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1 Supporting Information S1

2 Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer Wei Zhu,,,, Hui Chen,,, Yulan Wang,,, Jiang Wang,,, Xia Peng,, Xianjie Chen,,, Yinglei Gao,, Chunpu Li,,, Yulong He,,, Jing Ai *,,, Meiyu Geng,, Mingyue Zheng *,, and Hong Liu *,,, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, , China. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai , P. R. China. University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing , China. These authors contributed equally to this study. S2

3 Table of Contents (A) SMILES strings of 57 candidate compounds... S4 (B) HPLC analysis data of all target compounds... S7 (C) Illustration of the potential internal H-bond of compound 2m... S9 (D) The putative binding mode of 3m with FGFR1 protein... S11 S3

4 (A) SMILES strings of 57 candidate compounds Table S1. 57 candidate compounds with their SMILES strings, Glide XP Scores and inhibition rates of 50 µm against FGFR1. Inhibitio XP Compd. n rate Smiles GScore ID (%) at 50 µm DCL-1 C1(=O)N([H])c(cccc2)c2N1CCCSc3sc(cccc4)c n3 DCL-2 N1([H])\C(=N\N=C\c2ccco2)\S[C@H](CC(=O )N([H])c(cccc3C(C)=O)c3)C1=O DCL-3 c1(n([h])[h])ncc(cn1)cn([h])ccc2ccc(cl)cc Cl DCL-4 N1(c2cccc(Cl)c2)C(=O)\C(\N([H])C1=O)=C/c( ccc(o[h])c3oc)c3 DCL-5 n1(ccoc2ccc(c)cc2)c(ncnc3n([h])[h])c3nc1s C[C@@H](O[H])COc4ccccc4 DCL-6(1) c1(c2cc(c(c)nn3[h])c3cc2)cc(n([h])[c@h](c ccccc4)co[h])cnc1c5ccoc5 DCL-7 C(N([H])[H])(=O)c1cccc(c1)\N=C/c2ccc(cc2)\ C=N/c(cccc3C(N([H])[H])=O)c3 DCL-8 n1c(n([h])nc1scc(=o)n([h])c2ccccc2c(oc)= O)c3ccncc3 DCL-9 N1([H])C(S[C@@H](CC1=O)C(=O)N([H])c(c c(cc2c(oc)=o)c(oc)=o)c2)=n[h] DCL-10 n1cn([h])nc1n([h])cc(cccc2occ3ccc(cl)cc3c l)c2 DCL-11 N1(Cc2ccccc2)c(cccc3)c3[C@@](O[H])(CC(= O)c4c(C)nn([H])c4C)C1=O DCL-12 n1c(c(c(=o)n(ccc2c(cccc3)c3n([h])c2)c4=o )c4c(o[h])c1)c(occ)=o DCL-13 c12c(n=cn(n([h])c=o)c1=o)c3c(nc(cc3c4cc co4)c5ccc(c)cc5)o2 DCL-14 c1(cc(n([h])cc2cccc(cl)c2)n([h])n1)c3ccco DCL-15 c12c(ncnc1n([h])[h])n(cn2)ccoc3ccc(occ)c c3 DCL-16 n12c(n([h])c(ccc3)=c3c1=o)c(c(o[h])n2) Cc(cccn4)c4 DCL-17 c1(c2nc(ccs3)c3c(n([h])c4c(cccc4)c#n)n2)cc( O[H])ccc1 S4

5 DCL [H])=O)c(OC)c3)C(C#N)=C(N([H])[H])O2 DCL-19 C(=O)(c1ccco1)N2CCN(CC2)c3ccc(cc3)N([H] )C(C)=O DCL-20 n1c(n([h])nc1n([h])[h])scc(=o)n([h])c(ccc( F)c2Cl)c2 DCL-21 c1(c(=o)n([h])\n=c\c(cccn2)c2)nn([h])c(c3c (cccc3)cc4)c14 DCL )c4C1=O DCL-23 C1(=NC(c2c(cccc2)N1[H])=O)C(N([H])CCCN ([H])C(=O)c3cnccn3)=O DCL-24 N1=C(c2ccccc2)N([H])N([H])C(=O)c(cn([H])n )c13 DCL-25 c1(\n=c\c2cc(cl)cc(cl)c2o[h])sc(cccc3)c3c C(N([H])[H])=O DCL-26 3)=C/c(ccn4)cc4 DCL-27 n1([h])c(nnc1coc2ccc(cc2)c)c3ccccn DCL-28 c1(oc(cccc2)c2n1)c3ccc(cc3o[h])n([h])c(=o) c4c(cl)ccc(c4)n5cnnc5 DCL-29 c1(c[n+]([h])([h])ccn(c)c)cc(br)ccc1occ( cccn2)c2 DCL CCCCC3)c4c(cccc4)N(C)C1=O DCL-31 c1cc(c(=o)n([h])c(c2ccccc2)=n3)c3cc DCL-32 c12c(cccc1[n+]([h])=cc3cccc(oc)c3o[h])c( =O)N([H])[N-]C2=O DCL-33 N1([H])C(=O)C=C(CSCC(=O)c2ccc(Cl)cc2Cl) N([H])C1=O DCL-34 c1(oc)c(oc)ccc(c[n+]([h])([h])cccn(ccn2) c2)c1oc DCL-35 C1(=CC(=O)[N-]c(cccc2)c12)C(=O)OCC(=O)c ccc(cc3)OC(=O)c4ccco4 DCL c(occ)c(oc)c4)n(cc(cccn5)c5)c2=o DCL-37 N1([H])C(=NC(C)=C(Cc2ccccc2)C1=O)N([H]) c3nc(c)c(ccc(c)c4)c4n3 DCL-38 c12c(ncnc1scc3c(c)nc(cccc4)c4n3)n([h])cn DCL-39 C1(Cl)=C(N([H])CCC[N+]([H])(C)C)C=NN([ H])C1=O DCL-40 c1(oc2c(ccc(c)c2)n1)c3ccc(\n=c\c(ccc(oco4) c45)c5)cc3o[h] S5

6 DCL H](CO[H])c4ccccc4)cnc1 DCL-42 c1(n([h])ncc1)c(=o)n2ccn(cc2)cc(ccc(oc O3)c34)c4 DCL-43 C1(C2=Nc(cccc3)c3C(=O)N2[H])=C(N(CC1= O)CCN4CCOCC4)N([H])[H] DCL-44 n1(cc2n([h])c(cccc3)c3n2)c4c(cccc4)nc DCL-45 C1(=CN([H])C(=O)N([H])C1=O)\C=C(/C)\C( OCC)=O DCL )N1[H])=O)N([H])c3nc(cccc4)c4c(C)n3 DCL-47 C1(C(=O)N([H])C(OCc2ccccc2)=O)=CN(CCN ([H])CCO[H])C(=O)N([H])C1=O DCL-48 c12c(sc(c3ccccc3)c1)n=c(scc(cc4)ccc4f)n(n ([H])[H])C2=O DCL-49 C(=C/C1=Nc(cccc2)c2C(=O)N1[H])(/c3c(cccc )N4CC)\C4=O DCL H] DCL-51 c1(ccc(cl)cc1cl)c(occn(ccn2)c2)=o DCL OCC)=O)c(N([H])[H])n3 DCL DCL-54 c12c(n(c)nc1)ncn(nc(cc3ccc(oc)cc3)n4)c DCL-55 N1(c2ccccc2Cl)C(\C(=C(/N([H])CCc(c3c(cccc )n4[H])c4)\C)\C(=O)N([H])C1=O)=O DCL-56 N1(c2ccc(cc2)OC)C(\C(=C(/N([H])CCN(CC)C C)\C)\C(=O)N([H])C1=O)=O DCL-57 N1(CCSc2cnccn2)C(=O)c3c(cccc3)N([H])C1= O S6

7 (B) HPLC analysis data of all target compounds Table S2. HPLC analysis data of all tested compounds. HPLC analysis was conducted according to different eluent. The retention time (tr) is expressed in min at UV detection of 254 nm. HPLC analysis was performed on an Agilent Extend-C18 ( mm, 5 μm) at 30 C. Flow rate: 1 ml/min. Equipment Agilent 1260 with binary pump and photodiode array detector (DAD) Column Agilent Extend-C18 ( mm, 5 µm) Compound Results Retention time (min) Relactive purity (%) a > a a b a c a d a e a f a g a > 99 2h a i a j a k a l a m a n a o a p a a a 97.4 S7

8 3b a c a > 99 3d a > 99 3e a 96.6% 3f a 95.5% 3g b 95.1% 3h a i a j a > 99 3k a l b m a n a o a p a > 99 3q a 97.2 a CH3OH/H2O (65/35, v/v); b CH3OH/H2O (75/25, v/v). S8

9 (C) Illustration of the potential internal H-bond of compound 2m To form the H-bond, the 2-hydroxy phenyl needs to lie in the same plane of the pyridyl ring (considering the nitrogen lone pair in the sp2 orbital), as depicted below: Figure S1. Illustration of the potential internal H-bond in compound 2m. However, the planarity conformation is not energetically favorable due to the steric hindrance between the 2-hydroxy phenyl and the adjacent indazol group. We performed a coordinate scan of the dihedral angle between 2-hydroxy phenyl and pyridyl ring of 2m (highlighted in red in the above structure), using MacroModel module in Schrödinger software package. As shown in the following figure, the dihedral angle close to 0 or 360 correspond to the potential internal H-bond conformation (I or V), which is about 39 kj/mol higher than the preferential conformation when the diherdral angle is 50 or 310 (II or IV). Therefore, given the high energy barrier, it is unlikely to form an internal H-bond in compound 2m. Additionally, the diherdral of the putative binding mode of 2m is 110 (marked as green stars), of which the energy is closed to that of the preferential conformation. S9

10 Figure S2. Coordinates scan of the dihedral angle between 2-hydroxy phenyl and pyridyl ring of 2m. S10

5 Å to the carboxyl carbon of Glu531, which may form an important polar C-F C=O interaction.

11 (D) The putative binding mode of 3m with FGFR1 protein Figure S3. The putative binding mode of 3m in FGFR1 protein. Taking 3m as an example, its putative binding mode (Figure S3) suggests that the fluorine atom is located within 3.5 Å to the carboxyl carbon of Glu531, which may form an important polar C-F C=O interaction. Additionally, there are two polar residues of Lys514 and Glu531 adjacent to the hydrophobic pocket, and the strong electron-withdrawing effect of fluorine atom may induce molecular dipole in phenyl, and lead to dipole-charge interaction between phenyl and these polar residues. These extra interactions may account for the potency improvement of the derivatives with fluorine substituents in phenyl. S11

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