Supporting Information. Discovery of MK-8033: A Specific c-met/ron Dual Kinase Inhibitor with Preferential Affinity for the Activated State of c-met.

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1 S 1 1 Supporting Information Discovery of MK-8033: A Specific c-met/ron Dual Inhibitor with Preferential Affinity for the Activated State of c-met. Alan B. Northrup, a* Matthew H. Katcher, a Michael D. Altman, b Melissa Chenard, c Matthew H. Daniels, a Sujal V. Deshmukh, d Danielle Falcone, a David J. Guerin, a Harold Hatch, e Chaomin Li, a Wei Lu, e Bart Lutterbach, e Timothy J. Allison, f Sangita B. Patel, f John F. Reilly, c Michael Reutershan, a Keith W. Rickert, f Craig Rosenstein, g Stephen M. Soisson, f Alexander A. Szewczak, g Deborah Walker, h Kevin Wilson, a Jonathan R. Young, a Bo-Sheng Pan, e and Christopher J. Dinsmore a Departments of Chemistry, Oncology, In Vitro Pharmacology, Modeling and Informatics, In Vivo Pharmacology, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, and Basic Pharmaceutical Sciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA Table of Contents Table S1. Profile of 12 Table S2. Profile of 11r Table S3. Profile of 13 Table S4. Profile of 14 Table S5. Profile of 5g Table S6. Profile of 11a Table S7. Profile of 15 Table S8. Profile of 16 Table S9. Profile of 11u Table S10. Profile of 11w Table S11. X-ray structure-determination statistics of 16 Table S12. GTL-16 Tumor Xenograft Efficacy Results Figure S1. Plasma entrations of 11r in the GTL-16 Tumor Xenograft Efficacy Study Table S13. Plasma entrations of 11r in the GTL-16 Tumor Xenograft Efficacy Study Characterization data for Compounds 5b-d, 11a-f, 11i-m, 11p-q, 11s, 11u-w S2 S3 S4 S5 S6 S8 S9 S10 S11 S12 S13 S14 S14 S15 S16

2 S 2 2 Table S1. Profile of 12 A single concentration (1 µmol/l) of 12 was tested using 209 kinases by Upstate Biotechnology, Inc. (Millipore). Data is reported as activity remaining relative to DMSO control. ENZYME PERCENT ACTIVITY ENZYME PERCENT ACTIVITY ENZYME PERCENT ACTIVITY ENZYME PERCENT ACTIVITY ALK 0 C-RAF 72 HIPK2 94 MAPK DRAK1 0 LIMK1 72 PAK4 94 NLK 103 TRKA 1 BMX 73 SGK3 94 PKCE 103 FLT3(D835Y) 2 ARG 74 SYK 94 FRK 104 MET 2 BRSK1 74 C-KIT(D816V) 95 MAPKAPK2 104 FGFR3 4 MAP3K7 75 PKCZ 95 NEK3 104 FGFR1 5 RPS6KA1 76 AKT3 96 PRKCB1 104 FLT1 5 RPS6KA3 76 CAMKII 96 SRPK2 104 AURKA 7 PDGFRB 77 CSNK1 96 MINK 105 FLT4 10 KIT 78 EPHA3 96 PDK1 105 KDR 10 STK10 78 SGK 96 PKCA 105 FGFR2 12 WNK3 78 EGFR(L861Q) 97 PKCB2 105 IRAK4 14 EPHA2 80 PRAK 97 PLK3 105 MST1R 14 STK4 80 TYRO3 97 CDK9 107 TRKB 15 JAK3 81 CDK2 98 CDC42BPA 107 ABL 16 LYN 81 ASK1 98 PRKG1A 107 AXL 17 RPS6KB1 81 CAMK4 98 ROCK1 107 ITK 18 BLK 83 CHK1 98 CDK6 108 RET 23 BTK 83 CSNK1D 98 DDR2 108 FLT3 26 IRAK1 83 EPHB3 98 EPHA8 108 HCK 33 STK23 83 IKK_ALPHA 98 MAPK2 108 MNK2 33 TSSK2 83 IKK_BETA 98 PKCI 108 ABL(T315I) 35 ERBB4 84 JNK1A1 98 AKT1 109 RIPK2 35 RPS6KA1 84 P38-DELTA 98 IR 109 MELK 38 CSFR 85 PIM2 98 PAK6 109 EGFR(L858R) 41 CSK 85 PAK3 99 PKA 109 DYRK2 42 GSK3A 86 ALK4 100 PRKD2 109 JAK2 43 DAPK3 87 EGFR 100 CDK2 110 ABL 44 MAP2K4 87 MAPK2 100 CAMK I 110 ARK5 48 SNF1LK 87 MAPKK1 100 GSK3B 110 MUSK 48 CDK5/P25 88 PAK2 100 PRKX 110 LCK 50 FGFR4 88 PKA 100 PRKG1B 111 JNK3 53 JNK2A2 88 PKCQ 100 NEK7 112 BRSK2 55 AKT2 89 CDK3 101 P38-ALPHA(T106M) 112 FER 56 TSSK1 89 CDK7 101 FES 113 MARK2 57 DAPK1 90 DMPK 101 P38-BETA 113 PLK2 58 FGR 90 EPHA7 101 SGK2 114 PDGFRA 59 ROCK2 90 IGF1R 101 HIPK1 116 MAP3K9 61 STK3 90 PAK7 101 CK2 117 MYLK 61 STK33 90 PIM1 101 MAP2K6 117 MARK1 62 DAPK2 91 PKCG 101 NEK FYN 64 PASK 91 PTK2B 101 MAPK1 120 EPHA1 65 PKCD 92 RPS6KA5 101 RPS6KA4 121 NEK2 65 PRK2 92 EPHA5 102 CK2 ALPHA CDK1 66 ROCK2 92 HIPK3 102 P38-ALPHA 124 RPS6KA2 66 ARG 93 MAPKAPK3 102 SRC 125 TEK 66 CDK5/P35 93 SRPK1 102 PKCET 126 EPHB1 67 CHK2 93 STK WNK2 126 LYN 69 EEF2K 93 BRK 103 ZAP MKK7B 69 NEK6 93 EPHA4 103 STK AMPK 70 PRKD1 93 EPHB2 103 ROS1 71 TBK1 93 EPHB4 103 YES 71 CDC42BPB 94 IRR 103

3 S 3 3 Table S2. Profile of 11r A single concentration (1 µmol/l) of 11t was tested using 221 kinases by Upstate Biotechnology, Inc. (Millipore) in duplicate. Data is expressed as reduction of the kinase activity in the presence of 1 µm 11t (MK-8033) relative to that observed in the presence of the vehicle. Follow-up 10-point titrations for the top off-target activities established the following IC 50 's: Mer IC 50 = 880 nm, Flt4 IC 50 = 920 nm, FGFR3 IC 50 = 1,000 nm, FGFR1 IC 50 = 1,700 nm, KDR IC 50 = 1,700 nm, Fes IC 50 >10,000 nm Enzyme name Enzyme name Enzyme name Enzyme name Enzyme name Met(h) Ron(h) Mer(h) Flt4(h) FGFR3(h) Fes(h) PDGFRα(D842V)(h) Aurora-A(h) FGFR1(V561M)(h) MKK6(h) FGFR1(h) Fms(h) MAPK2(h) JAK2(h) PKCγ(h) ARK5(h) Flt1(h) Flt3(D835Y)(h) IRR(h) DYRK2(h) PRK2(h) TrkA(h) JNK1α1(h) CK1γ2(h) Axl(h) PKCµ(h) MLK1(h) Rse(h) CHK2(h) KDR(h) PAR-1Bα(h) Arg(h) MST1(h) Rsk2(h) ckit(v560g)(h) IRAK4(h) LIMK1(h) PKBß(h) EGFR(T790M,L858R)(h) MuSK(h) CaMKIIγ(h) Abl(T315I)(h) BrSK1(h) JAK3(h) TBK1(h) 95 CK1γ3(h) 6 MSSK1(h) -2 WNK2(h) -8 CaMKIV(h) ckit(h) 6 SAPK4(h) -2 BrSK2(h) -9 CK2α2(h) PDGFRα(V561D)(h) 6 TAO2(h) -2 CDK9/cyclin T1(h) -9 Lyn(h) PKD2(h) 6 TSSK1(h) -2 eef-2k(h) -9 p70s6k(h) PKG1α(h) 6 EphA1(h) -3 NEK2(h) -9 PRAK(h) FGFR4(h) 5 FAK(h) -3 PhKγ2(h) -9 CaMKIδ(h) MELK(h) 5 HIPK1(h) -3 PKBα(h) -9 EphB1(h) PTK5(h) 5 PKCι(h) -3 PKCßI(h) -9 PKCθ(h) MARK1(h) 4 TSSK2(h) -3 CaMKI(h) -10 EGFR(h) MRCKß(h) 4 Yes(h) -3 CDK6/cyclinD3(h) -10 EphB3(h) ASK1(h) 3 BRK(h) -4 LOK(h) -10 MAPKAP-K2(h) CK1γ1(h) 3 ckit(v654a)(h) -4 SAPK2a(h) -10 SRPK1(h) EphA5(h) 3 EGFR(T790M)(h) -4 DMPK(h) -11 CDK7/cyclinH/MAT1(h) EphB4(h) 3 GRK5(h) -4 EphA2(h) -11 Flt3(h) FGFR2(h) 3 JNK2α2(h) -4 EphA4(h) -11 Syk(h) MSK2(h) 3 CK1δ(h) -5 MKK7ß(h) -11 CDK2/cyclinA(h) MST3(h) 3 ckit(d816v)(h) -5 Pim-1(h) -11 CHK1(h) NEK11(h) 3 DCAMKL2(h) -5 RIPK2(h) -11 DRAK1(h) PKA(h) 3 NEK7(h) -5 Rsk4(h) -11 MEK1(h) SAPK2a(T106M)(h) 3 ckit(d816h)(h) -6 SGK(h) -11 BTK(h) STK33(h) 3 MINK(h) -6 TAK1(h) -11 PDGFRß(h) ZIPK(h) 3 Rsk3(h) -6 CK2(h) -12 GSK3ß(h) CaMKIIδ(h) 2 Snk(h) -6 csrc(h) -12 ROCK-I(h) GRK6(h) 2 WNK3(h) -6 DDR2(h) -12 Tie2(h) IRAK1(h) 2 VRK2(h) -6 IKKα(h) -12 TrkB(h) MAPKAP-K3(h) 2 EphA7(h) -7 NEK3(h) -12 CSK(h) Mnk2(h) 2 EphB2(h) -7 NEK6(h) -12 Fyn(h) PAK5(h) 2 MLCK(h) -7 PAK2(h) -12 IGF-1R(h) PKCα(h) 2 MRCKα(h) -7 PKCη(h) -12 SRPK2(h) Ret(h) 2 NLK (h) -7 PrKX(h) -12 CDK3/cyclinE(h) DAPK1(h) 1 PAK4(h) -7 Rsk1(h) -12 IR(h) EphA8(h) 1 PDK1(h) -7 CDK5/p25(h) -13 ZAP-70(h) PKCδ(h) 1 Pim-2(h) -7 DAPK2(h) -13 Bmx(h) SGK2(h) 1 PKBγ(h) -7 HIPK3(h) -13 ErbB4(h) Lck(h) 0 PKCζ(h) -7 EGFR(L858R)(h) -14 PDGFRα(h) Ros(h) 0 Pyk2(h) -7 JNK3(h) -14 ROCK-II(h) SIK(h) 0 SAPK3(h) -7 PAK3(h) -14 ALK(h) Abl(h) -1 CaMKIIß(h) -8 PKG1ß(h) -14 EGFR(L861Q)(h) EphA3(h) -1 CLK3(h) -8 Plk3(h) -14 PKCε(h) Fgr(h) -1 Hck(h) -8 ALK4(h) -15 c-raf(h) GSK3α(h) -1 IKKß(h) -8 CDK5/p35(h) -15 LKB1(h) HIPK2(h) -1 Itk(h) -8 MSK1(h) -15 PKCßII(h) PAK6(h) -1 MAPK1(h) -8 SGK3(h) CDK1/cyclinB(h) -2 MST2(h) -8 Fer(h) CDK2/cyclinE(h) -2 PASK(h) -8 SAPK2b(h) -16

4 S 4 4 Table S3. Profile of 13 assays for 13 were performed using commercially available ProfilerPro Selectivity Assay Kits from Caliper Life Sciences, Inc. at test concentrations of 0.1 and 1 µm. Data is reported as inhibition relative to DMSO control. MET LCK MET PRKCH FGFR BRSK FGFR MAP4K FGFR PAK PRKCD PKA AURKC AKT CAMK II BETA BTK AURKA RPS6KA TSSK ERK2(MAPK1) AURKB NEK FGFR RPS6KA KDR CSNK1A AURKA GSK3B FLT IKK_BETA FGFR RPS6KB BTK MAPK ABL(H396P) PIM FGFR RPS6KA AURKB PRAK FGFR2(N549H) CAMK II GAMMA LCK PKCZ ABL(H396P) TSSK KDR DYRK1A FLT3(D835Y) SYK CSNK1D HCK MAP4K P38-BETA ABL(T315I) ARG ABL(Q252H) RPS6KA PRKCG P38-ALPHA ABL ERK2(MAPK1) ROCK EGFR AMPK RPS6KB AKT PRKCQ CSNK1D FYN RPS6KA CDK BMX DCAMKL FGFR2(N549H) DCAMKL RPS6KA P38-ALPHA P38-BETA PAK ARG DYRK1A C-RAF RPS6KA PKCZ PRKCA ABL(Q252H) FER MARK PRKG1A PRKG1B BMX SGK CDK AURKC LYN LYN PRKCG SYK MARK SRC PRKD PKD P38-GAMMA PIM SGK FLT3(D835Y) PRKG1A CHK CAMK II DELTA CHK PRKCN PRAK MARK MAPKAPK CSNK1A ABL(T315I) MAPKAPK SGK RPS6KA IRAK ROCK BRSK SRC PRKCN MAPKAPK IKK_BETA MAPK CAMK PRKCH INSR P38-DELTA INSR AKT FLT FYN GSK3B SGK TSSK PRKD BRSK PKD MARK BRSK CHK TSSK ABL IRAK PKA P38-DELTA AMPK PIM PRKCD RPS6KA AKT PKCB HCK PRKG1B CAMK MAPKAPK C-RAF IGF1R CAMK II GAMMA RPS6KA PRKCE PKCB STK CAMK II DELTA PRKCB MARK CHK SGK P38-GAMMA PIM SGK PRKCA STK PRKCQ FGFR IGF1R AKT MARK PRKCE AKT PDGFRA

5 S 5 Table S4. Profile of 14 assays for 14 were performed using commercially available ProfilerPro Selectivity Assay Kits from Caliper Life Sciences, Inc. at test concentrations of 0.1 and 1 µm. Data is reported as inhibition relative to DMSO control. [nm] Inh [nm] Inh MET(M1250T) RPS6KA MET(M1250T) SGK MET PKCB MET BMX MER BMX MER PKCZ KDR FRK FLT3(D835Y) CDK AURKA CAMK AURKA PIM FLT3(D835Y) STK NTRK CAMK II NTRK RPS6KA AURKB ROS FGFR CSNK1A KDR FRK AURKB EGFR AURKC HIPK MST1R CHK AXL MAPK AXL BRSK FGFR TXK FGFR CSNK1G FGFR RSK AURKC SGK FER KIT(T670I) TYRO AKT MST1R PRKCA FLT DCAMKL ROCK P38-BETA PDGFRA(V561D) PASK TYRO CAMK II FGFR3(K650E) RSK MAP4K MAPKAPK FGFR2(N549H) HIPK PHKG ALK MAP4K MARK DYRK KIT ABL(Q252H) PAK PDGFRA(V561D) CAMK MELK AKT FGFR2(N549H) P38-DELTA RET PIM FGFR3(K650E) FYN RET(Y791F) BTK ROCK PKD ABL(H396P) PRKG1B AMPK MAPKAPK JAK CDK FLT SGK ABL(T315I) GSK3B MELK BRSK DYRK1A CDK EGFR(T790M) PRKCD ABL EPHA PRAK RPS6KB ITK CAMK II ALPHA RET(Y791F) PHK GAMMA AMPK DCAMKL PAK CHK PDGFRA PRKCE IKK_BETA MARK YES SGK PRKCH ABL(H396P) BLK PKCZ CSNK1G RPS6KA FGFR PRKCH DYRK EPHA LYN PTK2B HCK RPS6KA FGFR PRAK FGFR ARG DYRK EGFR(T790M PRKCE PIM KIT(T670I) MAPKAPK HIPK RPS6KA ROCK CHK SYK PRKCQ TXK PRKCD DCAMKL SRC IKK_BETA PIM ABL TSSK ARG RPS6KA PRKG1A RPS6KA AMPK α2 β1 g PKD PRKCN LCK PHK GAMMA P38-ALPHA DYRK1A MARK CLK EGFR(T790M) RET PTK2B MARK ERK2(MAPK1) MARK ERK2(MAPK1) IRAK ROCK IRAK AKT MARK DYRK ITK AKT SYK CSNK1G ABL(Q252H) P38-ALPHA HIPK SGK MARK EGFR HCK BRSK AKT TSSK SRC CAMK II GAMMA EGFR(T790M SGK RPS6KA P38-GAMMA CAMK II BETA CDK5/P PHKG PIM PRKD CAMK II MARK INSR DAPK RPS6KA ALK PRKCI BTK STK CAMK II BETA TSSK PRKG1B P38-GAMMA ROS C-RAF PIM NEK CDK5/P IGF1R PRKCI C-RAF PRKG1A CAMK II DELTA CHK GSK3B LCK PRKCQ CSNK1D YES DAPK MAPKAPK DCAMKL PRKCB P38-DELTA FER INSR CSNK1A EPHB PKA AMPK α2 β1 g PRKCG RPS6KA NEK ABL(T315I) CSNK1G PRKCN P38-BETA BRSK PASK DAPK RPS6KB CLK FGFR KIT PRKCG CDK PKA CSNK1D MAPK DAPK IGF1R PRKCB PRKD PKCB PDGFRA TSSK PRKCA LYN BLK AKT EPHB JAK [nm] Inh [nm] Inh 5

6 S 6 6 Table S5. Profile of 5g Compound 5g was evaluated by InVitrogen, Inc. using a Z -LYTE Assay format or Adapta Universal Assay at test concentrations of 0.1, 1, and 10 µm as indicated in the below table. AURKB EPHA PKN JAK KDR AKT2 BETA TAOK GRK ABL BTK MST SRPK FLT ZAP NEK STK22D DYRK1A SRC BMX AKT2 BETA MET AKT2 GAMMA FLT PLK LCK CDK5/P KDR AKT2 GAMMA NTRK DAPK AURKB CAMK FGFR CHEK MET PRKCI MINK MAP2K LCK PRKCZ CLK GRK NTRK NEK NTRK CSNK1A NTRK PDK IRAK MAP3K FGFR CSNK2A GSK3A SRPK DYRK1A MAP2K GSK3B CDK MINK ADRBK NUAK PASK IRAK MAPK SYK ROCK CSF1R CDC42BPA IRAK MAPK IRAK GSK3B CSF1R CDK9(CYCLIN T1) RAF1(Y340D Y341D) EPHB LRRK ADRBK LRRK TYK PIK3P110D/P85A CSNK2A MAP2K TBK PKG ALK MAP3K MAPKAPK HCK MAPK CLK RPS6KA AMPK PLK MAPK14 ALPHA BMX SGK NEK RPS6KB PRKACA KIT PRKACA HCK SRC TEK JAK CDK INSR CHEK AKT1 ALPHA PAK PRKCQ JAK PRKCI ZAP IKK_EPSILON PTK IKK_EPSILON SGK TAOK NEK CDC42BPA CHEK GRK GRK IKK_BETA AMPK CDK5/P ITK MAPKAPK MAPK MAPKAPK TBK PRKCQ IGF1R IKK_BETA AMPK MAP2K PKG EPHA JAK EGFR MARK CDK PDK RAF1(Y340D Y341D) ABL JAK RPS6KB PRKCZ NUAK PASK STK22D MAPK PKN AKT1 ALPHA EPHA EPHB NEK PIM TYK CAMK BRAF EPHA PIM INSR BTK CSNK1A MAPK14 ALPHA BRAF KIT TEK MAPKAPK SPHK SYK CDK9(CYCLIN T1) MARK ROCK ALK ITK RPS6KA MAPK JAK AMPK CDK ERBB GSK3A MAPK IGF1R PAK PTK ROCK

7 S 7 7 Table S5. Profile of 5g continued MST AMPK ALPHA2 BETA1 GAMMA MAPK ERBB AKT2 GAMMA AMPK ALPHA1 BETA1 GAMMA DAPK SRPK ITK EGFR SGK CDK MAPK BTK EGFR ROCK TAOK ROCK CHEK NEK TEK SPHK DYRK1A MAPK PIK3P110D/P85A PRKCI TBK NEK INSR EPHA MAP3K AKT2 BETA ROCK LCK KIT SPHK RAF1( Y340D Y341D) MAP2K ERBB MAP2K MAPKAPK NUAK FLT CDK9(CYCLIN T1) PIK3P110D/P85A CHEK ADRBK DAPK JAK KDR PRKCZ SYK PTK LRRK CLK MINK PLK ABL GSK3A IRAK EPHB AURKB CSNK2A PAK JAK NTRK IKK_EPSILON NTRK PASK ZAP GSK3B MAPK14 ALPHA BMX AKT1 ALPHA PRKCQ CDK IRAK HCK MST IGF1R CDK5/P NEK RPS6KA CSF1R PRKACA STK22D CDC42BPA MAPK PIM FGFR GRK CAMK RPS6KB GRK EPHA ALK MAPKAPK PKG NEK MAPK CSNK1A MET TYK BRAF IKK_BETA PKN JAK MARK SRC CHEK PDK

8 S 8 8 Table S6. Profile of 11a assays for 11a were performed using commercially available ProfilerPro Selectivity Assay Kits from Caliper Life Sciences, Inc. at test concentrations of 0.1 and 1 µm. Data is reported as inhibition relative to DMSO control. MET CHK MET SRC MARK P38-GAMMA AURKB ABL(Q252H) AURKC ROCK FGFR RPS6KA AURKA IGF1R KDR PRKG1A AURKB MAP4K AURKC MAPK FLT3(D835Y) AKT AURKA SGK KDR SRC FGFR TSSK FGFR PKCZ FGFR ABL(H396P) FLT TSSK FLT3(D835Y) SGK FGFR PAK MARK PRKCG FGFR2(N549H) ERK2(MAPK1) FGFR2(N549H) NEK DYRK1A CHK PIM CAMK CAMK II DELTA PRKCH RPS6KA AMPK ABL(Q252H) PKD EGFR P38-BETA SGK PKA INSR AKT ABL HCK RPS6KB MARK FGFR CAMK II GAMMA RPS6KA MAPKAPK AMPK LCK CSNK1D GSK3B PIM RPS6KA PRKD CSNK1A PDGFRA PRKCN MAP4K P38-DELTA RPS6KB LYN ABL CHK ABL(T315I) PRKD SGK FYN BRSK RPS6KA DYRK1A IGF1R SGK MARK C-RAF PIM CSNK1D C-RAF IRAK PRKCE TSSK CDK BRSK PKD PRKG1A CSNK1A MAPKAPK P38-GAMMA ABL(H396P) P38-BETA PRKCQ ERK2(MAPK1) GSK3B PRKG1B PRKCD PKA EGFR PKCB CAMK II DELTA PRKCH RPS6KA CAMK STK PKCZ DCAMKL NEK FLT CHK MAPKAPK PRAK PRKCA LYN STK IRAK AKT PRKCN SYK P38-DELTA ROCK PRKCB AKT CAMK II BETA PRKG1B IKK_BETA P38-ALPHA FER PKCB RPS6KA INSR LCK P38-ALPHA FYN SYK CAMK II GAMMA PRKCE AKT PDGFRA MAPKAPK DCAMKL CAMK II BETA IKK_BETA PAK TSSK RPS6KA BMX FER SGK ABL(T315I) HCK PIM PRAK MAPK RPS6KA AKT CDK

9 S 9 9 Table S7. Profile of 15 assays for 15 were performed using commercially available ProfilerPro Selectivity Assay Kits from Caliper Life Sciences, Inc. at test concentrations of 0.1 and 1 µm. Data is reported as inhibition relative to DMSO control. Inh [nm] Inh [nm] [nm] Inh [nm] Inh MET(M1250T) BTK MET(M1250T) MARK MET RPS6KA MET PKCZ RPS6KA SGK RPS6KB P38-BETA AURKB FGFR2(N549H) PRKCG FGFR AURKA MAPKAPK PTK2B CSNK1G PDGFRA(V561D) CAMK II BETA AMPK MARK MST1R PRKCQ EPHA PIM AXL MAPKAPK PRKCE MAPKAPK AURKC DYRK SGK BLK KDR FER AURKB GSK3B BLK IRAK PHK GAMMA CHK PRKCA CDK5/P PRKD SYK MER PIM AURKC PRKCI CSNK1G DAPK HIPK YES PAK PRKG1B PRKCH EGFR(T790M L858R) PKD PRKD FRK ABL NTRK HIPK PKD FLT3(D835Y) EGFR MAP4K ALK MAPKAPK P38-GAMMA PRKCE PASK ERK2(MAPK1) ROCK SYK NEK SGK ABL(Q252H) MAPK AXL DYRK FGFR CSNK1A P38-GAMMA AKT SRC RPS6KA NTRK KIT KIT P38-BETA RSK BRSK FRK MARK DYRK1A CAMK II BETA JAK AMPK α2 β1 g TSSK CAMK CSNK1G TSSK AMPK α2 β1 g FGFR3(K650E) DCAMKL PRKG1A INSR ABL(Q252H) MELK MARK ROS DAPK P38-ALPHA ITK MAP4K HCK EPHA RPS6KA CSNK1A P38-DELTA FGFR CAMK II GAMMA KDR SGK PKA CSNK1D PRKG1B RPS6KA STK LCK ROCK TSSK ROCK CAMK II ALPHA CHK PIM TYRO IKK_BETA TYRO ROCK CLK PIM AURKA JAK RPS6KA LYN HIPK IGF1R HIPK BRSK LYN KIT(T670I) P38-DELTA GSK3B CLK LCK PDGFRA FGFR BRSK FGFR ERK2(MAPK1) RPS6KB PKCB PIM INSR CAMK PRKCQ CAMK II GAMMA FLT3(D835Y) MARK C-RAF MST1R EPHB ARG ABL(T315I) CDK BMX EGFR(T790M L858R) MELK FYN PASK FLT CSNK1G RPS6KA HCK PIM ARG PRAK AKT MARK PKA MARK PRAK PHKG MER PRKG1A CHK DAPK DAPK ITK DYRK CAMK II DELTA CDK5/P TXK RET KIT(T670I) BTK RPS6KA FYN AMPK PAK MARK NEK YES DCAMKL FLT RET(Y791F) PRKCD RET EGFR PTK2B DCAMKL STK RPS6KA PRKCN SGK DYRK CSNK1D FGFR3(K650E) CDK MAPK AKT AKT DYRK1A EGFR(T790M) FGFR2(N549H) AKT SGK FGFR CAMK II ALPHA BRSK FGFR PDGFRA PRKCA ABL RSK FGFR CDK PRKCI PRKCH ABL(H396P) IRAK ABL(T315I) C-RAF PRKCB BMX IGF1R ALK IKK_BETA P38-ALPHA TSSK TXK SRC PDGFRA(V561D) CHK EGFR(T790M) RET(Y791F) AKT PKCZ PRKCB EPHB FER PHK GAMMA ROS PHKG PRKCN CDK PKCB PRKCD CAMK II DELTA ABL(H396P) PRKCG RPS6KA DCAMKL

10 S Table S8. Profile of 16 assays for 16 were performed using commercially available ProfilerPro Selectivity Assay Kits from Caliper Life Sciences, Inc. at test concentrations of 0.01 and 0.1 µm. Data is reported as inhibition relative to DMSO control. MET CDK MET IKK_BETA ABL(Q252H) GSK3B CAMK II BETA MAPKAPK AURKB AKT TSSK PKCZ FLT3(D835Y) IRAK ABL(T315I) FYN RPS6KA RPS6KB IRAK CDK CAMK II DELTA AKT PKCB MAPK AURKA MAPKAPK FGFR RPS6KA FGFR HCK PRKCD P38-ALPHA FGFR PRKCE BRSK INSR ROCK MARK RPS6KA P38-BETA RPS6KA NEK DCAMKL MARK PRKCB ABL(T315I) DYRK1A RPS6KA SYK ABL(H396P) TSSK GSK3B PKCB INSR RPS6KB ABL AURKC IGF1R CAMK II GAMMA BRSK ABL CSNK1D ROCK ERK2(MAPK1) AKT RPS6KA BTK NEK BTK MARK P38-DELTA PKD FLT BMX IGF1R CHK BRSK PRKCQ ABL(H396P) LCK SGK PKD ARG PRKCG PKCZ SRC PIM P38-GAMMA AMPK DYRK1A PRKCB SGK KDR PRKG1B FGFR SRC PDGFRA P38-GAMMA ABL(Q252H) KDR PRKG1A CAMK II BETA PRKCQ SGK PAK CHK PKA PRKCH FGFR2(N549H) TSSK AURKB SYK LCK PRKCN PRKCN AURKA ARG PRKD CAMK FGFR2(N549H) PIM RPS6KA AKT PRAK PRKCD P38-DELTA HCK PIM CAMK II GAMMA CHK FLT3(D835Y) RPS6KA RPS6KA TSSK AMPK CHK PRKCG PIM PRKG1B LYN MAPK P38-ALPHA CSNK1D PRKD PRAK PRKCH PRKG1A FER PRKCA FYN CAMK II DELTA AKT FER SGK STK MARK P38-BETA BRSK CSNK1A FGFR STK LYN C-RAF MAP4K IKK_BETA MARK PRKCE RPS6KA C-RAF MAP4K MAPKAPK BMX PKA FGFR PRKCA SGK ERK2(MAPK1) CAMK FLT PDGFRA MAPKAPK FGFR PAK AURKC CSNK1A SGK MARK EGFR DCAMKL EGFR AKT FGFR

11 S Table S9. Profile of 11u assays for 11u were performed using commercially available ProfilerPro Selectivity Assay Kits from Caliper Life Sciences, Inc. at test concentrations of 1 and 0.1 µm. Data is reported as inhibition relative to DMSO control. MET NEK MAP4K P38-DELTA BTK PKCB ROCK CSNK1A ABL STK ARG KDR KDR PRKG1A ABL(T315I) DCAMKL IRAK P38-ALPHA P38-ALPHA CAMK II GAMMA FLT BMX SRC PAK MARK CAMK PRKCH PKD AURKA MARK FGFR PKCZ PIM PRKCN NEK FGFR MAP4K ERK2(MAPK1) DYRK1A SGK FYN PRKCE CAMK II BETA PRKCE CAMK II DELTA RPS6KA AKT PRKCN PRKD RPS6KA BRSK FGFR AMPK PRKCD MARK MARK LYN PIM IKK_BETA PRKCQ SGK IGF1R CDK BMX CSNK1D BRSK ABL(Q252H) PRKCB BRSK CSNK1A FER PRKCA AKT P38-GAMMA CHK PRKCD MAPK SGK ERK2(MAPK1) INSR PRKCG RPS6KA GSK3B MARK PRKCB RPS6KA DYRK1A MET AKT PRKCQ AURKB TSSK SRC CAMK II DELTA SGK GSK3B IRAK RPS6KA AKT PIM RPS6KA CDK ABL STK PRKCH AURKC FLT3(D835Y) MAPKAPK CSNK1D BRSK PKCZ LCK P38-BETA PAK PDGFRA PKA CHK LYN RPS6KA SYK AMPK CAMK PKA ABL(H396P) HCK RPS6KA AURKA PRKG1B RPS6KB SYK TSSK PRKCA AKT MAPKAPK DCAMKL FLT RPS6KB RPS6KA RPS6KA FGFR2(N549H) CHK MAPKAPK P38-GAMMA SGK SGK PRKD C-RAF MAPK PRKG1A PRAK PRKCG MARK LCK C-RAF PRAK ROCK IGF1R PKCB PKD CHK PIM INSR FYN EGFR

12 S Table S10. Profile of 11w assays for 11w were performed using commercially available ProfilerPro Selectivity Assay Kits from Caliper Life Sciences, Inc. at test concentrations of 100 and 10 nm. Data is reported as inhibition relative to DMSO control. [nm] [nm] [nm] [nm] MET LYN MET(M1250T) NEK MET(M1250T) ABL MET PRKCI MST1R RPS6KA ROS AKT ROCK FRK ALK BLK DYRK RSK EPHA CSNK1G PDGFRA(V561D) INSR RET(Y791F) ABL(T315I) PASK FGFR CAMK II GAMMA MARK SGK CAMK DAPK FGFR STK MARK MST1R BRSK FGFR PRKCG MER PDGFRA BLK AKT RET FRK AURKC TSSK LYN AURKB ITK CDK JAK HIPK PHK GAMMA PRKCB CDK5/P PRKCE KIT GSK3B BTK FYN PHKG CSNK1G NTRK MAPKAPK FGFR2(N549H) CHK DYRK PTK2B RET PRKCI LCK FER DYRK RET(Y791F) RPS6KB FLT DCAMKL AMPK STK BMX JAK TSSK MARK DYRK1A AURKB ABL(H396P) PIM TYRO CDK EPHA FGFR SGK AXL DAPK RPS6KA AKT PKD ABL(T315I) PHK GAMMA YES PRKCN FER ROCK DAPK RPS6KA DAPK DCAMKL AURKC CSNK1A SGK RSK P38-ALPHA BRSK AMPK α2 β1 g AURKA PRKG1B FGFR PKA EPHB MAP4K MER IKK_BETA GSK3B BRSK MAP4K EGFR(T790M L858R) SGK CDK TYRO NTRK PAK FGFR3(K650E) PRKG1A MELK CAMK II BETA RPS6KA SGK MARK CSNK1G PRKCN PDGFRA CSNK1G CHK PKD CSNK1D MAPKAPK PDGFRA(V561D) ARG PRKCD EGFR IGF1R MARK MAPK PRKCQ ABL PRKCH DCAMKL SRC IKK_BETA PRAK FGFR MARK KDR ITK ABL(Q252H) BRSK HCK CHK HCK YES PHKG AKT AKT ALK RPS6KA CSNK1A LCK CDK5/P PRKG1A AMPK HIPK RPS6KA INSR AXL AURKA FLT ROCK FGFR PRAK P38-ALPHA AMPK α2 β1 g FLT3(D835Y) PTK2B NEK PKA TSSK FLT3(D835Y) CAMK II GAMMA TSSK CSNK1D IRAK P38-DELTA ABL(Q252H) MARK ROS FYN CAMK II DELTA KIT DYRK1A PRKD PRKCG RPS6KA PKCB CAMK II ALPHA ABL(H396P) FGFR2(N549H) MARK RPS6KA SRC FGFR BTK RPS6KA C-RAF EGFR(T790M) AKT ARG CAMK P38-DELTA PRKCA SYK SGK TXK P38-GAMMA PIM P38-GAMMA PRKCA FGFR3(K650E) ERK2(MAPK1) HIPK CDK PAK KIT(T670I) MAPK PRKCB P38-BETA PRKG1B EGFR(T790M L858R) CLK TXK CAMK II BETA PKCZ PRKCQ PIM CLK DYRK EGFR HIPK CAMK II DELTA MELK P38-BETA C-RAF BMX DCAMKL MAPKAPK PIM EGFR(T790M) PRKD PRKCD RPS6KB CHK PASK IRAK MAPKAPK IGF1R PKCB ERK2(MAPK1) ROCK EPHB SYK PIM PRKCE KDR RPS6KA PIM PKCZ PRKCH KIT(T670I) CAMK II ALPHA

13 S Table S11. X-ray structure-determination statistics of 16/c-Met co-crystal structure Compound 16/c-Met co-crystal Resolution range (Å) Unit cell parameters (Å) Space group a=40.134, b=63.789, c= P Molecules per a.s.u. 1 Rsym () 8.3 (40.7) Completeness () 98.6 (99.1) Redundancy 5.2 R Rfree MolProbity score 1.73 Residues in most-favored region of Ramachandran plot () 96.6 RMSD bond lengths (Å) RMSD bond angles ( ) 1.11 Numbers in parentheses denote statisitics in the highest resolution bin ( Angstroms)

14 S Table S12. GTL-16 Tumor Xenograft Efficacy Results Treatment Group Dose (mg/kg), Dosing Frequency Percent Tumor Growth Inhibition (Day 1-21) Tumor Weight Relative to Vehicle Body Weight Relative to Vehicle (Day 21) Vehicle QD Vehicle BID MK , BID r 100, QD r 10, BID r 30, BID r 100, BID Figure S1. Plasma entrations of 11r following the last dose in the GTL-16 Tumor Xenograft Efficacy Study

15 S 15 Table S13. Plasma entrations of 11r following the last dose in the GTL-16 Tumor Xenograft Efficacy Study Dose 11r BID 10 mpk 11r BID 100 mpk 11r BID 30 mpk 11r QD 100 mpk Time, hr Mean Plasma, µm SD

16 S Characterization data for Compounds 5b-d, 11a-f, 11i-m, 11p-q, 11s, 11u, 11v, 11w N-methyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]acetamide (5b). 8.7 mg, 24 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.19 (d, J = 1.5 Hz, 1H); 8.52 (d, J = 2.0 Hz, 1H); 8.46 (s, 1H); 8.12 (s, 1H); 8.03 (m, 2H); 7.67 (m, 2H); 7.37 (d, J = 10.5 Hz, 1H); 7.27 (d, J = 10.5 Hz, 1H); 3.88 (s, 3H); 3.56 (s, 2H); 2.57 (d, J = 3.5 Hz, 3H). MS (APCI) calculated for C 21 H 19 N 4 O 2 [M+H] +, 359.1; found N,N-dimethyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]acetamide (5c) mg, 33 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.19 (d, J = 1.5 Hz, 1H); 8.52 (d, J = 2.0 Hz, 1H); 8.45 (s, 1H); 8.12 (s, 1H); 7.98 (d, 1.5 Hz, 1H); 7.72 (d, J = 6.5 Hz, 1H); 7.63 (dd, J = 6.5, 1.5 Hz, 1H); 7.37 (d, J = 10.5 Hz, 1H); 7.27 (d, J = 10 Hz, 1H); 3.88 (s, 3H); 3.87 (s, 2H); 3.02 (s, 3H); 2.82 (s, 3H). MS (APCI) calculated for C 22 H 21 N 4 O 2 [M+H] +, 373.2; found [3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-Nphenylacetamide (5d) mg, 54 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ (s, 1H); 9.19 (d, J = 2.0 Hz, 1H); 8.52 (d, J = 1.5 Hz, 1H); 8.45 (s, 1H); 8.12 (s, 1H); 8.11 (s, 1H); 7.76 (s, 2H); 7.57 (m, 2H); 7.38 (d, J = 10.5 Hz, 1H); 7.28 (m, 3H); 7.02 (m, 1H); 3.88 (s, 3H); 3.83 (s, 2H). MS (APCI) calculated for C 26 H 21 N 4 O 2 [M+H] +, 421.2; found N-benzyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]acetamide (5e) mg, 41 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.19 (d, J = 2.0 Hz, 1H); 8.65 (m, 1H); 8.52 (d, J = 2.0 Hz, 1H); 8.45 (s, 1H); 8.12 (s, 1H); 8.06 (d, J = 1.5 Hz, 1H); 7.74 (d, J = 10 Hz, 1H); 7.69 (dd, J = 7.0, 1.5 Hz, 1H); 7.37 (d, J = 10 Hz, 1H); 7.28 (m, 3H); 7.21 (m, 3H); 4.26 (d, J = 4.5 Hz, 2H); 3.88 (s, 3H); 3.66 (s, 2H). MS (APCI) calculated for C 27 H 23 N 4 O 2 [M+H] +, 435.2; found N-(1,4-dioxan-2-ylmethyl)-N-methyl-2-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5Hbenzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]acetamide (5f) mg, 51 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.19 (m, 1H); 8.52 (m, 1H); 8.45 (s, 1H); 8.12 (s, 1H); 7.98 (m, 1H); 7.71 (m, 1H); 7.63 (m, 1H); 7.38 (m, 1H); 7.27 (m, 1H); 3.89 (s, 2H); 3.88 (s, 3H); (m, 9H); 2.83 (s, 3H). MS (APCI) calculated for C 26 H 27 N 4 O 4 [M+H] +, 459.2; found [3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2- ylmethyl)acetamide (5g) mg, 28 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.20 (d, J = 2.0 Hz, 1H); 8.75 (m, 1H); 8.57 (m, 1H); 8.52 (d, J = 1.5 Hz, 1H); 8.45 (m, 2H); 8.07 (d, J = 1.0 Hz, 1H); 7.75 (d, J = 6.5 Hz, 1H); 7.71 (dd, J = 7.0, 1.5 Hz, 1H); 7.38 (d, J = 10.5 Hz, 1H); 7.29 (d, J = 10.5 Hz, 1H); 7.21 (d, J = 5.0 Hz, 2H); 4.29 (d, J = 5.5 Hz, 2H); 3.89 (s, 3H); 3.71 (s, 2H). MS (APCI) calculated for C 26 H 22 N 5 O 2 [M+H] +, 436.2; found [3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide (11a): 6.2 mg, 13 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.22 (d, J = 1.5 Hz, 1H); 8.55 (m, 2H); 8.47 (s, 1H); 8.14 (m, 2H); 7.95 (m, 1H); 7.91 (m, 1H); 7.79 (m, 2H); 7.52 (d, J = 6.5 Hz, 1H); 7.42 (m, 2H); 7.34 (d, J = 10.5 Hz, 1H); 4.66 (s, 2H); 4.29 (d, J = 5.5 Hz, 2H); 3.88 (s, 3H). MS (APCI) calculated for C 19 H 17 N 4 O 3 S [M+H] +, 381.1; found N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide (11b): 6.8 mg, 70 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.21 (d, J = 2.0 Hz, 1H); 8.54 (d, J = 2.0 Hz, 1H); 8.47 (s, 1H); 8.15 (s, 1H); 7.76 (d, J = 6.5 Hz, 1H); 7.63 (dd, J = 6.5, 1.5 Hz, 1H); 7.40 (d, J = 10.5 Hz, 1H); 7.32 (d, J = 10 Hz, 1H); 6.98 (m, 1H); 4.55 (s, 2H); 3.88 (s, 3H); 2.58 (d, J = 4.0 Hz, 3H). MS (APCI) calculated for C 20 H 19 N 4 O 3 S [M+H] +, 395.1; found

17 S N,N-Dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide (11c): 91.5 mg, 34 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.21 (d, J = 2.0 Hz, 1H); 8.54 (d, J = 2.0 Hz, 1H); 8.47 (s, 1H); 8.19 (s, 1H); 8.14 (m, 2H); 7.81 (s, 1H); 7.40 (d, J = 10.5 Hz, 1H); 7.33 (d, J = 10.5 Hz, 1H); 4.63 (s, 2H); 3.88 (s, 3H); 2.74 (s, 6H). MS (APCI) calculated for C 21 H 21 N 4 O 3 S [M+H] +, 409.1; found [3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-Npropylmethanesulfonamide (11d): 41.4 mg, 63 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.21 (d, J = 2.0 Hz, 1H); 8.54 (d, J = 2.0 Hz, 1H); 8.47 (s, 1H); 8.15 (m, 2H); 7.80 (d, J = 7.0 Hz, 1H); 7.76 (dd, J = 6.5, 1.5 Hz, 1H); 7.40 (d, J = 10.5 Hz, 1H); 7.32 (d, J = 10.5 Hz, 1H); 7.12 (m, 1H); 4.52 (s, 2H); 3.88 (s, 3H); 2.86 (m, 2H); 1.40 (m, 2H); 0.81 (t, J = 6.5 Hz, 3H). MS (APCI) calculated for C 22 H 23 N 4 O 3 S [M+H] +, 423.2; found N-(1,4-dioxan-2-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl]methanesulfonamide (11e): 30 mg, 51 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.21 (d, J = 2.0 Hz, 1H); 8.53 (d, J = 1.5 Hz, 1H); 8.47 (s, 1H); 8.15 (d, J = 1.5 Hz, 1H); 8.14 (s, 1H); 7.80 (d, J = 6.5 Hz, 1H); 7.77 (dd, J = 6.5, 1.5 Hz, 1H); 7.40 (d, J = 10.5 Hz, 1H); 7.32 (d, J = 10 Hz, 1H); 7.28 (m, 1H); 4.56 (s, 2H); 3.88 (s, 3H); 3.70 (dd, J = 10, 1.5 Hz, 1H); 3.66 (dd, J = 10.5, 2.0 Hz, 1H); 3.58 (dd, J = 10, 0.5 Hz, 1H); 3.54 (m, 1H); 3.47 (m, 1H); 3.42 (m, 1H); 3.14 (dd, J = 9.5, 8.0 Hz, 1H); 2.94 (m, 2H). MS (APCI) calculated for C 24 H 25 N 4 O 5 S [M+H] +, 481.2; found N-benzyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide (11i): 32.9 mg, 57 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.21 (d, J = 2.0 Hz, 1H); 8.53 (d, J = 1.5 Hz, 1H); 8.47 (s, 1H); 8.14 (s, 1H); 8.13 (d, J = 1.5 Hz, 1H); 7.79 (d, J = 7.0 Hz, 1H); 7.73 (dd, J = 6.5, 1.5 Hz, 1H); 7.71 (m, 1H); 7.40 (d, J = 10.5 Hz, 1H); 7.32 (d, J = 10 Hz, 1H); 7.29 (m, 3H); 7.23 (m, 1H); 4.54 (s, 2H); 4.13 (d, J = 5.0 Hz, 2H); 3.89 (s, 3H). MS (APCI) calculated for C 26 H 23 N 4 O 3 S [M+H] +, 471.2; found [3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1- phenylethyl)methane-sulfonamide (11j): 38.7 mg, 53 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.21 (d, J = 2.0 Hz, 1H); 8.52 (d, J = 2.0 Hz, 1H); 8.48 (s, 1H); 8.15 (d, J = 0.5 Hz, 1H); 8.03 (d, J = 1.0 Hz, 1H); 7.78 (d, J = 7.0 Hz, 1H); 7.73 (d, J = 6.5 Hz, 1H); 7.61 (dd, J = 6.5, 1.5 Hz, 1H); 7.38 (d, J = 10.5 Hz, 1H); 7.31 (m, 4H); 7.19 (m, 1H); 4.48 (m, 1H); 4.36 (s, 2H); 3.89 (s, 3H); 1.35 (d, J = 6.0 Hz, 3H). MS (APCI) calculated for C 27 H 25 N 4 O 3 S [M+H] +, 485.2; found N-(2,4-difluorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2- b]pyridin-7-yl]methanesulfonamide (11k): 40.3 mg, 53 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.21 (d, J = 1.5 Hz, 1H); 8.54 (d, J = 2.0 Hz, 1H); 8.47 (s, 1H); 8.14 (s, 1H); 8.13 (d, J = 1.0 Hz, 1H); 7.80 (d, J = 6.5 Hz, 1H); 7.75 (m, 2H); 7.41 (m, 2H); 7.32 (d, J = 10 Hz, 1H); 7.17 (m, 1H); 7.04 (m, 1H); 4.59 (s, 2H); 4.15 (m, 2H); 3.89 (s, 3H). MS (APCI) calculated for C 26 H 21 F 2 N 4 O 3 S [M+H] +, 507.1; found [3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-3- ylmethyl)methane-sulfonamide (11p): 30.7 mg, 43 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.22 (d, J = 2.0 Hz, 1H); 8.63 (m, 2H); 8.54 (d, J = 2.0 Hz, 1H); 8.47 (s, 1H); 8.15 (m, 2H); 8.08 (d, J = 6.5 Hz, 1H); 7.89 (m, 1H); 7.80 (m, 2H); 7.68 (m, 1H); 7.40 (d, J = 10.5 Hz, 1H); 7.33 (d, J = 10.5 Hz, 1H); 4.66 (s, 2H); 4.29 (d, J = 5.0 Hz, 2H); 3.89 (s, 3H). MS (APCI) calculated for C 25 H 22 N 5 O 3 S [M+H] +, 472.1; found [3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-4- ylmethyl)methanesulfonamide (11q): 5.1 mg, 7 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.22 (d, J

18 S = 2.0 Hz, 1H); 8.71 (d, J = 5.0 Hz, 2H); 8.54 (d, J = 2.0 Hz, 1H); 8.47 (s, 1H); 8.16 (d, J = 1.5 Hz, 1H); 8.14 (d, J = 0.5 Hz, 1H); 8.03 (m, 1H); 7.81 (m, 2H); 7.69 (d, J = 5.0 Hz, 2H); 7.41 (d, J = 10.5 Hz, 1H); 7.33 (d, J = 10 Hz, 1H); 4.68 (s, 2H); 4.38 (d, J = 5.0 Hz, 2H); 3.89 (s, 3H). MS (APCI) calculated for C 25 H 22 N 5 O 3 S [M+H] +, 472.1; found N-[cis-2-aminocyclohexyl]-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl]methanesulfonamide (11f): 25.8 mg, 25 yield. 1 H NMR (500 MHz, CDCl 3 ) δ 9.04 (d, J = 1.4 Hz, 1H); 8.57 (d, J = 1.9 Hz, 1H); 8.29 (s, 1H); 7.93 (s, 1H); 7.83 (s, 1H); 7.81 (d, J = 8.1 Hz, 1H); 7.64 (d, J = 8.1 Hz, 1H); 7.40 (d, J = 12.2 Hz, 1H); 7.25 (d, J = 12.2 Hz, 1H); 5.09 (br s, 1H); 4.41 (d, J = 1.7 Hz, 2H); 4.00 (s, 3H); 3.32 (m, 1H); 3.08 (m, 1H); (m, 11H). MS (APCI) calculated for C 25 H 28 N 5 O 3 S [M+H] +, 478.2; found N-(2-chlorobenzyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 7-yl]methanesulfonamide (11l): 41 mg, 48 yield. 1 H NMR (600 MHz, DMSO-D 6 ) δ 9.23 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.15 (s, 2H), (m, 3H), 7.45 (dd, J = 1.2, 7.5 Hz, 1H), 7.41 (d, J = 12.5 Hz, 1H), 7.37 (dd, J = 1.2, 7.8 Hz, 1H), (m, 1H), 7.31 (dd, J = 1.2, 7.5 Hz, 1H), 7.25 (td, J = 1.6, 7.6 Hz, 1H), 4.63 (s, 2H), 4.17 (d, J = 6.2 Hz, 2H), 3.89 (s, 3H). MS (APCI) calculated for C 26 H 21 N 4 O 3 S [M+H] +, 505.1; found [3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]-cyclohepta[1,2-b]-pyridin-7-yl]-N- (pyridazin-3-yl-methyl)methane-sulfonamide (11m): 59 mg, 39 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.22 (d, J = 2.0, 1H); 9.11 (dd, J = 4.0, 1.5 Hz, 1H); 8.54 (d, J = 1.5, 1H); 8.48 (s, 1H); 8.15 (s, 2H); 7.95 (m, 1H); 7.80 (m, 2H); 7.68 (m, 2H); 7.40 (d, J = 10.5 Hz, 1H); 7.33 (d, J = 10.5 Hz, 1H); 4.69 (s, 2H); 4.46 (d, J = 5.5 Hz, 2H); 3.89 (s, 3H). MS (APCI) calculated for C 24 H 21 N 6 O 3 S [M+H] +, 473.1; found N-(isothiazol-4-ylmethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2- b]18yridine-7-yl]-methanesulfonamide (11o): 47.3 mg, 31 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 9.21 (d, J = 2.0, 1H); 8.83 (s, 1H); 8.54 (d, J = 2.0, 1H); 8.47 (s, 1H); 8.47 (s, 1H); 8.14 (d, J = 0.5 Hz, 1H); 8.13 (d, J = 1.5 Hz, 1H); 7.79 (d, J = 7.0 Hz, 1H); 7.74 (m, 2H); 7.40 (d, J = 10.5 Hz, 1H); 7.33 (d, J = 10.5 Hz, 1H); 4.59 (s, 2H); 4.26 (d, J = 5.0 Hz, 2H); 3.89 (s, 3H). MS (APCI) calculated for C 23 H 19 N 5 O 3 S 2 [M+H] +, 478.1; found N-ethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N- (pyridin-2-ylmethyl)-methanesulfonamide (11s): 29.4 mg, 28 yield. 1 H NMR (500 MHz, DMSO- D 6 ) δ 9.22 (d, J = 2.0, 1H); 8.54 (d, J = 2.0, 1H); 8.50 (m, 1H); 8.48 (s, 1H); 8.19 (s, 1H); 8.14 (d, J = 0.5 Hz, 1H); 7.81 (s, 2H); 7.57 (m, 1H); 7.40 (d, J = 10.5 Hz, 1H); 7.37 (d, J = 7.0 Hz, 1H); 7.33 (d, J = 10.5 Hz, 1H); 7.27 (m, 1H); 4.77 (s, 2H); 4.37 (d, J = 5.5 Hz, 2H); 3.89 (s, 3H); 3.16 (q, J = 6.0 Hz, 2H); 0.93 (t, J = 6.0 Hz, 3H). MS (APCI) calculated for C 27 H 26 N 5 O 3 S [M+H] +, 500.2; found [3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(piperidin- 2-ylmethyl)methanesulfonamide (11u): Step 1: According to the method to prepare 11g to afford Bocprotected intermediate tert-butyl 2-{[({[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5Hbenzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methyl}sulfonyl)amino]methyl}piperidine-1-carboxylate (78 mg, 64 yield). MS (APCI) calculated for C 30 H 36 N 5 O 5 S [M+H] +, 578.2; found Step 2: Trifluoroacetic acid (500 µl) was added dropwise to a solution of tert-butyl 2-{[({[3-(1-methyl- 1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methyl}sulfonyl)amino]methyl}piperidine-1-carboxylate (162 mg, mmol) in dichloromethane (1.5 ml). After 1 h of stirring at room temperature, the reaction mixture was concentrated under reduced pressure, taken up in dichloromethane (10 ml) and then washed with saturated aqueous NaHCO 3 (2 x 2 ml). The organic layer was dried over Na 2 SO 4, filtered, and concentrated under reduced