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

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 02115. 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

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 MAPK12 103 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 NEK11 118 FYN 64 PASK 91 PTK2B 101 MAPK1 120 EPHA1 65 PKCD 92 RPS6KA5 101 RPS6KA4 121 NEK2 65 PRK2 92 EPHA5 102 CK2 ALPHA 2 123 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 STK24 102 WNK2 126 LYN 69 EEF2K 93 BRK 103 ZAP70 127 MKK7B 69 NEK6 93 EPHA4 103 STK11 134 AMPK 70 PRKD1 93 EPHB2 103 ROS1 71 TBK1 93 EPHB4 103 YES 71 CDC42BPB 94 IRR 103

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) -17 93 ckit(h) 6 SAPK4(h) -2 BrSK2(h) -9 CK2α2(h) -17 67 PDGFRα(V561D)(h) 6 TAO2(h) -2 CDK9/cyclin T1(h) -9 Lyn(h) -17 63 PKD2(h) 6 TSSK1(h) -2 eef-2k(h) -9 p70s6k(h) -17 62 PKG1α(h) 6 EphA1(h) -3 NEK2(h) -9 PRAK(h) -17 60 FGFR4(h) 5 FAK(h) -3 PhKγ2(h) -9 CaMKIδ(h) -18 41 MELK(h) 5 HIPK1(h) -3 PKBα(h) -9 EphB1(h) -18 38 PTK5(h) 5 PKCι(h) -3 PKCßI(h) -9 PKCθ(h) -18 33 MARK1(h) 4 TSSK2(h) -3 CaMKI(h) -10 EGFR(h) -19 32 MRCKß(h) 4 Yes(h) -3 CDK6/cyclinD3(h) -10 EphB3(h) -19 29 ASK1(h) 3 BRK(h) -4 LOK(h) -10 MAPKAP-K2(h) -19 27 CK1γ1(h) 3 ckit(v654a)(h) -4 SAPK2a(h) -10 SRPK1(h) -19 27 EphA5(h) 3 EGFR(T790M)(h) -4 DMPK(h) -11 CDK7/cyclinH/MAT1(h) -20 26 EphB4(h) 3 GRK5(h) -4 EphA2(h) -11 Flt3(h) -20 26 FGFR2(h) 3 JNK2α2(h) -4 EphA4(h) -11 Syk(h) -20 24 MSK2(h) 3 CK1δ(h) -5 MKK7ß(h) -11 CDK2/cyclinA(h) -21 24 MST3(h) 3 ckit(d816v)(h) -5 Pim-1(h) -11 CHK1(h) -21 24 NEK11(h) 3 DCAMKL2(h) -5 RIPK2(h) -11 DRAK1(h) -22 22 PKA(h) 3 NEK7(h) -5 Rsk4(h) -11 MEK1(h) -22 20 SAPK2a(T106M)(h) 3 ckit(d816h)(h) -6 SGK(h) -11 BTK(h) -23 20 STK33(h) 3 MINK(h) -6 TAK1(h) -11 PDGFRß(h) -23 20 ZIPK(h) 3 Rsk3(h) -6 CK2(h) -12 GSK3ß(h) -24 19 CaMKIIδ(h) 2 Snk(h) -6 csrc(h) -12 ROCK-I(h) -24 16 GRK6(h) 2 WNK3(h) -6 DDR2(h) -12 Tie2(h) -24 14 IRAK1(h) 2 VRK2(h) -6 IKKα(h) -12 TrkB(h) -25 14 MAPKAP-K3(h) 2 EphA7(h) -7 NEK3(h) -12 CSK(h) -26 13 Mnk2(h) 2 EphB2(h) -7 NEK6(h) -12 Fyn(h) -26 13 PAK5(h) 2 MLCK(h) -7 PAK2(h) -12 IGF-1R(h) -26 12 PKCα(h) 2 MRCKα(h) -7 PKCη(h) -12 SRPK2(h) -26 12 Ret(h) 2 NLK (h) -7 PrKX(h) -12 CDK3/cyclinE(h) -27 12 DAPK1(h) 1 PAK4(h) -7 Rsk1(h) -12 IR(h) -27 11 EphA8(h) 1 PDK1(h) -7 CDK5/p25(h) -13 ZAP-70(h) -27 11 PKCδ(h) 1 Pim-2(h) -7 DAPK2(h) -13 Bmx(h) -28 11 SGK2(h) 1 PKBγ(h) -7 HIPK3(h) -13 ErbB4(h) -28 10 Lck(h) 0 PKCζ(h) -7 EGFR(L858R)(h) -14 PDGFRα(h) -29 10 Ros(h) 0 Pyk2(h) -7 JNK3(h) -14 ROCK-II(h) -33 10 SIK(h) 0 SAPK3(h) -7 PAK3(h) -14 ALK(h) -35 10 Abl(h) -1 CaMKIIß(h) -8 PKG1ß(h) -14 EGFR(L861Q)(h) -36 9 EphA3(h) -1 CLK3(h) -8 Plk3(h) -14 PKCε(h) -36 9 Fgr(h) -1 Hck(h) -8 ALK4(h) -15 c-raf(h) -48 8 GSK3α(h) -1 IKKß(h) -8 CDK5/p35(h) -15 LKB1(h) -52 7 HIPK2(h) -1 Itk(h) -8 MSK1(h) -15 PKCßII(h) -58 7 PAK6(h) -1 MAPK1(h) -8 SGK3(h) -15 7 CDK1/cyclinB(h) -2 MST2(h) -8 Fer(h) -16 7 CDK2/cyclinE(h) -2 PASK(h) -8 SAPK2b(h) -16

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 1 87.7 LCK 1 0.5 MET 0.1 52.0 PRKCH 0.1-2.0 FGFR2 1 64.7 BRSK1 1 0.3 FGFR3 0.1 34.5 MAP4K4 0.1-2.0 FGFR1 1 61.2 PAK2 1-0.3 PRKCD 0.1 21.9 PKA 0.1-2.1 AURKC 1 55.5 AKT2 1-0.5 CAMK II BETA 0.1 20.2 BTK 0.1-2.1 AURKA 1 48.0 RPS6KA1 1-0.8 TSSK2 0.1 19.8 ERK2(MAPK1) 0.1-2.4 AURKB 1 34.7 NEK2 1-0.9 FGFR2 0.1 18.3 RPS6KA5 0.1-2.5 KDR 1 28.2 CSNK1A1 1-0.9 AURKA 0.1 15.8 GSK3B 0.1-3.5 FLT3 1 24.2 IKK_BETA 1-1.2 FGFR1 0.1 12.3 RPS6KB1 0.1-3.5 BTK 1 22.0 MAPK3 1-1.3 ABL(H396P) 0.1 10.6 PIM2 0.1-3.6 FGFR4 1 15.7 RPS6KA3 1-1.3 AURKB 0.1 10.5 PRAK 0.1-3.6 FGFR2(N549H) 1 15.5 CAMK II GAMMA 1-1.5 LCK 0.1 9.2 PKCZ 0.1-4.2 ABL(H396P) 1 13.9 TSSK1 1-1.7 KDR 0.1 7.9 DYRK1A 0.1-4.6 FLT3(D835Y) 1 13.3 SYK 1-1.7 CSNK1D 0.1 7.8 HCK 0.1-5.1 MAP4K4 1 10.6 P38-BETA 2 1-1.8 ABL(T315I) 0.1 7.1 ARG 0.1-5.3 ABL(Q252H) 1 9.3 RPS6KA4 1-1.8 PRKCG 0.1 6.5 P38-ALPHA 0.1-5.7 ABL 1 11.6 ERK2(MAPK1) 1-1.9 ROCK2 0.1 6.4 EGFR 0.1-5.8 AMPK 1 11.5 RPS6KB1 1-2.1 AKT3 0.1 6.4 PRKCQ 0.1-6.1 CSNK1D 1 8.9 FYN 1-2.5 RPS6KA3 0.1 6.3 CDK2 0.1-6.3 BMX 1 8.8 DCAMKL2 1-2.5 FGFR2(N549H) 0.1 5.5 DCAMKL2 0.1-6.4 RPS6KA2 1 8.8 P38-ALPHA 1-2.7 P38-BETA 2 0.1 5.3 PAK2 0.1-6.6 ARG 1 6.8 DYRK1A 1-2.8 C-RAF 0.1 5.1 RPS6KA1 0.1-6.7 PKCZ 1 6.8 PRKCA 1-3.0 ABL(Q252H) 0.1 4.6 FER 0.1-6.8 MARK2 1 6.5 PRKG1A 1-3.3 PRKG1B 0.1 4.3 BMX 0.1-7.2 SGK3 1 6.2 CDK2 1-3.4 AURKC 0.1 4.3 LYN 0.1-7.4 LYN 1 5.9 PRKCG 1-3.4 SYK 0.1 3.4 MARK3 0.1-7.9 SRC 1 4.8 PRKD2 1-3.5 PKD1 0.1 3.2 P38-GAMMA 0.1-7.9 PIM2 1 4.7 SGK2 1-3.6 FLT3(D835Y) 0.1 2.5 PRKG1A 0.1-8.3 CHK2 1 4.5 CAMK II DELTA 1-3.6 CHK1 0.1 2.0 PRKCN 0.1-8.3 PRAK 1 4.4 MARK3 1-4.1 MAPKAPK3 0.1 1.8 CSNK1A1 0.1-8.6 ABL(T315I) 1 4.4 MAPKAPK2 1-4.4 SGK2 0.1 1.7 RPS6KA4 0.1-9.2 IRAK4 1 4.2 ROCK2 1-5.4 BRSK2 0.1 1.5 SRC 0.1-10.4 PRKCN 1 3.6 MAPKAPK3 1-5.4 IKK_BETA 0.1 1.4 MAPK3 0.1-10.8 CAMK4 1 3.5 PRKCH 1-5.7 INSR 0.1 1.4 P38-DELTA 0.1-11.0 INSR 1 3.5 AKT3 1-5.8 FLT3 0.1 1.3 FYN 0.1-11.5 GSK3B 1 3.0 SGK1 1-6.4 TSSK1 0.1 1.2 PRKD2 0.1-11.5 BRSK2 1 2.5 PKD1 1-6.6 MARK1 0.1 1.2 BRSK1 0.1-11.7 CHK1 1 2.5 TSSK2 1-7.1 ABL 0.1 0.2 IRAK4 0.1-12.0 PKA 1 2.4 P38-DELTA 1-7.1 AMPK 0.1 0.1 PIM1 0.1-13.0 PRKCD 1 2.1 RPS6KA5 1-7.4 AKT2 0.1-0.1 PKCB2 0.1-13.6 HCK 1 1.6 PRKG1B 1-9.8 CAMK4 0.1-0.1 MAPKAPK2 0.1-14.7 C-RAF 1 1.4 IGF1R 1-10.0 CAMK II GAMMA 0.1-0.2 RPS6KA2 0.1-15.2 PRKCE 1 1.1 PKCB2 1-10.6 STK3 0.1-0.3 CAMK II DELTA 0.1-16.1 PRKCB1 1 0.9 MARK1 1-13.9 CHK2 0.1-0.4 SGK1 0.1-19.5 P38-GAMMA 1 0.8 PIM1 1-16.7 SGK3 0.1-0.4 PRKCA 0.1-20.9 STK3 1 0.7 PRKCQ 1-19.7 FGFR4 0.1-0.6 IGF1R 0.1-23.8 AKT1 1 0.7 MARK2 0.1-1.3 PRKCE 0.1-36.0 AKT1 0.1-1.3 PDGFRA 0.1-38.4

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) 1000 98.6 RPS6KA5 1000 8.1 MET(M1250T) 100 97.4 SGK2 100 1.8 MET 1000 98.0 PKCB2 1000 8.1 MET 100 92.5 BMX 100 1.8 MER 1000 94.5 BMX 1000 8.0 MER 100 52.7 PKCZ 100 1.7 KDR 1000 93.1 FRK 1000 8.0 FLT3(D835Y) 100 49.8 CDK1 100 1.3 AURKA 1000 87.5 CAMK4 1000 8.0 AURKA 100 39.7 PIM2 100 1.2 FLT3(D835Y) 1000 86.5 STK3 1000 7.6 NTRK3 100 39.3 CAMK II 100 1.1 NTRK3 1000 83.6 RPS6KA4 1000 7.4 AURKB 100 37.1 ROS1 100 1.0 FGFR3 1000 81.0 CSNK1A1 1000 7.2 KDR 100 33.2 FRK 100 1.0 AURKB 1000 80.7 EGFR 1000 7.0 AURKC 100 31.7 HIPK1 100 1.0 MST1R 1000 78.2 CHK2 1000 6.9 AXL 100 30.6 MAPK3 100 0.9 AXL 1000 77.3 BRSK2 1000 6.6 FGFR2 100 29.4 TXK 100 0.6 FGFR2 1000 76.6 CSNK1G3 1000 6.5 FGFR3 100 26.3 RSK4 100 0.5 AURKC 1000 75.8 SGK1 1000 6.4 FER 100 24.1 KIT(T670I) 100 0.2 TYRO3 1000 66.3 AKT1 1000 6.2 MST1R 100 23.8 PRKCA 100 0.1 FLT3 1000 62.9 DCAMKL1 1000 5.9 ROCK2 100 21.3 P38-BETA 2 100-0.1 PDGFRA(V561D) 1000 61.1 PASK 1000 5.9 TYRO3 100 20.2 CAMK II 100-0.1 FGFR3(K650E) 1000 59.4 RSK4 1000 5.6 MAP4K4 100 18.6 MAPKAPK3 100-0.1 FGFR2(N549H) 1000 57.6 HIPK1 1000 5.5 PHKG2 100 17.8 ALK 100-0.1 MAP4K4 1000 56.3 MARK3 1000 5.3 DYRK4 100 16.9 KIT 100-0.2 ABL(Q252H) 1000 51.8 PAK2 1000 5.3 PDGFRA(V561D) 100 16.9 CAMK4 100-0.2 MELK 1000 45.5 AKT3 1000 5.2 FGFR2(N549H) 100 16.0 P38-DELTA 100-0.3 RET 1000 44.1 PIM2 1000 5.1 FGFR3(K650E) 100 15.1 FYN 100-0.3 RET(Y791F) 1000 43.4 BTK 1000 4.9 ROCK1 100 14.4 PKD1 100-0.4 ABL(H396P) 1000 42.1 PRKG1B 1000 4.9 AMPK 100 14.1 MAPKAPK2 100-0.4 JAK2 1000 41.2 CDK2 1000 4.8 FLT3 100 13.7 SGK1 100-0.4 ABL(T315I) 1000 41.1 GSK3B 1000 4.8 MELK 100 11.5 BRSK2 100-0.7 DYRK1A 1000 40.1 CDK1 1000 4.7 EGFR(T790M) 100 11.2 PRKCD 100-0.8 ABL 1000 36.3 EPHA8 1000 4.6 PRAK 100 10.5 RPS6KB1 100-1.0 ITK 1000 34.9 CAMK II ALPHA 1000 4.4 RET(Y791F) 100 10.2 PHK GAMMA1 100-1.3 AMPK 1000 33.5 DCAMKL2 1000 4.1 PAK2 100 10.2 CHK2 100-1.5 PDGFRA 1000 31.2 PRKCE 1000 3.9 IKK_BETA 100 10.0 MARK3 100-1.8 YES 1000 29.9 SGK2 1000 3.7 PRKCH 100 10.0 ABL(H396P) 100-1.8 BLK 1000 29.2 PKCZ 1000 3.7 CSNK1G3 100 9.7 RPS6KA3 100-1.9 FGFR1 1000 26.7 PRKCH 1000 3.2 DYRK3 100 9.6 EPHA8 100-1.9 LYN 1000 25.1 PTK2B 1000 3.2 HCK 100 9.4 RPS6KA4 100-2.2 FGFR4 1000 22.4 PRAK 1000 3.0 FGFR4 100 8.9 ARG 100-2.4 DYRK3 1000 21.5 EGFR(T790M 1000 2.9 PRKCE 100 8.8 PIM1 100-2.7 KIT(T670I) 1000 21.4 MAPKAPK2 1000 2.9 HIPK2 100 8.7 RPS6KA1 100-2.7 ROCK2 1000 20.8 CHK1 1000 2.6 SYK 100 8.7 PRKCQ 100-2.9 TXK 1000 19.0 PRKCD 1000 2.2 DCAMKL2 100 8.6 SRC 100-3.2 IKK_BETA 1000 18.6 PIM1 1000 2.1 ABL 100 8.2 TSSK2 100-3.3 ARG 1000 18.0 RPS6KA1 1000 2.1 PRKG1A 100 8.1 RPS6KA5 100-3.5 AMPK α2 β1 g1 1000 17.6 PKD1 1000 1.9 PRKCN 100 8.0 LCK 100-3.5 PHK GAMMA1 1000 17.4 P38-ALPHA 1000 1.9 DYRK1A 100 7.9 MARK2 100-3.7 CLK2 1000 16.8 EGFR(T790M) 1000 1.9 RET 100 7.4 PTK2B 100-3.9 MARK1 1000 16.4 ERK2(MAPK1) 1000 1.8 MARK4 100 7.3 ERK2(MAPK1) 100-4.0 IRAK4 1000 16.1 ROCK1 1000 1.7 IRAK4 100 7.0 AKT2 100-4.1 MARK4 1000 16.0 DYRK4 1000 1.3 ITK 100 7.0 AKT1 100-4.1 SYK 1000 15.8 CSNK1G2 1000 1.2 ABL(Q252H) 100 6.9 P38-ALPHA 100-4.5 HIPK2 1000 14.7 SGK3 1000 1.1 MARK1 100 6.6 EGFR 100-4.8 HCK 1000 14.6 BRSK1 1000 0.5 AKT3 100 6.2 TSSK1 100-4.8 SRC 1000 14.2 CAMK II GAMMA 1000 0.4 EGFR(T790M 100 6.2 SGK3 100-5.3 RPS6KA3 1000 12.9 P38-GAMMA 1000 0.4 CAMK II BETA 100 5.9 CDK5/P25 100-5.4 PHKG2 1000 12.7 PIM3 1000 0.2 PRKD2 100 5.7 CAMK II 100-5.5 MARK2 1000 12.6 INSR 1000-0.3 DAPK3 100 5.0 RPS6KA2 100-5.9 ALK 1000 12.2 PRKCI 1000-0.5 BTK 100 4.7 STK3 100-6.0 CAMK II BETA 1000 12.1 TSSK2 1000-0.8 PRKG1B 100 4.1 P38-GAMMA 100-6.0 ROS1 1000 12.0 C-RAF 1000-0.8 PIM3 100 4.0 NEK2 100-6.0 CDK5/P25 1000 11.9 IGF1R 1000-0.8 PRKCI 100 3.9 C-RAF 100-6.5 PRKG1A 1000 11.8 CAMK II DELTA 1000-1.3 CHK1 100 3.6 GSK3B 100-6.8 LCK 1000 11.3 PRKCQ 1000-2.0 CSNK1D 100 3.5 YES 100-7.2 DAPK3 1000 10.3 MAPKAPK3 1000-2.3 DCAMKL1 100 3.5 PRKCB1 100-7.7 P38-DELTA 1000 9.8 FER 1000-2.5 INSR 100 3.4 CSNK1A1 100-7.8 EPHB1 1000 9.7 PKA 1000-3.3 AMPK α2 β1 g1 100 3.4 PRKCG 100-8.6 RPS6KA2 1000 9.6 NEK2 1000-4.9 ABL(T315I) 100 3.3 CSNK1G2 100-9.0 PRKCN 1000 9.4 P38-BETA 2 1000-5.4 BRSK1 100 3.3 PASK 100-10.1 DAPK1 1000 9.2 RPS6KB1 1000-6.2 CLK2 100 3.2 FGFR1 100-11.4 KIT 1000 8.9 PRKCG 1000-6.9 CDK2 100 3.1 PKA 100-11.5 CSNK1D 1000 8.9 MAPK3 1000-7.3 DAPK1 100 3.0 IGF1R 100-12.2 PRKCB1 1000 8.8 PRKD2 1000-9.6 PKCB2 100 2.8 PDGFRA 100-13.5 TSSK1 1000 8.1 PRKCA 1000-10.6 LYN 100 2.5 BLK 100-30.4 AKT2 1000-15.8 EPHB1 100 1.8 JAK2 100-35.1 [nm] Inh [nm] Inh 5

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 10 96.4 EPHA3 10 16.4 PKN1 10-14.2 JAK1 1 12.3 KDR 10 93.9 AKT2 BETA 10 15.6 TAOK2 10-17.5 GRK4 1 11.9 ABL1 10 81.7 BTK 10 15.4 MST4 10-39.8 SRPK1 1 11.5 FLT3 10 80.0 ZAP70 10 15.2 NEK2 10-56.3 STK22D 1 11.4 DYRK1A 10 79.0 SRC 10 15.0 BMX 10-77.3 AKT2 BETA 1 11.3 MET 10 78.8 AKT2 GAMMA 10 14.6 FLT3 1 59.7 PLK1 1 11.2 LCK 10 77.3 CDK5/P25 10 14.5 KDR 1 54.7 AKT2 GAMMA 1 10.6 NTRK3 10 77.1 DAPK1 10 14.5 AURKB 1 51.8 CAMK4 1 10.4 FGFR2 10 74.0 CHEK1 10 14.2 MET 1 43.9 PRKCI 1 10.2 MINK1 10 71.1 MAP2K1 10 13.5 LCK 1 37.9 PRKCZ 1 9.9 CLK2 10 69.8 GRK6 10 13.4 NTRK1 1 37.2 NEK2 1 9.8 NTRK1 10 68.9 CSNK1A1 10 13.3 NTRK3 1 34.5 PDK1 1 9.3 IRAK1 10 66.3 MAP3K8 10 12.9 FGFR2 1 33.5 CSNK2A1 1 9.2 GSK3A 10 65.6 SRPK1 10 12.5 DYRK1A 1 33.3 MAP2K6 1 9.1 GSK3B 10 64.0 CDK7 10 11.8 MINK1 1 29.2 ADRBK1 1 8.9 NUAK1 10 63.9 PASK 10 11.1 IRAK1 1 27.1 MAPK1 1 8.8 SYK 10 61.6 ROCK1 10 10.9 CSF1R 1 25.8 CDC42BPA 1 8.7 IRAK4 10 59.0 MAPK9 10 10.8 IRAK4 1 25.5 GSK3B 1 8.1 CSF1R 10 58.3 CDK9(CYCLIN T1) 10 10.8 RAF1(Y340D Y341D) 1 25.4 EPHB2 1 8.0 LRRK2 10 54.3 ADRBK1 10 10.4 LRRK2 1 25.4 TYK2 1 8.0 PIK3P110D/P85A 10 53.6 CSNK2A1 10 10.2 MAP2K1 1 23.8 TBK1 1 7.8 PKG2 10 53.5 ALK4 10 10.1 MAP3K8 1 23.4 MAPKAPK2 1 7.8 HCK 10 51.8 MAPK13 10 10.0 CLK2 1 22.8 RPS6KA3 1 7.8 AMPK 10 51.5 PLK1 10 10.0 MAPK14 ALPHA 1 20.8 BMX 1 7.7 SGK 10 49.8 NEK6 10 9.6 RPS6KB1 1 19.7 PRKACA 1 7.7 KIT 10 48.1 PRKACA 10 9.5 HCK 1 19.1 SRC 1 7.4 TEK 10 45.3 JAK1 10 9.4 CDK2 1 18.6 INSR 1 7.3 CHEK2 10 43.6 AKT1 ALPHA 10 9.1 PAK1 1 18.5 PRKCQ 1 7.1 JAK2 10 41.0 PRKCI 10 8.8 ZAP70 1 17.4 IKK_EPSILON 1 7.0 PTK6 10 39.1 IKK_EPSILON 10 8.6 SGK 1 17.4 TAOK2 1 7.0 NEK4 10 37.8 CDC42BPA 10 8.6 CHEK2 1 17.1 GRK6 1 7.0 GRK4 10 37.1 IKK_BETA 10 8.5 AMPK 1 16.5 CDK5/P25 1 6.7 ITK 10 35.8 MAPKAPK5 10 7.9 MAPK13 1 15.8 MAPKAPK5 1 6.7 TBK1 10 33.2 PRKCQ 10 7.7 IGF1R 1 15.3 IKK_BETA 1 6.6 AMPK 10 25.8 MAP2K6 10 7.4 PKG2 1 14.8 EPHA8 1 6.4 JAK3 10 25.6 EGFR 10 7.1 MARK2 1 14.2 CDK7 1 6.4 PDK1 10 25.4 RAF1(Y340D Y341D) 10 7.0 ABL1 1 14.1 JAK3 1 6.1 RPS6KB1 10 25.1 PRKCZ 10 6.9 NUAK1 1 13.6 PASK 1 5.9 STK22D 10 24.9 MAPK8 10 6.2 PKN1 1 13.6 AKT1 ALPHA 1 5.5 EPHA8 10 24.3 EPHB2 10 3.5 NEK4 1 13.5 PIM1 1 5.4 TYK2 10 23.7 CAMK4 10 0.8 BRAF 1 13.5 EPHA3 1 5.2 PIM1 10 23.6 INSR 10 0.6 BTK 1 13.4 CSNK1A1 1 4.8 MAPK14 ALPHA 10 20.1 BRAF 10-0.3 KIT 1 13.2 TEK 1 4.6 MAPKAPK2 10 19.8 SPHK1 10-2.1 SYK 1 13.2 CDK9(CYCLIN T1) 1 4.4 MARK2 10 19.7 ROCK2 10-5.8 ALK4 1 12.6 ITK 1 3.8 RPS6KA3 10 18.9 MAPK1 10-8.1 JAK2 1 12.5 AMPK 1 3.8 CDK2 10 18.3 ERBB2 10-10.51 GSK3A 1 12.5 MAPK9 1 3.7 IGF1R 10 16.706 PAK1 10-12.11 PTK6 1 12.5 ROCK1 1 2.5

S 7 7 Table S5. Profile of 5g continued MST4 1 2.2 AMPK ALPHA2 BETA1 GAMMA1 0.1 11.6 MAPK8 0.1 2.8 ERBB2 1 2.2 AKT2 GAMMA 0.1 11.3 AMPK ALPHA1 BETA1 GAMMA1 0.1 2.1 DAPK1 1 2.1 SRPK1 0.1 11.1 ITK 0.1 1.8 EGFR 1 0.6 SGK 0.1 10.9 CDK7 0.1 1.0 MAPK8 1 0.1 BTK 0.1 10.9 EGFR 0.1 0.5 ROCK2 1-0.2 TAOK2 0.1 10.9 ROCK1 0.1 0.0 CHEK1 1-1.2 NEK4 0.1 10.8 TEK 0.1-0.9 SPHK1 1-4.1 DYRK1A 0.1 10.7 MAPK9 0.1-1.5 PIK3P110D/P85A 1-4.8 PRKCI 0.1 10.5 TBK1 0.1-1.6 NEK6 1-7.4 INSR 0.1 9.9 EPHA3 0.1-1.7 MAP3K8 0.1 28.0 AKT2 BETA 0.1 9.8 ROCK2 0.1-1.9 LCK 0.1 27.2 KIT 0.1 9.7 SPHK1 0.1-3.4 RAF1( Y340D Y341D) 0.1 26.2 MAP2K6 0.1 9.7 ERBB2 0.1-4.3 MAP2K1 0.1 25.7 MAPKAPK2 0.1 9.5 NUAK1 0.1-10.5 FLT3 0.1 24.6 CDK9(CYCLIN T1) 0.1 9.4 PIK3P110D/P85A 0.1-16.2 CHEK1 0.1 23.2 ADRBK1 0.1 9.4 DAPK1 0.1 21.9 JAK3 0.1 9.3 KDR 0.1 20.0 PRKCZ 0.1 9.2 SYK 0.1 19.9 PTK6 0.1 9.2 LRRK2 0.1 19.9 CLK2 0.1 9.2 MINK1 0.1 19.9 PLK1 0.1 8.9 ABL1 0.1 19.9 GSK3A 0.1 8.6 IRAK4 0.1 19.8 EPHB2 0.1 8.6 AURKB 0.1 19.7 CSNK2A1 0.1 8.2 PAK1 0.1 19.6 JAK1 0.1 7.6 NTRK1 0.1 18.9 IKK_EPSILON 0.1 7.5 NTRK3 0.1 18.8 PASK 0.1 7.5 ZAP70 0.1 18.4 GSK3B 0.1 7.3 MAPK14 ALPHA 0.1 17.9 BMX 0.1 7.2 AKT1 ALPHA 0.1 17.2 PRKCQ 0.1 7.2 CDK2 0.1 17.0 IRAK1 0.1 7.1 HCK 0.1 16.7 MST4 0.1 6.9 IGF1R 0.1 16.4 CDK5/P25 0.1 6.6 NEK2 0.1 15.7 RPS6KA3 0.1 6.4 CSF1R 0.1 15.7 PRKACA 0.1 6.3 STK22D 0.1 15.5 CDC42BPA 0.1 6.3 MAPK13 0.1 14.5 PIM1 0.1 6.0 FGFR2 0.1 14.2 GRK6 0.1 5.6 CAMK4 0.1 13.6 RPS6KB1 0.1 5.5 GRK4 0.1 12.9 EPHA8 0.1 5.4 ALK4 0.1 12.8 MAPKAPK5 0.1 5.2 PKG2 0.1 12.8 NEK6 0.1 5.2 MAPK1 0.1 12.7 CSNK1A1 0.1 5.1 MET 0.1 12.7 TYK2 0.1 5.1 BRAF 0.1 12.3 IKK_BETA 0.1 4.6 PKN1 0.1 12.2 JAK2 0.1 4.4 MARK2 0.1 12.1 SRC 0.1 3.7 CHEK2 0.1 11.8 PDK1 0.1 3.3

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 1 93.5 CHK1 1 3.1 MET 0.1 60.6 SRC 0.1 0.2 MARK1 1 81.8 P38-GAMMA 1 2.9 AURKB 0.1 41.7 ABL(Q252H) 0.1-0.1 AURKC 1 76.2 ROCK2 1 2.0 FGFR3 0.1 41.1 RPS6KA2 0.1-0.2 AURKA 1 75.5 IGF1R 1 1.8 KDR 0.1 32.6 PRKG1A 0.1-0.5 AURKB 1 75.0 MAP4K4 1 1.8 AURKC 0.1 27.7 MAPK3 0.1-0.7 FLT3(D835Y) 1 73.7 AKT1 1 1.3 AURKA 0.1 27.6 SGK2 0.1-0.9 KDR 1 64.0 SRC 1 1.3 FGFR2 0.1 21.8 TSSK1 0.1-0.9 FGFR3 1 57.9 PKCZ 1 1.0 FGFR4 0.1 21.1 ABL(H396P) 0.1-0.9 FLT3 1 48.8 TSSK1 1 1.0 FLT3(D835Y) 0.1 19.1 SGK3 0.1-1.4 FGFR2 1 47.9 PAK2 1 0.8 MARK1 0.1 16.5 PRKCG 0.1-1.4 FGFR2(N549H) 1 40.5 ERK2(MAPK1) 1 0.8 FGFR2(N549H) 0.1 15.5 NEK2 0.1-1.5 DYRK1A 1 32.9 CHK2 1 0.7 PIM2 0.1 15.4 CAMK4 0.1-1.6 CAMK II DELTA 1 25.1 PRKCH 1 0.2 RPS6KA4 0.1 15.2 AMPK 0.1-1.7 ABL(Q252H) 1 24.9 PKD1 1 0.2 EGFR 0.1 13.3 P38-BETA 2 0.1-1.8 SGK2 1 23.1 PKA 1-1.1 INSR 0.1 12.0 AKT1 0.1-2.2 ABL 1 22.9 HCK 1-1.6 RPS6KB1 0.1 10.0 MARK3 0.1-2.4 FGFR4 1 19.6 CAMK II GAMMA 1-1.6 RPS6KA5 0.1 8.0 MAPKAPK2 0.1-2.6 AMPK 1 17.2 LCK 1-1.7 CSNK1D 0.1 7.6 GSK3B 0.1-2.7 PIM2 1 16.5 RPS6KA3 1-1.7 PRKD2 0.1 7.3 CSNK1A1 0.1-2.8 PDGFRA 1 15.5 PRKCN 1-1.8 MAP4K4 0.1 7.1 P38-DELTA 0.1-3.2 RPS6KB1 1 13.5 LYN 1-2.3 ABL 0.1 6.9 CHK2 0.1-3.5 ABL(T315I) 1 12.7 PRKD2 1-2.6 SGK1 0.1 6.8 FYN 0.1-3.7 BRSK1 1 12.5 RPS6KA1 1-3.0 DYRK1A 0.1 6.2 IGF1R 0.1-3.7 SGK1 1 11.5 MARK3 1-3.3 C-RAF 0.1 6.2 PIM1 0.1-4.1 CSNK1D 1 11.1 C-RAF 1-3.8 IRAK4 0.1 6.0 PRKCE 0.1-4.6 TSSK2 1 10.5 CDK2 1-3.9 BRSK1 0.1 5.6 PKD1 0.1-5.2 PRKG1A 1 9.6 CSNK1A1 1-4.1 MAPKAPK3 0.1 5.4 P38-GAMMA 0.1-5.4 ABL(H396P) 1 9.4 P38-BETA 2 1-4.1 PRKCQ 0.1 5.2 ERK2(MAPK1) 0.1-5.5 GSK3B 1 9.3 PRKG1B 1-5.9 PRKCD 0.1 5.1 PKA 0.1-5.5 EGFR 1 9.2 PKCB2 1-6.0 CAMK II DELTA 0.1 4.9 PRKCH 0.1-6.7 RPS6KA2 1 9.0 CAMK4 1-6.4 STK3 0.1 4.4 PKCZ 0.1-6.7 DCAMKL2 1 8.4 NEK2 1-7.5 FLT3 0.1 4.2 CHK1 0.1-7.9 MAPKAPK2 1 8.0 PRAK 1-7.9 PRKCA 0.1 3.1 LYN 0.1-8.7 STK3 1 7.9 IRAK4 1-8.2 AKT3 0.1 3.1 PRKCN 0.1-8.8 SYK 1 7.6 P38-DELTA 1-9.3 ROCK2 0.1 3.0 PRKCB1 0.1-9.3 AKT2 1 7.1 CAMK II BETA 1-19.3 PRKG1B 0.1 2.6 IKK_BETA 0.1-12.0 P38-ALPHA 1 6.9 FER 1-24.2 PKCB2 0.1 2.6 RPS6KA1 0.1-12.4 INSR 1 6.4 LCK 0.1 2.4 P38-ALPHA 0.1-13.9 FYN 1 6.0 SYK 0.1 1.9 CAMK II GAMMA 0.1-17.9 PRKCE 1 5.9 AKT2 0.1 1.7 PDGFRA 0.1-19.1 MAPKAPK3 1 5.7 DCAMKL2 0.1 1.7 CAMK II BETA 0.1-21.3 IKK_BETA 1 4.2 PAK2 0.1 1.7 TSSK2 0.1-37.0 RPS6KA5 1 4.1 BMX 0.1 1.6 FER 0.1-53.2 SGK3 1 3.9 ABL(T315I) 0.1 1.4 HCK 0.1-59.1 PIM1 1 3.7 PRAK 0.1 1.3 MAPK3 1 3.6 RPS6KA3 0.1 1.2 AKT3 1 3.135 CDK2 0.1 1.2

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) 1000 98.4 BTK 1000 1.1 MET(M1250T) 100 87.0 MARK3 100 0.7 MET 1000 95.7 RPS6KA4 1000 1.0 MET 100 74.1 PKCZ 100 0.7 RPS6KA3 1000 62.5 SGK3 1000 1.0 RPS6KB1 100 10.9 P38-BETA 2 100 0.6 AURKB 1000 27.6 FGFR2(N549H) 1000 0.9 PRKCG 100 10.9 FGFR3 100 0.5 AURKA 1000 22.4 MAPKAPK2 1000 0.8 PTK2B 100 10.0 CSNK1G3 100 0.3 PDGFRA(V561D) 1000 21.5 CAMK II BETA 1000 0.8 AMPK 100 10.0 MARK4 100 0.0 MST1R 1000 20.5 PRKCQ 1000 0.5 EPHA8 100 9.4 PIM2 100-0.1 AXL 1000 20.3 MAPKAPK3 1000 0.5 PRKCE 100 9.3 MAPKAPK3 100-0.3 AURKC 1000 18.6 DYRK4 1000 0.5 SGK3 100 9.0 BLK 100-0.5 KDR 1000 16.8 FER 1000 0.5 AURKB 100 8.0 GSK3B 100-0.6 BLK 1000 16.6 IRAK4 1000 0.3 PHK GAMMA1 100 7.9 CHK1 100-0.6 PRKCA 1000 15.8 CDK5/P25 1000 0.3 PRKD2 100 7.5 SYK 100-0.6 MER 1000 15.5 PIM3 1000 0.3 AURKC 100 7.5 PRKCI 100-0.6 CSNK1G3 1000 15.2 DAPK1 1000 0.1 HIPK1 100 7.2 YES 100-0.7 PAK2 1000 13.1 PRKG1B 1000 0.1 PRKCH 100 7.2 EGFR(T790M L858R) 100-0.8 PKD1 1000 11.0 PRKD2 1000 0.0 FRK 100 7.1 ABL 100-1.0 NTRK3 1000 10.4 HIPK1 1000-0.1 PKD1 100 7.0 FLT3(D835Y) 100-1.0 EGFR 1000 9.3 MAP4K4 1000-0.2 ALK 100 6.9 MAPKAPK2 100-1.1 P38-GAMMA 1000 8.3 PRKCE 1000-0.4 PASK 100 6.7 ERK2(MAPK1) 100-1.2 ROCK1 1000 8.2 SYK 1000-0.5 NEK2 100 6.6 SGK2 100-1.4 ABL(Q252H) 1000 8.1 MAPK3 1000-0.5 AXL 100 6.1 DYRK3 100-1.4 FGFR2 1000 7.8 CSNK1A1 1000-0.6 P38-GAMMA 100 6.1 AKT2 100-1.5 SRC 1000 6.6 RPS6KA5 1000-0.9 NTRK3 100 6.0 KIT 100-1.6 KIT 1000 6.6 P38-BETA 2 1000-1.0 RSK4 100 5.9 BRSK1 100-1.6 FRK 1000 6.2 MARK1 1000-1.3 DYRK1A 100 5.6 CAMK II BETA 100-1.6 JAK2 1000 5.9 AMPK α2 β1 g1 1000-1.5 TSSK1 100 5.4 CAMK4 100-1.7 CSNK1G2 1000 5.8 TSSK1 1000-1.6 AMPK α2 β1 g1 100 5.1 FGFR3(K650E) 100-1.7 DCAMKL2 1000 5.8 PRKG1A 1000-1.6 INSR 100 5.1 ABL(Q252H) 100-1.7 MELK 1000 5.7 MARK2 1000-1.8 ROS1 100 5.1 DAPK3 100-1.7 P38-ALPHA 1000 5.1 ITK 1000-1.8 MAP4K4 100 5.0 HCK 100-1.8 EPHA8 1000 5.1 RPS6KA2 1000-2.5 CSNK1A1 100 5.0 P38-DELTA 100-1.8 FGFR3 1000 4.9 CAMK II GAMMA 1000-2.8 KDR 100 4.9 SGK1 100-2.2 PKA 1000 4.8 CSNK1D 1000-2.9 PRKG1B 100 4.5 RPS6KA1 100-2.2 STK3 1000 4.5 LCK 1000-2.9 ROCK1 100 4.2 TSSK2 100-2.3 ROCK2 1000 4.2 CAMK II ALPHA 1000-3.1 CHK2 100 4.2 PIM1 100-2.4 TYRO3 1000 4.2 IKK_BETA 1000-3.1 TYRO3 100 4.1 ROCK2 100-2.6 CLK2 1000 4.1 PIM2 1000-3.2 AURKA 100 3.7 JAK2 100-2.8 RPS6KA1 1000 4.0 LYN 1000-3.2 HIPK2 100 3.6 IGF1R 100-3.0 HIPK2 1000 3.9 BRSK2 1000-3.3 LYN 100 3.5 KIT(T670I) 100-3.3 P38-DELTA 1000 3.9 GSK3B 1000-3.3 CLK2 100 3.4 LCK 100-3.4 PDGFRA 1000 3.9 FGFR4 1000-3.3 BRSK2 100 3.4 FGFR4 100-3.4 ERK2(MAPK1) 1000 3.7 RPS6KB1 1000-3.3 PKCB2 100 3.3 PIM3 100-3.4 INSR 1000 3.5 CAMK4 1000-3.4 PRKCQ 100 3.3 CAMK II GAMMA 100-3.5 FLT3(D835Y) 1000 3.4 MARK4 1000-3.4 C-RAF 100 3.2 MST1R 100-3.6 EPHB1 1000 3.3 ARG 1000-3.4 ABL(T315I) 100 2.7 CDK1 100-3.9 BMX 1000 3.2 EGFR(T790M L858R) 1000-3.6 MELK 100 2.7 FYN 100-4.2 PASK 1000 3.2 FLT3 1000-4.0 CSNK1G2 100 2.7 RPS6KA2 100-4.2 HCK 1000 3.1 PIM1 1000-4.4 ARG 100 2.6 PRAK 100-4.3 AKT2 1000 3.1 MARK3 1000-4.4 PKA 100 2.5 MARK2 100-4.6 PRAK 1000 2.9 PHKG2 1000-4.4 MER 100 2.5 PRKG1A 100-5.0 CHK1 1000 2.9 DAPK3 1000-4.5 DAPK1 100 2.4 ITK 100-5.0 DYRK3 1000 2.9 CAMK II DELTA 1000-4.6 CDK5/P25 100 2.2 TXK 100-5.1 RET 1000 2.8 KIT(T670I) 1000-4.9 BTK 100 2.1 RPS6KA5 100-5.3 FYN 1000 2.7 AMPK 1000-5.1 PAK2 100 2.1 MARK1 100-5.4 NEK2 1000 2.7 YES 1000-5.3 DCAMKL2 100 2.0 FLT3 100-5.8 RET(Y791F) 1000 2.7 PRKCD 1000-5.4 RET 100 1.9 EGFR 100-5.8 PTK2B 1000 2.5 DCAMKL1 1000-5.4 STK3 100 1.9 RPS6KA4 100-5.8 PRKCN 1000 2.2 SGK1 1000-6.0 DYRK4 100 1.8 CSNK1D 100-7.1 FGFR3(K650E) 1000 2.1 CDK2 1000-6.6 MAPK3 100 1.7 AKT1 100-7.2 AKT3 1000 2.1 DYRK1A 1000-6.7 EGFR(T790M) 100 1.6 FGFR2(N549H) 100-8.4 AKT1 1000 1.7 SGK2 1000-7.4 FGFR1 100 1.5 CAMK II ALPHA 100-8.9 BRSK1 1000 1.6 FGFR1 1000-7.9 PDGFRA 100 1.5 PRKCA 100-9.4 ABL 1000 1.6 RSK4 1000-8.4 FGFR2 100 1.4 CDK2 100-10.0 PRKCI 1000 1.4 PRKCH 1000-8.7 ABL(H396P) 100 1.4 IRAK4 100-10.2 ABL(T315I) 1000 1.3 C-RAF 1000-9.1 PRKCB1 100 1.2 BMX 100-10.4 IGF1R 1000 1.3 ALK 1000-9.5 IKK_BETA 100 1.2 P38-ALPHA 100-10.6 TSSK2 1000 1.3 TXK 1000-9.7 SRC 100 1.1 PDGFRA(V561D) 100-12.5 CHK2 1000 1.2 EGFR(T790M) 1000-11.1 RET(Y791F) 100 1.1 AKT3 100-12.5 PKCZ 1000 1.2 PRKCB1 1000-12.2 EPHB1 100 1.0 FER 100-14.2 PHK GAMMA1 1000 1.2 ROS1 1000-12.4 PHKG2 100 1.0 PRKCN 100-21.2 CDK1 1000 1.2 PKCB2 1000-13.3 PRKCD 100 0.7 CAMK II DELTA 100-22.5 ABL(H396P) 1000 1.1 PRKCG 1000-15.0 RPS6KA3 100 0.7 DCAMKL1 100-26.1

S 10 10 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 0.1 99.3 CDK2 0.1-0.9 MET 0.01 94.7 IKK_BETA 0.01-0.2 ABL(Q252H) 0.1 26.3 GSK3B 0.1-1.0 CAMK II BETA 0.01 79.2 MAPKAPK3 0.01-0.3 AURKB 0.1 17.0 AKT1 0.1-1.1 TSSK2 0.01 55.4 PKCZ 0.01-0.3 FLT3(D835Y) 0.1 16.7 IRAK4 0.1-1.2 ABL(T315I) 0.01 19.6 FYN 0.01-0.4 RPS6KA1 0.1 13.5 RPS6KB1 0.1-1.3 IRAK4 0.01 19.1 CDK2 0.01-0.9 CAMK II DELTA 0.1 13.2 AKT2 0.1-1.6 PKCB2 0.01 14.8 MAPK3 0.01-1.0 AURKA 0.1 13.1 MAPKAPK2 0.1-1.9 FGFR4 0.01 12.6 RPS6KA3 0.01-1.1 FGFR1 0.1 10.7 HCK 0.1-2.0 PRKCD 0.01 11.0 P38-ALPHA 0.01-1.2 FGFR2 0.1 8.7 PRKCE 0.1-2.0 BRSK1 0.01 9.9 INSR 0.01-1.4 ROCK2 0.1 8.4 MARK3 0.1-2.2 RPS6KA4 0.01 9.3 P38-BETA 2 0.01-1.5 RPS6KA3 0.1 8.1 NEK2 0.1-2.3 DCAMKL2 0.01 8.7 MARK3 0.01-1.6 PRKCB1 0.1 6.7 ABL(T315I) 0.1-2.4 DYRK1A 0.01 7.6 RPS6KA1 0.01-1.6 SYK 0.1 6.2 ABL(H396P) 0.1-2.5 TSSK1 0.01 7.3 GSK3B 0.01-1.8 PKCB2 0.1 6.0 INSR 0.1-2.5 RPS6KB1 0.01 6.8 ABL 0.01-1.8 AURKC 0.1 5.6 IGF1R 0.1-2.7 CAMK II GAMMA 0.01 6.3 BRSK2 0.01-1.9 ABL 0.1 5.5 CSNK1D 0.1-2.8 ROCK2 0.01 5.8 ERK2(MAPK1) 0.01-2.5 AKT3 0.1 5.2 RPS6KA5 0.1-2.9 BTK 0.01 5.6 NEK2 0.01-2.6 BTK 0.1 5.1 MARK1 0.1-2.9 P38-DELTA 0.01 5.5 PKD1 0.01-2.8 FLT3 0.1 5.0 BMX 0.1-3.8 IGF1R 0.01 5.0 CHK1 0.01-2.8 BRSK2 0.1 4.8 PRKCQ 0.1-3.8 ABL(H396P) 0.01 4.8 LCK 0.01-2.9 SGK2 0.1 4.7 PKD1 0.1-4.1 ARG 0.01 4.8 PRKCG 0.01-3.2 PKCZ 0.1 4.6 SRC 0.1-4.2 PIM2 0.01 4.3 P38-GAMMA 0.01-3.3 AMPK 0.1 4.3 DYRK1A 0.1-4.3 PRKCB1 0.01 4.1 SGK1 0.01-3.6 KDR 0.1 4.1 PRKG1B 0.1-4.6 FGFR1 0.01 3.8 SRC 0.01-3.8 PDGFRA 0.1 4.1 P38-GAMMA 0.1-4.6 ABL(Q252H) 0.01 3.6 KDR 0.01-4.1 PRKG1A 0.1 3.8 CAMK II BETA 0.1-4.6 PRKCQ 0.01 3.4 SGK2 0.01-4.2 PAK2 0.1 3.6 CHK2 0.1-5.1 PKA 0.01 3.2 PRKCH 0.01-4.3 FGFR2(N549H) 0.1 3.3 TSSK1 0.1-5.2 AURKB 0.01 3.2 SYK 0.01-4.6 LCK 0.1 3.3 PRKCN 0.1-5.2 PRKCN 0.01 3.2 AURKA 0.01-4.6 ARG 0.1 3.1 PRKD2 0.1-5.2 CAMK4 0.01 2.8 FGFR2(N549H) 0.01-4.6 PIM2 0.1 2.9 RPS6KA4 0.1-5.3 AKT1 0.01 2.8 PRAK 0.01-4.7 PRKCD 0.1 2.4 P38-DELTA 0.1-5.7 HCK 0.01 2.6 PIM1 0.01-4.8 CAMK II GAMMA 0.1 2.1 CHK1 0.1-6.0 FLT3(D835Y) 0.01 2.3 RPS6KA5 0.01-5.1 RPS6KA2 0.1 2.0 TSSK2 0.1-6.2 AMPK 0.01 2.3 CHK2 0.01-5.2 PRKCG 0.1 1.8 PIM1 0.1-6.2 PRKG1B 0.01 2.1 LYN 0.01-6.0 MAPK3 0.1 1.7 P38-ALPHA 0.1-6.5 CSNK1D 0.01 2.0 PRKD2 0.01-6.3 PRAK 0.1 1.6 PRKCH 0.1-6.9 PRKG1A 0.01 2.0 FER 0.01-6.3 PRKCA 0.1 1.3 FYN 0.1-7.3 CAMK II DELTA 0.01 1.7 AKT3 0.01-6.5 FER 0.1 0.8 SGK3 0.1-7.3 STK3 0.01 1.5 MARK2 0.01-7.0 P38-BETA 2 0.1 0.7 BRSK1 0.1-7.5 CSNK1A1 0.01 1.4 FGFR2 0.01-8.2 STK3 0.1 0.6 LYN 0.1-9.2 C-RAF 0.01 1.4 MAP4K4 0.01-8.5 IKK_BETA 0.1 0.6 MARK2 0.1-10.0 PRKCE 0.01 1.3 RPS6KA2 0.01-8.9 C-RAF 0.1 0.6 MAP4K4 0.1-10.7 MAPKAPK2 0.01 0.4 BMX 0.01-12.1 PKA 0.1 0.4 FGFR3 0.1-12.3 PRKCA 0.01 0.2 SGK3 0.01-13.2 ERK2(MAPK1) 0.1-0.1 CAMK4 0.1-12.8 FLT3 0.01 0.2 PDGFRA 0.01-15.7 MAPKAPK3 0.1-0.3 FGFR4 0.1-18.4 PAK2 0.01 0.1 AURKC 0.01-15.8 CSNK1A1 0.1-0.5 SGK1 0.1-31.9 MARK1 0.01-0.1 EGFR 0.01-19.5 DCAMKL2 0.1-0.7 EGFR 0.1-36.5 AKT2 0.01-0.2 FGFR3 0.01-38.6

S 11 11 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 1 96.0 NEK2 1-2.2 MAP4K4 0.1 4.1 P38-DELTA 0.1-4.9 BTK 1 65.0 PKCB2 1-2.5 ROCK2 0.1 3.6 CSNK1A1 0.1-5.0 ABL 1 61.5 STK3 1-2.7 ARG 0.1 3.3 KDR 0.1-5.2 KDR 1 41.8 PRKG1A 1-2.7 ABL(T315I) 0.1 3.3 DCAMKL2 0.1-6.0 IRAK4 1 40.2 P38-ALPHA 1-2.7 P38-ALPHA 0.1 3.3 CAMK II GAMMA 0.1-7.4 FLT3 1 36.8 BMX 1-2.8 SRC 0.1 3.2 PAK2 0.1-7.9 MARK1 1 33.5 CAMK4 1-4.2 PRKCH 0.1 3.1 PKD1 0.1-8.3 AURKA 1 26.8 MARK3 1-4.3 FGFR2 0.1 3.0 PKCZ 0.1-8.3 PIM2 1 16.7 PRKCN 1-4.4 NEK2 0.1 2.7 FGFR4 0.1-8.7 MAP4K4 1 15.7 ERK2(MAPK1) 1-4.4 DYRK1A 0.1 2.3 SGK2 0.1-9.0 FYN 1 15.1 PRKCE 1-5.1 CAMK II BETA 0.1 2.1 PRKCE 0.1-9.1 CAMK II DELTA 1 15.1 RPS6KA2 1-5.3 AKT3 0.1 2.0 PRKCN 0.1-11.5 PRKD2 1 15.0 RPS6KA3 1-6.0 BRSK1 0.1 2.0 FGFR3 0.1-12.6 AMPK 1 11.6 PRKCD 1-8.2 MARK3 0.1 2.0 MARK2 0.1-12.6 LYN 1 9.6 PIM1 1-8.3 IKK_BETA 0.1 1.9 PRKCQ 0.1-15.1 SGK1 1 9.6 IGF1R 1-8.3 CDK2 0.1 1.9 BMX 0.1-17.3 CSNK1D 1 7.4 BRSK2 1-9.5 ABL(Q252H) 0.1 1.4 PRKCB1 0.1-20.8 BRSK1 1 5.2 CSNK1A1 1-11.0 FER 0.1 1.2 PRKCA 0.1-28.0 AKT1 1 5.2 P38-GAMMA 1-11.8 CHK1 0.1 1.1 PRKCD 0.1-38.2 MAPK3 1 2.8 SGK2 1-11.8 ERK2(MAPK1) 0.1 1.1 INSR 0.1-127.8 PRKCG 1 2.7 RPS6KA4 1-17.3 GSK3B 0.1 1.0 MARK2 1 2.4 PRKCB1 1-18.2 RPS6KA5 0.1 0.7 DYRK1A 1 2.1 MET 0.1 88.8 AKT2 0.1 0.7 PRKCQ 1 2.1 AURKB 0.1 34.7 TSSK2 0.1 0.7 SRC 1 2.1 CAMK II DELTA 0.1 32.0 SGK3 0.1 0.3 GSK3B 1 2.0 IRAK4 0.1 31.2 RPS6KA3 0.1 0.2 AKT2 1 1.9 PIM2 0.1 25.2 RPS6KA4 0.1 0.2 CDK2 1 1.4 ABL 0.1 23.1 STK3 0.1-0.1 PRKCH 1 1.4 AURKC 0.1 20.9 FLT3(D835Y) 0.1-0.3 MAPKAPK2 1 1.3 CSNK1D 0.1 20.4 BRSK2 0.1-1.3 PKCZ 1 1.3 LCK 0.1 18.4 P38-BETA 2 0.1-1.4 PAK2 1 0.9 PDGFRA 0.1 17.5 PKA 0.1-1.4 CHK1 1 0.4 LYN 0.1 17.3 RPS6KA2 0.1-1.6 SYK 1 0.3 AMPK 0.1 15.4 CAMK4 0.1-1.9 PKA 1 0.3 ABL(H396P) 0.1 14.9 HCK 0.1-2.1 RPS6KA1 1 0.0 AURKA 0.1 14.5 PRKG1B 0.1-2.5 RPS6KB1 1 0.0 SYK 0.1 13.6 TSSK1 0.1-2.7 PRKCA 1-0.1 AKT1 0.1 12.6 MAPKAPK3 0.1-2.7 DCAMKL2 1-0.3 FLT3 0.1 11.0 RPS6KB1 0.1-2.7 RPS6KA5 1-0.4 RPS6KA1 0.1 8.6 FGFR2(N549H) 0.1-2.9 CHK2 1-0.5 MAPKAPK2 0.1 7.6 P38-GAMMA 0.1-3.3 SGK3 1-0.7 SGK1 0.1 7.2 PRKD2 0.1-3.8 C-RAF 1-0.8 MAPK3 0.1 7.2 PRKG1A 0.1-3.8 PRAK 1-1.1 PRKCG 0.1 6.2 MARK1 0.1-3.9 LCK 1-1.2 C-RAF 0.1 5.4 PRAK 0.1-4.3 ROCK2 1-1.6 IGF1R 0.1 4.9 PKCB2 0.1-4.3 PKD1 1-1.9 CHK2 0.1 4.63 PIM1 0.1-4.7 INSR 1-1.996 FYN 0.1 4.37 EGFR 0.1-4.8

S 12 12 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 100 92.5 LYN 100 3.6 MET(M1250T) 10 72.3 NEK2 10 0.9 MET(M1250T) 100 92.1 ABL 100 3.4 MET 10 57.3 PRKCI 10 0.9 MST1R 100 37.6 RPS6KA1 100 3.4 ROS1 10 21.2 AKT1 10 0.8 ROCK2 100 21.2 FRK 100 3.2 ALK 10 17.8 BLK 10 0.8 DYRK3 100 19.6 RSK4 100 3.2 EPHA8 10 15.6 CSNK1G3 10 0.7 PDGFRA(V561D) 100 19.6 INSR 100 3.1 RET(Y791F) 10 14.9 ABL(T315I) 10 0.6 PASK 100 18.4 FGFR1 100 2.8 CAMK II GAMMA 10 13.5 MARK1 10 0.6 SGK3 100 17.7 CAMK4 100 2.3 DAPK1 10 13.1 FGFR2 10 0.5 STK3 100 17.7 MARK4 100 2.2 MST1R 10 11.8 BRSK2 10 0.3 FGFR2 100 16.5 PRKCG 100 2.1 MER 10 11.0 PDGFRA 10 0.2 BLK 100 15.8 AKT2 100 2.0 RET 10 10.4 FRK 10 0.2 AURKC 100 15.4 TSSK1 100 1.9 LYN 10 9.1 AURKB 10-0.1 ITK 100 15.3 CDK1 100 1.6 JAK2 10 8.9 HIPK2 10-0.3 PHK GAMMA1 100 14.9 PRKCB1 100 1.4 CDK5/P25 10 8.4 PRKCE 10-0.5 KIT 100 13.6 GSK3B 100 1.3 BTK 10 8.4 FYN 10-0.7 PHKG2 100 13.3 CSNK1G2 100 1.3 NTRK3 10 8.4 MAPKAPK2 10-0.8 FGFR2(N549H) 100 12.4 CHK1 100 1.3 DYRK4 10 8.3 PTK2B 10-1.0 RET 100 12.1 PRKCI 100 1.0 LCK 10 8.2 FER 10-1.0 DYRK4 100 12.1 RET(Y791F) 100 1.0 RPS6KB1 10 8.0 FLT3 10-1.0 DCAMKL1 100 12.0 AMPK 100 1.0 STK3 10 7.9 BMX 10-1.0 JAK2 100 11.9 TSSK2 100 0.7 MARK4 10 7.1 DYRK1A 10-1.0 AURKB 100 11.7 ABL(H396P) 100 0.5 PIM3 10 7.0 TYRO3 10-1.1 CDK2 100 11.7 EPHA8 100 0.3 FGFR1 10 6.8 SGK2 10-1.3 AXL 100 11.7 DAPK3 100 0.3 RPS6KA2 10 6.7 AKT2 10-1.3 PKD1 100 11.3 ABL(T315I) 100 0.3 PHK GAMMA1 10 6.4 YES 10-1.4 PRKCN 100 10.4 FER 100 0.2 ROCK2 10 6.2 DAPK3 10-1.6 RPS6KA2 100 10.4 DAPK1 100 0.1 DCAMKL1 10 5.9 AURKC 10-1.6 CSNK1A1 100 10.2 SGK2 100-0.1 RSK4 10 5.8 P38-ALPHA 10-1.7 BRSK2 100 9.7 AMPK α2 β1 g1 100-0.1 AURKA 10 5.8 PRKG1B 10-1.8 FGFR4 100 9.7 PKA 100-0.1 EPHB1 10 5.1 MAP4K4 10-2.1 MER 100 9.5 IKK_BETA 100-0.4 GSK3B 10 4.9 BRSK1 10-2.1 MAP4K4 100 9.2 EGFR(T790M L858R) 100-0.4 SGK3 10 4.9 CDK2 10-2.1 TYRO3 100 9.2 NTRK3 100-0.4 PAK2 10 4.4 FGFR3(K650E) 10-2.1 PRKG1A 100 9.2 MELK 100-0.5 CAMK II BETA 10 4.4 RPS6KA4 10-2.3 SGK1 100 9.1 MARK3 100-0.6 CSNK1G2 10 4.3 PRKCN 10-2.4 PDGFRA 100 9.0 CSNK1G3 100-0.7 CHK1 10 4.3 PKD1 10-2.4 CSNK1D 100 8.9 MAPKAPK2 100-0.9 PDGFRA(V561D) 10 4.1 ARG 10-2.4 PRKCD 100 8.3 EGFR 100-1.0 IGF1R 10 3.9 MARK2 10-2.5 MAPK3 100 8.1 PRKCQ 100-1.3 ABL 10 3.8 PRKCH 10-2.5 DCAMKL2 100 7.8 SRC 100-1.4 IKK_BETA 10 3.8 PRAK 10-2.5 FGFR3 100 7.8 MARK2 100-1.4 KDR 10 3.5 ITK 10-2.6 ABL(Q252H) 100 7.6 BRSK1 100-1.6 HCK 10 3.5 CHK2 10-2.6 HCK 100 7.6 YES 100-1.7 PHKG2 10 3.4 AKT3 10-2.7 AKT1 100 7.4 ALK 100-2.0 RPS6KA5 10 3.4 CSNK1A1 10-2.8 LCK 100 7.3 CDK5/P25 100-2.0 PRKG1A 10 3.2 AMPK 10-2.8 HIPK2 100 7.0 RPS6KA4 100-2.1 INSR 10 3.1 AXL 10-2.8 AURKA 100 6.9 FLT3 100-2.3 ROCK1 10 3.1 FGFR4 10-3.0 PRAK 100 6.9 P38-ALPHA 100-2.6 AMPK α2 β1 g1 10 2.9 FLT3(D835Y) 10-3.0 PTK2B 100 6.8 NEK2 100-2.6 PKA 10 2.8 TSSK1 10-3.1 FLT3(D835Y) 100 6.8 CAMK II GAMMA 100-2.8 TSSK2 10 2.5 CSNK1D 10-3.5 IRAK4 100 6.7 P38-DELTA 100-3.0 ABL(Q252H) 10 2.5 MARK3 10-3.5 ROS1 100 6.6 FYN 100-3.0 CAMK II DELTA 10 2.4 KIT 10-3.5 DYRK1A 100 6.4 PRKD2 100-3.6 PRKCG 10 2.4 RPS6KA3 10-3.6 PKCB2 100 5.7 CAMK II ALPHA 100-3.8 ABL(H396P) 10 2.2 FGFR2(N549H) 10-3.9 MARK1 100 5.5 RPS6KA3 100-3.8 SRC 10 2.2 FGFR3 10-4.0 BTK 100 5.5 RPS6KA5 100-4.2 C-RAF 10 2.2 EGFR(T790M) 10-4.4 AKT3 100 5.2 ARG 100-4.3 CAMK4 10 2.1 P38-DELTA 10-5.2 PRKCA 100 5.2 SYK 100-4.4 SGK1 10 2.1 TXK 10-5.5 P38-GAMMA 100 5.1 PIM1 100-4.6 P38-GAMMA 10 2.0 PRKCA 10-5.5 FGFR3(K650E) 100 5.1 ERK2(MAPK1) 100-4.8 HIPK1 10 1.9 CDK1 10-5.7 PAK2 100 4.9 KIT(T670I) 100-4.9 MAPK3 10 1.8 PRKCB1 10-6.0 P38-BETA 2 100 4.9 PRKG1B 100-4.9 EGFR(T790M L858R) 10 1.8 CLK2 10-6.3 TXK 100 4.8 CAMK II BETA 100-5.2 PKCZ 10 1.8 PRKCQ 10-6.4 PIM3 100 4.6 CLK2 100-5.2 DYRK3 10 1.8 EGFR 10-7.2 HIPK1 100 4.6 CAMK II DELTA 100-6.5 MELK 10 1.7 P38-BETA 2 10-7.7 C-RAF 100 4.5 BMX 100-7.1 DCAMKL2 10 1.7 MAPKAPK3 10-8.0 PIM2 100 4.3 EGFR(T790M) 100-7.2 PRKD2 10 1.6 PRKCD 10-8.7 RPS6KB1 100 4.2 CHK2 100-7.4 PASK 10 1.5 IRAK4 10-10.0 MAPKAPK3 100 4.1 IGF1R 100-7.9 PKCB2 10 1.4 ERK2(MAPK1) 10-10.5 ROCK1 100 4.0 EPHB1 100-8.0 SYK 10 1.3 PIM2 10-11.0 PRKCE 100 3.8 KDR 100-10.0 RPS6KA1 10 1.3 PIM1 10-11.4 PKCZ 100 3.6 PRKCH 100-14.9 KIT(T670I) 10 1.3 CAMK II ALPHA 10-12.3

S 13 13 Table S11. X-ray structure-determination statistics of 16/c-Met co-crystal structure Compound 16/c-Met co-crystal Resolution range (Å) 50.0-2.00 Unit cell parameters (Å) Space group a=40.134, b=63.789, c=112.435 P212121 Molecules per a.s.u. 1 Rsym () 8.3 (40.7) Completeness () 98.6 (99.1) Redundancy 5.2 R 20.66 Rfree 25.70 MolProbity score 1.73 Residues in most-favored region of Ramachandran plot () 96.6 RMSD bond lengths (Å) 0.010 RMSD bond angles ( ) 1.11 Numbers in parentheses denote statisitics in the highest resolution bin (2.07-2.00 Angstroms)

S 14 14 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 0 100 100 Vehicle BID 0 100 100 MK-2461 100, BID 90.6 31.4 100 11r 100, QD 67.1 46.5 99 11r 10, BID 18.6 87.8 103 11r 30, BID 57.5 50.6 103 11r 100, BID 86.2 31.5 97 Figure S1. Plasma entrations of 11r following the last dose in the GTL-16 Tumor Xenograft Efficacy Study

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 13 1.26 0.53 16 0.23 0.07 20 0.12 0.06 24 0.18 0.14 13 20.05 8.84 16 4.77 3.49 20 3.27 0.74 24 3.77 2.28 13 5.78 1.24 16 0.97 0.37 20 0.55 0.23 24 0.28 0.15 1 19.53 6.71 2 3.74 1.60 4 2.51 0.88 8 2.10 1.33 12 2.12 1.04 24 0.04 0.02 15

S 16 16 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 359.2. 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). 17.7 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 373.2. 2-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-Nphenylacetamide (5d). 22.8 mg, 54 yield. 1 H NMR (500 MHz, DMSO-D 6 ) δ 10.26 (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 421.2. 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). 18.2 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 435.2. 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). 23.8 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); 3.76 3.13 (m, 9H); 2.83 (s, 3H). MS (APCI) calculated for C 26 H 27 N 4 O 4 [M+H] +, 459.2; found 459.2. 2-[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). 17.2 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 436.1. 1-[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 381.1. 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 395.1.

S 17 17 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 409.1. 1-[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 423.1. 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 481.1. 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 471.1. 1-[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 485.1. 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 507.1. 1-[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 472.1. 1-[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

S 18 18 = 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 472.1. 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); 1.15-1.73 (m, 11H). MS (APCI) calculated for C 25 H 28 N 5 O 3 S [M+H] +, 478.2; found 478.2. 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), 7.83 7.75 (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), 7.36 7.32 (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 505.0. 1-[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 473.1. 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 478.0. 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 500.1. 1-[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 578.1. 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, 0.280 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