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2010286569 C1 (19) Australian Patent 0Ffice (12) STANDARD PATENT (11) Application No. AU 2010286569 C1 (19) AUSTRALIAN PATENT 0FFICE (54) Title Compounds and compositions as protein kinase inhibitors (51) International Patent Classification(s) C07D 401/14 (2006.01) A61P 35/00 (2006.01) A61K 31/506 (2006.01) C07D 403/04 (2006.01) (21) Application No: 2010286569 (22) Date of Filing: 2010.08.27 (87) WIPO No: WO11/025927 (30) Priority Data (31) Number (32) Date (33) Country 61/313,039 2010.03.11 US 61/238,073 2009.08.28 US (43) Publication Date: 2011.03.03 (44) Accepted Journal Date: 2013.10.10 (44) Amended Journal Date: 2019.11.28 (71) Applicant(s) Array BioPharma, Inc (72) Inventor(s) Huang, Shenlin;Jin, Xianming;Liu, Zuosheng;Poon, Daniel;Tellew, John E.;Wan, Yongqin;Wang, Xing;Xie, Yongping (74) Agent / Attorney Allens Patent & Trade Mark Attorneys, Deutsche Bank Place Corner Hunter and Phillip Streets, SYDNEY, NSW, 2000, AU (56) Related Art CAS Registry Number 27761-65-5; Entered STN: 16 November 1984; 2,4- Dibromo-3,6-dichloroaniline, (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization llllllllllllllllllllllllllllllhlllllllll International Bureau (10) International Publication Number (43) International Publication Date WO 2011/025927 Al 3 March 2011 (03.03.2011) PCT (51) International Patent Classification: (74) Agents: REID, Scott et al.; Genomics Institute of the No­ C07D 401/14 (2006.01) A61K31/506 (2006.01) vartis, Research Foundation, 10675 John Jay Hopkins C07D 403/04 (2006.01) A61P 35/00 (2006.01) Drive, San Diego, California 92121 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US2010/046930 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) International Filing Date: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 27 August 2010 (27.08.2010) DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (26) Publication Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (30) Priority Data: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 61/238,073 28 August 2009 (28.08.2009) US SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 61/313,039 11 March 2010 (11.03.2010) US TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicants (for all designated States except US): IRM (84) Designated States (unless otherwise indicated, for every LLC [US/—]; 131 Front Street, Hamilton, HM LX (BM). kind of regional protection available): ARIPO (BW, GH, NOVARTIS AG [CH/CHJ; Lichtstrasse 35, CH-4056 GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, Basel (CH). ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Ill (75) Inventors/Applicants (for US only): HUANG, Shcnlin LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, [CN/US]; 5768 Cape Jewels Trail, San Diego, California SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, III 92130 (US). JIN, Xianming [US/US]; 3516 Sleeping GW, ML, MR, NE, SN, TD, TG). Illi Meadow Way, San Ramon, California 94582 (US). LIU, III Zuosheng [CN/US]; 10280 Camino Ruiz, Apartment No. Declarations under Rule 4.17: 45, San Diego, California 92121 (US). POON, Daniel — as to applicant's entitlement to apply for and be granted Illi [US/US]; 54 Lake Avenue, Piedmont, California 94611 a patent (Rule 4.17(1()) ΙΙΙΙΙΙΙΙΙΙΗ (US). TELLEW, John [US/US]; 1340 Caminito Balada, — as to the applicant's entitlement to claim the priority of La Jolla, California 92037 (US). WAN, Yongqin the. earlier application (Rule 4.17(iii)) [CN/US]; 19 Santa Eugenia, Irvine, California 92026 (US). WANG, Xing [CN/US]; 16152 Avenida Venusto, Published: No. 4, San Diego, California 92128 (US). XIE, Yongping — with international search report (Art. 21(3)) [US/US]; 12596 Brickella Street, San Diego, California 92129 (US). (54) Title: COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS Compound 9 + Compound A3 ιν ζ,Ζ65ίθ/ιιθί Figure 1 (57) Abstract: The invention provides a novel class of compounds of formula 1, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulat­ OAk ed kinase activity, particularly diseases or disorders that involve abnormal activation of B-Raf. WO 2011/025927 PCT/US2010/046930 COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Patent Applications 61/238,073, filed 28 August 2009 and 61/313,039, filed 11 March 2010. The full disclosures of these applications are incorporated herein by reference in their entirety and for all purposes. BACKGROUND OF THE INVENTION Field of the Invention [0002] The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of B-Raf. Background [0003] The protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function. A partial, non-limiting, list of these kinases include: receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGF-R), the nerve growth factor receptor, trkB, Met, and the fibroblast growth factor receptor, FGFR3; non-receptor tyrosine kinases such as Abl and the fusion kinase BCR-Abl, Lek, Csk, Fes, Bmx and c-src; and serine/threonine kinases such as B-Raf, sgk, MAP kinases (e.g., MKK4, MKK6, etc.) and SAPK2oc, ΞΑΡΚ2β and SAPK3. Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems. [0004] The novel compounds of this invention inhibit the activity of B-Raf or mutant forms thereof (for example V600E) and are, therefore, expected to be useful in the treatment of B-Raf-associated diseases. WO 2011/025927 PCT/US2010/046930 SUMMARY OF THE INVENTION [0005] In one aspect, the present invention provides compounds of Formula I: [0006] in which: [0007] Y is selected from N and CRb: [0008] Ri is selected from hydrogen, -XiR8a, -X|OX2R8a, -XiC(O)NR8aR8b, - XiNR8aX2R8b, -X1NR8aC(O)X2OR8b, -XiNR8aC(O)X2NR8aR8b, -XiNR8aS(O)0_2R8b; wherein each Xi is independently C^alkylene; and Xi optionally has 1 to 3 hydrogens replaced with a group selected from hydroxy, halo, cyano, Ci_4alkyl, halo-substituted-Ci_4alkyl, Ci_4alkoxy and halo-substituted-Ci_4alkoxy; X2 is selected from a bond and Ci_4alkylene; wherein R8a and R8b are independently selected from hydrogen, Ci_6alkyl, halo-substituted-Ci_6alkyl, CY 8cycloalkyl, heteroaryl and C3_8heterocycloalkyl; wherein the cycloalkyl, heterocycloalkyl or heteroaryl of R8a or R8b is optionally substituted with 1 to 3 radicals independently selected from amino, cyano, Ci_4alkyl, Ci_4alkoxy, halo-substituted-Ci_4alkyl and halo-substituted-Cp 4alkoxy; with the proviso that R8b is not hydrogen when R i is selected from - XiNHC(O)OR8b and -XiNR8aS(O)0.2R8b; [0009] R2, R3, R5 and Rb are independently selected from hydrogen, halo, cyano, Ci_4alkyl, halo-substituted-Ci_4alkyl, Ci-4alkoxy and halo-substituted-Ci-4alkoxy; with the proviso that when R5 is fluoro and Rj is selected from hydrogen, -XiR8a, X|OX2R8;I, - XiC(O)NR8aR8b, -X!NR8aX2R8b, -XiNR8aC(O)X2OR8b and -XiNR^OkzRsb, R3 and R6 are not both hydrogen; [0010] R4 is selected from -R9 and -NR10R11; wherein R9 is selected from Ci_ r.alkyl, C3_8cycloalkyl, C3_8heterocycloalkyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R9 is optionally substituted with 1 to 3 WO 2011/025927 PCT/US2010/046930 radicals independently selected from halo, cyano, Ci^alkyl, halo-substituted-Ci_4alkyl, Ci_ 4alkoxy and halo-substituted-Ci.4alkoxy; and Ri0 and Rn are independently selected from hydrogen and R9; [0011] R7 is selected from hydrogen, Ci-4alkyl, C vscycloalkyl and C3- sheterocycloalkyl; wherein said alkyl, cycloalkyl or heterocycloalkyl of R7 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, hydroxyl, Ci^alkyl, halo-substituted-Ci_4alkyl, Ci_4alkoxy andhalo-substituted-Ci_4alkoxy; and the N-oxide derivatives, piodrug derivatives, protected derivatives, the tautomers, individual isomers and mixture of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds. [0012] In a second aspect, the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients. [0013] In a third aspect, the present invention provides a method of treating a disease in an animal in which inhibition of kinase activity, particularly B-Raf activity, can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof. [0014] In a fourth aspect, the present invention provides the use of a compound of Formula I in the manufacture of a medicament for treating a disease in an animal in which kinase activity, particularly B-Raf activity, particularly mutant B-raf (for example V600E), contributes to the pathology and/or symptomology of the disease.
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