{"id":3065,"date":"2023-07-06T03:48:03","date_gmt":"2023-07-06T08:48:03","guid":{"rendered":"https:\/\/www.bocsci.com\/blog\/?p=3065"},"modified":"2023-07-06T03:48:05","modified_gmt":"2023-07-06T08:48:05","slug":"fda-approved-small-molecule-kinase-inhibitors-part-3","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/fda-approved-small-molecule-kinase-inhibitors-part-3\/","title":{"rendered":"FDA-approved small molecule kinase inhibitors-Part 3"},"content":{"rendered":"\n

Fostamatinib<\/a> is the precursor drug of active metabolite R406. It is a Syk inhibitor<\/a> with an IC50 value of 41 nM. It strongly inhibits Syk but does not inhibit Lyn. Its effect on Flt3 is 5 times lower.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Cs2CO3, di-tert-butyl chloromethylphosphate, acetone, under N2 atmosphere, at room temperature, for 4 days; (ii) TFA, DCM, under N2 atmosphere, at 0 \u00b0C, for 1.5 hours.<\/p>\n\n\n

\n
\"Fostamatinib<\/a>
Figure 1. Fostamatinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Binimetinib<\/a> (MEK162, ARRY-162, ARRY-438162) is an effective MEK1\/2 inhibitor<\/a> with an IC50 of 12 nM in cell-based assays. Binimetinib can induce G1 cell cycle arrest and apoptosis as well as autophagy in human NSCLC cell lines.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Nitration, H2SO4, fuming HNO3, rt, 2.5 h;<\/p>\n\n\n\n

(ii) Amination, NH4OH, 0 \u00b0C to rt, 2.5 h; then HCl(aq), 0 \u00b0C;<\/p>\n\n\n\n

(iii) Methylation, trimethylsilyldiazomethane, THF: MeOH (4:1), 0 \u00b0C to rt, 0.5 h; then AcOH;<\/p>\n\n\n\n

(iv) SNAr reaction, 2-fluorophenylamine, xylene, 140 \u00b0C, 6 days;<\/p>\n\n\n\n

(v) Reductive cyclization, formic acid, Pd(OH)2\/C, EtOH, 40 \u00b0C, 2 h; then 95 \u00b0C, 16 h;<\/p>\n\n\n\n

(vi) Bromination, NBS, DMF, 30 min, rt;<\/p>\n\n\n\n

(vii) Methylation, ICH3, K2CO3, DMF, 75 \u00b0C, 1 h;<\/p>\n\n\n\n

(viii) Hydrolysis, NaOH, THF:H2O (2:1), rt, 2 h;ni<\/p>\n\n\n\n

(ix) Acid amine condensation, O-(2-(vinyloxy)ethyl)-hydroxylamine, HOBt, EDCI, Et3N, DMF, rt, 48 h;<\/p>\n\n\n\n

(x) Deprotection, HCl(aq) (1M), EtOH, 24 h.<\/p>\n\n\n

\n
\"Binimetinib<\/a>
Figure 2. Binimetinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Encorafenib<\/a> (LGX818) is a potent RAF inhibitor<\/a> that acts on cells expressing B-RAF(V600E), with selective anti-proliferative and apoptotic activity, with an EC50 of 4nM.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Protection of the primary amine with Cbz, ClCO2Bn, K2CO3, DCM, 5 \u00b0C, 3 h; then rt, overnight (on);<\/p>\n\n\n\n

(ii) Protection of the secondary amine with chloroformate, ClCO2Me, Et3N, DCM, 5 \u00b0C; then rt, on;<\/p>\n\n\n\n

(iii) Hydrogenation and debenzylation, H2 (50-60 psi), Pd\/C, MeOH, rt;<\/p>\n\n\n\n

(iv) Treatment with HCl, DCM, 0-5 \u00b0C, 30 min;<\/p>\n\n\n\n

(v) Introduction of formyl group via deprotonation, TMP, n-BuLi, THF, -75 \u00b0C, 1.5 h; then 2-bromo-4-chloro-1-fluorobenzene, -72 \u00b0C, 1 h; then DMF, -70 \u00b0C, 1 h;<\/p>\n\n\n\n

(vi) Aldehyde oxidation, KMnO4, t-BuOH, H2O, 30-60 \u00b0C, 2.5 h;<\/p>\n\n\n\n

(vii) Krische rearrangement, DPPA, Et3N, t-BuOH, PhCH3, 75-84 \u00b0C, 2.5 h;<\/p>\n\n\n\n

(viii) Preparation of boronic ester, B2Pin2, KOAc, PhCH3, PdCl2(dppf), 108 \u00b0C, 15 h;<\/p>\n\n\n\n

(ix) Schiffs base formation, benzaldehyde, NaOAc, EtOH, 20 \u00b0C, 20 h;<\/p>\n\n\n\n

(x) Cyclization, (ethoxyethylidine)malononitrile, DMAP, EtOH, 50 \u00b0C, 30 min;<\/p>\n\n\n\n

(xi) Treatment with HCl (12 N), MeOH, 63 \u00b0C, 30 min;<\/p>\n\n\n\n

(xii) Acetylation, MeLi\u00b7LiBr, CPME, -10 \u00b0C, 2.5 h; then 10 \u00b0C, 1 h;<\/p>\n\n\n\n

(xiii) Sandmeyer reaction, BF3\u00b7OEt2, isoamylnitrite, -20 to 10 \u00b0C, 30 min; then I2, KI, MeCN, rt, 30 min;<\/p>\n\n\n\n

(xiv) Bredereck’s reagent, DMF, 120 \u00b0C, 20 min;<\/p>\n\n\n\n

(xv) Guanidine amination, guanidine carbonate, NMP, 130 \u00b0C, 5 h;<\/p>\n\n\n\n

(xvi) Diazonium salt formation, NaNO2, TFA, DCM, 27 \u00b0C, 5 h; then K2CO3, H2O;<\/p>\n\n\n\n

(xvii) Removal of diazonium salt, POCl3, DIPEA, MeCN, DMF, 80 \u00b0C, 3 h;<\/p>\n\n\n\n

(xviii) SNAr reaction, XLVIIa, Na2CO3, DMSO, 90 \u00b0C, 18 h;<\/p>\n\n\n\n

(xix) Suzuki coupling, XLVIIb, Na2CO3, PdCl2(dppf), PhCH3, H2O, 80 \u00b0C, 2 h;<\/p>\n\n\n\n

(xx) Deprotection (removal of Box), HCl (12 N), PhCH3, rt, 1 h;<\/p>\n\n\n\n

(xxi) Sulfonation, MsCl, Et3N, MeTHF, 0-20 \u00b0C, 40 min;<\/p>\n\n\n\n

(xxii) Treatment with NaOH(aq) (3 N), MeTHF, H2O, 30 min; then HCl (2 N).<\/p>\n\n\n

\n
\"Encorafenib<\/a>
Figure 3. Encorafenib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Duvelisib<\/a> (IPI-145, INK1197) is a novel selective PI3K \u03b4\/\u03b3 inhibitor<\/a>. In cell-free assays, the Ki and IC50 values are 23 pM\/243 pM and 1 nM\/50 nM respectively, showing high selectivity towards PI3K \u03b4\/\u03b3 compared to other protein kinases.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i.1) Acylation: Acyl chloride (COCl)2, DCM, room temperature;<\/p>\n\n\n\n

(i.2) Acylation: Aniline, Et3N, room temperature;<\/p>\n\n\n\n

(ii.1) Dehydrogenation: HMPA, n-BuLi, THF, -78 \u00b0C, 2 hours;<\/p>\n\n\n\n

(ii.2) Nucleophilic substitution: (S)-methyl2-(tert-butoxycarbonylamino)propanoate, -50 \u00b0C, 10 minutes;<\/p>\n\n\n\n

(iii.1) Cyclization: HCl, MeOH, reflux, 16 hours;<\/p>\n\n\n\n

(iii.2) Separation: Enantioselective purification;<\/p>\n\n\n\n

(iv) SNAr reaction: 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine, DIPEA, n-BuOH, reflux, 16 hours;<\/p>\n\n\n\n

(v) Deprotection: HCl (3 M), EtOH, room temperature, 1 hour.<\/p>\n\n\n

\n
\"Duvelisib<\/a>
Figure 4. Duvelisib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Dacomitinib<\/a>, also known as PF299804 or PF299, is an effective and irreversible pan-ErbB inhibitor. It primarily targets EGFR, with an IC50 value of 6 nM in cell experiments. Dacomitinib also inhibits ERBB2 and ERBB4, with corresponding IC50 values of 45.7 nM and 73.7 nM, respectively. Dacomitinib shows high efficacy in treating NSCLCs carrying EGFR or ERBB2 mutations (resistant to Gefitinib<\/a>) as well as those carrying EGFR T790M mutations. It inhibits cell growth and induces apoptosis.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) SNAr reaction with MeOH, NaH, THF at 65 \u00b0C for 26 hours;<\/p>\n\n\n\n

(ii) Reduction of the nitro group using Raney-Ni, H2, THF;<\/p>\n\n\n\n

(iii) Acylation with BEt3N, THF at 0 \u00b0C for 1 hour;<\/p>\n\n\n\n

(iv) Alkylation using piperidine, Et3N, DMA at 0 \u00b0C for 17 hours.<\/p>\n\n\n

\n
\"Dacomitinib<\/a>
Figure 5. Dacomitinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Larotrectinib<\/a> (LOXO-101, ARRY-470) is an orally available, selective, ATP-competitive inhibitor of tropomyosin receptor kinases (TRKs). The inhibitory effect of larotrectinib on TRKs can induce cell apoptosis and G1 cell cycle arrest.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Dehydrogenation and coupling with aryl halides, (-)-Sparteine, MTBE, s-BuLi, ZnCl2, -78 \u00b0C to rt; then 2-bromo-1,4-difluorobenzene, Pd(OAc)2, t-Bu3PHBF4, rt;<\/p>\n\n\n\n

(ii) Deprotection, 4 N HCl, 1,4-dioxane;<\/p>\n\n\n\n

(iii) SNAr reaction, 5-chloropyrazolo[1,5-a]pyrimidine, n-butanol, DIPEA, 160 \u00b0C;<\/p>\n\n\n\n

(iv) Nitration, TFA, HNO3;<\/p>\n\n\n\n

(v) Nitro reduction, Zn powder, MeOH\/DCM, saturated NH4Cl aqueous solution;<\/p>\n\n\n\n

(vi) CDI urea formation, (S)-pyrrolidin-3-ol, DCM, CDI;<\/p>\n\n\n\n

(vii) H2SO4, MeOH.<\/p>\n\n\n

\n
\"Larotrectinib<\/a>
Figure 6. Larotrectinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

2019<\/p>\n\n\n\n

Entrectinib<\/a> (RXDX-101, NMS-E628) is an orally bioavailable pan-TrkA\/B\/C, ROS1, and ALK inhibitor<\/a> with an IC50 range of 0.1~1.7 nM. Entrectinib (RXDX-101) can induce autophagy.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Suzuki coupling, Pd(PPh3)4, K3PO4, toluene, 100 \u00b0C;<\/p>\n\n\n\n

(ii) cyclization, NH2NH2.H2O, n-BuOH, 120 \u00b0C;<\/p>\n\n\n\n

(iii) acylation, (COCl)2, DCM, DMF;<\/p>\n\n\n\n

(iv) esterification, LIII, DIPEA, THF, \u221220 \u00b0C;<\/p>\n\n\n\n

(v) deprotection, MeOH, Et3N, 65 \u00b0C.<\/p>\n\n\n

\n
\"Entrectinib<\/a>
Figure 7. Entrectinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Upadacitinib<\/a> is a selective JAK1 inhibitor<\/a> with IC50 values of 0.045 \u03bcM and 0.109 \u03bcM for JAK1 and JAK2, respectively, and IC50 values of 2.1 \u03bcM and 4.7 \u03bcM for JAK3 and TYK2.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Sonogashira coupling and cyclization, trimethylsilylacetylene, CuI, PdCl2(Ph3)2, THF, N2, 0-10 \u00b0C, 7 hours;<\/p>\n\n\n\n

(ii) Protection group, TsCl, NaH, DMF, 0 \u00b0C-rt, 16 hours;<\/p>\n\n\n\n

(iii) Buchwald reaction, t-butyl carbamate, Pd2(dba)3, t-BuXPhos, t-BuONa, 1,4-dioxane, N2, 80 \u00b0C, 16 hours;<\/p>\n\n\n\n

(iv) Alkylation, benzyl (3R,4S)-3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate, NaH, DMF, 0 \u00b0C-rt, 2 hours;<\/p>\n\n\n\n

(v.1) Cyclization, concH2SO4, rt, 30 minutes;<\/p>\n\n\n\n

(v.2) Debenzylation, Pd\/C, H2, MeOH, rt, 5 hours;<\/p>\n\n\n\n

(v.3) Detosylation, NaOH(aq), 1,4-dioxane, reflux, 1 hour;<\/p>\n\n\n\n

(vi) Urea formation, trifluoroethanamine, CDI, DMF, rt, 16 hours.<\/p>\n\n\n

\n
\"Upadacitinib<\/a>
Figure 8. Upadacitinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Alpelisib<\/a> (BYL719) is an effective selective inhibitor of PI3K\u03b1<\/a>. In cell-free experiments, it has an IC50 of 5 nM and shows very weak activity against PI3K\u03b2\/\u03b3\/\u03b4.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i.1) (COCl)2, CHCl3, reflux, 4 hours;<\/p>\n\n\n\n

(i.2) (E)-4-methoxy-buten-2-one, LiHMDS, THF, -78 \u00b0C, 1 hour; then HCl solution in THF, -78 \u00b0C, 2.5 hours to room temperature;<\/p>\n\n\n\n

(i.3) TFA, toluene, -10 \u00b0C to room temperature;<\/p>\n\n\n\n

(ii) aqueous ammonia, 65 \u00b0C, 1 hour;<\/p>\n\n\n\n

(iii) POBr3, DCE, 85 \u00b0C, 1 hour;<\/p>\n\n\n\n

(iv) 4-methyl-2-acetamidothiazole, Pd(OAc)2\/t-Bu3P\u00b7HBF4, Cs2CO3, DMF, 120 \u00b0C, 2 hours;<\/p>\n\n\n\n

(v) 6 N HCl, EtOH, 85 \u00b0C, 1 hour;<\/p>\n\n\n\n

(vi) carbonyldiimidazole, DMF, reflux, 15 hours;<\/p>\n\n\n\n

(vii) L-prolineamide, Et3N, DMF, room temperature, 15 hours.<\/p>\n\n\n

\n
\"Alpelisib<\/a>
Figure 9. Alpelisib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Erdafitinib<\/a> (JNJ-42756493) is an effective, selective, and orally active pan-fibroblast growth factor receptor (FGFR) inhibitor<\/a> with potential anti-tumor activity. Erdafitinib can also bind to RET (c-RET), CSF-1R, PDGFR-\u03b1\/PDGFR-\u03b2, FLT4, Kit (c-Kit), and VEGFR-2, and induce cell apoptosis.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Formation of internal amide chloride using POCl3 at 100 \u00b0C.<\/p>\n\n\n\n

(ii) SNAr reaction using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, Pd-(PPh3)4, 2 N Na2CO3(aq), N2, monoglyme, reflux.<\/p>\n\n\n\n

(iii) Bischwald reaction using 3,5-dimethoxyaniline, NaOC(CH3)3, rac-BINAP, Pd(OAc)2, 1,4-dioxane, N2, 90 \u00b0C.<\/p>\n\n\n\n

(iv) Alkylation using N-(2-chloroethyl)-2-propanamine, HCI, TBAB, KOH, THF\/H2O, 50 \u00b0C.<\/p>\n\n\n

\n
\"Erdafitinib<\/a>
Figure 10. Erdafitinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Pexidartinib<\/a> (PLX3397) is an orally effective multi-target inhibitor of CSF-1R, Kit (c-Kit), and FLT3 receptor tyrosine kinases, with IC50 values of 20 nM, 10 nM, and 160 nM, respectively. Pexidartinib (PLX3397) can induce apoptosis and necrosis and has anti-tumor activity.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Reductive amination, TFA, Et3SiH, toluene, reflux, 48 h;<\/p>\n\n\n\n

(ii) Dehydrogenate DMF to introduce formyl group, n-BuLi, THF, N2 atm, -78 \u00b0C, 90 min; then t-BuLi, hexane, 80 min; then DMF, -78 \u00b0C, 2 h; then rt, 1 h;<\/p>\n\n\n\n

(iii) Protection, (Boc)2O, DMAP, Et3N, DCM, rt, 48 h;<\/p>\n\n\n\n

(iv) Nucleophilic addition, 5-chloro-1H-pyrrolo[2,3-b]pyridine, KOH, MeOH, rt, 48 h;<\/p>\n\n\n\n

(v) Reduction of benzyl hydroxyl, TFA, Et3SiH, MeCN, reflux, 4 h.<\/p>\n\n\n

\n
\"Pexidartinib<\/a>
Figure 11. Pexidartinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Fedratinib<\/a> (SAR302503, TG101348) is a selective JAK2 inhibitor<\/a> with an IC50 of 3 nM in cell-free assays. It exhibits 35 and 334 times higher selectivity for JAK2 compared to JAK1 and JAK3, respectively. Fedratinib also inhibits FMS-like tyrosine kinase 3 (FLT3)<\/a> and Ret (c-RET), with IC50 values of 15 nM and 48 nM, respectively. Fedratinib has potential anti-tumor activity as it can inhibit cell proliferation and promote apoptosis.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Buchwald reaction: 3-bromo-N-tert-butyl-benzenesulfonamide, Pd2(dba)3, xantphos, Cs2CO3, 1,4-dioxane, Ar atmosphere, reflux, 3 h.<\/p>\n\n\n\n

(ii) SNAr reaction: 4-(2-pyrrolidin-1-yl-ethoxy)phenylamine, AcOH, 150\u00b0C, 20 min (\u03bcW).<\/p>\n\n\n

\n
\"Fedratinib<\/a>
Figure 12. Fedratinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Zanubrutinib<\/a> (BGB-3111) is an effective and specific irreversible BTK inhibitor<\/a> that has only weak off-target inhibitory effects on other kinases such as ITK, JAK3, and EGFR.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Cyclization: hydrazine hydrate, EtOH, room temperature, 16 hours;<\/p>\n\n\n\n

(ii) Cyclization: tert-butyl 4-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate, AcOH, reflux;<\/p>\n\n\n\n

(iii.1) Boc deprotection: HCl (concentrated), EtOH, 75\u00b0C;<\/p>\n\n\n\n

(iii.2) Reduction: NaBH4, EtOH, 60\u00b0C;<\/p>\n\n\n\n

(iv) Cyanide group hydrolysis to form acylamide: DMSO\/EtOH (ratio 1:1), 5 N NaOH, H2O2(30%), 60\u00b0C;<\/p>\n\n\n\n

(v.1) Acylation: DCM, Et3N, acryloyl chloride, room temperature;<\/p>\n\n\n\n

(v.2) Chiral separation.<\/p>\n\n\n

\n
\"Zanubrutinib<\/a>
Figure 13. Zanubrutinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

2020<\/p>\n\n\n\n

Avapritinib<\/a> (BLU-285) is a small molecule kinase inhibitor that effectively inhibits the activity of PDGFR\u03b1D842V mutation and self-phosphorylation of PDGFR\u03b1D842V in a cellular background (IC50=30nM). It is also an inhibitor of Kit(c-Kit)<\/a> mutation (Kit(c-Kit) D816V) (IC50=0.5nM).<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Amination of pyrrole N: diphenylphosphorylhydroxylamine, NaH, DMF, 0\u00b0C;<\/p>\n\n\n\n

(ii) Formamide cyclization, 180\u00b0C;<\/p>\n\n\n\n

(iii) Suzuki coupling: 4-pyrazoleboronic acid pinacol ester, Cs2CO3, PdCl2dppf, H2O, EtOH, 1,4-dioxane, 120\u00b0C;<\/p>\n\n\n\n

(iv) Formation of internal amide chloride: POCl3, reflux;<\/p>\n\n\n\n

(v) SNAr reaction: tert-butylpiperazine-l-carboxylate, DIPEA, 1,4-dioxane, rt;<\/p>\n\n\n\n

(vi) Ester hydrolysis: NaOH, THF, MeOH, H2O, 70\u00b0C;<\/p>\n\n\n\n

(vii) Weinreb amide formation: EDCI, HOBT, DCM, Et3N, rt;<\/p>\n\n\n\n

(viii) Grignard reagent preparation: 4-fluorobenzenemagnesium bromide, THF, 0\u00b0C to rt;<\/p>\n\n\n\n

(ix) Boc deprotection: HCl, 1,4-dioxane, rt;<\/p>\n\n\n\n

(x) SNAr reaction: LIXa, DIPEA, 1,4-dioxane;<\/p>\n\n\n\n

(xi) Schiffrin base: (S)-2-methylpropane-2-sulfinamide, Ti(OEt)4, THF, 70\u00b0C;<\/p>\n\n\n\n

(xii) Addition: MeMgBr, THF, 0\u00b0C;<\/p>\n\n\n\n

(xiii) Desulfonylation: 4 M HCl, 1,4-dioxane, rt.<\/p>\n\n\n

\n
\"Avapritinib<\/a>
Figure 14. Avapritinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Selumetinib<\/a> (AZD6244, ARRY-142886) is an effective and highly selective MEK inhibitor<\/a>, with an IC50 of 14 nM for MEK1 and a Kd value of 530 nM for MEK2. It also inhibits phosphorylation of ERK1\/2 with an IC50 of 10 nM. It has no inhibitory effect on p38\u03b1, MKK6, EGFR, ErbB2, ERK2, B-Raf, and others. Selumetinib inhibits cell proliferation, migration, and induces apoptosis.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Nitration, H2SO4, fuming HNO3, room temperature, 90 minutes;<\/p>\n\n\n\n

(ii) Amination, NH4OH(aq) (30%), H2O, 0\u00b0C to room temperature, 2.5 hours;<\/p>\n\n\n\n

(iii) Methylation, trimethylsilyldiazomethane (2 M in hexanes), THF\/MeOH, 0\u00b0C to room temperature, 30 minutes;<\/p>\n\n\n\n

(iv) SNAr reaction, aniline, xylenes, N2, 125\u00b0C, 16 hours;<\/p>\n\n\n\n

(v) Ring closure through reduction, AcOH, 20% Pd(OH)2\/C, EtOH, N2, 40\u00b0C, 2 hours, then 95\u00b0C, 16 hours;<\/p>\n\n\n\n

(vi) Bromination, NBS, DMF, N2, room temperature, 30 minutes;<\/p>\n\n\n\n

(vii) Chlorination, NCS, DMF, N2, 5-6 days;<\/p>\n\n\n\n

(viii) Methylation and hydrolysis, iodomethane, K2CO3, DMF, 75\u00b0C, 1 hour, NaOH, THF:H2O (2:1), 2 hours, room temperature;<\/p>\n\n\n\n

(ix) Acid amine condensation with O-(2-(vinyloxy)ethyl)hydroxylamine, HOBt, EDCI, Et3N, DMF, room temperature, 48 hours;<\/p>\n\n\n\n

(x) Hydrochloric acid treatment, HCl(aq) (1 N), EtOH, room temperature, 24 hours.<\/p>\n\n\n

\n
\"Selumetinib<\/a>
Figure 15. Selumetinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Pemigatinib<\/a> (INCB054828, Pemazyre) is an orally active selective inhibitor of FGFR<\/a>. Its IC50 values for FGFR1, FGFR2, FGFR3, and FGFR4 are 0.4 nM, 0.5 nM, 1.2 nM, and 30 nM, respectively. Pemigatinib (INCB054828) has the potential for treating cholangiocarcinoma.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) SNAr reaction: ethylamine (10 N in H2O), 2-methoxyethanol, 130 \u00b0C, overnight (on);<\/p>\n\n\n\n

(ii) Reductive amination: 2,6-difluoro-3,5-dimethoxyaniline, (+)-camphor-10-sulfonic acid, xylenes, reflux, 2 days;<\/p>\n\n\n\n

(iii) Trifluoromethyl diazomethane cyclization: THF, 0 \u00b0C to rt, 6 hours; then 0 \u00b0C, NaOH (1N in H2O), rt, on;<\/p>\n\n\n\n

(iv) Protection group: benzenesulfonyl chloride, NaH, DMF, 0 \u00b0C, 1.5 hours;<\/p>\n\n\n\n

(v) Formylation: LDA, DMF, THF, \u221278 \u00b0C, 1.5 hours;<\/p>\n\n\n\n

(vi) Reductive amination: morpholine, AcOH, DMF, rt, on; then NaBH(OAc)3, rt, 3 hours;<\/p>\n\n\n\n

(vii) Deprotection: TBAF, THF, 50 \u00b0C, 1.5 hours.<\/p>\n\n\n

\n
\"Pemigatinib<\/a>
Figure 16. Pemigatinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Tucatinib (Irbinitinib<\/a>, ONT-380, ARRY-380) is an orally active, reversible, ATP-competitive small molecule inhibitor of ErbB2 (HER2). In cell experiments, ARRY-380 showed IC50s of 8 nM and 7 nM for ErbB-2 and p95 HER2, respectively, and its selectivity for HER2 is 500 times stronger than for EGFR.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Substitution, BnOH, NaH, THF, reflux, 16 h;<\/p>\n\n\n\n

(ii) Substitution, hydrazine, pyridine, reflux, 18 h;<\/p>\n\n\n\n

(iii.1) Cyclization, TsOH, trimethyl orthoformate, 60 \u00b0C, 2 h;<\/p>\n\n\n\n

(iii.2) Deprotection by reduction, H2, Pd\/C, EtOH, 3 h, rt;<\/p>\n\n\n\n

(iv.1) SNAr reaction, 1-fluoro-2-methyl-4-nitrobenzene, K2CO3, DMF, 50 \u00b0C, 16 h;<\/p>\n\n\n\n

(iv.2) Nitro reduction, H2, Pd\/C, 2.5 h, rt;<\/p>\n\n\n\n

(v.1) DMF-DMA, 100 \u00b0C, 2 h;<\/p>\n\n\n\n

(v.2) Nitro reduction, 10% Pd\/C, H2, MeOH, rt, 10 h;<\/p>\n\n\n\n

(vi) Thiourea, 2-amino-2-methyl-1-propanol, TCDI, THF, \u221210 \u00b0C to rt, 16 h;<\/p>\n\n\n\n

(vii) Cyclization, LXVIa, AcOH, iPrOAc, rt, 16 h;<\/p>\n\n\n\n

(viii) Cyclization, NaOH, TsCl, THF, rt, 3 h.<\/p>\n\n\n

\n
\"Tucatinib<\/a>
Figure 17. Tucatinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Capmatinib <\/a>(also known as INCB28060, INC280, NVP-INC280) is a novel ATP-competitive c-MET inhibitor<\/a> with an IC50 of 0.13 nM in cell assays, and it shows no activity against RON\u03b2, EGFR, and HER-3. Capmatinib (INCB28060) inhibits the Wnt\/\u03b2-catenin and EMT signaling pathways and induces apoptosis in diffuse gastric cancer with c-MET amplification.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Heck reaction, 2-propen-1-ol, Pd2(dba)3, [(t-Bu)3PH]-BF4, N-cyclohexyl-Nmethylcyclohexanamine, 1,4-dioxane, 30 \u00b0C;<\/p>\n\n\n\n

(ii) NCS addition, N-chlorosuccinimide, L-proline, 0 \u00b0C, DCM;<\/p>\n\n\n\n

(iii) Acyl chloride preparation for Weinreb amide, (COCl)2, DCM, DMF; then N,O-dimethylhydroxylhydrochloride, K2CO3, DCM\/H2O, rt;<\/p>\n\n\n\n

(iv) Grignard reagent preparation for ketone, methylmagnesium chloride, (3 N in THF), THF, 0 \u00b0C;<\/p>\n\n\n\n

(v) \u03b1-bromine substitution of ketone, HBr(aq) (48%), DMSO, 60 \u00b0C;<\/p>\n\n\n\n

(vi) Condensation, ethylorthoformate, p-TsOH, toluene, reflux;<\/p>\n\n\n\n

(vii) Cyclization, aminoguanidine bicarbonate, KOH, EtOH\/H2O; then 0.2 N HCl, 110 \u00b0C;<\/p>\n\n\n\n

(viii) Cyclization, XL, isopropanol, 110 \u00b0C;<\/p>\n\n\n\n

(ix) Cyanation, Zn(CN)2, Pd2(dba)3, xantphos, TMEDA, DMF, 160 \u00b0C;<\/p>\n\n\n\n

(x) Cyanide hydrolysis, HCl(aq), 105 \u00b0C;<\/p>\n\n\n\n

(xi) Acid amine condensation, PyBOP, MeNH2 (2 N in THF), Et3N.<\/p>\n\n\n

\n
\"Capmatinib<\/a>
Figure 18. Capmatinib Synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Selpercatinib<\/a> (LOXO-292, ARRY-192) is an effective and specific RET (c-RET) inhibitor, with IC50 values of 1 nM, 2 nM, 2 nmM, 4 nM, 2 nM, and 2 nM against WT RET (c-RET), RET (c-RET)(V804M), RET (c-RET) (V804L), RET (c-RET) (A883F), RET (c-RET) (M918T), and RET (c-RET) (S891A), respectively.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) Amination of N, O-(mesitylsulfonyl) hydroxylamine, DCM, 0 \u00b0C, 3 h;<\/p>\n\n\n\n

(ii) Cyclization, ethyl propionate, DMF, Et3N, rt, 48 h;<\/p>\n\n\n\n

(iii) Decarboxylation, 48% HBr, 80 \u00b0C, 90 min; then rt, overnight (on);<\/p>\n\n\n\n

(iv) Formylation, POCl3, DMF, 0 \u00b0C\u2212rt, on;<\/p>\n\n\n\n

(v) Preparation of oxime, NH2OH\u00b7HCl, EtOH\/H2O (2:1), 50 \u00b0C, on;<\/p>\n\n\n\n

(vi) Dehydration to cyanide group, Ac2O, 140 \u00b0C, 25 h;<\/p>\n\n\n\n

(vii) Demethylation, AlCl3, DCE, N2, 76 \u00b0C, 19 h;<\/p>\n\n\n\n

(viii) Alkylation, 2,2-dimethyloxirane, K2CO3, DMF, 60 \u00b0C, 12 h; then 85 \u00b0C, 12 h;<\/p>\n\n\n\n

(ix) Suzuki coupling, 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2,-dioxoborolan-2-yl)piperidine, Ph-(Ph3)4, 2M Na2CO3(aq), 1,4-dioxane, N2, 85 \u00b0C, 12 h;<\/p>\n\n\n\n

(x.1) SNAr reaction, 3,6-diaza-bicyclo[3.1.1.] heptane-6-carboxylic acid tert-butyl ester, K2CO3, DMSO, 90 \u00b0C, 12 h;<\/p>\n\n\n\n

(x.2) Deprotection, 4 N HCl in 1,4-dioxane, DCM, rt, 12 h;<\/p>\n\n\n\n

(xi) Reduction amination, 6-methoxyniconaldehyde, NaBH(AcO)3, DCE, rt, on.<\/p>\n\n\n

\n
\"Selpercatinib<\/a>
Figure 19. Selpercatinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Ripretinib<\/a> (DCC-2618) is an orally active inhibitor of Kit (c-Kit) and PDGFR-alpha. The IC50 values for WT Kit (c-Kit), V654A Kit (c-Kit), T670I Kit (c-Kit), D816H Kit (c-Kit), and D816V Kit (c-Kit) are 4 nM, 8 nM, 18 nM, 5 nM, and 14 nM, respectively.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) SNAr reaction, ethylamine (65% in H2O), MeCN, 0\u00b0C\u2212rt, 3 h;<\/p>\n\n\n\n

(ii) Reduction of ester to alcohol, LiAlH4, THF, \u221250 to 0\u00b0C, 1 h;<\/p>\n\n\n\n

(iii) Oxidation to aldehyde, MnO2, DCM, rt, overnight (on);<\/p>\n\n\n\n

(iv) Nitration, HNO3, \u221215 to 5 \u00b0C, 15 min;<\/p>\n\n\n\n

(v) Esterification, H2SO4(conc), EtOH, 85 \u00b0C, on;<\/p>\n\n\n\n

(vi) Reduction of nitro group, Zn powder, NH4Cl, EtOH, 55 \u00b0C, 1 h;<\/p>\n\n\n\n

(vii) Cyclization, LXIII, KF on alumina (40 wt %), DMA, sonication, rt, 2 h;<\/p>\n\n\n\n

(viii) SNAr reaction, methylamine (40% in H2O), 1,4-dioxane, 100 \u00b0C, on;<\/p>\n\n\n\n

(ix) Preparation of urea, phenylisocyanate, Et3N, THF, rt, 4 days.<\/p>\n\n\n

\n
\"Ripretinib<\/a>
Figure 20. Ripretinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

Pralsetinib<\/a> (BLU-667, CS 3009, Gavreto) is a potent and selective inhibitor of RET (c-RET), with an IC50 value of 0.4 nM against WTRET (c-RET). It also exhibits effective inhibitory activity against several common RET (c-RET) oncogenic mutations, with an IC50 of ~0.4 nM.<\/p>\n\n\n\n

Synthetic route:<\/strong><\/p>\n\n\n\n

(i) SNAr reaction, K2CO3, DMF, 100 \u00b0C;<\/p>\n\n\n\n

(ii) Construction of auxiliary chiral amine, (R)-(+)-t-butylsulfinamide, Ti(OEt)4, THF, 75 \u00b0C; then \u221278 \u00b0C and L-selectride;<\/p>\n\n\n\n

(iii) Desulfinylation, 4 N HCl\/1,4-dioxane, MeOH;<\/p>\n\n\n\n

(iv) SNAr reaction, MeSNa(aq) (20%), THF, \u22125 \u00b0C to rt;<\/p>\n\n\n\n

(v) Coupling, methyl 4-iodo-1-methoxycyclohexanecarboxylate, Rieke zinc, THF, rt; then 2-chloro-4-methyl-6-(methylthio) pyrimidine, PdCl2dppf, 80 \u00b0C;<\/p>\n\n\n\n

(vi) Oxidation, mCPBA, DCM;<\/p>\n\n\n\n

(vii) HOAc, 80 \u00b0C;<\/p>\n\n\n\n

(viii) Chlorination, POCl3, 100 \u00b0C;<\/p>\n\n\n\n

(xv) Buchwald reaction, 3-methyl-1-pyrazol-5-amine, t-BuXPhos, Pd2(dba)3, KOAc, 1,4-dioxane, 100 \u00b0C;<\/p>\n\n\n\n

(x) Ester hydrolysis, conditions not specified;<\/p>\n\n\n\n

(xi) Acid amine condensation, LXIIa, PyBOP, DIPEA, DMF.<\/p>\n\n\n

\n
\"Pralsetinib<\/a>
Figure 21. Pralsetinib synthetic route<\/figcaption><\/figure><\/div>\n\n\n

<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

1.Xie, Z., et al.<\/em> (2021). “Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases.” J Med Chem.<\/p>\n","protected":false},"excerpt":{"rendered":"

Fostamatinib is the precursor drug of active metabolite R406. It is a Syk inhibitor with an IC50 value of 41 nM. It strongly inhibits Syk but does not inhibit Lyn. […]<\/p>\n","protected":false},"author":1,"featured_media":3089,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181,200,20],"tags":[857,860,859],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/3065"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=3065"}],"version-history":[{"count":2,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/3065\/revisions"}],"predecessor-version":[{"id":3091,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/3065\/revisions\/3091"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media\/3089"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=3065"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=3065"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=3065"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}