WO2013004709A1

WO2013004709A1 - Indolylmaleimides as soft pan-pkc inhibitors

Info

Publication number: WO2013004709A1
Application number: PCT/EP2012/062951
Authority: WO
Inventors: Dirk Leysen; Olivier Defert; Sandro Boland
Original assignee: Amakem Nv
Priority date: 2011-07-05
Filing date: 2012-07-04
Publication date: 2013-01-10
Also published as: GB201111427D0

Abstract

The present invention relates to new kinase inhibitors, more specifically soft PKC inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new soft PKC inhibitors compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including autoimmune and inflammatory diseases.

Description

INDOLYLMALEIMIDES AS SOFT PAN-PKC INHIBITORS

Field of the invention

The present invention relates to new kinase inhibitors, more specifically novel soft Protein Kinase C inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new soft nPKC/cPKC inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease.

Background of the invention

The protein kinase C (PKC) family is a family of lipid-activated serine/threonine kinases. PKC enzymes are key intracellular mediators of signal transduction pathways and are implicated in various cell functions throughout the body. They are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups on serine and threonine amino acid residues on these proteins. PKC family members are expressed in a wide range of tissues and cell types; precise mechanisms control their structure, function, and subcellular localization.

Several PKC isozymes, encoded by different genes but sharing high sequence and structure homology, exist. The PKC isozymes are classified according to the Ca²⁺ and/or diacylglycerol (DAG) signals needed for their activation. The conventional PKCs (cPKCs) require Ca²⁺ and DAG for activation; the cPKC subfamily includes PKCa, PKC3, and PKCy. The novel PKCs (nPKCs) require DAG, but not Ca²⁺ for their activation; the nPKC subfamily includes PKC5, PKCe, PKCn, and PKC9. The atypical PKCs (aPKCs) do not require DAG or Ca²⁺ for their activation; the aPKC subfamily includes Ρ^ζ andPKCi/λ.

PKCs are structurally closely related. All isozymes have a regulatory and a catalytic domain connected by a hinge region. The catalytic domain is highly conserved in all isozymes and includes the substrate- and the ATP-binding domains. The regulatory domain is structurally more divergent amongst isozymes and controls the activation of the enzyme. The regulatory domain contains an autoinhibitory pseudosubstrate domain and two discrete membrane-targeting domains, termed C1 and C2. cPKCs contain a C1 domain that functions as a DAG-binding motif, and a C2 domain that binds anionic phospholipids in a Ca²⁺-dependent manner. nPKCs do also contain a C1 and a C2 domain, but their C2 domain lacks Ca²⁺-binding properties, which largely underlies their distinct pharmacology compared to cPKCs. Also aPKCs do have a Ca²⁺-insensitive C2 domain, but besides contain an atypical C1 domain which does not bind DAG. Primed PKCs are activated to phosphorylate their substrates when their regulatory domains engage the appropriate combination of signals (DAG, Ca²⁺, and phospholipids in the case of cPKCs).

One of the most studied nPKC is the Θ isoform. PKC9 is expressed mainly in T-cells, muscle cells, and platelets. PKC9 is highly homologous to the other nPKCs.

PKC9 plays a key role in T-cell activation and survival. It has been well established that T- cells play an important role in regulating the immune response.

Another very well studied PKC's isotype is the classical β (β1 / β2) isoform. ΡΚΟβ is ubiquitously expressed but show higher expression in B-cells.

While PKC9 and / or β inhibition appear tolerated, the high sequence homology between the different members of the PKC family significantly complicates the development of isozyme-selective PKC inhibitors. Even though inhibition of multiple PKCs has sometimes been proposed as an interesting approach for the treatment of airway diseases such as asthma or chronic obstructive pulmonary disease (COPD), this situation is problematic in view of the multiple roles that are performed by PKCs in various tissues. As an example, inhibition of the closely related PKC5 could result in increased proliferation of B-cells and in increased production of inflammatory cytokines, thereby causing increased susceptibility to autoimmune disease. Hence, significant systemic exposure to pan-PKC inhibitors should be avoided, if not required by the pathology to be treated.

Local application is a first possibility to reduce systemic exposure to a drug compound, by directly delivering the drug compound to the intended site of action and possibly reducing the quantity of drug compound that is required in order to observe a clinically significant effect. Therefore local administration excludes direct systemic administration or delivery. Despite the fact that direct local application is preferred in medical practice, there can still be concerns regarding drug levels reached into the systemic circulation. For example, the treatment of airway diseases by local delivery by for instance inhalation, poses the risk of systemic exposure due to large amounts entering the Gl tract and/or systemic absorption through the lungs. For the treatment of eye diseases by local delivery, also significant amounts of compound can enter the Gl tract and/or systemic circulation due to the low permeability of the cornea, low capacity for fluid, efficient drainage and presence of blood vessels in the eyelids. Also for dermal applications, local injections and implantable medical devices, there is a severe risk of leakage into the systemic circulation. Therefore, in addition to the physical local application, it is preferable that the compounds display additional chemical or biological properties that will minimize systemic exposure.

Soft drugs are biologically active compounds that are inactivated once they enter the systemic circulation. This inactivation involves the controlled conversion of said soft drug into a predictable metabolite displaying markedly reduced functional activity or, preferably, negligible functional activity. Inactivation can be achieved in the liver, but the preferred inactivation should occur in the blood. These compounds, once applied locally to the target tissue / organ exert their desired effect locally. When they leak out of this target tissue / organ into the systemic circulation, they are very rapidly inactivated. Thus, soft drugs of choice are sufficiently stable in the target tissue / organ to exert the desired biological effect, but are rapidly degraded in the blood to biologically inactive compounds. In addition, it is highly preferable that the soft drugs of choice have retention at their biological target. This property will limit the number of daily applications and is highly desired to reduce the total load of drug and metabolites and in addition will significantly increase the patient compliance. In view of the potential of non-selective PKC inhibitors for generating undesirable side effects, it will be appreciated that soft drug approaches represent an attractive way of generating PKC inhibitors with improved properties; in particular PKC inhibitors associated with reduced systemic exposure and therefore lower potential for undesirable side effects.

Although soft drugs represent a potentially attractive approach for the inhibition of PKC and the treatment of PKC-associated diseases or conditions, the design and optimization of such compounds is however not trivial. Successful soft drugs have to retain strong on- target potency and functional efficacy. Additionally, successful soft drugs should display good stability at the intended site of action (eg eye, Gl tract or lung), so that a pharmacologically relevant concentration of the drug can be reached and maintained for a prolonged period of time (typically several hours) at this intended site of action. Furthermore, successful soft drugs should be rapidly degraded once they enter systemic circulation, so that systemic exposure and the undesired side effects associated with systemic exposure are avoided. As a result, the design and optimization of molecules successfully combining all of these aspects represents a significant technical problem.

In conclusion, there is a continuing need to design and develop soft PKCs inhibitors for the treatment of a wide range of disease states. The compounds described herein and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of a variety of disorders or conditions associated with PKCs activation. More specifically, the compounds of the invention are preferably used in the prevention and/or treatment of at least one disease or disorder, in which PKCs are involved, such as immunological disorders and inflammatory diseases which can be treated via local application of a drug compound including, but not limited to inflammatory eye diseases such as, but not limited to uveitis, conjunctivitis, contact allergy, retinopathy or post- trauma/post-surgery/post-laser treatment complications including corneal transplant rejection; inflammatory airway diseases; rheumatoid arthritis, skin diseases such as but not limited to contact dermatitis and psoriasis, organ transplant rejection or allergy, intestinal inflammatory diseases such as but not limited to ulcerative colitis, inflammatory bowel disease and Crohn's disease.

SUMMARY OF THE INVENTION

We have surprisingly found that the compounds described herein act as inhibitors of PKC, in particular as cPKCs and/or nPKCs inhibitors. Compared to art-known Bisindolyl maleimides compounds, such as for example described in WO2002/038561 , WO2003/082859, WO2008/074752, Davis et al. J. Med. Chem., 1992, 35, 177-184, Davis et al. J. Med. Chem., 1992, 35, 994-1001 and Davis et al. J. Med. Chem., 1993, 36, 21- 29, the compounds of the present invention differ in that they are rapidly converted into functionally inactive compounds when entering systemic circulation, yet retain good stability in target organs. Compound inactivation can occur in the liver, but is preferentially achieved in the blood flow, through blood enzymes, for example by carboxylic ester hydrolases (EC 3.1.1 ) such as Cholinesterase or Paraoxonase 1 (PON1 ) or by plasma proteins diplaying pseudoesterase activity such as Human serum albumin. The compounds of the present invention therefore solve the technical problem of successfully combining on-target potency (inhibitory activity against PKC) and functional efficacy, good stability in target organs and rapid conversion in blood or liver towards a predictable, species. As a result, the compounds of the invention can achieve a desired pharmacological effect through inhibition of PKC at the intended site of action (eg eye, Gl tract or lung), while avoiding a systemic inhibition of PKC and/or other PKCs, that would create potential for side effects.

Carboxylic ester hydrolases (EC 3.1.1 ) represent a large group of enzymes involved in the degradation of carboxylic esters into alcohols and carboxylic acids. As such, enzymes displaying this catalytic activity are of potential interest for the design of soft kinase inhibitors. EC 3.1 .1 includes the following sub-classes:EC 3.1 .1.1 carboxylesterase; EC 3.1 .1.2 arylesterase;EC 3.1 .1 .3 triacylglycerol lipase; EC 3.1.1 .4 phospholipase A2; EC 3.1.1.5 lysophospholipase; EC 3.1.1.6 acetylesterase; EC 3.1.1.7 acetylcholinesterase; EC 3.1.1.8 cholinesterase; EC 3.1.1.10 tropinesterase; EC 3.1.1.11 pectinesterase; EC 3.1.1.13 sterol esterase; EC 3.1.1.14 chlorophyllase; EC 3.1.1.15 L-arabinonolactonase; EC 3.1.1.17 gluconolactonase; EC 3.1.1.19 uronolactonase; EC 3.1.1.20 tannase; EC 3.1.1.21 retinyl-palmitate esterase; EC 3.1.1.22 hydroxybutyrate-dimer hydrolase; EC 3.1.1.23 acylglycerol lipase; EC 3.1.1.243-oxoadipate enol-lactonase; EC 3.1.1.25 1,4- lactonase; EC 3.1.1.26 galactolipase; EC 3.1.1.27 4-pyridoxolactonase; EC 3.1.1.28 acylcarnitine hydrolase; EC 3.1.1.29 aminoacyl-tRNA hydrolase; EC 3.1.1.30 D- arabinonolactonase; EC 3.1.1.316-phosphogluconolactonase; EC 3.1.1.32 phospholipase A1; EC 3.1.1.336-acetylglucose deacetylase; EC 3.1.1.34 lipoprotein lipase; EC 3.1.1.35 dihydrocoumarin hydrolase; EC 3.1.1.36 limonin-D-ring-lactonase; EC 3.1.1.37 steroid- lactonase; EC 3.1.1.38 triacetate-lactonase; EC 3.1.1.39 actinomycin lactonase; EC 3.1.1.40 orsellinate-depside hydrolase

EC 3.1.1.41 cephalosporin-C deacetylase; EC 3.1.1.42 chlorogenate hydrolase; EC 3.1.1.43 a-amino-acid esterase; EC 3.1.1.444-methyloxaloacetate esterase; EC 3.1.1.45 carboxymethylenebutenolidase; EC 3.1.1.46 deoxylimonate A-ring-lactonase; EC 3.1.1.47 1-alkyl-2-acetylglycerophosphocholine esterase; EC 3.1.1.48 fusarinine-C ornithinesterase; EC 3.1.1.49 sinapine esterase; EC 3.1.1.50 wax-ester hydrolase; EC 3.1.1.51 phorbol-diester hydrolase; EC 3.1.1.52 phosphatidylinositol deacylase; EC 3.1.1.53 sialate O-acetylesterase; EC 3.1.1.54 acetoxybutynylbithiophene deacetylase; EC 3.1.1.55 acetylsalicylate deacetylase; EC 3.1.1.56 methylumbelliferyl-acetate deacetylase; EC 3.1.1.57 2-pyrone-4,6-dicarboxylate lactonase; EC 3.1.1.58 N- acetylgalactosaminoglycan deacetylase; EC 3.1.1.59 juvenile-hormone esterase; EC 3.1.1.60 bis(2-ethylhexyl)phthalate esterase; EC 3.1.1.61 protein-glutamate methylesterase; EC 3.1.1.63 11-cis-retinyl-palmitate hydrolase; EC 3.1.1.64 all-trans- retinyl-palmitate hydrolase; EC 3.1.1.65 L-rhamnono-1,4-lactonase; EC 3.1.1.66 5-(3,4- diacetoxybut-1-ynyl)-2,2'-bithiophene deacetylase; EC 3.1.1.67 fatty-acyl-ethyl-ester synthase; EC 3.1.1.68 xylono-1,4-lactonase; EC 3.1.1.70 cetraxate benzylesterase; EC 3.1.1.71 acetylalkylglycerol acetylhydrolase; EC 3.1.1.72 acetylxylan esterase; EC 3.1.1.73 feruloyl esterase; EC 3.1.1.74 cutinase; EC 3.1.1.75 poly(3-hydroxybutyrate) depolymerase; EC 3.1.1.76 poly(3-hydroxyoctanoate) depolymerase; EC 3.1.1.77 acyloxyacyl hydrolase; EC 3.1.1.78 polyneuridine-aldehyde esterase; EC 3.1.1.79 hormone-sensitive lipase; EC 3.1.1.80 acetylajmaline esterase

EC 3.1.1.81 quorum-quenching N-acyl-homoserine lactonase; EC 3.1.1.82 pheophorbidase; EC 3.1.1.83 monoterpene ε-lactone hydrolase; EC 3.1.1.84 cocaine esterase; EC 3.1.1.85 mannosylglycerate hydrolase. An example of carboxylic ester hydrolase is PON1. PON1 is a Ca²⁺ dependent serum class A esterase, which is synthesized in the liver and secreted in the blood, where it associates exclusively with high-density lipoproteins (HDLs). Furthermore, it is able to cleave a unique subset of substrates including organophosphates, arylesters, lactones and cyclic carbonates. Therefore, the A substituent of the compounds of the present invention, generally represented by formula I hereinbelow, can be selected to comprise a substituent selected from the group of arylesters, lactones and cyclic carbonates, more specifically from arylesters and lactones.

Human serum albumin (HSA) is a major component of blood plasma, accounting for approximately 60% of all plasma proteins. HSA has been found to catalyze the hydrolysis of various compounds such as aspirin, cinnamoylimidazole, p-nitrophenyl acetate, organophosphate insecticides, fatty acid esters or nicotinic esters. HSA diplays multiple nonspecific catalytic sites in addition to its primary reactive site. The catalytic efficiency of these sites is however low, and HSA has often been described not as a true esterase, but as a pseudoesterase, In spite of its low catalytic efficiency, HSA can still play a significant role in the metabolism of drug-like compounds, because of its high concentration in plasma.

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

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

Wherein

R¹ is hydrogen or Ci_-6alkyl; A is selected from the group comprising -C(=0)-0-R³, -C(=0)-NH-R⁴, and -NH-C(=0)-R⁴; Wherein

R³ is selected from the group consisting of C_3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally substituted Ci_-8alkyl, optionally substituted C_3-8alkenyl, and optionally substituted C_3-8alkynyl; and

R⁴ is optionally substituted Ci_-8alkyl further substituted with one substituent selected from the group consisting of Het¹, -O-Het¹, -NH-Het¹, -S-Het¹, and - C(=0)-OR³; wherein Het¹ is

Wherein

each R⁵ is independently selected from Ci_-6alkyl;

m and n are each independently an integer from 0 to 2;

Wherein

R⁶ is Ci_-6alkyl optionally substituted with one or more substituents selected from hydroxyl and NR⁸R⁹;

wherein R⁸ and R⁹ are independently selected from the group consisting of hydrogen, Ci_-8alkyl, and C_3-8cycloalkyl; or

wherein R⁸ and R⁹ together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with Ci_-6alkyl;

R⁷ is selected from hydrogen, Ci_-8alkyl, or C_3-8cycloalkyl, wherein said Ci_-8alkyl is optionally substituted with a substituent selected from the group comprising C_3- scycloalkyl, heterocyclyl, aryl, and heteroaryl;

each X is independently selected from -CH- or -N-,;

Y is selected from -N-, -N(R¹²)-, or -O-;

wherein R¹² is hydrogen or Ci_-6alkyl;

E is -0-, -NH- or -CH₂-;

R¹⁰ is selected from the group consisting of hydrogen, Ci_-6alkyl, halogen, hydroxyl, and Ci_-6alkoxy;

R¹¹ is selected from hydrogen or Ci_-6alkyl; and

R¹³ is hydrogen or halogen;

provided that said com ound is not selected from the group consisting of

As is apparent from this definition, and in particular from the definition of A, the compounds of the invention all contain an ester or lactone (cyclic ester) moiety. Viewed from a further aspect, the invention provides the use of a compound of the invention, or a composition comprising such a compound, for inhibiting the activity of at least one kinase, in vitro or in vivo.

Viewed from a further aspect, the invention provides the use of a compound of the invention, or a composition comprising such a compound, for inhibiting the activity of at least one protein kinase C, for example novel or classical PKCs isoforms, more specifically PKC9 or ΡΚΟβ1/2.

Viewed from a further aspect, the invention provides the use of a compound of the invention, or a composition comprising such a compound, for treating a disease or a disorder associated with the activation of T-cells or B-cells in a patient; such use comprising administering to the patient a therapeutically effective amount of a compound of the present invention as described above.

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

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

Viewed from a still further aspect, the invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of immunological disorders and/or inflammatory diseases which can be treated via local application of a drug compound including, but not limited to inflammatory eye diseases such as, but not limited uveitis, conjunctivitis, contact allergy, retinopathy or post- trauma/post-surgery/post-laser treatment complications including corneal transplant rejection; inflammatory airway diseases; rheumatoid arthritis, skin diseases such as but not limited to contact dermatitis and psoriasis, organ transplant rejection or allergy, intestinal inflammatory diseases such as but not limited to ulcerative colitis, inflammatory bowel disease and Crohn's disease.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. Unless a context dictates otherwise, asterisks are used herein to indicate the point at which a mono- or bivalent radical depicted is connected to the structure to which it relates and of which the radical forms part.

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

As already mentioned hereinbefore, in a first aspect the present invention provides compounds of Formula I

wherein A, R¹ , R² and Cy are as defined hereinbefore, including the stereo-isomeric forms, solvates, and pharmaceutically acceptable addition salts thereof.

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

The term "alkyl" by itself or as part of another substituent refers to a fully saturated hydrocarbon of Formula C_xH_2x+i wherein x is a number greater than or equal to 1 . Generally, alkyl groups of this invention comprise from 1 to 20 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, Ci_-4alkyl means an alkyl of one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers; decyl and its isomers. CrC₆ alkyl includes all linear, branched, or cyclic alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl, cyclopentylmethylene, and cyclohexyl. The term "optionally substituted alkyl" refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, for example 1 , 2, 3, or 4 substituents, or 1 to 2 substituents, preferably one substituent) at any available point of attachment. Non-limiting examples of such substituents include halo, hydroxyl, carbonyl, nitro, amino, oxime, imino, azido, hydrazino, cyano, aryl, heteroaryl, cycloalkyi, heterocyclyl, acyl, alkylamino, alkoxy, thiol, alkylthio, carboxylic acid, acylamino, alkyl esters, carbamate, thioamido, urea, sullfonamido and the like. In a particular embodiment, such substituents are selected from the group consisting of halo, hydroxyl, nitro, amino, cyano, aryl (in particular phenyl), heteroaryl (more in particular pyridinyl), cycloalkyi, heterocyclyl (in particular pyrrolidinyl, oxolanyl, or thiolanyl; more in particular pyrrolidinyl or oxolanyl), alkoxy, alkylamino, and dialkylamino.

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

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

The term "cycloalkyi" by itself or as part of another substituent is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 , 2, or 3 cyclic structure. Cycloalkyi includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic, or polycyclic alkyl groups. Cycloalkyi groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 15 atoms. The further rings of multi-ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro atoms. Cycloalkyi groups may also be considered to be a subset of homocyclic rings discussed hereinafter. Examples of cycloalkyi groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl, bicyclo(2.2.1 )heptanyl and cyclodecyl with cyclopropyl, cyclopentyl, cyclohexyl, adamantanyl, and bicyclo(2.2.1 )heptanyl being particularly preferred. An "optionally substituted cycloalkyl" refers to a cycloalkyl having optionally one or more substituents (for example 1 to 3 substituents, for example 1 , 2, 3 or 4 substituents), selected from those defined above for substituted alkyl. When the suffix "ene" is used in conjunction with a cyclic group, hereinafter also referred to as "Cycloalkylene", this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups. Cycloalkylene groups of this invention preferably comprise the same number of carbon atoms as their cycloalkyl radical counterparts.

Where alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed "alkylene" groups. Non-limiting examples of alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1 ,2-dimethylethylene, pentamethylene and hexamethylene. Similarly, where alkenyl groups as defined above and alkynyl groups as defined above, respectively, are divalent radicals having single bonds for attachment to two other groups, they are termed "alkenylene" and "alkynylene" respectively.

Generally, alkylene groups of this invention preferably comprise the same number of carbon atoms as their alkyl counterparts. Where an alkylene or cycloalkylene biradical is present, connectivity to the molecular structure of which it forms part may be through a common carbon atom or different carbon atom, preferably a common carbon atom. To illustrate this applying the asterisk nomenclature of this invention, a C₃ alkylene group may be for example *-CH₂CH₂CH₂-*, *-CH(-CH₂CH₃)-*, or *-CH₂CH(-CH₃)-*. Likewise a C₃ cycloalkylene group may be

Where a cycloalkylene group is present, this is preferably a C₃-C₆ cycloalkylene group, more preferably a C₃ cycloalkylene (i.e. cyclopropylene group) wherein its connectivity to the structure of which it forms part is through a common carbon atom. Cycloalkylene and alkylene biradicals in compounds of the invention may be, but preferably are not, substituted.

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

Exemplary heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H-indolyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1- pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2- oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro- 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, phthalazinyl, oxetanyl, thietanyl, 3- dioxolanyl, 1 ,3-dioxanyl, 2,5-dioximidazolidinyl, 2,2,4-piperidonyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1 ,3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4- dithianyl, 1 ,3,5-trioxanyl, 6H-1 ,2,5-thiadiazinyl, 2H-1 ,5,2-dithiazinyl, 2H-oxocinyl, 1 H- pyrrolizinyl, tetrahydro-1 , 1-dioxothienyl, N- formylpiperazinyl, and morpholinyl.

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

The aryl ring can optionally be substituted by one or more substituents. An "optionally substituted aryl" refers to an aryl having optionally one or more substituents (for example 1 to 5 substituents, for example 1 , 2, 3 or 4) at any available point of attachment. Non- limiting examples of such substituents are selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyi, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -S0₂-NH₂, aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -S0₂R^a, alkylthio, carboxyl, and the like, wherein R^a is alkyl or cycloalkyl.

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

The term "heteroaryl" as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 3 rings which are fused together or linked covalently, typically containing 5 to 8 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by oxygen, nitrogen or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2, 1 -b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, benzopyranyl, 1 (4H)-benzopyranyl, 1 (2H)- benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3- benzoxazolyl, 1 ,2-benzisoxazolyl, 2, 1-benzisoxazolyl, 1 ,3-benzothiazolyl, 1 ,2- benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2, 1 ,3- benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1 ,2-a]pyridinyl, 6-oxo-pyridazin-1 (6H)-yl, 2-oxopyridin-1 (2H)-yl, 6-oxo-pyridazin- 1 (6H)-yl, 2-oxopyridin-1 (2H)-yl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.

The term "pyrrolyl" (also called azolyl) as used herein includes pyrrol-1 -yl, pyrrol-2-yl and pyrrol-3-yl. The term "furanyl" (also called "furyl") as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl). The term "thiophenyl" (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term "pyrazolyl" (also called 1 H-pyrazolyl and 1 ,2-diazolyl) as used herein includes pyrazol-1 -yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl. The term "imidazolyl" as used herein includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl. The term "oxazolyl" (also called 1 ,3-oxazolyl) as used herein includes oxazol-2-yl; oxazol-4-yl and oxazol-5-yl. The term "isoxazolyl" (also called 1 ,2-oxazolyl), as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term "thiazolyl" (also called 1 ,3-thiazolyl),as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4-thiazolyl and 5-thiazolyl). The term "isothiazolyl" (also called 1 ,2- thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. The term "triazolyl" as used herein includes 1 H-triazolyl and 4H-1 ,2,4-triazolyl, "1 H-triazolyl" includes 1 H-1 ,2,3-triazol-1-yl, 1 H-1 ,2,3-triazol-4-yl, 1 H-1 ,2,3-triazol-5-yl, 1 H-1 ,2,4-triazol- 1 -yl, 1 H-1 ,2,4-triazol-3-yl and 1 H-1 ,2,4-triazol-5-yl. "4H-1 ,2,4-triazolyl" includes 41-1-1 ,2,4- triazol-4-yl, and 4H-1 ,2,4-triazol-3-yl. The term "oxadiazolyl" as used herein includes 1 ,2,3-oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,2,4-oxadiazol -3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,5-oxadiazol-3-yl and 1 ,3,4-oxadiazol-2-yl. The term "thiadiazolyl" as used herein includes 1 ,2,3-thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5- yl, 1 ,2,5-thiadiazol-3-yl (also called furazan-3-yl) and 1 ,3,4-thiadiazol-2-yl. The term "tetrazolyl" as used herein includes 1 H-tetrazol-1 -yl, 1 H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term "oxatriazolyl" as used herein includes 1 ,2,3,4-oxatriazol-5-yl and 1 ,2,3,5-oxatriazol-4-yl. The term "thiatriazolyl" as used herein includes 1 ,2,3,4- thiatriazol-5-yl and 1 ,2,3,5-thiatriazol-4-yl. The term "pyridinyl" (also called "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2-pyridyl, 3- pyridyl and 4-pyridyl). The term "pyrimidyl" as used herein includes pyrimid-2-yl, pyrimid-4- yl, pyrimid-5-yl and pyrimid-6-yl. The term "pyrazinyl" as used herein includes pyrazin-2-yl and pyrazin-3-yl. The term "pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl. The term "oxazinyl" (also called "1 ,4-oxazinyl") as used herein includes 1 ,4- oxazin-4-yl and 1 ,4-oxazin-5-yl. The term "dioxinyl" (also called "1 ,4-dioxinyl") as used herein includes 1 ,4-dioxin-2-yl and 1 ,4-dioxin-3-yl. The term "thiazinyl" (also called "1 ,4- thiazinyl") as used herein includes 1 ,4-thiazin-2-yl, 1 ,4-thiazin-3-yl, 1 ,4-thiazin-4-yl, 1 ,4- thiazin-5-yl and 1 ,4-thiazin-6-yl. The term "triazinyl" as used herein includes 1 ,3,5-triazin- 2-yl, 1 ,2,4-triazin-3-yl, 1 ,2,4-triazin-5-yl, 1 ,2,4-triazin-6-yl, 1 ,2,3-triazin-4-yl and 1 ,2,3- triazin-5-yl. The term "imidazo[2,1 -b][1 ,3]thiazolyl" as used herein includes imidazo[2, 1- b][1 ,3]thiazoi-2-yl, imidazo[2,1 -b][1 ,3]thiazol-3-yl, imidazo[2, 1-b][1 ,3]thiazol-5-yl and imidazo[2, 1 -b][1 ,3]thiazol-6-yl. The term "thieno[3,2-b]furanyl" as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2- b]furan-5-yl. The term "thieno[3,2-b]thiophenyl" as used herein includes thieno[3,2-b]thien- 2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2-b]thien-6-yl. The term "thieno[2,3-d][1 ,3]thiazolyl" as used herein includes thieno[2,3-d][1 ,3]thiazol-2-yl, thieno[2,3-d][1 ,3]thiazol-5-yl and thieno[2,3-d][1 ,3]thiazol-6-yl. The term "thieno[2,3- d]imidazolyl" as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl and thieno[2,3-d]imidazol-5-yl. The term "tetrazolo[1 ,5-a]pyridinyl" as used herein includes tetrazolo[1 ,5-a]pyridine-5-yl, tetrazolo[1 ,5-a]pyridine-6-yl, tetrazolo[1 ,5-a]pyridine-7-yl, and tetrazolo[1 ,5-a]pyridine-8-yl. The term "indolyl" as used herein includes indol-1 -yl, indol-2- yl, indol-3-yl,-indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl. The term "indolizinyl" as used herein includes indolizin-1 -yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. The term "isoindolyl" as used herein includes isoindol-1 -yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl and isoindol-7-yl. The term "benzofuranyl" (also called benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl. The term "isobenzofuranyl" (also called benzo[c]furanyl) as used herein includes isobenzofuran-1 -yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl and isobenzofuran-7-yl. The term "benzothiophenyl" (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4- benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7-benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl). The term "isobenzothiophenyl" (also called benzo[c]thienyl) as used herein includes isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl and isobenzothien-7-yl. The term "indazolyl" (also called 1 H-indazolyl or 2-azaindolyl) as used herein includes 1 H- indazol-1-yl, 1 H-indazol-3-yl, 1 H-indazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol- 7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H-indazol-7-yl. The term "benzimidazolyl" as used herein includes benzimidazol-1 -yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term "1 ,3-benzoxazolyl" as used herein includes 1 ,3-benzoxazol-2- yl, 1 ,3-benzoxazol-4-yl, 1 ,3-benzoxazol-5-yl, 1 ,3-benzoxazol-6-yl and 1 ,3-benzoxazol-7-yl. The term "1 ,2-benzisoxazolyl" as used herein includes 1 ,2-benzisoxazol-3-yl, 1 ,2- benzisoxazol-4-yl, 1 ,2-benzisoxazol-5-yl, 1 ,2-benzisoxazol-6-yl and 1 ,2-benzisoxazol-7-yl. The term "2,1 -benzisoxazolyl" as used herein includes 2, 1-benzisoxazol-3-yl, 2, 1- benzisoxazol-4-yl, 2, 1-benzisoxazol-5-yl, 2,1 -benzisoxazol-6-yl and 2, 1 -benzisoxazol-7-yl. The term "1 ,3-benzothiazolyl" as used herein includes 1 ,3-benzothiazol-2-yl, 1 ,3- benzothiazol-4-yl, 1 ,3-benzothiazol-5-yl, 1 ,3-benzothiazol-6-yl and 1 ,3-benzothiazol-7-yl. The term "1 ,2-benzoisothiazolyl" as used herein includes 1 ,2-benzisothiazol-3-yl, 1 ,2- benzisothiazol-4-yl, 1 ,2-benzisothiazol-5-yl, 1 ,2-benzisothiazol-6-yl and 1 ,2- benzisothiazol-7-yl. The term "2, 1 -benzoisothiazolyl" as used herein includes 2, 1- benzisothiazol-3-yl, 2, 1 -benzisothiazol-4-yl, 2, 1-benzisothiazol-5-yl, 2,1 -benzisothiazol-6- yl and 2, 1 -benzisothiazol-7-yl. The term "benzotriazolyl" as used herein includes benzotriazol-1-yl, benzotriazol4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7- yl. The term "1 ,2,3-benzoxadiazolyl" as used herein includes 1 ,2,3-benzoxadiazol-4-yl, 1 ,2,3-benzoxadiazol-5-yl, 1 ,2,3-benzoxadiazol-6-yl and 1 ,2,3-benzoxadiazol-7-yl. The term "2, 1 ,3-benzoxadiazolyl" as used herein includes 2, 1 ,3-benzoxadiazol-4-yl, 2, 1 ,3- benzoxadiazol-5-yl, 2, 1 ,3-benzoxadiazol-6-yl and 2,1 ,3-benzoxadiazol-7-yl. The term "1 ,2,3-benzothiadiazolyl" as used herein includes 1 ,2,3-benzothiadiazol-4-yl, 1 ,2,3- benzothiadiazol-5-yl, 1 ,2,3-benzothiadiazol-6-yl and 1 ,2,3-benzothiadiazol-7-yl. The term "2, 1 ,3-benzothiadiazolyl" as used herein includes 2,1 ,3-benzothiadiazol-4-yl, 2, 1 ,3- benzothiadiazol-5-yl, 2, 1 ,3-benzothiadiazol-6-yl and 2,1 ,3-benzothiadiazol-7-yl. The term "thienopyridinyl" as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl. The term "purinyl" as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term "imidazo[1 ,2-a]pyridinyl", as used herein includes imidazo[1 ,2-a]pyridin-2-yl, imidazo[1 ,2-a]pyridin-3-yl, imidazo[1 ,2- a]pyridin-4-yl, imidazo[1 ,2-a]pyridin-5-yl, imidazo[1 ,2-a]pyridin-6-yl and imidazo[1 ,2- a]pyridin-7-yl. The term "1 ,3-benzodioxolyl", as used herein includes 1 ,3-benzodioxol-4-yl, 1 ,3-benzodioxol-5-yl, 1 ,3-benzodioxol-6-yl, and 1 ,3-benzodioxol-7-yl. The term "quinolinyl" as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6- yl, quinolin-7-yl and quinolin-8-yl. The term "isoquinolinyl" as used herein includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The term "cinnolinyl" as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term "quinazolinyl" as used herein includes quinazolin-2-yl, quiriazolin-4-yl, quinazolin-5- yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term "quinoxalinyl". as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl. The term "7- azaindolyl" as used herein refers to 1 H-Pyrrolo[2,3-b]pyridinyl and includes 7-azaindol-1- yl, 7-azaindol-2-yl, 7-azaindol-3-yl, 7-azaindol-4-yl, 7-azaindol-5-yl, 7-azaindol-6-yl. The term "6-azaindolyl" as used herein refers to 1 H-Pyrrolo[2,3-c]pyridinyl and includes 6- azaindol-1 -yl, 6-azaindol-2-yl, 6-azaindol-3-yl, 6-azaindol-4-yl, 6-azaindol-5-yl, 6-azaindol- 7-yl. The term "5-azaindolyl" as used herein refers to 1 H-Pyrrolo[3,2-c]pyridinyl and includes 5-azaindol-1 -yl, 5-azaindol-2-yl, 5-azaindol-3-yl, 5-azaindol-4-yl, 5-azaindol-6-yl,

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

6- yl, 4-azaindol-7-yl.

For example, non-limiting examples of heteroaryl can be 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1 -, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-thiazolyl, 1 ,2,3-triazol-1 -, -4- or -5-yl, 1 ,2,4- triazol-1-, -3-, -4- or -5-yl, 1 H-tetrazol-1 -, or-5-yl, 2H-tetrazol-2-, or -5-yl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-thiadiazol-4- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl, 1 ,2,5-thiadiazol-3- or -4-yl, 1 ,3,4-thiadiazolyl, 1- or 5- tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, 4-, 5- or 6-pyrimidyl, 2-, 3-, 4-, 5- 6-2H- thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 4-azaindol-1-, 2-, 3-, 5-, or 7-yl, 5-azaindol-1-, or 2-, 3-, 4-, 6-, or 7-yl, 6-azaindol-1 , 2-, 3-, 4-, 5-, or 7-yl, 7-azaindol-1-, 2-, 3-, 4, 5-, or 6-yl, 2-,

3- , 4-, 5-, 6- or 7-benzofuryl, 1-, 3-, 4- or 5-isobenzofuryl, 2-, 3-, 4-, 5-, 6- or 7- benzothienyl, 1-, 3-, 4- or 5-isobenzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2- or 3- pyrazinyl, 1 ,4-oxazin-2- or -3-yl, 1 ,4-dioxin-2- or -3-yl, 1 ,4-thiazin-2- or -3-yl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazin-2-, -4- or -6-yl, thieno[2,3-b]furan-2-, -3-, -4-, or -5-yl, benzimidazol-1-yl, -2-yl, -4-yl, -5-yl, -6-yl, or -7-yl, 1 -, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 3-,

4- , 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisothiazolyl, 1 ,3-benzothiazol-2-yl, -4-yl, -5-yl, -6-yl or -7-yl, 1 ,3-benzodioxol-4-yl, -5- yl, -6-yl, or -7-yl, benzotriazol-1-yl, -4-yl, -5-yl, -6-yl or -7-yl1 -, 2-thianthrenyl, 3-, 4- or 5- isobenzofuranyl, 1-, 2-, 3-, 4- or 9-xanthenyl, 1-, 2-, 3- or 4-phenoxathiinyl, 2-, 3-pyrazinyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7- or 8-indolizinyl, 2-, 3-, 4- or 5-isoindolyl, 1 H-indazol-1 -yl, 3-yl, -4-yl, -

5- yl, -6-yl, or -7-yl, 2H-indazol-2-yl, 3-yl, -4-yl, -5-yl, -6-yl, or -7-yl, imidazo[2, 1- b][1 ,3]thiazoi-2-yl, imidazo[2, 1 -b][1 ,3]thiazol-3-yl, imidazo[2, 1-b][1 ,3]thiazol-5-yl or imidazo[2, 1 -b][1 ,3]thiazol-6-yl, imidazo[1 ,2-a]pyridin-2-yl, imidazo[1 ,2-a]pyridin-3-yl, imidazo[1 ,2-a]pyridin-4-yl, imidazo[1 ,2-a]pyridin-5-yl, imidazo[1 ,2-a]pyridin-6-yl or imidazo[1 ,2-a]pyridin-7-yl, tetrazolo[1 ,5-a]pyridine-5-yl, tetrazolo[1 ,5-a]pyridine-6-yl, tetrazolo[1 ,5-a]pyridine-7-yl, or tetrazolo[1 ,5-a]pyridine-8-yl, 2-, 6-, 7- or 8-purinyl, 4-, 5- or

6- phthalazinyl, 2-, 3- or 4-naphthyridinyl, 2-, 5- or 6-quinoxalinyl, 2-, 4-, 5-, 6-, 7- or 8- quinazolinyl, 1-, 2-, 3- or 4-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl(quinolyl), 2-, 4-, 5-, 6-, 7- or 8-quinazolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl(isoquinolyl), 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl,2-, 4-, 6- or 7-pteridinyl, 1 -, 2-, 3-, 4- or 9-carbazolyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1 -, 2-, 3- or 4- acridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- (1 ,7)phenanthrolinyl, 1- or 2-phenazinyl, 1 -, 2-, 3-, 4-, or 10-phenothiazinyl, 3- or 4- furazanyl, 1-, 2-, 3-, 4-, or 10-phenoxazinyl, or additionally substituted derivatives thereof.

An "optionally substituted heteroaryl" refers to a heteroaryl having optionally one or more substituents (for example 1 to 4 substituents, for example 1 , 2, 3 or 4), selected from those defined above for substituted aryl.

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

The term "alkoxy" or "alkyloxy" as used herein refers to a radical having the Formula -OR^B wherein R^B is alkyl. Preferably, alkoxy is C-I-C-IO alkoxy, Ci-C₆ alkoxy, or C1-C4 alkoxy. Non-limiting examples of suitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. Where the oxygen atom in an alkoxy group is substituted with sulfur, the resultant radical is referred to as thioalkoxy. "Haloalkoxy" is an alkoxy group wherein one or more hydrogen atoms in the alkyl group are substituted with halogen. Non-limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1 , 1 ,2,2- tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy; trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4- trichlorobutoxy.

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

The term "arylcarbonyl" or "aroyl" as used herein denotes a group -C(0)-aryl, wherein aryl is as defined above.

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

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

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

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

The term "alkylcarbonyloxy" by itself or as part of another substituent refers to a -O- C(=0)R^e wherein R^e is as defined above for alkyl.

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

The term "thiocarbonyl" by itself or as part of another substituent refers to the group - C(=S)-. The term "alkoxy" by itself or as part of another substituent refers to a group consisting of an oxygen atom attached to one optionally substituted straight or branched alkyl group, cycloalkyi group, aralkyi, or cycloalkylalkyi group. Non-limiting examples of suitable alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, hexanoxy, and the like.

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

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

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

The term "haloalkoxy" alone or in combination refers to a group of Formula -O-alkyl wherein the alkyl group is substituted by 1 , 2, or 3 halogen atoms. For example, "haloalkoxy" includes -OCF₃, -OCHF₂, -OCH₂F, -0-CF₂-CF₃, -0-CH₂-CF₃, -0-CH₂-CHF₂, and -0-CH₂-CH₂F.

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

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

As used herein the terms such as "alkyl, aryl, or cycloalkyi, each being optionally substituted with" or "alkyl, aryl, or cycloalkyi, optionally substituted with" refers to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyi. As described herein, some of the compounds of the invention may contain one or more asymmetric carbon atoms that serve as a chiral center, which may lead to different optical forms (e.g. enantiomers or diastereoisomers). The invention comprises all such optical forms in all possible configurations, as well as mixtures thereof.

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

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

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

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

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

Wherein

R⁴ is optionally substituted Ci_-8alkyl further substituted with one substituent selected from the group consisting of Het¹, -O-Het¹, -NH-Het¹, -S-Het¹, and - C(=0)-OR³; wherein Het¹ is selected from the group consisting of:

Wherein

each R⁵ is independently selected from Ci_-6alkyl;

m and n are each independently an integer from 0 to 2;

in particular Het¹ is selected from the group consisting of:

more in particular Het¹ is

• R² is selected from the group comprising hydrogen, Ci_-8alkyl, Ci_-8alkoxy, and halogen; in particular R² is selected from the group comprising hydrogen, methyl, methoxy, and halogen; more in particular R² is hydrogen; 



in articular Cy is selected from the group consisting of:

• R⁶ is Ci_-6alkyl optionally substituted with one or more substituents selected from hydroxyl or NR⁸R⁹;

• R⁸ and R⁹ are independently selected from the group consisting of hydrogen, Ci_-8alkyl, and C₃-₈cycloalkyl; in particular R⁸ and R⁹ are independently selected from hydrogen or methyl;

• R⁸ and R⁹ together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with Ci_-6alkyl,

• R⁷ is selected from the group comprising hydrogen, Ci_-8alkyl, C_3-8cycloalkyl, and alkylheteroaryl; in particular R⁷ is selected from methyl and methylpyridinyl; more in particular, R⁷ is selected from methyl;

• each X is independently selected from -CH- or -N-; in particular X is -CH-;,

• Y is selected from -N-, -N(R¹²)-, or -0-;

• R¹² is hydrogen or Ci_-6alkyl; in particular R¹² is hydrogen or methyl;,

• E is -0-, -NH- or -CH₂-;

• R¹⁰ is selected from the group consisting of hydrogen, Ci_-6alkyl, halogen, hydroxyl, and Ci_-6alkoxy; in particular R¹⁰ is selected from the group consisting of hydrogen, methyl, halogen, hydroxyl, and methoxy; more in particular R¹⁰ is hydrogen;

• R¹¹ is selected from hydrogen or Ci_-6alkyl; in particular, R¹¹ is selected from hydrogen or methyl;

• R¹³ is hydrogen or halogen; in particular R¹³ is hydrogen or chloro; • A is located on position 6 or 7 of the indole ring in formula I;

• when Cy is 1 -methylindole and R¹ is methyl, then R³ is not methyl or ethyl; in particular when Cy is 1 -methylindole, then R³ is not methyl or ethyl; more in particular when Cy is 1 -alkylindole, then R³ is not methyl or ethyl;

• when Cy is indole, then R³ is not methyl; in particular R³ is not methyl or ethyl;

• when R¹ is methyl; in particular when R¹ is Ci_-6alkyl, then R³ is not ethyl or methyl;

• when Cy is selected from the group consisting of

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

In a preferred embodiment, the compounds of the present invention, or a composition comprising such a compound, are useful as kinase inhibitors, more in particular for the inhibition of at least one PKC isoform, in particular they are useful as soft nPKC and/or cPKC inhibitors.

In another embodiment, the compounds of the present invention, or a composition comprising such a compound, are useful for the prevention and/or treatment of at least one disease or disorder in which Proteine Kinase C's (PKCs) are involved. In yet another embodiment, the compounds of the present invention, or a composition comprising such a compound, are useful for the prevention and/or treatment of at least one disease or disorder associated with the activation of T-cells or B-cells in a patient. In particular, the compounds of the present invention, or a composition comprising such a compound, are useful in the prevention and/or treatment of at least one immunological disorders or inflammatory diseases.

In a preferred embodiment, the compounds according to the invention, or a composition comprising such a compound, can be used in the prevention and/or treatment of at least one disease of disorder selected from the group comprising:

• inflammatory eye diseases; in particular inflammatory airway diseases inflammatory eye disease such as, but not limited to, uveitis; conjunctivitis; contact allergy; retinopathy; or post-trauma/post-surgery/post-laser treatment complications including corneal transplant rejection;

• rheumatoid arthritis;

• skin diseases; in particular skin disease such as, but not limited to, contact dermatitis and psoriasis;

• organ transplant rejection or allergy; and

• intestinal inflammatory diseases; in particular intestinal inflammatory disease such as, but not limited to, ulcerative colitis; inflammatory bowel disease; and Crohn's disease.

The present invention provides the use of a compound of the invention, or a composition comprising such a compound for treating a disease or a disorder associated with the activation of T-cells and/or B-cells in a patient comprising administering to the patient a therapeutically effective amount of a compound of the present invention as described above.

In another embodiment, the present invention provides the use of a compound of the invention as a medicine. In a preferred embodiment, the present invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of immunological disorders and/or inflammatory diseases which can be treated via local application of a drug compound including, but not limited to inflammatory eye diseases such as, but not limited to uveitis, conjunctivitis, contact allergy, retinopathy or post-trauma/post-surgery/post-laser treatment complications including corneal transplant rejection; inflammatory airway diseases; rheumatoid arthritis, skin diseases such as but not limited to contact dermatitis and psoriasis, organ transplant rejection or allergy, intestinal inflammatory diseases such as but not limited to ulcerative colitis, inflammatory bowel disease and Crohn's disease. In another embodiment, the present invention provides the use of the compounds of the present invention, or a composition comprising such a compound, for the prevention and/or treatment of at least one disease or disorder in which Proteine Kinase C's (PKCs) are involved. In yet another embodiment, the present invention provides the use of the compounds of the present invention, or a composition comprising such a compound, for the prevention and/or treatment of at least one disease or disorder associated with the activation of T-cells or B-cells in a patient. In particular, the present invention provides the use of the compounds of the present invention, or a composition comprising such a compound, for the prevention and/or treatment of at least one immunological disorders or inflammatory diseases.

In a preferred embodiment, the present invention provides the use of the compounds of the present invention, or a composition comprising such a compound, for the prevention and/or treatment of at least one disease of disorder selected from the group comprising:

• rheumatoid arthritis;

• organ transplant rejection or allergy; and

METHOD OF TREATMENT

The present invention further provides a method for the prevention and/or treatment of at least one disease or disorder associated with the activation of T-cells and/or B-cells in a patient comprising administering to the patient a therapeutically effective amount of a compound of the present invention as described above. In another embodiment, the present invention provides a method for the prevention and/or treatment of at least one disease or disorder in which PKCs are involved; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound according to the invention, or a composition comprising such a compound. In particular, the present invention provides a method for the prevention and/or treatment of at least one immunological disorders or inflammatory diseases; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound according to the invention, or a composition comprising such a compound.

In a preferred embodiment, the present invention provides a method for the prevention and/or treatment of at least one disease of disorder selected from the group comprising:

• rheumatoid arthritis;

• organ transplant rejection or allergy; and

• intestinal inflammatory diseases; in particular intestinal inflammatory disease such as, but not limited to, ulcerative colitis; inflammatory bowel disease; and Crohn's disease;

said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound according to the invention, or a composition comprising such a compound.

In a preferred embodiment, the present invention provides the use of a compound of the invention in the preparation of a medicament for the prevention and/or treatment of immunological disorders and/or inflammatory diseases which can be treated via local administration of a drug compound including, but not limited to inflammatory eye diseases such as, but not limited uveitis, conjunctivitis, contact allergy, retinopathy or post- trauma/post-surgery/post-laser treatment complications including corneal transplant rejection; inflammatory airway diseases; rheumatoid arthritis, skin diseases such as but not limited to contact dermatitis and psoriasis, organ transplant rejection or allergy, intestinal inflammatory diseases such as but not limited to ulcerative colitis, inflammatory bowel disease and Crohn's disease..

In the invention, particular preference is given to compounds of Formula I or any subgroup thereof that in the inhibition assay for any PKCs described below inhibit at least one PKC isoform with an IC₅₀ value of less than 10 μΜ, preferably less than 1 μΜ. Said inhibition may be effected in vitro and/or in vivo, and when effected in vivo, is preferably effected in a selective manner (for the c/n PKCs families), as defined above.

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

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

The pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, benzoate, benzenesulfonate, bisulfate, citrate, camphorate, camphorsulfonate, fumarate, hemisulfate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2-naphthalene-sulfonate, oxalate, succinate, tartrate, and tosylate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. In addition, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts. Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation or pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US-A- 6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ α-, β- or γ-cyclodextrins or their derivatives. An interesting way of formulating the compounds in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721 ,331. In particular, the present invention encompasses a pharmaceutical composition comprising an effective amount of a compound according to the invention with a pharmaceutically acceptable cyclodextrin.

In addition, co-solvents such as alcohols may improve the solubility and/or the stability of the compounds. In the preparation of aqueous compositions, addition of salts of the compounds of the invention can be more suitable due to their increased water solubility.

Particular reference is made to the compositions, formulations (and carriers, excipients, diluents, etc. for use therein), routes of administration etc., which are known per se for analogous pyridinocarboxamides, such as those described in US-A-4,997,834 and EP-A-0 370 498.

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

For ophthalmic application, solutions, gels, tablets and the like are often prepared using a physiological saline solution, gel or excipient as a major vehicle. Ophthalmic formulations should preferably be prepared at a comfortable pH with an appropriate buffer system.

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

The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution". Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered.

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

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

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

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

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

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

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

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

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

When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

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

The compositions are of value in the veterinary field, which for the purposes herein not only includes the prevention and/or treatment of diseases in animals, but also - for economically important animals such as cattle, pigs, sheep, chicken, fish, etc. - enhancing the growth and/or weight of the animal and/or the amount and/or the quality of the meat or other products obtained from the animal. Thus, in a further aspect, the invention relates to a composition for veterinary use that contains at least one compound of the invention and at least one suitable carrier (i.e. a carrier suitable for veterinary use). The invention also relates to the use of a compound of the invention in the preparation of such a composition.

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

A. Physicochemical properties of the compounds

A.1. Compound purity

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

A.2. Attribution of the configuration:

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

A.3. Stereochemistry:

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

A.4. Name of the molecules

The software MDL ISIS™ / Draw 2.3 was used to assign the name of the molecules.

B. Compound synthesis

The compounds of the invention may be prepared by methods well known to those skilled in the art, and as described in the synthetic and experimental procedures shown below.

Otherwise described, the required intermediates were prepared according to procedures described in the PCT application PCT/EP201 1/053343. B.1: Intermediates

Intermediate 1 : Methyl 1 H-indole-7-carboxylate

To a solution of 1 H-indole-7-carboxylic acid (20 g, 124 mmol, 1 .0 eq) in MeOH (700 ml) was added H₂S0₄ (1.2 g, 12 mmol, 0.1 eq) and the mixture was stirred at reflux for 20 hrs. Then, MeOH was evaporated by rotavapor and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated Na₂C0₃, brine, dried over Na₂S0₄ and filtered. The solvent was removed under reduced pressure to give intermediate 1 (16.3 g, 75% yield) as a yellow solid.

Intermediate 2: Methyl 3-(2-methoxy-2-oxoacetyl)-1 H-indole-7-carboxylate

To a suspension of intermediate 1 (16.3 g, 93 mmol, 1 .0 eq) in Et₂0 (320 ml) was added dropwise oxalyl dichloride (13 g, 102 mmol, 1 .1 eq) at 0 °C under N₂. The reaction mixture was stirred at room temperature for 3 hrs. The yellow suspension was filtered and the solid was washed with Et₂0.

The obtained acid chloride was suspended in MeOH (300 ml) and stirred at room temperature for 2 hrs. The precipitate was filtered to give the intermediate 2 (16.7 g, 69% yield) as a yellow solid.

Intermediate 3: tert-butyl N-{3-[3-(2-aminoacetyl)-1 H-indol-1 -yl]propyl}carbamate

To a mixture of 3-bromopropan-1 -amine hydrobromide (98.5 g, 45 mmol, 1 .0 eq) and Boc₂0 (93.3 g, 42.8 mmol, 0.95 eq) in DCM (500 ml) was added dropwise DIPEA (64.0 g, 49.5 mmol). The resulting mixture was stirred at room temperature overnight. Then, the reaction mixture was washed with water, 1 N HCI and brine, dried over Na₂S0₄ and filtered. The solvent was evaporated to give the expected compound (95.8 g, 94% yield) as a white solid.

To a suspension of NaH (60 % in mineral oil) (1 1.1 g, 278 mmol, 1 .3 eq) in DMF (150 ml) was added dropwise a solution of 2-(1 H-indol-3-yl)acetamide (37.2 g, 214 mmol, 1 .0 eq) in DMF (150 ml) at 0°C under N₂ and the reaction mixture was stirred for 30 min. Then a solution of the previous compound (55.9 g, 235 mmol, 1.1 eq) in DMF (100 ml) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min and at room temperature for 10 hrs. The reaction mixture was diluted in water (500 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na₂S0₄ and filtered. The solvent was evaporated under vacuum. The crude product was purified by column chromatography over silica gel eluted with MeOH/DCM (0/100 to 3/97) to give the intermediate 3 (52.8 g, 75% yield) as a solid.

Intermediate 4: methyl 3-{4-[1 -(3-{[(tert-butoxy)carbonyl]amino}propyl)-1 H-indol-3- yl]-2,5-dioxo-2,5-dihydro-1 H- rrol-3-yl}-1 H-indole-7-carboxylate

To a suspension of intermediate 2 (14.7 g, 56.3 mmol, 1 .3 eq) and intermediate 3 (14.3 g, 43.3 mmol, 1.0 eq) in dry THF (400 ml) was added dropwise t-BuOK (20% solution in THF, 97.2 g, 173.2 mmol, 4 eq) at 0 °C under N₂. The resulting yellow suspension was stirred at 0 °C for 3 hrs and at 15 °C overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phases were washed with water, saturated NaHC0₃ and brine, dried over Na₂S0_4, filtered and concentrated under vacuum. The crude product was purified by column chromatography over silica gel, eluted with MeOH/DCM (1/150 to 1/100), to give the intermediate 4 (8.9 g, 38% yield) as an orange solid. Intermediate 5: 3-{4-[1 -(3-{[(tert-butoxy)carbonyl]amino}propyl)-1 H-indol-3-yl]-2,5- dioxo-2,5-dihydro-1 H-pyrrol-3- l}-1 H-indole-7-carboxylic acid

To a solution of intermediate 4 (4.4 g, 8.1 mmol, 1 .0 eq) in THF (160 ml) and MeOH (40 ml) was added LiOH (1 M in water) (40 ml, 40 mmol, 5 eq) and the reaction mixture was stirred at 65 °C for 4 hrs. After cooling to room temperature, cold water (600 ml) and 1 M HCI (60 ml) were added successively. The mixture was extracted with ethyl acetae (300 ml x2), and the combined organic phases were washed with brine, dried over Na₂S0₄, filtered, and concentrated under vacuum. The crude product was purified by column chromatography over silica gel, eluted with DCM/MeOH/HOAc (1000:80:1 to 1000:150:1 ) to give the intermediate 5 (3.1 g, 72.3% yield) as a red solid.

Intermediate 6: 3-{4-[1 -(3-{[(tert-butoxy)carbonyl]amino}propyl)-1 H-indol-3-yl]-2,5- dioxo-2,5-dihydro-1 H-pyrrol-3- l}-1 H-indole-6-carboxylic acid

Intermediate 6 was prepared as described for Intermediate 5 starting from 1 H-indole-6- carboxylic acid (3.1g, red powder). Intermediate 7: 3-(4-{1 -[3-(dimethylamino)propyl]-1 H-indol-3-yl}-2,5-dioxo-2,5- dihydro-1 H-pyrrol-3-yl)-1 H-indole-7-carbox lic acid

Intermediate 7 (3.4 g, red solid) was prepared as described for Intermediate 5 starting from 1 H-indole-6-carboxylic acid, 2-(1 H-indol-3-yl)acetamide, and 3-bromopropan-1- dimethylamine.

Intermediate 8: 3-{4-[2-(4-methylpiperazin-1 -yl)quinazolin-4-yl]-2,5-dioxo-2,5- dihydro-1 H-pyrrol-3-yl}-1 H-indole-7-carboxylic acid

Λ/, ν-dimethylaniline (33.4 g, 276 mmol, 1 .0 eq) was added dropwise to a solution of 2,4 (1 H, 3H)-quinazolinedione (50 g, 276 mmol, 1 .0 eq) in POCI₃ (300 ml) and the mixture was heated to reflux for 3 hrs. The solution was cooled to room temperature, poured onto ice water and the resulting precipitate was filtered off and washed with water. The solid was dissolved in EtOAc and washed with water and brine. The organic fraction was dried over Na₂S0₄, filtered, concentrated under reduced pressure, and washed with petroleum ether to give the corresponding dichloro-derivative (20 g, 34% yield).

Ethyl-3-oxobutanoate (31.2 g, 240 mmol, 2.0 eq) was added dropwise to a suspension of NaH (6 g, 156 mmol, 1 .3 eq) in THF (520 ml) at 0 °C. After stirring at 0 °C for 1 h and removal of THF under reduced pressure, a solution of 2,4-dichloroquinazoline (24 g, 120 mmol, 1.0 eq) in toluene (350 ml) was added and the reaction mixture was heated to reflux for 30 min. After removal of toluene under reduced pressure, NH₄OH (320 ml) was added. After stirring for 20 min, the mixture was concentrated to remove NH₄OH. EtOAc (100 ml) and water (50 ml) were added to the mixture, that was filtered to give 2-(2- chloroquinazolin-4-yl)acetamide (14.4 g, 54 % yield).

1 -Methylpiperazine (34 g, 339 mmol, 5.0 eq) was added to a solution of 2-(2- chloroquinazolin-4-yl)acetamide (14.4 g, 65 mmol, 1.0 eq) in NMP (250 ml) and stirred at 50 °C for 30 min. After cooling to room temperature, EtOAc (100 ml) was added and the suspension was filtered to give 2-(2-(4-methylpiperazin-1 -yl)quinazolin-4-yl)acetamide (10.5 g, 55 % yield).

fert-BuOK (215 ml_, 121 mmol, 3.0 eq) was added to a solution of 2-(2-(4-methylpiperazin- 1 -yl)quinazolin-4-yl)acetamide (10.5 g, 36.8 mmol, 1.0 eq) and Intermediate 2 (10.5 g, 40.5 mmol, 1.1 eq) in anhydrous THF (250 ml) at room temperature and the mixture was stirred for about 30 min, quenched with water, extracted with EtOAc, washed with brine, dried over Na₂S0₄, concentrated and purified by column chromatography (silicagel) to give the methyl-ester of intermediate 8 (1 1 g, 60 % yield). This methyl ester will be referred to in Table 5 as compound 37.

The previous compound (1 1 g, 22 mmol, 1.0 eq) and LiOH (2.7 g, 63 mmol, 3.0 eq) were dissolved in THF (250 ml) and MeOH (100 ml) and the mixture was heated to reflux for 3 hrs. After cooling to room temperature, the mixture was quenched with 0.5 M HCI until pH=5 and concentrated to give crude Intermediate 8 that was used as such for subsequent reactions.

The following intermediates were prepared by similar methods and / or procedures known in the art.

B.2: Compounds

General synthetic procedure for the ester formation

Protocol A

To a solution of acid intermediate 5-1 1 (1.0 eq) dissolved in the appropriate alcohol (66 eq) were added three drops of cone. H₂S0₄ and the reaction mixture was stirred at reflux or at 120 °C for 4 hrs.

After cooling to room temperature, Boc₂0 (1.5 eq) and DIPEA (12 eq) were added. The mixture was stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed successively with saturated Na₂C0₃, water, a 0.2 N HCI solution, water again, and dried over Na₂S0₄, filtered, and concentrated under vacuum.

To a solution of the crude residue in DCM was added TFA and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate, washed with saturated Na₂C0₃, dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The final compound was purified either by flash chromatography on silica gel, preparative TLC or preparative HPLC. Protocol B

To a solution of acid intermediate 5-1 1 (1.0 eq) in DMF or acetonitrile were added the appropriate alcohol (10 eq) and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1 .0 eq). After stirring the mixture at 0 °C for 5 min, NMM (6.0 eq) was added and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was diluted in water, extracted with EtOAc, washed with brine, dried over Na₂S0₄ filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel to give the Boc-protected intermediate.

To a solution of the Boc-protected intermediate (1.0 eq) in MeOH was added a 8 M solution of HCI in MeOH (100 eq) and the reaction mixture was stirred at 35 °C for 15 min. The solvent was concentrated under reduced pressure and the residue was dried under high vacuum.

The final compound was purified either by flash chromatography on silica gel, preparative TLC or preparative HPLC.

Protocol C

To a solution of acid intermediate 5-1 1 (1.0 eq) in DMF were added HATU (1 .5 eq), HOBT (0.5 eq), the appropriate alcohol (10 eq) and DIEA (5.0 eq), and the mixture was stirred at room temperature overnight. After quenching with water, the mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine and dried over Na₂S0₄. After filtration and removal of the solvent under reduced pressure, the final compound was purified either by flash chromatography on silica gel, preparative TLC or preparative HPLC.

Protocol D

SOCI₂ (3.0 eq) was added dropwise to a solution of acid intermediate 5-1 1 (1 .0 eq) in toluene at 10 °C. The mixture was refluxed for 3 h, and then cooled to room temperature.

In a separate flask, n-BuLi (9.0 eq) was added to the appropriate alcohol (9.0 eq) in anhydrous THF at -60 °C under inert atmosphere. The mixture was stirred at -60 °C for 30 min and then warmed to room temperature. This THF solution was added into the above toluene solution via syringe under inert atmosphere and stirred at room temperature for about 2 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness under reduced pressure. The final compound was purified either by flash chromatography on silica gel, preparative TLC or preparative HPLC.

Detailed synthetic procedures are hereby provided for the following compounds of the invention.

Compound 1 :

To a solution of intermediate 5 (800 mg, 1 .51 mmol, 1.0 eq) in ethane-1 ,2-diol (8 ml, 100 mmol, 66 eq) were added three drops of cone. H₂S0₄. The reaction mixture was stirred at 120 °C for 4 hrs.

After cooling to room temperature, Boc₂0 (500 mg, 2.29 mmol, 1.5 eq) and DIPEA (3 ml, 18 mmol, 12 eq) were added. The mixture was stirred at room temperature overnight, diluted with water (100 ml), and extracted with ethyl acetate (200 ml x 3). The combined organic phases were washed successively with saturated Na₂C0₃, water, 0.2N HCI, water, dried over Na₂S0₄ and concentrated under vacuum.

TFA (5 ml) was added to a solution of the residue in DCM (25 ml) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (800 ml), washed with saturated Na₂C0₃ (100 ml), dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC eluted with DCM/NH₃ (2M in MeOH) (6:1 ) to give the compound 1 (100 mg, 14% yield) as a red solid. Compound 2:

To a solution of intermediate 5 (300 mg, 0.57 mmol, 1.0 eq) in propan-1-ol (8 ml) were added three drops of cone. H₂S0₄ and the reaction mixture was stirred at 120 °C for 4 hrs.

After cooling to room temperature, the mixture was diluted in water (100 ml), and extracted with EtOAc (100 ml x 3). The combined organic phases were washed with brine, dried over Na₂S0₄, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC eluted with DCM/NH₃ (2M in MeOH) (8:1 ) to give the compound 2 (120 mg, 45% yield) as a red solid.

Compound 3:

To a solution of intermediate 5 (300 mg, 0.57 mmol, 1.0 eq) in (tetrahydrofuran-2- yl)methanol (8 ml) were added three drops of cone. H₂S0₄ and the reaction mixture was stirred at 120 °C for 4 hrs.

After cooling to room temperature, the mixture was diluted in water (100 ml), and extracted with EtOAc (100 ml x 3). The combined organic phases were washed with brine, dried over Na₂S0₄, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC eluted with DCM/NH₃ (2M in MeOH) (8:1 ) to give the compound 3 (100 mg, 34% yield) as a red solid after Boc-deprotection. Compound 4:

To a solution of intermediate 5 (1 10 mg, 0.21 mmol, 1.0 eq) in ACN (5 ml) were added the methyl 2-aminoacetate (20 mg, 0.23 mmol, 1 .1 eq) and 2-chloro-4,6-dimethoxy-1 ,3,5- triazine (CDMT) (34 mg, 0.21 mmol, 1.0 eq). After stirring the mixture at 0 °C for 5min, NMM (0.1 1 ml, 0.98 mmol, 4.7 eq) was added and the reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was diluted in water, extracted with EtOAc, washed with brine, dried over Na₂S0₄ filtered, and concentrated under vacuum. The crude product was purified by column chromatography over silica gel, eluted with DCM/MeOH (200/1 to 100/1 ) to give the Boc-compound 4 (120 mg, 96% yield) as a red solid.

To a solution of Boc-compound 4 (120 mg, 0.2 mmol, 1.0 eq) in MeOH (4 ml) was added a 8M solution of HCI in MeOH (4 ml, 20 mmol, 100 eq) and the reaction mixture was stirred at 35 °C for 15 min. The solvent was concentrated under vacuum and the residue was dried under high vacuum to give the compound 4 (66 mg, 61 % yield) as a dark red solid.

Compound 5:

To a solution of intermediate 5 (300 mg, 0.57 mmol, 1 .1 eq) in ACN (15 ml) were added 3- [(3-aminopropyl)thio]dihydrofuran-2(3H)-one (1 10 mg, 0.52 mmol, 1 .0 eq) and CDMT (120 mg, 0.68 mmol, 1 .3 eq). After stirring the mixture at 0 °C for 5 min, NMM (0.35 ml, 3.1 1 mmol, 6 eq) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted in EtOAc, washed with brine, dried over Na₂S0₄ and concentrated under vacuum. The crude product was purified by column chromatography over silica gel, eluted with DCM/MeOH (150/1 ) to give the Boc-compound 5 (120 mg, 31 % yield) as a red solid.

To a solution of Boc-compound 5 (90 mg, 0.13 mmol, 1 .0 eq) in dry THF (5 ml) was added a 5M solution of HCI in THF (1.5 ml, 7.5 mmol, 57.7 eq) and the reaction mixture was stirred at 40 °C for 3 hrs. The solvent was removed under vacuum and Et₂0 (20 ml) was added to the residue. The resulting precipitate was filtered and washed with Et₂0 to give the HCI salt of the compound 5 (60 mg, 73% yield) as an orange-red solid.

The following compounds (Table 2) were prepared according to the generic procedures described hereinabove, starting from Intermediate 6.

Table 2

# Cpd Structure Yield / Appearance

6 45% / Red powder

7 34% / Red powder

8 36% / Red powder

# Cpd Structure Yield / Appearance

9 60% / Red powder

10 30% / Red powder

The following compounds (Table 3) were prepared according to the same procedures starting from the corresponding Intermediate.

Table 3

The following compounds (Table 4) were prepared according to the same procedures starting from Intermediate 7.

Table 4

# Cpd Structure Yield / Appearance

35 12% / Red solid

1 1 % / Orange-red

36

powder

The following compounds (Table 5) were prepared according to the same procedures starting from Intermediate 8 (except for cpd 37, which is the precursor of intermediate 8).

Table 5

# Cpd Structure Yield / Appearance

37 45% / Yellow-orange powder

38 6% / Red solid

39 7% / Yellow-orange solid

# Cpd Structure Yield / Appearance

40 10% / Red solid

41 4% / Orange-red solid

42 M ^H 7% / Orange-red solid

0

C. In vitro and in vivo assays

C.1. PKC inhibitory activity screening

C.1.1. Kinase inhibition (PKC9 & β1)

On-target activity against PKCs was measured in a biochemical assay, using the following reagents: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCI₂, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na₃V0₄, 2 mM DTT, 1 % DMSO. Required cofactors are added individually to each kinase reaction. The reaction procedure first involved the preparation of a peptide substrate in a freshly prepared reaction buffer. Required cofactors were then added to the substrate solution. PKC (1 nM final concentration) was then delivered to the substrate solution. After gentle mix, DMSO solutions of the test compounds were added to the enzyme. Substrate mix ³³P-ATP (specific activity 0.01 pCi/pl final) was then delivered into the reaction mixture to initiate the reaction. The kinase reaction was incubated for 120 min. at room temperature. Reactions were then spotted onto P81 ion exchange paper (Whatman # 3698-915). Filters were washed extensively in 0.1 % Phosphoric acid. A radiometric count was then performed and IC₅o values were subsequently determined. When evaluated under such conditions, compounds of the invention display inhibitory activity against PKCs, with inhibitory concentration 50 (IC₅₀) under l OOOOnM, preferably under 1000 nM, more preferably under 100nM. Inhibition data is hereby provided for several compounds of the invention, against ΡΚΟβΙ , a classical PKC isoform, and PKC9, a novel PKC isoform.

Data (in nM):

# Cpd ICso ICso

(PKC9) (PKC l)

1 +++ +++

2 +++ +++

3 +++ +++

4 +++ +++

5 +++ +++

6 ++ +++

7 +++ +++

8 +++ +++

9 +++ +++

10 +++ +++

16 ++ +++

17 ++ +++

18 ++ +++

19 +++ +++

20 ++ +++

21 ++ +++

22 ++ +++

23 +++ +++

24 +++ +++

25 +++ +++

26 +++ +++

27 ++ ++

28 ND ++

29 ND ++

30 +++ +++

31 ++ +++

32 +++ +++

33 ++ +++

34 ++ +++

35 ++ +++

36 +++ +++

37 +++ +++

38 +++ +++ # Cpd ICso ICso

(PKC9) (PKC l)

39 +++ +++

40 +++ +++

41 +++ +++

42 +++ +++

+++ : IC₅₀≤ 100nM

++ :100nM < IC₅₀≤ 1000nM

+: 1000nM < IC₅₀≤ ΙΟΟΟΟηΜ

ND: not determined yet

From the provided data, it will be appreciated that compounds of the invention display inhibitory activity against PKCs.

C.2. Pharmacological Characterization

C.2.1. Stability assay in human and other species plasma

Compounds are incubated at a concentration of 1 μΜ in human or animal (ex: rat/ mice/rabbit/dog) plasma. Samples are taken at fixed time points and the percentage of remaining compound is determined by LC-MS/MS after protein precipitation.

When evaluated under such conditions, compounds of the invention display a half-life in human plasma that is inferior to 60 minutes. Preferred compounds display a half-life in human plasma that is inferior to 30 minutes. Most preferred compounds display a half-life in human plasma that is inferior to 15 minutes. Example data regarding stability in human plasma is hereby provided for selected compounds in the following table. Procaine (unstable reference) and Enalapril (stable reference) are included for comparison. Stability data is also provided for two art-known bisarylmaleimide derivatives, NVP-AEB071 and GF109203X.

# Cpd VA human

plasma

Procaine <10

Enalapril >100

1 45

3 5

5 5

7 25

10 < 5

25 9 # Cpd V/i human

plasma

31 < 5

34 <5

35 10

41 15

42 < 5

NVP-AEB071 * > 100

GF109203X** > 100

*: NVP-AEB071 was prepared according to the procedure described in J. Med. Chem. 2009, 52 (20), pp 6193-6196.

**: GF109203X was purchased from Tocris (structure shown below)

GF109203X NVP-AEB071

From these examples, it will be appreciated that compounds of the invention display low stability in human plasma and, by extension, low stability in human whole blood. More in particular, it will be appreciated that the compounds of the invention differ from the art- known bisarylmaleimides in that they are rapidly degraded in human plasma, while art- known bisarylmaleimide display high stability (t _/2>100') in human plasma.

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

A 1 μΜ solution of the compounds is incubated with a reaction mixture containing lung S9 (from smokers) as well as the cofactors NADPH, UDPGA, PAPS and GSH. Samples are collected at 0, 15, 30 and 60 minutes post incubation. Negative control samples incubated with PKC inhibitors and S9 fraction in the absence of cofactors are run in parallel. By using LC-MS/MS analysis, the percent of compounds remaining at each time point, the metabolic half-life of the compounds (expressed in minutes) and the metabolic half-life of the control compounds are determined. When evaluated under such conditions, selected compounds of the invention display a half-life in the lung S9 fraction that is superior to 60 minutes. Stability data is hereby provided for selected compounds. Ethoxyresorufin (stable ref) is included for comparison,

From this data, it will be appreciated that compounds of the invention display good stability in the human lungS9 fraction and, by extension, in human lung.

C.2.3. Stability assay in rabbit aqueous humor

Compounds are incubated at a concentration of 1 μΜ in rabbit aqueous humor (AH). Samples are taken at fixed time points and the remnant of compound is determined by LC-MS/MS after protein precipitation.

When evaluated under such conditions, selected compounds of the invention display a half-life in aqueous humor that is superior to 60 minutes. Preferred compounds display a half-life in aqueous humor that is superior to 120 minutes. Example data is hereby provided for selected compounds, which displays a half-life in rabbit aqueous humor that is superior to 120 minutes.

From this data, it will be appreciated that selected compounds of the invention display good stability in aqueous humor.

D. Soft PKC inhibitors for local treatment of PKC-associated diseases

D.1. Soft PKC inhibitor for the local treatment of lung diseases

From the data disclosed in points C.1 .1 , C.2.1 and C.2.2, it will be appreciated that compounds of the invention such as compound 10 simultaneously display inhibitory activity against PKC, good stability in lung and low stability in plasma. Such compounds therefore qualify as soft, locally acting PKC inhibitors for the treatment of lung diseases. Such compounds can be locally applied to lung by methods known in the art, such as (but not limited to) aerosols or dry powder inhalers, in order to modulate PKC activity in lung during a sustained period of time, typically several hours. Rapid degradation of such compounds in plasma / whole blood will however limit or prevent systemic PKC inhibition following administration.

D.2. Soft PKC inhibitor for the local treatment of eye diseases

From the data disclosed in points C.1 .1 , C.2.1 and C.2.3, it will be appreciated that compounds of the invention such as compounds 1 , 3 or 41 simultaneously display inhibitory activity against PKC, good stability in aqueous humor and low stability in plasma. Such compounds therefore qualify as soft, locally acting PKC inhibitors for the treatment of eye diseases. Such compounds can be locally applied to the eye by methods known in the art, such as (but not limited to) eye drops or intravitreal injections, in order to modulate PKC activity in the eye during a sustained period of time. Rapid degradation of such compounds in plasma / whole blood will however limit or prevent systemic PKC inhibition following administration.

Claims

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

Wherein

R¹ is hydrogen or Ci_-6alkyl;

Wherein

Wherein

each R⁵ is independently selected from Ci

m and n are each independently an integer from 0 to 2;

Wherein

R⁶ is Ci_-6alkyl optionally substituted with one or more substituents selected from hydroxyl or NR⁸R⁹;

each X is independently selected from -CH- or -N-;

Y is selected from -N-, -N(R¹²)-, or -O-;

wherein R¹² is hydrogen or Ci_-6alkyl;

E is -0-, -NH- or -CH₂-;

R¹¹ is selected from hydrogen or Ci_-6alkyl; and

R¹³ is hydrogen or halogen; provided that said com ound is not selected from the group consisting of

2. A compound of formula I wherein

R¹ is hydrogen or Ci_-6alkyl;

Wherein

in particular Het¹ is R² is selected from the group comprising hydrogen, Ci_-8alkyl, Ci_-8alkoxy, and halogen; and

Cy is selected from the group consisting of:

Wherein

each X is independently selected from -CH- or -N-;

Y is selected from -N-, -N(R¹²)-, or -O-;

wherein R¹² is hydrogen or Ci_-6alkyl;

E is -0-, -NH- or -CH₂-;

R¹¹ is selected from hydrogen or Ci_-6alkyl; and

3. A compound of formula I wherein

R¹ is hydrogen or Ci_-6alkyl;

Wherein

in particular Het¹ is ;

Cy is selected from the group consisting of:

in particular Cy is selected from the group consisting of:

Wherein

R⁷ is selected from hydrogen, Ci_-8alkyl, or C_3-8cycloalkyl, wherein said Ci_-8alkyl is optionally substituted with heteroaryl;

each X is independently selected from -CH- or -N-;

Y is selected from -N-, -N(R¹²)-, or -O-;

wherein R¹² is hydrogen or Ci_-6alkyl;

E is -0-, -NH- or -CH₂-;

R¹¹ is selected from hydrogen or Ci_-6alkyl; and

R¹³ is hydrogen or halogen;

provided that said com ound is not selected from the group consisting of

4. A compound of formula I wherein

R¹ is hydrogen or Ci_-6alkyl;

A is selected from the group comprising -C(=0)-0-R³, -C(=0)-NH-R⁴, and -N H-C(=0)-R⁴; Wherein

R⁴ is optionally substituted Ci_-8alkyl further substituted with one substituent selected from the group consisting of Het¹ , -O-Het¹, -NH-Het¹, -S-Het¹ , and - C(=0)-OR³; wherein Het¹ is selected from the roup consisting of:

in particular Het¹ is

Cy is selected from the group consisting of:

82

rticular C is selected from the group consisting of:

Wherein

8alkyl, and C₃-₈cycloalkyl; or

each X is independently selected from -CH- or -N-;

E is -0-, -NH- or -CH₂-;

R¹¹ and R¹² are each independently selected from hydrogen or Ci_-6alkyl;

R¹³ is hydrogen or halogen; and

o is an integer from 1 to 3;

provided that said compound is not selected from the group consisting of

5. A compound of formula I wherein

R¹ is hydrogen or methyl;

Wherein

in particular Het¹ is

R² is hydrogen or methyl; and Cy is selected from the group consisting of:

rticular C is selected from the group consisting of:

Wherein

R⁸ and R⁹ are independently selected from hydrogen and methyl;

each X is independently selected from -CH- or -N-;

E is -0-, -NH- or -CH₂-;

R¹¹ and R¹² are each independently selected from hydrogen or Ci_-6alkyl;

R¹³ is hydrogen or halogen; and

o is an integer from 1 to 3;

provided that said com ound is not selected from the group consisting of

6. A compound of formula I wherein

R¹ is hydrogen or methyl; in particular hydrogen;

A is selected from the group comprising -C(=0)-0-R³ and -C(=0)-NH-R⁴;

Wherein

and

in particular Het¹ is

R² is hydrogen or methyl; in particular hydrogen; and selected from the roup consisting of:

Wherein

R⁸ and R⁹ are independently selected from hydrogen and methyl;

each X is independently selected from -CH- or -N-; in particular X is -CH-;

o is an integer from 1 to 3; in particular 2;

provided that said com ound is not selected from the group consisting of

7. A compound according to claim 1 , wherein one or more of the following restrictions apply:

• R¹ is hydrogen or methyl; more in particular R¹ is hydrogen;

• A is selected from the group comprising -C(=0)-0-R³, -C(=0)-NH-R⁴, and -NH- C(=0)-R⁴; in particular A is selected from -C(=0)-0-R³ and -C(=0)-NH-R⁴;

• R³ is an optionally substituted group selected from Ci_-8alkyl, C_3-8alkenyl, and C_3- ₈alkynyl; in particular R³ is selected from C_3-8alkenyl, C_3-8alkynyl, and Ci_-8alkyl, wherein said Ci_-8alkyl, C_3-8alkenyl, and C_3-8alkynyl is optionally substituted with a substituent selected from the group comprising hydroxyl, cyano, C_3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, and NR¹⁴R¹⁵; more in particular R³ is selected from C_3-8alkenyl, C_3-8alkynyl, or Ci_-8alkyl, wherein said Ci_-8alkyl, C_3-8alkenyl, or C_3- ₈alkynyl is optionally substituted with a substituent selected from the group comprising hydroxyl, cyano, C_3-6cycloalkyl, pyrrolidinyl, oxolanyl, phenyl, pyrydinyl, Ci_-6alkoxy, and NR¹⁴R¹⁵;

• R³ is C_3-8alkenyl, C_3-8alkynyl, or optionally substituted Ci_-8alkyl; in particular R³ is C_3-8alkenyl, C_3-8alkynyl, or optionally substituted Ci_-8alkyl, wherein said Ci_-8alkyl is optionally substituted with a substituent selected from the group comprising hydroxyl, cyano, C_3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, and NR¹⁴R¹⁵; more in particular R³ is selected from C_3-8alkenyl, C_3-8alkynyl, or Ci_-8alkyl, wherein said Ci_-8alkyl is optionally substituted with a substituent selected from the group comprising hydroxyl, cyano, C_3-6cycloalkyl, pyrrolidinyl, oxolanyl, phenyl, pyrydinyl, Ci_-6alkoxy, and NR¹⁴R¹⁵;

• R⁴ is optionally substituted Ci_-8alkyl further substituted with one substituent selected from the group consisting of Het¹, -O-Het¹, -NH-Het¹, -S-Het¹, and - C(=0)-OR³; in particular R⁴ is C_1-8alkyl further substituted with -S-Het¹ or -NH- C(=0)-OR³; Het¹ is selected from the roup consisting of:

in particular Het¹ is

• R² is selected from the group comprising hydrogen, Ci_-8alkyl, Ci_-8alkoxy, and halogen; in particular R² is selected from the group comprising hydrogen, methyl, methoxy, and halogen; more in particular R² is hydrogen;

• Cy is selected from the group consisting of:

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in particular C is selected from the group consisting of:

• R⁷ is selected from the group comprising hydrogen, Ci_-8alkyl, C_3-8cycloalkyl, and alkylheteroaryl; in particular R⁷ is selected from methyl and methylpiridinyl; more in particular, R⁷ is selected from methyl;

• Y is selected from -N-, -N(R¹²)-, or -0-;

• E is -0-, -NH- or -CH₂-;

• R¹³ is hydrogen or halogen; in particular R¹³ is hydrogen or chloro.

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

9. A composition comprising a compound as defined in any one of claims 1 to 5, suitable for use as a human or veterinary medicine.

10. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of at least one disease or disorder in which Proteine Kinase C's (PKCs) are involved.

1 1. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of at least one disease or disorder associated with the activation of T-cells or B-cells in a patient.

12. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of at least one immunological disorders or inflammatory diseases.

13. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of at least one disease of disorder selected from the group comprising inflammatory eye diseases; inflammatory airway diseases; rheumatoid arthritis; skin diseases; organ transplant rejection or allergy; and intestinal inflammatory diseases.

14. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of an inflammatory eye disease such as, but not limited to, uveitis; conjunctivitis; contact allergy; retinopathy; or post- trauma/post-surgery/post-laser treatment complications including corneal transplant rejection.

15. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of a skin disease such as, but not limited to, contact dermatitis and psoriasis.

16. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of an intestinal inflammatory disease such as, but not limited to, ulcerative colitis; inflammatory bowel disease; and Crohn's disease.

17. Use of a compound as defined in any one of claims 1 to 7, or a composition as defined in claim 9, suitable for inhibiting the activity of a kinase, in particular a Proteine Kinase C (PKC).

18. Use of a compound as defined in any one of claims 1 to 7, or a composition as defined in claim 9 for the prevention and/or treatment of at least one disease or disorder in which PKCs are involved.

19. A method for the prevention and/or treatment of at least one disease or disorder in which PKCs are involved; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in any one of claims 1 to 7, or a composition as defined in claim 9.

20. A method for the prevention and/or treatment of at least one disease or disorder in which PKCs are involved; said method comprising locally administering to a subject in need thereof a therapeutic effective amount of a compound as defined in any one of claims 1 to 7, or a composition as defined in claim 9.