Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19 Stages of a Drug What Factors FDA Considers During Approval

1. Pre-clinical research - initial design, SAR, in vitro and animal testing, formulation, etc. 1. Analysis of a drug’s target and available treatments • Once a company has a viable candidate, they file an Investigational New Drug (IND) application to the FDA where they must disclose the drug’s composition and manufacturing, 2. Evaluation of a drug’s benefits and risks shown during clinical trials and a plan for human trials • In cases where the disease is rare/multiple trials aren’t feasible, convincing evidence 2. Clinical Trials - happen only after FDA reviews the IND to make sure they don’t place from one trial may be enough. Usually expect results from two well-designed clinical trials humans at an unreasonable risk of harm and that there is adequate informed consent 3. How risks will be managed • Phase 1: comprised of between 20-80 healthy volunteers; emphasis on safety, used to Other Designations determine side effects, metabolism, and excretion; takes about 1 year • Phase 2: 100-300 patients; emphasis on effectiveness; takes about 2 years • Accelerated Approval - applied to therapies treating serious/life-threatening conditions and • Phase 3: 1000-3000 patients; continues to study safety and effectiveness while also provide added benefit over all available therapies. Useful if drug treats disease whose course is evaluating effect on different populations, dosages, and combination with other drugs long/requires long time to measure its effect. Therefore you only need to demonstrate an effect on a “surrogate endpoint” that should predict clinical benefit, or endpoint that is earlier but may 3. NDA Review - can take up to two and a half years; after clinical trials drug sponsor formally not be as robust as a standard endpoint. Usually requires drug’s sponsor to conduct post- asks for FDA approval by submitting New Drug Application (NDA). Includes all animal and marketing clinical trials (if fail to show benefit FDA can withdraw approval) human data, analyses of the data, how drug behaves, and manufacturing. The FDA then has 60 days to decide whether to file NDA for review. During review FDA will review all data, label, and • Fast Track Designation - given to drugs based on promising animal/human data. Assigned to facilities where the drug is manufactured before either approving or issuing a response letter speed up process to review for drugs treating serious conditions and fill an unmet medical need

• Breakthrough Therapy - given to drugs intended to treat a serious condition where preliminary evidences demonstrates there is a substantial improvement over available therapy. Also eligible for Fast Track

• Priority Review - FDA aims to tact on an NDA within 6 months of filing compared to standard 10 months. Reserved for drugs that would significantly improve the treatment, diagnosis or prevention of serious conditions

• First-in-Class - indicator of innovative nature of a drug. Often mechanism of action different from other existing therapies

• Orphan - drugs that treat rare diseases that affect 200,000 or fewer Americans. Usually few or no drugs available to treat these conditions because of rarity Statistics of Drugs Approved in the Last 5 Years

2015 2016 2017 2018 2019* Total # Approved 45 22 46 59 43 # Small Molecules 32 11 29 38 30 # First-in-Class 16 8 15 19 # Orphan 21 9 18 34

# Fast Track 14 8 18 23 information available in the # Breathrough 10 7 17 14 new year # Priority 24 15 28 43 # Accelerated Approval 6 6 3 4 # First Cycle Approval 39 21 39 56 All information taken from FDA’s website Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19 Hepatitis C Drugs Recent Approved HCV Drugs BocN • Cause: Hepatitis C virus, transmitted to humans by tranfusion of body fluids O MeO O Me • Symptoms: affects the liver to develop liver Cirrhosis and carcinoma MeO O • Population: WHO declared 71 million individuals suffering with chronic Hepatitis C infections Daclatasvir - 2015 O O i NH ® HN i • Treatment: often involves a combination of direct acting antivirals (protease inhibitors, NS5B Pr (Daklinza , BMS) Pr O polymerase inhibitors, and NS5A inhibitors), pegylated interferon and ribavirin. α NS5A, EC50 = 0.83 nM 1. Br2, DCM N O genotype 1 and 3 O N 82% H H N N 2. Boc-L-proline DIPEA, MeCN N N O Me O H NH N OMe 1. NH4Ac, 95-100 ºC HO 63% (2 Steps) NH O iPr O N 1. HCl, MeOH O O HOBt•xH2O, EDC H HN 50 ºC DIPEA, MeCN N 79.4% 76.3% Daclatasvir BocN WO2009020825 A1 N Hepatitis C Virus Genome O • single stranded positive sence eveloped RNA virus iPr O HN • 7 types of genotypes (G1, G1a, G1b, G2, G3, G4, G5, G6 and mixed or others) O O OMe • Comprised of structural (Core Protein (Capsid), E1, E2 and Frameshift protein) and N NH N targets NS A nonstructural polyproteins (P7, NS2, NS3S, NS4A/NS4B and NS5A/NS5B) MeO H N Ph 5 • Structural proteins have the functions at viral entry period into the cell Me N N N EC = 0.002-0.13 nM H 50 • Non-structural proteins required for viral reporduction O Epclusa targets all 6 • Main targets to date in drug developmetn around HCV NS3/4A and NS5A/5B Velpatasvir - 2016 genotypes (1st ) ® • NS3-NS4A protein multifunctional role in affecting host cell pathways (Epclusa , in combo with Sofosbuvir, Gilead), HCV OMe • NS5A is vital for viral assembly, for interacting with RNA, the development of lipid raft composites which help in viral replication 1. iPrMgCl, THF; O • NS5B has RNA-dependant-RNA polymerase (RdRp) activity which is significant for Ac OMe Ac HO post-translational amendments of α-helical transmembrane; also interacts with numerous I then N Br cellular proteins to regulate replication Me Ac Br -10 to 20 ºC Br 2. MsCl, LiBr K2CO3, 70 ºC O O HO Et3N, DCM Br 1. Pd(OAc)2, PPh3 t K2CO3, BuCO2H DMA, 80 ºC 1. A, K3CO3, 20 ºC Br O 2. B, Cs2CO3, 40 ºC 2. py•Br3, DCM MeOH iPr O Br O MeO2CHN O 1. NH4OAc, IPA Boc tol, 90 ºC Me N O O O N 2. DDQ HOAc O O O OMe Eur. J. Med. Chem. 2019, 164, 576 2-MeTHF, 0 ºC O not isolated Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19

iPr J. Med. Chem. 2018, 61, 7004 1. K CO , H O O 2 3 2 O NH 2. HCl, MeOH, 45 ºC N HN Boc N NH Boc (92%, 2 Steps) MeO Boc 3 steps N N Elbasvir H N Velpatasvir N i Me N N N N 3. Pr H N O O • 4-NO C H CO H MeO CHN CO H Ph 2 6 4 2 2 2 NMM, HOBt, EDC Bulding Blocks A and B: OMe Boc 4. EtOH recrystallization (80%, 2 Steps) 1. LiNH , HMDS Boc tBuO C NHBoc 2 tBuO C N 7 Steps 2 THF, 50-60 ºC; 2 HO C N F F 2 A Pibrentasvir - 2017 O O F F then O O CO Me NS5A inhibitor 2 OMe (With Glecaprevir, treats all genotypes ® + CO2Me O H Mavyret , AbbVie) EC50 = 0.5-4.3 pM 1. TFA, DCM, 20 ºC HCV N H NO2 O Me iPr 1. MeMgBr, THF 1. HATU iPr 3. PhN(Tf) 1. K CO 100 2 2. NaBH(OAc)3 • p-TsOH DIPEA O 2 3 LiHMDS MeO2CHN B N ºC NBoc TFA, EtOAc NH MeO CHN CO H OMe MeO THF, -78 ºC 2 2 N F F 2. HCl, 50 ºC 3. p-TsOH•H O Me CO2H Me N N Me 60% (3 steps) 2 2. LiOH N N CO2Et EtOAc, 50 ºC CO2Et MeOH/THF HN O HN NH O NH F N CO2Me MeO2C Elbasvir - 2016 TfO N NO2 O O L = O (With Grazoprevir, Zepatier®, Merck) 1 R 1 S O F F NS5A inhibitor, treats genotypes 1 and 4 F MeO NH HN OMe O Ph NH O IC50 = 03 - 4 pM J. Med. Chem. 2019, 62, 7340 F i NH i 1. Pr HN Pr F B(OH) C, DIPEA, MeCN, 75 ºC 2 N N R HN Ph N 2 F N NH2 N N R1 = p-MeC6H4 51% Pd(PPh3)4, 2M Na2CO3 O O R2 = (CH2)3Ph F LiCl, DME, 100ºC, 54% O N NO Pd (dba) , 2. H2, Pd/C, THF, 99% Ph 2 2 NH 2 3 2 Xantphos, Cs CO , Br 1. NH , MeOH Ar 2 3 3 Cl Cl NBoc Diox, 100 ºC, 54% Br O 2. 0.3 mol% Ru[L1] N MsOH, Ms2O Br 70 ºC O 65 ºC, 91% 77% (2 steps) O O Br F F O2N NO2 O OH 98% ee 4 Steps prepared in 1 step Br Ar Br Pibrentasvir N HN NH N Boc Boc Br N Cl NO2 PhCHO, TFA Br CuI, Cs2CO3 MeCN Br DMF, 45 ºC Br Synthesis of C: F F NH 35 ºC 91% Cl NO NO2 HO NH2 OH 2 1. CBS 93%, 99:1 dr Br ZnCl2 F O reduction Cl n OMs F Br 1. Pd (dba) , BuP(Ad) , B (pin) , KOAc, DME, 80 ºC Et3N 97% Br 2 3 2 2 2 O F 2. Pd (dba) , 4-Me NC H P(tBu) , K CO , DME/H O, 80 ºC tBuOH N 2 3 2 6 4 2 2 3 2 F 2. MsCl O Boc HN then 4-NO C H CO H Benzene Et N F OMs 2 6 4 2 O Br 77% 3 Cl Ph (made in 4 steps from N 98% C Br (3 steps from acid) NO J. Med. Chem. 2018, 61, 7004 S-Boc-prolinol) N O2N Cl 2 Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19 Fragment A: Resolution Route: Med Chem: Cyclopropane Side Chains: RCM Cl 1. 1,4-dibromo- N PhCHO 2-butene 1. Et2Zn, TFA CH(OMe) tBuOLi, NMP, CH2I2 Cl O 3 2. H O , NaOH O S Et3N, PhMe TBME O O N OMe 2 2 rac O H2N CO2Me Ph N CO Me OH NH 2 Bpin 80% (2 Steps) H3N NMP, 5 ºC 2. HCl O NH 96% 3. Boc2O 1. HexLi, MTBE/THF; BocHN CO Me NaOH t N 2 Bu then st BocHN CO2Me 53% (3 steps) NH lithium acetylide- 1 used in 4 Steps enzymatic O resolution Process: O ethylene diamine, Asunaprevir macrolactamization O DMPU (BMS, HCV) 49% rac, single D NH 100% ee diastereomer Grazoprevir - 2016 O NS3/4A, OH 2. AcCl, Et3N 79% (2 Steps) Bioorg. Med. Chem. 2016, 24, 1937 S genotypes 3. Enzymatic resolution 1. Esterase (With Elbasvir, O 30%, 92% ee Zepatier®, Merck) 1/4, EC50= 2. HCl quench 0.3-0.5 nM 1. CO(NH ) •H O 3. DPPA, Et3N Me 2 2 2 2 1. CeCl3, NaI O TFAA, 92-95% EtO2C CO2Et tBuOH, PhCH3 O S Asymmetric Route: WO2015057611 A1 EtO OH diethyl malonate 30 to 90 ºC O 2. H N NH H2N NH2 EtOH, 65 ºC 4. LiOH 2 1. MgBr HexLi, 0 ºC; t F 2. Me3SOI, BuOK 5. EDCI, Et N CuI, 2-MeTHF 1. 3M MeMgCl then NaOH, 80-84% F F 3 F DMF DMAP 91.7% THF F O O 60 ºC, 90% F Cl t Br S Me F 2. NaO Bu, 2-MeTHF 2. py•Br , MeCN J. Med. Chem. 2019, 62, 7340 HN O CONMe 3 Br O 2 -5 ºC, 91-93% Ac EtO P CONMe2 82% EtO Cl N Mechanism? F F 1. H2N F F 1. In powder O N F F O H2N 1. oxalic acid, 3N HCl, 90 ºC O N OMe ethyl glyoxylate H N 2. POCl3, 98 ºC Br 2. TPAP, NMO 2 O OEt Et N H N OMe 3. HO CO Me DBU, DMA E O O N 3 2 2 2. POCl 90 ºC BocN 3 NBoc O NH DMF, 65 ºC 68% (3 steps) CO2Me F F F OH 45% (4 steps NH2 N N N 1. CDI, DIPEA; then tBu F 1. PhSO3H NH tBu CO H MeCN O D 2 O O N F F t O O N OMe BocN 2. E, Pd(OAc)2, P( Bu)3HBF4 2. HATU Glecaprevir - 2017 O CO Et N K2CO3, CPME, MeCN O NH DIPEA (Mavyret®, AbbVie) NH G 2 65% (2 Steps) O t 3. H2, Pd/C NS3/4A, all genotypes S Me BocN NaO Bu t N Cl N 80% (3 steps) Bu CO2Me 82% CO2H Boc EC50 = 0.08-4.6 nM O CO2Et

1. LiOH N J. Med. Chem. 2019, 62, 7340 O 1. COCl2 2. EDC O NH py O S 2 O O O N OMe H3N NH OH 1. Ac2O, py, DMAP O t O H 2. lipase, NaOH Bu CO2Me O NH 3. NaH, allyl Br 2. NaOH; O NH Grazoprevir N then HCl tBu J. Med. Chem. OH 4. LiOH, MeOH OH 3. recryst. from tBu CO H CO2Me 2018, 61, 7004 40% (4 steps) 2 acetone/H2O O Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19

F F Other Anti-Virals: HIV F F O N O N • Cause: Human immunodeficiency virus, transmitted to humans by tranfusion of body fluids • Symptoms: targets the immune system and weakens people’s defence against infections and O O N some types of cancer; advanced stage of infections is aquired immunodeficiency syndrome O O N (AIDS) 1. HCl O NH 1. LiOH • Population: WHO declared 37.9 million individuals living with HIV (end 2018) G O NH RCM N • Treatment: involves a combination of lifelong antiretroviral drugs t 2. F, HATU 2. H, HATU Bu • 5 drug targets: 1) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), integrase t N CO Et DIPEA DIPEA Bu O 2 CO Et strand transfer inhibitors (INSTIs), protease inhibitors (PIs), non-nucleoside reverse O 2 transcriptase inhibitors (NNRTIs) and entry inhibitors Glecaprevir

Bictegravir - 2018 O O O F ® 1. DMF-DMA H (Biktarvy , active ingredients F F O 2. MeMgBr N N include emtricitabine and N BocN BocN Me N H tenofovir alafenamide, Gilead) O F F t t HIV-1 INSTI CO2 Bu CO2 Bu O O N OMe H2 O ONa EC50 = 2.4±0.4 nM Pd/charcoal >50:1 dr O NH Et As an INSTI Bictegravir works by disabling integrase, an enzyme essential for allowing F OH O N HIV DNA to be put into human DNA inside CD4 T cells tBu F 1. ZnCl2, 95 ºC NH 2. NaBH , 25 ºC O Et 4 Et Initial Route: O BocN 3. citric acid BocN H H H H O MeO OMe Voxilaprevir - 2017 CO tBu CO tBu 1. HOAc/MeSO3H 2 2 HN O HN O (Vosevi®, in NH MeCN O 1. p-TsOH, MeOH CO H combination with S (similar prep to N 2 75 ºC O 2. MTBE piece in CO2H CO2H Sofosbuvir and F F I N N Me 3. Boc2O Glecaprevir) MeO2C O Velpatasvir, Gilead) Et3N N H2N OH OH OMe MeO2C O MeO2C O NS3/4A, all genotypes, EC50 = 0.2-6.6 nM 1. 2. K2CO3, MeCN Made in 4 steps OMe OMe Cl N OMe 85 ºC Et (all one pot) F BocN 1. LiOH Cs2CO3, 100-110ºC 1. 2. F, HATU 2. iPrOH O F H CO2Me H H2N DIPEA 3. pTsOH O O CO2H N N N F F F F N H N F F O F F i O N HATU, Pr2NEt N O OH 2. MgBr , 50ºC O OMe 2 No info on d.r. O O N OMe O O N OMe 1. EDCI + Gilead Process Route: F O NH OH Et 2. RCM O NH Et MeO t H2N O F N 3. Pt/C – BuCOCl tBu H N OTs O O O O 1. DMF-DMA CO Me tBu CO H 2 Et N, DMAP 2 2 CO Me 3 F F N O 2 O O O O H 2. TFA NH2 4 steps MeO CO2H O F F Me Me Me Me MeCN, 50 ºC OMe MeO OMe OH J. Med. Chem. 2019, 62, 7340 Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19 Other Anti-Virals: Cytomegalovirus (CMV) O O O F OMe O O F • Cause: Cytomegalovirus, a common herpes virus that can remain dormant in the body but can MeO 1. HOAc cause complications during pregnancy and if immune system is weakened; spread through MeO MeO MeSO H N O 3 bodily fluids N MeCN, 75 ºC H MeONa H • Symptoms: usually asymptomatic, if occur: fever, night sweats, tiredness, sore throat, swollen glands, joint and muscle pain, low appetite and weigh loss HN F F MeOH MeO2C N F F OH MeO • Population: Over half of adults by age 40 have been infected MeO • Treatment: only required for babies with signs of congenital CMV and those with weakened immune systems OMe OMe I

O F NH2 MeO Letermovir - 2017 HO2C ® CO2Me MgBr2, 40-50ºC H 2. K CO (Prevymis , Merck) O 2 3 (tBu) P-PD G Bictegravir MeCN, DCM N N MeCN Infection prevention after bone Br 3 2 N CF Cy NMe N H 75 ºC 3 marrow transplant; acts as a CMV 2 O F F iPrOAc, 80 ºC OPRD 2019, 23, 716 N N DNA terminase complex inhibitor NH O OMe 2 F N OMe EC50 = 0.7-6.1 nM F

Asymmetric Routes to I: (–)-Vince Lactam CO Me O CO2H PCl5 2 MeSO CN HOAc CF3 2 (+)-γ-lactamase 2-picoline Cl OPh DCM N H2O NH NH i CO2Me + Tol, 40 ºC O 1. Na2HPO4, PrOAc, H2O 92% H2N SO2Me O O NH NH2 N N 2 H H F F OMe MeO CF3 O Pd/C, H OH Me 2 2. DMAP, iPrOAc, 80 ºC, 87% (3 steps) 1. mCPBA 2-MeTHF NBoc Boc O • 2 HCl OMe Deprotection Tol, 25-30 ºC MeMgBr 2 HO C MeO I DMAP CO2Me 2 (not 2. LiOH, H O 2-MeTHF 2 HN N HO specified) MeOH O OMe NHBoc NHBoc not isolated HN CF3 N • • Et3N, Tol, H2O; HO C N then N N 2 O OAc enzymatic F HO F N OMe MeCO3H 1. Pd(Ph3)4, HOAc desymmetrization CF3 2. Ac2O, imidazole HO2C K3PO4, PhCH3, H2O; OAc 90% (3 steps) then MeO HO2C 1. hv, O2, thiourea, MeOH, rose bengal N 2. AcCl, Et3N CF3 N CF3 CF3 OH OH OH N N OH N 1. PtO , H , 2-PrOH PPh3, Pd2(dba)3 F N OMe 2 2 5 mol% CF t 3 I 2. HCl, 2-PrOH ( BuO2C)2NH K3PO4, PhCH3, H2O, 0 ºC, 98%, 76% ee NH N(Boc)2 OAc ee further enriched with crystallization with 2 tartaric acid derivative – final 99.6% ee OPRD 2019, 23, 716 OPRD. 2016, 20, 1097 Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19 Cystic Fibrosis Drugs 1st generation route: O O O Me • Cause: genetic autosomal recessive disease; mutations in the cystic fibrosis transmembrane S O 1. CF O conductance regulator (CFTR) gene which maintain salt and fluid balance inside cells N HO 3 H N CF3 • Symptoms: median survival 37-40 years, progressive lung damage, malabsorption in the N Me Me intestinal tract and pancreatic insufficiency Me N N N N NH N Me Me Me O Me N • Population: affects one in every 3500 infants in the US, estimated 75,000 cases worldwide Me N DIAD, PPh3 Me Boc • Treatment: “corrector” drugs which facilitate transport of proteins to the cell surface and Boc 110 ºC, 57% CF3 Me 2. HCl, 96% “potentiator” drugs that facilitate chloride trafficking at the cell surface by increasing the time the Elexacaftor - 2019 t K2CO3 gate of the protein is open (Trikafta®, in cobo with ivacaftor CO2 Bu DABCO and tezacaftor, Vertex) DMF O O H CFTR corrector Cl N Cl 99% F O N OH F t NH F O O O Me CO2 Bu O F O Me 1. HCl, 91% O F N Me S 2. CDI, DBU N Lumacaftor - 2015 N N Tezacaftor - 2018 N Me N N Cl Me (Orkambi®, in combo H O O Me Me O (Symdeko®, active N N with ivacaftor, Vertex) HO RO N N Cl S ingredient in combo OH Me H2N CF CFTR corrector N 3 with Ivacaftor, Vertex) HO C K2CO3 93% N 2 CFTR corrector 120 ºC Me O H N Me 1. LiAlH Me A H2N OBn 2 4 RaNi, H2 O N CO Me 60-63 ºC 2 2 O Cl HN Me 87% F Me Me Cl + + N Me 2. Aq. HCl Me Me Me N NH2 F O F Me Me O Me Lipase Elexacaftor resolution BnO å Rh or Ru cat. CO H F O CN OH asymmetric 45% 2 Br Cl + F hydrogenation O2N CO2Me O Asymmetric 91-92% Resolution Route: Route: 1. H , Pt(S)/C O O Me Me Me 2 1. MeBu3NCl O O2N Br iPrOAc, 30 ºC NO2 NBS OBn NaOH, CHCl3, DCM O2N O2N Br HN DBU, 50 ºC EtOAc 2. p-TsOH•H2O Me Me 2. HCl, DCM 99% Me Me Zn(ClO ) •2H O F NH N 55% Me Me CO Me 50% 4 2 2 Me Me 2 F NH2 F NH2 Tol, 4 A MS OH H Mechanism? Me 80 ºC Me Me 2nd generation route: O O Me OBn OBn + H2N Me S H3N Br CONH2 Cl H2N – N Pd(OAc)2 OTs CONH Me (MeCN) PdCl 2 Cl 2 2 dppb, K2CO3 Me NMe CuI, MeCN F NH Br N N Me F NH MeCN, 80 ºC K CO , MeCN Li-t-amoxide 80 ºC OH Br N F 2 3 Me 2-MeTHF OH Me Me 97% ee (no yield given) Me OBn O OBn O O Me H2N OBn OBn CuI S 1,2-Diaminocyclohexane Elexacaftor N Me 1. conc. HCl H N F N Me Me Me Me 2. Mg, THF Me Br N N N O N MeMe 1. A, Et3N CF Tezacaftor 3. Cl OBn OH 3 NH Me BnO OH 2. H2, Pd/C 4. KOH/MeOH TMS OPRD 2019, 23, 2302 Me Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19 Boron-Containing Drugs Urinary Tract Infections • Cause: Many different bacteria Due to boron’s empty p orbital, it can coordinate to heteroatoms such as oxygen and nitrogen • Symptoms: dysuria, urgency and frequency of micturition, pyuria, and the presence of high and form reversible covalent bonds with proteins. This has culminated in teh approval of new therapeutics that work by these covalent mechanism numbers of bacteria in the urine (>105/ml) • Population: 150 million people each year worldwide Multiple Myeloma • Treatment: antibiotics • Cause: Cancer in plasma cells Vaborbactam acts as a non-suicidal beta-lactamase inhibitor that protects Meropenem • Symptoms: uncontrolled proliferation of monoclonal plasma cells in the bone marrow leading (the penem antibacterial drug component of Vabomere) from degradation by certain to the production of abnormal proteins serine beta-lactamases • Population: 1% of all cancers worldwide, 5-year survival rate of 45% (2009-2010) H Vaborbactam - 2017 • Treatment: (proteasome inhibitors such as Bortezomib/carfilzomib or N (Vabomere®, in combo with Meropenem, The Medicines Co.) monoclonal antibody drugs), biological therapy (drugs such as thalidomide/lenalidomide/ Complicated UTIs caused by E. coli, pomalidomide), chemo, corticosteroids, bone marrow transplant, and/or radiation therapy S O B CO2H HO O K. pneumoniae, and E. cloacae Ixazomib is a prodrug that is immediately hydrolyzed in aqueous solution to the boronic acid Me works by reversibly binding to the CT-L (β5) subunit of the 20S proteasome Me OH Me Cl O t H CO2 Bu [Ir(COD)Cl]2 N HBpin Bpin t OH N iPr Cl O Cl O OTBS CO2 Bu H dppb, DCM H 3 step via lipase OTBS O B Cl N CO H 96% Me THF, rt, 91% O O H N CO H 2 resolution Me 2 2 H 40%, >99% ee Cl CO2H Me aq. NaOH, 0 ºC Cl 1. n-BuLi, heptane O THF, DCM O CO2H Cl 97% Cl Ixazomib Citrate - 2015 Me Me O t -60 to 70 ºC B TBTU B CO2 Bu H O t ® (Commercial, O 2. ZnCl , THF CO2 Bu (Ninlaro , Takeda Pharmaceuticals) •TFA Me DIPEA OTBS 2 made by Me O -20 ºC OTBS Multiple myeloma H2N B DMF Matteson O Me 5 ºC Me H S 90% (2 steps) Homologation) 1. LiHMDS, THF Citric acid iPr 88% Me -78 ºC Cl O 2. 2-thiopheneacetic H Cl O H O Me HN O N 1N HCl, MeOH acid, EDCI, HOBT, N iPr (CH ) CHCH B(OH) N B HCl, Diox 3 2 2 2 N O Me NMM Me O t H B CO2 Bu reflux Vaborbactam O B(OH)2 74% H O 70% iPr Me O OTBS 64% Cl Cl Me H

Atopic Dermatitis (Eczema) 1. F Crisaborole - 2016 O • Cause: Unclear, though suggestions that immunological system is involved/ cutaneous O (Eucrisa®, Pfizer) HO β-adrenoreceptors; physical or emotional stress can exacerbate O O NC Eczema • Symptoms: inflammation/skin irritation NC B K CO , DMF phosphodiesterase 2 3 • Population: 2-5% (in children and young adults ~10%, 2014, World Allergy Organization) OH Br 100 ºC 4 inhibitor • Treatment: usually resolves spontaneously between ages 5-8 but it can persist into 2. 3N HCl, THF i 66% (2 Steps) adulthood; topical hydrocortisone, corticosteroids, and oral antihistamines could all be 1. n-BuLi, B(O Pr)3 1. NaBH4 prescribed THF, -78 ºC O 2. 3,4-dihydro-2H-pyran O CHO Crisaborole 1st medication to treat atopic dermatitis that has been FDA-approved in more than 2. 6N HCl OTHP CSA, 93% 10 years. Works by targeting phosphodiesterase 4 enzymes which control cytokine function. 37-44% Overproduction of cytokines can trigger inflammation. (2 steps) NC Br NC Br Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19 Phosphorus-Containing Drugs NH2 1. simulated moving • Many instances of approved drugs containing phosphorus. N N • Most often act as prodrugs (For instance improves aqueous solubility/PK) and/or improve O bed chromatography Tenofovir Alafenamide activity N N P OPh 47%, 99% Fumarate O i diastereomeric purity Chronic Hepatitis B HN CO2 Pr • Cause: hepatitis B virus; passed from mother to child or contact with bodily fluids rac 2. fumaric acid, MeCN Me 83% J. Med. Chem. 2018, 61, 7004 • Symptoms: chronic if test positive for >6 months, many do not exhibit symptoms and can be Me diagnosed decades after their initial exposure. inflammation and damage of the liver or liver Arterial Thrombosis cancer • Cause: activated by turbulent blood flow in diseased vessels or the release of mediators from • Population: 257 million people living with chronic infection (WHO, 2015) other circulating cells and damaged endothelial cells lning the vessel • Treatment: Recombivax HB - Effective Vaccine to prevent contracting the virus; effective drug • Symptoms: result in a life-threatening partial or complete blood clots that can cause angina, therapies that control/stop further liver damage for those already infected heart attacks, or strokes • Population: - • Aryloxy phosphoramidate triesters (ProTide) effective prodrug strategy for the transport of • Treatment: for P2 prodrugs within the cell. Both the aryl group attached to the oxygen and the stereochemistry of • Cangrelor is a direct-acting P2Y12 platelet receptor inhibitor that blocks adenosine phosphate- the methyl on the amino group, and a bulky alkyl group on ester crucial for effective biological induced platelet activation and aggregation. P2 receptors are GCPRs that are only found on action platelets. Cangrelor acts as a antagonist to the receptor NH NH 2 • To prevent enzymatic/chemical hydrolysis of polyphospate side chain methylene unit placed 2 ChemMedChem NH N betwen terminal and 2nd phosphate and chlorination gives it a pKa close to ATP 2 N N 2019, 14, 190 N J. Med. Chem. 1999, 42, 213 N CF N N 3 Cangrelor - 2015 N N O N O (Kengreal®, The 1. NaOH, H O N O O P S S 2 N O O P OPh Medicines Co.) DMF O HN MeS HN O P OH HN Me CO2H N HO Anticoagulant CF3 Me N OH O NH I OH -Ala. -PhOH Me Me Me N Cl 94% -iPrOH Prodrug activation OH OH Cl Active Drug H N O O OH O 2. HNO3, AcOH N O P P P OH 80% NH 2 O O O •0.5 HO2C NH NH O N CO2H CF 2 2 N 3 CF NaOH O S 1. POCl DIPEA 3 N DMF N MeS CF3 3 S N N + O O N N P OPh N 15 to 110 ºC O CO iPr S 1 NH3, 85% HN 130 ºC HN 2 Cl N 80% N N N N N 2. HCl, CH(OEt)3 OH 75% Me O N H Me Me HN N 97% 2. AcOH, Fe H N Cl H2O/ETO Tenofovir Alafenamide Fumarate 3. NaOH, MeI 2 O N O Me ® quant. 2 2016, (Vemlidy , Gilead) N NH NH •HCl Mg(tBuO) O HS 2 2 chronic hepatitis B 88% DMF, 77 ºC TsO P 1. PO(OEt)2, POCl3 OEt functions as nucleoside analog 1. N,O-bis- OEt 1,8-diaminonaphthalene reverse transcriptase inhibitor (trimethylsilyl) CF 2. acetamide 3 Cl Cl HO OH n 1. TMSBr, 80 ºC 1. SOCl , MeCN • N( Bu)3 NH2 NH2 2 2. TMSOTf HO P P OH 50% 75-80 ºC AcO S N N OAc MeS O O N N Cangrelor O 2. phenol, DCC O 2.H N CO iPr N N HO 2 2 OH DMF, NBu3 Et3N, NMP AcO N N P OEt N N P OPh -29 to -18 OAc 3. aq. NH4CO3 O 100 ºC, 51% O Me ºC O N OEt OH H N OH 68% (3 steps) 3. Et3N, -18 ºC 3. NaOH N O 4. aq. NaHCO3 Me Me 46% 87% (3 steps) J. Med. Chem. 2018, 61, 7004 Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19 ALK-positive Non-Small Cell Lung Cancer Chronic Immune Thrombocytopenia • Cause: ALK positive tumors have an inversion in chromosome 2 that results in a novel • Cause: autoimmune disorder oncogene, EML4-ALK. 5% of NSCLC tumors have this mutation. Associated with light smoking • Symptoms: antiplatelet autoantibodies and specialized white blood cells destroy their blood history and younger age platelets and can damage their megakaryoocytes, decreasing platelet production. This then • Symptoms: cough, difficulty breathing, spitting/coughing blood, chest pain, hoarsness, causes excessive bleeding/bruising problems swallowing, and eventually death • Population: Rare, fewer than 200,000 US cases/year • Population: 5% of non-small cell lung cancer (NSCLC) contain this oncogene • Treatment: in children usually resolves itself, in adults steroids, splenectomy, immune globulin st Me OMe • Treatment: 1 in line treatment is followed by OMe O Me Me OMe O F OMe O Me Me N OMe P O N N NH2 H H Me H F H2N OMe N N N O N N N N N OMe N H H N O N Cl ONa Fostamatinib - 2018 Cl N Cl P ® Bioorg. Med. Chem. Lett. 2015, 25, 212 - 2017 O ONa (Tavalisse , Rigel Pharmaceuticals) N ® O (Alunbrig , Takeda) •6H O Chronic immune thrombocytopenia 1. 2 t MeN ALK-positive non-small cell lung cancer P O Bu Cl O t kinase inhibitor Making Prodrug: OMe O Bu Me Cs2CO3, DMAc O F OMe 74% Dimethylphosphine oxide essential for Me N Fostamatinib i Key insight from SAR: Et/ Pr both enhanced activity as it serves as a hydrogen- 2. AcOH, 55% selectivity but reduced bond acceptor which drives potency, O N N N N N OMe 3. recrystallization from H H H H NaOH/H O/IPA, 77% WO 2011/002999 potency over Me selectivity, and favorable absorption, 2 distribution, metabolism, and excretion Breast Cancer (ADME) properties Basic nitrogen critical • Population: 12% women will develop breat cancer, those with inherited BRCA mutations for driving cell-based 69-72% more likely to develop breast cancer activity; 6 membered R2 • Treatment: surgery, , or PARP inhibitors (Talazoparib falls in this class). PARP rings best O R5 H H inhibitors target poly (ADP-ribose) polymerases as they are important enzymes in DNA damage N N N Other functional groups repair. Therefore their inhibition causes more single strand breaks resulted in loss in H best; F less active, Me N cellular viability but did H equipotent cellular acitvity but R1 R4 O Originally targeting scaffolds such as: O N maintain enzymatic N loss in enzymatic activity R3 F Planned synthesis: activity NH N PhCHO Ph Process Route: NaOMe Me ethyl N O Cl N Cl HN N O Me O Me O proopionate O I P P H P N Me Me Me N Me N reflux H2N H H2N Cl Cl N N O Ph Novel K CO K3PO4, Pd(OAc)2 2 3 N structure for Xantphos, DMF n-Bu4NHSO4 Cl • TsOH O H further SAR DMF, 65 ºC NH2 NH2 120 ºC F O N IC HCl N 50 OMe Talazoparib - 2018 6.1 nM EtOH MeO2C O (Talzenna®, Pfizer) Ph GI DME Ph H2NNH2 50 > 300 M MeN N N NH2 20 ºC Breast cancer with germ- H2O, reflux µ WO 2016065028 A1 Brigatinib line BRCA mutations N Ph N Ph H (Note med chem route extremely similar except Pd C-P formation done on NO2 anisole) H Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19

Med Chem Route: O O O PhCH(OMe) 1. KHMDS O OHC N F F CO2Me 2 OR MeOH NHCbz BF •OEt O O O F 3 2 2. CF O Ph 68% 3 Ph MeN N 99% O O Ph CO H Et2O, 89%, Ph N (2 steps) Ph N Et N, Ac O N 2 >98% de, 95% ee 3 2 NO Cbz Cbz 2-MeTHF NO2 2 N Br O 1. LiAlH4 NO rt to 80 ºC MeN N CF3 2 MeN 2. KHCO3, NMP 78% N Et N, EtOH 1. 3 Me H2O H O 2 3. Ph3PCH3Br MeO C O MeN N TiCl3, THF A CHO 2 MeOH NaHMDS 1. H2NNH2 1. TMSI MeOH, 80% N 0 ºC to rt NH • TsOH OR O followed by Talazoparib • H O Tol, reflu OR 2. SFC chiral 2 2 step OR separation N OHC F 2. NaBH(OAc) recrystalization H Ph 3 H2N Ph BzCHN Ph J. Med. Chem. 99.3% ee N NH 3. TsOH•H O 95% O 2 2016, 59, 335 F H 88% (2 steps from A) Process Route: O O No N DMF, LiHMDS Me2N F F 1. TsOH, conditions distillation N + O O OR 1. NaOH -5 to 0 ºC given 2. HG-ll cat Rolapitant MeN N 2-MeTHF LiO 2. H2, Pd/C, 95% (2 Steps) MeN N RCM Hydrochloride 72.5% N 3. EtOH, HCl, iPrOH, H O NO NO Ph 2 Hydrate WO 2015069851 A1 2 2 N 3. 12N HCl O N NH 91% N 85% H Me Talazoparib Alternative Routes: US 7,049,320; US 2008003640; CN 107383008 Shown Route: WO 2010028232 A1 O O 1. HO C • Note: Varubi was discontinued in 2018 due to serious hypersensitivity reactions F 2 Ph Cl N N OMe MeO2C O MeO2C O MeN including anaphylaxis and anaphylactic shock. This may be due to the fact that the PPTS, MgSO 4 MeN N rolapitant IV emulsion contains soybean oil though other P/NK1 inhibitors that don’t Diox, reflux: N contain soybean oil but have been associated with similar reactions NaBH NaOEt NH 4 2 2. resolution F N Ph THF F N Ph WO 20172151166 A1 H H

Miscellaneous LHMDS O O Alternative routes: trimethyl HCO2Me 1,4-addition CO2H acetaldehyde CuCl, DMI, THF and N O NH CH SO H TMSCl HN lactamization O 3 3 O NMP, TFAA t -70 ºC to 0 ºC This Route: 72% Bu 61% RCM NH CF3 O 1. Ph3PCH3Br O OH A NaHMDS, 63% O t Me 2. LiAlH(O Bu)3 Rolapitant - 2015 N O CF3 O THF, -20 ºC, 83% N O (Varubi®, Tesaro) O tBu Chemo-induced nausea tBu Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19

CO2H MeO Ivabradine Brexpiprazole O iPr 2015 Me ® ® OH R= OH Cholic acid (Corlanor , Amgen) (Rexulti , Lundbeck/Otsuka) N Me (Cholbam®, Asklepion Pharmaceuticals) MeO Heart failure Schizophrenia MeO N O H Bile acid synthesis disorder S N O Me H Me OMe N R= H Deoxycholic acid N N N HN O N O (Kybella®, Kythera biopharmaceuticals) H H OMe H O HO R O Reduce chin fat Cangrelor CF3 H ® Me N Cl Cl Cariprazine NMe2 (Kengreal , The 2 ® Daclatasvir HN (Vraylar , Allergan/ ® Edoxaban Medicines Co.) S (Daklinza , BMS) N N Gedeon Richter) N HN (Savaysa®, Daiichi Anticoagulant Hepatitis C N HO Schizophrenia O N OH MeN Sankyo) MeS S OHN O Cl O NH Anticoagulant N H MeO N OH OH Cl O H O O OH O N O Cl HN O N O HN i Me O HN Cl P P P OH Pr HN • • HCl N N O O O O O N O N NH F CF3 O N N H B N NH F F A OH N H H O F HN O N Panobinostat OH O OH N Lumacaftor Me OAc (Farydak®, Novartis) OH N AcO O Me (Orkambi®, in combo Trifluridine (A) and Tipiracil (B) Multiple myeloma N + ® Cl with ivacaftor, Vertex) N N Me (Lonsurf , Taiho Oncology) OAc H NOC 2 Cystic fibrosis S Colon cancer Me O O Uridine triacetate HO2C • SO4H2 Cl Me + N HO2C (Xuriden®, Wellstat CF3 N O N NC MeN N NH Therapeutics) N O OSO Na OH H 3 Isavuconazonium Hereditary orotic N O N N S N MeHN aciduria H N sulfate Ph 2 ® O (Cresemba , O N S N N N Flibanserin O (Addyi®, Sprout Astellas) HN N (Cotellic®, - Antifungal Me O O Ceftazidime-avibactam CO2 Pharmaceuticals) Genentech) ® N O (Avycaz , Forest H H Low libido in N Me F NH Melanoma N N O Aripiprazole Laboratories) women 10 H2N NH2 F F lauroxil Antibiotic N Me O H (Aristada®, O O Cl CF O 3 O Eluxadoline O N Alkermes) ® OMe Me (Odomzo , Novartis) ® H N (Viberzi , Forest Laboratories) Schizophrenia 2 Basal cell carcinoma Me CO2H I O O ® IBS O (Lenvima , Eisai) Me MeO N O Thyroid cancer HN N O N N Rolapitant Me Me N NH H N HN (Varubi®, Tesaro) N N O Me HN Me O N Chemo-induced N Ph B nausea N Me Sacubitril (A) and Valsartan (B) NH Et CN ® (Entresto , Novartis) CF3 O N N N N O A H Me O Heart failure O O H Alectinib EtO n ® ® N Bu (Alecensa , Genentech/Roche) (Ibrance , Pfizer) N CO2H HO Me H H ALK-positive lung cancer Metastatic breast cancer O iPr O CF3 Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19

S H Cl Me F 2015 CO2Na 2016 N CO Na H CO H Me 2 O Me 2 Me S O O S MeHN O Me Obeticholic acid (Ocaliva®, Intercept Rucaparib ® O O CO2Na (Rubraca , Clovis N OHOH Pharmaceuticals) (Venclexta®, AbbVie) OH HO H N CO Na O Oncology) 2 HO HO OH Primary biliary Chronic lymphocytic OH O H BRCA-positive OH Et cholangitis O HO ovarian cancer N S H N S H NH2 O N O OH HO 18 Crisaborole F CO2H O O OH HO (Eucrisa®, Pfizer) O CO Na B O HO 2 Fluciclovine F 18 NC O OH Eczema OH OH (Axumin®, Blue OH NaO2C O Sugammadex Cl O S HN O ® Earth Diagnostics) Me O (Bridion , Merck) O O S O S O O S PET imaging agent N CO2H Anesthesia reversal H O Lifitegrast O N Cl (Xiidra®, Shire) S NaO2C NH2 O O Dry eye NO2 NaO2C •0.5 HO2C Trabectedin CO H Et HN N N 2 Lesinurad (Yondelis®, O H2N ® Brivaracetam (Zurampic , PharmaMar/J&J) N P OPh O N ® HO N O i (Briviact , UCB) AstraZeneca) Soft-tissue sarcoma CO2 Pr HN Epilepsy Hyperuricemia O Me Me nPr N O MeO NH OMe Br S Tenofovir Alafenamide Fumarate O HO Me Me H (Vemlidy®, Gilead) N N N OH O H N N AcO S chronic hepatitis B N O H MeO2C Me Me N N OMe N Me O N iPr H (Tagrisso®, AstraZeneca) N N OMe O Velpatasvir O N O EGFR T790M mutation- (Epclusa®, in combo with O OH MeO NH N positive lung cancer N Sofosbuvir, Gilead) NH O O A O i Me Pr O HCV CO2Me NH i O N O Pr O S HN N N O H N HN MeO H O O Selexipag NH N N NH OMe N N ® N H (Uptravi , O iPr N O N B N N MeN Pharmaceuticals) tBu O O Grazoprevir (A) and Ph NH O Pulmonary arterial Elbasvir (B) O S O Ph ® Cl O NMe2 hypertension (Zepatier , Merck) H Me N N HCV genotypes 1&4 i Non-Small Molecules N Pr Non-Small Molecules H i Pimavanserin O B(OH) F O Pr 2 • Patiromer • Tresiba • Empliciti ® H (Nuplazid , Acadia • Gallium Ga 68 • Tecentriq • Zinplava • Cosentyx • Praxbind • Kanuma dotatate (mixture • Defitelio • Lartruvo Cl Ixazomib • Natpara • Strensiq • Portrazza N N Pharmaceuticals) ® of known small • Cinqair • Exondys 51 (Ninlaro , Takeda Pharmaceuticals) • Unituxin • Nucala • Repatha Parkinson’s disease O molecules) • Taltz • Adlyxin Multiple myeloma • Praluent • Darzalex associated Psychosis • Spinraza • Anthim • Zinbryta Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19

AcO • MsOH 2017 CO Et Safinamide 2 HO C HN • 2 O ® O Me CO2H O F (Xadago , Newron Me N O NH H 2 N O Pharmaceuticals) HO N N N O O • H2N Parkinson’s disease Me H N CF3 N N N N NMe Me H Ph N CO H N N 2 H H NH 2 H 2 H MeO H (Kisqali®, Novartis) • 2TsOH O Telotristat Ethyl N Deflazacort ® HR-positive/HER2- N ® (Xermelo , Lexicon Pharmaceuticals) MeO Me (Emflaza , Marathon Pharmaceuticals) negative advanced or H S O B CO2 Carcinoid syndrome diarrhea HO O H Duchenne muscular dystrophy metastatic breast cancer Valbenazine Me Vaborbactam D3CO (Ingrezza®, Neurocrine O O (Vabomere®, in combo Biosciences) N O Me Me • TsOH H N O Me with Meropenem, The N 2 D3CO Me Tardive dyskinesia • TsOH • H2O H2N Medicines Co.) N H N N Me Me Complicated UTIs HO H HN O O N OH N O Deutetrabenazine H NH Me N HN OMe O Naldemedine Niraparib (Austedo®, racemic mixture of R,R and 2 CO2H ® (Symproic®, Purdue) (Zejula , Tesaro) S,S cis isomers, Teva Pharmaceutical) Betrixaban • OH O Opioid-induced constipation Ovarian, Fallopian, or Peritoneal Cancer (Bevyxxa®, Portola CO H Huntington’s disease-associated chorea HN Cl 2 O O O Pharmaceuticals) O Me NMe N P H H F Venous thromboembolism F F Me NMe OH N N N O N OH O OMe N N N • HO N OMe Cl O OH O O N H Me HO Cl F N A Brigatinib N HO N N N Me N (Alunbrig®, Takeda) O NH MeN H2N Edaravone O ALK-positive non-small cell lung cancer HO ® N O O F (Radicava , tBu Delafloxacin NH S CO2H Mitsubishi Tanabe) O N NMe N (Baxdela®, Melinta O Me 2 • Amyotrophic lateral F H O N F O Therapeutics) sclerosis CO2H H Skin infections F O maleate F ® Secnidazole Glecaprevir (A) and HN Cl ® (Rydapt , Novartis) F (Nerlynx , Puma O (Solosec®, Symbiomix Therapeutics) ® HN CN FLT3-positive acute Pibrentasvir (B) (Mavyret , Biotechnology) O N Bacterial vaginosis myeloid leukemia OH AbbVie) HER2-positive NH O Me Me Hepatitis C EtO N t breast cancer Bu N N N N N OMe B MeO N F F O Et OMe Me N N M N N Voxilaprevir F O2N e CF3 NH ® O NH (Vosevi , in HN O HN NH O NH • MsOH O F N N combination with Benznidazole CO Me N MeO C (Idhifa®, Celgene) O 2 2 Sofosbuvir and O N (Benznidazole®, CF3 N Me IDH2-positive acute NH N N N Velpatasvir, Gilead) S BnN F F H OH Chemo Research) Me myeloid leukemia Hepatitis C O NO Me 2 Chagas disease Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19

Me Ac Segesterone acetate O 2017 Copanlisib N 2018 OAc ® Cl O ® (Annovera , in F (Aliqopa , Bayer) NH N H H combination with N F N OMe Follicular Ethinyl estradiol N H H Me N N N O N NH TherapeuticsMD) Me HN N F O N O • 2HCl MeO Pregnancy prevention • H2O N NH N CF3 Me N O S N N O N N N iPr H2N N N N HO2C MeO N N O OMe Cl H HN Letermovir Me Me Me • TsOH ® HN N 5 F (Prevymis , Merck) NEt Duvelisib Lusutrombopag ® Infection prevention after bone ® Cl Talazoparib (Copiktra , ® N (Mulpleta , Shionogi) marrow transplant (Verzenio , Eli Lilly) HO C (Talzenna®, Pfizer) Verastem) Thrombocytopenia 2 Breast Cancer Breast cancer with germ-Chronic Lymphocytic F NMe2 HO MeHN N H H line BRCA mutations Leukemia, Follicular Me OH O O Lymphoma ONO2 N Me MeO N NH2 N O Latanoprostene Bunod N O ® H OH HO Ph (Vyzulta , Valeant Pharmaceutical) CO2H OH O OH O O • 2HCl N N HO Glaucoma/ocular hypertension O N • H O Eravacycline H 2 Ozenoxacin (Xerava®, Tetraphase Pharmaceuticals) HN Me (Xepi®, Medimetriks (Vizimpro®, Pfizer) Netarsudil Me Intra-abdominal infections N Non-small-cell lung cancer O Pharmaceuticals) F ophthalmic MeO NMe2 Impetigo H H Cl solution OH NMe2 NMe2 O Me ® H H (Rhopressa , Aerie Cl OH NH • 2MsOH Pharmaceuticals) 2 H t H Glaucoma/ocular N OH Bu N NH2 O OH O OH O O • 2HCl H2N N hypertension OH • TsOH NH EtO Sarecycline OH O OH O O ® O N OH (Seysara , Paratek Pharmaceuticals) O Omadacycline Acne Vulgaris CN (Calquence®, O O (Nuzyra®, Paratek Pharmaceuticals) NH2 OH Me AstraZeneca) O N Skin infections, pneumonia N NMe HN N N Mantle cell HO OH H CO2H OH N lymphoma N O Ertugliflozin CN • Me Me NH H •AcOH (Steglatro®, Merck CO H O F N 2 H H N and Pfizer) N Me Me O Me OH O NH Me N N Me Me N N N CHO Type 2 diabetes Me ONa OH H2N H Me O NH2 AcO Me NH Non-Small Molecules ® (Lorbrena , Pfizer) (Daurismo®, Pfizer) Macimorelin acetate ALK-positive metastatic Acute myeloid leukemia MeO O (Macrilen®, Aeterna • Trulance • Brineura • Fasenra non-small-cell lung cancer • Parsabiv • Tymlos • Mepsevii OH Zentaris) OH O • Siliq • Imfinzi • Hemlibra Me O Adult growth hormone • Bavencio • Kevzara • Ozempic Stiripentol Rifamycin tBu O ® deficiency • Dupixent • Tremfya • Giapreza (Diacomit , Biocodex) (Aemcolo®, Cosmo Pharmaceuticals) • Ocrevus • Besponsa O Seizures Traveler’s diarrhea Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19 HO C CO H 2018 Cl N 2 2 O F Me H O Cannabidiol OH O N (Epidiolex®, GW N N N N H OH 177 Me Pharmaceuticals) Lu H Cl •HCl N N N Seizures associated O F F O Lofexidine hydrochloride H H NH O ONa with Lennox- (Lucemyra®, US WorldMeds) Me HO2C N N OH 4 Gastaut and Dravet O N N Bictegravir Opioid withdrawal Me syndrome H S H (Biktarvy®, active ingredients CO H O O 2 O O O S O HN O include emtricitabine and S H H tenofovir alafenamide, Gilead) N N N N N NH2 Et HO N H Avatrombopag N HIV N H 4 S N (Doptelet®, Dova O O CyN Cl HO Me HO Me N Pharmaceuticals, N H N O CN O N OH CO H developed by AkaRx) Lutetium-177 dotatate F 2 ® Low platelet count in N (Lutathera , Novartis) F O Me S • O F N Me people with chronic kidney HN (Olumiant®, Eli Lilly) cancerous neuroendocrine tumors Cl CO2H Tezacaftor disease Rheumatoid arthritis (Symdeko®, active OMe HO NOMe OH ingredient in combo OH F Me Me OH NH2 O with Ivacaftor, Vertex) H O Me O OH Ph Cystic fibrosis Me HN N Elagolix O O O O NMe ® O NH (Orilissa , AbbVie) N S Me Me Me O N Me NC OH Endometriosis • 2.5H2SO4 NMe O O H N NH F N N Moxidectin 2 HO H CF F (Moxidectin®, Plazomicin NH2 3 O CO2Na CF F Apalutamide Medicines (Zemdri®, Achaogen) 3 S O OH ® Development for F (Erleada , J&J) O Me UTI H Global Health) Prostate cancer F OH River blindness N H OMe N Me F (Tibsovo®, Agios N O O F OMe O M N F Pharmaceuticals) N e N O O Br Me N N Acute Myeloid O N N N N N OMe H MeO O O O MeO C N N H Leukemia H H 2 Cl O N Cl N O H O Baloxavir marboxil Fostamatinib N ONa CF3 (Xofluza®, Shionogi, P (Tavalisse®, Rigel Pharmaceuticals) F F CN O ONa + Genentech) Chronic immune thrombocytopenia NH •6H2O N NH Influenza H N OH N N F O S Me O H N O Me Tafenoquine Me O OMe H Me (Krintafel®, GSK) O O • H2O Me Amifamprdine O Malaria NH Tecovirimat + 2 (Firdapse®, Catalyst ® MeO N NH N (TPOXX , (Mektovi® and Braftovi®, 2 N NH Pharmaceuticals) SigaTechnologies) CO2H O H Array BioPharma) HO C • H2N • H3PO4 Lambert-Eaton Smallpox 2 CF3 Metastatic melanoma Me N myasthenic syndrome Baran Group Meeting Lisa M. Barton FDA Approved Drugs: 2015-2019 12/14/19 • H2O

2019 Cl N Istradefylline O ® O SMe Me (Nourianz , Kyowa Kirin, Inc.) Cl NMe N Parkinson’s Disease Cl O N EtN N H (Brukinsa®, BeiGene Cl Triclabendazole O N N OMe USA Inc.) (Egaten®, Novartis) Et mantle cell lymphoma Cl Fascioliasis OMe N N O HN O O S CF3 Et O O N N HN H N NH Relebactam N H 2 H N O O (Recarbrio®, in combo with O OH N N O imipenem and cilastatin, Merck) N S O O (Rinvoq®, AbbVie) UTI/Intraabdominal infection O O NH H N N Rheumatoid arthritis 2 H O O OH N NH2•HCl O NMe OH N Solriamfetol NH2 N (Sunosi®, Jazz NH H N N O Erdafitinib Pharmaceuticals) O N N ® (Balversa , Janssen) narcolepsy or NH Me metastatic obstructive sleep apnea H2N N N MeO N Methotrexate i NH Pr Siponimod (RediTrex®, Cumberland Pharmaceuticals Inc.) Et (Mayzent®, Novartis) rheumatoid arthritis, polyarticular juvenile relapsing multiple sclerosis HN idiopathic arthritis, and psoriasis OMe N O O N CF3 O HN Me Ac OH Cefiderocol Me (Fetroja®, Me H Me OH O Shionogi&Co.) Me O Me H H complicated UTIs O N N O HO N O H N N N S O Brexanolone S NHtBu O H H O (Zulresso®, Sage N HN H Therapeutics) H2N S ® NH (Inrebic , Celgene) O Postpartum depression Myelofibrosis S N N+ O O Cl Non-Small Molecule Cl - HO2C O O O O NH • Givlaari • Polivy • Adakveo N • Skyrizi Cl • Reblozyl • Evenity Tafamidis meglumine Cl MeN Cl • ExEm Foam • Cablivi (Vyndaqel®, Pfizer) • Scenesse Tenapanor HO • Jeuveau heart disease cause by transthyretin • Beovu • Avsola (Ibsrela®, Ardelyx) OH mediated amyloidosis • Ga-68-DOTATOC IBS