Dabrafenib (GSK2118436) is a mutant BRAFV600-specific inhibitor, with an IC50 of 0.7 nM in cell-free assays. It shows 7-fold and 9-fold lower potency against B-Raf(wt) and c-Raf, respectively.

Synthetic route:

(1) Esterification, H2SO4, MeOH, reflux, 1 h;

(2) Buchwald reaction, 1,1-dimethylethyl carbamate, Pd2(dba)3·CHCl3, xantphos, Cs2CO3, toluene, N2 atm, 90 °C, overnight;

(3) Deprotection, TFA, DCM, rt, 1 h;

(4) Sulfonylation, 2,6-difluorobenzenesulfonyl chloride, pyridine, DCM, rt, overnight;

(5) Nucleophilic substitution, LiHMDS, THF, 0 °C, then 2-chloro-4-methylpyrimidine, 20 °C, 1 h;

(6) Bromination and formation of thiazole ring, NBS, DMA, 15 min, rt, then 2,2-dimethylpropanethioamide, 80 °C, 3 h;

(7) Ammonolysis, NH3(7 N MeOH), 90 °C, 24 h.

Afatinib (BIBW2992) irreversibly inhibits EGFR/ErbB, including EGFR(wt), EGFR(L858R), EGFR(L858R/T790M), ErbB2(HER2), and ErbB4(HER4), with IC50 values of 0.5 nM, 0.4 nM, 10 nM, 14 nM, and 1 nM, respectively, in cell-free assays. Afatinib can induce autophagy.

Synthetic route:

(1) Cyclization, Formamide acetate, ethyl glycol monomethyl ether;

(2) Nitration, HNO3/H2SO4, 100 °C;

(3) Formation of anilide chloride, SOCl2, MeCN, evaporation, Snar Reaction, 3-chloro-4-fluoroaniline, i-PrOH;

(4) SNAr reaction, (3S)-tetrahydrofuran-3-ol;

(5) Nitro reduction, H2;

(6) Acid amine condensation, CDI, THF, diethylphosphonoacetic acid, 40 to 30 °C;

(7) HWE reaction, HCl:H2O, (dimethylamino)acetaldehydediethylacetal, KOH, SM, LiCl, THF, −7 to 20 °C.

2014

Nintedanib, also known as BIBF 1120, Intedanib, Vargatef, and Ofev, is an effective triple kinase inhibitor that targets VEGFR1/2/3, FGFR1/2/3, and PDGFRα/β. In cell-free assays, the IC50 values for these targets are 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM, and 59 nM/65 nM, respectively.

Synthetic route:

(1) Alkylation: 1-methylpiperazine, K2CO3, acetone, room temperature, 3 hours;

(2) Reduction: H2 (50 psi), Pd/C, MeOH, room temperature, 1.5 hours;

(3) Reaction with electron-deficient carbon: methylchloroacetate, tBuOK, DMF, -10 °C, 10 minutes;

(4) Ring reduction: H2 (50 psi), Pd/C, AcOH, room temperature, 2.5 hours;

(5) N-acetylation of indole ring: Ac2O, 130 °C, 8 hours;

(6) Methylation condensation: o-benzoic acid trimethyl ester, Ac2O, 120 °C, 6 hours;

(7) Nucleophilic substitution: XXIXa, DMF, 80 °C, 1 hour, then piperidine, room temperature, 2 hours.

Idelalisib (CAL-101, GS-1101) is a selective p110δ inhibitor, with an IC50 of 2.5 nM in cell-free assays. It exhibits 40 to 300 times selectivity against p110α/β/γ, and 400 to 4000 times selectivity against C2β, hVPS34, DNA-PK, and mTOR. Idelalisib also induces autophagy.

Synthetic route:

(1) Acyl chloride amine condensation, (COCl)2, THF, DMFcat, rt, 2 h;

(2) Aniline, NaHCO3, 1,4-dioxane/H2O, 6 °C, 30 min;

(3) Acyl chloride amine condensation, SOCl2, DMFcat, reflux, 5 h;

(4) N-Boc-L-2-aminobutyric acid, Et3N, DCM, 10 °C−rt, 3 h;

(5) Reductive cyclization, Zn, AcOH, rt, 2 h;

(6) Deprotection, TFA, DCM, 1 h;

(7) K2CO3(aq.);

(8) SNAr reaction, 6-bromopurine, DIPEA, EtOH, t-BuOH, 80 °C, 24 h.

Ceritinib (LDK378) is an effective ALK inhibitor with an IC50 of 0.2nM in cell-free assays. Ceritinib also inhibits IGF-1R, InsR, STK22D, and FLT3 with IC50 values of 8nM, 7nM, 23nM, and 60nM, respectively.

Synthetic route:

(1) SNAr reaction, NaH, DMF/DMSO, 0 °C to rt;

(2) Nitration, KNO3, H2SO4, 0 °C to rt;

(3) SNAr reaction, 2-propanol, Cs2CO3, 60 °C;

(4) Suzuki coupling, 4-pyridineboronic acid, 1,4-dioxane/H2O, Pd2(dba)3, SPhos, K3PO4, N2, μW, 150 °C;

(5) Reduction, PtO2, H2, AcOH/TFA;

(6) Protection, Boc2O, DCM, TFA, rt;

(7) Buchwald reaction, XXVIIa, xantphos, Pd(OAc)2, Cs2CO3, THF, N2, μW, 150 °C;

(8) Deprotection, DCM, TFA, rt.

2015

Palbociclib (PD-0332991) HCl is a highly selective CDK4/6 inhibitor, with IC50 values of 11 nM and 16 nM in cell-free assays. It does not exhibit inhibitory activity against CDK1/2/5, EGFR, FGFR, PDGFR, InsR, etc.

Synthetic route:

(1) SNAr reaction, cyclopentylamine, Et3N, THF, rt, 1 h;

(2) Reduction of ester to alcohol, LiAlH4, THF, rt, 6 h;

(3) Oxidation to aldehyde, MnO2, CHCl3, rt, overnight;

(4) Nucleophilic addition to form alcohol, CH3MgBr, THF, 0 °C, 1 h;

(5) Oxidation to ketone, TPAP, NMO, DCM, rt, 2 h;

(6) HWE reaction followed by cyclization, (EtO)2P(O)CH2COOEt, NaH, THF, reflux, 60 h;

(7) Bromination, NBS, DMF, rt, 5 h;

(8) Oxidation, Davis oxaziridine, CHCl3, rt, overnight;

(9) SNAr reaction, tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, toluene, 120 °C, 1 h;

(10) Heck reaction, tributyl(1-ethoxyvinyl)tin, Pd(PPh3)4, toluene, 110 °C, 1 h;

(11) Deprotection of enol ether to ketone, HCl(g), MeOH/DCM (1:1), rt, overnight.

Osimertinib (AZD9291) is an orally administered irreversible, mutation-selective EGFR inhibitor. Its IC50 values against Exon 19 deletion EGFR, L858R/T790M EGFR, and WT EGFR in LoVo cells are 12.92, 11.44, and 493.8 nM, respectively.

Synthetic route:

(1) SNAr reaction, MeMgBr, EDC, 0 °C to room temperature;

(2) indole methylation, MeI, NaH, THF, 0 °C;

(3) SNAr reaction, 4-fluoro-2-methoxy-5-nitroaniline, p-TsOH, 2-pentanol, 105 °C, 2.5 h;

(4) SNAr reaction, N1,N1,N2-trimethylethane-1,2-diamine, DIPEA, TFE, 140 °C, in μW;

(5) Reduction of nitro group, Fe, NH4Cl, EtOH/H2O, reflux;

(6) acrylation, acrylolyl chloride, DIPEA, DCM, 0 °C.

Lenvatinib (E7080) is a multi-target inhibitor. In cell assays, it is most effective against VEGFR2 (KDR)/VEGFR3 (Flt-4), with an IC50 of 4 nM/5.2 nM. Its effect on VEGFR1/Flt-1 is slightly weaker. It has about 10 times higher selectivity for VEGFR2/3 than for FGFR1 and PDGFRα/β. Lenvatinib (E7080) is also an inhibitor of FGFR1-4, PDGFR, Kit (c-Kit), and RET (c-RET), and has potent anti-tumor activity.

Synthesis route:

(1) SNAr reaction, NaOMe, NMP, 100 °C, 7 h;

(2) Condensation, 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione, EtOH, reflux, 2 h;

(3) Cyclization, Dowtherm A, 200 °C, 1 h;

(4) Acid hydrolysis, KOH, glycerol, 160 °C, 3 h, then H2O, 80 °C, 0.5 h, then 2 M HCl;

(5) Chlorination, SOCl2, DMFcat, reflux, 2 h;

(6) Acylation, THF, NH3(aq), 0 °C−rt, 0.5 h;

(7) SNAr reaction, 4-amino-3-chlorophenol, DMSO, NaH, 100 °C, 2 h;

(8) Amino formate, DMF, pyridine, phenylchloroformate, rt, 3 h;

(9) Urea formation, cyclopropylamine, PhCl, reflux, 6h.

Cobimetinib (GDC-0973, RG7420) is a highly selective MEK1 inhibitor with an IC50 of 4.2 nM. Its selectivity for MEK1 is more than 100 times higher than for MEK2, and it does not significantly inhibit other serine-threonine and tyrosine kinases. Cobimetinib can induce apoptosis.

Synthetic route:

(1) Acylation: cyanuric fluoride, pyridine, DCM, 0 °C, 10 min; then rt, 2 h;

(2) Dehydrogenation, isobutyllithium, TMEDA, Et2O, −78 °C;

(3) Nucleophilic addition: benzyl 3-oxo-1-azetidinecarboxylate,

(4) (R)-(−)-α-methoxy-α-trifluoromethyl phenylacetyl chloride, DMAP, DCM, 0 °C, 12 h;

(5) Aqueous NaOH, MeOH, rt, 1 h;

(6) Deprotection: Pd/C (10%), H2 (1 atm.), MeOH, rt, 1 h;

(7) Acylation: XXXIa, DIPEA, THF, rt, 30 min;

(8) Deprotection: 4 N HCl in 1,4-dioxane, rt, 1h.

Alectinib (CH5424802, AF-802, RG-7853) is an effective ALK inhibitor, with an IC50 of 1.9 nM in in vitro assays. It is sensitive to the L1196M mutation and has higher selectivity for ALK compared to PF-02341066, NVP-TAE684, and PHA-E429.

Synthesis route:

(1) Bromination, NBS, MeCN, rt;

(2) Cyclization, 3-cyanophenylhydrazine, TFA, 100 °C;

(3) Oxidation, DDQ, THF/H2O, 0 °C;

(4) Demethylation, pyridinium hydrochloride, 190 °C;

(5) Formation of OTf, trifluoromethanesulfonic anhydride, pyridine, rt;

(6) SNAr reaction, 4-morpholinopiperidine, NMP, 120 °C;

(7) Coupling, TIPS-acetylene, Cs2CO3, X-Phos, MeCN, and Pd(CH3CN)2Cl2, 80 °C; then TBAF, THF, rt;

(8) Reduction, 10% Pd/C, MeOH/THF, rt.

2017

Brigatinib (AP26113) is an effective and selective ALK inhibitor with an IC50 of 0.6 nM. It is also a ROS1 inhibitor with an IC50 of 0.9 nM. It can inhibit IGF-1R, FLT3, FLT3(D835Y), and EGFR with relatively lower potency.

Synthetic route:

(1) Coupling, dimethylphosphine oxide, Pd(OAc)2, xantphos, K3PO4, DMF, 120 °C;

(2) SNAr reaction, 2,4,5-trichloropyrimidine, K2CO3, n-Bu4NHSO4, DMF, 65 °C;

(3) SNAr reaction, 1-methyl-4-(piperidin-4-yl)piperazine, K2CO3, MeCN, 80 °C;

(4) Reduction, Pd/C, 30 psi H2, EtOH, rt;

(5) SNAr reaction, XXXVII, 2-methoxyethanol, 2.5 M HCl in EtOH, 120 °C.

Ribociclib (LEE011) is an orally active and highly specific inhibitor of CDK4 and CDK6, with corresponding IC50 values of 10 nM and 39 nM.

Synthetic route:

(1) SNAr reaction, cyclopentylamine, DIPEA, EtOH, rt, overnight (on);

(2) Coupling reaction, 3,3-diethoxypropine, PdCl2(PPh3)2, CuI, Et3N, DMF, 100 °C, 13 h;

(3) Deprotection and cyclization, TBAF, THF, 65 °C, 2 h;

(4) Deprotection, HCl, 1,4-dioxane, rt, 10 min;

(5) Oxidation, potassium peroxymonosulfate, DMF, rt, 6 h;

(6) Acid amine condensation, Me2NH, HBTU, DIPEA, DMF, rt, 30 min;

(7) Buchwald reaction, 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, Pd2(dba)3, BINAP, t-BuONa, 1,4-dioxane, 100 °C, 1 h;

(8) HCl, 1,4-dioxane, rt, 16 h.

Baricitinib (LY3009104, INCB028050) is a selective inhibitor of JAK1 and JAK2, with IC50 values of 5.9 nM and 5.7 nM in cellular assays, respectively. It is approximately 70 and 10 times more selective for JAK1 and JAK2 compared to JAK3 and Tyk2, and does not inhibit c-Met and Chk2.

Synthesis route:

(1) Protection, SEM-Cl, DMAC, NaH, DMF, 0 °C;

(2 Suzuki coupling, 1-(1-ethoxyethyl)-1H-pyrazole-4-boronic acid pinacol ester, K2CO3, Pd(PPh3)4, n-BuOH/H2O, reflux;

(3) HCl(aq), THF, rt;

(4) Michael addition, 2-[1-(ethylsulfonyl)azetidinylidene]acetonitrile, DBU, MeCN, rt;

(5) Deprotection, TFA, rt.

Acalabrutinib (ACP-196) is a selective second-generation BTK inhibitor that inhibits the activation of the B-cell surface antigen receptor signaling pathway, with an IC50 of 3 nM. It has good target specificity, with 323-fold, 94-fold, 19-fold, and 9-fold selectivity for BTK compared to other TEC kinase family members such as ITK, TXK, BMK, and TEC. It does not have activity against EGFR.

Synthetic route:

(1) Reduction of cyano group using AcOH, Raney-Ni, H2 (4 bar), rt, overnight (on);

(2) Acid amine condensation, Cbz-L-proline, HATU, Et3N, DCM, 0 °C to rt, on;

(3) Cyclization, POCl3, MeCN, 0 °C to reflux, on;

(4) Bromination, NBS, DMF, rt, 3 h;

(5) Amination, NH3/i-PrOH, -78 to 110 °C, 18 h;

(6) Suzuki coupling, 4-(pyridin-2-ylaminocarbonyl)benzeneboronic acid, Pd(dppf)Cl2·DCM, aq.K2CO3/1,4-dioxane, 140 °C, 20 min;

(7) Deprotection of Cbz, 33% HBr/AcOH, rt, 1 h;

(8) Acid amine condensation, 2-butynoic acid, HATU, Et3N, DCM, 0 °C, 2 h.

Neratinib (HKI-272) is a highly selective inhibitor of HER2 and EGFR, with IC50 values of 59 nM and 92 nM in cell-free assays, respectively. It exhibits weak inhibition against KDR and Src, and does not significantly inhibit Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf, or c-Met.

Synthetic route:

(1) Nucleophilic substitution, ethyl 2-cyano-3-ethoxyacrylate, toluene, 90 °C;

(2) High-temperature cyclization, Dowtherm, 250 °C;

(3) Chlorination, POCl3, dimethyldiglycol, 100 °C;

(4) SNAr reaction, XL, MsOH, EtOH, 75 °C;

(5) Deacetylation, 2.7 N HCl(aq), followed by K2CO3, MeOH;

(6) Acylation, 4-(dimethylamino)-2-butenoyl chloride, NMP, 0 °C;

(7) SNAr reaction, piconol, KOH, MeCN, 40 °C;

(8) Reduction, Pt/C H2, THF, 30 °C;

(9) Preparation of acyl chloride, (COCl)2, DMF, i-PrOAc, 15 °C.

Abemaciclib (LY2835219) is a selective cell cycle inhibitor targeting CDK4/6, with IC50 values of 2 nM and 10 nM in cell-free assays.

Netarsudil (AR-13324) is a ROCK inhibitor with a Ki value of 0.2-10.3 nM. It has been clinically tested for the treatment of glaucoma and ocular hypertension.

Synthetic route:

(1) Protection, TIPS-OTf, 2,6-lutidine, DCM, 0 °C to rt, 4 h;

(2) Methylenation, N-bromomethylphthalamide, LiHMDS, THF, −78 to 0 °C, 2 h;

(3) Ester hydrolysis, LiOH·H2O, THF/H2O, rt, 1.5 h;

(4) Acid amide condensation, 6-aminoisoquinoline, EDC, DMAP, N2, pyridine, rt, overnight (on);

(5) Deprotection, NH2NH2, EtOH, reflux, 2 h;

(6) Protection, Boc2O, Et3N, DCM, 0 °C, 1 h;

(7) Deprotection, TBAF, THF, 0 °C, 45 min;

(8) Esterification, 2,4-dimethylbenzoic acid, EDC, DMAP, pyridine, rt, on;

(9) HCl/1,4-dioxane, DCM, rt, 10 h.

Copanlisib (BAY 80-6946) is a highly potent pan-class I PI3K inhibitor, with IC50 values of 0.5, 3.7, 6.4, and 0.7 nM for PI3Kα/β/γ/δ, respectively.

Synthetic route:

(1) Nitration, fuming HNO3, at a temperature below 10 °C;

(2) Deacetylation, K2CO3 and MeOH;

(3) Protection, BnBr and K2CO3 in DMF;

(4) Oximation of aldehyde to form cyano group, using NH4OH (28%), I2, and THF;

(5) Reduction of nitro group, Fe, AcOH, and H2O, 5 °C to rt;

(6) Cyclization, H2N(CH2)2NH2 and S at 100 °C;

(7) Cyclization, BrCN, Et3N, and DCM, 0 °C to rt;

(8) Debenzylation, using TFA at 60 °C;

(9) Alkylation of phenol, 3-(morpholin-4-yl)propyl chloride, Cs2CO3, and DMF at 70°C;

(10) Acid amine condensation, 2-aminopyrimidine-5-carboxylic acid, PyBOP, DIPEA, and DMF.

Midostaurin (pkc412, CGP 41251) is a multi-target kinase inhibitor that targets PKCα/β/γ, Syk, Flk-1, Akt, PKA, c-Kit, c-Fgr, c-Src, FLT3, PDFRβ, and VEGFR1/2, with IC50 values ranging from 80-500 nM.

Synthetic route:

(1) Benzoyl chloride, DIPEA, CHCl3, rt.

2018

Lorlatinib (PF-6463922) is a potent dual ALK/ROS1 inhibitor, with Ki values of

Synthesis route:

(1) Reduction of carbonyl compound, NaBH4, MeOH, 0 °C; then chiral separation by SFC;

(2) Sulfonylation, MsCl, Et3N, TBME, 0 °C;

(3) Nucleophilic substitution, 2-amino-3-hydroxypyridine, Cs2CO3, 2-MeTHF, acetone, 80 °C;

(4) Coupling to introduce carboxyl group, Pd(dppf)-Cl2, Et3N, MeOH, 100 °C, CO2 (6 bar);

(5) Bromination, NBS, MeCN,

(6) Suzuki coupling, CataCXium A, Pd(OAc)2, B2pin2, CsF, MeOH, H2O, t-butyl((4-bromo-5-cyano-1-methyl-1H-pyrazolyl)methyl(methyl)carbamate, 60 °C;

(7) Ester hydrolysis, NaOH, MeOH, H2O, 40 °C;

(8) Boc deprotection, 4 M HCl in 1,4-dioxane, MeOH 40 °C;

(9) Acid amine condensation, HATU, DIPEA, DMF, 0 °C.

Gilteritinib (ASP2215) is a small molecule FLT3/AXL inhibitor, with IC50 values of 0.29 nM and 0.73 nM for FLT3 and AXL, respectively.

Synthetic route:

(1) SNAr reaction, K2CO3, DMF, 80 °C, 20 h;

(2) Reduction of nitro group, EtOH/THF (2:1), 10% Pd/C, H2, rt, 3 h;

(3) SNAr reaction, XLIX, DIPEA, 1,4-dioxane, 170 °C, 17 h;

(4) SNAr reaction, 4-aminotetrahydropyran, NMP, 180 °C (μW), 20 min.