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WO 2013/037390 Al R (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/037390 Al 21 March 2013 (21.03.2013) P O P C T (51) International Patent Classification: (74) Agent: WINGEFELD, Renate; c/o Sanofi-Aventis C07D 471/04 (2006.01) A61P 9/00 (2006.01) Deutschland GmbH, Patents Germany, Industriepark A61K 31/437 (2006.01) A61P 25/00 (2006.01) Hochst, Geb. K 801, 65926 Frankfurt (DE). A61P 3/10 (2006.01) A61P 35/00 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/EP201 1/065715 AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 12 September 201 1 (12.09.201 1) HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (26) Publication Language: English OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (71) Applicant (for all designated States except US): SANOFI SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, [FR/FR]; 54, rue de la Boetie, F-75008 Paris (FR). TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors; and (84) Designated States (unless otherwise indicated, for every (75) Inventors/Applicants (for US only): LOEHN, Matthias kind of regional protection available): ARIPO (BW, GH, [DE/DE]; c/o Sanofi-Aventis Deutschland GmbH, 65926 GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, Frankfurt am Main (DE). MENDEZ-PEREZ, Maria ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, [ES/DE]; c/o Sanofi-Aventis Deutschland GmbH, 65926 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Frankfurt am Main (DE). PFEIFFER-MAREK, Stefania EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, [DE/DE]; c/o Sanofi-Aventis Deutschland GmbH, 65926 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Frankfurt am Main (DE). KANNT, Aimo [DE/DE]; c/o TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Sanofi-Aventis Deutschland GmbH, 65926 Frankfurt am ML, MR, NE, SN, TD, TG). Main (DE). BEGIS, Guillaume [FR/FR]; c/o Sanofi, De- Declarations under Rule 4.17: partement Brevets, 174, Avenue de France, F-75013 Paris — of inventorship (Rule 4.17(iv)) (FR). JEANNOT, Frederic [FR/FR]; c/o Sanofi, Departe- ment Brevets, 174, Avenue de France, F-75013 Paris (FR). Published: DUCLOS, Olivier [FR/—]; c/o Sanofi, Departement Brev ets, 174 Avenue de France, F-75013 Paris (FR). — with international search report (Art. 21(3)) (54) Title: 6-(4-HYDROXY-PHENYL)- 3-STYRYL-lH-PYRAZOLO[3,4-B]PYRIDINE-4-CARBOXYLIC ACID AMIDE DE- RIVATIVES AS KINASE INHIBITORS R (I) o © o (57) Abstract: The present invention relates to pyrazolo[3,4-b]pyridine compounds of the formula I, in which R 1, R2, R3, R4 and R5 are defined as indicated below. The compounds of the formula I are kinase inhibitors, and are useful for the treatment of diseases as - sociated with diabetes and diabetic complications, such as, diabetic nephropathy, diabetic neuropathy and diabetic retinopathy, for o example. The invention furthermore relates to the use of compounds of the formula I, in particular as active ingredients in pharma - ceuticals, and pharmaceutical compositions comprising them. 6-(4-Hydroxy-phenyl)-3-styryl-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors The present invention relates to pyrazolo[3,4-b]pyridine compounds of the formula I, in which R , R2, R3, R4 and R5 are defined as indicated below. The compounds of the formula I are kinase inhibitors, and are useful for the treatment of diseases associated with diabetes and diabetic complications, e.g., diabetic nephropathy, diabetic neuropathy and diabetic retinopathy, for example. The invention furthermore relates to the use of compounds of the formula I, in particular as active ingredients in pharma ceuticals, and pharmaceutical compositions comprising them. Protein kinase C (PKC) comprises a family of several related isoenzymes that function as serine/threonine kinases. PKC plays an important role in intercellular and intra cellular signaling, gene expression, and in the control of cell differentiation and growth. Currently, at least ten isoforms of PKC are known which are different in regulation, tissue distribution, and enzymatic specificity (Newton AC. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J 2003; 370(Pt 2):361-371 ; Newton AC. Protein kinase C : poised to signal. Am J Physiol Endocrinol Metab 201 0 ; 298(3): E395-E402; Nishizuka Y. Studies and prospectives of the protein kinase c family for cellular regulation. Cancer 1989; 63(1 0): 1892-1 903; Nishizuka Y. The Albert Lasker Medical Awards. The family of protein kinase C for signal transduction. JAMA 1989; 262(1 3): 1826-1 833). The PKC family of isoenzymes are grouped into three subclasses based on the domain composition of the regulatory moiety: ( 1 ) conventional PKCs (alpha, beta-ll, and beta-l), (2) novel PKCs (delta, epsilon, gamma, eta and theta) and (3) atypical PKCs (zeta and iota/lambda) (Newton AC. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J 2003; 370(Pt 2):361 -371 ; Mellor H , Parker PJ. The extended protein kinase C superfamily. Biochem J 1998; 332 ( Pt 2):281 -292). PKC is a mem brane-associated enzyme that is regulated by several distinct factors, such as mem brane phospholipids, calcium, and membrane lipids, e.g. diacylglycerol (Newton AC. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J 2003; 370(Pt 2):361 -371 ; Newton AC. Protein kinase C : poised to signal. Am J Physiol Endocrinol Metab 2010; 298(3): E395-E402; Mellor H , Parker PJ. The extended protein kinase C superfamily. Biochem J 1998; 332 ( Pt 2):281 -292; Kishi- moto A , Kikkawa U, Ogita K , Shearman MS, Nishizuka Y. The protein kinase C family in the brain: heterogeneity and its implications. Ann N Y Acad Sci 1989; 568: 181-1 86; Nishizuka Y. Calcium, phospholipid turnover and transmembrane signalling. Philos Trans R Soc Lond B Biol Sci 1983; 302(1 108): 10 1- 1 12.). All PKC isoforms have an autoinhibitory pseudosubstrate sequence that is N-terminal to the C 1 domain, which functions as a diacylglycerol sensor. Atypical PKCs have a diacylglycerol non- responsive C 1 domain. Conventional PKCs have a C2 domain that serves as a Ca2+- regulated phospholipid-binding module. The C2 domain in novel PKCs binds neither Ca2+ nor membrane phospholipids. Based on the structural differences conventional PKCs require membrane phospholipids, calcium and diacylglycerol for complete activation. Novel PKCs do not require calcium but diacylglycerol for activation. The zeta and iota/lambda forms of PKC are independent of both calcium and diacylglycerol for their activation (Newton AC. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J 2003; 370(Pt 2):361 -371 ; Newton AC. Lipid activation of protein kinases. J Lipid Res 2009; 50 Suppl:S266-S271 ) . PKC is involved in the regulation of smooth muscle contractility. Upon stimulation PKC phosphorylates the regulatory myosin light chain (MLC20) and inhibits the myosin associated phosphatase (MYPT). Phosphorylation of MLC20 and inhibition of MYPT leads to an increased activity of the acto-myosin complex and to vasoconstriction in different vascular beds, e.g. resistance-sized, retinal, cerebral, coronary, conduit arteries and veins (Merkel LA, Rivera LM, Colussi DJ, Perrone MH. Protein kinase C and vascular smooth muscle contractility: effects of inhibitors and down-regulation. J Pharmacol Exp Ther 1991 ; 257(1 ) :134-1 40; Sehic E , Malik KU. Influence of protein kinase C activators on vascular tone and adrenergic neuroeffector events in the isolated rat kidney. J Pharmacol Exp Ther 1989; 251 (2):634-639.). Overexpressed or overactivated PKC detrimentally affects heart function. Upon acti vation PKC affects the intracellular calcium homeostasis which results in reduced myo cardial contractility and relaxation of the myocardium. Overall this effect leads to myo cardial contractile insufficiency (Connelly KA, Kelly DJ, Zhang Y, Prior DL, Advani A , Cox AJ, Thai K , Krum H , Gilbert RE. Inhibition of protein kinase C-beta by ruboxi- staurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circ Heart Fail 2009; 2(2): 129-1 37). Moreover, activated PKC mediates organ damage during end-organ injuries, e.g. during ischemia in heart (Connelly KA, Kelly DJ, Zhang Y, Prior DL, Advani A , Cox AJ, Thai K , Krum H , Gilbert RE. Inhibition of protein kinase C-beta by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circ Heart Fail 2009; 2(2): 129-1 37; Hambleton M , Hahn H , Pleger ST, Kuhn MC, Klevitsky R , Carr AN, Kimball TF, Hewett TE, Dorn GW, Koch WJ, Molkentin JD. Pharmacological- and gene therapy-based inhibition of protein kinase Calpha/beta enhances cardiac contractility and attenuates heart failure. Circulation 2006; 114(6): 574-582) or kidney (Tuttle KR. Protein kinase C-beta inhibition for diabetic kidney disease. Diabetes Res Clin Pract 2008; 82 SuppI 1:S70-S74; Anderson PW, McGill JB, Tuttle KR.
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