WO2013030216A1 - Novel soft rock inhibitors - Google Patents

Novel soft rock inhibitors

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WO2013030216A1
WO2013030216A1 PCT/EP2012/066736 EP2012066736W WO2013030216A1 WO 2013030216 A1 WO2013030216 A1 WO 2013030216A1 EP 2012066736 W EP2012066736 W EP 2012066736W WO 2013030216 A1 WO2013030216 A1 WO 2013030216A1
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diseases
selected
compound
ch
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PCT/EP2012/066736
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French (fr)
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Dirk Leysen
Olivier Defert
Sandro Boland
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Amakem Nv
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to new kinase inhibitors, more specifically ROCK 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 ROCK 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 Respiratory and Gastro-lntestinal diseases.

Description

Novel soft ROCK inhibitors

Field of the invention

The present invention relates to new kinase inhibitors, more specifically ROCK 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 ROCK 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 serine/threonine protein kinase ROCK consists in humans of two isoforms ROCK I and ROCK I I. ROCK I is encoded on chromosome 18 whereas ROCK I I, also called Rho-kinase, is located on chromosome 12. They both have a molecular weight close to 1 60kDa. They share an overall homology of 65% while being 95% homologous in their kinase domains. Despite their sequence similarity, they differ by their tissue distributions. The highest levels of expression for ROCK I are observed in heart, lung and skeletal tissues whereas ROCK II is mostly expressed in brain. Recent data indicate that these two isoforms are partially function redundant, ROCK I being more involved in immunological events, ROCK I I in smooth muscle function . The term ROCK refers to ROCK I (ROK-β, p160ROCK, or Rho-kinase β) and ROCK II (ROCK- a or Rho-kinase a ).

ROCK activity has been shown to be enhanced by GTPase RhoA that is a member of the Rho (Ras homologous) GTP-binding proteins. The active GTP-bound state of RhoA interacts with Rho- binding domain (RBD) of ROCK that is located in an autoinhibitory carboxyl-terminal loop. Upon binding , the interactions between the ROCK negative regulatory domain and the kinase domain are disrupted. The process enables the kinase to acquire an open conformation in which it is fully active. The open conformation is also induced by the binding of lipid activators such as arachidonic acid to the PH domain in the kinase carboxyl-terminal domain. Another activation mechanism has been described during apoptosis and involves the cleavage of carboxyl terminus by caspase-3 and -2 (or granzyme B) for ROCK I and I I, respectively.

ROCK plays an important role in various cellular functions such as smooth muscle contraction, actin cytoskeleton organization, platelet activation, downregulation of myosin phosphatase cell adhesion, -migration, -proliferation and survival, thrombin-induced responses of aortic smooth muscle cells, hypertrophy of cardiomyocytes, bronchial smooth muscle contraction, smooth muscle contraction and cytoskeletal reorganization of non- muscle cells, activation of volume- regulated anion channels, neurite retraction , wound healing, cell transformation and gene expression. ROCK also acts in several signaling pathways that are involved in auto-immunity and inflammation. ROCK has been shown to play a part in the activation of NF- /c B, a critical molecule that leads to the production of TNF and other inflammatory cytokines. ROCK inhibitors are reported to act against TNF-alpha and IL-6 production in lipopolysaccharide (LPS)-stimulated THP-1 macrophages. Therefore, ROCK inhibitors provide a useful therapy to treat autoimmune and inflammatory diseases as well as oxidative stress.

In conclusion, ROCK is a major control point in smooth muscle cell function and a key signaling component involved in inflammatory processes in various inflammatory cells as well as fibrosis and remodeling in many diseased organs. There are clear indications that ROCK is involved in the pathogenesis of many diseases, including asthma, COPD and glaucoma. In addition, ROCK has been implicated in various diseases and disorders including eye diseases; airway diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative diseases; kidney diseases; sexual dysfunction; blood diseases; bone diseases; diabetes; benign prostatic hyperplasia, transplant rejection, liver disease, systemic lupus erythmatosis, spasm, hypertension, chronic obstructive bladder disease, premature birth, infection, allergy, obesity, pancreatic disease and AIDS.

ROCK appears to be a safe target, as exemplified by knockout models and a large number of academic studies. These KO mice data, in combination with post-marketing surveillance studies with Fasudil, a moderately potent ROCK inhibitor used for the treatment of vasospasm after subarachnoid hemorrhage, indicate that ROCK is a genuine and significant drug target.

ROCK inhibitors would be useful as therapeutic agents for the treatment of disorders implicated in the ROCK pathway. Accordingly, there is a great need to develop ROCK inhibitors that are useful in treating various diseases or conditions associated with ROCK activation, particularly given the inadequate treatments currently available for the majority of these disorders. Some non-limiting examples are inflammatory bowel disease, ulcerative colitis, Crohn's disease, asthma, COPD, pulmonary hypertension and idiopathic pulmonary fibrosis.

Allergic asthma is a chronic inflammatory airway disorder that results from maladaptive immune responses to ubiquitous environmental proteins in genetically susceptible persons. Despite reasonably successful therapies, the prevalence increases as these therapies do not cure; there are still exacerbations and an increasing number of non-responders. New, effective and steroid- sparing treatments that tackle all components of the disease are required.

Chronic Obstructive Pulmonary Disease (COPD) represents a group of diseases characterized by irreversible limitation of airflow, associated with abnormal inflammatory response, bronchoconstriction and remodeling and destruction of the tissue of the lung. It is one of the leading causes of death worldwide, with a steadily increasing prevalence. There is an urgent need for novel therapeutic approaches as the current regimen is inadequate. Until recently, only bronchodilators were used, since glucocorticoids have limited or no effect. Roflumilast (Daxas, Dallresp) was approved in 2010 for the treatment of COPD, but is associated with several dose- limiting side effects. Reference ROCK inhibitors, such as Y-27632 relax human isolated bronchial preparations, inhibit increases in airway resistance in anaesthetised animals, potentiate relaxing effects of β-agonists in vitro and in vivo and give rapid bronchodilatation upon inhalation. In addition, ROCK inhibitors block tracheal smooth muscle contractions induced by H202, the clinical marker for oxidative stress.

Related to airway inflammation, ROCK inhibitors counteract the increase in trans-endothelial permeability mediated by inflammatory agents, maintain the endothelial barrier integrity, inhibit the influx of eosinophils after ovalbumin challenge in vivo, protect against lung edema formation and neutrophile migration, suppress airway HR to metacholine and serotonin in allergic mice and block LPS-induced TNF release. With respect to airway fibrosis and remodeling, ROCK inhibitors block the induced migration of airway smooth muscle cells. In vitro evidences for the role of ROCK in airway remodeling were obtained in human lung carcinoma cell line, bovine tracheal smooth muscle cells and human airway smooth muscle. In vivo proof for a role of ROCK in fibrosis in general was generated with mice which exhibited attenuated myocardial fibrosis in response to the partial deletion of ROCK. The attenuation of myocardial fibrosis by Y-27632 in response to myocardial infarction and by fasudil in the case of congestive heart failure in a chronic hypertensive rat model brings additional indications of ROCK's importance in remodeling. Finally, ROCK inhibitors increase apoptotic cell loss of smooth muscle cells.

Several different classes of ROCK inhibitors are known. The current focus is oncology and cardiovascular applications. Until now, the outstanding therapeutic potential of ROCK inhibitors has only been explored to a limited extent. The reason is the fact that ROCK is such a potent and widespread biochemical regulator, that systemic inhibition of ROCK leads to strong biological effects that are considered as being side effects for the treatment of most diseases. Indeed, the medical use of ROCK inhibitors to treat diseases with a strong inflammatory component is hampered by the pivotal role of ROCK in the regulation of the tonic phase of smooth muscle cell contraction. Systemically available ROCK inhibitors induce a marked decrease in blood pressure. Therefore, ROCK inhibitors with different properties are highly required.

For the target specific treatment of disorders by regulating smooth muscle function and/or inflammatory processes and/or remodeling, it is highly desired to deliver a ROCK inhibitor to the target organ and to avoid significant amounts of these drugs to enter other organs. Therefore, local or topical application is desired. Typically, topical administration of drugs has been applied for the treatment of airway-, eye, sexual dysfunction and skin disorders. In addition, local injection / infiltration into diseased tissues further extend the potential medical use of locally applied ROCK inhibitors. Given certain criteria are fulfilled; these local applications allow high drug concentration to be reached in the target tissue. In addition, the incorporation of ROCK inhibitors into implants and stents can further expand the medical application towards the local treatment of CV diseases such as atherosclerosis, coronary diseases and heart failure.

Despite the fact that direct local application is preferred in medical practice, there are concerns regarding drug levels reached into the systemic circulation. For example the treatment of airway diseases by local delivery by for instance inhalation, poses the risk of systemic exposure due to large amounts entering the Gl tract and/or systemic absorption through the lungs. For the treatment of eye diseases by local delivery, also significant amounts enter the Gl tract and/or systemic circulation due to the low permeability of the cornea, low capacity for fluid, efficient drainage and presence of blood vessels in the eyelids. Also for dermal applications, local injections and implantable medical devices, there is a severe risk of leakage into the systemic circulation. Therefore, in addition to physical local application, the compounds should preferably have additional chemical or biological properties that will minimize systemic exposure.

Soft drugs are biologically active compounds that are inactivated once they enter the systemic circulation. This inactivation can be achieved in the liver, but the preferred inactivation should occur in the blood. These compounds, once applied locally to the target tissue / organ exert their desired effect locally. When they leak out of this tissue into the systemic circulation, they are very rapidly inactivated. Thus, soft drugs of choice are sufficiently stable in the target tissue / organ to exert the desired biological effect, but are rapidly degraded in the blood to biologically inactive compounds. In addition, it is highly preferable that the soft drugs of choice have retention at their biological target. This property will limit the number of daily applications and is highly desired to reduce the total load of drug and metabolites and in addition will significantly increase the patient compliance.

In conclusion, there is a continuing need to design and develop soft ROCK 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 ROCK 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 ROCK is involved, such as diseases linked to smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeration and remodeling. For example, the compounds of the invention may be used in the prevention and/or treatment of diseases and disorders such as: - 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,

- Throat, Nose and Ear diseases: including but not limited to sinus problems, hearing problems, toothache, tonsillitis, ulcer and rhinitis,

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

- Neurological disorders: including but not limited to neuropathic pain. The present compounds are therefore suitable for preventing neurodegeneration and stimulating neurogeneration in various neurological disorders.

- 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; malignoma; and melanoma.

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

- Sexual dysfunction: is meant to include both male and female sexual dysfunction caused by a defective vasoactive response. The soft ROCK inhibitors of the present invention may also be used to treat sexual dysfunction arising from a variety of causes. For example, in an embodiment, the soft ROCK inhibitors may be used to treat sexual dysfunction associated with hypogonadism and more particularly, wherein the hypogonadism is associated with reduced levels of androgen hormones. In another embodiment, the soft ROCK inhibitors may be used to treat sexual dysfunction associated with a variety of causes including, but not limited to, bladder disease, hypertension, diabetes, or pelvic surgery. In addition, the soft ROCK inhibitors may be used to treat sexual dysfunction associated with treatment using certain drugs, such as drugs used to treat hypertension, depression or anxiety.

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

- In addition, the compounds of the invention may be used in the prevention and/or treatment of diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive bladder disease, and allergy.

SUMMARY OF THE INVENTION

We have surprisingly found that the compounds described herein act as inhibitors of ROCK, in particular as soft ROCK inhibitors. As can be seen from the examples, the compounds of the present invention are very rapidly converted into functionally inactive compounds for example by carboxylic ester hydrolases (EC 3.1 .1 ) such as Cholinesterase or Paraoxonase 1 (PON1 ) or by plasma proteins displaying pseudoesterase activity such as Human serum albumin. Carboxylic ester hydrolases (EC 3.1 .1 ) represent a large group of enzymes involved in the degradation of carboxylic esters into alcohols and carboxylic acids. As such, enzymes displaying this catalytic activity are of potential interest for the design of soft kinase inhibitors. EC 3.1 .1 includes the following sub-classes: EC 3.1.1.1 carboxyl esterase; EC 3.1.1.2 arylesterase; EC 3.1.1.3 triacylglycerol lipase; EC 3.1.1.4 ; phospholipase A2; EC 3.1.1.5 lysophospholipase; EC 3.1.1.6 acetyl esterase; EC 3.1.1.7 acetylcholinesterase; EC 3.1.1.8 cholinesterase; EC 3.1.1.10 tropinesterase; EC 3.1.1.11 pectinesterase; EC 3.1.1.13 sterol esterase; EC 3.1.1.14 chlorophyllase; EC 3.1.1.15 L- arabinonolactonase; EC 3.1.1.17 gluconolactonase; EC 3.1.1.19 uronolactonase; EC 3.1.1.20 tannase; EC 3.1.1.21 retinyl-palmitate esterase; EC 3.1.1.22 hydroxybutyrate-dimer hydrolase; EC 3.1.1.23 acylglycerol lipase; EC 3.1.1.243-oxoadipate enol-lactonase; EC 3.1.1.251 ,4-lactonase; EC 3.1.1.26 galactolipase; EC 3.1.1.274-pyridoxolactonase; EC 3.1.1.28 acylcarnitine hydrolase; EC 3.1.1.29 aminoacyl-tRNA hydrolase; EC 3.1.1.30 D-arabinonolactonase; EC 3.1.1.31 6- phosphogluconolactonase; EC 3.1.1.32 phospholipase A1; EC 3.1.1.33 6-acetylglucose deacetylase; EC 3.1.1.34 lipoprotein lipase; EC 3.1.1.35 dihydrocoumarin hydrolase; EC 3.1.1.36 limonin-D-ring-lactonase; EC 3.1.1.37 steroid-lactonase; EC 3.1.1.38 triacetate-lactonase; EC 3.1.1.39 actinomycin lactonase; EC 3.1.1.40 orsellinate-depside hydrolase; EC 3.1.1.41 cephalosporin-C deacetylase; EC 3.1.1.42 chlorogenate hydrolase; EC 3.1.1.43 a-amino-acid esterase; EC 3.1.1.444-methyloxaloacetate esterase; EC 3.1.1.45 carboxymethylenebutenolidase; EC 3.1.1.46 deoxylimonate A-ring-lactonase; EC 3.1.1.47 1-alkyl-2-acetylglycerophosphocholine esterase; EC 3.1.1.48 fusarinine-C ornithinesterase; EC 3.1.1.49 sinapine esterase; EC 3.1.1.50 wax-ester hydrolase; EC 3.1.1.51 phorbol-diester hydrolase; EC 3.1.1.52 phosphatidylinositol deacylase; EC 3.1.1.53 sialate O-acetyl esterase; EC 3.1.1.54 acetoxybutynylbithiophene deacetylase; EC 3.1.1.55 acetylsalicylate deacetylase; EC 3.1.1.56 methylumbelliferyl-acetate deacetylase; EC 3.1.1.57 2-pyrone-4,6-dicarboxylate lactonase; EC 3.1.1.58 N- acetylgalactosaminoglycan deacetylase; EC 3.1.1.59 juvenile-hormone esterase; EC 3.1.1.60 bis(2-ethylhexyl)phthalate esterase; EC 3.1.1.61 protein-glutamate methylesterase; EC 3.1.1.63 11-cis-retinyl-palmitate hydrolase; EC 3.1.1.64 all-trans-retinyl-palmitate hydrolase; EC 3.1.1.65 L- rhamnono-1 ,4-lactonase; EC 3.1.1.665-(3,4-diacetoxybut-1-ynyl)-2,2'-bithiophene deacetylase; EC 3.1.1.67 fatty-acyl-ethyl-ester synthase; EC 3.1.1.68 xylono-1 ,4-lactonase; EC 3.1.1.70 cetraxate benzylesterase; EC 3.1.1.71 acetylalkylglycerol acetylhydrolase; EC 3.1.1.72 acetylxylan esterase; EC 3.1.1.73 feruloyl esterase; EC 3.1.1.74 cutinase; EC 3.1.1.75 poly(3-hydroxybutyrate) depolymerase; EC 3.1.1.76 poly(3-hydroxyoctanoate) depolymerase; EC 3.1.1.77 acyloxyacyl hydrolase; EC 3.1.1.78 polyneuridine-aldehyde esterase; EC 3.1.1.79 hormone-sensitive lipase; EC 3.1.1.80 acetylajmaline esterase; EC 3.1.1.81 quorum-quenching N-acyl-homoserine lactonase; EC 3.1.1.82 pheophorbidase; EC 3.1.1.83 monoterpene ε-lactone hydrolase; EC 3.1.1.84 cocaine esterase; EC 3.1.1.85 mannosylglycerate hydrolase;

An example of carboxylic ester hydrolase of particular relevance with respect to the compounds of the present invention is PON1. PON1 is a Ca2+ dependent serum class A-esterase, which is synthesized in the liver and secreted in the blood, where it associates exclusively with high-density lipoproteins (HDLs). Furthermore, it is able to cleave a unique subset of substrate including organophosphates, arylesters, lactones and cyclic carbonates. Therefore, the Y substituent of the compounds of the present invention, generally represented by formula I hereinbelow, are selected to comprise a substituent selected from the group of, lactones.

More specifically, the compounds of the present invention differ from those disclosed in co- application WO201 1 107608 from the same applicant in that they display an unexpected and more favorable combination of strong on-target potency and fast degradation in human plasma.

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, metabolite, pro- or predrug, salt, hydrate, or solvate thereof,

Figure imgf000008_0001

Wherein

R is selected from the group comprising hydrogen, alkyl, and cycloalkyl;

X is hydrogen or halo;

Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with -Z -(CH2)n-C(=0)-NHR2 or -Z -(CH2)n-NH-C(=0)-R2;

Wherein Z is a direct bond or -0-;

n is an integer selected from 0 to 6;

R2 is Het or Alk-Z2-Het1 ;

Wherein Alk is optionally substituted alkyl;

Z2 is selected from the group consisting of a direct bond, -0-, -NH-, and -S-;

-Het1 is selected from the group comprising

Figure imgf000009_0001

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 ROCK kinase, for example ROCKII and/or ROCKI 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 airway diseases; throat, nose and ear diseases; intestinal diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders; proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive bladder disease, allergy, .

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

Figure imgf000010_0001

wherein Y, R and X 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 CxH2x+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, d-4alkyl 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 C6 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.

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, carbonyl, nitro, amino, oxime, imino, azido, hydrazino, cyano, aryl, heteroaryl, cycloalkyl, acyl, alkylamino, alkoxy, thiol, alkylthio, carboxylic acid, acylamino, alkyl esters, carbamate, thioamido, urea, sullfonamido and the like. 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. 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 C3 alkylene group may be for example *-CH2CH2CH2-*, *-CH(- CH2CH3)-*, or *-CH2CH(-CH3)-*. Likewise a C3 cycloalkylene group may be

Figure imgf000012_0001

Where a cycloalkylene group is present, this is preferably a C3-C6 cycloalkylene group, more preferably a C3 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 "heterocycio" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom- containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. An optionally substituted heterocyclic refers to a heterocyclic having optionally one or more substituents (for example 1 to 4 substituents, or for example 1 , 2, 3 or 4), selected from those defined for substituted aryl.

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, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl,

1 .3.5- trioxanyl, 6H-1 ,2,5-thiadiazinyl, 2H-1 ,5,2-dithiazinyl, 2H-oxocinyl, 1 H-pyrrolizinyl, tetrahydro- 1 ,1 -dioxothienyl, N- formylpiperazinyl, and morpholinyl.

The term "aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthalene or anthracene) or linked covalently, typically containing 6 to 10 atoms; wherein at least one ring is aromatic. The aromatic ring may optionally include one to three additional rings (either cycloalkyi, 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, -S02-NH2, aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -S02Ra, alkylthio, carboxyl, and the like, wherein Ra 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, "1 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, indol-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 -ORb wherein Rb is alkyl. Preferably, alkoxy is C Ci0 alkoxy, C C6 alkoxy, or C C4 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 "cycloalkylalkyi" by itself or as part of another substituent refers to a group having one of the aforementioned cycloalkyl groups attached to one of the aforementioned alkyl chains. Examples of such cycloalkylalkyi radicals include cyclopropyl methyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1 -cyclopentylethyl, 1 -cyclohexylethyl, 2-cyclopentylethyl, 2- cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, 3-cyclopentylbutyl, cyclohexylbutyl and the like. The term "heterocyclyl-alkyl" by itself or as part of another substituents refers to a group having one of the aforementioned heterocyclyl group attached to one of the aforementioned alkyl group, i.e., to a group -Rd-Rc wherein Rd is alkylene or alkylene substituted by alkyl group and Rc is a heterocyclyl group.

The term "carboxy" or "carboxyl" or "hydroxycarbonyl" by itself or as part of another substituent refers to the group -C02H. Thus, a carboxyalkyl is an alkyl group as defined above having at least one substituent that is -C02H .

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)ORe, wherein Re is as defined above for alkyl.

The term "alkylcarbonyloxy" by itself or as part of another substituent refers to a -0-C(=0)Re wherein Re 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-alkyl wherein the alkyl group is substituted by 1 , 2, or 3 halogen atoms. For example, "haloalkoxy" includes -OCF3, - OCHF2, -OCH2F, -O-CF2-CF3, -O-CH2-CF3, -O-CH2-CHF2, and -O-CH2-CH2F.

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

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

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

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 as 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 second embodiment, the present invention provides those compounds of formula I wherein; R is selected from the group comprising hydrogen, alkyl, and cycloalkyl;

X is hydrogen or halo;

Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with a substituent selected from the group consisting of -(CH2)n-C(=0)-NHR2, -(CH2)n-NH-C(=0)-R2, and -0-(CH2)n-C(=0)-NHR2; Wherein n is an integer selected from 0 to 6;

R2 is Het or Alk-Z2-Het1 ;

Wherein Alk is optionally substituted alkyl;

Z2 is selected from the group consisting of a direct bond, -0-, -NH-, and -S-;

-Het1 is selected from the group comprising

Figure imgf000020_0001

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

R is selected from the group comprising hydrogen, alkyl, and cycloalkyl; in particular R is hydrogen or alkyl; more in particular hydrogen or d-6alkyl;

X is hydrogen or halo;

Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with a substituent selected from the group consisting of -(CH2)n-C(=0)-NHR2, -(CH2)n-NH-C(=0)-R2, and -0-(CH2)n-C(=0)-NHR2;

Wherein n is an integer selected from 0 to 6;

R2 is Het1 or Alk-Z2-Het1 ;

Wherein Alk is optionally substituted alkyl; in particular optionally substituted Ci_6alkyl;

Z2 is selected from the group consisting of a direct bond, -0-, -NH-, and -S-;

-Het1 is selected from the group comprising

Figure imgf000021_0001

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

wherein;

R is selected from the group comprising hydrogen, alkyl, and cycloalkyl; in particular R is hydrogen or alkyl; more in particular hydrogen or methyl;

X is hydrogen or halo; in particular hydrogen or fluoro;

Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted in the meta position with a substituent selected from the group consisting of -(CH2)n-C(=0)-NHR2, -(CH2)n-NH-C(=0)-R2, and -0-(CH2)n-C(=0)-NHR2;

Wherein n is an integer selected from 0 to 6; in particular from 0 to 4; more in particular n is 0 or 1 ;

R2 is Het or Alk-Z2-Het1 ;

Wherein Alk is optionally substituted alkyl; in particular optionally substituted d-6alkyl; more in particular Alk is unsubstituted Ci_6alkyl.

Z2 is selected from the group consisting of a direct bond, -0-, -NH-, and -S-;

-Het1 is selected from the group comprising

Figure imgf000021_0002
In another particular embodiment, the present invention provides those compounds of formula I as described herein before, wherein Y is aryl; in particular phenyl; substituted with -Z -(CH2)n-C(=0)- NHR2 or -Z -(CH2)n-NH-C(=0)-R2.

In a further particular embodiment, the present invention provides those compounds of formula I as described herein before, wherein Y is aryl; in particular phenyl; substituted in the meta position with -Z -(CH2)n-C(=0)-NHR2 or -Z -(CH2)n-NH-C(=0)-R2.

In yet another further embodiment, the present invention provides those compounds of formula I as described herein before; wherein

Y is phenyl substituted in the meta position with -(CH2)n-C(=0)-NHR2 or -(CH2)n-NH-C(=0)-R2; and n is 0 or 1 ; in particular 0.

In another particular embodiment, the present invention provides compounds of formula I as described herein before, wherein

Het is selected from

Figure imgf000022_0001
in particular Het1 is

Figure imgf000022_0002

It is also an object of the present invention to provide those compounds of formula I, wherein one or more of the following restrictions apply;

· R is selected from the group comprising hydrogen, alkyl, and cycloalkyl; in particular R is hydrogen or alkyl;

• R is hydrogen or d-6alkyl; in particular hydrogen or methyl;

• X is hydrogen or halo; in particular hydrogen or fluoro;

• Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with -Z -(CH2)n-C(=0)-NHR2 or -Z -(CH2)n-NH-C(=0)-R2;

• Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with -Z -(CH2)n-C(=0)-NHR2;

• Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with-Z -(CH2)n-NH-C(=0)-R2; • Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with a substituent selected from the group consisting of -(CH2)n-C(=0)-NHR2, -(CH2)n-NH-C(=0)-R2, and -0-(CH2)n-C(=0)-NHR2;

• Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted in the meta position with -Z - (CH2)n-C(=0)-NHR2 or -Z -(CH2)n-NH-C(=0)-R2;

· Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted in the meta position with a substituent selected from the group consisting of -(CH2)n-C(=0)-NHR2, -(CH2)n-NH-C(=0)-R2, and -0-(CH2)n-C(=0)-NHR2;

• Z is a direct bond or -0-;

• n is an integer selected from 0 to 6; in particular from 0 to 4; more in particular n is 0 or 1 ;

· R2 is Het or Alk-Z2-Het1 ;

• Alk is optionally substituted alkyl; in particular optionally substituted d-6alkyl;

• Z2 is selected from the group consisting of a direct bond, -0-, -NH-, and -S-;

• -Het1 is selected from the group comprising

Figure imgf000023_0001
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 ROCK kinase, selected from ROCKI and ROCKII, in particular soft ROCK inhibitors.

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 ROCK is involved, such as diseases linked to smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeration, function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeration and remodeling

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 airway diseases; throat, nose and ear diseases; intestinal diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders; proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive bladder disease, allergy,.

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 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 Throat, Nose and Ear diseases: including but not limited to sinus problems, hearing problems, toothache, tonsillitis, ulcer and rhinitis,

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, psoriasis, 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, treatment and/or management of neurological disorders: including but not limited to neuropathic pain. The present compounds are therefore suitable for preventing neurodegeneration and stimulating neurogeneration in various neurological disorders, and/or for preventing, treating and/or alleviating complications and/or symptoms 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 the breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate, or thyroid gland; Castleman disease 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 sexual dysfunction: including but not limited to hypogonadism, bladder disease, or pelvic surgery; and/or to treat sexual dysfunction associated with treatment using certain drugs, such as drugs used to treat hypertension, depression or anxiety.

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 diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive bladder disease, allergy, and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith. In a preferred 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 asthma, sexual dysfunction or COPD.

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 airway diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological disorders: proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia; transplant rejection; spasm; chronic obstructive bladder disease and allergy; 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 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, psoriasis, 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 neurological disorders: including but not limited to neuropathic pain. The present compounds are therefore suitable for preventing neurodegeneration and stimulating neurogeneration in various neurological disorders; 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 the 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 sexual dysfunction: including but not limited to hypogonadism, bladder disease, or pelvic surgery; and/or to treat sexual dysfunction associated with treatment using certain drugs, such as drugs used to treat hypertension, depression or anxiety; 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 diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive bladder disease, and allergy; 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 ofairways, intestinal and inflammatory 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 ROCK described below inhibit ROCK with an IC50 value of less than 10 μ. Μ, preferably less than 1 μ. Μ.

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

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

The pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. In addition, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.

Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation 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, 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, and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ -, β - or r -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 analogous pyridinocarboxamides, such as those described in US-A-4,997,834 and EP-A-0 370 498.

For the treatment of pain, the compounds of the invention may be used locally. For local administration, the compounds may advantageously be used in the form of a spray, ointment or transdermal patch or another suitable form for topical, transdermal and/or intradermal administration.

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 bio-availability 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, , transdermal, or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented. 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. Such amount will usually vary depending on the condition to be prevented or treated and the route of administration. 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.

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.

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. Physicochemical 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. Attribution of the configuration:

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

A.3. Stereochemistry:

It is known by those skilled in the art that specific enantiomers (or diastereoisomers) can be obtained by different methods such as, but not limited to chiral resolution (for example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I or any subgroup thereof), assymetric synthesis or preparative chiral chromatography (using different column such as Chiralcel OD-H (tris-3,5-dimethylphenylcarbamate, 46 x 250 or 100 x 250 mm, 5 μιη), Chiralcel OJ (tris-methylbenzoate, 46 x 250 or 100 x 250 mm, 5 μιη), Chiralpak AD (tris-3,5- dimethylphenylcarbamate, 46 x 250 mm, 10 μιη) and Chiralpak AS (tris-(S)-1 - phenylethylcarbamate, 46 x 250 mm, 10 μιη) from Chiral Technologies Europe (lllkirch, France)). Whenever it is convenient, stereoisomers can be obtained starting from commercial materials with known configuration (such compounds include aminoacid for instance).

B. Compound synthesis B.1. Intermediates

The compounds of the invention may be prepared by methods well known to those skilled in the art and described in the patent application WO201 1 /107608.

The following intermediates (Table B.1 .1 ) were prepared according to procedures described in the patent application WO201 1/107608.

Table B.1 .1 : Intermediates

Figure imgf000033_0001
Figure imgf000034_0001
Name Intermediate Structure

0

3-((2-oxo-tetra hydro-fu ra n-3-

15

yl)thio)-propanoic acid

3-((2- aminoethyl)amino)dihydrofuran- 16

2(3H)-one

HJM q

3-

((aminomethyl)amino)dihydrofur 17 S _ o

an-2(3H)-one

Intermediate 18: (5-Methyl-2-oxo-tetrahydro-furan-3-ylsulfanyl)-acetic acid

Figure imgf000035_0001

To a solution of 2-mercaptoacetic acid (1 g, 10.9 mmol, 755 μΙ_) and ET3N (3.02 mL, 21 .7 mmol) in DCM (40 mL) at 0°C was added the bromovalerolactone (21 .71 mmol, 3.91 g, 2.39 mL). The resulting solution was stirred at rt for 5h. The mixture was then evaporated under vacuum, diluted in anhydrous DMF (28 mL). the precipitate was filtered off and the title compound in solution (0.39 mol/L) was used directly in the next step.

Intermediate 19: (S)-2-(2-Oxo-tetrahydro-furan-3-ylamino)-propionic acid

Figure imgf000035_0002

A mixture of 3-bromodihydrofuran-2(3H)-one (0.825 g, 5 mmol,1 eq.), (S)-1 -tert-butoxy-1 - oxopropan-2-aminium chloride (0.908g, 5 mmol, 1 eq.) and K2C03 (2.28g, 3 eq.) in 25 mL acetonitrile was stirred at reflux (80°C) overnight. The mixture was concentrated under vacuum and the residue was taken off in ethylacetate and water. The organic layer was separated and washed 2% NaHC03 aqueous solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow oil (crude 410 mg). The residue was purified by flash chromatography (Hexane / Etylacetate 80/20 to 50/50) to give the corresponding t-Butyl ester (31 % yield).

The compound was solubilized in a mixture of DCM (2.5ml) and TFA (2.5 ml) and the mixture was stirred overnight. The mixture was concentrated under vacuum followed by addition of diethyether. The precipitate was collected by filtration washed with diethyl ether and dried to give the title compound as a white (40% yield).

B.2. Compounds of the invention

In the tableB.2.1 that is set forth below, exemplary compounds of the invention are described. In this table, the name of the compound, an arbitrarily assigned compound number and structural information are set out.

Table B.2.1 : Com ounds of the invention

Figure imgf000036_0001
Figure imgf000037_0001

3-ylmethyl)-amide]

Figure imgf000038_0001
Figure imgf000039_0001
Compounds 18 & 19 (enantiomers of compound 13) were obtained by chiral HPLC using a Chiralpak AS-H column.

C. In vitro and in vivo assays

C.1. ROCK inhibitory activity screening

C.1.1. Kinase inhibition

On-target activity against ROCK was measured in a biochemical assay, using the following reagents: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCI2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3V04, 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. ROCK (1 nM final concentration) was then delivered to the substrate solution. After gentle mix, DMSO solutions of the test compounds were added to the enzyme. Substrate mix 33P-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 IC50 values were subsequently determined.

When evaluated under such conditions, compounds of the invention inhibit ROCK2 with an IC50 < 1 μΜ. Specific aspects regarding the biological activity of compounds of the invention is further discussed in point C.3 of the present document (Comparison to prior art compounds).

C.1.2. Smooth muscle relaxing activity of generated soft ROCK inhibitors in vitro using organ baths of guinea pig trachea

Guinea pig trachea rings are prepared and incubated with a fixed concentration of the bronchoconstrictive agent carbachol. Then, increasing concentrations of the soft ROCK inhibitors are added and the contractive properties of the trachea measured for each of the compound concentrations. The study set-up allows the determination of an IC50, represented by the concentration of compound that induces a force equal to 50% of that observed for the vehicle- treated trachea.

In addition retention on the target is assessed using the above described organ baths of guinea pig trachea. In brief, upon induction of maximal relaxation with the ROCK inhibitors, trachea rings are thoroughly washed. Then, carbachol is added again and contractive properties are measured to determine whether the inhibitory activity of the ROCK inhibitors is prolonged upon the washout. A prolonged inhibitory activity after the washout is highly indicative for a prolonged retention of the compound at the lungs in vivo. Compounds of the invention are efficacious in this model. With preferred compounds displaying an EC50 < 500nM.

C.1.3. Anti-inflammatory activity of generated soft ROCK inhibitors in an acute LPS lung challenge model in mice

Half an hour after intratracheal compound administration, mice are challenged intratracheally with LPS. Twenty-four hours later, the mice are sacrificed, bronchoalveolar lavage fluid (BALF) collected and total cell number as well as percentage neutrophils determined. Anti-inflammatory activity is represented by a reduction in the total number of BALF cells and in the number of neutrophils as compared to a non-treated control group). Compounds of the invention are efficacious in this model with preferred compounds displaying an ED50 below 0.5 mg/kg.

C.2. Pharmacological Characterization

C.2.1. Stability assay in human and/or rat plasma

Compounds are incubated at a concentration of 1 μΜ in rat (mice, dog or rabbit) or human plasma. Samples are taken at fixed time points and the remnant of compound is determined by LC-MS/MS after protein precipitation. Half life in table C.2.1 is expressed in minutes.

Table C.2.1 : Half-life values in plasma

Figure imgf000041_0001

C.2.2. Stability towards drug metabolizing enzymes in lung S9

A 1 μΜ solution of the ROCK inhibitors is incubated with a reaction mixture containing lung S9 (from smokers) as well as the cofactors NADPH, UDPGA, PAPS and GSH. Samples are collected at 0, 15, 30 and 60 minutes post incubation. Negative control samples incubated with ROCK inhibitors and S9 fraction in the absence of cofactors are run in parallel. By using LC-MS/MS analysis, the percent of ROCK compounds remaining at each time point, the metabolic half-life of the ROCK compounds (expressed in minutes in table C.2.2) and the metabolic half-life of the control compounds are determined. Table C.2.2: Half-life values in lungS9

Figure imgf000042_0001

C.2.3. Stability towards drug metabolizing enzymes in intestinal S9

A 1 μΜ solution of the ROCK inhibitors is incubated with a reaction mixture containing human intestinal S9 as well as the cofactors NADPH, UDPGA, PAPS and GSH. Samples are collected at 0, 15, 30 and 60 minutes post incubation. Negative control samples incubated with ROCK inhibitors and S9 fraction in the absence of cofactors are run in parallel. By using LC-MS/MS analysis, the percent of ROCK compounds remaining at each time point, the metabolic half-life of the ROCK compounds (expressed in minutes in table C.2.3) and the metabolic half-life of the control compounds are determined.

Table C.2.3: Half-life values in intestinal S9

Figure imgf000042_0002

C.3. Comparison to prior art compounds

Other soft ROCK inhibitors have already been disclosed by the applicant in patent application PCT/EP201 1/053343. When comparing the compounds of the present invention with the compounds of PCT/EP201 1/053343 (Tables C.3.1 & C.3.2), we unexpectedly found that the compounds of the present invention display a better combination of on-target potency and fast degradation in human plasma, as can be seen in the following tables. t1/2 and IC50 values were determined as described above, results are ordered according to t1/2 values.

Table C.3.1 Representative compounds from WO201 1/107608.

Figure imgf000042_0003

Figure imgf000043_0001

Table C.3.2 Representative compounds of the invention

Figure imgf000043_0002

Claims

1 . A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof,
Figure imgf000044_0001
I
Wherein
R is selected from the group comprising hydrogen, alkyl, and cycloalkyi;
X is hydrogen or halo;
Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with -Z -(CH2)n-C(=0)-NHR2 or -Z -(CH2)n-NH-C(=0)-R2;
Wherein Z is a direct bond or -0-;
n is an integer selected from 0 to 6;
R2 is Het or Alk-Z2-Het1 ;
Wherein Alk is optionally substituted alkyl;
Z2 is selected from the group consisting of a direct bond, -0-, -NH-, and -S-;
-Het1 is selected from the group comprising
Figure imgf000044_0002
2. A compound of formula I wherein;
R is selected from the group comprising hydrogen, alkyl, and cycloalkyi;
X is hydrogen or halo; Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with a substituent selected from the group consisting of -(CH2)n-C(=0)-NHR2, -(CH2)n-NH-C(=0)-R2, and -0-(CH2)n-C(=0)-NHR2;
Wherein n is an integer selected from 0 to 6;
R2 is Het or Alk-Z2-Het1 ;
Wherein Alk is optionally substituted alkyl;
Z2 is selected from the group consisting of a direct bond, -0-, -NH-, and -S-;
-Het1 is selected from the group comprising
Figure imgf000045_0001
3. A compound of formula I wherein;
R is selected from the group comprising hydrogen, alkyl, and cycloalkyl; in particular R is hydrogen or alkyl; more in particular hydrogen or d-6alkyl;
X is hydrogen or halo;
Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with a substituent selected from the group consisting of -(CH2)n-C(=0)-NHR2, -(CH2)n-NH-C(=0)-R2, and -0-(CH2)n-C(=0)-NHR2;
Wherein n is an integer selected from 0 to 6;
R2 is Het1 or Alk-Z2-Het1 ;
Wherein Alk is optionally substituted alkyl; in particular optionally substituted Ci_6alkyl;
Z2 is selected from the group consisting of a direct bond, -0-, -NH-, and -S-;
-Het1 is selected from the group comprising
Figure imgf000046_0001
4. A compound of formula I wherein;
R is selected from the group comprising hydrogen, alkyl, and cycloalkyl; in particular R is hydrogen or alkyl; more in particular hydrogen or methyl;
X is hydrogen or halo; in particular hydrogen or fluoro;
Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted in the meta position with a substituent selected from the group consisting of -(CH2)n-C(=0)-NHR2, -(CH2)n-NH-C(=0)-R2, and -0-(CH2)n-C(=0)-NHR2;
Wherein n is an integer selected from 0 to 6; in particular from 0 to 4; more in particular n is 0 or 1 ; R2 is Het or Alk-Z2-Het1 ;
Wherein Alk is optionally substituted alkyl; in particular optionally substituted d-6alkyl; Z2 is selected from the group consisting of a direct bond, -0-, -NH-, and -S-;
-Het1 is selected from the group comprising
Figure imgf000046_0002
5. A compound according to claim 1 , wherein one or more of the following restrictions apply; • R is selected from the group comprising hydrogen, alkyl, and cycloalkyl; in particular R is hydrogen or alkyl;
• R is hydrogen or d-6alkyl; in particular hydrogen or methyl;
• X is hydrogen or halo; in particular hydrogen or fluoro;
· Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with -Z -(CH2)n-C(=0)-NHR2 or -Z -(CH2)n-NH-C(=0)-R2;
• Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with a substituent selected from the group consisting of -(CH2)n-C(=0)-NHR2, -(CH2)n-NH-C(=0)-R2, and -0-(CH2)n-C(=0)-NHR2;
• Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted in the meta position with -Z - (CH2)n-C(=0)-NHR2 or -Z -(CH2)n-NH-C(=0)-R2;
• Y is aryl or heteroaryl; wherein said aryl or heteroaryl is substituted in the meta position with a substituent selected from the group consisting of -(CH2)n-C(=0)-NHR2, -(CH2)n-NH-C(=0)-R2, and -0-(CH2)n-C(=0)-NHR2;
• Z is a direct bond or -0-;
· n is an integer selected from 0 to 6; in particular from 0 to 4; more in particular n is 0 or 1 ;
• R2 is Het or Alk-Z2-Het1 ;
• Alk is optionally substituted alkyl; in particular optionally substituted Ci_6alkyl;
• Z2 is selected from the group consisting of a direct bond, -0-, -NH-, and -S-;
• -Het1 is selected from the group comprising
Figure imgf000047_0001
6. A compound according to any one of claims 1 to 5 for use as a medicine.
7. A compound according to any one of claims 1 to 5 for use in the prevention and/or treatment of at least one disease or disorder selected from the group consisting of eye diseases; airway diseases; ear diseases; skin diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological disorders; proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia; transplant rejection; spasm; hypertension; chronic obstructive bladder disease; and allergy.
8. A composition comprising a compound as defined in any one of claims 1 to 5 for use as a human or veterinary medicine.
5 9. Use of a compound as defined in any one of claims 1 to 5, or a composition as defined in claim 8, suitable for inhibiting the activity of a kinase; in particular a ROCK kinase.
10. Use of a compound as defined in any one of claims 1 to 5, or a composition as defined in claim 8, for the prevention and/or treatment of at least one disease or disorder selected from the group 10 consisting of eye diseases; airway diseases; ear diseases; skin diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological disorders; proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia; transplant rejection; spasm; hypertension; chronic obstructive bladder disease; and allergy.
15 1 1 . Use of a compound as defined in any one of claims 1 to 5 or a composition as defined in claim 8, in the prevention and/or treatment of Intestinal diseases; including but not limited to inflammatory bowel disease (IBD), colitis, ulcerative colitis, gastroenteritis, ileus, ileitis, appendicitis and Crohn's disease.
12. Use of a compound of formula I according to any one of claims 1 to 5 or a composition 20 comprising a compound of formula I according to any one of claims 1 to 5, for the prevention and/or treatment of airway diseases selected from the group consisting of pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cytsis fibrosis, chronic obstructive pulmonary disease (COPD), bronchitis rhinitis, and respiratory distress syndrome; preferably asthma or COPD.
25
13. Use of a compound as defined in any one of claims 1 to 5 or a composition as defined in claim 8, for the prevention and/or treatment of sexual dysfunctions selected from the group consisting of erectile dysfunction, hypogonadism, bladder disease, hypertension, pulmonary hypertension, or pelvic surgery; and/or to treat sexual dysfunction associated with treatment using certain drugs,
30 such as drugs used to treat hypertension, depression or anxiety.
14. A method for the prevention and/or treatment of at least one disease or disorder selected from the group comprising eye diseases; airway diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative diseases; kidney diseases;
35 sexual dysfunction; bone diseases; benign prostatic hyperplasia; transplant rejection; spasm; hypertension; chronic obstructive bladder disease; and allergy;; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in claims 1 to 5, or a composition as defined in claim 8.
15. A method for the prevention and/or treatment of Intestinal diseases; including but not limited to inflammatory bowel disease (IBD), colitis, ulcerative colitis, gastroenteritis, ileus, ileitis, appendicitis and Crohn's disease.; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in claims 1 to 5, or a composition as defined in claim 8.
16. A method for the prevention and/or treatment of airway diseases selected from the group consisting of pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cytsis fibrosis, chronic obstructive pulmonary disease (COPD), bronchitis rhinitis, and respiratory distress syndrome; preferably asthma or COPD; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound of formula I according to any one of claims 1 to 5 or a composition comprising a compound of formula I according to any one of claims 1 to 5.
17. A method for the prevention and/or treatment of sexual dysfunctions selected from the group consisting of erectile dysfunction, hypogonadism, bladder disease, hypertension, diabetes, or pelvic surgery; and/or to treat sexual dysfunction associated with treatment using certain drugs, such as drugs used to treat hypertension, depression or anxiety.; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in claims 1 to 5, or a composition as defined in claim 8.
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