CDK2/cyclin A1 (IC 50 = 2 nm) CDK2/cyclin E (IC 50 = 4 nm)

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1 Electronic Supplementary Material (ESI) for ChemComm. This journal is The Royal Society of Chemistry 2018 Supplementary Information Tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-based CDK inhibitor 1. Supplemental Figures 120 % Activity CDK2/cyclin A1 (IC 50 = 2 nm) CDK2/cyclin E (IC 50 = 4 nm) CDK3/cyclin E (IC 50 = 3 nm) Log [Stuarosporine] (M) Figure S1. Dose-response curves of the inhibition of the indicated CDKs by staurosporine 1

2 Table S1. In vitro kinase selectivity of HSD992 Entry Kinase % inhibition Entry Kinase % inhibition Entry Kinase % inhibition Entry Kinase % inhibition Entry Kinase % inhibition 1 CDK3/cyclin E CDK1/cyclin E CDK18/cyclin Y CDK6/cyclin D ALK3/BMPR1A 0 2 CDK2/cyclin E CDK5/p PDGFRa MYO3b MEK2 0 3 CDK2/Cyclin A Aurora B ABL2/ARG MRCKb/CDC42BPB KSR2 0 4 CDK2/cyclin O MLCK/MYLK HCK SIK PLK3 0 5 CDK9/cyclin K PDGFRb SRPK CK1g CAMK1b 0 6 CDK2/cyclin A EPHA ARK5/NUAK EPHA GRK2 0 7 PKG1b STK CAMK2g MARK JNK3 0 8 DYRK p70s6kb/rps6kb PKCb TSSK IKKb/IKBKB 0 9 GCK/MAP4K EPHA FGFR CK1g NEK CLK PKCb CAMK PKD2/PRKD CK1a EPHB FGFR TAOK3/JIK ABL ZAP EPHB RIPK ULK JAK MAPKAPK CDK9/cyclin T EPHA PKA IRAK CAMK1a 0 14 CLK FLT4/VEGFR PEAK CDK6/cyclin D TNK RIPK PHKg ULK HPK1/MAP4K DYRK PKCd NEK CDK7/cyclin H FER TYRO3/SKY 0 17 PKCeta EPHA c-met ERK JNK CLK FGFR TBK CHK FRK/PTK MAK IR TESK SNARK/NUAK EGFR 0 20 PBK/TOPK HIPK WNK MKK MEKK DMPK SIK MST2/STK SSTK/TSSK STK25/YSK p70s6k/rps6kb AKT CSK CAMK2a PKAcg 0 23 STK39/STLK FYN MLK1/MAP3K BLK BRAF 0 24 ROCK c-src CDK4/cyclin D MARK2/PAR-1Ba MAPKAPK5/PRAK 0 25 LOK/STK MLCK2/MYLK ASK1/MAP3K AKT CDK14/cyclin Y 0 26 EPHB AKT BRSK MAPKAPK FLT1/VEGFR DDR HIPK IKKe/IKBKE ERBB2/HER MARK PRKX MYO3A ULK IGF1R SNRK 0 29 VRK PAK NEK CAMK1g CAMK1d 0 30 RSK HGK/MAP4K BTK EPHB FGFR TAOK2/TAO PLK4/SAK PKCa MINK/MINK PAK MUSK CDC7/DBF ERK2/MAPK JAK PKCmu/PRKD NEK CAMKK LCK LYN SYK 0 34 PIM FGR CLK COT1/MAP3K GRK TNIK NEK SGK ALK2/ACVR TIE2/TEK 0 36 TAOK CDK5/p LIMK SBK LYN B 0 37 Aurora A JNK LCK2/ICK RIPK LIMK KHS/MAP4K PKCtheta IRAK P38a/MAPK TLK AXL TAK MKK DAPK WNK LKB STK CK1d MEK SIK ROCK MST1/STK PLK ALK4/ACVR1B MEK CDK19/cyclin C RAF FES/FPS MLK DDR BRK GRK GRK ERK5/MAPK NEK ERK7/MAPK DMPK SRPK CK1a1L DAPK SLK/STK EPHA CK1epsilon TTBK IRR/INSRR 0 46 CDK9/cyclin T DCAMKL MST TGFBR OSR1/OXSR PYK GLK/MAP4K GRK VRK PDK1/PDPK CDK1/cyclin A STK38/NDR PAK CTK/MATK PIM STK32C/YANK MNK STK22D/TSSK ALK1/ACVRL DCAMKL RSK CDK4/cyclin D PKN2/PRK ALK5/TGFBR MKK c-kit STK38L/NDR KDR/VEGFR GRK PAK CDK17/cyclin Y NEK TYK PHKg IKKa/CHUK 0 53 STK32B/YANK MSSK1/STK ARAF TESK NEK RET NEK CK2a ALK6/BMPR1B CDK16/cyclin Y 0 55 TYK1/LTK TXK HIPK TSSK3/STK22C PAK HIPK MLK2/MAP3K PLK ITK KSR CK2a Aurora C P38d/MAPK ZIPK/DAPK WNK ALK FMS ZAK/MLTK TTBK ERBB4/HER c-mer DLK/MAP3K FAK/PTK MST3/STK SGK3/SGKL 0 60 CDK1/cyclin B P38g PKAcb MRCKa/CDC42BPA JAK2 0 2

3 Figure S2. Overlay of ATP (green) and HSD992 (black) in the catalytic pocket of CDK2 (PDB entry 1HCK). Some residues in the active site have been shown and labeled. Figure generated in PyMOL visualization software (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC). % inhibition of enzymatic activity ABL1 FGFR1 FGFR2 FGFR3 FGFR4 RET Figure S3. In vitro kinase inhibition by HSD992. The cell lines substantially inhibited by HSD992 are driven by ABL1, FGFR1-4 and RET kinases. However, HSD992 does not inhibit the in vitro activity of these driver kinases. 3

4 Biology 2. Experimental Section In vitro kinase inhibition assay The kinase inhibition assay was performed using the kinase profiling service of Reaction Biology Corporation (Malvern, PA, USA). Briefly, DMSO stock solutions of compounds were diluted into reaction mixture containing 100 µm ATP and kinase in a single dose mode at a concentration of 0.5 µm. Alternatively, compounds were tested in 10-dose IC50 duplicate mode with a 3- fold serial dilution starting at 3.33 μm. The kinase activity was determined relative to DMSO control. IC50 data were fit to a non-linear regression using GraphPad Prism 4 Software (GraphPad, La Jolla, CA, USA). Cell culture Purdue University compound ND992 was dissolved in DMSO in 20 mm stock. The reference compound staurosporine was dissolved in DMSO in 1 mm stock. Staurosporine was purchased from Sigma-Aldrich (Saint Louis, MI). Cell Titer-Glo 2.0 Luminescent cell viability assay reagent was purchased from Promega (Madison, WI, USA). KMS-11 cell line was purchased from Japan Cell Bank. UACC-62 cell line was purchased from Addexbio. HCC-78 and NOMO-1 cell lines were purchased from Reactive-Bioarray. LC-2/Ad was purchased from Sigma-Aldrich. Other cell lines were purchased from American Type Culture Collection. Apart from DMS114, HLY-1, NCI-H1703, NCI-H520, and LC-2/Ad, all cell lines were tested at Reaction Biology Corporation. Cell culture media are listed in the following table. Media were routinely supplemented with 100 µg/ml of penicillin, and 100 µg/ml of streptomycin. Cultures were maintained at 37 C in a humidified atmosphere of 5% CO 2 and 95% air. Table S1. Culture method for cell lines used in this study Cell line Medium NK-92 EMEM without ribonucleosides and deoxyribonucleosides %FBS %Horse serum + 0.2mM Myo-inositol + 0.1mM B- mercaptoethanol mM folic acid + 100unit/ml recombinant human IL g/L sodium bicarbonate MDA-MB-361 MDA-MB-468 HS578T A549 MDA-MB-157 HS578Bst BT474 DMEM/F %FBS DMEM + 10%FBS DMEM + 10%FBS mg/ml Bovine insulin F12K + 10%FBS F12K + 10%FBS Hybri-care + 10%FBS + EGF 30ng/ml Hybri-Care g/l sodium bicarbonate + 10%FBS HT-29 SK-BR-3 SK-OV3 Hep G2 U87MG McCoy's 5A + 10%FBS McCoy's 5A + 10%FBS McCoy's 5A + 10%FBS EMEM + 10%FBS EMEM + 10%FBS A-498 EMEM + 10%FBS SK-MEL-2 EMEM + 10%FBS 4

5 ZR-75-1 SNU-182 KMS-11 UACC-62 SU-DHL-1 SU-DHL-6 Molt-4 HCC-78 NCI-H441 NOMO-1 LnCap BT-549 OVCAR3 DMS114 LC-2/Ad NCI-H1703 NCI-H1755 NCI-H520 HLY-1 K mg/ml Bovine Insulin RPMI + 20%FBS mg/ml Bovine Insulin Waymouth + 10%FBS RPMI/F %FBS IMDM + 10%FBS Antiproliferative activity of compounds Compound ND992 was diluted in DMSO solution with 10-dose and 3-fold dilution in a source plate starting at 20 mm. The reference compound staurosporine was diluted in DMSO solution with 10-dose and 3-fold dilution in a source plate starting at 10 mm (for adherent cell lines) and 1 mm (for suspension cell lines) nl of each test compound was delivered from the source plate to each well of the 384-well cell culture plates by Echo 550 (Labcyte, San Jose, CA, USA). 25 µl of culture media containing 2000 cells was added to each of the wells in duplicates of the cell culture plate. The cells were incubated with the compounds at 37 C, 5% CO 2 for 72 hours. 25 µl of Cell Titer Glo 2.0 reagent was added to each well. The contents were mixed on an orbital shaker for 2 min and incubated at room temperature for 15 min to stabilize luminescent signal. Luminescence was recorded by Envision 2104 Multilabel Reader (PerkinElmer, Santa Clara, CA). The number of viable cells in culture was determined based on quantitation of the ATP present in each culture well. The IC50 curves were plotted and IC50 values were calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. Molecular Docking with GOLD program The PDB file for CDK2 (1HCK) was obtained from the RCSB Protein Data bank ( HSD992 was drawn in ChemDraw Professional software version 16.0 and Chem3D software version 16.0 (PerkinElmer Informatics) was used to generate an energy minimized 3D structure saved as a mol2 file. GOLD docking was run from the Hermes visualizer. For protein preparation, the wizard option was used to add hydrogens, delete water molecules and the crystalized ligand. HSD992 was then docked into 5

6 the binding site using the default 10 genetic algorithms and the ChemPLP scoring function. Following the docking, PyMOL visualization software (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC) was used to generate the figures. Chemistry General Considerations General Considerations All reagents and solvents were purchased from commercial suppliers and used them as received, unless otherwise stated. The 1 H and 13 C NMR spectra were obtained in CD 3 OD or (CD 3 ) 2 SO as solvent using a 500 MHz spectrometer with Me 4 Si as an internal standard. Chemical shifts were reported in parts per million (δ) downfield from internal standard Me 4 Si. Data for 1 H NMR spectra were reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, or combinations thereof. High resolution mass spectra (HRMS) were recorded using electron spray ionization (ESI) technique and as TOF mass analyzer. All the new synthesized compounds were characterized using 1 H NMR, 13 C NMR, and HRMS data. Substrate 2-amino-benzthiazole-6-carbaldehyde (95% purity) was purchased from Chemcia Scientific, LLC. Synthesized compounds 6

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8 General procedure for the multicomponent reaction: A screw capped 20 ml vial charged with amine (1 mmol) and aldehyde (1 mmol) in 5 ml of absolute ethanol was refluxed for 2 h. After complete conversion of substrates to imine, cyclic ketone (2.5 mmol) and a catalytic amount of conc. hydrochloric acid was added. The reaction was continued to reflux for 12 h. The resultant reaction mixture was concentrated under reduced pressure and was purified by flash silica gel chromatography (dichloromethane:methanol (99:01 to 80:20) to give the desired cyclized compound. (Note: In some cases, product may get precipitated out as solid after completion of reaction which was filtered, washed with ethanol and further purified using flash silica gel column chromatography). Compounds characterization data 5-(8,9,10,11-Tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)benzo[d]thiazol-2-amine Pale yellow solid (137 mg, 37%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.55 (s, 1H), (m, 3H), 7.55 (s, 2H), (m, 2H), 3.32 (s, 2H), 2.82 (t, J = 6.1 Hz, 2H), 1.99 (qq, J = 5.2, 2.7 Hz, 2H), 1.74 (dp, J = 9.1, 3.2, 2.8 Hz, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , 29.75, 29.18, 22.66, 22.62; HRMS (ESI) m/z calcd for C 21 H 18 N 5 S [M + H] , found

9 5-(8,9,10,11-Tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)thiazol-2-amine Yellow solid (166 mg, 52%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.50 (s, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.66 (d, J = 9.4 Hz, 1H), 7.51 (s, 1H), 7.23 (s, 2H), (m, 2H), 2.96 (t, J = 6.2 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , 29.95, 28.90, 22.52, 22.24; HRMS (ESI) m/z calcd for C 17 H 16 N 5 S [M + H] , found (1H-Pyrrolo[2,3-b]pyridin-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine Off-white solid (203 mg, 60%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), 8.78 (s, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.17 (q, J = 9.2 Hz, 2H), 7.65 (t, J = 3.0 Hz, 1H), 6.61 (dd, J = 3.5, 1.8 Hz, 1H), (m, 2H), 2.86 (t, J = 6.2 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , 30.71, 28.46, 21.95, 21.88; HRMS (ESI) m/z calcd for C 21 H 18 N 5 [M + H] , found (8,9,10,11-Tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)-1H-benzo[d]imidazol-2(3H)-one Off-white solid (178 mg, 50%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.78 (d, J = 9.1 Hz, 1H), (m, 2H), 7.00 (d, J = 7.8 Hz, 1H), 3.28 (t, J = 6.5 Hz, 2H), 2.77 (t, J = 6.1 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , 29.70, 29.28, 22.65, 22.62; HRMS (ESI) m/z calcd for C 21 H 18 N 5 O [M + H] , found Methyl-6-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)benzo[d]thiazole Off-white solid (207 mg, 56%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.83 (s, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.26 (d, J = 9.2 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 8.4, 1.8 Hz, 1H), 3.51 (t, J = 6.4 Hz, 2H), (m, 2H), 2.04 (dq, J = 8.8, 6.1, 4.4 Hz, 2H), 1.79 (tq, J = 9.4, 6.1, 4.2 Hz, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , 40.49, 40.32, 40.25, 40.16, 39.99, 39.82, 39.66, 39.49, 30.86, 28.22, 21.86, 21.70, 20.47; HRMS (ESI) m/z calcd for C 22 H 19 N 4 S [M + H] , found (2-Methyl-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)benzo[d]thiazol-2-amine Pale yellow solid (76 mg, 20%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 7.72 (dd, J = 1.8, 0.6 Hz, 1H), 7.67 (dd, J = 8.9, 0.7 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.49 (dd, J = 8.2, 0.6 Hz, 1H), 7.39 (dd, J = 8.2, 1.7 Hz, 1H), 6.87 (t, J = 0.9 Hz, 1H), 3.45 (t, J = 6.5 Hz, 2H), 2.76 (t, J = 6.2 Hz, 2H), (m, 3H), 2.03 (ddt, J = 10.1, 7.4, 3.8 Hz, 2H), (m, 2H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , , , , , , 29.95, 9

10 28.70, 22.51, 22.21, 12.08; HRMS (ESI) m/z calcd for C 23 H 21 N 4 S [M + H] , found (8,9,10,11-Tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)benzo[d]thiazol-2-amine Pale yellow solid (115 mg, 31%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (d, J = 2.2 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.52 (s, 2H), 7.48 (t, J = 2.9 Hz, 1H), 7.39 (s, 2H), 7.12 (t, J = 2.5 Hz, 1H), 3.38 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.1 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , , 30.01, 29.30, 22.94, 22.64; HRMS (ESI) m/z calcd for C 22 H 19 N 4 S [M + H] , found (1,2,4,9-Tetrahydropyrano[3,4-c]pyrrolo[3,2-f]quinolin-5-yl)phenol Yellow solid (193 mg, 61%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), 8.22 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.81 (t, J = 2.9 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.30 (t, J = 2.4 Hz, 1H), 7.03 (d, J = 8.5 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 3.61 (t, J = 5.8 Hz, 2H), 3.42 (s, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , 66.43, 64.15, 29.76; HRMS (ESI) m/z calcd for C 20 H 17 N 2 O 2 [M + H] , found N-(6-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)benzo[d]thiazol-2-yl)acetamide Compound 1 (HSD992) (93 mg, 0.25 mmol) was dissolved in a mixture of DMF (2 ml) and triethylamine (2 equiv), followed by addition of acetyl chloride (30 mg, 1.5 mmol). The reaction was continued for overnight at room temperature. After completion of reaction, reaction mixture was extracted with ethyl acetate (2 X 20 ml) and washed with brine solution and the crude was purified with dichloromethane:methanol (90:10) by flash coloumn chromatography to get the desired product as yellow solid (73 mg, 70%). 1 H NMR (500 MHz, Methanol-d 4 ) δ 8.76 (s, 1H), 8.38 (d, J = 9.3 Hz, 1H), (m, 1H), 8.20 (d, J = 9.3 Hz, 1H), (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), 4.32 (s, 3H), 3.67 (t, J = 6.3 Hz, 2H), 2.95 (t, J = 6.1 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , , , , , 35.36, 31.10, 27.83, 21.22, 21.15; HRMS (ESI) m/z calcd for C 23 H 20 N 5 O 2 S [M + H] , found amine 6-(3-methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)benzo[d]thiazol-2- Off-white solid (138 mg, 36%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.50 (d, J = 0.9 Hz, 1H), (m, 1H), (m, 2H), 7.63 (s, 2H), (m, 2H), 4.17 (s, 3H), 3.31 (t, J = 6.5 Hz, 2H), 2.82 (t, J = 6.1 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , 36.31, 29.76, 29.17, 22.58, HRMS (ESI) m/z calcd for C 22 H 20 N 5 S [M + H] , found

11 6-(1-Methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)benzo[d]thiazol-2-amine Off-white solid (116 mg, 30%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 7.77 (d, J = 9.1 Hz, 1H), (m, 2H), (m, 1H), 7.38 (dd, J = 8.2, 1.8 Hz, 1H), (m, 2H), 2.90 (s, 3H), 2.81 (q, J = 4.3, 3.1 Hz, 2H), (m, 4H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , , , , , 31.88, 27.83, 22.07, 21.90, 17.96; HRMS (ESI) m/z calcd for C 22 H 20 N 5 S [M + H] , found (2-Aminobenzo[d]thiazol-6-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-1-carbonitrile Pale yellow solid (174 mg, 45%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (m, 3H), 7.71 (s, 2H), 7.41 (d, J = 1.4 Hz, 2H), 3.50 (t, J = 6.5 Hz, 2H), 2.82 (t, J = 6.1 Hz, 2H), 1.91 (qd, J = 8.0, 6.6, 4.5 Hz, 2H), 1.74 (dp, J = 6.4, 4.3, 3.0 Hz, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , , 31.84, 28.91, 22.12, 21.96; HRMS (ESI) m/z calcd for C 22 H 17 N 6 S [M + H] , found Methyl 7-(2-aminobenzo[d]thiazol-6-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-1-carboxylate Off-white solid (126 mg, 30%); 1 H NMR (500 MHz, MeOD-d 4 ) δ 7.90 (d, J = 9.1 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.40 (dd, J = 8.2, 1.8 Hz, 1H), 4.03 (s, 3H), 3.15 (t, J = 6.1 Hz, 2H), 2.82 (t, J = 6.4 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , , , , , , 51.92, 29.50, 27.49, 21.91, 21.88; HRMS (ESI) m/z calcd for C 23 H 20 N 5 O 2 S [M + H] , found (5-Fluoro-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)benzo[d]thiazol-2-amine Off-white solid (148 mg, 38%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), (m, 1H), 7.70 (d, J = 9.8 Hz, 1H), 7.57 (d, J = 2.4 Hz, 2H), (m, 2H), (m, 2H), 2.84 (t, J = 6.1 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , (d, J = Hz), , , , , , , , , , , , , , , 98.20, 29.80, 29.24, 22.52, 22.44; HRMS (ESI) m/z calcd for C 21 H 17 FN 5 S [M + H] , found (8,9,10,11-Tetrahydro-3H-[1,2,3]triazolo[4,5-a]phenanthridin-7-yl)benzo[d]thiazol-2-amine Off-white solid (112 mg, 30%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.03 (d, J = 9.1 Hz, 1H), (m, 2H), 7.57 (s, 2H), 7.44 (dd, J = 8.2, 1.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 3.69 (t, J = 6.5 Hz, 2H), 2.85 (t, J = 6.2 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , 29.93, 29.07, 22.66, HRMS (ESI) m/z calcd for C 20 H 17 N 6 S [M + H] , found

12 7-(1H-Indol-2-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine Yellow solid (264 mg, 78%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), 8.76 (s, 1H), (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 8.2, 1.0 Hz, 1H), (m, 2H), 7.09 (td, J = 7.4, 6.9, 1.0 Hz, 1H), 3.45 (t, J = 6.4 Hz, 2H), (m, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , 30.84, 28.26, 21.91, 21.86, 21.86; HRMS (ESI) m/z calcd for C 22 H 19 N 4 [M + H] , found (2,3,4,8-Tetrahydro-1H-pyrrolo[3,2-b]phenanthridin-5-yl)phenol Off white solid (178 mg, 54%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), 8.85 (s, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.51 (t, J = 2.8 Hz, 1H), 7.13 (t, J = 2.5 Hz, 1H), 3.99 (s, 3H), 3.37 (t, J = 6.5 Hz, 2H), 2.84 (t, J = 6.2 Hz, 2H), (m, 2H), 1.75 (dd, J = 7.5, 4.3 Hz, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , 55.22, 29.96, 28.70, 22.75, 22.49; HRMS (ESI) m/z calcd for C 20 H 19 N 4 O [M + H] , found ,2'-((4-(8,9,10,11-Tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)phenyl)azanediyl)diethanol Yellow solid (209 mg, 70%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 8.00 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.59 (d, J = 3.1 Hz, 1H), (m, 2H), 7.28 (d, J = 3.2 Hz, 1H), 6.95 (d, J = 8.9 Hz, 2H), 3.79 (t, J = 6.0 Hz, 4H), 3.65 (t, J = 6.0 Hz, 4H), 3.57 (t, J = 6.5 Hz, 2H), 2.90 (t, J = 6.2 Hz, 2H), (m, 2H), 1.84 (td, J = 6.2, 3.2 Hz, 2H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , , , 58.85, 53.41, 30.85, 28.37, 21.94, 21.66; HRMS (ESI) m/z calcd for C 25 H 28 N 3 O 2 [M + H] , found (1-Methyl-1H-imidazol-5-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine Off- white solid (151 mg, 50%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 7.79 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J = 3.1 Hz, 1H), 3.60 (s, 3H), 3.38 (t, J = 6.5 Hz, 2H), 2.75 (t, J = 6.3 Hz, 2H), (m, 2H), 1.81 (q, J = 6.0, 5.6 Hz, 2H). 13 C NMR (126 MHz, Methanol-d 4 ) δ , , , , , , , , , , , , , 31.45, 29.82, 27.83, 22.28, 21.90; HRMS (ESI) m/z calcd for C 19 H 19 N 4 [M + H] , found N-(4-(8,9,10,11-Tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)phenyl)methanesulfonamide Pale yellow solid (245 mg, 74%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 7.78 (dd, J = 9.0, 0.8 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), (m, 2H), 7.41 (d, J = 3.1 Hz, 1H), (m, 2H), 7.18 (dd, J = 3.2, 0.9 Hz, 1H), 3.47 (t, J = 6.5 Hz, 2H), 2.75 (t, J = 6.2 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , 12

13 127.48, , , , , , , 37.83, 29.92, 28.63, 22.47, 22.15; HRMS (ESI) m/z calcd for C 22 H 22 N 3 O 2 S [M + H] , found (8,9,10,11-Tetrahydrothieno[3,2-a]phenanthridin-7-yl)phenol Off-white solid (245 mg, 74%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.36 (d, J = 8.9 Hz, 1H), 8.32 (d, J = 5.6 Hz, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 3.49 (q, J = 6.5 Hz, 2H), 2.80 (t, J = 6.2 Hz, 2H), 1.94 (dp, J = 6.6, 4.6, 2.8 Hz, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , 31.70, 29.13, 22.58, 21.88; HRMS (ESI) m/z calcd for C 21 H 18 NOS [M + H] , found (Pyridin-4-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine Off white solid (183 mg, 61%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), 8.67 (dt, J = 4.4, 1.5 Hz, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), (m, 2H), (m, 1H), 7.14 (s, 1H), 3.40 (t, J = 6.6 Hz, 2H), 2.77 (t, J = 6.1 Hz, 2H), (m, 2H), 1.75 (q, J = 5.9 Hz, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , 29.94, 28.67, 22.76, 22.39; HRMS (ESI) m/z calcd for C 20 H 18 N 3 [M + H] , found (8,9,10,11-Tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)aniline Bright yellow solid (194 mg, 62%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.09 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.26 (s, 1H), 6.75 (d, J = 8.3 Hz, 2H), 5.79 (s, 2H), 3.51 (t, J = 6.5 Hz, 2H), 3.32 (s, 2H), 2.85 (t, J = 6.2 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , 31.13, 28.60, 22.25, 21.94; HRMS (ESI) m/z calcd for C 21 H 20 N 3 [M + H] , found (1H-Indazol-5-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine White solid (173 mg, 51%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.5, 1.5 Hz, 1H), 7.48 (t, J = 2.8 Hz, 1H), 7.11 (t, J = 2.6 Hz, 1H), 3.37 (d, J = 6.9 Hz, 2H), 2.77 (t, J = 6.2 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , , 30.01, 29.35, 22.91, 22.62; HRMS (ESI) m/z calcd for C 22 H 19 N 4 [M + H] , found (Pyrimidin-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine Yellow solid (144 mg, 48%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.26 (s, 1H), 9.07 (s, 2H), 8.55 (s, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 3.31 (s, 2H), 2.84 (t, J = 6.1 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , 13

14 143.91, , , , , , , , , , 29.62, 28.44, 22.43, 22.38; HRMS (ESI) m/z calcd for C 19 H 17 N 4 [M + H] , found Benzyl (7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-9-yl)carbamate Off-white solid (241 mg, 52%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 8.66 (d, J = 9.1 Hz, 1H), 8.08 (dd, J = 9.2, 6.3 Hz, 1H), 7.93 (dd, J = 9.3, 5.3 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), (m, 5H), 7.02 (d, J = 8.2 Hz, 2H), 5.01 (s, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H). 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , , , , , , , , 66.04, 48.13, 48.08, 47.96, 47.79, 47.62, 47.45, 47.28, 47.11, 45.66, 33.71, 29.28, 26.87; HRMS (ESI) m/z calcd for C 28 H 25 N 4 O 3 [M + H] , found (1-Bromo-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)phenol Off-white solid (153 mg, 39%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 8.18 (d, J = 9.1 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 3.99 (s, 2H), 2.97 (s, 2H), 1.97 (t, J = 3.5 Hz, 4H). 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , , , 36.01, 27.02, 20.91, 20.80; HRMS (ESI) m/z calcd for C 20 H 17 BrN 3 O [M + H] , found (7-(4-Hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-9-yl)isoindoline-1,3-dione Off-white solid (239 mg, 52%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.56 (s, 1H), 8.57 (s, 1H), (m, 2H), (m, 5H), 7.36 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , , 47.46, 32.19, 31.15, 26.15; HRMS (ESI) m/z calcd for C 28 H 21 N 4 O 3 [M + H] , found Methyl 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)benzoate Off-white solid (105 mg, 30%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 7.68 (dd, J = 8.9, 0.8 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.22 (dd, J = 11.8, 2.0 Hz, 1H), 7.13 (ddd, J = 8.2, 2.1, 0.9 Hz, 1H), 7.03 (dt, J = 8.9, 8.2 Hz, 1H), 6.87 (s, 1H), (m, 2H), 2.76 (t, J = 6.2 Hz, 2H), 2.54 (s, 3H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, MeOD) δ , (J = Hz), , , , , , , , , , , , , , , , , 29.98, 28.55, 22.44, 22.14, 12.07; HRMS (ESI) m/z calcd for C 22 H 22 FN 2 O [M + H] , found

15 4-(8,9,10,11-Tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)benzonitrile Off-white solid (195 mg, 60%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.81 (dd, J = 8.9, 0.8 Hz, 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.64 (d, J = 8.9 Hz, 1H), 7.51 (t, J = 2.8 Hz, 1H), (m, 1H), 3.38 (t, J = 6.1 Hz, 2H), 2.73 (t, J = 6.1 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , 29.95, 28.81, 22.76, 22.41; HRMS (ESI) m/z calcd for C 22 H 20 N 3 [M + H] , found (1H-indol-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine White solid (183 mg, 54%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 8.72 (s, 1H), 8.14 (d, J = 8.7 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), 3.49 (t, J = 6.2 Hz, 2H), 2.99 (t, J = 6.1 Hz, 2H), (m, 2H), 1.87 (q, J = 5.7 Hz, 2H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , , , 30.80, 27.71, 21.46, 21.29; HRMS (ESI) m/z calcd for C 22 H 19 N 4 [M + H] , found ,5-Dimethyl-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)isoxazole White solid (229 mg, 72%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 8.92 (s, 1H), 8.35 (d, J = 9.3 Hz, 1H), 8.06 (dd, J = 9.2, 2.4 Hz, 1H), (m, 2H), (m, 2H), 2.45 (s, 3H), (m, 5H), (m, 2H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , 30.94, 26.68, 21.17, 20.88, 10.39, 8.99; HRMS (ESI) m/z calcd for C 19 H 19 N 4 O [M + H] , found tert-butyl (6-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)pyridin-2-yl)carbamate White solid (245 mg, 51%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 8.79 (s, 1H), 8.23 (d, J = 9.3 Hz, 1H), (m, 3H), 7.65 (dd, J = 5.7, 2.6 Hz, 1H), 3.53 (d, J = 6.0 Hz, 2H), 3.08 (t, J = 6.1 Hz, 2H), (m, 2H), (m, 2H), 1.58 (s, 9H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , , , , 80.98, 30.97, 27.41, 27.15, 21.16, 21.06; HRMS (ESI) m/z calcd for C 24 H 26 N 5 O 2 [M + H] , found Cyclopropyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine Off-white solid (181 mg, 69%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.45 (s, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 9.1 Hz, 1H), 3.18 (q, J = 5.3, 4.6 Hz, 2H), 2.94 (t, J = 6.2 Hz, 2H), 2.21 (tt, J = 8.1, 4.9 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 2H) ; 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , 29.49, 26.38, 22.40, 22.37, 13.67, 9.14; HRMS (ESI) m/z calcd for C 17 H 18 N 3 [M + H] , found

16 4-(8,9,10,11-Tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)benzonitrile Off-white solid (182 mg, 56%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.20 (t, J = 7.4 Hz, 2H), 8.10 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), (m, 2H), 2.73 (t, J = 6.2 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , 30.63, 28.01, 21.85, 21.68; HRMS (ESI) m/z calcd for C 21 H 17 N 4 [M + H] , found (1H-Indazol-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine Off-white solid (224 mg, 65%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.83 (d, J = 5.8 Hz, 2H), 7.61 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), (m, 2H), 2.78 (t, J = 6.1 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , 29.69, 29.22, 22.64, 22.59; HRMS (ESI) m/z calcd for C 21 H 18 N 5 [M + H] , found (3-(Trifluoromethyl)-1H-pyrazol-4-yl)-8,9,10,11-tetrahydro-3H-imidazo[4,5-a]phenanthridine Off-white solid (75 mg, 21%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 8.30 (s, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 3.68 (d, J = 6.7 Hz, 2H), 2.68 (t, J = 6.3 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , (q, J = Hz), , , , , 94.71, 29.26, 27.75, 22.04, HRMS (ESI) m/z calcd for C 18 H 15 F 3 N 5 [M + H] , found (Trifluoromethyl)-7-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-8,9,10,11-tetrahydro-3H-imidazo[4,5-a]phenanthridine Off-white solid (106 mg, 25%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 7.99 (s, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), (m, 2H), 2.68 (t, J = 6.3 Hz, 2H), (m, 2H), (m, 2H). 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , (q, J = Hz), , (q, J = Hz), , , 29.42, 27.82, 21.99, HRMS (ESI) m/z calcd for C 19 H 14 F 6 N 5 [M + H] , found (8,9,10,11-Tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)benzamide Off-white solid (172 mg, 50%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.60 (s, 1H), 8.05 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 9.1 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.41 (s, 1H), (m, 2H), 2.77 (t, J = 6.1 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , 29.68, 28.86, 22.58, 22.49; HRMS (ESI) m/z calcd for C 21 H 21 N 4 O [M + H] , found

17 4-(3-(2-Hydroxyethyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)phenol Off-white solid (177 mg, 49%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.59 (s, 1H), 8.51 (s, 1H), 7.96 (d, J = 9.1 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), (m, 2H), 4.55 (t, J = 5.6 Hz, 2H), (m, 2H), (m, 2H), 2.79 (t, J = 6.2 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , 60.84, 51.76, 29.69, 29.23, 22.64; HRMS (ESI) m/z calcd for C 12 H 24 N 3 O 2 [M + H] , found (9-(Trifluoromethyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)phenol Off-white solid (165 mg, 43%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), 8.60 (s, 1H), (m, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H); 13 C NMR (126 MHz, DMSO) δ , , , , , (q, J = Hz), , , , , , 37.62(q, J = Hz), 29.44, 27.22, 20.90; HRMS (ESI) m/z calcd for C 21 H 19 F 3 N 3 O [M + H] , found (3-(Trifluoromethyl)-1H-pyrazol-4-yl)-8,9,10,11-tetrahydro-3H-[1,2,3]triazolo[4,5-a]phenanthridine Off-white solid (72 mg, 20%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 8.40 (d, J = 9.2 Hz, 1H), 8.33 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 4.01 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 6.3 Hz, 2H), 2.13 (dp, J = 9.3, 3.1 Hz, 2H), (m, 2H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , (q, J = Hz), , , , , 30.87, 27.26, 21.12, 21.07; HRMS (ESI) m/z calcd for C 17 H 14 F 3 N 6 [M + H] , found (3-(Trifluoromethyl)-1H-pyrazol-4-yl)-8,9,10,11-tetrahydroisothiazolo[4,5-a]phenanthridine Off-white solid (120 mg, 32%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 9.94 (s, 1H), 8.78 (d, J = 8.9 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 3.85 (t, J = 6.1 Hz, 2H), 2.87 (t, J = 6.1 Hz, 2H), (m, 2H), 2.00 (td, J = 11.2, 9.5, 5.6 Hz, 2H); 13 C NMR (126 MHz, MeOD) δ , , , , , , , , , , , , , , , , 32.51, 27.76, 21.37, 20.63; HRMS (ESI) m/z calcd for C 18 H 14 F 3 N 4 S [M + H] , found Methyl-7-(3-(trifluoromethyl)-1H-pyrazol-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine Off-white solid (148 mg, 40%). 1 H NMR (500 MHz, MeOD-d 4 ) δ 8.77 (d, J = 0.9 Hz, 1H), 8.42 (dd, J = 9.3, 0.9 Hz, 1H), 8.38 (d, J = 0.9 Hz, 1H), 8.07 (d, J = 9.3 Hz, 1H), 4.32 (s, 3H), 3.68 (t, J = 6.3 Hz, 2H), 2.82 (t, J = 6.2 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, MeOD) δ , , (q, J = 37.8 Hz), , , , , , , (q, J = Hz), , , , , 35.32, 30.84, 27.26, 21.19, 20.86; HRMS (ESI) m/z calcd for C 19 H 17 F 3 N 5 [M + H] , found

18 4-(9-(Trifluoromethyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)phenol Off-white solid (157mg, 41%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), 9.74 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), (m, 1H), (m, 2H), 3.65 (dd, J = 18.1, 5.8 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , (q, J = 26.6 Hz), 29.04, 27.78, 21.66; HRMS (ESI) m/z calcd for C 22 H 20 F 3 N 2 O [M + H] , found 4-(9,9-Difluoro-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)phenol Off-white solid (180 mg, 49%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 3.0 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 3.1 Hz, 1H), 6.88 (d, J = 8.1 Hz, 2H), 3.63 (t, J = 7.1 Hz, 2H), 3.33 (t, J = 14.5 Hz, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , , 37.50(J =26.46 Hz), 29.55(J =23.94 Hz), 28.22; HRMS (ESI) m/z calcd for C 21 H 19 F 2 N 2 O [M + H] , found (8,9,10,11-Tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)pyridin-3-ol Off-white solid (107 mg, 34%). 1 H NMR (500 MHz, DMSO-d 6 ) δ (s, 1H), (s, 1H), 8.18 (d, J = 2.8 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 12.0, 8.7 Hz, 2H), 7.49 (t, J = 2.8 Hz, 1H), 7.29 (dd, J = 8.5, 2.9 Hz, 1H), 7.12 (d, J = 2.5 Hz, 1H), (m, 2H), 2.95 (t, J = 6.3 Hz, 2H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , 30.10, 28.50, 22.89, 22.51; HRMS (ESI) m/z calcd for C 20 H 18 N 3 O [M + H] , found (8,9,10,11-Tetrahydrofuro[3,2-a]phenanthridin-7-yl)phenol Off-white solid (218 mg, 69%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.47 (d, J = 2.1 Hz, 1H), 8.36 (q, J = 9.2 Hz, 2H), 7.79 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 3.56 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 6.2 Hz, 2H), 2.00 (dq, J = 8.7, 5.8, 4.5 Hz, 2H), (m, 2H); 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , 30.67, 28.32, 21.74, 21.57; HRMS (ESI) m/z calcd for C 21 H 18 NO 2 [M + H] , found 18

19 19