HK1197403A - Novel soft rock inhibitors - Google Patents

Description

Novel soft ROCK inhibitors

Technical Field

The present invention relates to novel kinase inhibitors, more particularly ROCK inhibitors, compositions, especially medicaments, comprising such inhibitors and the use of said inhibitors in the treatment and prevention of disease. In particular, the present invention relates to novel ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and the use of the inhibitors in the treatment and prevention of disease.

Background

The serine/threonine protein kinase ROCK consists of two isoforms, ROCK I and ROCK II, in humans. ROCK I encodes on chromosome 18, while ROCK II (also known as Rho-kinase) is located on chromosome 12. Both have a molecular weight of approximately 160 kDa. They have 65% overall homology and 95% homology in their kinase domain. Despite their sequence similarity, the tissue distribution differs. The highest level of ROCK I expression was observed in cardiac, lung and skeletal tissues, whereas ROCK II was predominantly expressed in brain. Recent data show that there is partial functional redundancy in both isoforms, ROCK I is more involved in immunological events, while ROCK II is involved in smooth muscle function. The term ROCK denotes ROCKI (ROK-. beta., p160ROCK or Rho-kinase. beta. and ROCK II (ROCK-. alpha. or Rho-kinase. alpha.).

ROCK activity has been shown to be enhanced by GTPase RhoA, a member of the Rho (Ras homolog) GTP-binding protein. RhoA in the active GTP-bound state interacts with the Rho-binding domain (RBD) of ROCK located at the self-inhibiting carboxy terminal ring. Upon binding, the interaction between the ROCK negative regulatory domain and the kinase domain is disrupted. This process allows the kinase to adopt an open conformation that is completely active. This open conformation is also caused by the binding of a lipid activator (e.g., arachidonic acid) to the PH domain of the kinase carboxy-terminal domain. Another activation mechanism during apoptosis is also described and involves carboxy-terminal cleavage of ROCK I and II by caspases-3 and-2 (or granzyme B), respectively.

ROCK plays an important role in various cellular functions, such as smooth muscle contraction, actin cytoskeletal organization, platelet activation, down regulation of myosin phosphatase cell adhesion, migration of aortic smooth muscle cells, proliferation, survival and thrombin-induced responses, cardiomyocyte hypertrophy, bronchial smooth muscle contraction, smooth muscle contraction and non-muscle cytoskeletal reorganization, activation of volume-regulated anion channels, neurite retraction, wound healing, cellular transformation and gene expression. ROCK also plays a role in many signaling pathways involved in autoimmunity and inflammation. ROCK has been shown to play a role in the activation of NF- κ B, a key molecule responsible for the production of TNF and other inflammatory cytokines. ROCK inhibitors have been reported to counteract the production of TNF-alpha and IL-6 factors in Lipopolysaccharide (LPS) -stimulated THP-1 macrophages. ROCK inhibitors therefore provide a beneficial therapy for the treatment of autoimmune diseases, inflammatory diseases and oxidative stress.

In conclusion, ROCK is a major regulatory point for smooth muscle cell function and is a key signaling component of the inflammatory process of various inflammatory cells and the process of fibrosis and remodeling of many diseased organs. Furthermore, ROCK has been implicated in a variety of diseases and disorders, including: eye diseases; airway disease (airway disease); cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders; proliferative diseases (proliferative diseases); renal disease; sexual dysfunction; blood diseases; bone disease; diabetes mellitus; benign prostatic hyperplasia, transplant rejection, liver disease, systemic lupus erythematosus, spasticity, hypertension, chronic obstructive bladder disease, premature labor, infection, allergy, obesity, pancreatic disease, and AIDS.

ROCK appears to be a safe target as evidenced by gene knockout models and extensive academic research. The data from these knockout mice was combined with post-market monitoring studies of Fasudil (Fasudil), a moderately potent ROCK inhibitor for the treatment of cerebral vasospasm following subarachnoid hemorrhage, indicating that ROCK is a true and significant drug target.

ROCK inhibitors are useful as therapeutic agents for the treatment of disorders involving the ROCK pathway. Therefore, there is a strong need to develop a ROCK inhibitor that can be used to treat a variety of diseases or disorders associated with ROCK activation, particularly given the current inadequacy of treatment for most of these diseases. One non-limiting example is glaucoma.

Glaucoma is a neurodegenerative disease that is the second leading cause of irreversible blindness. The disease is characterized by elevated intraocular pressure (IOP) and progressive retinal ganglion cell apoptosis, resulting in irreversible visual field loss. Current treatments for this disease are directed to the reduction of IOP, which is the major, but not the only, risk factor for glaucoma. Since current treatments only control and fail to cure the disease and further incur irritating, local and systemic side effects, improved therapies are needed. In addition, other positive effects, such as anti-inflammatory and neuroregenerative components of ROCK inhibitors, are highly preferred. Reference ROCK inhibitors (such as Y-27632) cause alterations in cell morphology and decrease the tonofibrosis, focal adhesion and MLC phosphorylation of cultured human TM cells; they dilate human trabecular meshwork cultured in vitro, dilate human Schlemm's ductal endothelial cells in vitro, and when applied topically to animals will significantly increase trabecular efflux, resulting in a substantial decrease in intraocular pressure.

There are several known types of ROCK inhibitors. The current focus is on the use of tumors and cardiovascular diseases. To date, the excellent therapeutic potential of ROCK inhibitors has been exploited only to a limited extent, since ROCK is a potent and ubiquitous biochemical regulator, and systemic inhibition of ROCK results in strong biological effects that are considered as side effects of the treatment of most diseases. Indeed, the medical use of ROCK inhibitors for non-cardiological indications is hampered by the critical role of ROCK in regulating the tonic phase of smooth muscle cell contraction. Systemically available ROCK inhibitors induce a significant drop in blood pressure. Therefore, there is a high demand for ROCK inhibitors of different properties.

To develop a targeted specific treatment of disease by modulating smooth muscle function and/or inflammatory processes and/or remodeling, it is highly desirable that ROCK inhibitors be able to target organs to avoid significant amounts of drug from entering other organs. Therefore, topical application or external application is desirable. Generally, topically applied drugs have been used to treat respiratory, ocular, sexual dysfunction and skin disorders. In addition, local injection/infiltration into diseased tissue further expands the potential medical use of locally applied ROCK inhibitors. These topical applications can allow high concentrations of the drug to reach the target tissue if certain conditions are met. Furthermore, the incorporation of ROCK inhibitors into implants and stents can further expand the medical applications for the local treatment of cardiovascular diseases, such as atherosclerosis, coronary heart disease and heart failure.

Although direct topical application is a priority in medical practice, the level of drug entering the systemic circulation is of concern. For example, local delivery by inhalation to treat airway diseases poses a risk of systemic exposure, since large amounts of the drug are passed into the gastrointestinal tract and/or absorbed systemically through the lungs. For the treatment of locally delivered eye conditions, large amounts of drug enter the gastrointestinal tract and/or systemic circulation due to low corneal permeability, low fluid capacity, efficient drainage, and the presence of eyelid vessels. With respect to dermal drug delivery, topical injection and implantable medical devices, there is a serious risk of leakage into the systemic circulation. Thus, in addition to topical application, it is desirable that the compounds have additional properties that avoid significant systemic exposure.

Soft drugs (soft drugs) are biologically active compounds that are inactivated once they enter the systemic circulation. This inactivation can be achieved in the liver, but preferably the inactivation should occur in the blood. These compounds, once applied topically to the target tissue/organ, will exert their intended effect locally. In the case of their leakage from the tissue into the systemic circulation, they are inactivated very rapidly. Thus, the soft drug of choice is sufficiently stable in the target tissue/organ to exert the desired biological effect, but rapidly degrades in the blood to a biologically inactive compound. Furthermore, it is highly preferred that the soft drug of choice be retained at its biological target. This property will limit the number of daily applications and it is highly desirable to reduce the total loading of drugs and metabolites and in addition will also significantly improve patient compliance.

In view of the foregoing, 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 various disorders or conditions associated with ROCK activation. More specifically, the compounds of the present invention are preferably used for the prevention and/or treatment of at least one disease or disorder involving ROCK, such as diseases associated with smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction (barrier dysfunction), neurodegeneration, and remodeling. For example, the compounds of the present invention are useful for the prevention and/or treatment of the following diseases and disorders:

eye diseases or disorders including, but not limited to, retinopathy, optic neuropathy, glaucoma and degenerative retinal diseases such as macular degeneration, proliferative vitreoretinopathy, proliferative diabetic retinopathy, retinitis pigmentosa and inflammatory eye diseases (such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis), glaucoma filtration surgery failure, dry eye, allergic conjunctivitis, posterior capsular opacification, corneal diseases (such as, but not limited to, fukes' dystrophy and keratitis), abnormal healing of corneal wounds and eye pain.

-an airway disease; 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 (sinus problems), hearing problems, dental pain, tonsillitis, ulcers and rhinitis.

-skin diseases: including but not limited to hyperkeratosis, parakeratosis, thickening of the stratum granulosum, thickening of the stratum spinosum, parakeratosis, edema of the stratum spinosum, and ulceration.

-intestinal disorders: including but not limited to Inflammatory Bowel Disease (IBD), inflammatory bowel disease, gastroenteritis, ileus, 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 diseases: including but not limited to neuropathic pain. The compounds of the present invention are therefore useful in the prevention of neurodegeneration and in the stimulation of nerve regeneration in various neurological disorders.

-proliferative diseases: cancers such as, but not limited to, breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, ovary, pancreas, prostate, or thyroid; giant lymph node hyperplasia; a sarcoma; malignant cell tumors (malignoma) and melanoma.

-renal diseases: including but not limited to renal fibrosis or renal insufficiency.

-sexual dysfunction: male and female sexual dysfunction due to defective vasoactive responses are intended to be included. The soft ROCK inhibitors of the present invention are also useful in the treatment of sexual dysfunction due to a variety of causes. For example, in one embodiment, soft ROCK inhibitors are useful for treating sexual dysfunction associated with hypogonadism, more specifically, associated with decreased androgen levels. In another embodiment, 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, soft ROCK inhibitors are useful in the treatment of sexual dysfunction caused by the use of certain drugs, for example, drugs for the treatment of hypertension, depression or anxiety.

Bone diseases including but not limited to osteoporosis and osteoarthritis.

Furthermore, the compounds of the present invention are useful for the prevention and/or treatment of diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasticity, chronic obstructive bladder disease, and allergy.

Disclosure of Invention

We have surprisingly found that the compounds described herein are useful as inhibitors of ROCK, in particular as soft ROCK inhibitors. The compounds of the invention are very rapidly converted into functionally inactive compounds, for example by carboxylic ester hydrolases (ec3.1.1) such as cholinesterase or carboxylesterase or by plasma proteins showing pseudoesterase activity such as human serum albumin. Carboxylic ester hydrolases (EC3.1.1) represent a large group of enzymes involved in the degradation of carboxylic esters to alcohols and carboxylic acids. Therefore, enzymes exhibiting this catalytic activity are of potential interest for the design of soft kinase inhibitors. Ec3.1.1 includes the following subclasses:

ec 3.1.1.1.1 carboxylesterase; ec3.1.1.2 aryl esterase; ec3.1.1.3 triacylglycerol lipase; ec3.1.1.4 phospholipase a 2; ec3.1.1.5 lysophospholipase; ec3.1.1.6 acetyl esterase; ec3.1.1.7 acetylcholinesterase; ec3.1.1.8 cholinesterase; EC3.1.1.10 tropine esterase; EC3.1.1.11 a pectinesterase; ec3.1.1.13 sterol esterase; EC3.1.1.14 chlorophyllase; EC3.1.1.15L-arabinonolactonase; ec3.1.1.17 gluconolactonase; EC3.1.1.19 urolactonase; ec3.1.1.20 tannase; EC3.1.1.21 retinoyl palmitate esterase; EC3.1.1.22 Hydroxybutanoic acid dimer hydrolase; ec3.1.1.23 acylglycerol lipase; EC3.1.1.243-oxoadipate enollactonase; EC3.1.1.251, 4-lactonase; ec3.1.1.26 galactolipase; EC3.1.1.274-pyridoxol lactonase; EC3.1.1.28 acyl carnitine hydrolase; EC3.1.1.29 aminoacyl-tRNA hydrolase; EC3.1.1.30D-arabinonolactonase; EC3.1.1.316-phosphogluconolactonase; ec3.1.1.32 phospholipase a 1; EC3.1.1.336-acetyl glucose deacetylase; EC3.1.1.34 lipoprotein lipase; EC3.1.1.35 dihydrocoumarin hydrolase; EC3.1.1.36 limonin-D-cyclo-lactonase; EC3.1.1.37 steroid-lactonase; EC3.1.1.38 lactonase triacetate; EC3.1.1.39 actinomycin lactonase; EC3.1.1.40 bryozoate depside hydrolase (orsellinate-depside hydroxide); EC3.1.1.41 cephalosporin-C deacetylase; EC3.1.1.42 chlorogenic acid hydrolase; EC3.1.1.43 alpha-amino acid esterase; EC3.1.1.444-methyloxaloacetate esterase; EC3.1.1.45 carboxymethylethenylbutenylcarboxylic acid lactonase (carboxymethyl ethenylbutenolidase); EC3.1.1.46 deoxycitric acid A-cyclo-lactonase; EC3.1.1.471-alkyl-2-acetyl glycerophosphocholinesterase; EC3.1.1.48 Fusarium-C ornithine esterase; EC3.1.1.49 a erucin esterase; ec3.1.1.50 wax ester hydrolase; EC3.1.1.51 phorbol-diester hydrolase; EC3.1.1.52 phosphatidylinositol deacylase; EC3.1.1.53 sialic acid O-acetyl esterase; EC3.1.1.54 acetoxybutynyl bithiophene deacetylase; EC3.1.1.55 acetylsalicylic acid deacetylase; EC3.1.1.56 Methyleumbelliferyl acetate deacetylase; EC3.1.1.572-pyrone-4, 6-dicarboxylate lactonase; EC3.1.1.58N-acetyl galactosaminyl glycan deacetylase; EC3.1.1.59 juvenile hormone esterase; EC3.1.1.60 bis (2-ethylhexyl) phthalate esterase; EC3.1.1.61 protein-glutamic acid methylesterase; EC3.1.1.6311-cis-retinyl-palmitohydrolase; EC3.1.1.64 all trans-retinyl-palmitohydrolase; EC3.1.1.65L-rhamnose-1, 4-lactonase; EC3.1.1.665- (3, 4-diacetoxybut-1-ynyl) -2,2' -bithiophene deacetylase; EC3.1.1.67 a fat-acyl-ethyl-ester synthase; EC3.1.1.68 xylose (xylono) -1, 4-lactonase; EC3.1.1.70 cetroratate benzyl esterase; EC3.1.1.71 Acetylalkylglyceroacetylhydrolase; EC3.1.1.72 acetyl xylan esterase; ec3.1.1.73 feruloyl esterase; ec3.1.1.74 cutinase; EC3.1.1.75 Poly (3-hydroxybutyrate) depolymerase; EC3.1.1.76 Poly (3-hydroxyoctanoate) depolymerizing enzyme; EC3.1.1.77 acyl oxy acyl hydrolase; EC3.1.1.78 Polycerebramine-aldehyde esterase; EC3.1.1.79 hormone sensitive lipase; EC3.1.1.80 acetyl ajmaline esterase; EC3.1.1.81 population quenching N-acyl-homoserine lactonase; EC3.1.1.82 pheophorbidase (pheophorbidase); EC3.1.1.83 monoterpene epsilon-lactone hydrolase; EC3.1.1.84 cocaine esterase; EC3.1.1.85 mannosylglycerate hydrolase.

Cholinesterases are enzymes known primarily for their role in the degradation of the neurotransmitter acetylcholine. Acetylcholinesterase (EC3.1.1.7) is also known as cholinesterase I, true cholinesterase, RBC cholinesterase, erythrocyte cholinesterase or acetylcholinesterase. As some of its alternative names suggest, acetylcholinesterase is present not only in the brain, but also in the red blood cell fraction of the blood. In addition to its effect on acetylcholine, acetylcholinesterase also hydrolyzes various acetates, as well as catalyzing transacetylation. Acetylcholinesterase usually shows preference for short chain substrates, such as acetyl of acetylcholine. Butyrylcholinesterase (EC3.1.1.8) is also known as benzoylcholinesterase, cholinesterase II, nonspecific cholinesterase, pseudocholinesterase, plasma cholinesterase or acylcholinohydrolase, and although it is mainly present in the liver, butyrylcholinesterase is also present in the plasma. As some of their alias names suggest, they are less specific than acetylcholinesterase and generally hydrolyze larger acid chains (such as butyryl of butyrylcholine or benzoyl of benzoylcholine) at a faster rate than acetylcholinesterase. In addition to its effect on acetylcholine, butyrylcholinesterase is also known to be involved in the metabolism of several ester drugs such as procaine.

Carboxyesterases (CES) represent a multigene family and show ubiquitous expression profiles with high levels in liver, intestine and lung. Most of the carboxyesterases can be classified in the family carboxyesterase 1(CES1) or carboxyesterase 2(CES 2). Interestingly, these different CES families show differences in tissue distribution and substrate specificity. Human CES1 is widely distributed among many tissues, but is present at low levels in the intestine. CES1 preferentially hydrolyzes esters with relatively small alcohol groups and larger acid groups. As a typical example, hCES1 preferentially catalyzes the hydrolysis of cocaine methyl ester. Human CES2 is mainly present in the intestine, liver and kidney. CES2 preferentially hydrolyzes esters with smaller alcohol groups and larger acid groups. As a typical example, human CES2 catalyzes the hydrolysis of the benzoyl ester of cocaine. Yet another interesting phenomenon of CES enzymes is the lack of carboxyesterase activity in human plasma. In summary, carboxylesterases can play a major role in the biotransformation of ester-containing drugs and xenobiotics.

Paraoxonase 1(PON1) is also known as an aryl esterase (EC3.1.1.2) or A esterase.PON1 is a Ca²⁺Dependent serogroup a esterases, which are synthesized in the liver and secreted in the blood and bind exclusively to High Density Lipoproteins (HDLs). In addition, it is capable of cleaving a unique subset of substrates comprising organophosphates, aryl esters, lactones, and cyclic carbonates. Thus, the R2 substituent of the compounds of the present invention (hereinafter generally represented by formula I) may be selected to include substituents selected from aryl esters, lactones, and cyclic carbonates, more specifically aryl esters and lactones.

Human Serum Albumin (HSA) is the major component of plasma, accounting for approximately 60% of all plasma proteins. HSA has been found to catalyze the hydrolysis of a variety of compounds such as aspirin, cinnamoyl imidazole, p-nitrophenyl acetate, organophosphate insecticides, fatty acid esters, or nicotinic esters. In addition to its primary reaction site, HSA exhibits a variety of non-specific catalytic sites. However, the catalytic efficiency of these sites is low and HSA is often not described as a true esterase but as a pseudoesterase, although its catalytic efficiency is low, HSA may still have a measurable contribution in the metabolism of drug-like compounds because of its high concentration in plasma.

An asterisk as used herein indicates the point at which a monovalent or divalent group is attached to its associated structure and the structure of which the group forms a part, unless the context dictates otherwise.

Viewed from a first aspect the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate or solvate thereof,

wherein the content of the first and second substances,

x is hydrogen or halogen;

y is-NH-C (= O) -or-C (= O) -NH-;

Z¹，Z²and Z³Each independently selected from C, N, O and S;

R¹selected from the group comprising: hydrogen, C_1-20Alkyl and C_3-15A cycloalkyl group;

R²selected from the group comprising: hydrogen, C_1-20Alkyl, halogen and C_1-20An alkoxy group;

R³is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl, and C_3-19A heterocyclic group; wherein said C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl, and C_3-19The heterocyclyl group is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino radical, C_1-6Alkyl, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto (thiol), C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates (carbamate), thioamido (thioamido), ureas, and sulfonamido; and

n is 0 or 1.

Viewed from another 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 a compound as described above, for inhibiting 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 further aspect the invention provides a compound of the invention for use in human or veterinary medicine.

Viewed from another aspect the invention provides the use of a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of at least one disease and/or disorder selected from: eye diseases; airway disease; throat, nose and ear diseases; intestinal disease; cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders; proliferative diseases; renal disease; sexual dysfunction; bone disease; benign prostatic hyperplasia, transplant rejection, spasticity, chronic obstructive bladder disease, and allergies.

Detailed Description

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

An asterisk as used herein indicates the point at which a monovalent or divalent group is attached to its associated structure and the structure of which the group forms a part, unless the context dictates otherwise.

Undefined (racemic) asymmetric centers that may be present in the compounds of the present invention are interchangeably indicated by plotting either a wavy bond or a direct bond to reveal the undefined steric nature of the bond.

As already mentioned above, in a first aspect, the present invention provides compounds of formula I

I

Wherein, X, Y, Z¹，Z²，Z³，R¹，R²，R³And n is as defined hereinbefore, including stereoisomeric forms, solvates and pharmaceutically acceptable addition salts thereof.

When describing the compounds of the present invention, the terms used are to be construed according to the following definitions, unless the context dictates otherwise:

the term "alkyl" by itself or as part of another group denotes the formula C_xH_2x+1Wherein x is a number greater than or equal to 1. Generally, the alkyl groups of the present invention contain 1 to 20 carbon atoms. Alkyl groups may be straight or branched chain and may be substituted as indicated herein. When a carbon atom is followed by a subscript, that subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, C_1-4Alkyl refers to alkyl groups having 1 to 4 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl and isomers thereof (e.g., n-butyl, isobutyl and tert-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers; decyl and isomers thereof. C₁-C₆Alkyl includes all straight, branched, or cyclic alkyl groups having 1 to 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, isopropyl, butyl, and isomers thereof (e.g., n-butyl, isobutyl, and tert-butyl); pentyl and its isomers, hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl, cyclopentylmethylene (cyclo) and cyclohexyl.

The term "optionally substituted alkyl" denotes an alkyl group optionally substituted at any available point of attachment by one or more substituents (e.g. 1 to 4 substituents, such as 1,2,3 or 4 substituents or 1 to 2 substituents; preferably 1 substituent). Non-limiting examples of such substituents include halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, alkoxy, haloalkoxy, haloalkyl, mercapto, alkylthio, carboxylic acid, acylamino, alkyl ester, carbamate, thioamido, urea, sulfonamido, and the like. In particular embodiments, the substituents are selected from halo, hydroxy, nitro, amino, cyano, aryl (especially phenyl and halophenyl such as fluorophenyl), heteroaryl (more especially pyridyl), cycloalkyl, heterocyclyl, alkoxy, alkylamino, and dialkylamino. In yet another particular embodiment, the substituents are selected from cyano, aryl, heteroaryl, cycloalkyl, heterocyclyl, dialkylamino, and alkoxy.

The term "alkylamino" as used herein refers to an amino group substituted with one or more alkyl chains. This definition includes quaternary ammonium derivatives.

The term "alkenyl" as used herein, unless otherwise specified, refers to a straight, cyclic or branched chain hydrocarbon group containing at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, E-and Z-propenyl, isopropenyl, E-and Z-butenyl, E-and Z-isobutenyl, E-and Z-pentenyl, E-and Z-hexenyl, E-, E, Z-, Z, E-, Z-hexadienyl, and the like. Optionally substituted alkenyl denotes alkenyl optionally having one or more (e.g. 1,2,3 or 4) substituents selected from those defined above for substituted alkyl.

The term "alkynyl" as used herein, unless otherwise specified, refers to a straight or branched chain hydrocarbon radical containing at least one carbon-carbon triple bond. Examples of alkynyl residues include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like. Optionally substituted alkynyl denotes alkynyl optionally bearing one or more (e.g. 1,2,3 or 4) substituents 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, a monovalent, saturated or unsaturated hydrocarbon group having 1,2 or 3 cyclic structures. Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic, and polycyclic alkyl groups. Cycloalkyl groups may contain 3 or more carbon atoms in the ring, while 3 to 15 atoms are generally included according to the invention. Further rings of the polycyclic cycloalkyl group may be fused, bridged and/or added through one or more spiro atoms. Cycloalkyl groups may also be considered to be a subset of homocyclic rings (homocyclic rings) as discussed below. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantyl, bicyclo (2.2.1) heptanyl and cyclodecyl, with cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and bicyclo (2.2.1) heptanyl being particularly preferred. "optionally substituted cycloalkyl" means cycloalkyl optionally having one or more substituents (e.g., 1-3 substituents, such as 1,2,3, or 4 substituents) selected from those defined above for substituted alkyl. When the prefix "ene" is used in conjunction with a cyclic group, also referred to hereinafter as "cycloalkylene", this means that the cyclic group as defined herein has two single bonds as points of attachment to other groups. Cycloalkylene groups of the present invention preferably contain the same number of carbon atoms as their cycloalkyl residue counterparts.

If an alkyl group is defined as divalent, i.e., two single bonds are attached to two other groups, they will be referred to as "alkylene" groups. Non-limiting examples of alkylene groups include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1, 2-dimethylethylene, pentamethylene, and hexamethylene. Similarly, if an alkenyl group as defined above and an alkynyl group as defined below are divalent, i.e., have a single bond attached to two other groups, they will be referred to as "alkenylene" and "alkynylene," respectively.

In general, the alkylene groups of the present invention preferably contain the same number of carbon atoms as their alkyl counterparts. If alkylene or cycloalkylene diradicals are present, they will be linked through a common carbon atom or through different carbon atomsTo the molecular structure of which they form part, among which a common carbon atom is preferred. To illustrate this, the asterisk nomenclature of the present invention, C, is used₃Alkylene may be, for example, -CH₂CH₂CH₂-*、*-CH(-CH₂CH₃) -CH₂CH(-CH₃) - *. Likewise, C₃The cycloalkylene group may be

If cycloalkylene is present, it is preferably C₃-C₆Cycloalkylene, more preferably C₃Cycloalkylene (i.e. cyclopropylene) groups, in which the moieties are attached through a common carbon atom. Cycloalkylene and alkylene diradicals in the compounds of the invention may be, but preferably are not, substituted.

The term "heterocyclyl" or "heterocycle" as used herein by itself or as part of another group refers to a non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., a 3 to 13 membered monocyclic, or 7 to 17 membered bicyclic, or 10 to 20 membered tricyclic ring system, or containing 3 to 10 ring atoms in total) in which at least one heteroatom in at least one carbon atom-containing ring must be present. For each ring containing a heteroatom in the heterocyclic group, there may be 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 to any heteroatom or carbon atom of the ring or ring system, as valency permits. The rings of the polycyclic heterocycle may be fused, bridged and/or added through one or more spiro atoms. Optionally substituted heterocycle means a heterocycle optionally having one or more substituents (e.g., 1 to 4 substituents, or such as 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, piperidinyl, succinimidyl, 3H-indolyl, isoindolinyl, chromenyl, isochroman, xanthyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4 aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3, 4-dihydro-2H-pyranyl, phthalazinyl, oxetanyl, thietanyl, 3-dioxocyclopentylpentyl, oxazanyl, and the like, 1, 3-dioxanyl, 2, 5-dioxoimidazolidinyl (dioxozolidinyl), 2, 4-piperidinonyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl (oxypyrrolidinyl), 2-oxazepinyl (2-oxoazepinyl), indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl (thiomorpholinyl), thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxolyl, 1, 4-oxathiacyclohexyl, 1, 4-dithianyl, 1,3, 5-trioxepanyl (trioxanyl), 6H-1,2, 5-thiadiazinyl, 2H-1,5, 2-dithiazinyl, 2H-oxocyclooctatrienyl (oxocinninyl), 1H-pyrrolizinyl, Tetrahydro-1, 1-dioxothienyl, N-formylpiperazinyl and morpholinyl.

The term "aryl" as used herein means a polyunsaturated aromatic hydrocarbon group containing a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthalene or anthracene) or covalently bonded, typically containing from 6 to 10 atoms; wherein at least one ring is aromatic. The aromatic ring may optionally contain one to three additional rings (cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylene, 5-or 6-tetrahydronaphthyl (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-acenaphthenyl (acenaphthenyl), 3-, 4-, or 5-dihydroacenaphthenyl (acenaphthenyl), 1-, 2-, 3-, 4-, or 10-phenanthrenyl, 1-or 2-pentalenyl, 1,2-, 3-, or 4-fluorenyl, 4-or 5-dihydroindenyl, tetralinyl, and the like, 5-, 6-, 7-, or 8-tetrahydronaphthyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl, dibenzo [ a, d ] cycloheptenyl, and 1-, 2-, 3-, 4-, or 5-pyrenyl.

The aryl ring may be optionally substituted with one or more substituents. "optionally substituted aryl" means an aryl group optionally having one or more substituents (e.g., 1-5 substituents, e.g., 1,2,3, or 4) at any available point of attachment. Non-limiting examples of such substituents are selected from: halogen, hydroxy, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -SO₂-NH₂Aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -SO₂R^aAlkyl thio, carboxyl, etc., wherein R^aIs an alkyl or cycloalkyl group.

If a carbon atom of an aryl group is replaced by a heteroatom, the resulting ring is referred to herein as a heteroaryl ring.

The term "heteroaryl" as used herein by itself or as part of another group refers to, but is not limited to, an aromatic ring or ring system of 5 to 12 carbon atoms, wherein 1 to 3 rings are fused together or covalently bonded, typically 5 to 8 atoms; at least one of which is aromatic, wherein one or more of the carbon atoms within one or more of these rings may be replaced by oxygen, nitrogen or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. These rings may be fused to aryl, cycloalkyl, heteroaryl or heterocyclyl rings. Non-limiting examples of these heteroaryl groups include: pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxadienyl, thiazinyl, triazinyl, imidazo [2,1-b ] [1,3] thiazolyl, thieno [3,2-b ] furyl, thieno [3,2-b ] thienyl, thieno [2,3-d ] [1,3] thiazolyl, thieno [2,3-d ] imidazolyl, tetrazolo [1,5-a ] pyridyl, indolyl, indolizinyl, isoindolyl, benzofuryl, benzopyranyl, 1(4H) -benzopyranyl, 1(2H) -benzopyranyl, 3, 4-dihydro-1 (2H) -benzopyranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, benzimidazolyl, 1, 3-benzoxazolyl, 1, 2-benzisoxazolyl, 2, 1-benzisoxazolyl, 1, 3-benzothiazolyl, 1, 2-benzisothiazolyl, 2, 1-benzisothiazolyl, benzotriazolyl, 1,2, 3-benzoxadiazolyl, 2,1, 3-benzoxadiazolyl, 1,2, 3-benzothiadiazolyl, 2,1, 3-benzothiadiazolyl, thienopyridyl, purinyl, imidazo [1,2-a ] pyridyl, 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 known as-pyrrolyl) as used herein includes pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl. The term "furyl" (also referred to as "furyl") as used herein includes furan-2-yl and furan-3-yl (also referred to as furan-2-yl and furan-3-yl). The term "thienyl" (also referred to as "thienyl") as used herein includes thien-2-yl and thien-3-yl (also referred to as thien-2-yl and thien-3-yl). The term "pyrazolyl" (also known as 1H-pyrazolyl and 1, 2-oxadiazolyl) 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 referred to as 1, 3-oxazolyl) as used herein includes oxazol-2-yl; oxazol-4-yl and oxazol-5-yl. The term "isoxazolyl" (also known as 1, 2-oxazolyl) as used herein includes isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl. The term "thiazolyl" (also known as 1, 3-thiazolyl) as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also known as 2-thiazolyl, 4-thiazolyl and 5-thiazolyl). The term "isothiazolyl" (also known as 1, 2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl. The term "triazolyl" as used herein includes 1H-triazolyl and 4H-1,2, 4-triazolyl, and "1H-triazolyl" includes 1H-1,2, 3-triazol-1-yl, 1H-1,2, 3-triazol-4-yl, 1H-1,2, 3-triazol-5-yl, 1H-1,2, 4-triazol-1-yl, 1H-1,2, 4-triazol-3-yl and 1H-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 "oxadiazol" 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 known as furazan-3-yl) and 1,3, 4-thiadiazol-2-yl. The term "tetrazolyl" as used herein includes 1H-tetrazol-1-yl, 1H-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 "pyridyl" (also referred to as "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl (also referred to as 2-pyridyl, 3-pyridyl, and 4-pyridyl). The term "pyrimidinyl" as used herein includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-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 referred to as "1, 4-oxazinyl") as used herein includes 1, 4-oxazin-4-yl and 1, 4-oxazin-5-yl. The term "dioxadienyl" (also referred to as "1, 4-dioxadienyl") as used herein includes 1, 4-dioxadien-2-yl and 1, 4-dioxadien-3-yl. The term "thiazinyl" (also referred to as "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 group" 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] thiazol-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 ] furyl" 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 ] thiophen-2-yl, thieno [3,2-b ] thiophen-3-yl, thieno [3,2-b ] thiophen-5-yl and thieno [3,2-b ] thiophen-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 ] pyridyl" as used herein includes tetrazolo [1,5-a ] pyridin-5-yl, tetrazolo [1,5-a ] pyridin-6-yl, tetrazolo [1,5-a ] pyridin-7-yl and tetrazolo [1,5-a ] pyridin-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 referred to as 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 referred to as 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 "benzothienyl" (also referred to as benzo [ b ] thienyl) as used herein includes 2-benzo [ b ] thienyl, 3-benzo [ b ] thienyl, 4-benzo [ b ] thienyl, 5-benzo [ b ] thienyl, 6-benzo [ b ] thienyl and 7-benzo [ b ] thienyl (also referred to as benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl). The term "isobenzothiophenyl" (also referred to as benzo [ c ] thiophenyl) as used herein includes isobenzothiophen-1-yl, isobenzothiophen-3-yl, isobenzothiophen-4-yl, isobenzothiophen-5-yl, isobenzothiophen-6-yl and isobenzothiophen-7-yl. The term "indazolyl" (also referred to as 1H-indazolyl or 2-azaindolyl) as used herein includes 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-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-benzisoxazol-yl" 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-benzisoxazol-yl" 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-benzisothiazolyl" 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-benzisothiazolyl" 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 "benzotriazol-yl" as used herein includes benzotriazol-1-yl, benzotriazol 4-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-benzothiadiazol-yl" 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 "thienopyridyl" as used herein includes thieno [2,3-b ] pyridyl, thieno [2,3-c ] pyridyl, thieno [3,2-c ] pyridyl and thieno [3,2-b ] pyridyl. 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 ] pyridyl" 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 "quinolyl" 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 "cinnolin-based" 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, quinazolin-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 denotes 1H-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 denotes 1H-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 denotes 1H-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 denotes 1H-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 groups 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, 2-, 4-triazol-1-, -3-, -4-or-5-yl, and, 1H-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-oxadiazol, 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-pyrimidinyl, 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-, 4-, 5-, or 6-yl, 3-, 4-, 5-, 6-or 7-benzofuranyl, 1-, 3-, 4-or 5-isobenzofuranyl, 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, p-tolyl-N-methyl-phenyl, p-tolyl-phenyl, p-phenyl, 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-yl, 1-, 2-thianthryl, 3-, 4-or 5-isobenzofuranyl, 1-, 2-, 3-, 4-or 9-xanthenyl, 1-, 2-, 3-or 4-thioxanthyl (phenoxathiinyl), 2-, 3-pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-indolizinyl, 2-, 3-, 4-or 5-isoindolyl, 1H-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] thiazol-2-yl, imidazo [2,1-b ] [1,3] thiazol-3-yl, imidazo [2,1-b ] [1,3] thiazol-yl, 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 ] pyridin-5-yl, tetrazolo [1,5-a ] pyridin-6-yl, tetrazolo [1,5-a ] pyridin-7-yl, Or a tetrazolo [1,5-a ] pyridin-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-quinolyl (quinolyl), 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 1-, 3-, 4-, 5-, (meth) acrylic acid or methacrylic acid, 6-, 7-or 8-isoquinolinyl (isoquinolinyl), 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-perimidine, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10- (1,7) phenanthroline, 1-or 2-phenazine, 1-, 2-, 3-, 4-, or 10-phenothiazinyl, 3-or 4-furazanyl, 1-, 2-, 3-, 4-, or 10-phenoxazinyl, or further substituted derivatives thereof.

"optionally substituted heteroaryl" means heteroaryl (e.g., 1-4 substituents, e.g., 1,2,3, or 4) optionally having one or more substituents selected from those defined above for substituted aryl.

The term "oxo" as used herein denotes the group = O.

The term "alkoxy" as used herein means having the formula-OR^bWherein R is^bIs an alkyl group. Preferably, alkoxy is C₁-C₁₀Alkoxy radical, C₁-C₆Alkoxy or C₁-C₄An alkoxy group. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. If the oxygen atom of an alkoxy group is substituted with sulfur, the resulting group is referred to as thioalkoxy. "haloalkoxy" is alkoxy wherein one or more hydrogen atoms in the alkyl group are replaced by halogen. Is suitable forNon-limiting examples of alkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2, 2-trifluoroethoxy, 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 the group-O-aryl, wherein aryl is as defined above.

The term "arylcarbonyl" or "aroyl" as used herein denotes the group-c (o) -aryl, wherein aryl is as defined above.

The term "heterocyclyl-alkyl" by itself or as part of another substituent denotes a group having one of the aforementioned heterocyclyl groups attached to one of the aforementioned alkyl groups, i.e. the group-R^d-R^cWherein R is^dIs alkylene or alkylene substituted by alkyl, and R^cIs a heterocyclic group.

The term "carboxy" or "carboxyl group" or "hydroxycarbonyl" by itself or as part of another substituent denotes the group-CO₂H. Thus, carboxyalkyl is-CO with at least one substituent₂H is an alkyl group as defined above.

The term "alkoxycarbonyl" by itself OR as part of another substituent means a carboxyl group attached to an alkyl residue, i.e., -C (= O) OR is formed^eWherein R is^eAs defined above for alkyl.

The term "alkylcarbonyloxy" by itself or as part of another substituent means-O-C (= O) R^eWherein R is^eAs defined above for alkyl.

The term "alkylcarbonylamino" by itself or as part of another substituent, denotes a group of formula-NH (C = O) R or-NR '(C = O) R, wherein R and R' are each independently alkyl or substituted alkyl.

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

The term "alkoxy" by itself or as part of another substituent means a group consisting of an oxygen atom attached to an optionally substituted straight or branched chain alkyl, cycloalkyl, aralkyl or cycloalkylalkyl group. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, hexyloxy, and the like.

The term "halo" or "halogen" as a group or part of a group is a generic term for fluorine, chlorine, bromine or iodine.

The term "haloalkyl", employed alone or in combination, denotes an alkyl residue having the meaning as defined above wherein one or more hydrogens are replaced by a halogen as defined above. Non-limiting examples of such haloalkyl residues include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, and the like.

The term "haloaryl", alone or in combination, denotes an aryl residue having the meaning as defined above, wherein one or more hydrogens are replaced by halogens as defined above.

The term "haloalkoxy", alone or in combination, signifies a group of formula-O-alkyl, wherein alkyl is substituted with 1,2 or 3 halogen atoms. For example, "haloalkoxy" includes-OCF₃、-OCHF₂、-OCH₂F、-O-CF₂-CF₃、-O-CH₂-CF₃、-O-CH₂-CHF₂and-O-CH₂-CH₂F。

Whenever the term "substituted" is used in the present invention, it is intended to indicate that in the expression using "substituted by … …" one or more hydrogens on an atom are replaced with a group selected from the indicated group, provided that the normal valency of the indicated atom is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that: it is robust enough to withstand isolation from the reaction mixture to useful purity levels, and formulation into a therapeutic agent.

As used herein, terms such as "alkyl, aryl or cycloalkyl, each optionally substituted with … …" or "alkyl, aryl or cycloalkyl, optionally substituted with … …" refer to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.

As described herein, some compounds of the present invention may contain one or more asymmetric carbon atoms as chiral centers, which may result in different optically isomeric forms (e.g., enantiomers or diastereomers). The present invention includes all possible configurations of these optically isomeric forms, as well as mixtures thereof.

More generally, from the foregoing, it will be apparent to the skilled artisan that the compounds of the invention may exist in different isomeric and/or tautomeric forms, including, but not limited to, geometric isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e., enantiomers and diastereomers), and isomers of the same substituent corresponding to different positions of a ring in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are intended to be within the scope of the invention.

Whenever the term "compounds of the invention" or similar terms are used in the present invention, it is intended to include compounds of formula I and any subset thereof. This term also refers to the compounds described in the examples, their derivatives, N-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogs, and their quaternized nitrogen analogs. The N-oxide form of the compound is intended to include compounds that: in which one or more nitrogen atoms are oxidized to the so-called N-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 other terms used in the specification are well understood by those skilled in the art.

In a further embodiment, the present invention provides a compound of formula I as described above, wherein;

R¹selected from the group comprising: hydrogen, C_1-6Alkyl and C_3-6A cycloalkyl group; especially hydrogen.

In a preferred embodiment, the present invention provides a compound of formula I, wherein;

x is hydrogen or halogen; especially halogen; more particularly fluorine;

y is-NH-C (= O) -or-C (= O) -NH-;

Z¹，Z²and Z³Each is independently selected from C, N, O and S; in particular selected from C and N; more particularly Z¹，Z²And Z³Each is C;

R¹selected from the group comprising: hydrogen, C_1-20Alkyl and C_3-15A cycloalkyl group; especially hydrogen;

R²selected from the group comprising: hydrogen, C_1-20Alkyl, halogen and C_1-20An alkoxy group;

R³is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl, and C_3-19A heterocyclic group; wherein said C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl, and C_3-19The heterocyclyl group is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_1-6Alkyl radical, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea, and sulfonamido; and

n is 0 or 1; in particular n is 1.

In a further embodiment, the present invention provides a compound of formula I as described above, wherein;

R²selected from hydrogen, C_1-20Alkyl and halogen; in particular from hydrogen, C_1-6Alkyl and halogen; more particularly from hydrogen, methyl and fluorine;

in a further embodiment, the present invention provides a compound of formula I as described hereinbefore, wherein;

R³is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl and C_3-19A heterocyclic group; wherein said C_1-20Alkyl radical, C_3-20Alkenyl and C_3-20Alkynyl is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_1-6Alkyl radical, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea and sulfonamido;

in particular, R³Is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl and C_3-19A heterocyclic group; wherein said C_1-20The alkyl group is optionally selected fromSubstituted with one or more substituents: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea and sulfonamido.

In a further embodiment, the present invention provides a compound of formula I as described above, wherein;

R³is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl and aryl groups; wherein said C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20The alkynyl and aryl groups are optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_1-6Alkyl radical, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea and sulfonamido;

especially R³Is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl and aryl groups; wherein said C_1-20Alkyl is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea and sulfonamido;

in a particular embodiment, the present invention provides a compound of formula I as described above, wherein:

R³said one or more optional substituents of (a) are selected from halo, hydroxy, nitro, amino, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy and halo-C_1-20An alkyl group; in particular from cyano, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkoxy, di (C)_1-20Alkyl) amino, aryl and heteroaryl; more particularly from cyano, C_3-6Cycloalkyl radical, C_3-6Heterocyclic radical, C_1-6Alkoxy, di (C)_1-6Alkyl) amino, aryl and heteroaryl.

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

x is halogen; especially fluorine;

y is-C (= O) -NH-;

Z¹，Z²and Z³Each is independently selected from C and N;

Z¹，Z²and Z³Is C;

R¹is hydrogen;

R²selected from the group comprising: hydrogen, C_1-20Alkyl and halogen; especially hydrogen, C_1-6Alkyl and halogen; more particularly hydrogen, methyl and fluorine

R²Is hydrogen;

R²is fluorine;

R³is selected from C_1-20Alkyl radical, C_3-20An alkenyl group, which is a radical of an alkenyl group,C_3-20alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl and C_3-19A heterocyclic group; wherein said C_1-20Alkyl radical, C_3-20Alkenyl and C_3-20Alkynyl is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea and sulfonamido; especially R³Is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl, and C_3-19A heterocyclic group; wherein said C_1-20Alkyl is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea and sulfonamido;

R³is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl and aryl groups; wherein said C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20The alkynyl and aryl groups are optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_1-6Alkyl radical, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea and sulfonamido; especially R³Is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl and aryl groups; wherein said C_1-20Alkyl is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea and sulfonamido;

R³is C_1-6An alkyl group optionally substituted with a substituent selected from the group consisting of: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea and sulfonamido;

R³said one or more optional substituents of (a) are selected from halo, hydroxy, nitro, amino, cyano, aryl, heteroaryl, C_1-6Alkyl radical, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy and halo-C_1-20An alkyl group; in particular from cyano, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkoxy, di (C)_1-20Alkyl) amino, aryl and heteroaryl; more particularly from cyano, C_3-6Cycloalkyl radical, C_3-6Heterocyclic radical, C_1-6Alkoxy, di (C)_1-6Alkyl) amino, aryl and heteroaryl;

R³said one or more optional substituents of (a) are selected from cyano, C_3-6Cycloalkyl, pyrrolidinyl, tetrahydrofuranyl, C_1-6Alkoxy, di (C)_1-6Alkyl) amino, phenyl and pyridyl;

n is 1.

The compounds of the present invention may be prepared according to the reaction schemes provided in the examples below, but those skilled in the art will appreciate that these are merely exemplary of the present invention and that the compounds of the present invention may be prepared according to any standard synthetic procedure commonly used by those skilled in organic chemistry.

In a preferred embodiment, the compounds of the invention are useful as kinase inhibitors in vitro or in vivo, more particularly for inhibiting at least one ROCK kinase selected from ROCK i and ROCK ii, especially soft ROCK inhibitors. Accordingly, the present invention provides a compound as defined herein, or a composition comprising said compound, for use as a medicament.

The present invention further provides the use of a compound as defined above or a composition comprising said compound as a human or veterinary drug, in particular for the prevention and/or treatment of at least one disease or disorder involving ROCK, such as diseases associated with smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeneration, and remodeling.

In another embodiment, the present invention provides the use of a compound as defined above or a composition comprising said compound for the prevention and/or treatment of at least one disease or disorder selected from: eye diseases; airway disease; throat, nose and ear diseases; intestinal disease; cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders; proliferative diseases; renal disease; sexual dysfunction; bone disease; benign prostatic hyperplasia, transplant rejection, spasticity, hypertension, chronic obstructive bladder disease, and allergies.

In a preferred embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined hereinbefore for the prevention and/or treatment of ocular diseases including but not limited to retinopathy, optic neuropathy, glaucoma and degenerative retinal diseases such as macular degeneration, retinitis pigmentosa and inflammatory ocular diseases (such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis), corneal diseases (such as but not limited to fukes' dystrophy and keratitis), abnormalities in corneal wound healing and ocular pain, and/or for the prevention, treatment and/or alleviation of complications and/or symptoms associated therewith.

In another embodiment, the present invention provides the use of a compound or composition comprising said compound as defined above 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 and rhinitis and respiratory distress syndrome.

In another embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined above for the prevention and/or treatment of cardiovascular diseases and vascular diseases including but not limited to pulmonary hypertension and pulmonary vasoconstriction, and/or for the prevention, treatment and/or alleviation of complications and/or symptoms associated therewith.

In another embodiment, the present invention provides the use of a compound as defined above or a composition comprising said compound for the prevention and/or treatment of disorders of the larynx, nose and ears including but not limited to sinus problems, hearing problems, dental pain, tonsillitis, ulcers and rhinitis.

In another embodiment, the present invention provides the use of a compound as defined above or a composition comprising said compound for the prevention and/or treatment of skin diseases including, but not limited to, hyperkeratosis, parakeratosis, stratum granulosum thickening, stratum spinosum thickening, dyskeratosis, edema of the stratum spinosum and ulcer formation.

In another embodiment, the invention provides the use of a compound as defined above or a composition comprising said compound for the prevention and/or treatment of bowel diseases including, but not limited to, Inflammatory Bowel Disease (IBD), ulcerative colitis, gastroenteritis, ileus, ileitis, appendicitis and crohn's disease.

In another embodiment, the invention provides the use of a compound or composition comprising said compound as defined above 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 and/or for the prevention, treatment and/or alleviation of the complications and/or symptoms and/or inflammatory responses associated therewith.

In another embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined above for the prevention, treatment and/or management of neurological diseases and central nervous system diseases, including but not limited to neuropathic pain. The compounds of the present invention are therefore suitable for use in the prevention of neurodegeneration and the stimulation of nerve regeneration in various neurological diseases and/or for the prevention, treatment and/or alleviation of complications and/or symptoms associated therewith.

In another embodiment, the present invention provides the use of a compound or composition comprising said compound as defined above for the prevention and/or treatment of proliferative diseases including, but not limited to, cancers of the breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, ovary, pancreas, prostate or thyroid gland; giant lymph node hyperplasia; a sarcoma; malignant cell tumors; and melanoma.

In another embodiment, the present invention provides the use of a compound or composition comprising said compound as defined above for the prevention and/or treatment of renal diseases including, but not limited to, renal fibrosis or renal dysfunction and/or the use for the prevention, treatment and/or alleviation of complications and/or symptoms and/or inflammatory reactions associated therewith.

In another embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined above for the prevention and/or treatment of sexual dysfunction including, but not limited to, hypogonadism, bladder disease, hypertension, diabetes or pelvic surgery and/or for the treatment of sexual dysfunction associated with treatment with certain drugs, such as drugs for the treatment of hypertension, depression or anxiety.

In another embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined above for the prevention and/or treatment of bone diseases including, but not limited to, osteoporosis and osteoarthritis and/or for the prevention, treatment and/or alleviation of complications and/or symptoms and/or inflammatory reactions associated therewith.

In another embodiment, the invention provides the use of a compound or a composition comprising said compound as defined above for the prevention and/or treatment of and/or for the prevention, treatment and/or alleviation of complications and/or symptoms associated with diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasticity, chronic obstructive bladder disease and allergy.

In a preferred embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined hereinbefore for the prevention and/or treatment of ocular diseases.

Method of treatment

The present invention further provides a method for the prevention and/or treatment of at least one disease or disorder selected from the group consisting of: eye diseases; airway disease; cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders; proliferative diseases; renal disease; sexual dysfunction; bone disease; benign prostatic hyperplasia; transplant rejection; spasm; hypertension; chronic obstructive bladder disease and allergies; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In a preferred embodiment, the present invention provides a method for preventing and/or treating ocular diseases including, but not limited to, retinopathy, optic neuropathy, glaucoma, and degenerative retinal diseases such as macular degeneration, retinitis pigmentosa, and inflammatory ocular diseases (such as anterior uveitis, panuveitis, intermediate uveitis, and posterior uveitis); corneal diseases (such as, but not limited to, fukes dystrophy and keratitis); the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for preventing and/or treating airway diseases including, but not limited to, pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, Chronic Obstructive Pulmonary Disease (COPD) bronchitis, rhinitis, and respiratory distress syndrome; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present 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; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present 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; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for preventing and/or treating neurological and central nervous system diseases, including but not limited to neuropathic pain. The compounds of the invention are therefore suitable for the prevention of neurodegeneration and for the stimulation of nerve regeneration in different neurological disorders; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the invention provides a method for preventing and/or treating a proliferative disease including, but not limited to, cancer of the breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate or thyroid; giant lymph node hyperplasia; leukemia; a sarcoma; lymphoma; malignant cell tumors; and melanoma; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for the prevention and/or treatment of renal diseases including, but not limited to, renal fibrosis or renal dysfunction; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or 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, hypertension, diabetes or pelvic surgery, and/or for the treatment of sexual dysfunction associated with treatment with certain drugs, such as drugs used to treat hypertension, depression or anxiety; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for preventing and/or treating bone diseases including, but not limited to, osteoporosis and osteoarthritis; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for the prevention and/or treatment of diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasticity, chronic obstructive bladder disease, and allergy; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In preferred embodiments, the present invention provides a method for the prevention and/or treatment of glaucoma, asthma, sexual dysfunction or COPD; the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In the present invention, it is particularly preferred that the IC in the ROCK inhibition assay described hereinafter can be less than 10. mu.M, preferably less than 1. mu.M, more preferably less than 0.1. mu.M₅₀A compound of formula I or any subset thereof that value inhibits ROCK.

Said inhibition may occur in vitro and/or in vivo, and when occurring in vivo, is preferably performed in a selective manner as defined above.

The term "ROCK-mediated disorder" or "disease" as used herein refers to any disease or other deleterious condition known to function. The term "ROCK-mediated disorder" or "disease" also refers to a disease or disorder in which remission by a ROCK inhibitor is achieved. Accordingly, another embodiment of the present invention relates to the treatment or lessening the severity of one or more diseases in which ROCK acts.

In terms of pharmaceutical use, the compounds of the invention may be used as the free acid or base, and/or in the form of pharmaceutically acceptable acid addition and/or base addition salts (e.g. as obtained by non-toxic organic or inorganic acids or bases), hydrates, solvates and/or complexes, and/or as pro-drugs or pro-drugs (e.g. esters). The term "solvate" as used herein means, unless otherwise indicated, any combination of a compound of the present invention with a suitable inorganic solvent (e.g., hydrate) or organic solvent.

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 formed, for example, from inorganic or organic acids. 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, palmitate (palmoate), pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

Generally, for pharmaceutical use, the compounds of the invention may be formulated as a pharmaceutical formulation or 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 other pharmaceutically active compounds.

By way of non-limiting example, such formulations may be in a form suitable for oral administration, parenteral administration (such as by intramuscular or subcutaneous injection or intravenous infusion), topical administration (including ophthalmic), inhalation administration, by dermal patch, by implant, by suppository and the like. Suitable administration forms, which may be solid, semi-solid or liquid depending on the mode of administration, as well as the methods and carriers, diluents and excipients used in their preparation, will be apparent to the skilled person.

Some preferred, but non-limiting examples of such formulations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions, and sterile packaged powders (which typically need to be reconstituted prior to use) for rapid bolus administration and/or continuous administration, and may be formulated with carriers, excipients, and diluents that are inherently suitable for use in such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, acacia, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl-propylhydroxybenzoate, polyvinylpyrrolidone, sodium chloride, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations may optionally contain other pharmaceutically active substances, which may or may not act synergistically with the compounds of the present invention, and other substances conventionally used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, bulking agents, fillers, preservatives, sweetening agents, flavoring agents, flow control agents, mold release agents, and the like. The compositions may also be formulated to provide rapid, sustained or delayed release of the active compounds 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 stability of the compounds of the pharmaceutical composition according to the invention, it may be advantageous to employ alpha-, beta-or gamma-cyclodextrins or derivatives thereof.

In addition, co-solvents such as alcohols may improve the solubility and/or stability of the compounds. In preparing aqueous compositions, it will be more appropriate to add salts of the compounds of the invention because of their higher water solubility.

For pain treatment, the compounds of the present invention may be used topically. For topical administration, sprays, ointments or transdermal patches or other forms of compounds suitable for topical, transdermal and/or intradermal administration may be beneficial.

For ophthalmic applications, solutions, gels, tablets, and the like will typically employ a physiological saline solution, gel, or excipient as the primary vehicle. Ophthalmic formulations are best prepared at a comfortable pH using an appropriate buffer system.

More specifically, the compositions can be formulated into pharmaceutical formulations comprising a therapeutically effective amount of particles comprised of a solid dispersion of the compound of the present invention and one or more pharmaceutically acceptable water-soluble polymers.

The term "solid dispersion" means a solid (rather than a liquid or gaseous) system comprising at least two components, one of which is capable of more or less uniformly dispersing into the other component or components. Such solid dispersions will be referred to as "solid solutions" when the components are dispersed such that the system is uniform in chemical and physical properties or homogeneous throughout or consists of a thermodynamically defined single phase. Solid solutions are a preferred physical system because the components are generally bioavailable to the organism to which they are administered.

It may be further convenient to formulate the compound in the form of nanoparticles having surface modifiers adsorbed on their surface sufficient to maintain an effective average particle size of less than 1000 nm. Suitable surface-modifying agents are preferably selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface modifying agents include nonionic and anionic surfactants.

Another interesting way of formulating the compounds of the present invention comprises a pharmaceutical composition wherein the compounds are incorporated in a hydrophilic polymer and this mixture is then applied as a film coating on a number of beads, resulting in a composition with good bioavailability which is easy to prepare and suitable for the preparation of pharmaceutical dosage forms for oral use. Materials suitable for use as cores in beads may take a variety of forms, provided that the material is pharmaceutically acceptable and has the appropriate size and hardness. Examples of such materials are polymers, inorganic substances, organic substances, saccharides and derivatives thereof.

The formulations may be prepared in a manner known per se, which generally involves mixing at least one compound of the invention with one or more pharmaceutically acceptable carriers, if necessary under sterile conditions, in combination with other pharmaceutically active compounds. The pharmaceutical preparations of the present invention are preferably in unit dosage form or suitably packaged, e.g. in a box, blister, vial, bottle, sachet, ampoule or any other suitable single or multi-dose holder or container (with suitable label); optionally plus one or more brochures containing product information and/or instructions for use. The compounds can be administered by a variety of routes including oral, rectal, ocular, transdermal, subcutaneous, intramuscular, or intranasal routes, depending primarily on the particular formulation used and the condition to be treated or prevented, with oral and intravenous administration generally being preferred. At least one compound of the present invention is typically administered in an "effective amount," that is, any amount of the compound of formula I, or any subset thereof, that is sufficient, upon suitable administration, to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered. Generally, depending on the condition to be prevented or treated and the route of administration, the effective amount will generally be from 0.001 to 1000mg, more often from 0.1 to 500mg, for example from 1 to 250mg, per kg of patient body weight per day, such as about 5, 10, 20, 50, 100, 150, 200 or 250mg per kg of patient body weight per day, in single daily doses, divided into one or more daily doses, or administered substantially continuously. The treating physician will determine the amount to be administered, the route of administration and the further course of treatment, depending on factors such as age, sex, general condition of the patient and the nature and severity of the disease/condition. 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 other prior art mentioned above, as well as standard manuals such as the latest version of Remington's Pharmaceutical Sciences.

According to the methods of the present invention, the pharmaceutical compositions may be administered separately at different times during the course of therapy or simultaneously in divided or single combination forms. Accordingly, the invention is to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

For oral forms, the compositions of the invention may be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and converted into suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions, using customary means. Examples of suitable inert carriers are gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the preparation can be carried out both as dry granules and as wet granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for the aqueous or alcoholic solution are water, ethanol, sugar solutions or mixtures thereof. Polyethylene glycol and polypropylene glycol are also suitable for further adjuvants in other application 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 aqueous salt solutions, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and employing fluorocarbons and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in aerosol or spray form include solutions, suspensions or emulsions of a compound of the invention or a physiologically tolerable salt thereof in a pharmaceutically acceptable solvent, for example ethanol or water, or mixtures of such solvents. The formulation may additionally contain other pharmaceutical adjuvants, such as surfactants, emulsifiers, stabilizers and propellants, if desired.

For subcutaneous injection, the compounds of the present invention may be formulated as solutions, suspensions or emulsions with conventional materials, such as solubilizers, emulsifiers or other adjuvants, if desired. The compounds of the invention may also be lyophilized and the lyophilized powders obtained used, for example, in the manufacture of injectable or infusible formulations. Suitable solvents are, for example, water, physiological saline solutions or alcohols, such as ethanol, propanol, glycerol, furthermore sugar solutions, such as glucose solutions or mannitol solutions, or mixtures of the various solvents mentioned above. Injections or suspensions may be formulated according to techniques known in the art using suitable non-toxic parenterally acceptable diluents or solvents, for example mannitol, 1, 3-butanediol, water, ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting agents and suspending agents, for example sterile, non-irritating, non-volatile oils including synthetic mono-or diglycerides and fatty acids, including oleic acid.

When administered rectally by suppository means, these formulations may be prepared by mixing the compounds of the present invention with suitable non-irritating excipients, such as cocoa butter, synthetic glycerides 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 present invention are used topically, e.g., for topical or adsorptive and non-adsorptive applications.

The composition has value in the veterinary field for purposes including not only the prevention and/or treatment of disease in animals, but also the promotion of growth and/or their weight and/or the quantity and/or quality of meat or other products obtained from animals which are also economically important. Thus, in another aspect, the present invention relates to a composition for veterinary use comprising at least one compound of the invention and at least one suitable carrier (i.e. a carrier suitable for animal use). The invention also relates to the use of the compounds of the invention for the preparation of such compositions.

The present invention will now be explained by the following synthetic examples and biological examples, but the examples do not limit the scope of the present invention in any way.

Examples

A. Physical and chemical properties of the compound

A.1. Purity of the compound

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

A.2. Attribution of configuration:

the Cahn-Ingold-Prelog system, in which 4 groups on asymmetric carbons are arranged according to a preferential rule, is used to partition the absolute configuration of the chiral center. Reference may be made to Cahn; ingold; prelogangew.chem.int.ed.engl.1966, 5, 385-.

A.3. Stereochemistry:

it is known to those skilled in the art that a particular enantiomer (or diastereomer) can be obtained by different methods such as, but not limited to, chiral resolution (for example, salts with optically active acids or bases can be used to form diastereomeric salts, which can facilitate separation of an optically active isomer of a compound of formula I or any subset thereof), asymmetric synthesis or preparative chiral chromatography. Stereoisomers may be obtained from commercially available materials having known configurations (such compounds include, for example, amino acids), if convenient.

B. Synthesis of compounds

B.1. Compounds of the invention

The compounds of the invention can be prepared according to the following general procedure:

reaction a: to an organic solvent of carboxylic acid (1 equivalent), such as DMF, is added an appropriate coupling agent (such as TBTU (1.5 equivalents)/HOBt (0.3 equivalent)) and DIEA (3 to 10 equivalents) as needed at room temperature. After 5 minutes, the corresponding aniline (1.5 eq) was added and the mixture was stirred at room temperature until the reaction was complete. The solvent was then removed in vacuo and the residue diluted in EtOAc. The organic phase was saturated NaHCO₃Washed with brine, over Na₂SO₄Drying and filtering. After evaporation of the solvent, the residue was purified by flash chromatography, e.g. eluting with DCM/EtOAc (100/0 to 50/50), to afford the desired product as a white powder.

And b, reaction: to a suspension of the corresponding methyl ester in acetonitrile/water 2/1 was added dropwise a 1.6M aqueous solution of LiOH. The mixture was stirred at room temperature until the reaction was complete. Then 0.5M aqueous HCl was added until pH =4 and the mixture was extracted with EtOAc (× 3). The combined organic phases were washed with brine, over Na₂SO₄Drying and filtering. The solvent was removed in vacuo to afford the desired compound as a white powder. The compounds are generally used in subsequent steps without purification.

And c, reaction: HCl (gas) was bubbled through a solution or suspension of Boc-protected amine in DCM (or dioxane or diethyl ether) at room temperature for 5 to 10 minutes. The mixture was stirred at room temperature until the reaction was complete. The resulting precipitate was filtered, washed with diethyl ether (× 3) and dried in vacuo to afford the HCl salt of the desired compound as a white powder.

Reaction d: to an organic solvent of carboxylic acid (1 equivalent), such as DMF, is added an appropriate coupling agent (such as TBTU (1.5 equivalents)/HOBt (0.3 equivalent)) and DIEA (3 to 10 equivalents) as needed at room temperature. After 5 minutes, alcohol (R) was added³-OH; 6 equivalents), the mixture was stirred at room temperature until the reaction was complete. Subsequently, the solvent was removed in vacuo and the residue diluted in EtOAc. The organic phase was saturated NaHCO₃Washed with brine, over Na₂SO₄Drying and filtering. After evaporation of the solvent, the residue was purified by flash chromatography, e.g. eluting with DCM/EtOAc (100/0 to 50/50), to afford the desired product as a white powder.

Similarly, amino-heterocyclic starting materials can be used (examples 50 to 52).

In the case of Y = -nhc (o) -the compounds of the invention can be obtained in a similar manner from the corresponding aniline intermediate and the appropriate carboxylic acid.

The preparation of the desired intermediates is known to the skilled worker, for example from PCT application WO2011/107608a 1.

In the following table, exemplary compounds of the present invention are listed in tabular form. In the table, compounds are artificially numbered and structural information is listed.

TABLE 1

TABLE 2

TABLE 3

C. In vitro and in vivo assays

C.1.ROCK inhibitory Activity screening

C.1.1. Kinase inhibition (ROCKI or ROCKII)

The activity at the target on ROCK was measured in a biochemical assay using the following reagents: basic reaction buffer, 20mM Hepes (pH7.5), 10mM MgCl₂，1mM EGTA，0.02%Brij35，0.02mg/ml BSA，0.1mM Na₃VO₄2mM DTT, 1% DMSO. The required cofactors were added individually to each kinase reactant. The reaction procedure first involves the preparation of the peptide substrate in a freshly prepared reaction buffer. The required cofactor is then added to the substrate solution. ROCK (1nM final concentration) was then delivered to the substrate solution. After gentle mixing, a DMSO solution of the test compound was added to the enzyme. Then mixing the substrate mixture³³P-ATP (final specific activity 0.01. mu. Ci/. mu.l) was delivered into the reaction mixtureTo initiate the reaction. The kinase reaction was incubated at room temperature for 120 min. The reaction was then blotted (spotted) on P81 ion exchange paper (Whatman # 3698-915). The filter was washed thoroughly in 0.1% phosphoric acid. Then performing radiometric counting and subsequently determining IC₅₀The value is obtained.

When evaluated under the conditions described, the compounds of the invention are identified as IC₅₀<100nM inhibits ROCK 2.

C.1.2. Myosin light chain phosphorylation assay

The rat smooth muscle cell line A7r5 was used. Endogenous expression of ROCK results in constitutive phosphorylation of the regulatory myosin light chain at T18/S19. A7r5 cells were placed in DMEM supplemented with 10% FCS in multi-well cell culture plates. After overnight serum starvation, cells were incubated with compounds in serum-free medium.

Quantification of MLC-T18/S19 phosphorylation was assessed by ELISA in 96-well plates using a phspho-MLC-T18/S19 specific antibody and a second detection antibody. Raw data were converted to percent substrate phosphorylation relative to high control (set at 100%). EC was determined using GraphPad prism5.01 software using nonlinear regression curve fitting with varying slopes₅₀The value is obtained.

When evaluated under the conditions described, the compounds of the invention exhibit an EC of less than 10. mu.M₅₀The value is obtained. Preferred compounds show an EC of less than 1. mu.M₅₀The value is obtained.

C.2. Pharmacological characterization

C.2.1. Stability assay in human (and/or animal) plasma

Each compound was incubated in human plasma or in animal (rat, mouse, dog, monkey, mini-pig or rabbit) plasma at a concentration of 1. mu.M. Samples were taken at fixed time points and the residual compounds were then determined by LC-MS/MS after protein precipitation. The half-life is expressed in minutes.

In human plasma, the compounds of the invention (examples 1-10, 12-24, 26-31, 40, 41, 43-48) have a half-life of <60 minutes.

Human or rat (or other species) plasma can be replaced with whole blood while maintaining the same protocol.

C.2.2. Stability assay in Rabbit aqueous Room Water

The compounds were incubated in rabbit Aqueous Humor (AH) at a concentration of 1 μ M. Samples were taken at fixed time points and the residual compounds were then determined by LC-MS/MS after protein precipitation. The half-life values of the compounds of the invention are provided in table 4.

TABLE 4

Claims (14)

1. A compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, or solvate thereof,

wherein the content of the first and second substances,

x is hydrogen or halogen;

y is-NH-C (= O) -or-C (= O) -NH-;

Z¹，Z²and Z³Each is independently selected from C, N, O and S;

R¹selected from the group comprising: hydrogen, C_1-20Alkyl and C_3-15A cycloalkyl group;

R²selected from the group comprising: hydrogen, C_1-20Alkyl, halogen and C_1-20An alkoxy group;

R³is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl, and C_3-19A heterocyclic group; wherein said C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl, and C_3-19The heterocyclyl group is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea, and sulfonamido; and

n is 0 or 1.

2. A compound of formula I according to claim 1, wherein;

R¹selected from the group comprising: hydrogen, C_1-6Alkyl and C_3-6A cycloalkyl group; especially hydrogen.

3. A compound of formula I according to claim 1 or 2, wherein;

x is halogen; especially fluorine;

y is-NH-C (= O) -or-C (= O) -NH-;

Z¹，Z²and Z³Each is independently selected from C, N, O and S; in particular selected from C and N; more particularly Z¹，Z²And Z³Each of which isIs C;

R¹selected from the group comprising: hydrogen, C_1-20Alkyl and C_3-15A cycloalkyl group; especially hydrogen;

R²selected from the group comprising: hydrogen, C_1-20Alkyl, halogen and C_1-20An alkoxy group;

R³is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl, and C_3-19A heterocyclic group; wherein said C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl, and C_3-19The heterocyclyl group is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea, and sulfonamido; and

n is 0 or 1; in particular n is 1.

4. A compound of formula I according to any one of the preceding claims, wherein;

R²selected from hydrogen, C_1-20Alkyl and halogen; in particular from hydrogen, C_1-6Alkyl and halogen; more particularly from hydrogen, methyl and fluorine.

5. A compound of formula I according to any one of the preceding claims, wherein;

R³is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl and aryl groups; wherein said C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20The alkynyl and aryl groups optionally have one or more substituents selected fromAnd (3) substitution: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea, and sulfonamido.

6. A compound of formula I according to any one of the preceding claims, wherein one or more of the following restrictions apply:

x is halogen; especially fluorine;

y is-C (= O) -NH-;

Z¹，Z²and Z³Each is independently selected from C and N;

Z¹，Z²and Z³Is C;

R¹is hydrogen;

R²selected from the group comprising: hydrogen, C_1-20Alkyl and halogen; especially hydrogen, C_1-6Alkyl and halogen; more particularly hydrogen, methyl and fluorine;

R²is hydrogen;

R²is fluorine;

R³is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl and C_3-19A heterocyclic group; wherein said C_1-20Alkyl radical, C_3-20Alkenyl and C_3-20Alkynyl is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea, and sulfonamido; especially R³Is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl, C_3-15Cycloalkyl, aryl, heteroaryl, and C_3-19A heterocyclic group; wherein said C_1-20Alkyl is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea, and sulfonamido;

R³is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl and aryl groups; wherein said C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20The alkynyl and aryl groups are optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea, and sulfonamido; especially R³Is selected from C_1-20Alkyl radical, C_3-20Alkenyl radical, C_3-20Alkynyl and aryl groups; wherein said C_1-20Alkyl is optionally substituted with one or more substituents selected from: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea, and sulfonamido;

R³is C_1-6An alkyl group optionally substituted with a substituent selected from the group consisting of: halo, hydroxy, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy, halo-C_1-20Alkoxy, halo-C_1-20Alkyl, mercapto, C_1-20Alkylthio, carboxylic acid, acylamino, C_1-20Alkyl esters, carbamates, sulfonamido, urea, and sulfonamido;

R³said one or more optional substituents of (a) are selected from halo, hydroxy, nitro, amino, cyano, aryl, heteroaryl, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkylamino, di (C)_1-20Alkyl) amino, C_1-20Alkoxy and halo-C_1-20An alkyl group; in particular from cyano, C_3-15Cycloalkyl radical, C_3-19Heterocyclic radical, C_1-20Alkoxy, di (C)_1-20Alkyl) amino, aryl and heteroaryl; more particularly from cyano, C_3-6Cycloalkyl radical, C_3-6Heterocyclic radical, C_1-6Alkoxy, di (C)_1-6Alkyl) amino, aryl and heteroaryl;

R³said one or more optional substituents of (a) are selected from cyano, C_3-6Cycloalkyl, pyrrolidinyl, tetrahydrofuranyl, C_1-6Alkoxy, di (C)_1-6Alkyl) amino, phenyl and pyridyl;

n is 1.

7. A compound according to any one of claims 1 to 6 for use as a medicament.

8. A composition comprising a compound as defined in any one of claims 1 to 6 for use as a human or veterinary drug.

9. A compound according to any one of claims 1 to 6 or a composition according to claim 8, for use in the prevention and/or treatment of a disease or disorder in which ROCK is implicated, such as diseases associated with smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, angiogenesis, hyperreactivity, barrier dysfunction, neurodegeneration and remodeling.

10. A compound according to any one of claims 1 to 6 or a composition according to claim 8 for use in the prevention and/or treatment of at least one disease or disorder according to claim 9 selected from the group comprising: eye diseases; airway disease; throat, nose and ear diseases; bowel disease; cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders; proliferative diseases; renal disease; sexual dysfunction; bone disease; benign prostatic hyperplasia, transplant rejection, spasticity, hypertension, chronic obstructive bladder disease, and allergies.

11. A compound according to any one of claims 1 to 6 or a composition according to claim 8 for use in the prevention and/or treatment of ocular diseases according to claim 9 or 10, including but not limited to retinopathy, optic neuropathy, glaucoma and degenerative retinal diseases such as macular degeneration, retinitis pigmentosa and inflammatory ocular diseases (such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis), neurodegeneration, corneal diseases (such as but not limited to fukes dystrophy and keratitis), abnormalities in corneal wound healing and ocular pain, and/or for the prevention, treatment and/or alleviation of complications and/or symptoms associated with them.

12. Use of a compound according to any one of claims 1 to 6 or a composition according to claim 8 for inhibiting the in vitro or in vivo activity of at least one kinase.

13. Use of a compound according to any one of claims 1 to 6 or a composition according to claim 8 as a kinase inhibitor; in particular as ROCK inhibitors, for example as ROCKI and/or ROCKII inhibitors; more particularly as soft ROCK inhibitors.

14. A method for the prevention and/or treatment of at least one disease or disorder selected from the group comprising: eye diseases; airway disease; cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders: proliferative diseases; renal disease; sexual dysfunction; bone disease; benign prostatic hyperplasia; transplant rejection; spasm; hypertension; chronic obstructive bladder disease; and allergies; the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a composition according to claim 8.