Nefextinib

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Nefextinib

CAS 2070931-57-4

MF C22H23FN6OS MW 438.52

7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-[1-(piperidin4-yl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-2-amine

7-(4-FLUORO-2-METHOXYPHENYL)-6-METHYL-N-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL) THIENO (3,2-D)PYRIMIDIN-2-AMINE
tyrosine kinase inhibitor, antineoplastic, DL772G3NN7, MAX-40279, MAX 40279

Nefextinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) and FMS-like tyrosine kinase 3 (FLT3; CD135; STK1; FLK2), with potential antineoplastic activity. Upon oral administration, nefextinib binds to and inhibits both FGFR and FLT3, including FLT3 mutant forms, which results in the inhibition of FGFR/FLT3-mediated signal transduction pathways. This inhibits proliferation in FGFR/FLT3-overexpressing tumor cells. FGFR, a family of receptor tyrosine kinases, is upregulated in many tumor cell types. FLT3, a class III receptor tyrosine kinase (RTK), is overexpressed or mutated in most B-lineage neoplasms and in acute myeloid leukemias. They both play key roles in cellular proliferation and survival.

A Phase 2 Study to Evaluate the Safety and Efficacy of Max-40279-01 in Patients With Advanced Gastric Cancer or Gastroesophageal Junction CancerCTID: NCT05395780Phase: Phase 2Status: Unknown statusDate: 2022-06-02
MAX-40279 in Subjects With Acute Myelogenous Leukemia (AML)CTID: NCT03412292Phase: Phase 1Status: Unknown statusDate: 2022-01-19
MAX-40279-01 in Patients With Advanced Solid TumorsCTID: NCT04183764Phase: Phase 1Status: Unknown statusDate: 2022-01-19
Study of MAX-40279 in Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)CTID: NCT04187495Phase: Phase 1Status: Unknown statusDate: 2022-01-19
A Clincal Study of Max-40279-01 in Patients With Advanced Colorectal CancerCTID: NCT05130021Phase: Phase 2Status: Unknown statusDate: 2021-12-06

SYN

example 31 [CN106366093A]

SYN

WO-2017012559

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017012559&_cid=P22-MHRG1L-67142-1

Example 31

[0488]N-[7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-d]pyrimidin-2-yl]-1-(piperidin-4-yl)-1H-pyrazol-4-amine (compound 31)

Synthesis of compound 31-e

[0491]2,4-Dichloro-6-methylthiophene[3,2-d]pyrimidine (10 g, 45.6 mmol) was dissolved in tetrahydrofuran (100 mL) and ethanol (100 mL). The reaction mixture was cooled to 0 °C, and sodium borohydride (12.5 g, 198 mmol) was added in portions. The reaction mixture was brought to room temperature and stirred for 16 hours. It was then diluted with water (500 mL) and adjusted to pH 7 with 1 N hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate (150 mL × 3). The organic phase was washed successively with water (100 mL × 3) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 31-e (7.5 g, yield: 88%). This product required no further purification. LC-MS (ESI): m/z = 187 [M+H] ⁺ .

[0492]Synthesis of compound 31-d

[0493]Compound 31-e (7.5 g, 40 mmol) was dissolved in chloroform (300 mL) at 0 °C, and activated manganese dioxide (35 g, 400 mmol) was added. The reaction mixture was brought to room temperature and stirred for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with chloroform (100 mL × 3). The combined filtrates were concentrated under reduced pressure to give a white solid 31-d (6.6 g, yield: 89%), which did not require further purification. LC-MS (ESI): m/z = 185 [M + H]+.

[0494]Synthesis of compound 31-c

[0495]Compound 31-d (3.1 g, 16.8 mmol) was dissolved in trifluoroacetic acid (30 mL) at 0 °C. N-iodosuccinimide (5.7 g, 25.3 mmol) was added in portions. The reaction mixture was brought to room temperature and stirred for 1 hour. The reaction was quenched with water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic phase was washed successively with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 31-c (4.9 g, yield: 94%). This product required no further purification. LC-MS (ESI): m/z = 311 [M + H] ⁺ .

[0496]Synthesis of compound 31-b

[0497]Compound 31-c (615 mg, 1.98 mmol), 2-methoxy-4-fluorophenylboronic acid (405 mg, 2.38 mmol), and sodium carbonate (630 mg, 5.94 mmol) were suspended in dioxane (5 mL) and water (5 mL). A [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (163 mg, 0.2 mmol) was added. The mixture was purged three times with nitrogen and heated to 80 °C for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was separated into layers by dichloromethane (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:1) to give a white solid 31-b (240 mg, yield: 39%). LC-MS (ESI): m/z = 309 [M+H] ⁺ .

[0498]Synthesis of compound 31-a

[0499]Compound 31-b (240 mg, 0.78 mmol) and compound 32-c (208 mg, 0.78 mmol) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (323 mg, 2.34 mmol), 2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (112 mg, 0.24 mmol), and tris(dibenzylacetone)palladium (134 mg, 0.24 mmol) were added. The reaction was carried out under nitrogen protection at 110 °C for 16 hours. After cooling to room temperature, the reaction mixture was separated into layers by dichloromethane (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow viscous oil 31-a (190 mg, yield: 45%). LC-MS(ESI): m/z = 539[M+H] ⁺ .

[0500]Synthesis of Compound 31

[0501]31-a (190 mg, 0.35 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated into layers by ethyl acetate (50 mL) and 1N hydrochloric acid aqueous solution (50 mL). The aqueous phase was adjusted to pH = 10 with saturated potassium carbonate aqueous solution, and a solid precipitated. The solid was filtered, and the filter cake was washed with water (20 mL × 3). The solid was dried under vacuum to give a light yellow solid 31 (22 mg, yield: 14%). LC-MS (ESI): m/z = 439 [M+H] ⁺ .

[0502]

¹H-NMR(400MHz,MeOD)δ:8.78(d,J＝5Hz,1H),7.87(s,1H),7.48(s,1H),7.35(m,1H),7.05(dd,J＝11Hz,J＝2Hz,1H),6.91(m,1H),4.10(m,1H),3.79(s,3H),3.22(m,2H),2.77(m,2H),2.47(s,3H),2.03(m,2H),1.73(m,2H)ppm

PAT