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WO 2013/004709 Al 10 January 2013 (10.01.2013) P O P C T

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WO 2013/004709 Al 10 January 2013 (10.01.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/004709 Al 10 January 2013 (10.01.2013) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, C07D 401/14 (2006.01) C07D 471/04 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, C07D 403/14 (2006.01) A61K 31/4015 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C07D 405/14 (2006.01) A61K 31/404 (2006.01) HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/EP2012/06295 1 OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (22) International Filing Date: SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 4 July 2012 (04.07.2012) TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 1111427.9 5 July 201 1 (05.07.201 1) GB TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant (for all designated States except US): MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, AMAKEM NV [BE/BE]; Life Sciences Incubator, Agora- TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, laan A bis, B-3590 Diepenbeek (BE). ML, MR, NE, SN, TD, TG). (72) Inventors; and Declarations under Rule 4.17: (75) Inventors/Applicants (for US only): LEYSEN, Dirk — as to applicant's entitlement to apply for and be granted a [BE/BE]; Life Sciences Incubator, Agoralaan A bis, B- patent (Rule 4.1 7(H)) 3590 Diepenbeek (BE). DEFERT, Olivier [FR/BE]; Life Sciences Incubator, Agoralaan A bis, B-3590 Diepenbeek — as to the applicant's entitlement to claim the priority of the (BE). BOLAND, Sandro [BE/BE]; Life Sciences Incubat earlier application (Rule 4.1 7(in)) or, Agoralaan A bis, B-3590 Diepenbeek (BE). — of inventorship (Rule 4.17(iv)) (74) Agent: LAENEN, Bart; LC Patents, Crutzenstraat 26, B- Published: 3500 Hasselt (BE). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, © o © (54) Title: INDOLYLMALEIMIDES AS SOFT PAN-PKC INHIBITORS (57) Abstract: The present invention relates to new kinase inhibitors, more specifically soft PKC inhibitors, compositions, in partic o ular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In par ticular, the present invention relates to new soft PKC inhibitors compositions, in particular pharmaceuticals, comprising such inhib - itors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treat o ment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications in cluding autoimmune and inflammatory diseases. 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 C 1 and C2. cPKCs contain a C 1 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 C 1 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 C 1 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.
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