ₆ alkyl, amino, C ₆ - i _O aryl, C ₆ -ioarylCi_ ₄ alkyl, heteroaryl, heteroarylCi_ ₄ alkyl, heterocyclyl, heterocyclylCi_ ₄ alkyl, C ₃ . ₆ cycloalkyl, or Cs-ecycloalkyld-βalkyl, or fused to said C ₆ -ioaryl, arylCi_ ₄ alkyl, heteroaryl, heteroarylCi- ₄ alkyl, heterocyclyl, heterocyclylCi_ ₄ alkyl, C ₃ . ₆ cycloalkyl, or C ₃ . ₆ cycloalkylCi_ ₄ alkyl, group may be one or more C ₃ . ₆ cycloalkyl, C ₆ -ioaryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituents selected from hydroxyl, Ci_ ₆ alkoxy, Ci_ ₆ alkyl, amino, cyano, nitro, halo, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, Ci_ ₆ alkylamino, preferably R ⁷ is hydrogen or a group selected from d- ₆ alkyl, hydroxyd- ₆ alkyl, d- ₆ alkoxy, d. ₆ alkoxyd. ₆ alkyl, hydroxyl, Ci- ₆ alkyloxycarbonyl, carboxyl, aminod. ₆ alkyl, amino, C ₆ -ioaryl, C ₆ -ioaryld. ₄ alkyl, heteroaryl, heteroarylCi_ ₄ alkyl, heterocyclyl, heterocyclylCi. ₄ alkyl, C ₃ . ₆ cycloalkyl, or Cs-ecycloalkyld-βalkyl, or fused to said C ₆ -ioaryl, arylCi. ₄ alkyl, heteroaryl, heteroarylCi. ₄ alkyl, heterocyclyl, heterocyclylCi. ₄ alkyl, C ₃ . ₆ cycloalkyl, or C ₃ . ₆ cycloalkyld. ₄ alkyl, group may be one or more C ₃ . ₆ cycloalkyl, C ₆ -ioaryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituents selected from hydroxyl, d_ ₆ alkoxy, d_ ₆ alkyl, amino, cyano, nitro, halo, halod_ ₆ alkyl, haloCi. ₆ alkoxy, d_ ₆ alkylamino,

or R ⁷ is -(C(R ⁹ )R ¹⁰ ) _p -C(=A)-N(R ¹¹ )R ¹² , wherein p is 0 or 1 , A is an oxygen or sulfur atom;

R ⁸ is hydrogen or a group selected from C-|. ₆ alkyl, C ₆ -ic>aryl, hydroxyC-|. ₆ alkyl, C-|. ₆ alkoxy, C ₁ . ₆ alkoxyC-|. ₆ alkyl, hydroxyl, C-|. ₆ alkyloxycarbonyl, carboxyl, aminoC-|. ₆ alkyl, amino, heteroaryl, C ₆ - -ιoarylC-|. ₆ alkyl, heteroarylC-|. ₆ alkyl, C ₃ . ₆ cycloalkyl, d-ecycloalkyld-ealkyl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, Ci_ ₆ alkyl, amino, cyano, nitro, halo, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, Ci_ ₆ alkylamino, or R ⁷ and R ⁸ are fused together and form an Ci_ ₆ alkylene or Ci- ₆ alkyleneaminoCi. ₆ alkylene optionally substituted with one or more substituent selected from hydroxyl, C-|. ₆ alkoxy, C-|. ₆ alkyl, amino, cyano, nitro, halo, haloC-|. ₆ alkyl, haloC-|. ₆ alkoxy, C-|. ₆ alkylamino, R ⁹ and R ¹⁰ are each independently selected from hydrogen or C-|. ₆ alkyl,

R ¹¹ and R ¹² are each independently hydrogen or a group selected from C-|. ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ - ₆ alkenyl, amino, aminoC-|. ₆ alkyl, C-|. ₆ alkylamino, C-|. ₆ alkylaminoC-|. ₆ alkyl, d- ₆ alkylsulfonylanninod- ₆ alkyl, Ci_ ₆ alkylsulfonylamino, Ci_ ₆ alkylcarbonyl, formylamino, formylaminoCi. ₆ alkyl, Ci- ₆ alkylcarbonylamino, d-ealkylcarbonylaminod-ealkyl, Ci_ ₆ alkoxyl, Ci. ₆ alkoxyCi. ₆ alkyl, cyanoCi. ₆ alkyl, Ce-ioaryloxyCe-ioaryld-βalkyl, Ce-ioaryld-βalkylheteroaryl, hydroxyd- ₆ alkyl, C ₃ . ₆ cycloalkyl, C ₃ . ecycloalkylCi-βalkyl, C ₆ -ioaryl, C ₆ -ioarylCi. ₆ alkyl, heterocyclyl, heterocyclyld-βalkyl, heteroaryl, heteroarylCi_ ₆ alkyl, heteroarylCe-ioaryld-βalkyl, or fused to said C ₃ . ₆ cycloalkyl, C ₃ . ₆ cycloalkylCi_ ₆ alkyl, C ₆ -ioaryl, C ₆ -ioarylCi. ₆ alkyl, heterocyclyl, heterocyclyld-βalkyl, heteroaryl, heteroarylCi_ ₆ alkyl, or heteroarylCe-ioarylCi-βalkyl group may be one or more C ₃ . ₆ cycloalkyl, C ₆ -ioaryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituent selected from halo, oxo, hydroxyl, nitro, cyano, or a group selected from d- ₆ alkyl, d- ₆ alkoxy, amino, Ci- ₆ alkylamino, halod_ ₆ alkyl, halod_ ₆ alkoxy, C ₂ - ₆ alkenylaminooxy, d_ ₆ alkylsulfonyl, sulfo, Ci- ₆ alkylsulfonylamino, d_ ₆ alkylaminosulfonyl, d_ ₆ alkylcarbonyl, d_ ₆ alkylcarbonylamino, Ci- ₆ alkyloxyaminoC ₂ . ₆ alkenyl, d_ ₆ alkyloxycarbonyl, d_ ₆ alkylthio, C ₆ -ioarylC ₂ .

₆ alkenylaminooxy, C ₆ -ioaryld- ₆ alkylanninooxy, C ₃ . ₆ cycloalkyl, Cs-ecycloalkyld-βalkyl, heterocyclyl, C ₆ -ioaryl, C ₆ -ioarylCi. ₆ alkyl, C ₆ -ioaryloxy, Ce-ioaryloxyCe-ioaryld-βalkyl, C ₆ . i ₀ arylamino, C ₆ -ioarylaminosulfonyl, C ₆ -ioarylcarbonyl, C ₆ -ioarylcarbonylamino, haloC ₆ . i _O aryl, heteroaryl, heteroarylC ₂ . ₆ alkenylaminooxy, heteroaryld_ ₆ alkyl, heteroarylC ₆ -ic>aryld- ₆ alkyl, heteroarylcarbonylamino, heteroaryld_ ₆ alkylaminooxy, hydroxyd_ ₆ alkyl, or fused to the C ₃ . ₆ cycloalkyl, C ₆ -ioaryl, heterocyclyl substituent or heteroaryl may be one or more C ₃ . ₆ cycloalkyl, C ₆ -ioaryl, heterocyclyl or heteroaryl, each of said group being optionally substituted by one or more further substituent selected from halo, d_ ₆ alkoxy, d_ ₆ alkyl, d_ ₆ alkylamino, d_ ₆ alkylcarbonyl, Ci- ₆ alkyl heteroaryl, d_ ₆ alkylsulfonyl, C ₆ -ioarylCi. ₆ alkyl, C ₆ -ioaryl, C ₆ -ioarylamino, C ₆ -ioaryloxy, cyano, halod_ ₆ alkoxy, halod_ ₆ alkyl, heteroaryl, heteroaryld_ ₆ alkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, nitro, oxo, or sulfonyl,

or R ¹¹ and R ¹² may together with the common nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring, said ring being optionally fused with one or more C ₆ -ioaryl, heteroaryl, C ₃ . ₈ cycloalkyl, or heterocyclyl ring, said ring or fused ring being optionally substituted with one or more substituent selected from halo, C ₂ - ₆ alkenylaminooxy, Ci_ ₆ alkoxy, Ci_ ₆ alkyl, Ci_ ₆ alkylamino, Ci_ ₆ alkylaminosulfonyl, Ci- _{6 alkylcarbonyl, Ci_ 6 alkylcarbonylamino, Ci. 6 alkyloxyaminoC 2 - 6 alkenyl, d- 6 alkyloxycarbonyl, Ci- 6 alkylsulfonyl, Ci_ 6 alkylsulfonylamino, Ci_ 6 alkylthio, amino, C 6 -ioarylCi. 6 alkyl, C 6 -ioaryl, C 6 . i 0 arylC 2 - 6 alkenylaminooxy, C 6 -ioarylamino, C 6 -ioarylaminosulfonyl, C 6 -ioarylcarbonyl, C 6 . i 0 arylcarbonylamino, C 6 -ioaryloxy, cyano, cycloalkyl, haloCi_ 6 alkoxy, haloCi_ 6 alkyl, haloaryl, heteroaryl, heteroarylcarbonyl, heteroarylC 2 - 6 alkenylaminooxy, heteroarylCi_ 6 alkyl, heteroarylcarbonylamino, heterocyclyl, hydroxyd- 6 alkyl, nitro, oxo, sulfonyl, or fused to the C 3 . scycloalkyl, aryl, heterocyclyl or heteroaryl substituent may be one or more cycloalkyl, C 6 -ioaryl, heterocyclyl or heteroaryl, each of said substituent being optionally substituted by one or more further substituent selected from halo, Ci_ 6 alkoxy, Ci_ 6 alkyl, Ci_ 6 alkylamino, Ci_ 6 alkylcarbonyl, Ci- 6 alkyloxycarbonyl, Ci_ 6 alkyl heteroaryl, Ci_ 6 alkylsulfonyl, C 6 -ioarylCi. 6 alkyl, C 6 -ioaryl, arylamino, aryloxy, cyano, haloCi_ 6 alkoxy, haloCi_ 6 alkyl, heteroaryl, heteroarylCi_ 6 alkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, nitro, oxo, or sulfonyl, or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof, with the proviso that when L is SO 2 in formula V, Vl, VII, VIII, IX, or X, R ⁷ is not hydrogen or Ci- 6 alkyl.}

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise:

The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C _n H _2n+I wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 20 carbon atoms, more preferably from 1 to 10 carbon atoms, still more preferably 1 to 8 carbon atoms, in particular 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, d- ₄ alkyl means an alkyl of one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers; decyl and its isomers. CrC ₆ alkyl includes all linear, branched alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, and hexyl and its isomers.

The term "optionally substituted alkyl" refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, or example 1 , 2, 3 or 4 substituents or 1 to 2 substituents) at any available point of attachment. Non-limiting examples of such substituents

include halogen, hydroxyl, carbonyl, nitro, amino, oximes, imines, azido, hydrazino, cyano, alkyl, aryl, heteroaryl, cycloalkyl, acyl, alkylamino, alkoxy, thio, alkylthio, carboxylic acid, acylamino, alkyl esters, carbamates, thioamides, urea, sulfonamides and the like.

When the term "alkyl" is used as a suffix following another term, as in "hydroxyalkyl," this is intended to refer to an alkyl group, as defined above, being substituted with one or two (preferably one) substituent(s) selected from the other, specifically-named group, also as defined herein. The term "hydroxyalkyl" refers to a -R ^a -OH group wherein R ^a is alkylene as defined herein. For example, "hydroxyalkyl" includes 2-hydroxyethyl, 1-(hydroxymethyl)-2-methylpropyl, 3,4- dihydroxybutyl, and so forth. "Alkoxyalkyl" refers to an alkyl group substituted with one to two of OR', wherein R' is alkyl as defined below. For example, "aralkyl" or "arylalkyl" refers to a substituted alkyl group as defined above wherein at least one of the alkyl substituents is an aryl as defined below, such as benzyl. For example, "heteroarylalkyl" refers to a substituted alkyl group as defined above wherein at least one of the alkyl substituents is a heteroaryl as defined below, such as pyridinyl. The term "cycloalkyl group" as used herein is a cyclic alkyl group, that is to say, a monovalent, hydrocarbyl group having 1 , 2 or 3 cyclic structure. Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic or polycyclic alkyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. The further rings of multi- ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro atoms. Cycloalkyl groups may also be considered to be a subset of homocyclic rings discussed hereinafter. Examples of cycloalkyl groups, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl with cyclopropyl being particularly preferred. An "optionally substituted cycloalkyl" refers to a cycloalkyl having optionally one or more substituents (for example 1 to 3 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl. When the suffix "ene" is used in conjunction with a cyclic group, this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups. Where alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed "alkylene" groups. Non-limiting examples of alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1 ,2- dimethylethylene, pentamethylene and hexamethylene. Similarly, where alkenyl groups as defined above and alkynyl groups as defined above, respectively, are divalent radicals having single bonds for attachment to two other groups, they are termed "alkenylene" and "alkynylene" respectively.

Generally, alkylene groups of this invention preferably comprise the same number of carbon atoms as their alkyl counterparts. "Cycloalkylene" herein refers to a saturated homocyclic hydrocarbyl biradical of Formula C _n H _2n - ₂ - Cycloalkylene groups of this invention preferably comprise the same

number of carbon atoms as their cycloalkyl radical counterparts. Where an alkylene or cycloalkylene biradical is present, connectivity to the molecular structure of which it forms part may be through a common carbon atom or different carbon atom, preferably a common carbon atom. To illustrate this applying the asterisk nomenclature of this invention, a C ₃ alkylene group may be for example ^CH ₂ CH ₂ CH ₂ -*, *-CH(-CH ₂ CH ₃ )-* or *-CH ₂ CH(-CH ₃ )-*. Likewise a C ₃ cycloalkylene group may be

Where a cycloalkylene group is present, this is preferably a C ₃ -C ₆ cycloalkylene group, more preferably a C ₃ cycloalkylene ( i.e. cyclopropylene group) wherein its connectivity to the structure of which it forms part is through a common carbon atom. Cycloalkylene and alkylene biradicals in compounds of the invention may be, but preferably are not, substituted.

The term "alkenyl" as used herein refers to an unsaturated hydrocarbyl group, which may be linear, branched or cyclic, comprising one or more carbon-carbon double bonds. Alkenyl groups thus comprise two or more carbon atoms, preferably between 2 and 20 carbon atoms, more preferably between 2 and 10 carbon atoms, still more preferably between 2 and 8 carbon atoms, for example, between 2 and 6 carbon atoms. Similarly to cycloalkyl groups, cycloalkenyl groups may be considered to be a subset of homocyclic rings discussed hereinafter. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2-heptenyl and its isomers, 2-octenyl and its isomers, 2,4-pentadienyl and the like. An optionally substituted alkenyl refers to an alkenyl having optionally one or more substituents (for example 1 , 2 or 3 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl. Similarly to cycloalkyl groups, cycloalkenyl groups may be considered to be a subset of homocyclic rings discussed hereinafter.

The term "alkynyl" as used herein, similarly to alkenyl, refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon- carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkenyl groups. Examples alkynyl groups are ethynyl, 2- propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers, 2-heptynyl and its isomers, 2-octynyl and its isomers and the like. An optionally substituted alkynyl refers to an alkynyl having optionally one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl. Similarly to cycloalkyl groups, cycloalkynyl groups may be considered to be a subset of homocyclic rings discussed hereinafter.

The term "homocyclic ring" as used herein is a ring wherein the ring atoms comprise only carbon atoms. Examples of homocyclic rings thus include cycloalkyl, cycloalkenyl and cycloalkynyl, with cycloalkyl and cycloalkenyl being preferred. Where a ring carbon atom is replaced with a heteroatom, preferably nitrogen, oxygen of sulfur, the heteroatom-containing ring resultant from

such a replacement is referred to herein as a heterocyclic ring. More than one carbon atom in a ring may be replaced so forming heterocyclic ring having a plurality of heteroatoms.

The terms "heterocyclyl" or "heterocyclo" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom- containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. An optionally substituted heterocyclic refers to a heterocyclic having optionally one or more substituents (for example 1 to 4 substituents, or for example 1 , 2, 3 or 4), selected from those defined above for substituted aryl. Exemplary heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H- indolyl, indolinyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro- 2H-pyranyl, phthalazinyl, oxetanyl, thietanyl, 3-dioxolanyl, 1 ,4-dioxanyl, 2,5-dioximidazolidinyl, 2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, 6H-1 ,2,5-thiadiazinyl, 2H-1 ,5,2-dithiazinyl, 2H-oxocinyl, 1 H-pyrrolizinyl, tetrahydro- 1 ,1-dioxothienyl, N- formylpiperazinyl, and morpholinyl.

The term "aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthalene or anthracene) or linked covalently, typically containing 5 to 8 atoms; wherein at least one ring is aromatic. The aromatic ring may optionally include one to three additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1-, 2-, 3-, A-, 5-, 6-, 7- or 8-azulenyl, 1- or 2-naphthyl, 1-, 2- or 3-indenyl, 1-, 2- or 9-anthryl, 1- 2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1-, 2-, 3-, 4- or 10-phenanthryl, 1- or 2-pentalenyl, 1 , 2-, 3- or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8- tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, dibenzo[a,d]cylcoheptenyl, 1-, 2-, 3-, 4- or 5-pyrenyl.

The aryl ring can optionally be substituted by one or more aromatic substituents. An "optionally substituted aryl" refers to an aryl having optionally one or more substituents (for example 1 to 5

substituents, or 1 to 2 substituents) at any available point of attachment. Non-limiting examples of such substituents are selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, - SO ₂ -NH ₂ , aryl, heteroaryl, arylalkyl, haloalkyl, haloalkoxy, alkyloxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -SO ₂ R ¹⁵ , alkylthio, carboxy, and the like, wherein R ¹⁵ is alkyl or cycloalkyl.

The term "arylene" as used herein is intended to include divalent carbocyclic aromatic ring systems such as phenylene, biphenylylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, pentalenylene, azulenylene and the like. Arylene is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthylene, 1 ,4- dihydronaphthylene and the like.

Where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.

The term "heteroaryl" as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 3 rings which are fused together or linked covalently, typically containing 5 to 8 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by oxygen, nitrogen or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of a heterocyclyl include: pyrrolyl, furanyl (or furyl), thiophenyl (or thienyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1 ,3- benzothiazolyl, 1 ,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1 ,2-a]pyridinyl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

In particular, non-limiting examples of heteroaryl can be 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3- pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-thiazolyl, 1 ,2,3-triazol-1-, -2-, -4- or -5-yl, 1 ,2,4-triazol-1-, -3-, -A- or -5-yl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-thiadiazol-4- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl, 1 ,2,5-thiadiazol-3- or -4-yl, 1 ,3,4-thiadiazolyl, 1- or 5-tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, A-, 5- or 6-pyrimidinyl, 2-, 3-, A-, 5- 6-2H-

thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 2-, 3-, A-, 5-, 6- or 7-benzofuryl, 1-, 3-, 4- or 5-isobenzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 3-, 4- or 5-isobenzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2- or 3-pyrazinyl, 1 ,4-oxazin-2- or -3-yl, 1 ,4-dioxin-2- or -3-yl, 1 ,4-thiazin-2- or -3-yl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazin-2-, -4- or -6-yl, thieno[2,3-b]furan-2-, -3-, -4-, or -5-yl, 1-, 2-, 4- or 5- benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 3-, A-, 5-, 6- or 7-benzisoxazolyl, 2-, A-, 5-, 6- or 7-benzoxazolyl, 3-, A-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2- thianthrenyl, 3-, 4- or 5-isobenzofuranyl, 1-, 2-, 3-, 4- or 9-xanthenyl, 1-, 2-, 3- or 4-phenoxathiinyl, 2-, 3-pyrazinyl, 1-, 2-, 3-, A-, 5-, 6-, 7- or 8-indolizinyl, 2-, 3-, 4- or 5-isoindolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 6-, 7- or 8-purinyl, 4-, 5- or 6-phthalazinyl, 2-, 3- or 4-naphthyridinyl, 2-, 5- or 6- quinoxalinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1-, 2-, 3- or 4-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8- quinolinyl(quinolyl), 2-, A-, 5-, 6-, 7- or 8-quinazolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8- isoquinolinyl(isoquinolyl), 3-, A-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4- or 9- carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- phenanthridinyl, 1-, 2-, 3- or 4-acridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-(1 ,7)phenanthrolinyl, 1- or 2-phenazinyl, 1-, 2-, 3-, 4-, or 10-phenothiazinyl, 3- or A- furazanyl, 1-, 2-, 3-, 4-, or 10-phenoxazinyl, or additionally substituted derivatives thereof.

An "optionally substituted heteroaryl" refers to a heteroaryl having optionally one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents), selected from those defined above for substituted aryl. The term "oxo" as used herein refers to the group =0.

The term "alkoxy" as used herein refers to a radical having the Formula -OR wherein R is alkyl. Preferably, alkoxy is C ₁ -C ₁₀ alkoxy or CrC ₆ alkoxy. Where the oxygen atom in an alkoxy group is substituted with sulfur, the resultant radical is referred to as thioalkoxy. Haloalkoxy is an alkoxy group wherein one or more hydrogen atoms in the alkyl group are substituted with halo. The term "aryloxy" as used herein denotes a group -O-aryl, wherein aryl is as defined above. The term "aroyl" as used herein denotes a group -C(O)-aryl, wherein aryl is as defined above.

The term "cycloalkylalkyl" by itself or as part of another substituent refers to a group having one of the aforementioned cycloalkyl groups attached to one of the aforementioned alkyl chains. Examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2- cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, 3-cyclopentylbutyl, cyclohexylbutyl and the like.

The term "heterocyclyl-alkyl" by itself or as part of another substituents refers to a group having one of the aforementioned heterocyclyl group attached to one of the aforementioned alkyl group, i.e., to a group -R ^b -R ^c wherein R ^b is alkylene or alkylene substituted by alkyl group and R ^c is a heterocyclyl group.

The term "acyl" by itself or as part of another substituent refers to an alkanoyl group having 2 to 6 carbon atoms or a phenylalkanoyl group whose alkanoyl moiety has 1 to 4 carbon atoms, i.e. a carbonyl group linked to a radical such as, but not limited to, alkyl, aryl, more particularly, the group -COR ¹⁰ , wherein R ¹⁰ can be selected from alkyl, aryl, substituted alkyl, or substituted aryl, as defined herein. The term acyl therefore encompasses the group alkylcarbonyl (-COR ¹⁰ ), wherein R ¹⁰ is alkyl. Preferably, acyl is C ₂ -C ₁₁ acyl or C ₂ -C ₇ acyl. Where the oxygen atom is an acyl group is substituted with sulfur, the resultant radical is referred to as thioacyl. Said acyl can be exemplified by acetyl, propionyl, butyryl, valeryl and pivaloyl, benzoyl, phenylacetyl, phenylpropionyl and phenylbutytyl. The term "amino" refers to the group -NH ₂ .

The term "alkylamino" by itself or as part of another substituent refers to a group consisting of an amino groups attached to one or two independently selected and optionally substituted alkyl groups, cycloalkyl groups, arylalkyl or cycloalkylalkyl groups i.e., alkyl amino refers to -N(R ⁸ )(R ⁹ ) wherein R ⁸ and R ⁹ are each independently selected from hydrogen, cycloalkyl, arylalkyl, cycloalkylalkyl or alkyl. Non-limiting examples of alkylamino groups include methylamino (NHCH ₃ ), ethylamino (NHCH ₂ CH ₃ ), n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec- butylamino, tert-butylamino, n-hexylamino, and the like.

The term "aminoalkyl" refers to the group -R ^b -NR ^d R ^e wherein R ^b is alkylene or substituted alkylene, R ^d is hydrogen or alkyl or substituted alkyl as defined herein, and R ^e is hydrogen or alkyl as defined herein.

The term "aminocarbonyl" refers to the group -(C=O)-NH ₂ .

The term "alkylaminocarbonyl" refers to a group -(C=0)-NR ^d R ^e wherein R ^d is hydrogen or alkyl or substituted alkyl as defined herein, and R ^e is alkyl or substituted alkyl as defined herein.

The term "alkylaminocarbonylamino" refers to a group -NH(C=O)-NR ^d R ^e or -NR'(C=0)-NR ^d R ^e wherein R ^d is hydrogen or alkyl or substituted alkyl as defined herein, and R ^e is alkyl or substituted alkyl as defined herein, wherein R' is alkyl or substituted alkyl.

The term "carboxy" or "carboxyl" refers to the group -CO ₂ H. Thus, a carboxyalkyl is an alkyl group as defined above having at least one substituent that is -CO ₂ H.

The term "alkoxycarbonyl" refers to a carboxy group linked to an alkyl radical i. e. to form - C(=O)OR ¹⁰ , wherein R ¹⁰ is as defined above for acyl.

The term "alkylcarbonyloxy" refers to a -0-C(=0)R ¹¹ wherein R ¹¹ is as defined above for alkyl.

The term "alkylcarbonylamino" refers to an group of Formula -NH(C=O)R or -NR'(C=0)R, wherein R and R' are each independently alkyl or substituted alkyl.

The term "alkylcarbonylaminoalkyl" refers to a group -R ^b -NR ^d -C(=0)-R ^e wherein R ^b is alkylene or substituted alkylene, R ^d is hydrogen or alkyl as defined herein, and R ^e is alkyl as defined herein.

The term "alkoxy" by itself or as part of another substituent refers to a group consisting of an oxygen atom attached to one optionally substituted straight or branched alkyl group. Non-limiting examples of suitable alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, hexanoxy and the like. The term "alkylthio" by itself or as part of another substituent refers to a group consisting of a sulfur atom attached to one optionally substituted alkyl group. Non-limiting examples of alkylthio groups include methylthio (SCH ₃ ), ethylthio (SCH ₂ CH ₃ ), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-hexylthio, and the like.

The term "acylamino" by itself or as part of another substituent refers to a group consisting of an amino group attached to one or two independently selected acyl groups as described before. In case the two acyl groups of a dicarboxylic acid are attached to the amino group these represent imides such as phtalimides, maleimides and the like, and are encompassed in the meaning of the term acylamino.

The term "halo" or "halogen" as a group or part of a group is generic for fluoro, chloro, bromo or iodo.

The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non- limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1 -trifluoroethyl and the like. The term "haloalkoxy" alone or in combination refers to a group of Formula -O-alkyl wherein the alkyl group is substituted by 1 , 2 or 3 halogen atoms. For example, "haloalkoxy" includes -OCF ₃ and -OCHF ₂ .

The term "sulfonyl" alone or in combination refers to a group of Formula -SO ₂ -R ^Z wherein R ^z is alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl as defined herein. As used herein the term alkylsulfonyl is a group of formula -SO ₂ -R ^Z wherein R ^z is alkyl.

The term "sulfonamide" alone or in combination refers to a group of Formula -SO ₂ -NRR wherein each R independently is hydrogen or alkyl as defined herein.

The term "alkylsulfonylamino" alone or in combination refers to a group of Formula -NR ^d -SO ₂ -R wherein R ^d is hydrogen or alkyl as defined herein, and R is alkyl as defined herein.

Whenever the term "substituted" is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.

Where groups may be optionally substituted, such groups may be substituted with once or more, and preferably once or twice. Substituents may be selected from, for example, the group comprising halo, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.

As used herein the terms such as "alkyl, aryl, or cycloalkyl, each being optionally substituted with" or "alkyl, aryl, or cycloalkyl, optionally substituted with" refers to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.

Whenever used in the present invention the term "compounds of the invention" or a similar term is meant to include the compounds of general Formula I or Il and any subgroup thereof. This term also refers to the compounds as depicted in Tables 1 to 9 and their derivatives, λ/-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, pro-drugs, esters and metabolites, as well as their quaternized nitrogen analogues. The N-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called λ/-oxide.

As used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.

The terms described above and others used in the specification are well understood to those in the art.

Preferred features of the compounds of this invention are now set forth. In a particular embodiment, in compounds of Formula I, II, III, IV, V, Vl, VII, VIII, IX, X, L is - CR ⁹ R ¹⁰ -, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , X, Y, Z, r, s, p, q, m have the same meaning as that defined above. Preferably, L is -CR ⁹ R ¹⁰ - , R ⁹ and R ¹⁰ are each independently selected from hydrogen or alkyl, and heterocyclyl is selected from piperidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl,

2H-pyrrolyl, pyrrolinyl, pyrrolidinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, thietanyl, dioxolanyl, 1 ,4-dioxanyl, 2,5-dioximidazolidinyl,

2,2,4-piperidonyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1 ,3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, 61-1-1 ,2,5- thiadiazinyl, 2H-1 ,5,2-dithiazinyl, 2H-oxocinyl, 1 H-pyrrolizinyl, tetrahydro-1 ,1-dioxothienyl, N- formylpiperazinyl, and morpholinyl, preferably aryl is selected from phenyl, biphenylyl, biphenylenyl, naphthyl, or indenyl, preferably heteroaryl is selected from pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl,

indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, purinyl, benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl. More preferably, L is CH ₂ . In another particular embodiment, in compounds of Formula II, III, IV, V, Vl, VII, VIII, IX, X, L is - SO ₂ -, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , X, Y, Z, r, s, p, q, m have the same meaning as that defined above.

According to an embodiment of the present invention, in compounds of Formula II, V, Vl, VII, VIII, IX and X, R ⁷ is hydrogen or a group selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, or aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, or fused to said aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, and

R ⁸ is hydrogen or a group selected from alkyl, aryl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , R ¹⁰ , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , L, X, Y, Z, r, s, p, q, m have the same meaning as that defined above.

According to another embodiment of the present invention, in compounds of Formula II, V, Vl, VII, VIII, IX and X, R ⁷ is -(C(R ⁹ )R ¹⁰ ) _p -C(=A)-N(R ¹¹ )R ¹² , wherein p is 0 or 1 , A is an oxygen or sulfur atom; R ⁸ is hydrogen or a group selected from alkyl, aryl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino,

R ⁹ and R ¹⁰ are each independently selected from hydrogen or alkyl, R ¹¹ and R ¹² are each independently hydrogen or a group selected from alkyl, alkenyl, alkenyl, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylsulfonylaminoalkyl, alkylsulfonylamino, alkylcarbonyl, formylamino, formylaminoalkyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkoxyl, alkoxyalkyl, cyanoalkyl, aryloxyaralkyl, aralkylheteroaryl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroarylarylalkyl, or fused to said cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or heteroarylarylalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl,

each group being optionally substituted with one or more substituent selected from halo, oxo, hydroxyl, nitro, cyano, or a group selected from alkyl, alkoxy, amino, alkylamino, haloalkyl, haloalkoxy, alkenylaminooxy, alkylsulfonyl, sulfo, alkylsulfonylamino, alkylaminosulfonyl, alkylcarbonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylthio, arylalkenylaminooxy, arylalkylaminooxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, aryloxy, aryloxyaralkyl, arylamino, arylaminosulfonyl, arylcarbonyl, arylcarbonylamino, haloaryl, heteroaryl, heteroarylalkenylaminooxy, heteroarylalkyl, heteroarylaralkyl, heteroarylcarbonylamino, heteroarylalkylaminooxy, hydroxyalkyl, or fused to the cycloalkyl, aryl, heterocyclyl substituent or heteroaryl may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each of said group being optionally substituted by one or more further substituent selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, nitro, oxo, or sulfonyl, or R ¹¹ and R ¹² may together with the common nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring, said ring being optionally fused with one or more aryl, heteroaryl, cycloalkyl, or heterocyclyl ring, said ring or fused ring being optionally substituted with one or more substituent selected from halo, alkenylaminooxy, alkoxy, alkyl, alkylamino, alkylaminosulfonyl, alkylcarbonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylsulfonyl, alkylsulfonylamino, alkylthio, amino, aralkyl, aryl, arylalkenylaminooxy, arylamino, arylaminosulfonyl, arylcarbonyl, arylcarbonylamino, aryloxy, cyano, cycloalkyl, haloalkoxy, haloalkyl, haloaryl, heteroaryl, heteroarylcarbonyl, heteroarylalkenylaminooxy, heteroarylalkyl, heteroarylcarbonylamino, heterocyclyl, hydroxyalkyl, nitro, oxo, sulfonyl, or fused to the cycloalkyl, aryl, heterocyclyl or heteroaryl substituent may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each of said substituent being optionally substituted by one or more further substituent selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkyloxycarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, nitro, oxo, or sulfonyl wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , L, X, Y, Z, r, s, p, q, m have the same meaning as that defined above.

According to another embodiment of the present invention, in compounds of Formula II, V, Vl, VII, VIII, IX and X, R ⁷ and R ⁸ are fused together and form an alkylene or alkyleneaminoalkylene optionally substituted with one or more substituent selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , L, X, Y, Z, r, s, p, q, m have the same meaning as that defined above.

According to an embodiment of the present invention, some preferred compounds of Formula Il or V are compounds having one of the structural Formula V1 , V2, V3, V4:

wherein R ³ , R ⁴ , R ⁵ , R ¹¹ , R ¹² , L and A have the same meaning as that defined above.

In a particular embodiment, in compounds of formula V1 , V2, V3, V4, A is O and R ³ , R ⁴ , R ⁵ , R ¹¹ , R ¹² , L have the same meaning as that defined above.

In another particular embodiment, in compounds of formula V1 , V2, V3, V4, A is S and R ³ , R ⁴ , R ⁵ , R ¹¹ , R ¹² , L have the same meaning as that defined above.

According to another embodiment of the present invention, some preferred compounds of Formula II, V, V1 , V2, V3, V4, are compounds of Formula:

wherein R ⁴ , R ⁵ , R ¹¹ , R ¹² have the same meaning as that defined above.

According to an embodiment of the present invention, in compounds of Formula Vl, VII, VIII, IX or X, R ⁷ is preferably hydrogen or a group selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, or aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, or fused to said aryl,

aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl, group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, and R ⁸ is hydrogen or a group selected from alkyl, aryl, hydroxyalkyl, alkoxy, alkoxyalkyl, hydroxyl, alkyloxycarbonyl, carboxyl, aminoalkyl, amino, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, each group being optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl, amino, cyano, nitro, halo, haloalkyl, haloalkoxy, alkylamino, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , R ¹⁰ , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , L, X, Y, Z, r, s, p, q, m have the same meaning as that defined above.

In another particular embodiment, compounds of Formula I, have structural Formula III or IV,

III IV wherein r is an integer selected from 1 , 2, 3, 4 or 5, preferably 1 , 2, 3, or 4, p is an integer selected from 0, 1 or 2, preferably 0 or 1 m is an integer selected from 0 or 1 ,

R ¹³ and R ¹⁴ are each independently selected from hydrogen, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, alkoxy, amino, aminoalkyl, alkylaminoalkyl, preferably R ¹³ and R ¹⁴ are each independently selected from hydrogen or alkyl,

R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, haloalkyl, preferably R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl,

R ¹⁷ is selected from hydrogen, hydroxyl, amino, aryl, arylalkyl, alkyl, aminoalkyl, alkylamino, heteroaryl, heteroarylalkyl, halogen, haloalkyl, haloalkoxy, alkoxy, cycloalkyl, heterocyclyl, preferably, R ¹⁷ is selected from hydrogen, hydroxyl, amino, aryl, arylalkyl, alkyl,

X and Z are each independently selected from -C(R ¹⁸ )R ¹⁹ - or -NR ¹⁸ -, wherein R ¹⁸ is hydrogen or a group selected from alkyl, alkylcarbonyl, aryl, arylalkyl, haloarylalkyl, amino, aminoalkyl, cycloalkyl,

cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, each group being optionally substituted by one or more substituents selected from alkyl, aryl, halo, haloalkyl, haloalkoxy, amino, alkoxy, heteroaryl, heterocyclyl, cycloalkyl, and R ¹⁹ is selected from hydrogen or alkyl,

R ² is selected from hydrogen or alkyl, said alkyl being optionally substituted with one or more substituents selected from amino, aryl, arylalkyl, alkyl, aminoalkyl, alkylamino, heteroaryl, heteroarylalkyl, halogen, haloalkyl, haloalkoxy, heterocyclyl, alkoxy, cycloalkyl,

R ⁴ is selected from hydrogen, alkyl, alkoxy, cyano, nitro, halogen,

R ⁵ is selected from hydrogen , and

L is -CR ⁹ R ¹⁰ -; wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen or alkyl.

According to another embodiment of the present invention, some preferred compounds of Formula II, V, V1 , V2, V3, V4, are compounds of Formula:

wherein R ⁴ , R ⁵ are each independently hydrogen and R ¹¹ is hydrogen or alkyl,

R ¹² is hydrogen or a group selected from alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroarylarylalkyl, or fused to said cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or heteroarylarylalkyl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl, each group being optionally substituted with one or more substituent selected from halo, oxo, hydroxyl, nitro, cyano, alkyl, alkoxy, amino, alkylamino, haloalkyl, haloalkoxy, alkenylaminooxy.

In an embodiment, some preferred compounds of Formula II, V, V1 , V2, V3, V4, are compounds of Formula V5, V6, V7, V8, V9, V10, V1 1 , V12, wherein aryl is phenyl or naphthyl, wherein heterocyclyl is selected from piperazinyl, piperidinyl, pyrrolidinyl, diazepanyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidinyl, indolinyl, dioxolanyl, and wherein heteroaryl is selected from indolyl, benzoxazolyl, furanyl, thiazolyl, piridinyl, thienyl, pyrazolyl, or imidazolyl.

According to another embodiment of the present invention, some preferred compounds of Formula III or IV, are compounds of Formula:

1111 IV1 r is an integer selected from 1 or 2, p is an integer selected from 0, 1 or 2, m is an integer selected from 0 or 1 ,

R ¹³ and R ¹⁴ are each independently selected from hydrogen or alkyl, R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl,

R ¹⁷ is selected from hydrogen, hydroxyl, amino, aryl, arylalkyl, alkyl,

X and Z are each independently selected from -C(R ¹⁸ )R ¹⁹ - or -NR ¹⁸ -, wherein R ¹⁸ is hydrogen or a group selected from alkyl, alkylcarbonyl, aryl, arylalkyl, haloarylalkyl, amino, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, each group being optionally substituted by one or more substituents selected from alkyl, aryl, halo, haloalkyl, haloalkoxy, amino, alkoxy, heteroaryl, heterocyclyl, cycloalkyl, and R ¹⁹ is selected from hydrogen or alkyl,

R ² is selected from hydrogen or alkyl,

R ⁴ is selected from hydrogen or halogen, and L ¹ is -CR ⁹ R ¹⁰ -, wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen or CH ₃ . Preferably, L is CH ₂ .

It is clear to a person skilled in the art that the compounds of Formula I or Il may contain at least one asymmetric center and thus may exist as different stereoisomeric forms. The absolute

configuration of each asymmetric center that may be present in the compounds of Formula I or Il may be indicated by the stereochemical descriptors R and S.

The compounds of the invention may be in the form of pharmaceutically and/or veterinary acceptable salts, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and/or inorganic acids are as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the prior art referred to below).

When the compounds of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I or Il above. The invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I or II, for which general reference is made to the prior art cited hereinbelow.

The term "pro-drug" as used herein means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated. Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component. Typical examples of pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference. Pro-drugs are characterized by increased bio-availability and are readily metabolized into the active inhibitors in vivo. The term "pre-drug", as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the pre-drug reaches the area of the body where administration of the drug is indicated.

As described, above, some of the compounds of the invention may contain one or more asymmetric carbon atoms that serve as a chiral center, which may lead to different optical forms

(e.g. enantiomers or diastereoisomers). The invention comprises all such optical forms in all possible configurations, as well as mixtures thereof.

More generally, from the above, it will be clear to the skilled person that the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the invention.

The compounds of Formula I or Il may be prepared as described in the experimental section below using methods and chemistries with which those skilled in the art shall be familiar.

It will also be clear that when the desired compounds of the invention, and/or the starting materials, precursors and/or intermediates used in the preparation thereof, contain functional groups that are sensitive to the reaction conditions used in the preparation of the compounds of the invention (i.e. that would undergo undesired reactions under those conditions if they were not suitably protected) can be protected during said reaction with one or more suitable protective group, which protective group can then be suitably removed after either completion of said reaction and/or as a later or final step in the preparation of the compounds of the invention. Protected forms of the inventive compounds are included within the scope of the present invention. Suitable protective groups, as well as methods and conditions for inserting them and removing them, will be clear to the skilled person and are generally described in the standard handbooks of organic chemistry, such as Greene and Wuts, "Protective groups in organic synthesis", 3 ^rd Edition, Wiley and Sons, 1999, which is incorporated herein by reference in its entirety. It will also be clear to the skilled person that compounds of the invention in which one or more functional groups have been protected with suitable functional groups can find use as intermediates in the production and/or synthesis of the compounds of the invention, and as such form a further aspect of the invention.

Generally, the compounds of the invention can be prepared from aldehyde (such as, but not limited to isoquinoline-5-carbaldehyde) or carboxylic acid-containing intermediates 1 to 8 described hereinafter which may be reacted with complementary reactive molecules so as to form the desired compound. The intermediates and complementary reactive molecules are either commercially available or may be easily prepared by the skilled person.

The compounds of the invention may be used for the inhibition of kinases in vitro or in vivo, preferably in vitro, for modulating biological pathways and/or processes in which such kinases are involved; and/or to prevent and/or treat diseases or disorders in which such kinases, pathways and/or processes are involved. According to one preferred, but non-limiting embodiment, the compounds of the invention may be used to inhibit (at least one isoform of) ROCK; and as such may be used for any purposes known per se for inhibitors of ROCK.

In the invention, particular preference is given to compounds of Formula I or Il above that in the inhibition assay for ROCK described below inhibit ROCK with an IC ₅₀ value of less than 100 μM, preferably less than 50 μM, more preferably less than 10 μM, preferably less than 5 μM, even more preferably less than 1 μM, preferably less than 0.1 μM, and in particular less than 10 nM, for example less than or 1 nM, as determined by a suitable assay, such as the assay used in the Examples below.

The present invention also relates to the use of the compounds of Formula I or Il above in (the preparation of a composition for) inhibiting at least one kinase, in particular for inhibiting at least one isoform of ROCK, more in particular for inhibiting ROCK I and/or ROCK Il isoforms. As used herein, the term "ROCKI" can also be referred as ROK-β, p160ROCK, or Rho-kinase β and the term "ROCKM" can also be referred as ROK-α or Rho-kinase α. Said inhibition may be effected in vitro and/or in vivo, and when effected in vivo, is preferably effected in a selective manner, as defined above.

The present invention also relates to a compound of Formula I or II, for use in the prevention and/or treatment of at least one disease and/or disorder selected from the group comprising eye diseases; erectile dysfunction; cardiovascular diseases; vascular diseases; inflammatory diseases; proliferative diseases; neurological diseases and disease of the central nervous system (CNS); bronchial asthma; osteoporosis; renal diseases; and AIDS.

According to an embodiment, the invention provides a method for treating or lessening the severity of a ROCK-mediated disease or condition in a patient comprising the step of administering to said patient a compound according to the present invention.

The term "ROCK-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which is known to play a role. The term "ROCK-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a ROCK inhibitor. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which ROCK is known to play a role.

According to particularly preferred embodiments, the compounds of the invention are preferably used in the prevention and/or treatment of at least one disease or disorder, preferably in which at least one isoform of ROCK is involved. According to an even more particularly preferred embodiment, the compounds of the invention may be used in the prevention and/or treatment of at least one disease or disorder in which the ROCK I or ROCK Il is involved, such as, such as inflammatory diseases, chronic obstructive bladder disease (COBD) and the related erectile dysfunction as well as in diabetes related ED.

Specifically, the present invention relates to the use of a compound according to the invention for the preparation of a medicament for treating or lessening the severity of a disease or condition selected from eye disease or disorder (such as but not limited to retinopathy, glaucoma and degenerative retinal diseases such as macular degeneration and retinitis pigmentosa), kidney

disease (such as but not limited to renal dysfunction), and bladder dysfunction (such as but not limited to chronic obstructive bladder disease), erectile dysfunction (such as but not limited to bladder disease related erectile dysfunction and diabetes related erectile dysfunction) neurological and CNS (brain) disease or disorder (such as but not limited to Alzheimer, meningitis, convulsions), hypertension, lung disease (such as but not limited to asthma, fibrosis, pneumonia, cystic fibrosis, respiratory distress syndrome), premature birth, cancer (such as but not limited to cancer of the brain (gliomas), breast, colon, head and neck, prostate, kidney, lung, intestine, nerve, skin, pancreas, liver, uterus, ovary, brain, thyroid gland; leukemia; lymphoma, and melanoma), cardiovascular and vascular (blood vessel, artery) disease or disorder (such as but not limited to cerebrovascular contraction, ischemia, reperfusion, pulmonary vasoconstriction, acute stroke, congestive heart failure, cardiovascular ischemia, heart disease, cardiac remodeling, hypoxia peripheral circulation disorder, atherosclerosis, thrombosis, aneurism, and hemorrhage), blood disease (such as but not limited to sepsis, eosinophilia, endotoxemia), musculoskeletal disease (such as but not limited to spasm), infection, allergy and autoimmune diseases or disorders, AIDS, bone disease (such as but not limited to osteoporosis), inflammatory diseases, diabetes (such as but not limited to hyperglycemia), obesity and pancreas disease.

For example, the compounds of the invention may be used in the prevention and/or treatment of diseases and disorders such as:

- Cardiovascular and vascular diseases: including but not limited to acute stroke, congestive heart failure, cardiovascular ischemia, heart disease, cardiac remodeling, angina, coronary vasospasm, cerebral vasospasm, restenosis, hypertension, (pulmonary) hypertension, pulmonary vasoconstriction, arteriosclerosis, thrombosis (including deep thrombosis) and platelet related diseases.

- Neurological and CNS disorders: including but not limited to stroke, multiple sclerosis, brain or spinal cord injury, inflammatory and demyelinating diseases such as Alzheimer ^' s disease, MS and neuropathic pain. The present compounds are therefore suitable for preventing neurodegeneration and stimulating neurogeneration in various neurological disorders.

- Proliferative diseases: such as cancer including but not limited to cancer of the brain (gliomas), breast, colon, intestine, skin, head and neck, kidney, lung, liver, ovarian, pancreatic, prostate, or thyroid; leukemia; sarcoma; lymphoma; and melanoma.

- Inflammatory diseases: including but not limited to contact dermatitis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis. Preferably, the compound may be used in (the preparation of a medicament for ) the prevention and/or treatment of Inflammatory diseases selected from contact dermatitis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.

In addition, the compounds of the invention may be used in the prevention and/or treatment of diseases and disorders such as erectile dysfunction; bronchial asthma; osteoporosis; renal

diseases; AIDS; eye diseases such as glaucoma, macular degeneration and retinopathy, . Preferably, the compound may be used in the prevention and/or treatment of glaucoma and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.

The present invention therefore relates to a method of treating or lessening the severity of a disease or condition selected from cardiovascular and vascular diseases: including but not limited to acute stroke, congestive heart failure, cardiovascular ischemia, heart disease, cardiac remodeling, angina, coronary vasospasm, cerebral vasospasm, pulmonary vasoconstriction, restenosis, hypertension, (pulmonary) hypertension, arteriosclerosis, thrombosis (including deep thrombosis) and platelet related diseases; neurological and CNS disorders: including but not limited to stroke, multiple sclerosis, spinal or brain cord injury, brain or spinal cord injury, inflammatory and demyelinating diseases such as Alzheimer ^' s disease, MS and neuropathic pain; proliferative diseases such as cancer including but not limited to cancer of the brain (gliomas), breast, colon, intestine, skin, head and neck, kidney, lung, liver, ovarian, pancreatic, prostate or thyroid cancer; leukemia; sarcoma; lymphoma; melanoma; erectile dysfunction; bronchial asthma; osteoporosis; eye diseases such as glaucoma, macular degeneration and retinopathy; renal diseases; AIDS; preterm labor; vascular smooth muscle cell proliferation; myocardial hypertrophy; malignoma; ischemia/reperfusion-induced injury; endothelial dysfunction; Crohn's Disease and colitis; neurite outgrowth; Raynaud's Disease; benign prostatic hyperplasia; and atherosclerosis, wherein said method comprises administering to a patient in need thereof a compound or a composition according to the present invention.

For pharmaceutical use, the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g. obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form or a pro-drug or pre-drug, such as an ester. As used herein and unless otherwise stated, the term "solvate" includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like. Such salts, hydrates, solvates, etc. and the preparation thereof will be clear to the skilled person; reference is for instance made to the salts, hydrates, solvates, etc. described in US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733.

The pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,

propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. In addition, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts. Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US-A-6,372,778,

US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic

polymers. In order to enhance the solubility and/or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ o, β- or γ-cyclodextrins or their derivatives. In addition, co-solvents such as alcohols may improve the solubility and/or the stability of the compounds. In the preparation of aqueous compositions, addition of salts of the compounds of the invention can be more suitable due to their increased water solubility.

Appropriate cyclodextrins are o, β- or γ-cyclodextrins (CDs) or ethers and mixed ethers thereof wherein one or more of the hydroxyl groups of the anhydroglucose units of the cyclodextrin are substituted with alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyalkyl, particularly carboxymethyl or carboxyethyl; alkylcarbonyl, particularly acetyl; alkoxycarbonylalkyl or carboxyalkoxyalkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; alkylcarbonyloxyalkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl- β-CD, 2-hydroxyethyl-β-CD, 2- hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2-carboxymethoxy)propyl- β-CD, and in particular 2-hydroxypropyl- β-CD (2-HP- β-CD). The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl. An interesting way of formulating the compounds in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721 ,331. Although the formulations described therein are with antifungal active ingredients, they are equally interesting for formulating the compounds. Said formulations may also be rendered more palatable by adding pharmaceutically acceptable sweeteners and/or flavors. In particular, the present invention encompasses a pharmaceutical composition comprising an effective amount of a compound according to the invention with a pharmaceutically acceptable cyclodextrin. The present invention also encompasses cyclodextrin complexes consisting of a compound according to the invention and a cyclodextrin.

Particular reference is made to the compositions, formulations (and carriers, excipients, diluents, etc. for use therein), routes of administration etc., which are known per se for analogous pyridinocarboxamides, such as those described in US-A-4,997,834 and EP-A-O 370 498. For the treatment of pain, the compounds of the invention may be used locally or systemically. For local administration, the compounds may advantageously be used in the form of a spray, ointment or transdermal patch or another suitable form for topical, transdermal and/or intradermal administration; and for systemic administration, the compounds of the invention may advantageously be administered orally. For ophthalmic application, solutions, gels, tablets and the like are often prepared using a physiological saline solution, gel or excipient as a major vehicle. Ophthalmic formulations should preferably be prepared at a comfortable pH with an appropriate buffer system.

More in particular, the compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.

The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution". Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. The term "a solid dispersion" also comprises dispersions that are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.

The water-soluble polymer is conveniently a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at 2O ⁰ C solution. Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule.

It may further be convenient to formulate the compounds in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the compounds according to the invention involves a pharmaceutical composition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration. Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of a hydrophilic polymer and an antiretroviral agent and (c) a seal- coating polymer layer. Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.

The preparations may be prepared in a manner known per se, which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions. Reference is again made to US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733 and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.

The compounds can be administered by a variety of routes including the oral, rectal, ocular, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred. The at least one compound of the invention will generally be administered in an "effective amount", by which is meant any amount of a compound of the Formula I or Il above that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight day of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion. The amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is again made to US-A- 6,372,778,US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733 and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

Thus, in a further aspect, the invention relates to a composition, and in particular a composition for pharmaceutical use, that contains at least one compound of the invention (i.e. a compound that has been identified, discovered and/or developed using a nematode or method as described herein) and at least one suitable carrier (i.e. a carrier suitable for pharmaceutical use). The invention also relates to the use of a compound of the invention in the preparation of such a composition.

In accordance with the method of the present invention, said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

For an oral administration form, the compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case, the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.

For subcutaneous or intravenous administration, the compound according to the invention, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug. The compositions are of value in the veterinary field, which for the purposes herein not only includes the prevention and/or treatment of diseases in animals, but also - for economically important animals such as cattle, pigs, sheep, chicken, fish, etc. - enhancing the growth and/or weight of the animal and/or the amount and/or the quality of the meat or other products obtained from the animal. Thus, in a further aspect, the invention relates to a composition for veterinary use that contains at least one compound of the invention (e.g. a compound that has been identified, discovered and/or developed using a nematode or method as described herein) and at least one suitable carrier (i.e. a carrier suitable for veterinary use). The invention also relates to the use of a compound of the invention in the preparation of such a composition.

The invention will now be illustrated by means of the following synthetic and biological examples, which do not limited the scope of the invention in any way.

EXAMPLES

Analytical (or preparative) techniques:

Unless indicated otherwise, the purity of the compounds was confirmed by liquid chromatography/mass spectrometry (LC/MS), as follows: - HPLC system: Waters 2690 with photodiode array detector Waters 996; Column:

C18; Gradient: solvent A (H ₂ O/formic acid 26.5 nM) 0%, to solvent B (CH ₃ CN/formic acid 17 nM) 80% in 3 min. Flow: 2.75 ml/min.

Mass spectrometer: Micromass Platform LC. Ionization: electrospray (polarity: negative and positive). Unless indicated otherwise, purification by preparative HPLC, was performed on a Shimadzu SCL- 10A (UV detection at 215 and 254 nm, detector SPD-10A) using C-18 column (Nucleosil, 100A, 100μm, 20 x 200 mm) and different gradients (water, acetonitrile, formic acid).

Chiral HPLC (analytical and preparative) was performed on a Shimadzu SCL-10A (UV detection at 215 and 254 nm, detector SPD-10A) using different column such as Chiralcel OD-H (tris-3,5- dimethylphenylcarbamate, 46 x 250 or 100 x 250 mm, 5 μm), Chiralcel OJ (tris-methylbenzoate, 46 x 250 or 100 x 250 mm, 5 μm), Chiralpak AD (tris-3,5-dimethylphenylcarbamate, 46 x 250 mm, 10 μm) and Chiralpak AS (tris-(S)-i-phenylethylcarbamate, 46 x 250 mm, 10 μm) from Chiral Technologies Europe (lllkirch, France):

• Eluent: mixture of solvent such as ethanol, 1-propanol, 2-propanol, methanol, butanol, pentane, hexane, heptane, cyclohexane, diisopropylethyamine, triethylamine.

• Flow: between 1 and 50 ml/min.

NMR spectra were determined on a Varian Mercury 300 MHz NMR using the indicated solvent as an internal reference. Melting points were determined on a Bϋchi B-540 and are non-corrected. All reagents used either were obtained commercially or were prepared in a manner known per se.

Attribution of the configuration: The Cahn-lngold-Prelog system was used to attribute the absolute configuration of chiral center, in which the four groups on an asymmetric carbon are ranked to a set of sequences rules. Reference is made to Cahn; Ingold; Prelog Angew. Chem. Int. Ed. Engl. 1966, 5, 385-415.

Name of the molecule

The software MDL ISIS™ / Draw 2.5 was used to assign the name of the molecules. Example 1

The following intermediates and general procedures were used to prepare the compounds described herein.

Intermediates:

Intermediate 1: S-carboxymethyl-^isoquinolin-δ-ylmethyl-piperazine-i-carbox ylic acid tert-butyl ester.

To a solution of isoquinoline-5-carbaldehyde (1.35 g) in DCM, were successively added a solution of S-methoxycarbonylmethyl-piperazine-i-carboxylic acid tert-butyl ester (1.1 eq.) in DCM (25 ml) and NaBH(OAc) ₃ (2.5 eq.). The reaction mixture was stirred at RT for 24 hours, diluted in DCM and 1 M sodium bicarbonate. After separation, the organic layer was washed with brine, dried with magnesium sulfate, filtered off and evaporated. The residue was by chromatography on C-18 (water/CH3CN 100/0 to 40/60) to afford the intermediate methyl ester as a white powder (56 % yield).

The methyl ester (1.92 g) was dissolved in a mixture of MeOH (20 ml) and water (20 ml). Lithium hydroxide hydrate (5 eq.) was added and the reaction mixture was stirred at 6O ⁰ C for 30 minutes and then, was concentrated. The resulting solution, was diluted with aqueous citric acid solution

(pH 5, 50 ml) and then slowly acidified to pH 4-5 with 2N hydrochloric acid. The compound was extracted with DCM (250 ml). The organic layer was dried over magnesium sulfate, filtered off and evaporated. The title compound was obtained as a white powder (80 % yield) and was used without further purification (mp: 104-106 ⁰ C).

Intermediate 2: 2-carboxymethyl-4-isoquinolin-5-ylmethyl-piperazine-1-carbox ylic acid tert-butyl ester.

The title compound was obtained using the protocol described for Intermediate 1 , starting from 2- methoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester (27 % overall yield).

Intermediate 3: 4-isoquinolin-5-ylmethyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester.

The title compound was obtained using the protocol described for Intermediate 1 , starting from piperazine-1 ,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (52 % overall yield). Intermediate 4: 4-isoquinolin-5-ylmethyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester.

The title compound was obtained using the protocol described for Intermediate 5, starting from piperazine-1 ,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (64 % overall yield).

Intermediate 5: 3-carboxymethyl-4-(isoquinoHne-5-sulfonyl)-piperazine-1-carb oxylic acid tert-butyl ester.

To a solution of isoquinoline-5-sulfonyl chloride hydrochloride (930 mg) in THF (20 ml) were added DIPEA (2.2 eq.) and (S-methoxycarbonylmethyl-piperazine-i-carboxylic acid tert-butyl ester (1 eq.). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was taken in DCM. The DCM layer was washed with 1 N sodium carbonate and then, with brine. The organic layer was evaporated and the residue was purified by chromatography on C-18 (water/CH ₃ CN 100/0 to 50/50) to afford the intermediate methyl ester as a white powder (66 % yield).

The methyl ester (1.0 g) was dissolved in a mixture of MeOH (20 ml) and water (20 ml). Lithium hydroxide hydrate (5 eq.) was added and the reaction mixture was stirred at 6O ⁰ C for 30 minutes and then, was concentrated. The resulting solution, was diluted with aqueous citric acid solution (pH 5, 50 ml) and then slowly acidified to pH 4-5 with 2N hydrochloric acid. The compound was extracted with DCM (250 ml). The organic layer was dried over magnesium sulfate, filtered off and evaporated. The title compound was obtained as a white powder (72 % yield) and was used without further purification (mp: 119-121 ⁰ C).

Intermediate 6: 2-carboxymethyl-4-(isoquinoline-5-sulfonyl)-piperazine-1-car boxylic acid tert-butyl ester.

The title compound was obtained using the protocol described for Intermediate 5, starting from 2- methoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester (29 % overall yield).

Intermediate 7: 4-(isoquinoline-5-sulfonyl)-piperazine-1,3-dicarboxylic acid 1 -tert-butyl ester.

The title compound was obtained using the protocol described for Intermediate 5, starting from piperazine-1 ,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (30 % overall yield). Intermediate 8: 4-(isoquinoline-5-sulfonyl)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester.

The title compound was obtained using the protocol described for Intermediate 5, starting from piperazine-1 ,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (55 % overall yield).

General procedures: Protocol A:

To a solution of the corresponding aldehyde (1 eq.) in DCM (0.25 M) were successively added the corresponding amine (1 to 1.1 eq.) in DCM (0.25 M) and sodium triacetoxyborohydride (2.5 eq.). The reaction mixture was stirred at RT for 16 to 24 hours. Sodium carbonate 1 M was then added, and the reaction mixture was further stirred at RT for 1 hour. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered off, and finally evaporated. The residue was purified by flash chromatography on silica gel or on C-18.

Deprotection of tert-butoxycarbonylamino group (when applicable): The product was dissolved in freshly distillated 1 ,4-dioxane. HCI gas was bubbled in the solution for 10 to 30 minutes. The solvent was then evaporated and the final compound was dried under vacuum. Protocol B:

To a solution of the corresponding carboxylic acid (5.25 μmol) in DMF (0.437 M) with DIEA (3 eq) was added 1 eq of a solution of TBTU / HOBt (1 / 0.2) in DMF (0.4 M). The reaction mixture was stirred at RT for 3 to 10 minutes and a solution of the corresponding amine (1 eq) in DMF (0.1 M) at neutrality (with DIEA). The reaction mixture was stirred at RT for 3 hours, and then 0.7 eq of a solution of TBTU / HOBt (1 / 0.2) in DMF (0.4 M) was added. After 4 hours the reaction mixture was evaporated.

Deprotection of tert-butoxycarbonylamino group: a mixture of DCM and trifluoroacetic acid (1 / 1 ; 100 μl) was added to the residue. The solution was stirred at RT for 2 hours, and then evaporated under reduced pressure. Compounds were used without further purification.

Protocol C: To a solution of the corresponding carboxylic acid (1 eq) in DMF (0.25 M) with DIEA (3 eq) was added TBTU (1.3 eq) and HOBt (0.3 eq). The reaction mixture was stirred at RT for 3 to 10 minutes and the corresponding amine (1 eq) was added. The reaction mixture was stirred at RT for 3 hours to 3 days. The solvent was evaporated. The residue was partitioned between EtOAc and 2N Na ₂ CO ₃ (or 1 N NaOH). The product was extracted with EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated.

Alternative protocol: To a solution of the corresponding carboxylic acid (1 eq) in a mixture DMF/DCM (0.25 M) were successively added DCC (1 eq), HOBt (1 eq) and DIEA (3 eq). The solution was stirred at RT for 30 minutes before the addition of the corresponding amine (1 eq). The reaction mixture was stirred at RT for 2 hours to 3 days. The solvent was evaporated. The residue was partitioned between DCM and water. The product was extracted with DCM. The organic layer was separated, washed with 2N Na ₂ CO ₃ (or 1 N NaOH), brine, dried over magnesium sulfate, and evaporated.

Deprotection of tert-butoxycarbonylamino group: The crude product was dissolved in freshly distillated 1 ,4-dioxane. HCI gas was bubbled in the solution for 10 to 30 minutes. The solvent was evaporated and then, the residue was purified by preparative HPLC.

Biological activity

The compounds were tested for inhibition of human ROCKα/ROCKII mix.

The inhibition assays were performed with a fluorescence polarization (FP) assay using the commercially available ROCK IMAP Kit from Molecular Devices (Product ID. No. R8093), essentially in accordance with the protocol supplied by the manufacturer. The S6 ribosomal protein- derived substrate used was (FI)-AKRRRLSSLRA, also obtained from Molecular Devices (Product ID No. R7184). The enzyme mix ROCKα/ROCKII was obtained from Upstate Biotechnology (Product ID No 14-451 ).

In summary, all compounds were screened in the wells of a 384 well plate for enzymatic inhibition with concentrations varying from 100μM to 0.3nM using a stepwise 3 (or 2)-fold dilution. Y-27632 (commercially available from Tocris) was used as a reference (0.4 μM).

To perform the assay, 1 μl of a solution of the compound to be tested in DMSO (at each concentration) was added to 2 μl of a solution of the enzyme in 1OmM Tris-HCI , 1 OmM MgCI ₂ , 0.1 % BSA, 0.05% NaN ₃ , pH 7,2. The final concentration of the enzyme was 2.6nM.

After incubating for 30 minutes at RT, 2 μl of a mixture of ATP and the protein substrate in 1OmM Tris-HCI, 1 OmM MgCI ₂ , 0.1 % BSA, 0.05% NaN ₃ , pH 7.2 was added. The final concentration of the ATP was 10 μM and final concentration of protein substrate was 0.2 μM.

After incubating for 60 minutes at RT, 12 μl of the IMAP Binding Solution (mix of the IMAP Binding Buffer A (1x) and the IMAP Binding Reagent (from the ROCK IMAP kit)) was added.

The mixture thus obtained (total volume: 17 μl) was incubated for 60 minutes at RT, upon which the fluorescence polarization was measured using an automated plate reader (Perkin Elmer, Model Envision 2100-0010 HTS) with FP filters: excitation filter FITC FP 480 and emission filters FITC FP P-pol 535 and FITC FP S-pol 535 (Perkin-Elmer). The results were fitted to a curve using the XL-Fit algorithm and IC50 values were calculated for each fitted curve, again using the XL-Fit algorithm.

The IC ₅₀ value for the reference compound (Y compound Y-27632) was 0.4μM. Compounds of the invention

In the tables 1 to 9 that are set forth below, exemplary compounds of the invention are set out in tabulated form. In these tables, the name of the compound, an arbitrarily assigned compound number and structural information are set out. In addition, the protocol by which the compounds were made is provided and the IC ₅₀ value obtained (in accordance with the protocol set forth above) is represented as follows: "+++" means IC ₅₀ below 0.1 μM; "++" means IC ₅₀ between 0.1 and 1 μM; "+" means IC ₅₀ between 1 and 50 μM.

Table 1 shows the results for compounds of Formula I or II. As used herein the term "ND" means "not determined".

Table 1

Table 2 shows the results for compounds of Formula V5 wherein R ⁴ and R ⁵ are each independently hydrogen. As used herein the term "ND" means "not determined" and Pr means "protocol". Compounds of Formula V5 wherein R ⁴ and R ⁵ are each independently hydrogen were prepared starting from Intermediate 1 and from the corresponding amine HNR ¹¹ R ¹² following the general protocol B or C.

V5 Table 2

Table 3 shows the results for compounds of Formula V7 wherein R ⁴ and R ⁵ are each independently hydrogen. As used herein the term "ND" means "not determined" and Pr means "protocol". Compounds of Formula V7 wherein R ⁴ and R ⁵ are each independently hydrogen were prepared starting from Intermediate 2 and from the corresponding amine HNR ¹¹ R ¹² following the general protocol B or C.

V7 Table 3

Table 4 shows the results for compounds of Formula V6 wherein R ⁴ and R ⁵ are each independently hydrogen. As used herein the term "ND" means "not determined" and Pr means "protocol". Compounds of Formula V6 wherein R ⁴ and R ⁵ are each independently hydrogen were prepared starting from Intermediate 3 and from the corresponding amine HNR ¹¹ R ¹² following the general protocol B or C.

Table 5 shows the results for compounds of Formula V8 wherein R ⁴ and R ⁵ are each independently hydrogen. As used herein the term "ND" means "not determined" and Pr means "protocol". Compounds of Formula V8 wherein R ⁴ and R ⁵ are each independently hydrogen were prepared starting from Intermediate 4 and from the corresponding amine HNR ¹¹ R ¹² following the general protocol B or C.

Table 6 shows the results for compounds of Formula V9 wherein R ⁴ and R ⁵ are each independently hydrogen. As used herein the term "ND" means "not determined" and Pr means "protocol". Compounds of Formula V9 wherein R ⁴ and R ⁵ are each independently hydrogen were prepared starting from Intermediate 5 and from the corresponding amine HNR ¹¹ R ¹² following the general protocol B or C.

Table 7 shows the results for compounds of Formula V11 wherein R ⁴ and R ⁵ are each independently hydrogen. As used herein the term "ND" means "not determined" and Pr means "protocol". Compounds of Formula V11 wherein R ⁴ and R ⁵ are each independently hydrogen were prepared starting from Intermediate 6 and from the corresponding amine HNR ¹¹ R ¹² following the general protocol B or C.

V11 Table 7

Table 8 shows the results for compounds of Formula V10 wherein R ⁴ and R ⁵ are each independently hydrogen. As used herein the term "ND" means "not determined" and Pr means "protocol". Compounds of Formula V10 wherein R ⁴ and R ⁵ are each independently hydrogen were prepared starting from Intermediate 7 and from the corresponding amine HNR ¹¹ R ¹² following the general protocol B or C.

V10 Table 8

Table 9 shows the results for compounds of Formula V12 wherein R ⁴ and R ⁵ are each independently hydrogen. As used herein the term "ND" means "not determined" and Pr means "protocol". Compounds of Formula V12 wherein R ⁴ and R ⁵ are each independently hydrogen were prepared starting from Intermediate 8 and from the corresponding amine HNR ¹¹ R ¹² following the general protocol B or C.

The present invention encompasses compounds 1 to 431 and stereoisomers, tautomers, racemics or a pharmaceutically acceptable salt and/or solvate thereof.

All patents, patent applications, and published references cited herein are hereby incorporated by reference in their entirety. While this invention has been particularly shown and described with references to preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the scope of the invention encompassed by the claims.