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Tambiciclib
Tambiciclib
CAS 2247481-08-7
MF C25H35ClN6O2S, 519.10
4-[[[4-[5-chloro-2-[[4-[[(2R)-1-methoxypropan-2-yl]amino]cyclohexyl]amino]-4-pyridinyl]-1,3-thiazol-2-yl]amino]methyl]oxane-4-carbonitrile
cyclin-dependent kinase inhibitor, antineoplastic, GFH 009, JSH 009, XDZ7VK8CXC, Orphan Drug , Acute myeloid leukaemia, Peripheral T-cell lymphoma
Tambiciclib (GFH009, JSH-009) is an orally active, highly potent and selective CDK9 inhibitor (IC50 = 1 nM), demonstrating >200-fold selectivity over other CDKs, >100-fold selectivity over DYRK1A/B, and excellent selectivity over 468 kinases/mutants. Tambiciclib demonstrates potent in vitro and in vivo antileukemic efficacy in acute myeloid leukemia (AML) mouse models by inhibiting RNA Pol II phosphorylation, downregulating MCL1 and MYC, and inducing apoptosis. Tambiciclib can be used for AML research.
Tambiciclib is a selective inhibitor of the serine/threonine cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the RNA polymerase II (RNA Pol II) elongation factor positive transcription elongation factor b (PTEF-b; PTEFb), with potential antineoplastic activity. Upon administration, tambiciclib targets, binds to and blocks the phosphorylation and kinase activity of CDK9, thereby preventing PTEFb-mediated activation of RNA Pol II, leading to the inhibition of gene transcription of various anti-apoptotic proteins. This induces cell cycle arrest and apoptosis and prevents tumor cell proliferation. CDK9 regulates elongation of transcription through phosphorylation of RNA Pol II at serine 2 (p-Ser2-RNAPII). It is upregulated in various tumor cell types and plays a key role in the regulation of Pol II-mediated transcription of anti-apoptotic proteins. Tumor cells are dependent on anti-apoptotic proteins for their survival.
- OriginatorGenFleet Therapeutics
- DeveloperGenFleet Therapeutics; Sellas Life Sciences Group
- ClassAntineoplastics; Small molecules
- Mechanism of ActionCyclin-dependent kinase 9 inhibitors
- Orphan Drug StatusYes – Acute myeloid leukaemia; Peripheral T-cell lymphoma
- Phase IIAcute myeloid leukaemia
- Phase I/IIDiffuse large B cell lymphoma; Haematological malignancies; Peripheral T-cell lymphoma
- Phase ISolid tumours
- PreclinicalColorectal cancer; T-cell prolymphocytic leukaemia
- 13 Oct 2025Preclinical trials in T-cell prolymphocytic leukaemia (Combination therapy) in USA (Parenteral)
- 13 Oct 2025Preclinical trials in T-cell prolymphocytic leukaemia (Monotherapy) in USA (Parenteral)
- 13 Oct 2025Pharmacodynamics data from preclinical studies in T-cell prolymphocytic leukaemia released by SELLAS Life Sciences
CLINICAL
- A Study of GFH009 in Combination With Zanubrutinib in Subjects With Relapsed or Refractory DLBCLCTID: NCT06375733Phase: Phase 1/Phase 2Status: RecruitingDate: 2025-08-12
- A Study of GFH009 Monotherapy in Patients with Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL)CTID: NCT05934513Phase: Phase 1/Phase 2Status: RecruitingDate: 2024-12-13
Publication Name: European Journal of Medicinal Chemistry
Publication Date: 2018-10-05
PMID: 30253346
DOI: 10.1016/j.ejmech.2018.09.025
SYN
SYN
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018192273&_cid=P12-MJ18VV-17351-1
Example 1: Synthesis of 4-(((4-(5-chloro-2-(((1R,4r)-4-(((R)-1-methoxypropyl-2-yl)amino) cyclohexyl)amino)pyridin-4-yl)thiazolyl)amino)methyl)tetrahydro-2H-pyran-4- carboxynitrile
Step 1: Synthesis of 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine
[0102]5-Chloro-2-fluoropyridine-4-boronic acid (0.7 g, 4.46 mmol) and pinacol (0.63 g, 5.35 mmol) were added to 50 mL of toluene, and the mixture was refluxed at 120 °C overnight. TLC showed a small amount of starting material remaining. The reaction mixture was cooled to room temperature and concentrated, then dried by an oil pump to give 0.92 g of a white solid compound, 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridine, yield 80%, MS (ESI): m/z 258.1 (M+H) + .
[0103]Step 2: Synthesis of (S)-1-methoxypropyl-2-yl-4-toluenesulfonyl ester
[0104]60% sodium hydride (NaH) (6.52 g, 283 mmol) was added to anhydrous tetrahydrofuran (THF) (200 mL). The mixture was cooled to 0 °C in an ice bath under nitrogen protection, and (S)-(+)-1-methoxy-2-propanol (21 g, 233 mmol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 1.5 hours. The reaction mixture was then cooled back to 0 °C, and a tetrahydrofuran (THF) solution of p-toluenesulfonyl chloride (45.3 g, 283 mmol) (200 mL) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. TLC showed that the starting material had reacted completely. The reaction mixture was diluted with ethyl acetate (500 mL), and the reaction was quenched by adding water (500 mL) dropwise while cooling in an ice bath. The mixture was separated, and the aqueous phase was extracted once more with ethyl acetate (200 mL). The combined organic phases were washed with water (200 mL) and then with saturated brine (200 mL). The crude product was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 43 g of a pale yellow oily substance. Column separation (petroleum ether/ethyl acetate = 5/1) yielded 37 g of (S)-1-methoxypropyl-2-yl-4-toluenesulfonyl ester, a pale yellow oily substance, with a yield of 65.1%. MS (ESI): m/z 245.1 (M+H) + .
[0105]Step 3: Synthesis of (1r,4R)-N
1 -((R)-1-methoxypropyl-2-yl)cyclohexane-1,4-diamine
[0106](S)-1-methoxypropyl-2-yl 4-toluenesulfonyl ester (5 g, 20.5 mmol) and trans-1,4-cyclohexanediamine (5.84 g, 51.2 mmol) were added to 50 mL of acetonitrile and heated to 90 °C overnight. The reaction was monitored by TLC until complete. After cooling, the reaction solution was filtered, the filtrate was concentrated, and the residue was dissolved in dichloromethane and separated by silica gel stirring column (dichloromethane/methanol = 10/1) to give 2.5 g of the pale yellow liquid compound (1r,4R)-N
1 -((R)-1-methoxypropyl-2-yl)cyclohexane-1,4-diamine, yield 65%, MS (ESI): m/z 187.3 (M+H) + .
[0107]Step 4: Synthesis of tert-butyl 5-bromothiazol-2-ylcarbamate
[0108]105 g (403 mmol) of 5-bromothiazol-2-amine hydrobromide was suspended in 500 mL of tetrahydrofuran. Dimethylaminopyridine (2.41 g, 20 mmol) was added, resulting in a white turbidity. A tetrahydrofuran solution of di-tert-butyl dicarbonate (105.6 g, 484.6 mmol) was slowly added dropwise, and the reaction was allowed to proceed at room temperature for two days. The reaction solution was concentrated and dissolved in 300 mL of dichloromethane. The solution was mixed with silica gel and separated by column chromatography (petroleum ether/ethyl acetate = 10/1-6/1 gradient elution) to give 45 g of off-white solid, yield 40%. MS (ESI): m/z 278.98 (M+H) + .
[0109]Step 5: Synthesis of tert-butyl 4-bromothiazol-2-ylcarbamate
[0110]A 200 mL solution of diisopropylamine (64 mL, 446 mmol) in tetrahydrofuran was added to a dry three-necked flask. Under nitrogen protection, the mixture was cooled to 0 °C, and n-butyllithium (2.5 M, 173 mL, 431.7 mmol) was added dropwise. The reaction was allowed to proceed for 1 hour after the addition was complete. Then, a 400 mL solution of 5-bromothiazol-2-ylcarbamate in tetrahydrofuran was added dropwise at 0 °C. The reaction was allowed to proceed for 2 hours after the addition was complete. TLC showed that the reaction was complete. At 0℃, ice water (5 mL) was slowly added dropwise to quench the reaction. After stirring for 30 minutes, saturated ammonium chloride (500 mL) aqueous solution was added. The mixture was separated, and the aqueous layer was extracted with dichloromethane (2 × 300 mL). The organic layers were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated, and recrystallized from petroleum ether:ethyl acetate = 30:1. 31 g of tert-butyl 4-bromothiazol-2-ylcarbamate was obtained as a white solid, yield 77.5%. MS (ESI): m/z 278.98 (M+H) + .
[0111]Step Six: Synthesis of Methyl 4-cyano-tetrahydro-2H-pyran-4-carbonate
[0112]Methyl cyanoacetate (39.1 g, 395.3 mmol) and 2,2-dibromoethyl ether (100 g, 434.8 mmol) were added to 600 mL of dimethylformamide, followed by DBU (90 g, 593 mmol). The mixture was heated to 85 °C and reacted for 3 hours. TLC showed that the starting material reacted completely. The solid was filtered off, washed with ethyl acetate (2 × 300 mL), and the mother liquor was concentrated to obtain a brown oily substance. The oil was distilled under reduced pressure at an internal temperature of 65-70 °C, and the fraction collected was a colorless liquid. Crystallization was observed to give 42 g of a white solid, 4-cyano-tetrahydro-2H-pyran-4-carbonate. Yield: 62.8%, MS (ESI): m/z 178.2 (M+H) + .
[0113]Step 7: Synthesis of 4-(hydroxymethyl)-tetrahydro-2H-pyran-4-carboxynitrile
[0114]4-Cyano-tetrahydro-2H-pyran-4-carbonate methyl ester (42 g, 248.4 mmol) was dissolved in 400 mL of ethylene glycol dimethyl ether and 40 mL of methanol. The mixture was cooled to 0 °C in an ice bath, and sodium borohydride (11.1 g, 149 mmol) was added in portions. After the addition was complete, the mixture was allowed to rise to room temperature and stirred for 16 hours. The reaction was completed by TLC. The reaction solution was concentrated, and methanol was added to quench excess sodium borohydride. The solution was then concentrated again. Column chromatography (petroleum ether/ethyl acetate = 5/1) yielded 28 g of 4-(hydroxymethyl)-tetrahydro-2H-pyran-4-carboxynitrile, a pale yellow oil, yield: 79.5%, MS (ESI): m/z 142.1 (M+H) + .
[0115]Step 8: Synthesis of tert-butyl (4-bromothiazolyl)((4-cyanotetrahydro-2H-pyran-4-yl)methyl)carbamate
[0116]4-(hydroxymethyl)-tetrahydro-2H-pyran-4-carboxynitrile, 4-bromothiazol-2-ylcarbamate tert-butyl ester, and triphenylphosphine were added to anhydrous tetrahydrofuran (THF) and cooled to 0°C. Diisopropyl azodicarbonate (DIAD) was added dropwise. The mixture was stirred at room temperature for 10 minutes, then heated to 40°C overnight. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was mixed with silica gel and separated by column chromatography (petroleum ether/ethyl acetate = 50/1, 30/1, 20/1) to obtain (4-bromothiazol-2-yl)((4-cyanotetrahydro-2H-pyran-4-yl)methyl)carbamate tert-butyl ester, a white solid of 365 mg, yield 50%. MS (ESI): m/z 402.1 (M+H) + .
[0117]Step Nine: Synthesis of tert-butyl (4-(5-chloro-2-fluoropyridin-4-yl)thiazolyl)((4-cyano-tetrahydro-2H-pyran-4-yl)methyl)carbamate
[0118]5-Chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridine and sodium carbonate were added to a mixture of dimethyl ether/H₂O
/ dioxane. The system was purged with nitrogen twice. Then, tert-butyl (4-bromothiazolyl)((4-cyanotetrahydro-2H-pyran-4-yl)methyl)carbamate and tetraphenylphosphine palladium Pd(pph 3 )
4 were added . The system was purged with nitrogen three times. The temperature was then raised to 70°C and the reaction was carried out for 6 hours. TLC showed that only half of the starting material remained. Heating was then stopped and the reaction was terminated. The reaction solution was cooled to room temperature, ethyl acetate and methanol were added, and the mixture was filtered. The filter cake was washed with ethyl acetate, the filtrate was concentrated, and the residue was dissolved in dichloromethane. The residue was washed with saturated brine, separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and silica gel was added for mixing. The sample was separated by column chromatography (petroleum ether/ethyl acetate = 30/1) to give 3.2 g of (4-(5-chloro-2-fluoropyridin-4-yl)thiazolyl)((4-cyano-tetrahydro-2H-pyran-4-yl)methyl)carbamate, a white foamy solid, with a yield of 55%. MS (ESI): m/z 453.1 (M+H) + .
[0119]Step 10: Synthesis of 4-(((4-(5-chloro-2-(((1R,4r)-4-(((R)-1-methoxypropyl-2-yl)amino)cyclohexyl)amino)pyridin-4-yl)thiazolyl)amino)methyl)tetrahydro-2H-pyran-4-carboxynitrile
[0120]The tert-butyl carbamate (4-(5-chloro-2-fluoropyridin-4-yl)thiazolyl)((4-cyano-tetrahydro-2H-pyran-4-yl)methyl)carbamate (3.2 g, 7.1 mmol) and (1r,4R)-N
1 -((R)-1-methoxypropyl-2-yl)cyclohexane-1,4-diamine (3.9 g, 21.2 mmol) and diisopropylethylamine (DIPEA) were added to 30 mL of dimethyl sulfoxide. Under nitrogen protection, the mixture was heated to 100-110 °C and reacted for two days. The reaction was monitored by TLC and LCMS. The starting material (4-(5-chloro-2-fluoropyridin-4-yl)thiazolyl)((4-cyano-tetrahydro-2H-pyran-4-yl)methyl)carbamate tert-butyl ester had completely disappeared, with some BOC-free intermediate remaining. The reaction was stopped, and the reaction solution was cooled and diluted with ethyl acetate (60 mL). Water (150 mL) was added under ice bath. The mixture was separated, and the aqueous layer was extracted again with ethyl acetate (2 × 50 mL). The organic layers were combined, washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of yellowish-brown oil. Column separation (acetonitrile/water/trifluoroacetic acid = 80/20/0.001) yielded 700 mg of 4-(((4-(5-chloro-2-(((1R,4r)-4-(((R)-1-methoxypropyl-2-yl)amino)cyclohexyl)amino)pyridin-4-yl)thiazolyl)amino)methyl)tetrahydro-2H-pyran-4-carboxynitrile, a pale yellow solid. Yield: 19.1%. ¹H NMR (400 MHz, CDCl₃
) )δ8.06(s,1H),7.38(s,1H),6.97(s,1H),5.92(brs,1H),4.45(d,J＝8.0Hz,1H),4.02(dd,J 1＝2.8Hz, J2＝12Hz,2H),3.71-3.74(m,4H),3.54-3.56(m,1H),3.35(s,3H),3.21-3.25(m,2 H),3.00-3.05(m,1H),2.50-2.60(m,1H),2.15(d,J＝9.6Hz,2H),2.04-2.07(m,1H),1.95(d ,J＝12.8Hz,3H),1.74-1.82(m,3H),1.10-1.30(m,4H),1.00(d,J＝.4Hz,3H),MS(ESI):m/z 519.3(M+H) + .
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US376039987&_cid=P12-MJ18R0-12787-1
PAT
- A novel cyclin-dependent kinase CDK9 inhibitorPublication Number: CN-108727363-BPriority Date: 2017-04-19Grant Date: 2020-06-19
- Inhibitor of cyclin-dependent kinase CDK9Publication Number: US-10952999-B2Priority Date: 2017-04-19Grant Date: 2021-03-23
- Novel inhibitor of cyclin-dependent kinase cdk9Publication Number: EP-3613737-B1Priority Date: 2017-04-19Grant Date: 2021-12-29
- Pharmaceutical combination and use thereof in treatment of cancerPublication Number: WO-2024239512-A1Priority Date: 2023-05-22
- Polymorph of cdk9 inhibitor and preparation method for polymorph and use thereofPublication Number: WO-2020244612-A1Priority Date: 2019-06-06
- Polymorphic substance of CDK9 inhibitor and preparation method and application thereofPublication Number: CN-113966332-APriority Date: 2019-06-06
- Novel inhibitor of cyclin-dependent kinase cdk9Publication Number: EP-3613737-A1Priority Date: 2017-04-19
- Novel inhibitor of cyclin-dependent kinase cdk9Publication Number: US-2020078343-A1Priority Date: 2017-04-19
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//Tambiciclib, cyclin-dependent kinase inhibitor, antineoplastic, GFH 009, JSH 009, XDZ7VK8CXC, Orphan Drug , Acute myeloid leukaemia, Peripheral T-cell lymphoma
Talorasib
Talorasib
CAS 2648584-48-7
MFC32H34ClFN6O3 MW605.10
- (2S)-4-[(7S)-7-(8-Chloro-1-naphthalenyl)-7,8-dihydro-2-[[(2S)-1-methyl-2-pyrrolidinyl]methoxy]-5H-pyrano[4,3-d]pyrimidin-4-yl]-1-(2-fluoro-1-oxo-2-propen-1-yl)-2-piperazineacetonitrile
- [(2S)-4-[(7S)-7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile
- 2-Piperazineacetonitrile, 4-[(7S)-7-(8-chloro-1-naphthalenyl)-7,8-dihydro-2-[[(2S)-1-methyl-2-pyrrolidinyl]methoxy]-5H-pyrano[4,3-d]pyrimidin-4-yl]-1-(2-fluoro-1-oxo-2-propen-1-yl)-, (2S)-
[(2S)-4-[(7S)-7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile
Kirsten rat sarcoma viral oncogene homologue (KRAS)inhibitor, antineoplastic, 727W6T7DPK
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN380619664&_cid=P20-MJ0TAW-52678-1
| Preparation Example 1: Synthesis of the compound shown in formula (I) |
| (1) Synthesis of Compound 1 |
| Synthetic route of compound 1: |
| Synthesis of compound 1-j |
| 1-Bromo-8-chloronaphthalene (500 mg, 2.07 mmol) was dissolved in THF (20 mL), cooled to -78 °C, and n-BuLi (2.5 M, 1.66 mL, 4.14 mmol) was added dropwise under nitrogen protection. After the addition was complete, the mixture was stirred at -78 °C for 10 min, and then DMF (800 μL, 10.35 mmol) was added dropwise at -78 °C. After the addition was complete, the reaction mixture was stirred at -78 °C for 30 min, then heated to room temperature and stirred for 2 h. The reaction was quenched with 50 mL of saturated ammonium chloride solution and extracted with ethyl acetate (50 mL * 2). The organic phase was washed with saturated brine (50 mL * 2), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (EA/PE = 1/10) to give compound 1-j (330 mg, 84% yield) as a white solid. LC-MS (ESI): m/z=191.0[M+H] + ; 1 H NMR (400MHz, CDCL 3 ):δ11.31(s,1H),8.03(dd,1H,J 1 =1.2Hz,J 2 =8.4Hz), 7.92(dd,1H,J 1 =1.2Hz,J 2 ＝7.2Hz),7.86(1H,J＝8.4Hz),7.70(dd,1H,J 1 =1.2Hz,J 2 ＝7.6Hz), 7.59(t,1H,J＝7.6Hz), 7.47(t,1H,J＝8Hz). |
| Synthesis of compound 1-i |
| At room temperature, NaH (60%, 242 mg, 6.05 mmol) was added to 6 mL of THF. Then, methyl acetoacetate (543 μL, 5.04 mmol) was added under nitrogen atmosphere at room temperature. The mixture was stirred for 30 minutes under nitrogen atmosphere at room temperature, and then n-BuLi (2.5 M, 2.4 mL, 6.05 mmol) was added dropwise at -15 °C to -10 °C. After the addition was complete, the mixture was maintained at this temperature for 30 minutes, and then a 10 mL solution of compound 1-j (320 mg, 1.68 mmol) in THF was added dropwise. After the addition was complete, the mixture was stirred at low temperature (-10 °C to 0 °C) for 2 hours, then quenched with saturated ammonium chloride solution (50 mL), and then extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL * 2), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (EA/DCM = 1/10) to give compound 1-i (510 mg, 99% yield) as a white solid. LC-MS (ESI): m/z = 329.1 [M + Na] ⁺ ; 1H NMR (400 MHz, CDCl₂) 3 ): δ8.06(d,1H,J＝6.4Hz),7.79(d,2H,J＝8Hz),7.58(dd,1H,J 1 =7.6Hz,J 2 ＝1.6Hz),7.53(t,1H,J＝7.6Hz),7.34(t,1H,J＝7.6Hz),6.91(dd,1H,J 1 =9.2Hz, J 2 =2.4Hz),3.74(s,3H),3.54(s,2H),3.36(dd,1H,J 1 =18Hz,J 2 ＝1.6Hz),3.24(d,1H,J＝3.6Hz),2.85-2.75(m,1H). |
| Synthesis of compound 1-h |
| Compound 1-i (510 mg, 1.66 mmol) was dissolved in DCM (18 mL) at room temperature, followed by the addition of DMF-DMA (245 μL, 1.83 mmol) under nitrogen atmosphere at room temperature. After stirring the reaction mixture for 45 minutes at room temperature, BF was added. 3 Et 2 O (232 μL, 1.83 mmol). After addition, the mixture was stirred at room temperature for 1 hour, then diluted with 100 mL of ethyl acetate. The organic phase was then sequentially quenched with saturated NaHCO3. 3 The sample was washed with a solution (100 mL) and saturated saline solution (100 mL * 2), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 1-h (520 mg). The crude product required no purification and was used directly in the next reaction. LC-MS (ESI): m/z = 317.1 [M+1] + . |
| Synthesis of compound 1-g |
| Compound 1-h (520 mg, 1.64 mmol) was dissolved in THF (20 mL) at room temperature, and then tri-sec-butylborohydride (1 M, 1.64 mL, 1.64 mmol) was added dropwise under nitrogen atmosphere at -78 °C. After addition, the mixture was stirred at -78 °C for 1 hour, the reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL * 2), the organic matter was washed with saturated brine (50 mL * 2), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (PE/EA = 4/1) to give compound 1-g (338 mg, 65% yield) as a yellow oil. LC-MS (ESI): m/z = 319.0 [M+1] + . |
| Synthesis of compound 1-f |
| Compound 1-g (338 mg, 1.06 mmol) was dissolved in methanol (20 mL) at room temperature. Then, under nitrogen atmosphere at 0 °C, sodium methoxide (286 mg, 5.3 mmol) and compound 2-methyl-2-mercaptourea sulfate (265 mg, 0.954 mmol) were added sequentially. After the addition was complete, the mixture was brought to room temperature and stirred for 20 hours. The pH of the reaction solution was adjusted to 5 with 1 N dilute hydrochloric acid, and a solid precipitated. The solid was filtered, the filter cake was washed with water (5 mL * 2), and the solid was collected and dried under vacuum to give crude product 1-f (313 mg) as a white solid. LC-MS (ESI): m/z = 359.1 [M+1] + . |
| Synthesis of compound 1-e |
| Compound 1-f (313 mg, 0.87 mmol) was dissolved in DCM (10 mL) at room temperature. Then, under nitrogen atmosphere in an ice-water bath, DIPEA (431 μL, 2.61 mmol) and trifluoromethanesulfonic anhydride (219 μL, 1.31 mmol) were added sequentially. After addition, the reaction mixture was stirred in an ice-water bath for 2 hours, quenched with saturated sodium bicarbonate solution (50 mL), extracted with DCM (50 mL x 2), and the organic phase was treated with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid column chromatography (EA/PE = 1/10) to give compound 1-e (83 mg, 16% yield in 2 steps) as a white solid. LC-MS (ESI): m/z = 491.0 [M+1] + . |
| Synthesis of compound 1-d |
| Compound 1-e (83 mg, 0.169 mmol) was dissolved in DMF (10 mL) at room temperature, followed by the sequential addition of DIPEA (84 μL, 0.507 mmol) and (S)-2-cyanomethylpiperazine-1-carboxylate hydrochloride (59.9 mg, 0.203 mmol). After addition, the mixture was stirred for 1 hour at 100 °C under nitrogen protection, cooled to room temperature, quenched with saturated brine (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 3), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid column chromatography (EA/PE = 1/1) to give compound 1-d (101 mg, 99% yield) as a white solid. LC-MS (ESI): m/z = 600.2 [M+1] + . |
| Synthesis of compound 1-c |
| Compound 1-d (101 mg, 0.168 mmol) was dissolved in ethyl acetate (10 mL) at room temperature, followed by the addition of MCPBA (85%, 88.4 mg, 0.437 mmol) at room temperature. After addition, the mixture was stirred at room temperature for 2 hours, quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (25 mL x 2), and the organic phase was treated with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid column chromatography (EA/PE = 1/4) to give compound 1-c (88 mg, 82% yield) as a white solid. LC-MS (ESI): m/z = 632.1 [M+1] + . |
| Synthesis of compound 1-b |
| Compound 1-c (88 mg, 0.139 mmol) was dissolved in toluene (10 mL) at room temperature. The reaction mixture was then cooled to 0 °C, and N-methylprolyl (29 μL, 0.243 mmol) and t-BuONa (27 mg, 0.278 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred for 0.5 hours under nitrogen in an ice-water bath, quenched with water (20 mL), and extracted with ethyl acetate (30 mL * 2). The organic phase was treated with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid column chromatography (MeOH/DCM = 1/10) to give compound 1-b (78 mg, 84% yield) as a white solid. LC-MS (ESI): m/z = 667.3 [M+1] + . |
| Synthesis of compound 1-a |
| Compound 1-b (72 mg, 0.108 mmol) was dissolved in methanol (50 mL) at room temperature. The reaction solution was then cooled to -78 °C, purged twice with nitrogen, and then Pd/C (150 mg) and ZnBr were added. 2 (24.3 mg, 0.108 mmol), the reaction mixture was purged with hydrogen three times, brought to room temperature, and stirred under hydrogen atmosphere for 5 hours. The reaction mixture was filtered and concentrated to obtain a crude product, which was then purified by a rapid separation column (MeOH/DCM = 1:4) to give compound 1-a (20 mg, 35% yield) as a white solid. LC-MS (ESI): m/z = 533.0 [M+1] + . |
| Synthesis of Compound 1 |
| At room temperature, compound 2-fluoroacrylic acid (5.1 mg, 0.0563 mmol) was dissolved in DMF (2 mL). Then, at 0 °C, HATU (25.6 mg, 0.0675 mmol) and DIPEA (18.6 μL, 0.113 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at 0 °C under nitrogen for 20 minutes. Then, a DMF solution of compound 1-a (20 mg, 0.0375 mmol) (3 mL) was added to the above reaction mixture. The mixture was brought to room temperature and stirred for another 5 hours. The reaction mixture was quenched with saturated brine (20 mL), extracted with ethyl acetate (25 mL * 2), washed with saturated brine (50 mL * 3), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by PREP-TLC (MeOH/DCM = 1/10) to obtain compound 1 (6 mg, 26% yield) as a white solid. LC-MS (ESI): m/z=605.2[M+1] + ; 1 H NMR (400MHz, CDCl 3 ): δ7.99-7.93(m,1H),7.83(t,2H,J＝8.8Hz),7.62-7.49(m,2H),7.36(t,1H,J＝7.6Hz),6.5 5-6.44(m,1H),5.51-5.31(m,1H),5.25(d,1H,J＝16.8Hz),5.02-4.93(m,1H),4.82(dd,1H,J 1 =2.4Hz, J 2 ＝13.6Hz),4.48-4.38(m,1H),4.32-4.19(m,1H),4.17-4.04(m,1H),4. 00(d,1H,J＝14Hz),3.87-3.70(m,1H),3.66-3.36(m,2H),3.31-3.16(m ,2H),3.14-2.98(m,1H),2.96-2.69(m,4H),2.59(d,3H,J=18Hz),2.52 -2.34(m,1H),2.15-2.06(m,1H),1.87-1.74(m,2H),0.93-0.76(m,2H). |
| (2) Resolution of compound 1 |
| Synthesis of compounds 1-1 and 1-2 |
| |
| The challenge lay in obtaining the compound shown in formula (I) through chiral resolution of compound 1. Despite trying various conditions, the two isomers of compound 1 could not be separated on a thin-layer chromatography plate, making separation impossible by thin-layer chromatography. Even in HPLC, the separation of the two isomers of compound 1 was poor, making separation impossible by preparative HPLC. Finally, chiral resolution had to be resorted to. After trying several conditions (as shown in Table 1 below), chiral resolution condition 9 was finally found, which enabled the separation of the compound shown in formula (I) and its diastereomers. |
SYN
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022081655&_cid=P20-MJ0T2K-48115-1
PAT
- Substituted dihydropyranopyrimidine compounds as kras inhibitorsPublication Number: US-2022112204-A1Priority Date: 2020-10-14
- Substituted dihydropyranopyrimidine compounds as kras inhibitorsPublication Number: WO-2022081655-A1Priority Date: 2020-10-14
- Oxygen-containing heterocyclic compound, preparation method and application thereofPublication Number: WO-2021109737-A1Priority Date: 2019-12-02
- Oxygen-containing heterocyclic compound, preparation method and application thereofPublication Number: EP-4015520-A1Priority Date: 2019-12-02
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///////////talorasib, antineoplastic, 727W6T7DPK
Talogreptide mesaroxetan
Talogreptide mesaroxetan
CAS 1801418-23-4
MF C86H140N22O18 MW1770.17
{MeCOSar}-PEG4-{d-Phe}-Gln-Trp-Ala-Val-Gly-His-{Sta}-Leu-NH2
(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(3S,4S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-6-methyl-1-oxoheptan-4-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2R)-2-[3-[2-[2-[2-[2-[[5-[(8-methyl-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosan-1-yl)amino]-5-oxopentanoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-3-phenylpropanoyl]amino]pentanediamide
N-{21-[(8-methyl-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosan-1-yl)amino] -17,21-dioxo-4,7,10,13-tetraoxa-16-azahenicosan-1-oyl}-D-phenylalanyl-L-glutaminyl-L-tryptophyl-L-alanyl-Lvalylglycyl-L-histidyl-(3S,4S)-4-amino-3-hydroxy-6-methylheptanoyl-L-leucinamide
diagnostic imaging agent, antineoplastic, ZUN64K4H2X, SAR-BBN
Talogreptide mesaroxetan (CAS 1801418-23-4) is a synthetic peptide, a complex molecule used as a diagnostic imaging agent with potential antitumor effects, targeting G-protein coupled receptors (GRPr) often overexpressed in cancers, allowing for specific tumor visualization in PET scans, particularly for metastatic disease detection, known for its high specificity and contrast for imaging tumors like those expressing GRPr.
Key Characteristics:
- Type: A peptide-based diagnostic agent, often labeled with radioisotopes like Copper-64 ($^{64}$Cu) for Positron Emission Tomography (PET) imaging, notes Patsnap Synapse.
- Structure: It’s a modified peptide sequence incorporating elements like PEG4 and specific amino acids, MedchemExpress.com.
- Function: Binds strongly to GRPr, helping to highlight tumors and metastatic sites.
- Application: Used in research to create high-contrast PET scans for better tumor detection and monitoring, showing promise in visualizing lymph node metastasis.
In Simple Terms:
Imagine it as a “smart tracer” that seeks out specific cancer cells. When attached to a radioactive tag, it lights up tumors on a PET scan, helping doctors see cancer more clearly, notes Patsnap Synapse.
Syn
WO2024086891
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024086891&_cid=P10-MIZEJM-53111-1
67Cu radioisotope
where R is CH3C(0)-;
(67CU-SAR-BBN)
Paper
Molecular Pharmaceutics (2015), 12(8), 2781-2790
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/////////Talogreptide mesaroxetan, diagnostic imaging agent, antineoplastic, ZUN64K4H2X, SAR-BBN
Surzetoclax
Surzetoclax
CAS 2858632-01-4
MF C53H63ClN8O10S, 1039.64
NAMES
4-[(4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12Hpyrazino[2,1-g][1,5,8]benzodioxaazacycloundecin3(4H)-yl]-2-(3,4-dihydro-2Hpyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-[4-({[(2S,5R)-5-methoxyoxan-2-yl]methyl}amino)-3-nitrobenzene-1-sulfonyl]benzamide
4-(14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide
D-erythro-Hexitol, 1,5-anhydro-6-[[4-[[[4-[(4aS,10aR)-14-(4-chlorophenyl)-1,2,4a,5,8,9,10a,11,13,15-decahydro-12,12-dimethyl-7H,12H-pyrazino[2,1-g][1,5,8]benzodioxaazacycloundecin-3(4H)-yl]-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl]amino]sulfonyl]-2-nitrophenyl]amino]-3,4,6-trideoxy-2-O-methyl-
1,5-Anhydro-6-[[4-[[[4-[(4aS,10aR)-14-(4-chlorophenyl)-1,2,4a,5,8,9,10a,11,13,15-decahydro-12,12-dimethyl-7H,12H-pyrazino[2,1-g][1,5,8]benzodioxaazacycloundecin-3(4H)-yl]-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl]amino]sulfonyl]-2-nitrophenyl]amino]-3,4,6-trideoxy-2-O-methyl-D-erythro-hexitolB-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, ABBV 453, C3TU3CHH6L, Bcl-2-IN-16
Surzetoclax, also known as ABBV 453; is a highly potent and selective BCL-2 inhibitor with a Ki of approximately 0.07 nM. It induces apoptosis in BCL-2–dependent hematologic cancer cells, showing EC50 values typically below 10 nM in sensitive models. In vivo, Surzetoclax causes rapid tumor regression in xenograft models of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). It is orally bioavailable and demonstrates dose-dependent target engagement with favorable pharmacokinetics. Compared to Venetoclax, Surzetoclax was designed to reduce risks of tumor lysis syndrome and other dose-limiting toxicities.
Surzetoclax is a small molecule drug. The usage of the INN stem ‘-toclax’ in the name indicates that Surzetoclax is a B-cell lymphoma 2 (Bcl-2) inhibitor. Surzetoclax has a monoisotopic molecular weight of 1038.41 Da.
- A Study to Assess Adverse Events and Change in Disease Activity of Oral ABBV-453 Alone or in Combination With Subcutaneous and/or Oral Antimyeloma Agents in Adult Participants With Multiple Myeloma (MM)CTID: NCT06953960Phase: Phase 1/Phase 2Status: RecruitingDate: 2025-12-01
- A Study to Assess the Adverse Events and Change in Disease Activity in Adult Participants With Relapsed or Refractory Multiple Myeloma Receiving Oral ABBV-453 TabletsCTID: NCT05308654Phase: Phase 1Status: Active, not recruitingDate: 2025-08-14
- A Study Assessing Adverse Event and How Oral ABBV-453 Moves Through the Body in Adult Participants With Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)CTID: NCT06291220Phase: Phase 1Status: Active, not recruitingDate: 2025-06-06
SYN
The synthesis of surzetoclax (ABBV-453), a complex, next-generation BCL-2 inhibitor, can be accomplished through a patented 27-step convergent route or a more streamlined, AI-assisted method that involves the modular assembly of three key fragments.
Patented Synthesis (Literature Route)
The published synthesis (described in patent WO 2023/141536 A1) is a 27-step convergent route with a 12-step longest linear sequence. The molecule is assembled from three main components: a 6,11,6-fused tricyclic core, a trans-1,2-disubstituted tetrahydropyran (THP) unit, and a 5,6,7-fused heteroaromatic system.
Key Steps and Intermediates:
- Core Tricycle Assembly: The 6,11,6-fused macrocycle is formed by a sequence initiated from dimedone, involving a macrocyclization step using an 11-membered ring bis-triflate intermediate.
- THP Fragment Construction: The THP moiety’s synthesis includes an enzymatic resolution step using porcine pancreatic lipase to establish the required stereochemistry.
- Heteroaromatic System: The 7-azaindole-oxazepane tricycle is formed via a microwave-assisted, copper-mediated cyclization reaction.
- Final Coupling: The fragments are joined through Buchwald–Hartwig and N-sulfonylamide coupling reactions to yield the final surzetoclax molecule.
AI-Assisted Synthesis (ChemAIRS Route)
A more efficient, human-directed AI retrosynthesis approach developed by Chemical.AI offers a more convergent and experimentally practical alternative. This route also uses three fragments but employs different, more efficient coupling strategies.
Key Features of the Revised Route:
- Fragment 25a (Core Tricycle): Assembled in 10 steps using more accessible starting materials and a Mizoroki-Heck coupling to incorporate an aryl group.
- Fragment 12a (THP Motif): The synthesis is streamlined to four steps from simple building blocks, utilizing a Mitsunobu reaction to introduce the azide precursor instead of the patent’s longer tosylation/displacement sequence.
- Fragment 12b (Azaindole-Oxazepane Tricycle): An efficient nickel-photoredox C–N coupling is used to form an intermediate that then undergoes a base-promoted cyclization.
- Final Assembly: Fragments 12a and 12b are joined using a palladium-catalyzed amidocarbonylation, followed by deprotection and a final SNAr coupling with fragment 25a to form surzetoclax.
The AI-assisted route achieves greater modularity and adaptability for potential scale-up compared to the patented process.
PAT
1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepine bcl-2 inhibitors
Publication Number: US-11964990-B2
Priority Date: 2022-01-21
Grant Date: 2024-04-23
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US403063458&_cid=P10-MIWJNM-88215-1
Example 25
4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide
Example 25A
(S)-(3,4-dihydro-2H-pyran-2-yl)methanol
Example 25B
(S)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran
Example 25C
(3R,6S)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol
Example 25D
(2S,5R)-2-((benzyloxy)methyl)-5-methoxytetrahydro-2H-pyran
Example 25E
((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate
Example 25F
(2S,5R)-2-(azidomethyl)-5-methoxytetrahydro-2H-pyran
Example 25G
4-((((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide
Example 25H
7,7-dimethyl-4,6,7,8-tetrahydro-2H,5H-1,3-benzodioxin-5-one
Example 251
4′-chloro-2-(hydroxymethyl)-5,5-dimethyl-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one
Example 25J
4′-chloro-2-(chloromethyl)-5,5-dimethyl-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one
Example 25K
(R)-4′-chloro-2-(chloromethyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-3-ol
Example 25L
tert-butyl (S)-4-(((R)-4′-chloro-3-hydroxy-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-3-(hydroxymethyl)piperazine-1-carboxylate
Example 25M
tert-butyl (4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecine-3(4H)-carboxylate
Example 25N
(4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,3,4,4a,5,7,8,9,10a,11,12,13,15-tetradecahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecine
Example 250
ethyl 2-bromo-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H,7H,15H)-yl)benzoate
Example 25P
5-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide
Example 25Q
5-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine
Example 25R
5-bromo-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine
Example 25S
N-(3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide
Example 25T
1-tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepane
Example 25U
7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepane
Example 25V
ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H,7H,15H)-yl)-2-(7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate
Example 25W
ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H, 7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate
Example 25X
4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H,7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoic acid
Example 25Y
4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide
SYN
https://www.chemical.ai/blog/dl7xc1h1477b1hp21ajpef87z13c73
Thanks and CREDIT, https://www.chemical.ai/chemairs
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///////Surzetoclax, antineoplastic, ABBV 453, C3TU3CHH6L, Bcl-2-IN-16
Soquelitinib
Soquelitinib
CAS 2226636-04-8
MF C25H30N4O4S2, 514.7 g/mol
N-[5-({4-methoxy-2-methyl-5-[(3R)-3-methyl-4-(prop-2-enoyl)-1,4-diazepane-1-carbonyl]phenyl}sulfanyl)-1,3-thiazol-2-yl]cyclopropane-1-carboxamide
tyrosine kinase inhibitor, antineoplastic, CPI818, CPI-000818, CPI596, CP I818, CPI 000818, CP I596, 6I5H17AN3I,
Soquelitinib (CPI-818) is an experimental drug which acts as a selective inhibitor of the enzyme interleukin-2-inducible T-cell kinase (ITK). It is in clinical trials for the treatment of T-cell lymphoma.[1][2]
Soquelitinib is an orally available, small-molecule, irreversible inhibitor of interleukin-2 inducible T-cell kinase (ITK) with potential immunomodulatory and antineoplastic activities. Upon oral administration, soquelitinib selectively and covalently binds to the cysteine residue at position 442 (CYS-442) of ITK, thereby disrupting ITK-mediated signal transduction, while sparing tyrosine-protein kinase TXK (resting lymphocyte kinase, RLK) activity. This may abrogate T-cell receptor (TCR) signaling through ITK and inhibit TCR-induced proliferation of malignant T-cells. Additionally, inhibiting ITK activation may prevent the upregulation of GATA-3, a transcription factor that drives T-helper 2 (Th2) cell differentiation and is overexpressed in certain T-cell lymphomas. Thus, selective inhibition of ITK may inhibit Th2 responses without affecting T-helper 1 (Th1)-dependent immunity. ITK, a member of the Tec family of non-receptor protein tyrosine kinases plays a significant role in the T-cell development, differentiation and production of pro-inflammatory cytokines.
- Safety, Tolerability, and Preliminary Efficacy of Soquelitinib in Participants With Moderate to Severe ADCTID: NCT06345404Phase: Phase 1Status: RecruitingDate: 2025-07-22
- Study of the ITK Inhibitor Soquelitinib to Reduce Lymphoproliferation and Improve Cytopenias in Autoimmune Lymphoproliferative Syndrome (ALPS)-FAS PatientsCTID: NCT06730126Phase: Phase 2Status: RecruitingDate: 2025-05-31
- Soquelitinib vs Standard of Care in Participants With Relapsed/Refractory Peripheral T-cell Lymphoma Not Otherwise Specified, Follicular Helper T-cell Lymphomas, or Systemic Anaplastic Large-cell LymphomaCTID: NCT06561048Phase: Phase 3Status: RecruitingDate: 2025-04-17
- A Dose Escalation Study Evaluating CPI-818 in Relapsed/Refractory T-Cell LymphomaCTID: NCT03952078Phase: Phase 1Status: Active, not recruitingDate: 2025-04-16
Syn
- US11008314,
- https://patentscope.wipo.int/search/en/detail.jsf?docId=US278926237&_cid=P10-MISM56-82578
- SIMILAR
Syn
- WO2018089261 COMPD 44
- https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018089261&_cid=P10-MISM0C-78029-1
SYN
Embodiment B23. A method for an Th2/ITK-mediated disease in a patient in need thereof, the method comprising administering to the patient about 250 mg to about 1,000 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (A) is:
REF
https://www.nature.com/articles/s44386-024-00002-1
Pat
- Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: US-2022363676-A1Priority Date: 2016-11-03
- Compounds and methods for modulating Interleukin-2-inducible T-cell kinasePublication Number: US-11897874-B2Priority Date: 2016-11-03Grant Date: 2024-02-13
- Itk inhibitors for increasing th1 cell activityPublication Number: WO-2023196278-A1Priority Date: 2022-04-05
- Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: US-2019375743-A1Priority Date: 2016-11-03
- Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: WO-2018089261-A2Priority Date: 2016-11-03
- Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: US-11008314-B2Priority Date: 2016-11-03Grant Date: 2021-05-18
- Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: EP-3534899-B1Priority Date: 2016-11-03Grant Date: 2022-06-01
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References
- Khodadoust MS, Feldman TA, Yoon DH, Yannakou CK, Radeski D, Kim YH, et al. (November 2020). “Cpi-818, an oral interleukin-2-inducible T-cell kinase inhibitor, is well-tolerated and active in patients with T-cell lymphoma”. Blood. 136: 19–20. doi:10.1182/blood-2020-137782.
- Hsu LY, Rosenbaum JT, Verner E, Jones WB, Hill CM, Janc JW, et al. (December 2024). “Synthesis and characterization of soquelitinib a selective ITK inhibitor that modulates tumor immunity”. npj Drug Discovery. 1 (1) 2: 1–4. doi:10.1038/s44386-024-00002-1.
| Identifiers | |
|---|---|
| IUPAC name | |
| CAS Number | 2226636-04-8 |
| PubChem CID | 134517711 |
| DrugBank | DB18749 |
| ChemSpider | 129629996 |
| UNII | 6I5H17AN3I |
| KEGG | D12762 |
| Chemical and physical data | |
| Formula | C25H30N4O4S2 |
| Molar mass | 514.66 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
//////////////Soquelitinib, tyrosine kinase inhibitor, antineoplastic, CPI818, CPI-000818, CPI596, CP I818, CPI 000818, CP I596, 6I5H17AN3I,
Setidegrasib
Setidegrasib
CAS 2821793-99-9
MF C60H65FN12O7S MW1117.30
(2S,4R)-1-[(2S)-2-[4-[4-[[6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(oxan-4-yloxy)quinazolin-8-yl]oxymethyl]phenyl]triazol-1-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide
Kirsten rat sarcoma viral oncogene homologue (KRAS) degradation
inducer, antineoplastic, ASP-3082, ASP 3082, 3NQ4ME292X, KRAS G12D inhibitor 17
Setidegrasib (KRAS G12D inhibitor 17, ASP3082) is a PROTAC KRAS degrader (DC50: 37 nM). Setidegrasib induces the degradation of G12D-mutation KRAS protein. Setidegrasib suppresses p-ERK, p-AKT, p-S6 levels in AsPC-1 cells. Setidegrasib exhibits anti-tumor activity in various cancer xenograft models in mice. Setidegrasib can be used for the study of KRAS(G12D)-mutated solid tumors. (Blue: VHL ligase ligand (HY-168699); Black: linker (HY-168698); Pink: G12D ligand (HY-168700)).
Setidegrasib is a small molecule drug. The usage of the INN stem ‘-rasib’ in the name indicates that Setidegrasib is a Ras protein inhibitor. Setidegrasib has a monoisotopic molecular weight of 1116.48 Da.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022173032&_cid=P21-MIPU3D-50779-1
PAT
- Combination of anticancer agents comprising a bifunctional compound with g12d mutant kras inhibitory activityPublication Number: WO-2024033537-A1Priority Date: 2022-08-12
- Combination of anticancer agents comprising a bifunctional compound with g12d mutant kras inhibitory activityPublication Number: WO-2024033538-A1Priority Date: 2022-08-12
- Quinazoline compound for inducing degradation of g12d-mutation kras proteinPublication Number: WO-2022173032-A1Priority Date: 2021-02-15
- Quinazoline compound for inducing degradation of g12d-mutation kras proteinPublication Number: EP-4293024-A1Priority Date: 2021-02-15
- Quinazoline compound for inducing degradation of g12d mutant kras proteinPublication Number: US-2024182483-A1Priority Date: 2021-02-15
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- [1]. Yoshinari, et al. Preparation of quinazoline-linked (4R)-4-hydroxy-L-prolinamide compounds for inducing degradation of G12D-mutation KRAS protein: World Intellectual Property Organization, WO2022173032[P]. 2022-08-18.[2]. Yoshinari T, et al. Discovery of KRAS(G12D) selective degrader ASP3082. Commun Chem. 2025 Aug 23;8(1):254. [Content Brief]
////////Setidegrasib, antineoplastic, ASP-3082, ASP 3082, 3NQ4ME292X, KRAS G12D inhibitor 17
Sendegobresib
Sendegobresib
CAS 2704617-96-7
MFC37H45F3N6O5, 710.79
2,6-PIPERIDINEDIONE, 3-((4-(4-((4S)-1-((4-(1,6-DIHYDRO-1,4,5-TRIMETHYL-6-OXO-3-PYRIDINYL)-2,6-DIMETHOXYPHENYL)METHYL)-3,3-DIFLUORO-4-PIPERIDINYL)-1-PIPERAZINYL)-3-FLUOROPHENYL)AMINO)-, (3S)-
(3S)-3-[4-[4-[(4S)-1-[[2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridinyl)phenyl]methyl]-3,3-difluoropiperidin-4-yl]piperazin-1-yl]-3-fluoroanilino]piperidine-2,6-dione
bromodomain-containing protein 9 (BRD9) degradation inducer, antineoplastic, AW8PEP3VZ3, CFT 8634, ORPHAN DRUG
Sendegobresib is an orally bioavailable heterobifunctional protein degrader of bromodomain-containing protein 9 (BRD9; sarcoma antigen NY-SAR-29; rhabdomyosarcoma antigen MU-RMS-40.8), with potential antineoplastic activity. Sendegobresib is comprised of an E3 ligase-binding moiety and a BRD9-binding moiety. Upon oral administration, sendegobresib targets and binds to BRD9 with its BRD9-binding moiety. Upon BRD9 binding, the E3 ligase-binding moiety binds to cereblon (CRBN), a component of the CRL4-CRBN E3 ubiquitin ligase complex, which directs proteins for destruction, resulting in the proteasome-mediated degradation of BRD9. This leads to an inhibition of the growth of tumor cells that rely on BRD9 for survival. BRD9, a component of one form of the Brg/Brahma-Associated Factor (BAF) complex, is needed for the survival of certain cancer cells due to mutations.
A Study to Assess the Safety and Tolerability of CFT8634 in Locally Advanced or Metastatic SMARCB1-Perturbed Cancers, Including Synovial Sarcoma and SMARCB1-Null Tumors
CTID: NCT05355753
Phase: Phase 1
Status: Terminated
Date: 2024-12-17
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US355912448&_cid=P11-MINYJY-62955-1
Synthesis of Compound 172
| Step-1: To a stirred solution of compound tert-butyl piperazine-1-carboxylate (85.40 g, 536.82 mmol) in DMF (500 mL) was added cesium carbonate (262.4 g, 805.4 mmol) and stirred for 15 min before adding 1,2-difluoro-4-nitro-benzene (100 g, 536.82 mmol). The reaction mixture stirred at RT for 16 h while monitoring by TLC. After completion, the reaction mass was quenched with ice flakes and the precipitated solid was filtered, dried under vacuum to afford tert-butyl 4-(2-fluoro-4-nitro-phenyl) piperazine-1-carboxylate 172-3 (152 g, 88.85% yield, 97.94% purity) as a yellow solid. |
PAT
PAT
PAT
- Enhanced hyt-induced protein degradation using lipid nanoparticle deliveryPublication Number: US-2023414723-A1Priority Date: 2020-10-26
- Compounds for targeted degradation of brd9Publication Number: WO-2021178920-A1Priority Date: 2020-03-05
- Compounds for targeted degradation of brd9Publication Number: US-2022098194-A1Priority Date: 2020-03-05
- Compounds for targeted degradation of brd9Publication Number: US-2023060334-A1Priority Date: 2020-03-05
- Compounds for targeted degradation of BRD9Publication Number: US-11691972-B2Priority Date: 2020-03-05Grant Date: 2023-07-04
- Selected compounds for targeted degradation of brd9Publication Number: US-2024245677-A1Priority Date: 2021-09-09
- Exosome-based cancer assaysPublication Number: US-11938164-B2Priority Date: 2021-04-07Grant Date: 2024-03-26
- Exosome-based cancer assaysPublication Number: US-2022331390-A1Priority Date: 2021-04-07
- Exosome-based cancer assaysPublication Number: WO-2022216765-A1Priority Date: 2021-04-07
- Enhanced hyt-induced protein degradation using lipid nanoparticle deliveryPublication Number: WO-2022093809-A1Priority Date: 2020-10-26
- Directed degron molecules and applications thereofPublication Number: WO-2023081400-A1Priority Date: 2021-11-04
- Directed degron molecules and applications thereofPublication Number: WO-2023081400-A9Priority Date: 2021-11-04
- Directed degron molecules and applications thereofPublication Number: EP-4426687-A1Priority Date: 2021-11-04
- Selected compounds for targeted degradation of brd9Publication Number: WO-2023039208-A1Priority Date: 2021-09-09
- Selected compounds for targeted degradation of brd9Publication Number: EP-4398904-A1Priority Date: 2021-09-09
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/////////Sendegobresib, antineoplastic, AW8PEP3VZ3, CFT 8634, ORPHAN DRUG
Segigratinib, Ratangratinib
Segigratinib, Ratangratinib
CAS 1882873-93-9
MF C27H28Cl2N6O3 MW 555.5 g/mol
N-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-(3,3-dimethylpiperazin-1-yl)benzamide
N-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[5,4-b]pyridin-3-yl]-4-(3,3-dimethylpiperazin-1-yl)benzamide
fibroblast growth factor receptor tyrosine kinase inhibitor, antineoplastic, 3D 185, Ratangratinib, 3D-185, G0Z5E4YTB4, HH 185
Ratangratinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3) and colony stimulating factor 1 receptor (CSF1R; CSF-1R; CD115; M-CSFR), with potential immunomodulatory and antineoplastic activities. Upon administration, ratangratinib binds to and inhibits FGFR1/2/3, which may result in the inhibition of FGFR1/2/3-mediated signal transduction pathways. This inhibits proliferation in FGFR1/2/3-overexpressing tumor cells. 3D185 also targets and binds to CSF1R, thereby blocking CSF1R activation and CSF1R-mediated signaling. This inhibits the activities of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), and prevents immune suppression in the tumor microenvironment (TME). This enhances antitumor T-cell immune responses and inhibits the proliferation of tumor cells. FGFR, a family of receptor tyrosine kinases (RTKs) upregulated in many tumor cell types, plays a key role in cellular proliferation, migration and survival. CSF1R, also known as macrophage colony-stimulating factor receptor (M-CSFR) and CD115 (cluster of differentiation 115), is a cell-surface receptor that plays major roles in tumor cell proliferation and metastasis.
Efficacy and Safety of 3D185 Monotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Cholangiocarcinoma
CTID: NCT05039892
Phase: Phase 2
Status: Not yet recruiting
Date: 2025-05-20
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016026445&_cid=P20-MIMK7T-68502-1
N-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6-(3,3-dimethylpiperazin-1-yl)nicotinamide
1H NMR(DMSO-d6,400MHz)δppm 13.39(s,1H),10.86(s,1H),8.81(d,1H,J＝2.0Hz),8.40(d,1H,J＝8.0Hz),8.16(dd,1H,J 1＝2.4Hz,J 2＝2.4Hz),7.08(t,2H,J＝8.4Hz),6.90(d,1H,J＝9.2Hz),3.99(s,6H),3.60(t,2H,J＝4.0Hz),3.43(s,2H),2.82(t,2H,J＝4.4Hz),1.04(s,6H).LCMS:556.2[M+H] +，RT＝1.21min。
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US204149576&_cid=P20-MIMK4B-66027-1
1H NMR (d-MeOD, 400 MHz) δ ppm 8.52 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.15-7.13 (m, 3H), 6.94 (s, 1H), 3.99 (s, 6H), 3.58-3.57 (m, 2H), 3.44-3.40 (m, 4H), 10.50 (s, 6H).
PAT
- Indazole compounds as fgfr kinase inhibitor, preparation and use thereofPublication Number: EP-3184521-A1Priority Date: 2014-08-19
- Indazole compounds as FGFR kinase inhibitor, preparation and use thereofPublication Number: US-10562900-B2Priority Date: 2014-08-19Grant Date: 2020-02-18
- Indazole compounds as fgfr kinase inhibitor, preparation and use thereofPublication Number: US-2017275291-A1Priority Date: 2014-08-19
- Indazole compounds as fgfr kinase inhibitor, preparation and use thereofPublication Number: WO-2016026445-A1Priority Date: 2014-08-19
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////////segigratinib, antineoplastic, 3D 185, Ratangratinib, 3D-185, G0Z5E4YTB4, HH 185
Rupitasertib
Rupitasertib
CAS 1379545-95-5
MF C21H19ClF3N5O 449.9 g/mol
4-({(1S)-2-(azetidin-1-yl)-1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)quinazoline-8-carboxamide
4-[[(1S)-2-(azetidin-1-yl)-1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl]amino]quinazoline-8-carboxamide
serine/ threonine kinase inhibitor, antineoplastic, EMD SERONO, Gastric cancer; HER2 positive breast cancer; Solid tumours, M2698 HCl, M2698 hydrochloride, MSC2363318A, MSC 2363318A, MSC-2363318A, M2698, M-269, M 2698. Rupitasertib HCl, 0DXG50I4WD
- OriginatorEMD Serono
- DeveloperEMD Serono; Evexta Bio
- ClassAntineoplastics; Small molecules
- Mechanism of Action70 kDa ribosomal protein S6 kinase inhibitors; Proto-oncogene protein c-akt inhibitors
- PreclinicalGlioblastoma; HER2 negative breast cancer
- No development reportedGastric cancer; HER2 positive breast cancer; Solid tumours
- 28 Oct 2025No recent reports of development identified for preclinical development in Gastric-cancer in France (PO)
- 28 Jun 2025No recent reports of development identified for phase-I development in HER2-positive-breast-cancer(Combination therapy, Late-stage disease, Metastatic disease) in USA (PO)
- 28 Jun 2025No recent reports of development identified for phase-I development in Solid-tumours(Combination therapy, Late-stage disease) in USA (PO)
- First-in-Human Dose Escalation Trial in Subjects With Advanced Malignancies
- CTID: NCT01971515
- Phase: Phase 1
- Status: Completed
- Date: 2018-09-19
Rupitasertib is an orally available inhibitor of the serine/threonine protein kinases ribosomal protein S6 Kinase (p70S6K) and Akt (protein kinase B), with potential antineoplastic activity. Upon administration, rupitasertib binds to and inhibits the activity of p70S6K and Akt. This prevents the activation of the PI3K/Akt/p70S6K signaling pathway and inhibits tumor cell proliferation in cancer cells that have an overactivated PI3K/Akt/p70S6K signaling pathway. Constitutive activation and dysregulated signaling of the PI3K/Akt/p70S6K pathway are frequently associated with tumorigenesis of many tumor types; targeting multiple kinases in this pathway is more efficacious than targeting a single kinase.
An optimized S6K inhibitor to overcome limitations of PAM pathway inhibitors
In just over 20 years, protein kinase inhibitors have changed the face of oncology and opened the new eras of targeted therapies and precision medicine. However, with few exceptions, no patient can be cured by one of these drugs alone. Today, scientists seek to develop novel kinase inhibitors[1] with improved efficacy and the potential to overcome resistances. The dual S6K AKT1/3 inhibitor rupitasertib (formerly DIACC3010, acquired from Merck KGaA, Darmstadt, Germany) has both of these characteristics and reaches brain metastases. After successfully completing a Phase I trial in patients with advanced/refractory solid tumors, including breast cancer, the drug candidate will be evaluated in a Phase 2/3 trial in ER+ HER2 breast cancer, which is expected to start in 2024.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012069146&_cid=P10-MIJPKI-12294-1
Example 4 was prepared following the general synthesis of A-E starting with (S)-2- amino-2-(3,4-di-fluoro-phenyl)-ethanol.LCMS [384.20 (M+1)]. 1H NMR (DMSO-d6, ppm) 1.92 (2H), 2.75 (1H), 2.93 (1H), 3.15 (4H), 5.43 (1H), 7.34 (2H), 7.53 (1H), 7.68 (1H), 7.81 (1H), 8.58 (4H), 10.30 (1H).
4-[(S)-2-Azetidin-1-yl-1-(4-chloro-3-trifluoromethylphenyl)-ethylamino]-guinazoline-8- carboxylic acid amide (5)
IC50 P70S6K [nM]: 0.9
pS6 MDA-MB-468 [nM]: 11
Akt1 IC50 [nM]: 1.4
Aurora B IC50 [nM]: 100
PAT
- Quinazoline carboxamide azetidinesPublication Number: SG-190318-A1Priority Date: 2010-11-24
- Quinazoline carboxamide azetidinesPublication Number: US-2013252942-A1Priority Date: 2010-11-24
- Quinazoline carboxamide azetidinesPublication Number: US-8946247-B2Priority Date: 2010-11-24Grant Date: 2015-02-03
- SMAC Mimetic for Treating Myelodysplastic SyndromesPublication Number: US-2015158908-A1Priority Date: 2009-07-02
- Methods of treating a ras protein-related disease or disorderPublication Number: US-2025049810-A1
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- p70S6K/Akt dual inhibitor DIACC3010 is efficacious in preclinical models of gastric cancer alone and in combination with trastuzumabPublication Name: Scientific ReportsPublication Date: 2023-09-25PMCID: PMC10520030PMID: 37749105DOI: 10.1038/s41598-023-40612-9
- TTD: Therapeutic Target Database describing target druggability informationPublication Name: Nucleic Acids ResearchPublication Date: 2023-09-15PMCID: PMC10767903PMID: 37713619DOI: 10.1093/nar/gkad751
- Identification of Clinical Candidate M2698, a Dual p70S6K and Akt Inhibitor, for Treatment of PAM Pathway-Altered CancersPublication Name: Journal of Medicinal ChemistryPublication Date: 2021-10-01PMID: 34596404DOI: 10.1021/acs.jmedchem.1c01087
- Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancerPublication Name: Journal of Hematology & OncologyPublication Date: 2021-08-18PMCID: PMC8371902PMID: 34407844DOI: 10.1186/s13045-021-01132-z
- M2698 is a potent dual-inhibitor of p70S6K and Akt that affects tumor growth in mouse models of cancer and crosses the blood-brain barrierPublication Name: American journal of cancer researchPublication Date: 2016PMCID: PMC4859885PMID: 27186432
////////////Rupitasertib, antineoplastic, EMD SERONO, Gastric cancer; HER2 positive breast cancer; Solid tumours, M2698 HCl, M2698 hydrochloride, MSC2363318A, MSC 2363318A, MSC-2363318A, M2698, M-269, M 2698. Rupitasertib HCl, 0DXG50I4WD
Potrasertib
Potrasertib
CAS 2226938-19-6
MFC28H30Cl2N8O MW 565.5 g/mol
6-(2,6-dichlorophenyl)-2-{3-methyl-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]anilino}-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one
7-(2,6-dichlorophenyl)-12-[3-methyl-4-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]anilino]-2,5,7,11,13-pentazatricyclo[7.4.0.02,6]trideca-1(13),5,9,11-tetraen-8-one
serine/ threonine kinase inhibitor, antineoplastic, IMP 7068, WEE1-IN-10, orb2664172, 621K13UG4B, Phase 1, Solid tumours
- OriginatorIMPACT Therapeutics
- ClassAntineoplastics; Small molecules
- Mechanism of ActionWEE1 protein inhibitors
- Phase ISolid tumours
- 28 Mar 2024No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease, Monotherapy) in Taiwan (PO)
- 28 Mar 2024No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease, Monotherapy) in USA (PO)
- 20 Oct 2023Efficacy, adverse events, pharmacodynamics and pharmacokinetics data from the phase I WEE1 trial in Solid tumours presented at the 48th European Society for Medical Oncology Congress (ESMO-2023)
Potrasertib is an investigational drug that is a selective inhibitor of WEE1 kinase, a protein crucial for the cell cycle. It is being studied for the treatment of various advanced solid tumors, including small cell lung cancer, ovarian, and colorectal cancers. By blocking the WEE1 kinase, potrasertib causes cancer cells with DNA damage to undergo premature, error-prone mitosis, which leads to cell death.
How it works
- Potrasertib is a serine/threonine kinase inhibitor.
- It works by targeting WEE1 kinase, which regulates the cell’s response to DNA damage.
- By inhibiting WEE1, it prevents cancer cells from repairing DNA damage before dividing, forcing them into a state that leads to cell death.
- This mechanism is particularly effective in tumors with a defective p53 gene, as these tumors rely more heavily on the WEE1 checkpoint for survival.
Potential uses
- Combination therapy: It is being explored in combination with chemotherapy (like gemcitabine and cisplatin) or radiotherapy to enhance their effectiveness against cancer.
- Monotherapy: It is also being studied as a standalone treatment for certain cancers, including ovarian, colorectal, and non-small cell lung cancer, especially those with high replication stress or WEE1 dependency.
Current status
- Potrasertib is still an investigational drug and is not yet approved for widespread clinical use.
- It is undergoing clinical trials to evaluate its safety and effectiveness in treating advanced cancers.
Potrasertib is an investigational new drug that is being evaluated by IMPACT Therapeutics for the treatment of advanced solid tumors. It is oral inhibitor of WEE1 kinase, a key regulator of cell cycle checkpoints.[1][2]
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018090939&_cid=P21-MI6TEY-70275-1
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021073491&_cid=P21-MI6TF3-70349-1
Example 1
SIMILAR NOT SAME
[0117]6-(2,6-dichlorophenyl)-2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one
SIMILAR NOT SAME
[0128]6-(2,6-dichlorophenyl)-2-((4-((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one
[0130]a) Preparation of (2S,6R)-2,6-dimethyl-1-(methyl-d3)-4-(2-methyl-4-nitro)piperazine: Sodium hydride (385.03 mg, 9.63 mmol, 60% purity) was added to a solution of (3S,5R)-3,5-dimethyl-1-(2-methyl-4-nitro)piperazine (2 g, 8.02 mmol) in N,N-dimethylformamide (15 mL). The mixture was stirred at 0 °C for 25 hours, then trideuterated iodomethane (1.16 g, 8.02 mmol, 499.09 μL) was added, and the mixture was stirred at 0 °C for 2 hours. The reaction was quenched by adding an aqueous sodium bicarbonate solution (30 mL) at 0 °C, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target crude product (1.5 g, yellow-green solid). LC-MS(ESI): m/z(M+1) + 267.1. 1 H NMR (400MHz, CDCl
3 ): δ8.04-8.01 (m, 2H), 6.96 (d, J = 12.0Hz, 1H), 3.10 (d, J = 12Hz, 2H), 2.65 (t , J=12Hz, 2H), 2.45-2.43 (m, 2H), 2.36 (s, 3H), 1.16-1.15 (d, J=4.0Hz, 6H).
[0131]b) Preparation of 4-((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylaniline: Under nitrogen protection, palladium on carbon (281.58 μmol, 10% purity) was added to a methanol (5 mL) solution of (2S,6R)-2,6-dimethyl-1-(methyl-d3)-4-(2-methyl-4-nitro)piperazine (1.5 g, 5.63 mmol). The resulting suspension was purified multiple times under vacuum with hydrogen. The mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the target crude product (1.3 g, black solid). LC-MS (ESI): m/z (M+1) + 237.1.
[0132]c) Preparation of 6-(2,6-dichlorophenyl)-2-((4-(((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one: 4-((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylaniline (459.32 mg, 1.94 mmol) and the prepared 6-(2,6-dichlorophenyl)-2- A mixture (700 mg, crude) of crude (methanesulfonyl)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one and 6-(2,6-dichlorophenyl)-2-(methanesulfonyl)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one was dissolved in acetonitrile (5 mL) and trifluoroacetic acid (20.14 mg, 0.177 mmol, 13.08 μL) was added. The mixture was stirred at 20–25 °C for 2 hours, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by reversed-phase HPLC to give the target compound (56.89 mg, 100.00 μmol, yellow solid, 5.66% yield). LC-MS (ESI): m/z (M+1) + 568.0.
1 H NMR (400MHz, CDCl 3 ): δ8.81 (s, 1H), 7.49 (d, J=3.8Hz, 3H), 7.41-7.34 (m, 3H), 7.02 (d, J=4.2Hz, 1H), 4.25-4.21 (m, 2H), 4.02 (t, J=8.0Hz, 2H), 2.95 (d, J=6.0Hz 2H), 2.62 (t, J=6.0Hz, 2H), 2.46-2.41 (m, 2H), 2.34 (s, 6H), 1.15 (d, J=6.4Hz, 6H).
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022188802&_cid=P21-MI6TVM-79837-1
PAT
- 8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-onesPublication Number: US-11345711-B2Priority Date: 2016-11-16Grant Date: 2022-05-31
- 8,9-dihydroimidazole[1,2-a]pyrimido[5,4-e]pyrimidine-5(6h)-ketone compoundPublication Number: EP-3543242-B1Priority Date: 2016-11-16Grant Date: 2024-01-03
- Compound 8,9-dihydroimidazole[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-ketonePublication Number: ES-2968252-T3Priority Date: 2016-11-16Grant Date: 2024-05-08
- 8,9-dihydroimidazole[1,2-a]pyrimido[5,4-e]pyrimidine-5(6h)-ketone compoundPublication Number: EP-3543242-A1Priority Date: 2016-11-16
- 8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-onesPublication Number: US-10703759-B2Priority Date: 2016-11-16Grant Date: 2020-07-07
- 8,9-DIHYDROIMIDAZO[1,2-a]PYRIMIDO[5,4-e]PYRIMIDIN-5(6H)-ONESPublication Number: US-2019308984-A1Priority Date: 2016-11-16
- 8,9-DIHYDROIMIDAZO[1,2-a]PYRIMIDO[5,4-e]PYRIMIDIN-5(6H)-ONESPublication Number: US-2020385394-A1Priority Date: 2016-11-16
- 8,9-Dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-onesPublication Number: CN-109906227-BPriority Date: 2016-11-16Grant Date: 2022-03-11
- Dihydroimidazo pyrimido pyrimidinone compoundPublication Number: WO-2021073491-A1Priority Date: 2019-10-16
- DihydroimidazopyrimidopyrimidinonesPublication Number: CN-114502559-APriority Date: 2019-10-16
- Dihydroimidazopyrimidopyrimidinone compoundsPublication Number: CN-114502559-BPriority Date: 2019-10-16Grant Date: 2024-02-02
- Dihydroimidazo pyrimido pyrimidinone compoundPublication Number: US-2024010655-A1Priority Date: 2019-10-16
- 8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6h)-onesPublication Number: CA-3043945-A1Priority Date: 2016-11-16
- Use of Wee1 kinase inhibitors in the treatment of cancerPublication Number: CN-118338905-APriority Date: 2021-11-26
- Use of wee1 kinase inhibitors in the treatment of cancerPublication Number: WO-2023093840-A1Priority Date: 2021-11-26
- Use of wee1 kinase inhibitors in the treatment of cancerPublication Number: WO-2022188802-A1Priority Date: 2021-03-10
- The use of Wee1 kinase inhibitors in the treatment of cancer diseasesPublication Number: CN-117202908-APriority Date: 2021-03-10
- Use of wee1 kinase inhibitors in the treatment of cancerPublication Number: US-2024091233-A1Priority Date: 2021-03-10
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| Clinical data | |
|---|---|
| Other names | IMP7068 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2226938-19-6 |
| PubChem CID | 139503236 |
| UNII | 621K13UG4B |
| Chemical and physical data | |
| Formula | C28H30Cl2N8O |
| Molar mass | 565.50 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
References
- “IMP 7068”. AdisInsight. Springer Nature Switzerland AG.
- Wang Z, Li W, Li F, Xiao R (January 2024). “An update of predictive biomarkers related to WEE1 inhibition in cancer therapy”. Journal of Cancer Research and Clinical Oncology. 150 (1): 13. doi:10.1007/s00432-023-05527-y. PMC 10794259. PMID 38231277.
///////potrasertib, antineoplastic, IMP 7068, WEE1-IN-10, orb2664172, 621K13UG4B, Phase 1, Solid tumours
New Drug Approvals 
