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Title:
LIM KINASE INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2015/150337
Kind Code:
A1
Abstract:
The present invention relates to new kinase inhibitors, more specifically LIM Kinase inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and Prophylaxis of disease. In particular, the present invention relates to new LIMK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and Prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said Compounds in the manufacture of a medicament for the application to a number of therapeutic indications including Ophthalmic and intestinal diseases.

Inventors:
BOURIN, Arnaud Pierre Jean (Life Sciences Incubator, Agoralaan A bis, Diepenbeek, B-3590, BE)
BOLAND, Sandro (Life Sciences Incubator, Agoralaan A bis, Diepenbeek, B-3590, BE)
DEFERT, Olivier (Life Sciences Incubator, Agoralaan A bis, Diepenbeek, B-3590, BE)
Application Number:
EP2015/056920
Publication Date:
October 08, 2015
Filing Date:
March 30, 2015
Export Citation:
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Assignee:
AMAKEM NV (Life Sciences Incubator, Agoralaan A bis, Diepenbeek, B-3590, BE)
International Classes:
C07D487/04; A61K31/519; A61P21/00
Domestic Patent References:
WO2012125746A12012-09-20
WO2009131940A12009-10-29
WO2009021169A22009-02-12
WO2009131940A12009-10-29
WO2012061565A12012-05-10
Foreign References:
US6372778B12002-04-16
US6369086B12002-04-09
US6369087B12002-04-09
US6372733B12002-04-16
EP0721331A11996-07-17
Other References:
MOLECULAR VISION, vol. 14, 2008, pages 1951 - 1959
CIRCULATION RESEARCH, vol. 105, no. 6, 2009, pages 549 - 556
HARRISON ET AL., J. MED. CHEM., vol. 52, 2009, pages 6515 - 6518
ACS MED. CHEM. LETT., vol. 6, no. 1, 2015, pages 84 - 88
Attorney, Agent or Firm:
LAENEN, Bart Roger Albert (Crutzenstraat 26, Hasselt, B-3500, BE)
Download PDF:
Claims:
CLAIMS

1 . A compound of Formula I or a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof,

Wherein,

Ar is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R5 groups;

X is a direct bond or an optionally substituted d-6 alkylene;

m is an integer from 1 to 3;

n is an integer from 0 to 6;

R is H or Ci-6 alkyl;

R2 and R3 are independently selected from H , Ci_6 alkyl;

or R2 and R3 are joined together so that they form a C3.6 nitrogen-containing heterocycle;

L is a direct bond or an optionally substituted Ci_6alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S02, S02NR', NR'C(=0)NR", NR'S(=0)NR", and NR'S(=0)(=0)NR"; and wherein the optional substituents are selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, and halo;

Cy is a direct bond or an optionally substituted cyclic structure selected from Ci_8cycloalkyl, d.

8heterocyclyl, aryl and heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_6alkyl, amino, alkylamino, dialkylamino, hydroxyl, thiol, alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl;

L2 is a direct bond or an optionally substituted Ci_8 alkylene, Ci_8alkenylene, or Ci_8alkynylene; wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S02, S02NR', NR'C(=0)NR', NR'S(=0)NR', or NR'S(=0)(=0)NR'; and wherein the optional substituents are selected from the group consisting of hydroxyl, amino, alkylamino, dialkylamino, alkoxyl, haloalkoxyl, alkylthio, thiol, halo, cyano, and carboxyl;

R4 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, halo, and heterocyclyl; wherein said heterocyclyl is optionally substituted with one or more groups selected from Ci_6 alkyl, halo, and oxo;

R5 is selected from oxo, halo, d-6alkyl, Ci_6alkenyl, Ci_6alkynyl, hydroxyl, Ci_6alkoxyl, amino, mono- or di(Ci-6alkyl)amino, nitro, cyano, thio, and Ci_6alkylthio;

R6 and R6' are independently selected from hydrogen and fluoro; and

R' and R" are in each instance independently hydrogen or Ci_6alkyl.

2. The compound of claim 1 , wherein

Ar is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R5 groups;

X is a direct bond or an optionally substituted Ci_6 alkylene;

m is an integer from 1 to 3;

n is an integer from 0 to 6;

R is H or Ci-6 alkyl;

R2 and R3 are independently selected from H , Ci_6 alkyl;

or R2 and R3 are joined together so that they form a C3.6 nitrogen-containing heterocycle;

R5 is selected from oxo, halo, Ci_6alkyl, hydroxyl, Ci_6alkoxyl, amino, mono- or di(Ci_6alkyl)amino, nitro, cyano, thio, and Ci_6alkylthio;

L is a direct bond or an optionally substituted Ci_6alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S02, S02NR', NR'C(=0)NR', NR'S(=0)NR', or NR'S(=0)(=0)NR'; and wherein the optional substituents are selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, and halo;

Cy is a direct bond or an optionally substituted cyclic structure selected from aryl or heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_6alkyl, amino, alkylamino, dialkylamino, hydroxyl, thiol, alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl;

L2 is a direct bond or an optionally substituted Ci_8 alkylene, Ci_8alkenylene, or Ci_8alkynylene; wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S02, S02NR', NR'C(=0)NR', NR'S(=0)NR', or NR'S(=0)(=0)NR'; and wherein the optional substituents are selected from the group consisting of hydroxyl , amino, alkylamino, dialkylamino, alkoxyl, haloalkoxyl , alkylthio, thiol, halo, cyano, and carboxyl;

R4 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol , cyano, halo, and heterocyclyl; wherein said heterocyclyl is optionally substituted with one or more groups selected from Ci_6 alkyl, halo, and oxo; and

R' is in each instance independently chosen from hydrogen and d-6alkyl; and

R6 and R6 are hydrogen .

3. The compound of claim 1 or 2, wherein

Ar is aryl or heteroaryl , wherein said aryl or heteroaryl is optionally substituted with one or more R5 groups;

X is a direct bond or an optionally substituted Ci_6 alkylene;

m is an integer from 1 to 3;

n is an integer from 0 to 6;

R is H or C-i-6 alkyl;

R2 and R3 are independently selected from H , Ci_6 alkyl;

or R2 and R3 are joined together so that they form a C3.6 nitrogen-containing heterocycle;

L is a direct bond or an optionally substituted Ci_6alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR' , NR'C(=0), NR'C(=0)0, OC(=0)NR' , NR'S02, S02NR', NR'C(=0)NR" ,

NR'S(=0)NR", and NR'S(=0)(=0)NR" ; and wherein the optional substituents are selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, and halo;

Cy is a direct bond or an optionally substituted cyclic structure selected from Ci_8cycloalkyl, d.

8heterocyclyl , aryl, and heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_6alkyl, amino, alkylamino, dialkylamino, hydroxyl , thiol , alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl ;

L2 is a direct bond;

R4 is hydrogen ;

R5 is selected from oxo, halo, Ci_6alkyl, Ci_6alkenyl, Ci_6alkynyl, hydroxyl, Ci_6alkoxyl, amino, mono- or di(Ci-6alkyl)amino, nitro, cyano, thio, and Ci_6alkylthio;

R6 and R6' are independently selected from hydrogen or fluoro; and

R' and R" are in each instance independently chosen from hydrogen and Ci_6alkyl .

4. The compound of claim 1 or 2, wherein

L is a direct bond;

Cy is a direct bond; and

L2 is an optionally substituted d-8alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', or NR'C(=0)NR"; and wherein the optional substituents are selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, halo, cyano, and carboxyl.

5. The compound of claim 1 or 2, wherein

L is a direct bond;

Cy is an optionally substituted aryl or heteroaryl, in particular an optionally substituted heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_6alkyl, amino, alkylamino, dialkylamino, hydroxyl, thiol, alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl;

L2 is a direct bond or a Ci_8 alkylene optionally substituted with one or more substituents selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, halo, cyano, and carboxyl;

R4 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, and halo.

6. The compound of claim 1 or 2 the compound being of formula II

Wherein

X, Ar, R , R2, R3, R6, R6 , R' and R" are as defined in claim 1 or 2; and

W is selected from the group consisting of a) hydrogen;

b) an optionally substituted d-6alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S02, S02NR', NR'C(=0)NR", NR'S(=0)NR", or

NR'S(=0)(=0)NR"; and wherein the optional substituents are selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, and halo; and c) an optionally substituted cyclic structure selected from Ci_8cycloalkyl, Ci_8heterocyclyl, aryl, and heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_6alkyl, amino, alkylamino, dialkylamino, hydroxyl, thiol, alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl.

7. The compound of any one of the previous claims, wherein

X is a direct bond.

8. A compound according to any one of claims 1 to 7 for use as a medicine.

9. A composition comprising a compound as defined in any one of claims 1 to 7, for use as a human or veterinary medicine.

10. A compound according to any one of claims 1 to 7, or a composition according to claim 8, for use in the prevention and/or treatment of at least one disease or disorder in which LIMK is involved, such as diseases linked to smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis and neurodegeneration.

1 1 . A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of at least one disease or disorder selected from the group comprising eye diseases, airway diseases, skin diseases, intestinal diseases, proliferative diseases ; cardiovascular and vascular diseases, kidney diseases, bone diseases, inflammatory diseases, and neurodegeneration.

12. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of an eye disease including but not limited to glaucoma and degenerative retinal diseases such as macular degeneration, vision loss due to diabetic macular edema, vision loss due to macular edema secondary to retinal vein occlusion proliferative vitreoretinopathy; inflammatory eye diseases such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis, glaucoma filtration surgery failure, dry eye, allergic conjunctivitis, posterior capsule opacification, cataract formation, abnormalities of corneal wound healing, ocular pain and ocular hypertension.

13. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of an airway disease; including but not limited to pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cytsis fibrosis, chronic obstructive pulmonary disease (COPD); bronchitis and rhinitis and respiratory distress syndrome, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith.

14. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of a cardiovascular and/or vascular disease; including but not limited to pulmonary hypertension and pulmonary vasoconstriction, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith and/or alleviating complications and/or symptoms associated therewith.

15. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of an intestinal disease; including but not limited to inflammatory bowel disease (IBD), colitis, gastroenteritis, ileus, ileitis, appendicitis and Crohn's disease.

16. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of an inflammatory disease; including but not limited to contact dermatitis, atopic dermatitis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis, and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.

17. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of a viral disease, in particular a retroviral disease, more in particular human immunodeficiency virus (HIV).

Description:
LIM KINASE INHIBITORS

Field of the invention

The present invention relates to new kinase inhibitors, more specifically LIMK1 /2 inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new LIMK1/2 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

The LIM kinase (Lin-1 1/lsl-1/Mec-3 domain-containing protein kinase) family consists of two members: LIM kinase 1 (LIMK1 ) and LIM kinase 2 (LIMK2). LIMK1 and LIMK2 are closely related proteins composed of two N-terminal LIM domains and one C-terminal kinase domain. The LIM domains are protein-binding domains that are frequently found among cytosolic proteins interacting with the actin cytoskeleton. Consistent with the presence of these LIM domains, both LIM kinases have been shown to influence the architecture of the actin cytoskeleton by regulating the activity of the cofilin family proteins cofilinl , cofilin2 and destrin. Although the LIM kinases are very homologous, particularly when comparing kinase domains, there is emerging evidence that each may be subject to different regulatory pathways and may contribute to both distinct and overlapping cellular and developmental functions.

Regulation of actin reorganization and contractility allows cells to control their shape, movement, division and secretion. Such reorganization is one of the earliest cellular responses to many extracellular signals. An important group of effectors regulating this process is composed by the small GTPases from the Rho Family. Active Rho GTPases will allow signal transmission towards Rho- associated, coiled-coil containing protein kinase 1 (ROCK-1 ) and/or p21 -activated protein kinase 1 (PAK1 ). Both PAK1 and ROCK-1 can phosphorylate and activate LIMK1 and LIMK2, which will in turn influence the architecture of the actin cytoskeleton via their action on cofilinl , cofilin2 and destrin.

LIMK also appears to play a role in inflammatory processes. Downregulation of LIMK1 in corneal fibroblasts impaired fibronectin secretion and assembly, diminished actin polymerization and focal adhesion formation, and retarded cell migration. In a mouse model of ocular inflammation, genetic deletion or downregulation of LIMK1 by siRNA reduced the inflammatory response (Molecular Vision (2008), 14, 1951 -1959). LIMK1 was also found to promote endothelial barrier disruption and neutrophil infiltration in lungs. In a mouse model of acute lung injury, LIMK1 deficiency significantly reduces the effects (lung edema formation, lung microvascular permeability, neutrophil infiltration) and mortality induced by endotoxin challenge (Circulation Research (2009), 105(6), 549-556).

Transforming growth factor-β, a family of cytokines, is known to be a key mediator of fibrotic responses such as fibronectin deposition and cell migration to wounding site. Several reports have demonstrated interactions between LIM kinases and TGF-β. A direct association between LIMK1 and BMPR-II (Bone Morphogenic Protein Receptor II), a member from the TGF-β superfamily, has been shown to influence actin cytoskeleton dynamics. LIMK-2 can also be indirectly activated by TGF-β type I receptor, through Rho and ROCK-I. Phosphorylation of LIMK2 following stimulation by TGF-βΙ can indeed be prevented by pre-treatment with Y-27632, a ROCK-selective inhibitor. Finally, Downregulation of LIMK1 via genetic deletion or application of LIMK1 -targeted siRNA reduced TGF-β- associated responses in an animal model of ocular inflammation (Molecular Vision (2008), 14, 1951 - 1959).

LIMK1 activity is involved in cancer metastasis. High levels of LIMK1 are observed in highly invasive breast and cancer cell lines and in human prostate tumors. Overexpression of LIMK1 in non-invasive breast and cancer cell lines increases their invasiveness. In addition, TGF-β as discussed above influences epithelial-mesenchymal transitions, which are important processes in tumor cell invasiveness and metastasis.

LIM kinases are expressed in brain, and LIMKs have also been associated with neurological disorders, including Alzheimer disease (AD). Immunofluorescence analysis of AD brain showed a significant increase in the number of phospho-LIMK1 (P-LIMK1 ) positive neurons in areas affected with AD pathology. Treatment of primary hippocampal neurons with fibrillar amyloid β increases phosphor-ADF/cofilin and P-LIMK1 and results in remodeling of actin filaments, neuritic dystrophy and neuronal cell death. Inhibition of cofilin phosphorylation by LIMK1 prevented actin filament remodeling and neuronal degeneration.VEGFR2 is the major signaling endothelial cell receptor for VEGF in adults and regulates all the major steps of angiogenesis, including endothelial cell proliferation and migration. Activation of the p38 MAP kinase pathway is one of the major contributions to actin remodeling in response to VEGF. Activation of p38 MAP kinase will result in the phosphorylation, and therefore activation of MAPKAPK2 (MAP kinase-activated protein kinase 2, also known as MK2), which in turn activates LIMK1 . LIMK1 subsequently phosphorylates annexinl (ANXA1 ). This phosphorylation has been shown to regulate the angiogenic effects, such as endothelial cell migration and capillary like tube formation, which are associated with the activation of the p38/MAPKAPK2/LIMK1 axis by VEGF.

The current focus for LIMK inhibitor application is oncology and ophthalmic applications and only a few different classes of LIMK inhibitors have been described. However, in view of the multiple regulatory pathways involving LIMK1 and LIMK2, it will be appreciated that modulation of LIMK activity is of interest for the treatment of multiple diseases and conditions. Additionally, LIMKs represent downstream effectors of ROCK, and known selective ROCK inhibitors have been shown to prevent LIMK activation. For example, treatment with Y-27632 prevents the phosphorylation / activation of LIMK2 by ROCK1 , and the subsequent phosphorylation of cofilin in fibroblasts and trabecular meshwork cells. As a consequence, it can be appreciated that at least part of the in vitro, ex vivo or in vivo effects associated with ROCK inhibitors can be reproduced via the use of LIMK inhibitors. Potential applications of ROCK inhibitors involve the treatment and/or prevention of multiple additional diseases with inflammatory and/or fibrotic component, which is also in line with the identified roles of LIMK in inflammatory and fibrotic processes. As discussed hereinabove, the potential uses of LIMK inhibitors include, but are not limited to, the treatment of several eye diseases and conditions.

As the angiogenic effects of VEGF are mediated by LIMK1 , LIMK inhibitors are of interest for the treatment of diseases and condition where anti-VEGF activity is desirable. Such diseases include, but are not limited to, several eye diseases, as highlighted by the approval of Lucentis, an anti-VEGF antibody, for the treatment of age-related macular degeneration (AMD), vision loss due to diabetic macular edema and vision loss due to macular edema secondary to retinal vein occlusion.

Glaucoma is a neurodegenerative disease that is the second most important cause of irreversible blindness. This disease is characterized by a raised IOP and by progressive retinal ganglion cell apoptosis, resulting in irreversible visual field loss. Current treatment of this disease is directed towards the reduction of IOP, which is the main -but not only- risk factor for glaucoma. There is a need for improved treatment as the current therapy does only control and not cure the disease and further suffers from irritation, local and systemic side effects. LIMK inhibitors have been suggested for the treatment of glaucoma. LIMKs are expressed in the trabecular meshwork and are downstream of ROCK in the pathway regulating the polymerization of actin filaments. Knock out studies have shown that LIMK2 -/- KO mice had significantly lower intra-ocular pressure (IOP). LIMK inhibitors have also been shown to inhibit cofilin phosphorylation in pig trabecular meshwork cells. When topically applied to animals, LIMK inhibitors give a significant increase in trabecular outflow, resulting into a strong lowering of intra ocular pressure (Harrison ef a/., J. Med. Chem., 2009, 52, 6515-6518).

When medication regimens and possibly laser treatments fail to control the progression of glaucoma, a glaucoma filtration procedure (also known as trabeculectomy) may be recommended. In such procedures, postoperative fibrosis or scarring at the wound site is a critical determinant of surgical success. Although several anti-scarring agents are currently available, such agents are often associated with severe, potentially blinding complications. There is therefore a need for improved anti scarring agents that could be used after the glaucoma filtration surgery procedure. In this context, it will be appreciated that LIMK inhibitors represent an interesting option for the development of such agents, since downregulation of LIMK1 can simultaneously suppress ocular inflammation and fibrosis., consistent with the role of LIMKs in VEGF/p38/MAPKAPK2 signaling and TGF-β signaling. TGF-β is a key mediator of fibrotic responses, and has been implicated in a variety of eye diseases and conditions in addition to the subconjunctival scarring resulting from glaucoma filtration surgery. These conditions include proliferative vitreoretinopathy, cataract formation and corneal opacities. In view of the links between LIMKs and receptors from the TGF-β superfamily, it will be appreciated that LIMK inhibitors are of interest for the treatment and/or prevention of proliferative vitreoretinopathy, cataract formation and corneal opacities.

Uveitis is an eye disease involving inflammation of the middle layer of the eye (uvea). By extension, uveitis can also refer to inflammatory processes involving the interior of the eye. Uveitis may be classified anatomically into anterior, intermediate, posterior and panuveitic forms, based on which part of the eye is primarily affected by the inflammation. As downregulation of LIMK1 can suppress eye inflammation in animal models, it will be appreciated that LIMK inhibitors are of interest for the treatment of inflammatory eye diseases including, but not limited to, uveitis.

As discussed hereinabove, in view of the roles played by LIM kinases in various biological processes, including inflammatory, angiogenic and fibrotic processes, the potential uses of LIMK inhibitors extend beyond the simple field of eye diseases.

Anti-angiogenic agents have been developed for the treatment of various types of cancer. Examples of such agents include anti VEGF-agents such as Avastin, an anti-VEGF antibody, and Votrient, a multi-targeted receptor tyrosine kinase inhibitor displaying potent inhibitory activity among VEGFR1 , VEGFR2 and VEGFR3. Other kinase inhibitors such as Sunitinib, Sorafenib or Pazopanib also display potent inhibitory activity against VEGFR. In this context, it will be appreciated that LIMK inhibitors offer the possibility of a combined action on VEGF signaling and TGF-β signaling, which can be of particular relevance for the treatment of several types of cancers.

Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process, following injury or long term inflammation. Fibrotic diseases are characterized by the accumulation of extracellular matrix together with distortion and disruption of tissue architecture. Among them, Pulmonary Fibrosis (PF) involves the overgrowth, hardening, and/or scarring of lung tissue due to excess collagen. The most common variation of this disease is Idiopathic (unknown cause) Pulmonary Fibrosis (IPF). IPF patients show decline in gas exchange and reduction in total lung volume. TGF-β has been shown to play a role in multiple fibrotic diseases, including pulmonary fibrosis, renal fibrosis, cardiac fibrosis and vascular fibrosis. In view of the links between LIMKs and receptors from the TGF-β superfamily, it will be appreciated that LIMK inhibitors are of interest for the treatment and/or prevention of fibrotic diseases.

Additionally, BMPR-II, a member from the TGF-β superfamily is mutated in a large majority of familial pulmonary arterial hypertension (PAH). Based on animal models, functional consequences of BMPR2 mutation include alterations in expression of actin organization related genes, possibly related to focal adhesions; alterations in cytokines and inflammatory cell recruitment; increased proliferation and apoptosis; and increased collagen and matrix. Direct association between LIMK1 and BMPR-II has been shown to influence actin cytoskeleton dynamics. In view of the links between BMPR-II and LIMK, it will be understood that LIMK inhibitors are of potential value for the treatment of PAH.

The role of LIMK in inflammation has been evidenced in models of eye inflammation (Molecular Vision (2008), 14, 1951 -1959) and lung inflammation (Circulation Research (2009), 105(6), 549-556). Consequently, it will be appreciated that LIMK inhibitors are of potential value in the treatment of various inflammatory diseases and disorders. In particular, the combined involvement of LIMK in inflammatory processes and fibrotic processes make LIMK inhibitors an attractive option for the treatment of diseases and conditions combining an inflammatory component with a fibrotic component including but not limited to, chronic obstructive pulmonary disease (COPD), or Crohn's disease.

Inhibition of cofilin phosphorylation by LIMK1 prevented actin filament remodeling and neuronal degeneration induced by fibrillar amyloid β. Consequently, LIMK inhibitors might also be of interest for the treatment of neurodegenerative diseases and disorders including, but not limited to, Alzheimer's disease.

Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune Deficiency Syndrome (AIDS). Treatment of HIV-infected patients is currently based on the use of chemical compounds that interfere with various steps of the viral replication cycle (chemotherapy).

An important step in viral infection is the entry of viral particles into the host cell. For many such pathogens, this entry involves some degree of interaction with the cytoskeleton of the host cell as well as with cellular (co-)receptors, In the case of HIV-1 , binding and entry into host cells are mediated by the involvement of actin and co-receptors (such as CD4, CCR5 and CXCR4) upon exposure of T lymphocytes to the viral envelope glycoprotein gp120. Targeting such cellular co-factors is an interesting approach for antiviral therapy, because an antiviral agent binding to a protein of the host cells is potentially less sensitive to the effect of viral mutations than agents binding to viral proteins. Maraviroc (Selzentry® or Celsentri®) is an anti-HIV agent blocking the CCR5 co-receptor. A later step of the HIV-1 life cycle involves retrotranscription of the viral genome, which is initially in the form of signle-stranded RNA, into double-stranded DNA. This reverse transcription involves formation of a reverse transcription complex including HIV-1 reverse transcriptase, as well as several other viral proteins and host cell proteins. Establishment of a functional reverse transcription process involves interaction with the cytoskeleton, including actin.

Both LIM kinases have been shown to influence the architecture of the actin cytoskeleton by regulating the activity of the cofilin family proteins cofilinl , cofilin2 and destrin, It will therefore be appreciated that LIMKs represent potential targets for antiviral therapies. Indeed, LIM kinase 1 (LIMK1 ) modulates cortical actin and CXCR4 cycling and is activated by HIV-1 to initiate viral infection

In conclusion, there is a continuing need to design and develop LIMK inhibitors for the treatment of a wide range of disease states. The compounds described herein and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of a variety of disorders or conditions associated with LIMK activation. More specifically, the compounds of the invention are preferably used in the prevention and/or treatment of at least one disease or disorder, in which LIMK is involved, such as diseases linked to smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, and neurodegeneration. For example, the compounds of the invention may be used in the prevention and/or treatment of diseases and disorders such as:

- Eye diseases or disorders: including but not limited to glaucoma and degenerative retinal diseases such as macular degeneration, vision loss due to diabetic macular edema, vision loss due to macular edema secondary to retinal vein occlusion proliferative vitreoretinopathy; inflammatory eye diseases such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis, glaucoma filtration surgery failure, dry eye, allergic conjunctivitis, posterior capsule opacification, cataract formation, abnormalities of corneal wound healing, ocular pain and ocular hypertension. - Airway diseases; including but not limited to pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, chronic obstructive pulmonary disease (COPD); bronchitis and rhinitis and respiratory distress syndrome

- Skin diseases: including but not limited to scarring, hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis and ulceration.

- Intestinal diseases; including but not limited to inflammatory bowel disease (IBD), colitis, gastroenteritis, ileus, ileitis, appendicitis and Crohn's disease.

- Cardiovascular and vascular diseases: including but not limited to, pulmonary hypertension and pulmonary vasoconstriction.

- Inflammatory diseases: including but not limited to contact dermatitis, atopic dermatitis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis.

- Proliferative diseases: such as but not limited to cancer of breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, ovary, pancreas, prostate, or thyroid gland; Castleman disease; sarcoma; malignoma; and melanoma.

- Kidney diseases: including but not limited to renal fibrosis or renal dysfunction

- Bone diseases: including but not limited to osteoporosis and osteoarthritis

- Neurodegenerative diseases: including but not limited to Alzheimer's disease.

Additionally, compounds of the invention can be used in the prevention or and/or treatment of several viral diseases, in particular retroviral diseases, including infection by HIV. In another particular embodiment, the compounds of the invention are used for the treatment and/or prevention of sclerosis.

SUMMARY OF THE INVENTION

We have surprisingly found that the compounds described herein act as inhibitors of LIM kinases. Art- known LIMK inhibitors such as those disclosed in WO2009/021 169, WO2009/131940 and WO2012/061565, have a pyrrolopyrimidine (i.e. bicyclic) structure. The present inventors have surprisingly found that compounds with a larger, tricyclic structure retain LIMK inhibitory activity. Even more surprisingly, the tricyclic structure of the compounds of the invention provides increased selectivity for LIMKs vs. other kinases.

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.

Viewed from a first aspect, the invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof,

I

Wherein,

Ar is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 5 groups;

X is a direct bond or an optionally substituted d- 6 alkylene;

m is an integer from 1 to 3;

n is an integer from 0 to 6;

R is H or Ci-6 alkyl;

R 2 and R 3 are independently selected from H , Ci_ 6 alkyl;

or R 2 and R 3 are joined together so that they form a C 3 . 6 nitrogen-containing heterocycle;

L is a direct bond or an optionally substituted Ci_ 6 alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S0 2 , S0 2 NR', NR'C(=0)NR", NR'S(=0)NR", and NR'S(=0)(=0)NR"; and wherein the optional substituents are selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, and halo;

Cy is a direct bond or an optionally substituted cyclic structure selected from Ci_ 8 cycloalkyl, d.

8heterocyclyl, aryl and heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_ 6 alkyl, amino, alkylamino, dialkylamino, hydroxyl, thiol, alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl;

L 2 is a direct bond or an optionally substituted Ci_ 8 alkylene, Ci_ 8 alkenylene, or Ci_ 8 alkynylene; wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S0 2 , S0 2 NR', NR'C(=0)NR', NR'S(=0)NR', or NR'S(=0)(=0)NR'; and wherein the optional substituents are selected from the group consisting of hydroxyl, amino, alkylamino, dialkylamino, alkoxyl, haloalkoxyl, alkylthio, thiol, halo, cyano, and carboxyl; R 4 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, halo, and heterocyclyl; wherein said heterocyclyl is optionally substituted with one or more groups selected from Ci_ 6 alkyl, halo, and oxo;

R 5 is selected from oxo, halo, d- 6 alkyl, Ci_ 6 alkenyl, Ci_ 6 alkynyl, hydroxyl, Ci_ 6 alkoxyl, amino, mono- or di(Ci- 6 alkyl)amino, nitro, cyano, thio, and Ci_ 6 alkylthio;

R 6 and R 6 ' are independently selected from hydrogen and fluoro; and

R' and R" are in each instance independently hydrogen or Ci_ 6 alkyl.

Viewed from a 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 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 LIM kinase, for example LIMK1 and/or LIMK2 isoforms.

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, airway diseases, intestinal diseases, proliferative diseases; cardiovascular and vascular diseases, kidney diseases, bone diseases, neurodegeneration and viral infections, including infection by H IV.

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 the present invention are interchangeably indicated by drawing a wavy bonds or a straight bond in order to visualize the undefined steric character of the bond. As already mentioned hereinbefore, in a first aspect the present invention provides compounds of Formula I

I

Wherein m, n, X, Ar, R , R 2 , R 3 , L , Cy, L 2 , R 4 , R 6 and R 6 are as defined hereinbefore, including the stereo-isomeric forms, solvates, and pharmaceutically acceptable addition salts thereof.

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 fully saturated hydrocarbon of Formula C x H 2x+ i wherein x is a number greater than or equal to 1 . Generally, alkyl groups of this invention comprise from 1 to 20 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, Ci- 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. C C 6 alkyl includes all linear, branched, or cyclic 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, hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl, cyclopentylmethylene, and cyclohexyl. In a preferred embodiment, alkyl refers to d- 6 alkyl .

The term "optionally substituted alkyl" refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, for 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 halo, hydroxyl, oxo, carbonyl, nitro, amino, amido, oxime, imino, azido, hydrazino, cyano, aryl, heteroaryl , cycloalkyl, heterocyclyl, acyl, alkylamino, alkoxy, haloalkoxy, haloalkyl, thiol, alkylthio, carboxylic acid, acylamino, alkyl esters, carbamate, thioamido, urea, sullfonamido and the like.

The term "alkylamino", as used herein refers to an amino group substituted with one or more alkyl chain(s). This definition includes quaternary ammonium derivatives. The term "alkenyl", as used herein, unless otherwise indicated, means straight-chain, cyclic, or branched-chain hydrocarbon radicals containing at least one carbon-carbon double bond. Examples of alkenyl radicals include ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z- isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, Ε,Ε-, Ε,Ζ-, Ζ,Ε-, Ζ,Ζ-hexadienyl, and the like. An optionally substituted alkenyl refers to an alkenyl having optionally one or more substituents (for example 1 , 2, 3 or 4), selected from those defined above for substituted alkyl.

The term "alkynyl", as used herein, unless otherwise indicated, means straight-chain or branched- chain hydrocarbon radicals containing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like. An optionally substituted alkynyl refers to an alkynyl having optionally one or more substituents (for example 1 , 2, 3 or 4), selected from those defined above for substituted alkyl.

The term "cycloalkyl" by itself or as part of another substituent is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated 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 15 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 include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl, bicyclo(2.2.1 )heptanyl and cyclodecyl with cyclopropyl, cyclopentyl, cyclohexyl, adamantanyl, and bicyclo(2.2.1 )heptanyl being particularly preferred. In a preferred embodiment, cycloalkyl refers to a mono- or bicyclic alkyl group consisting of 3 to 15 carbon atoms.

An "optionally substituted cycloalkyl" refers to a cycloalkyl having optionally one or more substituents (for example 1 to 3 substituents, for example 1 , 2, 3 or 4 substituents), selected from those defined above for substituted alkyl. When the suffix "ene" is used in conjunction with a cyclic group, hereinafter also referred to as "Cycloalkylene", this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups. Cycloalkylene groups of this invention preferably comprise the same number of carbon atoms as their cycloalkyl radical counterparts.

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. 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 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 heterocyclyl refers to a heterocyclyl having optionally one or more substituents (for example 1 to 4 substituents, or for example 1 , 2, 3 or 4), selected from those defined for substituted aryl. In a particular embodiment, heterocyclyl refers to a mono- or bicyclic alkyl group consisting of 4 to 15 carbon atoms wherein 1 to 4 carbon atoms have been replaced with a heteroatom selected from nitrogen, oxygen and/or sulfur.

Exemplary heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H-indolyl, 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 ,3-dioxanyl, 2,5-dioximidazolidinyl, 2,2,4-piperidonyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, 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, 21-1-1 ,5,2- dithiazinyl, 2H-oxocinyl, 1 H-pyrrolizinyl, tetrahydro-1 ,1 -dioxothienyl, N- formyl piperazinyl, 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 6 to 10 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-, 4-, 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, and 1 -, 2-, 3-, 4-, or 5-pyrenyl.

The aryl ring can optionally be substituted by one or more substituents. An "optionally substituted aryl" refers to an aryl having optionally one or more substituents (for example 1 to 5 substituents, for example 1 , 2, 3 or 4) 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, -S0 2 -NH 2 , aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -S0 2 R a , alkylthio, carboxyl, and the like, wherein R a is alkyl or cycloalkyl.

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 such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, 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, benzopyranyl, 1 (4H)-benzopyranyl, 1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)- benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl, 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, 6-oxo-pyridazin-1 (6H)-yl, 2-oxopyridin-1 (2H)-yl, 6-oxo- pyridazin-1 (6H)-yl, 2-oxopyridin-1 (2H)-yl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.

The term "pyrrolyl" (also called azolyl) as used herein includes pyrrol-1 -yl, pyrrol-2-yl and pyrrol-3-yl. The term "furanyl" (also called "furyl") as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl). The term "thiophenyl" (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term "pyrazolyl" (also called 1 H-pyrazolyl and 1 ,2-diazolyl) as used herein includes pyrazol-1 -yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl. The term "imidazolyl" as used herein includes imidazol-1 -yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl. The term "oxazolyl" (also called 1 ,3-oxazolyl) as used herein includes oxazol-2-yl; oxazol-4-yl and oxazol-5-yl. The term "isoxazolyl" (also called 1 ,2-oxazolyl), as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term "thiazolyl" (also called 1 ,3-thiazolyl),as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4-thiazolyl and 5- thiazolyl). The term "isothiazolyl" (also called 1 , 2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. The term "triazolyl" as used herein includes 1 H-triazolyl and 4H- 1 ,2,4-triazolyl, Ί H-triazolyl" includes 1 H-1 ,2,3-triazol-1 -yl, 1 H-1 ,2,3-triazol-4-yl, 1 H-1 ,2,3-triazol-5-yl, 1 H-1 ,2,4-triazol-1 -yl, 1 H-1 ,2,4-triazol-3-yl and 1 H-1 ,2,4-triazol-5-yl. "4H-1 ,2,4-triazolyl" includes 4H- 1 ,2,4-triazol-4-yl, and 4H-1 ,2,4-triazol-3-yl. The term "oxadiazolyl" as used herein includes 1 ,2,3- oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,2,4-oxadiazol -3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,5-oxadiazol-3-yl and 1 ,3,4-oxadiazol-2-yl. The term "thiadiazolyl" as used herein includes 1 ,2,3-thiadiazol-4-yl, 1 ,2,3- thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl (also called furazan-3-yl) and 1 ,3,4-thiadiazol-2-yl. The term "tetrazolyl" as used herein includes 1 H-tetrazol-1 -yl, 1 H-tetrazol-5- yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term "oxatriazolyl" as used herein includes 1 ,2,3,4- oxatriazol-5-yl and 1 ,2,3,5-oxatriazol-4-yl. The term "thiatriazolyl" as used herein includes 1 ,2,3,4- thiatriazol-5-yl and 1 ,2,3,5-thiatriazol-4-yl. The term "pyridinyl" (also called "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2-pyridyl, 3-pyridyl and 4-pyridyl). The term "pyrimidyl" as used herein includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl and pyrimid-6-yl. The term "pyrazinyl" as used herein includes pyrazin-2-yl and pyrazin-3-yl. The term "pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl. The term "oxazinyl" (also called "1 ,4-oxazinyl") as used herein includes 1 ,4-oxazin-4-yl and 1 ,4-oxazin-5-yl. The term "dioxinyl" (also called "1 ,4-dioxinyl") as used herein includes 1 ,4-dioxin-2-yl and 1 ,4-dioxin-3-yl. The term "thiazinyl" (also called "1 ,4- thiazinyl") as used herein includes 1 ,4-thiazin-2-yl, 1 ,4-thiazin-3-yl, 1 ,4-thiazin-4-yl, 1 ,4-thiazin-5-yl and 1 ,4-thiazin-6-yl. The term "triazinyl" as used herein includes 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3-yl, 1 ,2,4- triazin-5-yl, 1 ,2,4-triazin-6-yl, 1 ,2,3-triazin-4-yl and 1 ,2,3-triazin-5-yl. The term "imidazo[2,1 - b][1 ,3]thiazolyl" as used herein includes imidazo[2,1 -b][1 ,3]thiazoi-2-yl, imidazo[2,1 -b][1 ,3]thiazol-3-yl, imidazo[2, 1 -b][1 ,3]thiazol-5-yl and imidazo[2,1 -b][1 ,3]thiazol-6-yl. The term "thieno[3,2-b]furanyl" as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl. The term "thieno[3,2-b]thiophenyl" as used herein includes thieno[3,2-b]thien- 2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2-b]thien-6-yl. The term "thieno[2,3- d][1 ,3]thiazolyl" as used herein includes thieno[2,3-d][1 ,3]thiazol-2-yl, thieno[2,3-d][1 ,3]thiazol-5-yl and thieno[2,3-d][1 ,3]thiazol-6-yl. The term "thieno[2,3-d]imidazolyl" as used herein includes thieno[2,3- d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl and thieno[2,3-d]imidazol-5-yl. The term "tetrazolo[1 ,5- a]pyridinyl" as used herein includes tetrazolo[1 ,5-a]pyridine-5-yl, tetrazolo[1 ,5-a]pyridine-6-yl, tetrazolo[1 ,5-a]pyridine-7-yl, and tetrazolo[1 ,5-a]pyridine-8-yl. The term "indolyl" as used herein includes indol-1 -yl, indol-2-yl, i ndol-3-yl ,-indol-4-yl , indol-5-yl, indol-6-yl and indol-7-yl. The term "indolizinyl" as used herein includes indolizin-1 -yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin- 6-yl, indolizin-7-yl, and indolizin-8-yl. The term "isoindolyl" as used herein includes isoindol-1 -yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl and isoindol-7-yl. The term "benzofuranyl" (also called benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl. The term "isobenzofuranyl" (also called benzo[c]furanyl) as used herein includes isobenzofuran-1 -yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl and isobenzofuran-7-yl. The term "benzothiophenyl" (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3- benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7- benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl). The term "isobenzothiophenyl" (also called benzo[c]thienyl) as used herein includes isobenzothien-1 -yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl and isobenzothien-7-yl. The term "indazolyl" (also called 1 H-indazolyl or 2- azaindolyl) as used herein includes 1 H-indazol-1 -yl, 1 H-indazol-3-yl, 1 H-indazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H- indazol-6-yl, and 2H-indazol-7-yl. The term "benzimidazolyl" as used herein includes benzimidazol-1 - yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term "1 ,3-benzoxazolyl" as used herein includes 1 ,3-benzoxazol-2-yl, 1 ,3-benzoxazol-4-yl, 1 ,3- benzoxazol-5-yl, 1 ,3-benzoxazol-6-yl and 1 ,3-benzoxazol-7-yl. The term "1 ,2-benzisoxazolyl" as used herein includes 1 ,2-benzisoxazol-3-yl, 1 ,2-benzisoxazol-4-yl, 1 ,2-benzisoxazol-5-yl, 1 ,2-benzisoxazol- 6-yl and 1 ,2-benzisoxazol-7-yl. The term "2,1 -benzisoxazolyl" as used herein includes 2,1 - benzisoxazol-3-yl, 2,1 -benzisoxazol-4-yl, 2,1 -benzisoxazol-5-yl, 2,1 -benzisoxazol-6-yl and 2,1 - benzisoxazol-7-yl. The term "1 ,3-benzothiazolyl" as used herein includes 1 ,3-benzothiazol-2-yl, 1 ,3- benzothiazol-4-yl, 1 ,3-benzothiazol-5-yl, 1 ,3-benzothiazol-6-yl and 1 ,3-benzothiazol-7-yl. The term "1 ,2-benzoisothiazolyl" as used herein includes 1 ,2-benzisothiazol-3-yl, 1 ,2-benzisothiazol-4-yl, 1 ,2- benzisothiazol-5-yl, 1 ,2-benzisothiazol-6-yl and 1 ,2-benzisothiazol-7-yl. The term "2,1 - benzoisothiazolyl" as used herein includes 2,1 -benzisothiazol-3-yl, 2,1 -benzisothiazol-4-yl, 2,1 - benzisothiazol-5-yl, 2,1 -benzisothiazol-6-yl and 2,1 -benzisothiazol-7-yl. The term "benzotriazolyl" as used herein includes benzotriazol-1 -yl, benzotriazol4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl. The term "1 ,2,3-benzoxadiazolyl" as used herein includes 1 ,2,3-benzoxadiazol-4-yl, 1 ,2,3-benzoxadiazol-5-yl, 1 ,2,3-benzoxadiazol-6-yl and 1 ,2,3-benzoxadiazol-7-yl. The term "2,1 ,3- benzoxadiazolyl" as used herein includes 2,1 ,3-benzoxadiazol-4-yl, 2,1 ,3-benzoxadiazol-5-yl, 2,1 ,3- benzoxadiazol-6-yl and 2,1 ,3-benzoxadiazol-7-yl. The term "1 ,2,3-benzothiadiazolyl" as used herein includes 1 ,2,3-benzothiadiazol-4-yl, 1 ,2,3-benzothiadiazol-5-yl, 1 ,2,3-benzothiadiazol-6-yl and 1 ,2,3- benzothiadiazol-7-yl. The term "2,1 ,3-benzothiadiazolyl" as used herein includes 2,1 ,3- benzothiadiazol-4-yl, 2,1 ,3-benzothiadiazol-5-yl, 2,1 ,3-benzothiadiazol-6-yl and 2,1 ,3-benzothiadiazol- 7-yl. The term "thienopyridinyl" as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl. The term "purinyl" as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term "imidazo[1 ,2-a]pyridinyl", as used herein includes imidazo[1 ,2-a]pyridin-2-yl, imidazo[1 ,2-a]pyridin-3-yl, imidazo[1 ,2-a]pyridin-4-yl, imidazo[1 ,2-a]pyridin- 5-yl, imidazo[1 ,2-a]pyridin-6-yl and imidazo[1 ,2-a]pyridin-7-yl. The term "1 ,3-benzodioxolyl", as used herein includes 1 ,3-benzodioxol-4-yl, 1 ,3-benzodioxol-5-yl, 1 ,3-benzodioxol-6-yl, and 1 ,3-benzodioxol- 7-yl. The term "quinolinyl" as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5- yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl. The term "isoquinolinyl" as used herein includes isoquinolin-1 -yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The term "cinnolinyl" as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term "quinazolinyl" as used herein includes quinazolin-2-yl, quiriazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term "quinoxalinyl". as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl. The term "7-azaindolyl" as used herein refers to 1 H-Pyrrolo[2,3-b]pyridinyl and includes 7-azaindol-1 - yl, 7-azaindol-2-yl, 7-azaindol-3-yl, 7-azaindol-4-yl, 7-azaindol-5-yl, 7-azaindol-6-yl. The term "6- azaindolyl" as used herein refers to 1 H-Pyrrolo[2,3-c]pyridinyl and includes 6-azaindol-1 -yl, 6-azaindol-

2- yl, 6-azaindol-3-yl, 6-azaindol-4-yl, 6-azaindol-5-yl, 6-azaindol-7-yl. The term "5-azaindolyl" as used herein refers to 1 H-Pyrrolo[3,2-c]pyridinyl and includes 5-azaindol-1 -yl, 5-azaindol-2-yl, 5-azaindol-3- yl, 5-azaindol-4-yl, 5-azaindol-6-yl, 5-azaindol-7-yl. The term "4-azaindolyl" as used herein refers to 1 H-Pyrrolo[3,2-b]pyridinyl and includes 4-azaindol-1 -yl, 4-azaindol-2-yl, 4-azaindol-3-yl, 4-azaindol-5- yl, 4-azaindol-6-yl, 4-azaindol-7-yl.

For example, 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 -, -4- or -5-yl, 1 ,2,4-triazol-1 -, -3-, -4- or -5-yl, 1 H- tetrazol-1 -, or-5-yl, 2H-tetrazol-2-, 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-, 4-, 5- or 6- pyrimidyl, 2-, 3-, 4-, 5- 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 4-azaindol-1 -, 2-, 3-, 5-, or 7-yl, 5- azaindol-1 -, or 2-, 3-, 4-, 6-, or 7-yl, 6-azaindol-1 , 2-, 3-, 4-, 5-, or 7-yl, 7-azaindol-1 -, 2-, 3-, 4, 5-, or 6- yl, 2-, 3-, 4-, 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, benzimidazol-1 -yl, -2-yl, -4-yl, -5-yl, -6-yl, or -7-yl, 1 -, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisothiazolyl, 1 ,3-benzothiazol-2-yl, -4-yl, -5-yl, -6-yl or -7-yl, 1 ,3-benzodioxol-4-yl, -5-yl, -6-yl, or -7-yl, benzotriazol-1 -yl, -4-yl, -5-yl, -6-yl or -7-yl1 -, 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-, 4-, 5-, 6-, 7- or 8- indolizinyl, 2-, 3-, 4- or 5-isoindolyl, 1 H-indazol-1 -yl, 3-yl, -4-yl, -5-yl, -6-yl, or -7-yl, 2H-indazol-2-yl, 3- yl, -4-yl, -5-yl, -6-yl, or -7-yl, imidazo[2,1 -b][1 ,3]thiazoi-2-yl, imidazo[2,1 -b][1 ,3]thiazol-3-yl, imidazo[2, 1 -b][1 ,3]thiazol-5-yl or imidazo[2,1 -b][1 ,3]thiazol-6-yl, imidazo[1 ,2-a]pyridin-2-yl, imidazo[1 ,2-a]pyridin- 3-yl, imidazo[1 ,2-a]pyridin-4-yl, imidazo[1 ,2-a]pyridin-5-yl, imidazo[1 ,2-a]pyridin-6-yl or imidazo[1 ,2- a]pyridin-7-yl, tetrazolo[1 ,5-a]pyridine-5-yl, tetrazolo[1 ,5-a]pyridine-6-yl, tetrazolo[1 ,5-a]pyridine-7-yl, or tetrazolo[1 ,5-a]pyridine-8-yl, 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-, 4-, 5-, 6-, 7- or 8-quinazolyl, 1 -, 3-, 4-, 5-, 6-, 7- or 8- isoquinolinyl(isoquinolyl), 3-, 4-, 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 4- 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, for example 1 , 2, 3 or 4), selected from those defined above for substituted aryl.

The term "oxo" as used herein refers to the group =0.

The term "alkoxy" or "alkyloxy" as used herein refers to a radical having the Formula -OR b wherein R b is alkyl. Preferably, alkoxy is C Ci 0 alkoxy, C C 6 alkoxy, or C C 4 alkoxy. Non-limiting examples of suitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- butoxy, pentyloxy and hexyloxy. 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 halogen. Non-limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1 ,1 ,2,2- tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy; trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy.

The term "aryloxy" as used herein denotes a group -O-aryl, wherein aryl is as defined above.

The term "arylcarbonyl" or "aroyl" as used herein denotes a group -C(0)-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 cycloalkyi 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, cyclohexyl butyl 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 d -R c wherein R d is alkylene or alkylene substituted by alkyl group and R c is a heterocyclyl group.

The term "carboxy" or "carboxyl" or "hydroxycarbonyl" by itself or as part of another substituent refers to the group -C0 2 H. Thus, a carboxyalkyl is an alkyl group as defined above having at least one substituent that is -C0 2 H.

The term "alkoxycarbonyl" by itself or as part of another substituent refers to a carboxy group linked to an alkyl radical i.e. to form -C(=0)OR e , wherein R e is as defined above for alkyl.

The term "alkylcarbonyloxy" by itself or as part of another substituent refers to a -0-C(=0)R e wherein R e is as defined above for alkyl. The term "alkylcarbonylamino" by itself or as part of another substituent refers to an group of Formula -NH(C=0)R or -NR'(C=0)R, wherein R and R' are each independently alkyl or substituted alkyl.

The term "thiocarbonyl" by itself or as part of another substituent refers to the group -C(=S)-.

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, cycloalkyl group, aralkyl, or cycloalkylalkyl 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 "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 "haloaryl" alone or in combination, refers to an aryl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.

The term "haloalkoxy" alone or in combination refers to a group of Formula -O-alkyI wherein the alkyl group is substituted by 1 , 2, or 3 halogen atoms. For example, "haloalkoxy" includes -OCF 3 , -OCHF 2 , -OCH 2 F, -O-CF2-CF3, -O-CH2-CF3, -O-CH2-CH F2, and -0-CH 2 -CH 2 F.

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.

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.

As described herein, 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. 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 and any subgroup thereof. This term also refers to the compounds as depicted in examples, their derivatives, /v-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 v-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called /v-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.

In a particular embodiment, the present invention provides those compounds wherein R 6 and R 6 are hydrogen. In another particular embodiment, R' is the same as R".

In a further embodiment, the present invention provides those compounds of formula I wherein

Ar is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 5 groups;

X is a direct bond or an optionally substituted Ci_ 6 alkylene;

m is an integer from 1 to 3;

n is an integer from 0 to 6;

R is H or Ci -6 alkyl;

R 2 and R 3 are independently selected from H , Ci_ 6 alkyl;

or R 2 and R 3 are joined together so that they form a C 3 . 6 nitrogen-containing heterocycle;

R 5 is selected from oxo, halo, d- 6 alkyl, hydroxyl, Ci_ 6 alkoxyl, amino, mono- or di(Ci_ 6 alkyl)amino, nitro, cyano, thio, and Ci_ 6 alkylthio;

L is a direct bond or an optionally substituted Ci_ 6 alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S0 2 , S0 2 NR', NR'C(=0)NR',

NR'S(=0)NR', or NR'S(=0)(=0)NR'; and wherein the optional substituents are selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, and halo;

Cy is a direct bond or an optionally substituted cyclic structure selected from aryl or heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_ 6 alkyl, amino, alkylamino, dialkylamino, hydroxyl, thiol, alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl;

L 2 is a direct bond or an optionally substituted Ci_ 8 alkylene, d- 8 alkenylene, or Ci_ 8 alkynylene; wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR',

NR'S0 2 , S0 2 NR', NR'C(=0)NR', NR'S(=0)NR', or NR'S(=0)(=0)NR'; and wherein the optional substituents are selected from the group consisting of hydroxyl, amino, alkylamino, dialkylamino, alkoxyl, haloalkoxyl, alkylthio, thiol, halo, cyano, and carboxyl;

R 4 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, halo, and heterocyclyl; wherein said heterocyclyl is optionally substituted with one or more groups selected from Ci_ 6 alkyl, halo, and oxo; and

R' is in each instance independently chosen from hydrogen and Ci_ 6 alkyl; and

R 6 and R 6 are hydrogen.

In a further embodiment, the present invention provides compounds of formula I, wherein;

Wherein,

Ar is aryl or heteroaryl; in particular aryl; wherein said aryl or heteroaryl is optionally substituted with one or more R 5 groups;

X is a direct bond or an optionally substituted alkylene; in particular a direct bond;

m is an integer from 1 to 3, in particular 2;

n is an integer from 0 to 6, in particular from 0 to 1 ;

R is H or C1-6 alkyl; in particular H or methyl;

R 2 and R 3 are independently H or Ci_ 6 alkyl;

or R 2 and R 3 can be joined together so that they form a C 3 . 6 nitrogen-containing heterocycle; in particular, R 2 , R 3 are selected from H or methyl;

R 5 is selected from oxo, halo, Ci_ 6 alkyl, hydroxyl, Ci_ 6 alkoxyl, amino, mono- or di(Ci_ 6 alkyl)amino, nitro, cyano, thio, and Ci_ 6 alkylthio; in particular H, Ci_ 6 alkyl or halo;

R 6 and R 6 ' are independently selected from H or F; in particular H;

and wherein L -Cy-L 2 -R 4 is as defined herein.

In an even further embodiment, the present invention provides compounds of formula I, wherein; Ar is aryl; in particular phenyl; wherein said aryl is optionally substituted with one or more R 6 groups; X is a direct bond; m is an integer from 1 to 3, in particular 1 ;

n is an integer from 0 to 6, in particular from 0 to 1 ;

R is H or methyl, in particular H;

R 2 and R 3 are independently H or methyl, in particular methyl;

R 5 is selected from d- 6 alkyl, cyano and halo; in particular from H, methyl, and fluoro;

R 6 and R 6 ' are both selected from H or F; in particular H;

and wherein L -Cy-L 2 -R 4 is as defined herein.

In yet another embodiment, the present invention provides those compounds of formula I, wherein Cy is a direct bond; in particular wherein Cy and L are a direct bond.

In another particular embodiment, the present invention provides those compounds of formula I, wherein L or L 2 is a direct bond; in particular wherein L 2 is a direct bond.

In yet another particular embodiment, the present invention provides those compounds as described herein, wherein L is not a direct bond and wherein Cy is not a direct bond. In a further embodiment, the present invention provides those compounds wherein

L is selected from O, NR', S, C(=0), C(=0)0, OC(=0), C(=0)NR', NR'C(=0), NR'C(=0)0,

OC(=0)NR', or NR'C(=0)NR"; in particular from C(=0)NR' and NR'C(=0); and

Cy is an optionally substituted cyclic structure selected from aryl or heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_ 6 alkyl, amino, alkylamino, dialkylamino, hydroxyl, thiol, alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl.

In a further embodiment, the present invention provides those compounds of formula I, wherein

L is a direct bond;

Cy is a direct bond; and

L 2 is an optionally substituted Ci_ 8 alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', or NR'C(=0)NR"; and wherein the optional substituents are selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, halo, cyano, and carboxyl.

In another embodiment, the present invention provides those compounds of formula I, wherein L is a direct bond; Cy is a direct bond ;

L 2 is a Ci- 8 alkylene wherein optionally a single methylene unit is replaced by a functional group selected from O, NR\ S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0),

NR'C(=0)0, OC(=0)NR' , NR'S0 2 , S0 2 NR', NR'C(=0)N R", NR'S(=0)NR", or NR'S(=0)(=0)N R"; and R 4 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl , alkylthio, hydroxyl , thiol, cyano, halo, and heterocyclyl; wherein said heterocyclyl is optionally substituted with one or more groups selected from Ci_ 6 alkyl, halo, and oxo.

In another embodiment, the present invention provides those compounds of formula I, wherein

Ar is aryl , which is optionally substituted with one or more R 5 groups;

X is a direct bond;

m is an integer from 1 to 3, in particular 1 to 2;

n is 0 or 1 ;

R is H ;

R 2 and R 3 are independently H or Ci_ 6 alkyl;

R 5 is selected from oxo, halo, d- 6 alkyl, hydroxyl , Ci_ 6 alkoxyl , amino, mono- or di(Ci_ 6 alkyl)amino, nitro, cyano, thio, and Ci_ 6 alkylthio; in particular H , Ci_ 6 alkyl or halo;

R 6 and R 6 ' are independently H or F;

L is a direct bond;

Cy is an optionally substrituted aryl or heteroaryl, in particular heteroaryl;

L 2 is a direct bond or an optionally substituted Ci_ 8 alkylene; and

R 4 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl , alkylthio, and halo.

In a further embodiment, the present invention provides those compounds of formula I, wherein Ar is phenyl;

X is a direct bond;

m is an integer from 1 to 3, in particular 1 to 2;

n is 0 or 1 ;

R is H ;

R 2 and R 3 are independently H or methyl;

R 5 is H ;

R 6 and R 6 ' are both selected from H or F; L is a direct bond;

Cy is an optionally substrituted aryl or heteroaryl, in particular heteroaryl;

L 2 is a direct bond; and

R 5 is hydrogen.

In another embodiment, the present invention provides compounds of formula I, wherein

R 6 and R 6 ' are both F.

Ar is aryl or heteroaryl; in particular aryl; wherein said aryl or heteroaryl is optionally substituted with one or more R 5 groups;

X is a direct bond or an optionally substituted d- 6 alkylene; in particular a direct bond;

m is an integer from 1 to 3, in particular 2;

n is an integer from 0 to 6, in particular from 0 to 1 ;

R is H or C-i-6 alkyl; in particular H or methyl;

R 2 and R 3 are independently H or Ci_ 6 alkyl;

or R 2 and R 3 can be joined together so that they form a C 3 . 6 nitrogen-containing heterocycle;

in particular, R 2 , R 3 are selected from H or methyl;

R 5 is selected from oxo, halo, Ci_ 6 alkyl, hydroxyl, Ci_ 6 alkoxyl, amino, mono- or di(Ci_ 6 alkyl)amino, nitro, cyano, thio, and Ci_ 6 alkylthio; in particular H, Ci_ 6 alkyl or halo;

and wherein L -Cy-L 2 -R 4 is as defined herein.

In further embodiment, the present invention provides compounds of formula I, wherein

R 6 and R 6 ' are both F;

Ar is aryl; in particular phenyl; wherein said aryl is optionally substituted with one or more R 5 groups; X is a direct bond;

m is 2;

n is an integer from 0 to 1 ;

R is H or methyl, in particular H;

R 2 and R 3 are independently H or Ci_ 6 alkyl; in particular, R 2 , R 3 are selected from H or methyl;

R 5 is selected from oxo, halo, Ci_ 6 alkyl, hydroxyl, Ci_ 6 alkoxyl, amino, mono- or di(Ci_ 6 alkyl)amino, nitro, cyano, thio, and Ci_ 6 alkylthio; in particular H, Ci_ 6 alkyl or halo;

and wherein L -Cy-L 2 -R 4 is as defined herein. In another particular embodiment, the present invention provides compounds of formula I wherein

Ar is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R 5 groups;

X is a direct bond or an optionally substituted Ci_ 6 alkylene;

m is an integer from 1 to 3;

n is an integer from 0 to 6;

R is H or Ci -6 alkyl;

R 2 and R 3 are independently selected from H , Ci_ 6 alkyl;

or R 2 and R 3 are joined together so that they form a C 3 . 6 nitrogen-containing heterocycle;

L is a direct bond or an optionally substituted d- 6 alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S0 2 , S0 2 NR', NR'C(=0)NR", NR'S(=0)NR", and NR'S(=0)(=0)NR"; and wherein the optional substituents are selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, and halo;

Cy is a direct bond or an optionally substituted cyclic structure selected from Ci_ 8 cycloalkyl, d.

8heterocyclyl, aryl, and heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_ 6 alkyl, amino, alkylamino, dialkylamino, hydroxyl, thiol, alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl;

L 2 is a direct bond;

R 4 is hydrogen;

R 5 is selected from oxo, halo, Ci_ 6 alkyl, Ci_ 6 alkenyl, Ci_ 6 alkynyl, hydroxyl, Ci_ 6 alkoxyl, amino, mono- or di(Ci- 6 alkyl)amino, nitro, cyano, thio, and Ci_ 6 alkylthio;

R 6 and R 6 ' are independently selected from hydrogen or fluoro; and

R' and R" are in each instance independently chosen from hydrogen and Ci_ 6 alkyl.

In a particular embodiment, the present invention provides compounds of formula I wherein m is 1 or 2;

n is 0 or 1 ; in particular 1 .

In a preferred embodiment, compounds of the present invention are provided wherein R is hydrogen.

In another embodiment, the present invention provides compounds of formula I wherein R 2 and R 3 are hydrogen or methyl. In yet another particular embodiment, R 5 is selected from halo, d- 6 alkyl, Ci_ 6 alkoxyl, di(d- 6 alkyl)amino, and cyano.

In another embodiment, the present invention provides compounds of formula II

II

Wherein

X, Ar, R , R 2 , R 3 , R 6 , R 6 , R' and R" are as defined for compounds of formula I; and

W is selected from the group consisting of

a) hydrogen;

b) an optionally substituted Ci_ 6 alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S0 2 , S0 2 NR', NR'C(=0)NR", NR'S(=0)NR", or

NR'S(=0)(=0)NR"; and wherein the optional substituents are selected from the group consisting of amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl, alkylthio, hydroxyl, thiol, cyano, and halo; and c) an optionally substituted cyclic structure selected from Ci_ 8 cycloalkyl, Ci_ 8 heterocyclyl, aryl, and heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_ 6 alkyl, amino, alkylamino, dialkylamino, hydroxyl, thiol, alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl.

In a particular embodiment, the present invention provides compounds of formula II wherein W is hydrogen.

In yet another particular embodiment, the present invention provides compounds of formula II wherein W is Ci- 6 alkylene, wherein optionally a single methylene unit is replaced by a functional group selected from O, NR', S, C(=0), C(=0)0, OC(=0), S(=0), S(=0)(=0), C(=0)NR', NR'C(=0), NR'C(=0)0, OC(=0)NR', NR'S0 2 , S0 2 NR'. In yet another particular embodiment, the present invention provides compounds of formula II wherein W is selected from Ci_ 8 cycloalkyl, Ci_ 8 heterocyclyl, aryl, and heteroaryl; in particular wherein W is aryl or heteroaryl; more in particular wherein W is heteroaryl.

Embodiments of the present invention as described herein may be combined. In particular, if two separate particular embodiments are described herein, it is an express goal of the present invention to provide those compounds that are part of the overlapping scope of said two embodiments.

The compounds of the present invention can be prepared according to the reaction schemes provided in the examples hereinafter, but those skilled in the art will appreciate that these are only illustrative for the invention and that the compounds of this invention can be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry.

In a preferred embodiment, the compounds of the present invention are useful as kinase inhibitors, more in particular for the inhibition of at least one LIM kinase, selected from LIMK1 and LIMK2.

The present invention further provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound, as a human or veterinary medicine, in particular for prevention and/or treatment of at least one disease or disorder, in which LIMK is involved, such as diseases linked to smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis and neurodegeneration.

In a further embodiment, the invention provides the use of a compound as defined hereinbefore, or the use of a composition comprising said compound in the prevention and/or treatment of at least one disease or disorder selected from the group comprising eye diseases, airway diseases, intestinal diseases, proliferative diseases; cardiovascular and vascular diseases, kidney diseases, bone diseases, skin diseases and neurodegeneration.

In a preferred embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of eyes diseases including but not limited to glaucoma and degenerative retinal diseases such as macular degeneration, vision loss due to diabetic macular edema, vision loss due to macular edema secondary to retinal vein occlusion proliferative vitreoretinopathy; inflammatory eye diseases such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis, glaucoma filtration surgery failure, dry eye, allergic conjunctivitis, posterior capsule opacification, cataract formation, abnormalities of corneal wound healing, ocular pain and ocular hypertension.

In another preferred embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of airway diseases; including but not limited to pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, chronic obstructive pulmonary disease (COPD); bronchitis and rhinitis and respiratory distress syndrome, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith. In a further embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of cardiovascular and vascular diseases: including but not limited to pulmonary hypertension and pulmonary vasoconstriction, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith and/or alleviating complications and/or symptoms associated therewith.

In a further embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of skin diseases: including but not limited to hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis and ulceration.

In a further embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of Intestinal diseases; including but not limited to inflammatory bowel disease (IBD), colitis, gastroenteritis, ileus, ileitis, appendicitis and Crohn's disease.

In yet another embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of inflammatory diseases: including but not limited to contact dermatitis, atopic dermatitis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis, and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.

In another embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of proliferative diseases: such as but not limited to cancer of breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, ovary, pancreas, prostate, or thyroid gland; Castleman disease; lymphoma; malignoma; and melanoma; and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.

In another embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of kidney diseases: including but not limited to renal fibrosis or renal dysfunction; and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.

In another embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of bone diseases: including but not limited to osteoporosis and osteoarthritis; and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.

In another embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of viral infections, including but not limited to infection by HIV. In another embodiment the present invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of eye diseases.

METHOD OF TREATMENT

The present invention further provides a method for the prevention and/or treatment of at least one disease or disorder selected from the group comprising eye diseases, airway diseases, intestinal diseases, proliferative diseases; cardiovascular and vascular diseases, kidney diseases, bone diseases and neurodegeneration; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.

In a preferred embodiment, the invention provides a method for the prevention and/or treatment of eye diseases including but not limited to glaucoma and degenerative retinal diseases such as macular degeneration, vision loss due to diabetic macular edema, vision loss due to macular edema secondary to retinal vein occlusion proliferative vitreoretinopathy; inflammatory eye diseases such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis, glaucoma filtration surgery failure, dry eye, allergic conjunctivitis, posterior capsule opacification, cataract formation, abnormalities of corneal wound healing, ocular pain and ocular hypertension; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for the prevention and/or treatment of airway diseases including but not limited to pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, chronic obstructive pulmonary disease (COPD) bronchitis, rhinitis, and respiratory distress syndrome; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for the prevention and/or treatment of cardiovascular and vascular diseases: including but not limited to pulmonary hypertension and pulmonary vasoconstriction; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for the prevention and/or treatment of inflammatory diseases: including but not limited to contact dermatitis, atopic dermatitis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease and ulcerative colitis; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for the prevention and/or treatment of proliferative diseases: such as but not limited to cancer of breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate, or thyroid gland; Castleman disease; sarcoma; malignoma; and melanoma; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein. In another embodiment, the invention provides a method for the prevention and/or treatment of kidney diseases: including but not limited to renal fibrosis or renal dysfunction; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for the prevention and/or treatment of bone diseases: including but not limited to osteoporosis and osteoarthritis; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for the prevention and/or treatment of viral infections: including but not limited to infection by HIV; said method comprising administering to a subject in need thereof a pharmacologically effective amount of a compound or a composition as defined herein.

In another embodiment, the invention provides a method for preventing transmission of viral infections: including but not limited to infection by HIV; said method comprising the application of compositions in the form of liquids, solutions, oils, creams, ointments, emulsions or lubricants containing a pharmacologically effective amount of a compound of the invention as defined herein, be it alone or in combination with other compounds, compositions or devices (e.g. condoms) allowing a reduced risk of viral infection. In a another embodiment, the invention provides a method for the prevention and/or treatment of eye diseases; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.

In the invention, particular preference is given to compounds of Formula I or any subgroup thereof that in the inhibition assay for LIMK described below inhibit LIMK with an IC 50 value of less than 10 μΜ, preferably less than 1 μΜ, even more preferably less than 0.1 μΜ.

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

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, malonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, 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 or pharmaceutical composition 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 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, micro-crystalline 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 α-, β- or γ-cyclodextrins or their derivatives. An interesting way of formulating the compounds in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721 ,331 . 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.

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.

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 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.

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 bioavailability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration. 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, or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and ocular 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 any subgroup thereof 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 0.001 to 1000 mg per kilogram body weight 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 of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously,. 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. 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 ocular administration, the compound according to the invention can be if desired mixed with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries and 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 eyedrop preparations. Suitable solvents are, for example, water, physiological saline solution or polyethylene glycols, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. Eyedrops, injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, no-irritating diluents or solvents.

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. In preferred embodiments, the compounds and compositions of the invention are used locally, for instance topical or in both absorbed and non-adsorbed applications.

For prevention of viral infection, including but not limited to HIV transmission, the compounds and compositions of the present invention can be prepared in the form of liquids, solutions, oils, creams, ointments, emulsions or lubricants containing a pharmacologically effective amount of a compound of the invention as defined herein. For preparing such forms, the compounds or compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers, or inert diluents. Such forms can subsequently be used either alone or in combination with other compounds, compositions or devices (e.g. condoms) allowing a reduced risk of viral infection.

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 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 limit the scope of the invention in any way.

EXAMPLES

A. Phvsicochemical properties of the compounds

A.1. Compound purity

Unless indicated otherwise, the purity of the compounds was confirmed by liquid chromatography/mass spectrometry (LC/MS).

A.2. Compound identity

Besides LC/MS data, identity of final compounds was controlled by H NMR.

B. Compound synthesis

B.1. Chemical intermediates:

Intermediate 1: methyl 1-benzyl-4-cyanopiperidine-4-carboxylate

Benzylbis(2-chloroethyl) amine (1 12 g, 420 mmol), powdered anhydrous potassium carbonate (220 g,1 .6 mol) and tetra-n-butylammonium bromide (13 g, 40 mmol) in DMF (150 mL) were vigorously stirred at room temperature and methyl 2-cyanoacetate (39.6 g, 400 mmol) was added dropwise. The mixture was stirred over 6-8 hrs at 80°C. After cooling to room temperature, inorganic salts were filtered off. Water (800 mL) was added to the filtrate and the phases were extracted with toluene (5 x 400 mL). Organic layers were dried over anhydrous magnesium sulfate and concentrated to give the crude product, which was purified by column chromatography (hexane: EtOAc = 20:1 ) to provide intermediate 1 (54 g, 50% yield) as a white solid.

Intermediate 2: methyl 4-cyanopipehdine-4-carboxylate

Intermediate 1 (51 g, 200 mmol) was dissolved in 500 mL of anhydrous dichloroethane, and 3- chlorobutanoyl chloride (700 g, 500 mmol) was added. The resulting mixture was heated to reflux overnight. Dichloroethane was removed under vaccum and 500 mL MeOH was added. The mixture was heated to reflux for 1 h andMeOH was subsequently removed under vacuum to give intermediate 2 (39 g, 95% yield) as a white solid.

Intermediate 3: 1-tert-butyl 4-methyl 4-cyanopiperidine-1,4-dicarboxylate

Intermediate 2 (39 g, 191 mmol) was dissolved in THF/H 2 0 (500 mL, v/v=1 :1 ) with ice bath. Then Boc 2 0 (45 g, 206 mmol) was added portion wise. NaHC0 3 (16.8 g, 200 mmol) was subsequently added portion wise and the reaction mixture was stirred overnight. THF was removed and the residue was extracted with MTBE (3 x 200 mL). The organic layer was dried on anhydrous Na 2 S0 4 and concentrated to give the crude product, which was purified by column chromatography (hexane: EtOAc = 20:1 ) to give intermediate 3 (41 g, 80% yield) as a colorless oil.

Intermediate 4: 1-tert-butyl 4-methyl 4-(aminomethyl)piperidine-1,4-dicarboxylate

To a solution of intermediate 3 (10 g, 37.3 mmol) and triethylamine (1 mL) in MeOH (200 mL) was added Raney-Ni carefully. The resulting mixture was hydrogenated (40 psi H 2 ) overnight. The reaction was filtered through celite, concentrated under vacuum, and purified by preparative HPLC to give intermediate 4 (6 g, 60% yield) as a colorless oil.

Intermediate 5: 1-tert-butyl 4-methyl 4-[(dimethylamino)methyl]pipehdine-1,4-dicarboxylate

Intermediate 4 (27.2 g, 100 mmol) was dissolved in MeOH (500 mL) and formaldehyde (6 g, 200 mmol) was added. The mixture was stirred at room temperature for 10min. NaBH 3 CN (18.8 g, 300 mmol) was then added portion wise. The reactive mixture was stirred for another 2h. Upon completion of the reaction, the solution was basified with aqueous NaHC0 3 (pH = 8) then extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 S0 4 and evaporated to give crude product, which was purified by column chromatography (Hexane: EA = 20:1 ) to give intermediate 5 (21 g, 70% yield) as a white solid.

Intermediate 6: 1-tert butyl 4-methyl 4-(dimethylamino)piperidine-1,4-dicarboxylate

Intermediate 6 can be obtained from 1 -tert butyl 4-methyl 4-aminopiperidine-1 ,4-dicarboxylate, by following the experimental procedure described for intermediate 5.

Intermediate 7: 1-[(tert-butoxy)carbonyl]-4-[(dimethylamino)methyl]piperidin e-4-carboxylic acid

To a solution of intermediate 5 (21 g, 70 mmol) in ethanohwater 1 :1 (250 mL) was added NaOH (5.6 g, 140 mmol). The resulting mixture was heated to reflux overnight. Ethanol was then removed under vaccum and the water solution was acidified by 2M HCI to pH 5-6. Then the solution was extracted by EtOAc/i-PrOH (3:1 , v/v). The combined organic layers were washed with brine, dried over anhydrous Na 2 S0 4 and filtered. The solvent was then evaporated under vacuum to give intermediate 7 (10 g, 50% yield) as a white solid.

Intermediate 8: 1-[(tert-butoxy)carbonyl]-4-(dimethylamino) pipehdine-4-carboxylic acid

Intermediate 8 can be obtained from intermediate 6, by following the experimental procedure described for intermediate 7.

Intermediate 9: 1-[(tert-butoxy)carbonyl]-4-aminopiperidine-4-carboxylic acid

Intermediate 9 can be obtained from 1 -tert butyl 4-methyl 4-aminopiperidine-1 ,4-dicarboxylate, by following the experimental procedure described for intermediate 7.

Intermediate 10: tert-butyl 4[(dimethylamino)methyl]-4-{[3-(methoxycarbonyl)phenyl]carba moyl}- piperidine- 1 -carboxylate

To a solution of Intermediate 7 (10 g, 35 mmol) and DIEA (18.3 mL, 105 mmol) in anhydrous dichloroethane (150 mL) was added HATU (26.6 g, 70 mmol). The mixture was stirred at room temperature for 0.5 h. Then methyl 3-aminobenzoate (7.3 g, 48 mmol) was added. The resulting mixture was refluxed overnight. The mixture was washed with water and brine, dried on anhydrous Na 2 S0 4 , and concentrated under vacuum. The residue was purified by column chromatography (hexane: EtOAc = 5:1 ) to give intermediate 10 (7.5 g, 51 % yield) as a yellow oil. Intermediate 11: methyl 3-{4-[(dimethylamino)methyl]piperidine-4-amido}benzoate

To a solution of intermediate 10 (5 g, 12 mmol) in dichloroethane (100 mL) at 0°C was added TFA (10 mL). The reaction mixture was stirred at room temperature for 48 h. LC-MS indicated complete conversion. A saturated aqueous solution of K 2 C0 3 (50 mL) was then added and the resulting mixture was stirred for 0.5 h at 0°C. The water layer was extracted with dichloroethane (3 x 50 mL). The combined organic layers were dried on anhydrous Na 2 S0 4 , and concentrated to give intermediate 1 1 (3.7 g, 97% yield) as a yellow solid.

Intermediate 12: tert-butyl 4-[(dimethylamino)methyl]-4-{[5-(methoxycarbonyl)thiophen-2- yl]carbamoyl} piperidine- 1 -carboxylate

To a solution of intermediate 7 (7 g, 24.4 mmol) and DIEA (6.3 g, 44.9 mmol) in anhydrous DMF (100 mL) was added HATU (13.9 g, 36.8 mmol). The mixture was stirred at room temperature for 0.5 h. Methyl 5-aminothiophene-2-carboxylate (5.8 g, 36.8 mmol) was then added. The resulting mixture was stirred at 30°C for 18h and was then poured into water, extracted with EtOAc (3 χ 300 mL), dried over Na 2 S0 4 and concentrated under reduced pressure. The crude product (10g) was purified by column chromatography (petroleum ether: DCE = 10:1 to DCE: MeOH = 100:1 ) to give intermediate 12 (4 g, 39% yield) as a white solid.

Intermediate 13: methyl 5-{4-[(dimethylamino)methyl]piperidine-4-amido}thiophene-2-c arboxylate

To a solution of intermediate 12 (4 g, 9.4 mmol) in dichloroethane (100 mL) at 0°C was added TFA (10 mL). The reaction mixture was stirred at room temperature for 48 h. LC-MS indicated complete conversion. A saturated aqueous solution of K 2 C0 3 (50 mL) was then added and the resulting mixture was stirred for 0.5 h at 0°C. The water layer was extracted with dichloroethane (3 x 100 mL). The combined organic layers were dried on anhydrous Na 2 S0 4 and concentrated to give intermediate 13 (2.7 g, 88% yield) as a yellow solid.

Intermediate 14: tert-butyl 4-[(dimethylamino)methyl]-4-{[2-fluoro-5-(methoxycarbonyl)ph enyl] carbamoyljpiperidine- 1 -carboxylate

To a solution of intermediate 7 (7 g, 24.4 mmol) and DIEA (6.3 g, 44.9 mmol) in anhydrous DMF (100 mL) was added HATU (13.9 g, 36.8 mmol). The mixture was stirred at r.t. for 0.5 h. Methyl 3-amino-4- fluorobenzoate (6.2 g, 36.8 mmol) was then added. The resulting mixture was stirred at 30°C for 18h and was then poured into water, extracted with EtOAc (3 χ 300 mL), dried over Na 2 S0 4 and concentrated under reduced pressure. The crude product (10g) was purified by column chromatography (petroleum ether: DCE = 10:1 to DCE: MeOH = 100:1 ) to give intermediate 14 (3.5 g, 33% yield) as a white solid.

Intermediate 15: methyl 3-{4-[(dimethylamino)methyl]piperidine-4-amido}-4-fluorobenz oate

To a solution of intermediate 14 (3.5 g, 8 mmol) in dichloroethane (100 mL) at 0°C was added TFA (10 mL). After the addition, the reaction mixture was stirred at room temperature for 48 h. LC-MS indicated complete conversion. A saturated aqueous solution of K 2 C0 3 (50 mL) was then added and the resulting mixture was stirred for 0.5 h at 0°C. The water layer was extracted with dichloroethane (3 x 100 mL). The combined organic layers were dried on anhydrous Na 2 S0 4 and concentrated to give intermediate 15 (2.3 g, 85% yield) as a yellow solid.

Intermediate 16:6-( 2-cyclohexylidenehydrazin- 1 -yl)-1 ,4-dihydropyrimidin-4-one

To a suspension of 6-hydrazino-4(1 H)-pyrimidinone (50 g, 396 mmol) in EtOH (1 .0 L) was added the cyclohexanone (58 g, 594 mmol). The reaction mixture was stirred at 80 °C for 3 hours and then cooled to 10 °C with an ice-water bath. The solid was collected by filtration and dried under high vacuum to afford intermediate 16 (55 g, 67% yield) as a white solid.

Intermediate 17: 1H,4 ,5H,6H, 7H,8H,9H-pyrimido[4,5-b]indol-4-one

Intermediate 16 (55 g, 267 mmol) in phenyl ether (400 mL) was heated for 6 h at 250 °C in a heating mantel under nitrogen. The reaction mixture was cooled to room temperature, and the solid were collected by filtration, washed with petroleum ether (200 ml) and EtOH (100 ml), and dried under high vacuum to afford intermediate 17 (40 g, 79% yield) as a light yellow solid.

Intermediate 18: 4-chloro-5H, 6H, 7H, 8H, 9H-pyrimido[4, 5-b]indole

Intermediate 17 (40 g, 210 mmol) in POCI 3 (400 g) was heated at 100 °C for 1 hr. The resulting mixture was poured into ice-water (1 .0 L) and extracted with ethyl acetate (1 .0 L x 3). The combined organic layers were concentrated and the residue was purified by column chromatography (0-10% MeOH with 0.1 % NH 4 OH/dichloroethane) and washed with EtOAc, to afford intermediate 18 (20.4 g, 47% yield) as a yellow solid.

Intermediate 19: 4-(dimethylamino)piperidine-4-carboxylic acid

To a mixture of intermediate 8 (1 .1 15 g, 4.09 mmol) in water (10 mL) was added aqueous HCI (10 mL, 120 mmol). The resulting solution was stirred overnight, concentrated, suspended in ACN and concentrated again. The product was suspended in Et 2 0, filtered and washed with Et 2 0 to afford intermediate 19 (641 mg, 91 % yield) as a white powder.

Similarly, the following intermediates (20-22) can be obtained by following an analogous experimental procedure and using the corresponding Boc-protected starting material. Intermediate 20 : Methyl 4-(aminomethyl)piperidine-4-carboxylate

Intermediate 21 : 4-aminopiperidine-4-carboxylic acid

Intermediate 22 : 4-[(dimethylamino)methyl]piperidine-4-carboxylic acid

4-(dimethylamino)-1-{5H,6H, 7H,8H,9H-pyrimido[4,5-b]indol-4-yl} piperidine-4-

To a mixture of intermediate 18 (4.76 g, 22.92 mmol) and intermediate 19 (6.74 g, 27.5 mmol) in Water/DMSO (35 mL/35 mL) was added DIPEA (32.0 mL, 183 mmol). The resulting mixture was refluxed overnight and cooled to room temperature. The suspension was diluted with H 2 0 (500 ml) and neutralized by dropwise addition of concentrated aqueous HCI to pH 6.3. The solid was collected by filtration and washed with H 2 0. The solid was then dissolved in 1 M aqueous NaOH (200 ml) and filtered. The filtrate was neutralized by dropwise addition of concentrated HCI to pH 6.7, resulting in a beige precipitation. The solid was collected by filtration and washed with H20, ACN (2x) and Et20. The obtained powder was suspended in ACN and freeze-dried to afford intermediate 23 (4.22 g, 52% yield) as a beige powder. Similarly, the following intermediates (24-26) can be obtained by following an analogous procedure and using the corresponding piperidine analogue as starting material.

Intermediate 24: 4-[(dimethylamino)methyl]-1-{5H,6H, 7H,8H,9H-pyhmido[4,5-b]indol-4-yl} piperidine-4- carbocylic acid

Intermediate 25: 4-amino- 1 -{5H, 6H, 7H, 8H, 9H-pyrimido[4, 5-b]indol-4-yl}piperidine-4-carbocylic acid

Intermediate 26: 4-({[(tert-butoxy)carbonyl]amino}methyl)-1 -{5H, 6H, 7H, 8H, 9H-pyrimido[4, 5-b ]indol-4- yl}piperidine-4-carbocylic acid

Intermediate 27:6-(2-cyclopentylidenehydrazin-1-yl)-1,4-dihydropyrimidin- 4-one

To a suspension of 6-hydrazino-4(1 H)-pyrimidinone (50 g, 396 mmol) in EtOH (1 .0 L) was added the cyclopentanone (57 g, 675 mmol). The reaction mixture was stirred at 80 °C for 4 hours and then cooled to 10 °C with an ice-water bath. The solid was collected by filtration and dried under high vacuum to afford intermediate 27 (61 g, 76% yield) as a white solid.

Intermediate 28: 1H,5H,6H, 7H,8H-cyclopenta[4,5]pyrrolo[2,3-d]pyhmidin-4-one

Intermediate 27 (55 g, 267 mmol) in phenyl ether (400 mL) was heated at 250 °C in a heating mantel under nitrogen for 6 h. The solid was collected by filtration, washed with petroleum ether (200 mL) and ethanol (100 mL), dried under high vacuum to afford intermediate 28 (40 g, 79% yield) as a light yellow solid.

Intermediate 29: 4-chloro-5H, 6H, 7H, 8H-cyclopenta[4, 5]pyrrolo[2, 3-d]pyrimidine

Intermediate 28 (40 g, 228 mmol) in POCI 3 (400 g) was heated at 1 10 °C for 6 h. The resulting mixture was poured into ice-water (1 .0 L) and extracted with ethyl acetate (1 .0 L x 3). The combined organic layers were concentrated and the residue was purified by column chromatography (0-10% MeOH with 0.1 % NH 4 OH/dichloroethane) and washed with EtOAc, to afford intermediate 29 (24 g, 53% yield) as a grey solid.

Intermediate 30: 4-(dimethylamino)-1 -{5H,6H, 7H,8H- cyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl} piperidine-4-carbocylic acid

To a mixture of intermediate 29 (5 g, 25.8 mmol) and intermediate 19 (7.60 g, 31 .0 mmol) in Water/DMSO (43.0 mL/43 mL) was added DIPEA (36.1 mL, 207 mmol). The resulting mixture was refluxed overnight and cooled to room temperature. The suspension was diluted with H 2 0 (500 mL) and neutralized by dropwise addition of concentrated aqueous HCI to pH 6.9. The solid was collected by filtration and washed with H 2 0. The solid was then dissolved in 1 M aqueous NaOH (200 mL) and filtered. The filtrate was neutralized by dropwise addition of concentrated HCI to pH 6.7, resulting in a beige precipitation. The solid was collected by filtration and washed with H 2 0, ACN (2x) and Et 2 0. The obtained powder was suspended in ACN and freeze-dried to afford intermediate 30 (6.4 g, 74% yield) as a beige powder.

Similarly, the following intermediate (31 ) can be obtained by following an analogous procedure and using the corresponding piperidine analogue as starting material.

Intermediate 31: 4-({[(tert-butoxy)carbonyl]amino}methyl)-1-{5H,6H, 7H,8H- cyclopenta[4,5]pyrrolo[2,3- d]pyhmidin-4-yl} pipehdine-4-carbocylic acid

Intermediate 32: 6-(2-(4,4-difluorocyclohexylidene)hydrazin-1-yl)-1,4-dihydro pyrimidin-4-one

To a suspension of 6-hydrazino-4(1 H)-pyrimidinone (27.6 g, 219 mmol) in EtOH (600 mL) was added the 4,4-difluorocyclohexanone (50.00 g, 372.80 mmol). The reaction mixture was stirred at 80 °C for 5 hours and then cooled to 10 °C with an ice-water bath. The solid was collected by filtration and dried under high vacuum to afford intermediate 32 (40 g, 75% yield) as a white solid. Intermediate 33: 6, 6-difluoro- 1 H, 5H, 6H, 7H, 8H, 9H-pyrimido[4, 5-b]indol-4-one

Intermediate 32 (35 g, 144.5 mmol) in phenyl ether (250 mL) was heated at 250 °C in a heating mantel under nitrogen for 6 h and cooled to room temperature. The solid was collected by filtration, washed with EtOH (50 mL X 2), dried under high vacuum to afford intermediate 33 (30 g, 92% yield) as a light yellow solid.

Intermediate 34: 4-chloro-6,6-difluoro-5H,6H, 7H,8H,9H-pyrimido[4,5-b]indole

Intermediate 33 (28 g, 124.3 mmol) in POCI 3 (185 mL) was heated at 100 °C for 1 h and the resulting mixture was poured into ice-water (500 mL). The solid, collected by filtration, was washed with EtOAc (100 mL x 2) and purified by flash chromatography (Petroleum ether/EtOAc 70/30) to afford intermediate 34 (10.4 g, 34% yield) as a grey solid.

Intermediate 35: 4-(dimethylamino )- 1 -{6, 6-difluoro-5H, 6H, 7H, 8H, 9H-pyrimido[4, 5-b]indol-4-yl} piperidine-4-carbocylic acid

To a mixture of intermediate 34 (2 g, 8.21 mmol) and intermediate 19 (4.83 g, 9.85 mmol) in Water/DMSO (20 mL/20 mL) was added DIPEA (65.7 mL, 207 mmol). The resulting mixture was refluxed overnight and cooled to room temperature. The suspension was diluted with H 2 0 (300 mL) and neutralized by dropwise addition of concentrated aqueous HCI to pH 6.9. The solid was collected by filtration and washed with H 2 0. The solid was then dissolved in 1 M aqueous NaOH (100 mL) and filtered. The filtrate was neutralized by dropwise addition of concentrated HCI to pH 6.7, resulting in a beige precipitation. The solid was collected by filtration and washed with H 2 0, ACN (2x) and Et 2 0. The obtained powder was suspended in ACN and freeze-dried to afford intermediate 30 (2.9 g, 94% yield) as a beige powder.

Similarly, the following intermediate (36) can be obtained by following the procedure described above and using the intermediate 20 as starting material.

Intermediate 36: 4-({[(tert-butoxy)carbonyl]amino}methyl)-1 -{6, 6-difluoro-5H, 6H, 7H, 8H, 9H- pyhmido[4,5-b]indol-4-yl} pipehdine-4-carbocylic acid

B.2. Compounds of the invention:

In the tables that are set forth below, exemplary compounds of the invention are set out in tabulated form. In these tables, an arbitrarily assigned compound number and structural information are set out.

Compounds of the invention can be obtained by coupling intermediates 23 to 26, 30, 31 , 35 and 36 with appropriate anilines using the general procedure described below and performing the final Boc- deprotection step when appropriate.

General procedure:

To a suspension of carboxylic acid (100 mg) and DMAP (6 eq) in DCM (0.2 M) under nitrogen at -15°C was added T3P (3 eq) dropwise over a period of 20 min. The resulting mixture was stirred at -15°C until a solution was obtained (2h) and the aniline (3 eq) was added dropwise. The reaction mixture was stirred at -15 °C for 1 h, slowly warmed to room temperature and stirred overnight. Saturated aq. NaHC0 3 was then added and the aqueous layer extracted with EtOAc. The organic phase was washed with saturated aq. NH4CI (x 2), NaHC0 3 and brine, dried over Na 2 S0 4 , filtered and concentrated under vacuum.

The residue was dissolved in DCM and purified by flash chromatography (DCM/MeOH 97/3 to 92/8).

Alternatively, compounds of the invention can be obtained by directly reacting intermediate 18 with advanced piperidine intermediates such as intermediate 1 1 , intermediate 13 or intermediate 15, by adapting the procedure used for synthesis of intermediates 23-26.

Example NMR data for 5H,6H,7H,8H,9H-pyrimido[4,5-blindole derivatives:

Cpd 1.3 (TFA salt), H NMR (DMSO-c/6, 300 MHz): δ 12.02 (bs, 1H), 9.84 (s, 1H), 8.25 (s, 1H), 7.95 (bs, 2.5 H), 7.58-7.52 (m, 1H), 7.50-7.44 (m, 1H), 7.36-7.29 (m, 1H), 6.90-6.84 (m, 1H), 3.90-3.75 (m, 2H), 3.55-3.40 (m, 2H), 3.35-3.20 (m, 2H), 3.04 (s, 3H), 2.91 (s, 3H), 2.80-2.65 (m, 4H), 2.45-2.35 (m, 2H), 1.90-1.62 (m, 6H).

Example NMR data for 7,9,11 ,-triazatricyclo[6.4.0.0 ]dodeca-1 (8), 2(6)9,11 -tetraene derivatives:

Cpd 2.2, Ή NMR (DMSO-c/6, 400 MHz): δ 11.48 (s, 1H), 9.63 (s, 1H), 8.42 (s, 1H), 8.09 (s, 1H), 8.03 (s, 1H), 7.70 (d, 1 H, J = 7.5 Hz), 7.61 (s, 1H), 7.44-7.35 (m, 2H), 4.30-4.18 (d, 2H, J = 13.0 Hz), 3.38 (t, 2H, J = 11.1 Hz), 2.89-2.83 (m, 2H), 2.81-2.94 (m, 2H), 2.40-2.30 (m, 2H), 2.22 (s, 6H), 2.16-2.08 (m, 2H), 1.88-1.77 (m, 2H).

Example NMR data for 6,6-difluoro-5H,7H,8H,9H-pyrimido[4,5-blindole derivatives:

Cpd 3.3, Ή NMR (DMSO-c/6, 400 MHz): δ 11.69 (s, 1H), 9.46 (s, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 7.59 (d , 1 H , J = 8 Hz), 7.25 (t, 1 H, J = 8 Hz), 6.97 (d , 1 H , J = 8 Hz), 3.83 (d, 2H, J = 12 Hz), 3.65 (s, 2H), 3.62 (s, 3H), 3.29 (m, 4H), 2.88 (t, 2H, J = 12 Hz), 2.41-2.27 (m, 2H), 2.25 (s, 6H), 2.16 (d, 2H, J = 12 Hz), 1.91 (td, 2H, J = 12, 4 Hz). C. In vitro and in vivo assays

C.1: Reference compound

In the examples that are set forth below, compound LX-7101 (Lexicon Pharmaceuticals) is used as comparator. LX-7101 was initially disclosed as example 20 in WO2009/131940 and is later featured in WO2012/061565, which covers the solid forms of the same compound. LX-7101 is also discussed in a later journal article (ACS Med. Chem. Lett., 2015, 6 (1 ), pp 84-88).

LX-7101 (depicted hereinbelow) was chosen as comparator because it represents the closest structural analog of compounds of the invention.

C.2. Kinase activity screening

C.2.1. On-target activity (LIMK1 & LIMK2)

On-target activity against LIMK kinases was measured in a biochemical assay, using the following reagents: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCI 2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na 3 V0 4 , 2 mM DTT, 1 % DMSO. Required cofactors are added individually to each kinase reaction. The reaction procedure first involved the preparation of a peptide substrate in a freshly prepared reaction buffer. Required cofactors were then added to the substrate solution. LIMK was then delivered to the substrate solution. After gentle mix, DMSO solutions of the test compounds were added to the enzyme. Substrate mix 33 P-ATP (specific activity 0.01 μθί/μΐ final) was then delivered into the reaction mixture to initiate the reaction. The kinase reaction was incubated for 120 min. at room temperature. Reactions were then spotted onto P81 ion exchange paper (Whatman # 3698-915). Filters were washed extensively in 0.1 % Phosphoric acid. A radiometric count was then performed and IC 50 values were subsequently determined.

When evaluated under such conditions, compounds of the invention display IC 50 values <10μΜ against LIMK kinases. Preferred compounds display IC 50 values <1 μΜ. Most preferred compounds display IC 50 values <0.1 μΜ. Selected data is displayed in table 4. LX-7101 , the LIM kinase inhibitor disclosed in WO2009/131940 (example 20, Lexicon Pharmaceuticals) was tested as reference. Table 4: Inhibitory activity against LIMK1 & LIMK2

+: IC 50 = 1 -10 μΜ, ++: IC 50 = 0.1 -1 μΜ, +++: IC 50 <0.1 μΜ , ND: not determined yet

C.2.2. Kinase selectivity data

C.2.2.1. Screening panel

Compound 1 .3 and LX-7101 (Lexicon Pharmaceuticals) were tested in a kinase panel (Reactions Biology Corp.) so to compare their selectivity against other kinases. Compound 1 .3 and LX-7101 are solely distinguished by the tricyclic scaffold that is the common feature of compounds of the invention. Both compounds were tested at a concentration of 300nM, in presence of 10μΜ ATP. Selectivity data is expressed in table 5, wherein results are expressed as % remaining enzymatic activity in presence of the tested compound.

Table 5: Selectivity data against selected kinases.

As can be seen from this table, LX-7101 affects a significant number of kinases at the tested concentration of 300nM. In particular, this compound displays equivalent or higher inhibitory potency against AKT1 , MSK1 , P70S6K, PKA, PRKX or ROCK2. The provided data also indicate that Cpd1 .3 has equivalent or higher inhibitory activity against LIMK1 and LIMK2 (lower % remaining activity), while it does not significantly affect the other tested kinases in this panel. As Compound 1 .3 only differs from tLX-7101 by the presence of a tricyclic scaffold, it will be appreciated that the increased selectivity of Compound 1 .3 can only result from the presence of this tricyclic scaffold; which is the distinguishing feature of compounds of the invention.

C.2.2.2. IC 50 data against ROCK2

Rho-kinases, also known as ROCKs, are serine/threonine kinases which have LIMK kinases as substrates. In functional in-vitro and in-vivo assays, selectivity between LIMKs and ROCKs is important in order to discriminate between LIMK-associated effects and ROCK-associated effects. In a kinase screening panel, LX-7101 displayed significant inhibition of ROCKs when tested at a concentration of 300 nM (See C.2.1 ). In addition to Cpd 1 .3, selected compounds of the invention were therefore counter-screened against ROCK2 (Reaction Biology Corp) and compared to LX-7101 . Results are shown in table 6. IC 50 data is provided in nM.

Table 6: Inhibition data against ROCK2.

From these data, it will be appreciated that compounds of the invention generally display improved selectivity vs ROCK2.

C.2.2.3. IC 50 data against PKA

Protein kinase A (PKA) is another kinase that was inhibited by LX-7101 in a selectivity panel (See C. 2.1 ). In addition to Cpd 1 .3, selected compounds of the invention were therefore counter-screened against PKA (Reaction Biology Corp) and compared to LX-7101 . Results are shown in table 7. IC 50 data is provided in nM.

Table 7: Inhibition data against PKA.

From this data, it will be appreciated that compounds of the inversion generally display improved selectivity vs PKA. C.2.2.4. IC 50 data against AKT1

Protein kinase B (AKT) is another kinase that was inhibited by LX-7101 in a selectivity panel (See C. 2.1 ). In addition to data already provided for Cpd 1 .3, selected compounds of the invention were therefore counter-screened against AKT1 (Reaction Biology Corp) and compared to LX-7101 . Results are shown in table 8. IC 50 data is provided in nM.

Table 8: Inhibition data against AKT1

From these data, it will be appreciated that compounds of the inversion generally display improved selectivity vs AKT1 .

C.2.2.5. IC 50 data against P70S6K

P70S6K is another kinase that was inhibited by LX-7101 in a selectivity panel (See C. 2.1 ). In addition to data already provided for Cpd 1 .3, IC 50 values against P70S6K were determined (Reaction Biology Corp.) for Cpd 1 .2 and LX-7101 . Results are shown in table 9. IC 50 data is provided in nM.

Table 9: Inhibition data against P70S6K

C.2.2.6. Inhibition data against TSSK1.

Dual specificity testis-specific protein kinases, also known as TESKs or TSSKs are besides LIMKs among the very few protein kinases which can phosphorylate cofilin. The protein kinase domain of TSSKs is most closely related to those of the LIMKs. In functional in-vitro and in-vivo assays, selectivity between LIMKs and TSSKs is important in order to discriminate between LIMK-associated effects and TSSK-associated effects. Selected compounds of the invention were therefore counter- screened against TSSK1 (Reaction Biology Corp) and compared to LX-7101 . Results are shown in table 10. IC 50 data is provided in nM.

Table 10: Inhibition data against TSSK1

From these data, it will be appreciated that compounds of the inversion generally display improved selectivity vs TSSK1 .

C.2.3. Cofilin phosphorylation assay

AlphaScreen® SureFire® technology allows the detection of phosphorylated proteins in cellular lysates in a highly sensitive and quantitative way. In these assays, sandwich antibody complexes, which are only formed in the presence of analyte, are captured by AlphaScreen® donor and acceptor beads, bringing them into close proximity. The excitation of the donor bead provokes the release of singlet oxygen molecules that triggers a cascade of energy transfer in the acceptor beads, resulting in the emission of light at 520-620nm.

Hela cells were treated for 1 hour with LIMK inhibitors. Next, cell were lysed and the assay was performed according to vendors (Perkin Elmer) instructions. The EC 50 for cofilin phosphorylation was determined by fitting the collected data with Graphpad Prism, using a nonl-linear regression function with variable hill slope.

When evaluated under such conditions, compounds of the invention display IC 50 values <10μΜ. Preferred compounds display IC 50 values <0.5μΜ.

Table 1 1 : Example results from Cofilin-PP assay.

+: Ο.δμΜ < EC 50 < 5μΜ ; ++ : Ο.δμΜ < EC 50 C.2.4. Myosin Light Chain Phosphorylation assay

As LIMK represents a downstream effector of ROCK, it may be of use to differentiate between ROCK- associated and LIMK-associated effects in cells. Myosin light chain is an important substrate of ROCK, and its phosphorylation is a functional readout of ROCK activity in cells. Myosin light chain is however not phosphorylated by LIMK and a LIMK inhibitor is therefore not expected to influence Myosin light chain phosphorylation. As a result, MLC phosphorylation can be used as a functional counter screen for ROCK activity.

Rat smooth muscle cell line A7r5 is used. The endogenous expression of ROCK results in a constitutive phosphorylation of the regulatory myosin light chain at T18/S19. A7r5 cells were plated in DMEM supplemented with 10%FCS in multiwall cell culture plates. After serum starvation overnight, cells were incubated with compounds in serum-free medium.

Quantification of MLC-T18/S19 phosphorylation is assessed in 96 well-plates via ELISA using a phspho-MLC-T18/S19 specific antibody and a secondary detection antibody. Raw data were converted into percent substrate phosphorylation relative to high controls, which were set to 100%. IC 50 values were determined using GraphPad Prism 5.01 software using a nonlinear regression curve fit with variable hill slope.

Selected compounds of the invention were counter-screened in the MLC-PP assay and compared to LX-7101 and the reference ROCK inhibitors Y-27632 and Ripasudil. Results are shown in table 12. IC 50 data is provided in nM.

Table 12: Example results from MLC-PP assay.

-: EC 50 > 5μΜ; +: Ο.δμΜ < EC 50 < 5μΜ ; ++ : EC 50 < Ο.δμΜ