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Fused Nitrogen Containing Heterocycles And (19) TZZ ¥ZZ_T (11) EP 2 300 469 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 471/04 (2006.01) C07D 487/04 (2006.01) 24.06.2015 Bulletin 2015/26 A61K 31/4985 (2006.01) A61K 31/4353 (2006.01) A61P 37/00 (2006.01) (21) Application number: 09747213.8 (86) International application number: (22) Date of filing: 07.05.2009 PCT/US2009/043073 (87) International publication number: WO 2009/140128 (19.11.2009 Gazette 2009/47) (54) FUSED NITROGEN CONTAINING HETEROCYCLES AND COMPOSITIONS THEREOF AS KINASE INHIBITORS KONDENSIERTE STICKSTOFF ENTHALTENDE HETEROZYKLEN SOWIE ZUSAMMENSETZUNGEN DAVON ZUR VERWENDUNG ALS KINASE INHIBITOREN HÉTÉROCYCLES CONDENSÉS AZOTÉS ET LEURS COMPOSITIONS COMME INHIBITEURS DE KINASE (84) Designated Contracting States: •FAN,Yi AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Poway HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL CA 92064 (US) PT RO SE SI SK TR • RUCKER, Paul, Vincent Designated Extension States: Carlsbad AL BA RS CA 92010 (US) • WANG, Zhicheng (30) Priority: 13.05.2008 US 52879 P San Diego 16.02.2009 US 152872 P CA 92130 (US) (43) Date of publication of application: (74) Representative: Bailey, Sam Rogerson et al 30.03.2011 Bulletin 2011/13 Mewburn Ellis LLP City Tower (73) Proprietor: Novartis AG 40 Basinghall Street 4056 Basel (CH) London EC2V 5DE (GB) (72) Inventors: (56) References cited: • ALBAUGH, Pamela, A. WO-A-01/00213 US-A1- 2007 093 490 Carlsbad CA 92009 (US) Remarks: • CHOI, Ha-Soon Thefile contains technical information submitted after San Diego the application was filed and not included in this CA 92128 (US) specification • CHOPIUK, Gregory Vancouver, Bristish Columbia V6G 1T9 (CA) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 300 469 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 300 469 B1 Description CROSS-REFERENCE TO RELATED APPLICATIONS 5 [0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 61/052,879, filed May 13,2008 and U.S. Provisional Patent Application No. 61/152,872, filed February 16, 2009. FIELD OF THE INVENTION 10 [0002] The invention relates to protein kinase inhibitors, and methods of using such compounds. BACKGROUND OF THE INVENTION [0003] Protein kinases (PK) are a large set of structurally related phosphoryl transferases having highly conserved 15 structures and catalytic functions. Protein kinases are enzymatic components of the signal transduction pathways which catalyze the transfer of the terminal phosphate from ATP to the hydroxy group of tyrosine, serine and/or threonine residues of proteins, and are therefore categorized into families by the substrates they phosphorylate: Protein Tyrosine Kinases (PTK), and Protein Serine/Threonine Kinases. [0004] Protein kinases play a critical role in the control of cell growth and differentiation and are responsible for the 20 control of a wide variety of cellular signal transduction processes, wherein protein kinases are key mediators of cellular signals leading to the production of growth factors and cytokines. The overexpression or inappropriate expression of normal or mutant protein kinases plays a significant role in the development of many diseases and disorders including, central nervous system disorders such as Alzheimer’s, inflammatory disorders such as arthritis, bone diseases such as osteoporosis, metabolic disorders such as diabetes, blood vessel proliferative disorders such as angiogenesis, autoim- 25 mune diseases such as rheumatoid arthritis, ocular diseases, cardiovascular disease, atherosclerosis, cancer, throm- bosis, psoriasis, restenosis, schizophrenia, pain sensation, transplant rejection and infectious diseases such as viral, and fungal infections. [0005] Examples of protein-tyrosine kinases include, but are not limited to, Irk, IGFR-1, Zap-70, Bmx, Btk, CHK (Csk homologous kinase), CSK (C-terminal Src Kinase), Itk-1, Src (c-Src, Lyn, Fyn, Lck, Syk, Hck, Yes, Blk, Fgr and Frk), 30 Tec, Txk/Rlk, Abl, EGFR (EGFR-1/ErbB-1, ErbB-2/NEU/HER-2, ErbB-3 and ErbB-4), FAK, FGF1R (also FGFR1 or FGR-1), FGF2R (also FGR-2), MET (also Met-I or c-MET), PDGFR ( α and β), Tie-1, Tie-2 (also Tek-1 or Tek), VEGFR1 (also FLT-1), VEGFR2 (also KDR), FLT-3, FLT-4, c-KIT, JAK1, JAK2, JAK3, TYK2, LOK, RET, TRKA, TRKB, TRKC, PYK2, ALK (Anaplastic Lymphoma Kinase), EPHA (1-8), EPHB (1-6), RON, Ros, Fes, Fer or EPHB4 (also EPHB4-1). [0006] Examples of protein-serine/threonine kinases include, but are not limited to, Ark, ATM (1-3), CamK (1-IV), 35 CamKK, Chk1 and 2 (Checkpoint kinases), CKI, CK2, Erk, IKK-I (also IKK-ALPHA or CHUK), IKK-2 (also IKK-BETA), Ilk, Jnk (1-3), LimK (1 and 2), MLK3Raf (A, B and C), CDK (1-10), PKC (including all PKC subtypes), Plk (1-3), NIK, Pak (1-3), PDK1, PKR, RhoK, RIP, RIP-2, GSK3 α( and β), PKA, P38, Erk (1-3), PKB (including all PKB subtypes) (also AKT-1, AKT-2, AKT-3 or AKT3-1), IRAK1, FRK, SGK, TAK1 or Tp1-2 (also COT). [0007] US20070093490 relates to substituted imidazopyridazines as inhibitors of kinases. 40 SUMMARY OF THE INVENTION [0008] Provide herein are compounds and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors. 45 [0009] In one aspect, the present invention provides compounds having Formula (I), and the pharmaceutically accept- able salts, and pharmaceutically acceptable solvates (e.g. hydrates) thereof: 50 55 2 EP 2 300 469 B1 wherein: R1 is 5 10 wherein, X1 and X2 are both N and X3 and X4 are both C 15 k is 1, 2, or 3; each R3 is phenyl optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C8alkyl and halo-substituted-C1-C8alkyl; 2 R is C6-C14aryl, C2-C13heteroaryl or C2-C14heterocycloalkyl, wherein the C6-C14aryl, C2-C13heteroaryl 2 or C2-C14heterocycloalkyl of R are optionally substituted with 1 to 3 substituents independently se- 20 lected from halogen, C2-C14heterocycloalkyl, C2-C13heteroaryl, C1-C8alkyl, C3-C8cycloalkyl, -CN, 4 4 4 4 4 9 9 9 4 6 6 1 5 -C(O)N(R )2, -N(R )C(O)OR ,-N(R )C(O)R , -C(O)R , -OR , -C(O)OR , -N(R )2, -R , -OR , -L R , 1 6 1 5 1 6 9 4 4 4 9 -L R , -YR ,-Y R , -S(O)2R , -S(O)2N(R )2, -NRS(O)2R , -OC(O)R, C1-C8alkoxy, hydroxyl- C1-C8alkyl, halo-substituted C1-C8alkyl and halo-substituted C1-C8alkoxy; 4 1 5 1 1 8 each R is independently selected from H, C1-C8 alkyl, -L R , -L R6, -L R , C2-C13heteroaryl, C6-C14aryl, 25 C2-C14heterocycloalkyl and 3-CC 8cycloalkyl, wherein the 1-CC8alkyl, C2-C13heteroaryl and C3-C8cycloalkyl are optionally substituted with 1 to 3 substituents independently selected from halogen, 9 9 9 9 deuterium, -CD3, -S(O)2R , -CN, C1-C8alkyl, -OR , -N(R )2 and -(CH2)pOR ; 1 9 L is a bond,1-C 8alkylene,C 2-CC8alkenylene, -O(CH2)p-, -C(O)-, )-, -N(R (CH2)pC(O)-,-C(O)(CH2)pO(CH2)p- or -C(O)O-; 30 1 Y is 6C-C14arylene, 2C-C13heteroarylene, 3C-C8cycloalkylene, 2C-C14heterocycloalkylene or C1-C8alkoxylene, each of which is optionally substituted with 1 to 3 substituents independently selected from halogen, 2C-C14heterocycloalkyl, C2-C13heteroaryl, C1-C8alkyl, C3-C8cycloalkyl, -CN, - 4 4 4 4 4 9 9 9 4 6 6 1 5 C(O)N(R )2, -N(R )C(O)OR , -N(R )C(O)R , -C(O)R , -OR , -C(O)OR , - N(R )2, -R , -OR , -L R , 1 6 1 5 1 6 9 4 4 2 4 9 -L R , -Y R , -Y R , -S(O)2R , -S(O)2N(R )2, - NRS(O) R , -OC(O)R , C1-C8alkoxy, hydroxyl- 35 C1-C8alkyl, halo-substituted C1-C8alkyl and halo-substituted C1-C8alkoxy; 5 9 9 9 9 R is C6-C14aryl, C2-C13heteroaryl, C2-C14heterocycloalkyl, -N(R)2, -N(R)C(O)R ,-C(O)N(R )2, 9 9 -(CH2)pOR or -OR . 6 7 7 R is C6-C14aryl, C2-C13heteroaryl, C2-C14heterocycloalkyl, -OCH(R)2, -C(O)R, C1-C8alkyl, or C3-C8cycloalkyl, wherein the 1-CC8alkyl, C3-C8cycloalkyl, C6-C14aryl, C2-C13heteroaryl, and 40 6 C2-C14heterocycloalkyl of R are optionally substituted with 1 to 3 substituents independently selected 9 9 1 8 1 8 1 5 9 9 9 from halogen, -CN,-OR, -(CH2)pOR ,-L C(O)R , -L R , -L R , -C(O)R , -OC(O)R , -C(O)OR , 8 4 9 9 9 4 4 4 4 -C(O)R , OC(O)N(R )2, -N(R )2, -C(O)C(O)OR ,-(CH 2)pN(R )2, -N(R )2, -C(O)N(R )2, -N(R )C(O)R , 4 4 9 9 4 4 4 4 9 N(R )C(O)OR , -(CH2)pS(O)2R , -S(O)2R , -S(O)2N(R )2, -NRS(O)2R ,-NR S(O)2R , C2-C14heterocycloalkyl, C2-C13heteroaryl, C1-C8alkyl, C2-C8alkene, C1-C8alkoxy, hydroxyl-substitut- 45 ed C1-C8alkyl, halo-substituted C1-C8alkyl and halo-substituted C1-C8alkoxy; 6 or R is C6-C14aryl, C1-C13heteroaryl, C2-C14heterocycloalkyl or C3-C8cycloalkyl having a C 1-C4alkyl bridge; 6 or R is a C 2-C14heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected 9 9 1 8 1 8 1 5 9 9 9 from halogen, =O, -CN,-OR , -(CH2)pOR , -L C(O)R , -L R , -L R , -C(O)R , -OC(O)R , -C(O)OR , 50 8 4 9 9 9 4 4 4 -C(O)R , OC(O)N(R )2, -N(R )2,-C(O)C(O)OR , -(CH2)pN(R )2, -N(R )2, -C(O)N(R )2, -N(R )C(O)R 4 4 4 9 9 4 4 4 4 9 ,-N(R )C(O)OR , -(CH2)pS(O)2R , -S(O)2R , -S(O)2N(R )2, -NRS(O)2R , NRS(O)2R , C2-C14heterocycloalkyl, C1-C13heteroaryl, C1-C8alkyl, C2-C8alkene, C1-C8alkoxy, hydroxyl-substitut- ed C1-C8alkyl, halo-substituted C1-C8alkyl and halo-substituted C1-C8alkoxy; 7 1 8 each R is independently selected from H, C1-C8alkyl and -L R ; 55 8 9 4 9 R is H, -N(R )2, -N(R )2, -SR , -CN, C1-C8alkyl, C3-C8cycloalkyl and C2-C14heterocycloalkyl, wherein 8 the C1-C8alkyl, C3-C8cycloalkyl and C2-C14heterocycloalkyl of R are optionally substituted with 1 to 9 9 1 8 3 substituents independently selected from halogen, C 1-C6alkyl, -CN,-OR , -(CH2)pOR ,-L C(O)R ,- 9 9 9 9 4 4 4 4 4 4 C(O)R , -OC(O)R, -C(O)OR, -N(R)2, -N(R)2, -C(O)N(R)2,-N(R )C(O)R , -N(R)C(O)OR , 3 EP 2 300 469 B1 9 4 4 -S(O)2R , -S(O)2N(R )2, and -NR S(O)2; 9 each R is independently selected from H, C3-C8cycloalkyl and C1-C8alkyl, and each p is independently 1, 2, 3, 4, 5 or 6.
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