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Zidesamtinib

July 24, 2026 2:44 am / Leave a comment

Zidesamtinib

CAS 2739829-00-4

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,9,10,11,23-hexazapentacyclo[19.3.1.0^2,6.0^8,12.0^13,18]pentacosa-1(25),2(6),4,8,11,13(18),14,16,21,23-decaen-22-amine

To treat adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer after receiving a ROS1 kinase inhibitor

FDA 2026, APPROVALS 2026, Jideytro, NVL-520, NUV-520, NU-520, NVL 520, NUV 520, NU 520, MX5KQV5XHC

Zidesamtinib (sold under the brand name Jideytro) is an oral, highly selective, next-generation kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) on July 22, 2026, to treat adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who have previously been treated with at least one ROS1 kinase inhibitor. Developed originally by Nuvalent and subsequently acquired by GSK, it represents a major milestone as GSK’s first approved therapeutic targeting lung cancer.

Mechanism of Action

Zidesamtinib functions by targeting and inhibiting the receptor tyrosine kinase c-ros oncogene 1 (ROS1). It is custom-engineered to solve the primary clinical challenges that limit previous therapies:

Overcoming Resistance Mutations: It binds tightly to wild-type ROS1 and remains robustly active against a broad array of treatment-emergent point mutants. This includes G2032R (the most common solvent-front resistance mutation), as well as S1986Y/F, L2026M, and D2033N mutations.
Blood-Brain Barrier Penetration: It features high central nervous system (CNS) penetrance to effectively treat and control brain metastases, which are frequent in aggressive ROS1-positive cancers.
TRK-Sparing Design: Unlike older dual-acting inhibitors, it deliberately avoids inhibiting the structurally similar tropomyosin receptor kinase (TRK) family. This minimizes off-target TRK-related neurological toxicities like severe dizziness and ataxia.

Clinical Trial Outcomes

The FDA approval was heavily supported by data from the ongoing global, single-arm, Phase 1/2 ARROS-1 clinical trial (N=117 heavily pretreated patients):

Overall Response: Delivered an Objective Response Rate (ORR) of 44% in patients who had exhausted alternative TKI options.
Subgroup Efficacy: Achieved a 51% ORR in patients who had received only one prior ROS1 inhibitor, a 54% ORR in those harboring the G2032R mutation, and an intracranial ORR of 48% for patients with active brain metastases.
Durability: Showed prolonged disease control, with a 12-month duration of response (DOR) rate standing at 69%.

Administration and Side Effects

Jideytro is formulated as an oral tablet taken once daily, with or without food. It demonstrates a highly tolerable safety profile, with only a 10% dose reduction rate and a 2% treatment discontinuation rate due to adverse events.

Common Adverse Reactions (≥ 15%): Edema (swelling), peripheral neuropathy, constipation, fatigue, and dyspnea (shortness of breath).
Warnings & Precautions: Includes risks of mild CNS reactions (dizziness, cognitive alterations), QTc interval prolongation, skeletal fractures, pancreatic toxicity, and interstitial lung disease (ILD)/pneumonitis.

Zidesamtinib, sold under the brand name Jideytro, is an anti-cancer medication used for the treatment of previously treated locally advanced or metastatic ROS1+ non-small cell lung cancer.^[1]^[2]^[3] It is taken by mouth once daily.^[1]^[2]^[3]

Medical uses

Indication

Zidesamtinib is a prescription medicine used to treat adults with non-small cell lung cancer that has spread within the chest or other parts of the body and is caused by an abnormal ROS1 gene, and who have received a ROS1 kinase inhibitor.^[1]^[2]^[3]

Mechanism of action

Zidesamtinib is a kinase inhibitor that works by blocking ROS1, an abnormal protein that drives some lung cancers to grow, including forms that have become resistant to earlier ROS1 treatments.^[4] Jideytro also works on the related proteins ALK and TRK. In laboratory and animal studies, Zidesamtinib stopped cancer cells with ROS1 changes from growing and slowed tumor growth, including tumors in the brain.^[2]

PAT

Example 5 [US383715659]

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023056405&_cid=P10-MRYBTX-59205-1

Scheme 3. Synthesis of Compound 1.

[00548] Synthesis of Compound 5. To a reactor was charged THF (10 vol ), water (1 vol ), followed by Compound 6 (850.0 g, 2.68 mol, 1 equiv.) and Compound 7 (534.0 g, 3.22 mol, 1.2 equiv ) at 20~30°C. The solids were completely dissolved at 20~30°C while stirring for 15 min and K2CO3 (1.11 kg, 3 equiv.) was added in portions over 10-15 min at 20~30°C. The reaction mixture was fully refdled with nitrogen, and was added Pd(dppf)C12 (78.5 g, 0.04 equiv.) in one portion under nitrogen. The reaction mixture was fully refdled with nitrogen again, then heated to 60-65 °C and stirred at 60~65°C for 16 h under nitrogen. The reaction mixture was cooled to 20~30°C, fdtered through a 10 cm celite pad (2X, 2.4 kg celite). The combined fdtrates were washed with EtOAc (10 vol., 21 L) and separated. The organic phase was washed with water (5 vol., 10.5 L) and separated. The organic phase was stirred for 1 h at 40-45°C in 5 w% aqueous L-cysteine (2.0 eq., 1.61 kg in 30.6 kg water) and separated. The organic phase was washed with water (5 vol., 10.5 L) and separated. The resulting organic phase was concentrated at 45-50°C in vacuum to afford crude product as a light brown oil (2.28 kg). To the crude product was charged MTBE (228 mL, 0.1 vol. relative to crude product), heated to 50°C over 15 min, followed by isopropyl ether (2.28 L, 1 vol.) dropwise over 1 h at 45~50°C, then cooled to 10°C over 2 h. A large amount of solids came out and the resulting slurry was stirred for 2 h at 10-15°C. The solids were collected by fdtration, dried in oven at 45°C for 16 h to get crude Compound 5 as a pale-yellow solid (1.67 kg, 96.3% /220 nm, >99.9%/220 nm chiral purity). 1.67 kg of crude Compound 5 was purified by silica gel chromatography (EtOAc/ n-heptane=l: 1, 2.5X silica gel, 100-200 meshes) to get Compound 5 as an off-white solid (1.58 kg, 99.6%/220 nm, >99.9%/220 nm chiral purity, 97.9 w%, 72% yield). H NMR (400 MHz, DMSO) 5 7.44 (dd, J = 10.5, 2.5

Hz, 1H), 7.36 (s, 1H), 7.22 (dd, J = 8.3, 6.0 Hz, 1H), 7.16 – 7.08 (m, 2H), 5.25 (d, J = 4.2 Hz, 1H), 4.86 – 4.68 (m, 1H), 4.14 (s, 3H), 4.00 (q, J = 7.2 Hz, 2H), 3.72 (s, 2H), 1.27 (t, J = 7.3 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H). MS (ESI, m/z): 330.20 (M + H)⁺.

[00549] In another example, a similar procedure was run in a 0.5:2 biphasic mixture of toluene and water (2.5 vol.) with a catalystic amount (e.g. 0.002 mol equiv.) Pd(Amphos)C12 (instead of 0.04 mol equiv. of PdidppfhCE) used as the catalyst. Potassium phosphate (K3PO4 3 H2O) substituted potassium carbonate (K2CO3) 3.0 mol equiv. as the base, and the amount of Compound 7 employed was 1.02 mol equiv. The improved process was conducted at 50 °C. At the end of the reaction, the organic layer was fdtered and treated with activated carbon and concentrated, and the final material was crystallized from toluene/heptane/water to give Compound 5 in 92% yield and 99.9% purity.

[00550] Synthesis of Compound 3. To a 50 L reactor was charged dichloromethane (11.25 L), Compound 5 (750 g, >99.9%/220 nm chiral purity) and triethylamine (920.0 g) at r t. (20~30°C). The resulting mixture was refilled with nitrogen and cooled to 0°C. To it was added a solution of MS2O (793.0 g) in dichloromethane (3.75 L) drop-wise over 45 min while keeping the temperature at 0~5°C. The reaction mixture was stirred at 0~5°C for 1 h under nitrogen. The reaction mixture was quenched with cooled water (7.5 L) at 5~15°C and separated. The organic phase was washed with cooled water (3.75 L) and separated. The organic phase was dried over anhydrous Na2SC>4, filtered and concentrated at 25~30°C in vacuum to around 2 vol., then switched to n-heptane (2.25 L) and concentrated at 25~30°C in vacuum to around 2 vol. of Compound 3 in n-heptane. n-heptane /EtOAc (3.0 L, lOv/lv) was added to the above mixture and the mixture was slurried for 1 h at 0~10°C under nitrogen and filtered. The filter cake was washed with n-heptane (1.5 L), dried in vacuum at 25~30°C for 5 h to afford Compound 3 as an off-white solid (845 g, 98.9 w%, 99.98%/220 nm chiral purity, 91% yield). H NMR (400 MHz, CDC13) 5 7.35 (dd, J = 9.6, 2.5 Hz, 1H), 7.24 – 7.18 (m, 2H), 7.12 (s, 1H), 7.08 (td, J = 8.3, 2.6 Hz, 1H), 5.78 (d, J = 6.4 Hz, 1H), 4.21 (s, 3H), 4.05 (q, J = 7.3 Hz, 2H), 3.90 – 3.76 (m, 2H), 2.78 (s, 3H), 1.58 (d, J = 6.5 Hz, 3H), 1.40 (t, J = 7.3 Hz, 3H). MS (ESI, m/z): 408.20 (M + H)⁺.

[00551] In another example, triethylamine base (1.3 mol equiv.), MS2O (1.2 mol equiv.), and dichloromethane solvent (10 vol) were used. The reaction mixture was quenched with aqueous sodium bicarbonate to remove excess MS2O, and crystallization from dichloromenthane/hexane results in 98% yield with 100% purity of Compound 3.

[00552] Synthesis of Compound 2. A 20 L reactor was refilled with nitrogen, then charged with DMA (12.6 L) at r.t. (20~25°C) To the reactor was charged Compound 4 (390.0 g) and Compound 3 (840.0 g, 99.98%/220 nm chiral purity) in one portion at 20~25°C through a dry nitrogen flow. The reaction mixture was heated to 35°C over 15 min and stirred for 5-10 min at 35~40°C to get a clear solution. To the reaction mixture was charged powder K3PO4 (875.0 g) in one portion at 35~45°C. After complete addition, the resulting mixture was heated to 60°C over 20 min and stirred at 58~63°C for 1.5 h through a dry nitrogen flow. The reaction mixture was cooled to 25~30°C, filtered through a celite pad (5 cm, 1.5 kg) and rinsed the filter cake with EtOAc (2 L, 2-3 vol.). The filtrate was poured into water (16.8 L, 20 vol.) at 0-10°C, extracted with EtOAc (10 L, 12 vol.) and separated. The aqueous phase was extracted with EtOAc (5 L, 6 vol.). The combined organic phases were washed with water (5 L*3, 6 vol. *3), concentrated at 50°C in vacuum to afford crude product as a gray solid (956 g). The crude product was dissolved in EtOAc (950 mL, 1 vol. relative to crude product) at 35~40°C, then was added dropwise n-heptane (950 mL, 1 vol. relative to crude product) at 30~40°C over 20 min. The resulting mixture was cooled to 20~25°C over 30 min and stirred for 1 h at 30-40°C. Some solids came out slowly and n-heptane (1.9 L, 2 vol. relative to crude product) was added dropwise to the slurry mixture at 20~25°C over 30 min. The precipitates were stirred at 15~20°C for 3 h and filtered. The filter cake was washed with n-heptane (1.5 L) and dried in oven at 45-50°C for 16 h to afford Compound 2 as a pale-yellow solid (743 g, 98.6%/220 nm, 96.9 w%, 99.98%/220 nm chiral purity, 0.48%KF, 72% yield). H NMR (400 MHz, DMSO) 5 7.54 (dd, J = 10.2, 2.7 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.42 (s, 1H), 7.31 (dd, J = 8.5, 5.8 Hz, 1H), 7.22 (td, J = 8.4, 2.7 Hz, 1H), 7.17 (s, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.14 (s, 2H), 5.47 (q, J = 6.0 Hz, 1H), 4.22 (s, 3H), 4.02 (q, J = 7.3 Hz, 2H), 3.78 (q, J = 16.1 Hz, 2H), 1.40 (d, J = 6.3 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H). MS (ESI, m/z): 500.30 (M + H)⁺.

[00553] In another example, a process was developed where Compound 4 (1.1 mol equiv. to Compound 3) was used. Potassium phosphate base (K2PO4, 4. 1 mol equiv.) and DMA (16 vol.) were substituted with cesium carbonate (CS2CO3, 2.2 mol equiv.) and NMP (5.6 vol.). The reaction was carried out at 20~30°C. Following completion of the reaction, the crude product was precipitated with water. The material was then dissolved in ethyl acetate, washed with water, and treated with activated carbon. The product is subsequently crystallized from toluene/ethyl acetate/heptane to give Compound 2 in 80% yield and 99.9% purity.

[00554] Synthesis of Compound 1. To a reactor was charged t-AmOH (20 vol.), Compound 2 (700.0 g, 99.99% chiral purity) and potassium pivalate (588.0 g). The reaction mixture was fully refilled with nitrogen. To the reaction mixture was added cataCXium A (120.4 g) and Pd(OAc)2 (37.8 g) at r.t. under nitrogen. The resulting mixture was heated to 100°C and stirred for 18 h under nitrogen. The reaction mixture was cooled to 30°C , filtered through a celite pad and washed the filter cake with EtOAc (3 vol.). The filtrate was washed with water (5 vol. *2) and separated. The upper organic phase was concentrated in vacuum to afford a brown oil. The oil was dissolved in EtOAc (27 L) then added 5w% aqueous L-cysteine (0.98 kg in 18.6 kg water), stirred for 1 h at 40~45°C and separated. The organic phase was washed with water (6.75 L) and separated. 5w% aqueous L-cysteine (0.98 kg in 18.6 kg water) was charged to the above organic phase, stirred for 1 h at 40~45°C and separated. The organic phase was washed with water (6.75 L.) and separated. The organic phase was concentrated in vacuum at 45~50°C to afford a brown solid (1.12 kg). The crude solid (1.12 kg) was further purified by silica gel chromatography eluted with EtOAc/DCM (dry loading, 3X, 100-200 meshes, EtOAc:DCM=l : 1) to afford a pale-yellow solid ( 1.02 kg). The solid was dissolved in EtOAc (600 mL, 2 vol.) at 50~60°C, then was added n-heptane (1.8 L, 6 vol.) dropwise over 50 min at 50~60°C. A large of solids came out during addition. The resulting slurry was cooled to 15~20°C over 50 min and stirred for 30 min at 15~20°C. The slurry was concentrated in vacuum at 45~50°C to 2-3 vol. mixture, n-heptane (1.2 L, 4 vol.) was added to the

above mixture (2-3 vol.), concentrated in vacuum at 45~50°C to 2-3 vol. mixture. The mixture was cooled to 10~15°C over 2 h, stirred at 10~15°C for 1 h and filtered. The filtered cake was rinsed with n-heptane (600 mb) and dried in vacuum at 50°C for 20 h to afford Form 1 of Compound 1 as an off-white solid (280 g, 99.0%). H NMR (400 MHz, DMSO) 57.79 (dd, J = 10.3, 2.2 Hz, 1H), 7.58 (s, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.24 – 7.16 (m, 2H), 6.13 (s, 2H), 6.08 (d, J = 1.7 Hz, 1H), 5.31 – 5.23 (m, 1H), 4.16 (s, 3H), 4.05 – 3.94 (m, 2H), 3.78 (d, J = 15.6 Hz, 1H), 2.98 (d, J = 15.5 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H). MS (ESI, m/z): 420.30 (M + H)⁺. XRPD (FIG. 1), TG/DTA (FIG. 2), DSC (FIG. 3), DVS (FIG. 4), and FT-IR (FIG. 5) results for a sample of Form 1 were obtained.

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References

“JIDEYTRO™ (zidesamtinib) for Patients”. Jideytro. 2026-02-05. Retrieved 2026-07-23.
“Jideytro: Uses, Dosage, Side Effects & Warnings”. Drugs.com. Retrieved 2026-07-23.
“Nuvalent Announces FDA Acceptance of New Drug Application for Zidesamtinib for the Treatment of TKI Pre-treated Patients with Advanced ROS1-positive NSCLC”. Nuvalent Investors. Retrieved 2026-07-23.
Wespiser M, Gille R, Pérol M (2026). “ROS1-positive non-small cell lung cancer: from genomics to treatment decisions”. Frontiers in Oncology. 16 1739598. doi:10.3389/fonc.2026.1739598. PMC 12907153. PMID 41704605.
“New FDA Drug Approvals for 2026”. Drugs.com. Retrieved 2026-07-23.
Center for Drug Evaluation and Research (2026-07-22). “Novel Drug Approvals for 2026”. FDA.

Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant MutationsPublication Name:Molecular Cancer TherapeuticsPublication Date:2025-05-09PMCID:PMC12214885PMID:40299789DOI:10.1158/1535-7163.mct-25-0025
Targeting Solvent-Front Mutations for Kinase Drug Discovery: From Structural Basis to Design StrategiesPublication Name:Journal of Medicinal ChemistryPublication Date:2024-08-15PMID:39143914DOI:10.1021/acs.jmedchem.4c00361
NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance MutationsPublication Name:Cancer DiscoveryPublication Date:2022-12-13PMCID:PMC9975673PMID:36511802DOI:10.1158/2159-8290.cd-22-0968
Electron transport by C-type cytochromes. I. The reaction of horse heart cytochrome c with anionic reductantsPublication Name:Biophysics of structure and mechanismPublication Date:1975-02-19PMID:10021DOI:10.1007/bf00539772

PAT

Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compoundsPublication Number:WO-2023056405-A1Priority Date:2021-10-01
Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compoundsPublication Number:US-12043626-B2Priority Date:2021-10-01Grant Date:2024-07-23
Methods of treating solid tumor using heteroaromatic macrocyclic ether compoundsPublication Number:US-2024398768-A1Priority Date:2021-10-01
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number:US-12054498-B2Priority Date:2020-05-05Grant Date:2024-08-06
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number:US-2023107663-A1Priority Date:2020-05-05
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number:US-11542278-B1Priority Date:2020-05-05Grant Date:2023-01-03
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number:WO-2021226208-A2Priority Date:2020-05-05
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number:US-2024352037-A1Priority Date:2020-05-05


Clinical data
Pronunciation	jih-DAY-troh^[1]^[2]
Trade names	Jideytro
Other names	NUV-520; NVL 520
AHFS/Drugs.com	jideytro
Routes of administration	By mouth
Drug class	Tyrosine kinase inhibitor
Legal status
Legal status	US: ℞-only
Identifiers
IUPAC name
CAS Number	2739829-00-4
PubChem CID	166560233
IUPHAR/BPS	12392
DrugBank	DB21623
ChemSpider	128922073
UNII	MX5KQV5XHC
KEGG	D12899
ChEBI	CHEBI:747901
ChEMBL	ChEMBL5314497
Chemical and physical data
Formula	C₂₂H₂₂FN₇O
Molar mass	419.464 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

////////zidesamtinib, anax labs, CANCER, FDA 2026, APPROVALS 2026, Jideytro, NVL-520, NUV-520, NU-520, NVL 520, NUV 520, NU 520, MX5KQV5XHC

Lonitoclax

June 27, 2026 2:30 am / Leave a comment

Lonitoclax

CAS 2952589-57-8

MF C43H45ClN4O5 MW733.3 g/mol

5-[5-chloro-2-[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-N-(4-hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethylpyrrole-3-carboxamide

5-(5-chloro-2-{(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl}phenyl)-N-(4-
hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide
B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, ZE50-0134, ZE50 0134, Lomond Therapeutics, CANCER, 76NBC3X6A3

Lonitoclax (also known as ZE50-0134) is an investigational, next-generation, orally administered B-cell lymphoma 2 (Bcl-2) inhibitor being developed for the treatment of hematologic malignancies like Acute Myeloid Leukemia (AML) and Chronic Lymphocytic Leukemia (CLL). Developed by Lomond Therapeutics, the drug is engineered as a highly selective option to improve upon existing first-generation Bcl-2 inhibitors like venetoclax.

Mechanism and Advantages Over Venetoclax

Unlike earlier therapies, lonitoclax features a unique binding mode and a structurally distinct chemotype. Its design yields several pharmacology advantages:

Higher Selectivity: It binds tightly to Bcl-2 while demonstrating exceptional selectivity over Bcl-xL, which helps lower hematologic toxicities.
Limited Immune Suppression: In preclinical data, lonitoclax spared healthy non-malignant immune cells (B cells, CD8 T cells, and NK cells), a major shift from the immunosuppressive profile of venetoclax.
Reduced Drug Interaction & Accumulation: It features a shorter half-life (~9–10 hours) and minimal CYP3A4 (P4503A4) inhibition. This prevents the drug from building up dangerously and mitigates the risk of Tumor Lysis Syndrome (TLS), potentially enabling safer outpatient treatments.

Clinical Development Status

Lonitoclax is currently advancing through early-phase clinical trials:

IND Clearances: The U.S. FDA cleared Investigational New Drug (IND) applications evaluating lonitoclax for CLL/SLL and as a combination treatment for relapsed or refractory AML.
Healthy Volunteer Studies: Phase 1 single ascending dose (SAD) studies in healthy adults confirmed that the drug is well tolerated with linear pharmacokinetics and no significant safety issues. Target engagement was confirmed through plasma apoptosis assays.
Combination Trials: Active Phase 1b multicenter trials are underway evaluating the safety, efficacy, and synergy of lonitoclax when combined with hypomethylating agents like azacitidine in AML patients.

SYN

US20250115577, Compound 7

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023129553&_cid=P11-MQVQMH-93381-1

ADVERISEMENT

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References

Bcl-2 inhibitorsPublication Number: WO-2023129553-A1Priority Date: 2021-12-29
BCL-2 InhibitorsPublication Number: US-2025115577-A1Priority Date: 2021-12-29
Bcl-2 inhibitorsPublication Number: EP-4457223-A1Priority Date: 2021-12-29

///////Lonitoclax, ANAX LABS, B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, ZE50-0134, ZE50 0134, Lomond Therapeutics, CANCER, 76NBC3X6A3

Imlunestrant

October 1, 2025 2:39 am / Leave a comment

Imlunestrant

CAS 2408840-26-4

as tosylate: 2408840-41-3

(5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol

(5r)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-8-(trifluoromethyl)-5h-(1)benzopyrano(4,3-c)quinolin-2-ol
5h-(1)benzopyrano(4,3-c)quinolin-2-ol, 5-(4-(2-(3-(fluoromethyl)-1-azetidinyl)ethoxy)phenyl)-8-(trifluoromethyl)-, (5r)-

MF C₂₉H₂₄F₄N₂O₃ MW 524.516

FDA 9/25/2025, Inluriyo, LY3484356, LY-3484356, To treat estrogen receptor-positive, human epidermal growth factor receptor 2-negative, estrogen receptor-1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy

Imlunestrant, sold under the brand name Inluriyo, is an anti-cancer medication used for the treatment of breast cancer.^[1] It is an is an estrogen receptor antagonist.^[1] It is used as the salt, imlunestrant tosylate.^[2] It is taken by mouth.^[1] It was developed by Eli Lilly and Company.^[2]

The most common adverse events and laboratory abnormalities include decreased hemoglobin, musculoskeletal pain, decreased calcium, decreased neutrophils, increased AST, fatigue, diarrhea, increased ALT, increased triglycerides, nausea, decreased platelets, constipation, increased cholesterol, and abdominal pain.^[2]

Imlunestrant was approved for medical use in the United States in September 2025.^[2]

SYN

Imlunestrant with or without Abemaciclib in Advanced Breast CancerPublication Name: The New England journal of medicinePublication Date: 2025-03-27PMID: 39660834DOI: 10.1056/nejmoa2410858
Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and ChallengesPublication Name: Journal of Medicinal ChemistryPublication Date: 2023-06-28PMID: 37377342DOI: 10.1021/acs.jmedchem.3c00136
Novel endocrine therapies: What is next in estrogen receptor positive, HER2 negative breast cancer?Publication Name: Cancer Treatment ReviewsPublication Date: 2023-06PMID: 37146385DOI: 10.1016/j.ctrv.2023.102569
Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical PerspectivePublication Name: International Journal of Molecular SciencesPublication Date: 2021-07-22PMCID: PMC8345926PMID: 34360578DOI: 10.3390/ijms22157812

PAT

US10654866,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US281655517&_cid=P12-MG7DCV-14904-1

Example 1A

5-(4-{2-[3-(Fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol, Isomer 1Separate the two enantiomers of 5-(4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol by chiral SFC with the following conditions: Column: LUX® Cellulose-1, 5×25 cm; eluting with a mobile phase of 30% iPrOH (with 0.5% DMEA) in CO ₂; column temperature: 40° C.; flow rate: 300 g/minute; UV detection wavelength: 270 nm to give Example 1A as the first eluting enantiomer (Isomer 1). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 1 by chiral analytical SFC, >99% ee, t _(R): 1.30 minutes; column: CHIRALCEL® OD-H, 4.6×150 mm; eluting with a mobile phase of 30% MeOH (0.2% IPA) in CO ₂; column temperature: 40° C.; flow rate: 5 mL/minute; UV detection wavelength: 225 nm. Isolate the title compound of Example 1B to give the second eluting enantiomer (Isomer 2). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 2 by chiral analytical SFC, 98% ee, t _(R): 2.03 minutes; column: CHIRALCEL® OD-H, 4.6×150 mm; eluting with a mobile phase of 30% MeOH (0.2% IPA) in CO ₂; column temperature: 40° C.; flow rate: 5 mL/minute; UV detection wavelength: 225 nm.

Alternate Preparation Example 1B

Crystalline 5-(4-{2-[3-(Fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol, Isomer 2

Stir 5-(4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid, Isomer 2 (23.8 g, 0.034 mol) in water (250 mL) at 1000 rpm. Add NaOH (76 μL) and stir the solution for 2 hours. Add DCM (600 mL). Separate the mixture, dry the DCM extract with magnesium sulfate, filter the material through a syringe filter (0.45 μm), and concentrate to dryness. Allow the material to sit under a N ₂stream over a weekend. Add 1:1 EtOH/water (80 mL) and stir the mixture with sonication. Collect a tan solid by filtration on a nylon membrane to give the title compound (10.47 g, 0.02 mol, 59%).

PAT

WO2020014435

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020014435&_cid=P12-MG7DHN-18354-1

EXAMPLE 1

Racemic 5-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [ 1 ]benzopyrano[4,3 -c]quinolin-2-ol

Cool a solution of (4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl){3-[2-fluoro-4-(trifluoromethyl)phenyl]-7-hydroxyquinolin-4-yl}methanone (5.27 g, 9.71 mmol) in 1,4-dioxane (100 mL) to 5 °C. Add lithium triethylborohydride (1 M in THF, 30.0 mL, 30.0 mmol). Remove the cooling bath and stir for 1.5 hours at room temperature. Quench the mixture with water. Add saturated NH₄Cl solution and EtOAc. Separate the layers and extract the aqueous layer with EtOAc. Combine the organic extracts, dry over anhydrous MgS0₄, filter, and concentrate the filtrate. Dissolve the crude residue in THF (100 mL).

Add sodium hydride (60% in mineral oil, 1.94 g, 48.5 mmol). Reflux the solution for 1.5 hours. Add additional sodium hydride (60% in mineral oil, 1.94 g, 48.5 mmol), then reflux for an additional 30 minutes. Cool the solution to room temperature and quench with water. Add EtOAc and saturated NH₄Cl solution. Separate the layers and extract the aqueous layer with EtOAc. Combine the organic extract, dry over anhydrous MgS0₄, filter, and concentrate the filtrate. Purify the residue by silica gel column chromatography eluting with a gradient of 5-7% MeOH in DCM to give the title compound (3.70 g, 72%) as a light yellow foam. ES/MS (m/z): 525.2 (M+H).

Prepare the following compounds in a manner essentially analogous to the method of Example 1, with the following variations in procedure. For the reduction, use 3 to 5 equivalents of lithium triethylborohydride with reaction times from 30 minutes to one hour and drying of the organic layers over magnesium sulfate or sodium sulfate. ETse the crude residue directly or purify by silica gel column chromatography eluting with a gradient of 0-5-7.5-10% MeOH in DCM before cyclization. Complete the cyclization by refluxing in THF for up to 16 hours, or in DMF, from 2 hours at room temperature for Ex 2, to 2 hours at 85 °C for Ex 8. Extract with DCM or EtOAc and dry organic layers over magnesium sulfate or sodium sulfate. Purify by silica gel column chromatography using up to 10% (MeOH or 7 M ammoniated MeOH) in DCM (Ex 2: gradient 0-10% MeOH in DCM; Ex 5: gradient 4-10% 7 M ammoniated MeOH in DCM; Ex 8: gradient 5-7.5% 7 M ammoniated MeOH in DCM) or by high pH reversed phase HPLC as noted.

EXAMPLE 1A

-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [l]benzopyrano[4,3-c]quinolin-2-ol, Isomer 1

and

EXAMPLE 1B

5-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [l]benzopyrano[4,3-c]quinolin-2-ol, Isomer 2

Separate the two enantiomers of 5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[l]benzopyrano[4,3-c]quinolin-2-ol by chiral SFC with the following conditions: Column: LUX® Cellulose-l, 5 x 25 cm; eluting with a mobile phase of 30% iPrOH (with 0.5% DMEA) in C0₂; column temperature: 40 °C; flow rate: 300 g/minute; UV detection wavelength: 270 nm to give Example 1 A as the first eluting enantiomer (Isomer 1). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 1 by chiral analytical SFC, >99% ee, /(R>: 1.30 minutes; column: CHFRALCEL® OD-H, 4.6 x 150 mm; eluting with a mobile phase of 30% MeOH (0.2% IP A) in C0₂; column temperature: 40 °C; flow rate: 5 mL/minute; UV detection wavelength: 225 nm. Isolate the title compound of Example 1B to give the second eluting enantiomer (Isomer 2). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 2 by chiral analytical SFC, 98% ee, /_(R>: 2.03 minutes; column: CHIRALCEL® OD-H, 4.6 x 150 mm; eluting with a mobile phase of 30% MeOH (0.2% IP A) in C0₂; column temperature: 40 °C; flow rate: 5 mL/minute; UV detection wavelength: 225 nm.

Alternate Preparation EXAMPLE 1B

Crystalline 5-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [l]benzopyrano[4,3-c]quinolin-2-ol, Isomer 2

Stir 5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[l]benzopyrano[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid, Isomer 2 (23.8 g, 0.034 mol) in water (250 mL) at 1000 rpm. Add NaOH (76 pL) and stir the solution for 2 hours. Add DCM (600 mL). Separate the mixture, dry the DCM extract with magnesium sulfate, filter the material through a syringe filter (0.45 pm), and concentrate to dryness. Allow the material to sit under a N₂ stream over a weekend. Add 1 : 1 EtOH/water (80 mL) and stir the mixture with sonication. Collect a tan solid by filtration on a nylon membrane to give the title compound (10.47 g, 0.02 mol, 59%).

PAT

Selective estrogen receptor degradersPublication Number: US-2023234960-A1Priority Date: 2018-07-12
Selective estrogen receptor degraderPublication Number: CN-112424205-BPriority Date: 2018-07-12Grant Date: 2023-10-31
selective estrogen receptor degraderPublication Number: CN-117379428-APriority Date: 2018-07-12
Selective estrogen receptor degradersPublication Number: US-11993608-B2Priority Date: 2018-07-12Grant Date: 2024-05-28
Selective estrogen receptor degradersPublication Number: US-12128040-B2Priority Date: 2018-07-12Grant Date: 2024-10-29

PAT

https://patents.google.com/patent/US11926634B2/en

Selective estrogen receptor degraders (SERDs) bind to the estrogen receptor (ER) and downregulate ER-mediated transcriptional activity. The degradation and downregulation caused by SERDs can be useful in the treatment of various proliferative immune mediated disorders, cell proliferation disorders, including cancers such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer as well as mutations due to emerging resistance. Some small molecule examples of SERDs have been disclosed in the literature (see, e.g., WO2005073204, WO2014205136, and WO2016097071). Nonetheless, there is a need for new SERDs to treat ER-positive cancers, such as breast cancer, gastric cancer, and/or lung cancer.

As described in U.S. Pat. No. 10,654,866 (the ‘866 patent) a series of SERDs of the following formula have been discovered, along with pharmaceutically acceptable salts thereof:

wherein one of R₁and R₂are independently Cl, F, —CF₃, or —CH₃, and the other is H.

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Clinical data

Trade names	Inluriyo
Other names	LY3484356, LY-3484356
AHFS/Drugs.com	Inluriyo
License data	US DailyMed: Imlunestrant
Routes of administration	By mouth
Drug class	Estrogen receptor antagonist
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
IUPAC name
CAS Number	2408840-26-4as tosylate: 2408840-41-3
PubChem CID	146603228
DrugBank	DB19043
ChemSpider	115010421
UNII	9CXQ3PF69Uas tosylate: F7UDT90EW5
KEGG	D12216as tosylate: D12217
ChEMBL	ChEMBL5095183
Chemical and physical data
Formula	C₂₉H₂₄F₄N₂O₃
Molar mass	524.516 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

References

https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218881s000lbl.pdf
“FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer”. U.S. Food and Drug Administration (FDA). 25 September 2025. Retrieved 27 September 2025. This article incorporates text from this source, which is in the public domain.
“U.S. FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer” (Press release). Eli Lilly. 25 September 2025. Retrieved 27 September 2025 – via PR Newswire.
World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.

External links

Clinical trial number NCT04975308 for “A Study of Imlunestrant, Investigator’s Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3)” at ClinicalTrials.gov

/////////Imlunestrant, FDA 2025, APPROVALS 2025, Inluriyo, CANCER, LY3484356, LY 3484356, 9CXQ3PF69U

Envonalkib

August 17, 2025 6:02 am / Leave a comment

Envonalkib

CAS 1621519-26-3
QB7KTQ7VW9
5-((1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((2S)-2-methyl-1-piperazinyl)(3,3′-bipyridin)-6-amine
506.4 g/mol, C₂₄H₂₆Cl₂FN₅O₂

TQ-B3139, Chia Tai Tianqing, Anluoqing, cancer

ENVONALKIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.

SYN

WO2014117718

https://patentscope.wipo.int/search/en/WO2014117718

Example 27: 5-[(2,6-dichloro-3-fluorophenyl)ethoxy-4′-methoxy-6′ …

Step 1: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methyl-4-tert-butoxycarbonylpiperazin-1-yl)-3,3′-bipyridin-6-amine

To dioxane (10 mL) and water (1.5 mL) were added tert-butyl (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperidin-1-carboxylate (106 mg, 0.275 mmol), (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-aminopyridine (140 mg, 0.33 mmol), tetrakis(triphenylphosphine)palladium (32 mg, 0.0275 mmol) and cesium carbonate (179 mg, 0.55 mmol), the atmosphere was replaced with nitrogen, and the reaction was carried out at 100 ° C. overnight. After cooling, the mixture was separated by silica gel column chromatography to give 5-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6-(5-(2-methyl-4-tert-butoxycarbonylpiperidin-1-yl)-3,3′-bipyridin-6-amine) (70 mg) in a yield of 42%. MS m/z [ESI]: 606.2 [M+1].

Step 2: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-3,3′-bipyridin-6-amine

To a stirred dichloromethane solution (10 mL) of 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methyl-4-tert-butoxycarbonylpiperidin-1-yl)-3,3′-bipyridin-6-amine (67 mg, 0.11 mmol) was added trifluoroacetic acid (1 mL) and stirred for 1 hour. The pH was adjusted to greater than 13 with sodium hydroxide solution, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated and purified by column chromatography (with dichloromethane:methanol = 8:1 as eluent) to give 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperidin-1-yl)-3,3′-bipyridin-6-amine (30 mg). Yield: 55%, MS m/z [ESI]: 506.1[M+1]. 1H-NM (400 MHz, CDC1 ₃ ):5= 7.94(1H, s), 7.71(1H, s), 7.28-7.32(lH, m), 7.07(1H, t, J=8.4Hz), 6.97(1H, s), 6.04-6.13(2H, m), 4.86 (2H _: s), 4.57-4.59(lH, m), 4.03 (1H, d, J=14Hz), 3.76(3H, s), 3.07-3.33(4H, m), 2.88-3.00(lH, m), 1.84(3H, d, J=6.8Hz), 1.34 (3H, d, J=6.8Hz).

SYN

CN107949560

SYN

US9708295, 27

https://patentscope.wipo.int/search/en/detail.jsf?docId=US154015806&_cid=P11-MEF9W1-27198-1

Example 27: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine

General Synthetic Methods:

Step 1: (S)-tert-butyl 4-(6′-amino-5′-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4-methoxy-[3,3′-bipyridin]-6-yl)-3-methylpiperazine-1-carboxylate

(S)-tert-butyl 4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylate (106 mg, 0.275 mmol), (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-am ine (140 mg, 0.33 mmol), Pd(PPh ₃) ₄(32 mg, 0.0275 mmol), and Cs ₂CO ₃(179 mg, 0.55 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1.5 mL), purged with nitrogen, and the resultant was stirred at 100° C. overnight. After the resultant was cooled, it was purified by silica gel column chromatography to give (S)-tert-butyl 4-(6′-amino-5′-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4-methoxy-[3,3′-bipyridin]-6-yl)-3-methylpiperazine-1-carboxylate (70 mg, 42% yield). MS m/z [ESI]: 606.2 [M+1].

Step 2: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine

To a stirred solution of (S)-tert-butyl 4-(6′-amino-5′-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4-methoxy-[3,3′-bipyridin]-6-yl)-3-methylpiperazine-1-carboxylate (67 mg, 0.11 mmol) in CH ₂Cl ₂(10 mL), trifluoroacetate (1 mL) was added, and the mixture was then stirred for 1 hour. Concentrated NaOH was added to adjust the pH value to greater than 13, and the resultant was extracted by CH ₂Cl ₂. The extract was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica gel column chromatography (CH ₂Cl ₂: methanol=8:1) to give 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine (55% yield). MS m/z[ESI]: 506.1 [M+1]. ¹H-NMR (400 MHz, CDCl ₃): δ=7.94 (1H, s), 7.71 (1H, s), 7.28-7.32 (1H, m), 7.07 (1H, t, J=8.4 Hz), 6.97 (1H, s), 6.04-6.13 (2H, m), 4.86 (2H, s), 4.57-4.59 (1H, m), 4.03 (1H, d, J=14 Hz), 3.76 (3H, s), 3.07-3.33 (4H, m), 2.88-3.00 (1H, m), 1.84 (3H, d, J=6.8 Hz), 1.34 (3H, d, J=6.8 Hz).

SYN

European Journal of Medicinal Chemistry 291 (2025) 117643

Envonalkib, also known as TQ-B3139, is a novel small-molecule TKI, developed by Chia Tai Tianqing Pharmaceutical Group. It targets ALK, ROS1, and c-Met kinases, exhibiting potent antitumor activity against cancers harboring these genetic alterations. In 2024, the NMPA approved Envonalkib under the brand name Anluoqing for the treatment of adult patients with ALK-positive locally advanced or metastatic NSCLC who have not received prior ALK inhibitor therapy [24]. Envonalkib exerts its therapeutic effects through selective inhibition of the kinase activities of ALK, ROS1, and c-Met, thereby interrupting the downstream signaling pathways that are crucial for tumor cell proliferation and survival [25]. The inhibition of these targets results in cell cycle arrest and apoptosis in cancer cells。The clinical efficacy of Envonalkib was evidenced in a Phase III randomized, open-label, multicenter clinical trial (NCT04009317), which compared Envonalkib with crizotinib in treatment-naïve patients with ALK-positive advanced NSCLC [25,26]. In the reported study, Envonalkib demonstrated a me dian PFS of 24.87 months, which was markedly superior to the 11.60 months achieved with crizotinib (hazard ratio [HR] = 0.47, p < 0.0001). Notably, in patients harboring brain metastases, Envonalkib exhibited a
central nervous system objective response rate (CNS-ORR) of 78.95 %, a substantial improvement over the 23.81 % observed with crizotinib. In terms of safety profile, Envonalkib was generally well-tolerated. Treat ment-related adverse events (TRAEs) of Grade ≥3 were noted in 55.73 % of patients receiving Envonalkib, contrasting with the 42.86 % incidence in the crizotinib cohort. The predominant TRAEs encompassed elevated liver enzymes, neutropenia, and gastrointestinal symptoms, all of which
were amenable to effective management through appropriate support ive care measures. The regulatory approval of Envonalkib thus in troduces a novel therapeutic modality for patients with ALK-positive NSCLC, effectively addressing a significant unmet medical need within this patient population [25].
The synthesis of Envonalkib, illustrated in Scheme 6, initiates with Mitsunobu coupling of Envo-001 and Envo-002, affording Envo-003 [27]. Sequential reduction and NBS-bromination converts Envo-003 to
Envo-005 via Envo-004. Miyaura borylation of Envo-005 constructs Envo-006, which undergoes Suzuki-Miyaura cross-coupling with Envo-007 followed by deprotection to deliver Envonalkib. In parallel,
Envo-009 reacts with Envo-010 through Buchwald-Hartwig cross coupling to form Envo-011. This intermediate is brominated to produce Envo-007, which is used in the Suzuki-Miyaura coupling with Envo-006

[24] X. Li, Y. Xia, C. Wang, S. Huang, Q. Chu, Efficacy of ALK inhibitors in Asian
patients with ALK inhibitor-naïve advanced ALK-Positive non-small cell lung
cancer: a systematic review and network meta-analysis, Transl. Lung Cancer Res.
13 (2024) 2015–2022.
[25] Y. Yang, J. Min, N. Yang, Q. Yu, Y. Cheng, Y. Zhao, M. Li, H. Chen, S. Ren, J. Zhou,
W. Zhuang, X. Qin, L. Cao, Y. Yu, J. Zhang, J. He, J. Feng, H. Yu, L. Zhang, W. Fang,
Envonalkib versus crizotinib for treatment-naive ALK-Positive non-small cell lung
cancer: a randomized, multicenter, open-label, phase III trial, Signal Transduct
Target Ther 8 (2023) 301.
[26] R. Garcia-Carbonero, A. Carnero, L. Paz-Ares, Inhibition of HSP90 molecular
chaperones: moving into the clinic, Lancet Oncol. 14 (2013) e358–e369.
[27] F. Gong, X. Li, R. Zhao, X. Zhang, X. Xu, X. Liu, D. Xiao, Y. Han, Process for
Preparation of Pyridine Substituted 2-aminopyridine Protein Kinase Inhibitor
Crystal, 2017. CN107949560B.

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New drugs approved by the NMPA in 2024: Synthesis and clinical applicationsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2025-07-05PMID: 40262297DOI: 10.1016/j.ejmech.2025.117643
Efficacy of ALK inhibitors in Asian patients with ALK inhibitor-naïve advanced ALK-positive non-small cell lung cancer: a systematic review and network meta-analysisPublication Name: Translational Lung Cancer ResearchPublication Date: 2024-08-31PMCID: PMC11384493PMID: 39263024DOI: 10.21037/tlcr-24-604
Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trialPublication Name: Signal Transduction and Targeted TherapyPublication Date: 2023-08-14PMCID: PMC10423717PMID: 37574511DOI: 10.1038/s41392-023-01538-w
Pharmacokinetic, pharmacodynamic, and behavioural studies of deschloroketamine in Wistar ratsPublication Name: British Journal of PharmacologyPublication Date: 2021-10-31PMID: 34519023DOI: 10.1111/bph.15680

//////////Envonalkib, china 2024, approvals 2024, TQ-B3139, TQ B3139, Chia Tai Tianqing, Anluoqing, cancer, QB7KTQ7VW9

Befotertinib

August 11, 2025 2:34 am / Leave a comment

Befotertinib

D-0316, 0XT2CPR891

CAS No. : 1835667-63-4, MESYLATE CAS No. 2226167-02-6

2-propenamide, n-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-(2,2,2-trifluoroethyl)-1h-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-(2,2,2-trifluoroethyl)-1h-indol-3-yl)pyrimidin-2-yl)amino)phenyl)prop-2-enamide
N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-[1-(2,2,2-trifluoroethyl)indol-3-yl]pyrimidin-2-yl]amino]phenyl]prop-2-enamide

Molecular Weight	567.61
Formula	C₂₉H₃₂F₃N₇O₂

Befotertinib (D-0316) is an orally active EGFR tyrosine kinase inhibitor. Befotertinib can inhibit the proliferation of tumor cells. Befotertinib can be used in the research of EGFR T790M-positive non-small cell lung cancer (NSCLC).

Befotertinib is an orally available inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. Upon administration, befotertinib specifically binds to and inhibits EGFR T790M, a secondarily acquired resistance mutation, which prevents EGFR-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. Compared to some other EGFR inhibitors, befotertinib may have therapeutic benefits in tumors with T790M-mediated drug resistance. EGFR, a receptor tyrosine kinase that is mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.

PAPER

J. Med. Chem. 2017, 60, 6480−6515.

PATENT

WO 2019218987

https://patentscope.wipo.int/search/en/WO2019218987

Method of Preparation

[0054]

U.S. Publication No. 2017/0355696 A1 describes a method of preparing Compound 4 and various pharmaceutically acceptable salts thereof. The exemplified synthetic process in U. S. Publication No. 2017/0355696 A1 includes a two-step conversion from the aniline compound, corresponding to Compound 1 of this disclosure, into the bismesylate of Compound 4, which has a low yield.

[0055]

As shown herein, representative methods of preparation of Compound 4, or a pharmaceutically acceptable salt, (or alternatively referred to as synthetic methods) , can provide the desired Compound 4, or a pharmaceutically acceptable salt, in improved yield and high purity and can be adapted for large-scale manufacture.

[0056]

In various embodiments, the present invention provides a novel method of preparing Compound 4, or a pharmaceutically acceptable salt thereof. The method typically includes converting a compound of Formula III, or a salt thereof, into compound 4, typically under an elimination reaction condition:

Syn

https://doi.org/10.1021/acs.jmedchem.4c02079
J. Med. Chem. 2025, 68, 2147−2182

Befotertinib (Surmana). Befotertinib (17), an oral, highly selective, third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed by Betta Pharmaceuticals and InventisBio, was approved in China in May 2023 for the second-line treatment of patients
with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) with positive EGFR T790 M mutation who have disease progression on previous EGFR TKI therapy. 140 139 NSCLC
has a high incidence and disease burden in China, which has spurred the development of multiple EGFR TKIs by Chinese companies.
Achromatography-free process route to befotertinib (17) has been reported in the patent literature by researchers at InventisBio (Scheme 29), although details about scale and yields were not provided.
141 142 The reaction sequence closely follows that of osimertinib, a third generation EGFR inhibitor
that was first approved in 2015 and was covered in our previous review.
Osimertinib and befotertinib share a common backbone, differing only in N-substitution on the indole ring.
Friedel−Crafts arylation of 1H-indole with 2,4-dichloropyrimidine (17.1) gave the 3-pyrimidinyl indole 17.2. The trifluoroethyl moiety in indole 17.4 was introduced via Nalkylation of 17.2 with triflate 17.3. This was followed by an SAr reaction with nitroaniline 17.5 to provide amino pyrimidine 17.6. Next, N,N,N′-trimethylethylenediamine (17.7) displaced the electrophilic aryl fluoride in an SNArreaction to generate intermediate 17.8. The acrylamide moiety was installed using a three-step sequence: hydrogenolytic
reduction of the nitro group to the corresponding aniline, acylation with 3-chloropropanoyl chloride, and immediate elimination to the acrylamide. Mesylate salt formation and crystallization furnished befotertinib mesylate (17) in eight steps from 17.1.

(139) Blair, H. A. Befotertinib: first approval. Drugs 2023, 83, 1433−
1437.
(140) Lau, S. C. M.; Ou, S.-H. I. And still they come over troubled
waters: can Asia’s third-generation EGFR tyrosine kinase inhibitors
(Furmonertinib, Aumolertinib, Rezivertinib, Limertinib, Befotertinib,
SH-1028, and Lazertinib) affect global treatment of EGFR+ NSCLC. J.
Thorac. Oncol. 2022, 17, 1144−1154.
(141) Dai, X.; Jiang, Y. Preparation of pyrimidine derivative and its
pharmaceutical salt as EGFR inhibitors for the treatment of cancer and
other diseases. WO 2019218987, 2019.
(142) Flick, A. C.; Ding, H. X.; Leverett, C. A.; Kyne, R. E.; Liu, K. K.
C.; Fink, S. J.; O’Donnell, C. J. Synthetic approaches to the new drugs
approved during 2015. J. Med. Chem. 2017, 60, 6480−6515.

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[1]. Nagasaka M, et, al. Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC. J Thorac Oncol. 2021 May;16(5):740-763. [Content Brief][2]. Blair HA. Befotertinib: First Approval. Drugs. 2023 Oct;83(15):1433-1437. [Content Brief]

/////////Befotertinib, APPROVALS 2023, CHINA 2023, Betta Pharmaceuticals, InventisBio, CANCER, D-0316, D 0316, 0XT2CPR891

Olverembatinib

July 30, 2025 6:29 am / Leave a comment

Olverembatinib

1257628-77-5
3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
HQP1351
4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide
HQP1351 is under investigation in clinical trial NCT03883100 (A Pivotal Study of HQP1351 in Patients of Chronic Myeloid Leukemia in Accelerated Phase With T315I Mutation).
4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide
D-824
GZD824

WeightAverage: 532.571
Monoisotopic: 532.219844002, Chemical FormulaC₂₉H₂₇F₃N₆O

1421783-64-3

Molecular Weight	724.77
Formula	C₃₁H₃₅F₃N₆O₇S₂

Olverembatinib (GZD824) dimesylate is a potent and orally active pan-Bcr-Abl inhibitor. Olverembatinib dimesylate potently inhibits a broad spectrum of Bcr-Abl mutants. Olverembatinib dimesylate strongly inhibits native Bcr-Abl and Bcr-Abl^T315I with IC₅₀s of 0.34 nM and 0.68 nM, respectively. Olverembatinib dimesylate has antitumor activity. Olverembatinib (dimesylate) is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.

Olverembatinib is a BCR-ABL1 tyrosine kinase inhibitor developed by Ascentage Pharma. In 2021, it was approved in China “for the treatment of adult patients with TKI-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP) harbouring the T315I mutation”.^[1][2][3]

SYN

Ren, Xiaomei;Pan, Xiaofen;Zhang, Zhang;Wang, Deping;Lu, Xiaoyun;Li, Yupeng;Wen, Donghai;Long, Huoyou;Luo, Jinfeng;Feng, Yubing;Zhuang, Xiaoxi;Zhang, Fengxiang;Liu, Jianqi;Leng, Fang;Lang, Xingfen;Bai, Yang;She, Miaoqin;Tu, Zhengchao;Pan, Jingxuan;Ding, Ke [Journal of Medicinal Chemistry,2013,vol. 56,# 3,p. 879 – 894]

https://pubs.acs.org/doi/10.1021/jm301581y

PATENT

CN 114163434

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN355399053&_cid=P10-MDPKRT-75688-1

Example

The following examples further illustrate but do not limit the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the inventive concept of the present invention, all of which are included in the scope of protection of the present invention.

The specific conditions not disclosed in the experimental methods of the following examples can be selected according to conventional methods and conditions, or according to the product instructions.

Unless otherwise specified, “room temperature” in the following examples refers to 20°C to 25°C. The term “h” used herein refers to hours.

Example 1

Step 1:

Under nitrogen, N-methylpyrrolidone (137.6 g) was heated to 30-35°C to obtain the compound of Formula 1 (14.4 g, 1.3 eq) and the compound of Formula 2 (19.14 g, 1 eq). Bis(triphenylphosphate)palladium dichloride (0.46 g, 0.01 eq) and cuprous iodide (0.113 g, 0.01 eq) were added sequentially. Triethylamine (9.45 g, 1.5 eq) was then added under nitrogen. The reaction mixture was heated to 65-75°C and maintained at this temperature for 2 hours. The reaction process was monitored by liquid chromatography-mass spectrometry. The reaction was terminated when the content of the compound of Formula 2 was ≤0.1%. After completion of the reaction, the reaction solution was cooled to 35-45°C and N-acetyl-L-cysteine (1 g, 0.1 eq) was added directly. The reaction was stirred for 4-5 hours. The resulting product was cooled to room temperature, precipitated with water, centrifuged, and washed with pure water to obtain a crude filter cake. The crude filter cake was vacuum-dried and then slurried with a mixture of ethyl acetate and n-heptane (5 mL of the mixed solvent, wherein the volume ratio of ethyl acetate to n-heptane was 1:1) at a rate of 5 mL per gram of crude filter cake. The resulting slurry was vacuum-dried to yield the compound of Formula 3 with a yield of 85.97% and a purity of 98.2%.

The NMR data for the compound of Formula 3 are as follows : ¹ H NMR (400 MHz, d-DMSO): δ ppm: 8.93 (1H, d, J = 2.0 Hz); 8.63 (1H, d, J = 2.0 Hz); 8.49 (1H, s); 8.11 (1H, d, J = 2.0 Hz); 7.92 (1H, dd, J = 1.6 Hz; J = 8.0 Hz); 7.52 (1H, d, J = 8.0 Hz); 3.88 (3H, s); 2.59 (3H, s); 1.65 (9H, s).

Step 2:

Under nitrogen, methanol (160 g) and water (50 g) were sequentially added to the compound of formula 3 (20 g, 1.0 eq). The reaction system was stirred at reflux for 18 hours with process control. The resulting product was cooled to room temperature and filtered to obtain a filter cake (no drying required). Recrystallization was performed by adding 10 times the mass of the filter cake in methanol. The resulting mixture was stirred at 60-70°C for 8-10 hours, then cooled to 40-50°C and subjected to a gradient cooling process at a cooling rate of 5°C per 1 to 1.5 hours to slowly form a solid precipitate. The resulting mixture was filtered, the filter cake was washed with methanol, and vacuum dried to obtain the compound of formula 4 in a 91% yield and 99.7% purity.

The NMR data for the compound of Formula 4 are as follows : ¹ H NMR (400 MHz, d-DMSO): δ ppm: 8.73 (1H, d, J = 2.0 Hz); 8.52 (1H, t, J = 2.0 Hz); 8.21 (1H, d, J = 2.0 Hz); 8.06 (1H, s); 7.86 (1H, dd, J1 = 2.0 Hz; J2 = 8.0 Hz); 7.49 (1H, dd, J1 = 1.6 Hz; J2 = 7.6 Hz); 3.86 (3H, s); 2.56 (3H, s).

Step 3:

Under nitrogen, THF (448 mL), compound of formula 4 (29.1 g, 1 eq), and compound of formula 5 (24.6 g, 0.9 eq) were added, stirred, and cooled to -65°C to -60°C. At this temperature, potassium tert-butoxide (19 g x 3) was added in batches every 0.5 h. The reaction process was controlled by liquid phase detection. After 2 hours, the reaction temperature was raised to -5 to 0°C. The reaction solution was washed with purified water, stirred for 0.5-1 hour, washed with brine, and separated to obtain an organic phase. N-acetyl-L-cysteine (11.41 g, 0.7 eq) was added to the organic phase, stirred, washed with brine, neutralized, and concentrated under reduced pressure. The resulting filter cake was washed with purified water and made into a slurry. The resulting product was washed again with purified water and dried under vacuum to obtain compound of formula 6 with a yield of 88.2% and a purity of 98.6%.

The NMR data for the compound of formula 6 are as follows : ¹ H NMR (400 MHz, d-DMSO): δ ppm: 10.53 (1H, s); 8.75 (d, J = 2.0); 8.53 (d, J = 2.4); 8.24 (1H, s); 8.23 (d, J = 2.4); 8.21 (d, J = 1.6); 8.09 (dd, J1 = 1.6; J2 = 8.4); 7.94 (dd, J1 = 2.0; J2 = 8.0); 7.71 (d, J = 8.8); 7.53 (d, J = 8.0); 3.56 (2H, s); 2.59 (3H, s); 2.34-2.35 (8H, m), 2.16 (3H, s).

Its carbon spectrum data are ¹³ C NMR (100 MHz, d-DMSO): δ ppm: 20.38, 45.65, 52.64, 54.67, 57.41, 88.26, 91.86, 111.76, 113.98, 117.19, 122.14, 123.43, 127.35 (q), 124.30 (q), 128.10, 129.89, 130.49, 131.15, 132.02, 132.13, 132.93, 133.66, 138.15, 143.65, 150.55, 164.64.

PATENT

CN 101885722

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN84081329&_cid=P10-MDPKML-68458-1

Example 23

3-((1H-pyrazolo[3,4-b]pyridine-5-substituted)ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-substituted)methyl)3-(trifluoromethyl)phenyl)benzamide (D824)

(3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)m ethyl)-3-(trifluoromethyl)phenyl)benzamide)

The synthesis method is the same as in Example 1.

¹ HNMR (400MHz, d-DMSO), δ13.92 (s, 1H), 10.55 (s, 1H), 8.72 (d, J=2.0Hz, 1H), 8.52 (d, J=2.0Hz, 1H), 8.17 (m, 3H), 8.10 (d, J=8.0Hz, 1H), 7.92 (dd, J=8.0, 2.0Hz, 1H), 7.70 (d, J=8.8Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 3.80 (s, 2H), 3.10 (brs, 8H), 2.71 (s, 3H), 2.57 (s, 3H).

MS(ESI), m/z: 533, (M ⁺ +H ⁺ ).

SYN

Olverembatinib(24) wasdeveloped by Ascentage Pharma as anorally available, third-generation
tyrosinekinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), acute myeloid leukemia, acute lymphoblastic leukemia (ALL), and solid tumors.167 It received its first approval inChina inNovember 2021 and was approved for use in adults with TKI-resistant CML chronicphaseandCML-acceleratephaseharboringtheT315I “gatekeeper” mutation.168 The current mainstay of CML
treatmentiscenteredaroundTKIs;however,resistancetoTKItherapy, often through BCR-ABL1 kinase domain point mutations, remains a challenge for early generation therapies.169Olverembatinibretainsitsefficacybyfunctioningasan ATP-bindingsiteinhibitorofwild-typeBCR-ABL1kinaseand broadly relatedmutants including T315I, which otherwise confers resistance against all first and second generation TKIs.168
Thesynthesisofolverembatinibhasbeenreportedinseveral patents,170−172 aswell as a journal article173 that details the divergentapproachtorelatedanalogues. Inarecentpatent,170 the synthesis of olverembatinib began with a Sonogashira coupling of commercially available alkyne 24.1 with
bromopyridine24.2toaffordester24.3in98%yield(Scheme43). Cleavage of the N-Boc group was accomplished by refluxingcarbamate24.3inaMeOHandwatermixturetogive pyrazole24.4 in91%yield. AfinalKOtBumediatedamide formation with aniline 24.5 resulted in the isolation of
olverembatinib(24) in88%yield.

(167) Dhillon, S. Olverembatinib: First approval. Drugs 2022, 82,
469−475.
(168) Braun, T. P.; Eide, C. A.; Druker, B. J. Response and resistance
to BCR-ABL1-targeted therapies. Cancer Cell 2020, 37, 530−542.
(169) Shoukier, M.; Kubiak, M.; Cortes, J. Review of new-generation
tyrosine kinase inhibitors for chronic myeloid leukemia. Curr. Oncol.
Rep. 2021, 23, 91.
(170) Wen, J.; Feng, J.; Wu, T.; Cai, M.; Teng, S. Preparation
method of alkynyl containing compound and its intermediate. China
Patent CN 114163434, 2022.
(171) Guo, M.; Wen, J.; Teng, S.; Wu, T.; Feng, J. Preparation of
(trifluoromethylphenyl)(pyrazolo[3,4-b]pyridinylethynyl)benzamide
derivative. China Patent CN 113292556, 2021.
(172) Ding, K.; Wang, D.; Pei, D.; Zhang, Z.; Shen, M.; Luo, K.;
Feng, Y. Heterocyclic alkynylbenzene derivatives as cancer cell line
inhibitors and their preparation, pharmaceutical compositions and use
in the treatment of cancer. China Patent CN 101885722, 2010.
(173) Ren, X.; Pan, X.; Zhang, Z.; Wang, D.; Lu, X.; Li, Y.; Wen, D.;
Long, H.; Luo, J.; Feng, Y.; et al. Identification of GZD824 as an
orally bioavailable inhibitor that targets phosphorylated and non
phosphorylated breakpoint cluster region−abelson (Bcr-Abl) kinase
and overcomes clinically acquired mutation-induced resistance against
imatinib. J. Med. Chem. 2013, 56, 879−894.

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References

Dhillon, Sohita (March 2022). “Olverembatinib: First Approval”. Drugs. 82 (4): 469–475. doi:10.1007/s40265-022-01680-9. PMID 35195876. S2CID 247027755.
Jiang, Qian; Li, Zongru; Qin, Yazhen; Li, Weiming; Xu, Na; Liu, Bingcheng; Zhang, Yanli; Meng, Li; Zhu, Huanling; Du, Xin; Chen, Suning; Liang, Yang; Hu, Yu; Liu, Xiaoli; Song, Yongping; Men, Lichuang; Chen, Zi; Niu, Qian; Wang, Hengbang; Lu, Ming; Yang, Dajun; Zhai, Yifan; Huang, Xiaojun (18 August 2022). “Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial”. Journal of Hematology & Oncology. 15 (1): 113. doi:10.1186/s13045-022-01334-z. PMC 9389804. PMID 35982483.
Jiang, Qian; Huang, Xiaojun; Chen, Zi; Niu, Qian; Shi, Dayu; Li, Zongru; Hou, Yue; Hu, Yu; Li, Weiming; Liu, Xiaoli; Xu, Na; Song, Yongping; Zhang, Yanli; Meng, Li; Hong, Zhenya; Liu, Bingcheng; Zeng, Shan; Men, Lichuang; Li, Yan; Chen, Suning; Xue, Mengxing; Zhu, Huanling; Li, He; Du, Xin; Lou, Jin; Zhang, Xiaohan; Liang, Yang; Dai, Yujun; Lu, Ming; Wang, Hengbang; Ji, Jiao; Yue, Changai; Yang, Dajun; Zhai, Yifan (5 November 2020). “Novel BCR-ABL1 Tyrosine Kinase Inhibitor (TKI) HQP1351 (Olverembatinib) Is Efficacious and Well Tolerated in Patients with T315I-Mutated Chronic Myeloid Leukemia (CML): Results of Pivotal (Phase II) Trials”. Blood. 136 (Supplement 1): 50–51. doi:10.1182/blood-2020-142142. S2CID 228875477.

Clinical data

Other names	GZD-824; GZD824
Legal status
Legal status	Investigational
Identifiers
IUPAC name
CAS Number	1257628-77-5
PubChem CID	51038269
IUPHAR/BPS	10630
DrugBank	DB16185
ChemSpider	29395146
UNII	KV1M7Q3CBP
ChEMBL	ChEMBL2316582
CompTox Dashboard (EPA)	DTXSID301352011
Chemical and physical data
Formula	C₂₉H₂₇F₃N₆O
Molar mass	532.571 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

[1]. Ren X, Pan X, Zhang Z, Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib. J Med Chem. 2013 Feb 14;56(3):879-94. [Content Brief]

//////////Olverembatinib, approvals 2021, china 2021, Ascentage Pharma, cancer, HQP1351, HQP 1351, D-824, D 824, KV1M7Q3CBP, GZD824

Sontigidomide

July 18, 2025 2:53 am / Leave a comment

Sontigidomide

CAS 2560577-69-5

Molecular Weight	513.47
Formula	C₂₆H₂₂F₃N₃O₅

N-[[2-(2,6-Dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α-oxo-4-[1-(trifluoromethyl)cyclopropyl]benzeneacetamide

enzeneacetamide, N-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α-oxo-4-[1-(trifluoromethyl)cyclopropyl]-

FDD2NVW84X, Sontigidomida

Sontigidomide (Compound 5) is an antineoplastic compound. Sontigidomide inhibits MOLM-13 cell proliferation more than 80% at 1 μM (3 days).

SCHEME

COUPLER………….

MAIN……….

PATENTS

WO2023070120 BioTheryX, Inc.

PATENT

US20200369679

https://patentscope.wipo.int/search/en/detail.jsf?docId=US311579044&_cid=P20-MD87Y5-18242-1

Example 5

Compound I-5: N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide

Compound I-5 was synthesized as shown in Scheme 5.

To a solution of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 8 (80 mg, 0.258 mmol) in DCM (4 mL) at 0° C. was added TEA (52.2 mg, 0.516 mmol). After stirring for 2 min, 2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetyl chloride 13 (71.3 mg, 0.258 mmol) was added and the mixture was stirred at RT for 2 h. After concentration, the residue was purified using prep-HPLC eluting with ACN/H ₂O (0.1% TFA) from 10% to 95% to afford compound I-5 (16.1 mg) in 12% yield. MS (ESI) m/z: 514.0 [M+H] ⁺; ¹H NMR (400 MHz, DMSO-d ₆) δ 10.98 (s, 1H), 9.57 (t, J=6.0 Hz, 1H), 8.03-8.01 (m, 2H), 7.74-7.48 (m, 7H), 5.13-5.09 (m, 1H), 4.59-4.57 (m, 2H), 4.49-4.31 (m, 2H), 2.95-2.87 (m, 1H), 2.63-2.58 (m, 1H), 2.45-2.38 (m, 1H), 2.03-1.99 (m, 1H), 1.43-1.40 (m, 2H), 1.24-1.21 (m, 2H).

[1]. Kyle W.H. Chan, et al. Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applications. US20200369679.

Ketoamides for treating malignancyPublication Number: WO-2023070120-A1Priority Date: 2021-10-22
Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: US-2020369679-A1Priority Date: 2019-05-24
Compounds targeting proteins and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: WO-2020242960-A1Priority Date: 2019-05-24
Compounds targeting proteins and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: AU-2020283744-A1Priority Date: 2019-05-24
Targeted protein compound, its pharmaceutical composition and therapeutic applicationPublication Number: CN-114502543-APriority Date: 2019-05-24

Compounds targeting proteins and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: EP-3976623-A1Priority Date: 2019-05-24
Protein targeting compounds, pharmaceutical compositions thereof and therapeutic applications thereofPublication Number: KR-20220023343-APriority Date: 2019-05-24
Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: US-11345712-B2Priority Date: 2019-05-24Grant Date: 2022-05-31
Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: US-2022298172-A1Priority Date: 2019-05-24

////////Sontigidomide, FDD2NVW84X, CANCER, Sontigidomida

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Taletrectinib

June 30, 2025 2:49 am / Leave a comment

Taletrectinib

CAS 1505514-27-1

as salt: 1505515-69-4, Taletrectinib adipate

FDA 6/11/2025, Ibtrozi, To treat locally advanced or metastatic ROS1-positive non-small cell lung cancer ALSO CHINA 2024 APPROVED

AB-106, DS-6051a

405.5 g/mol, C₂₃H₂₄FN₅O, UNII-W4141180YD

3-[4-[(2R)-2-aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine

Taletrectinib adipate

WeightAverage: 551.619
Monoisotopic: 551.254397378

Chemical FormulaC₂₉H₃₄FN₅O₅

DS-6051B, CAS 1505515-69-4,
6KLL51GNBG, 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine; hexanedioic acid

Taletrectinib, sold under the brand name Ibtrozi, is an anti-cancer medication used for the treatment of non-small cell lung cancer.^[1]^[2] It is used as the salt, taletrectinib adipate.^[1] Taletrectinib is a kinase inhibitor.^[1] It is taken by mouth.^[1]

Taletrectinib was approved for medical use in the United States in June 2025.^[3]

SYN

US20200062765

https://patentscope.wipo.int/search/en/detail.jsf?docId=US289038418&_cid=P12-MCIHV1-02369-1

Example 1

tert-Butyl [(2R)-1-(4-bromophenoxy)propan-2-yl]carbamate (1)

Under the nitrogen atmosphere, 1-bromo-4-fluorobenzene (100 g, 0.57 mol, 1 equiv.), N-methylpyrrolidone (500 mL), and D-alaninol (51.5 g, 0.69 mol, 1.2 equiv.) were added, and then potassium tert-butoxide (96.1 g, 0.86 mol, 1.5 equiv.) was added thereto at 40° C. or less. The resulting mixture was stirred at an internal temperature of about 65° C. for 3 hours and cooled to 20° C. or less. After that, isopropyl acetate (500 mL) and water (1000 mL) were added thereto, and the resulting mixture was stirred. After standing and separating, the aqueous layer was extracted twice with isopropyl acetate (500 mL), and all the organic layers were combined. The combined organic layer was washed twice with water (500 mL), and the obtained organic layer was concentrated under reduced pressure to 300 mL. The operation of further adding ethanol (1000 mL) thereto and concentrating the obtained mixture under reduced pressure to 300 mL was repeated twice. To this solution, tetrahydrofuran (200 mL) was added, and the resulting mixture was cooled to 5° C. or less. tert-Butyl dicarbonate (162 g, 0.74 mol, 1.3 equiv.) was dissolved in tetrahydrofuran (100 mL), and the resulting solution was added dropwise to the mixture at 6° C. or less over about 2 hours. The resulting mixture was stirred at 5° C. or less for 1 hour, and then raised to about 20° C. and stirred overnight. Ethanol (230 mL) was added thereto, and then water (800 mL) was added dropwise over 1.5 hours. The resulting mixture was stirred at about 50° C. for 1 or more hours, and then gradually cooled to 25° C., and stirred overnight. The precipitated solid was filtered and washed with a mixed solution of ethanol (230 mL) and water (270 mL). The solid was dried under vacuum at an external temperature of 40° C. to obtain the title compound (1) (170 g).

Example 2

6-Fluoroimidazo[1,2-b]pyridazine methanesulfonate (2)

Under the nitrogen atmosphere, benzyltriethylammonium chloride (445 g, 1.95 mol, 1 equiv.) and 6-chloroimidazo[1,2-b]pyridazine (300 g, 1.95 mol, 1 equiv.) (available from Combi-Block or the like) were successively added to dimethyl sulfoxide (1500 mL). Cesium fluoride (534 g, 3.51 mol, 1.8 equiv.) was further added thereto, and then the resulting mixture was stirred at an internal temperature of 79° C. to 81° C. for 4 hours. The mixture was cooled to room temperature, toluene (1500 mL) and sodium bicarbonate (48 g, 0.59 mol, 0.3 equiv.) were added to the mixture, and then water (1500 mL) was added thereto. Acetonitrile (600 mL) was added to the mixture, the resulting mixture was stirred, and then the organic layer and the aqueous layer were separated. Furthermore, the operation of extracting this aqueous layer with a mixed solution of toluene (1500 mL) and acetonitrile (300 mL) was repeated three times, and all the organic layers were combined. The combined organic layer was concentrated under reduced pressure to adjust the liquid volume to 2400 mL. Activated carbon (30 g) moistened with toluene (150 mL) was added thereto. The resulting mixture was stirred around 25° C. for 1 hour, and then filtered and washed with toluene (750 mL). Acetonitrile (900 mL) was added thereto, and then methanesulfonic acid (188 g, 1.95 mol, 1 equiv.) was added dropwise at an internal temperature of 22° C. to 37° C. over 1 hour. The resulting mixture was stirred at 27° C. to 31° C. for 1.5 hours, and then the precipitated solid was filtered and washed with toluene (900 mL). The solid was dried under reduced pressure at an external temperature of 40° C. for 5 hours to obtain the title compound (2) (396.9 g).

Example 3

tert-Butyl {(2R)-1-[4-(6-fluoroimidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate (3)

Under the nitrogen atmosphere, methyl tert-butyl ether (12 L), water (2.6 L), potassium carbonate (691 g, 5.0 mol, 1.1 equiv.), and the compound of the formula (2) (1.17 kg, 5.0 mol, 1.1 equiv.) were successively added. The resulting mixture was stirred at an internal temperature of 19° C. for 5 minutes and allowed to stand, and then the aqueous layer was discharged. The obtained organic layer was concentrated under reduced pressure to adjust the liquid volume to 7.5 L. Diethylene glycol dimethyl ether (7.5 L) was added thereto, and the resulting mixture was concentrated under reduced pressure again to adjust the liquid volume to 8.25 L. To this solution, the compound of the formula (1) (1.5 kg, 4.54 mol, 1 equiv.), tris(2-methylphenyl)phosphine (27.7 g, 0.09 mol, 0.02 equiv.), potassium carbonate (1.26 kg, 9.12 mol), and palladium acetate (20.4 g, 0.09 mol, 0.02 equiv.) were successively added, followed by washing with diethylene glycol dimethyl ether (0.3 L). The resulting mixture was stirred at an internal temperature of 95° C. to 108° C. for 9 hours and then stirred at an internal temperature of 58° C. to 61° C. for 11 hours. Purified water (7.5 L) was added thereto, and the resulting mixture was warmed to an internal temperature of 71° C., and then the aqueous layer was discharged. To the organic layer, 1-methylimidazole (1.5 L) was added, and the resulting mixture was cooled. The mixture was stirred at 25° C. to 30° C. for 40 minutes, and then water (9 L) was intermittently added thereto at an internal temperature of 25° C. to 29° C. over 1.5 hours. The resulting mixture was stirred around 25° C. for 19 hours, and then crystals were filtered and washed with a mixed solution of diethylene glycol dimethyl ether (3 L) and water (3 L) and then with water (3 L). The obtained solid was dried under reduced pressure at an external temperature of 40° C. to obtain the title compound (3) (1.65 kg, 94.1% (gross weight)).

¹HNMR (500 MHz, CDCl ₃): δ=1.32 (d, J=7.0 Hz, 3H), 1.47 (s, 9H), 4.00 (d, J=4.0 Hz, 2H), 4.10 (brs, 1H), 4.80 (brs, 1H), 6.87 (d, J=7.6 Hz, 1H), 7.02-7.08 (m, 2H), 7.92-7.97 (m, 2H), 8.00 (s, 1H), 8.06 (dd, J=7.6, 6.0 Hz, 1H)

Example 4

tert-Butyl {(2R)-1-[4-(6-{[(1R)-1-(3-fluorophenyl)ethyl]amino}imidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate hydrochloride (4)

Under the nitrogen atmosphere, (1R)-1-(3-fluorophenyl)ethanamine (400 g, 2.87 mol, 1 equiv.), trisodium phosphate (471 g, 2.87 mol, 1 equiv.), and the compound of the formula (3) (1.22 kg (net weight: 1.12 kg), 3.16 mol, 1.1 equiv.) were successively added to dimethyl sulfoxide (2.4 L). This mixed solution was warmed, and stirred at an internal temperature of 95° C. to 99° C. for 55 hours. The solution was cooled, and cyclopentyl methyl ether (4 L) and water (8 L) were added thereto at an internal temperature of 24° C. The resulting mixture was warmed to 50° C., and the aqueous layer was discharged. After that, water (4 L) was added to the organic layer remaining, and the aqueous layer was discharged again. The obtained organic layer was concentrated under reduced pressure to adjust the liquid volume to 4 L. The liquid was filtered using cyclopentyl methyl ether (0.4 L).

A portion of the obtained solution in an amount equal to ⅝ times the amount thereof was taken out thereof and used in the subsequent reaction. To the solution, cyclopentyl methyl ether (0.25 L), tetrahydrofuran (3 L), and water (0.05 L) were successively added, and concentrated hydrochloric acid (74.9 g, 1.15 mol, 0.4 equiv.) was added thereto at an internal temperature of 23° C. The resulting mixture was stirred at 25° C. for 1.5 hours, and then a mixed solution of cyclopentyl methyl ether (1.5 L) and tetrahydrofuran (1.5 L) was added thereto. The resulting mixture was further stirred for 1.5 hours, and then concentrated hydrochloric acid (112 g, 1.72 mol, 0.6 equiv.) was added thereto in three portions every hour. The resulting mixture was stirred at an internal temperature of 25° C. for 18 hours. The precipitated solid was filtered and washed with a mixed solution of cyclopentyl methyl ether (1.25 L), tetrahydrofuran (1.25 L), and water (0.025 L). The solid was dried under reduced pressure at an external temperature of 40° C. to obtain the title compound (4) (808.0 g).

Example 5

3-{4-[(2R)-2-Aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethylimidazo[1,2-b]pyridazin-6-amine dihydrochloride (5)

Under the nitrogen atmosphere, the compound of the formula (4) (120.0 g) was dissolved in ethanol (1080 mL), and then activated carbon (12 g) moistened with ethanol (60 mL) was added thereto. The resulting mixture was stirred for 1 hour, and then filtered and washed with ethanol (120 mL). To the obtained solution, concentrated hydrochloric acid (43.3 g) was added, and the resulting mixture was warmed, and stirred at 65° C. to 70° C. for 4 hours. The mixture was cooled to an internal temperature of 20° C. over 2 hours and stirred at that temperature for 1 hour, and then further cooled to 1° C. over 1 hour. The mixture was stirred at an internal temperature of −1° C. to 1° C. for 19.5 hours. After that, the precipitated solid was filtered and washed with a mixed solution of cold ethanol (240 mL) and water (6 mL). The solid was dried under reduced pressure at an external temperature of 40° C. to obtain the title compound (5) (100.5 g).

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023272701&_cid=P12-MCIHPU-95869-1

The NMR data for the crystalline form A of Compound 1 adipate are as follows: 1H NMR (500 MHz, DMSO) δ 1.13-1.14 (d, J=5.0 Hz, 3H) , 1.47-1.48 (d, J=5.0 Hz, 7H) , 2.15-2.18 (t, J=5.0 Hz, J=10.0 Hz, 4H) , 3.25-3.29 (m, 1H) , 3.79-3.83 (m, 2H) , 4.80-4.85 (m, 1H) , 6.76-6.77 (d, J=5.0 Hz, 1H) , 6.92-6.94 (d, J=10.0 Hz, 2H) , 7.01-7.05 (t, J=10.0 Hz, 1H) , 7.23-7.28 (m, 2H) , 7.37-7.42 (m, 1H) , 7.64-7.65 (d, J=5.0 Hz, 1H) , 7.72-7.76 (t, J=10.0 Hz, 4H) .

[0148]

The IR data for the crystalline form A of Compound 1 adipate are as follows: IR (cm ^-1) : 1701, 1628, 1612, 1586, 1463, 1333, 1246, 1110, 829, 821.

Example 5: Preparation and Characterization of Crystalline Form A of Compound 1 Free Base

[0212]

Compound 1 HCl (75.5 g) (e.g., obtained by using the method described in Example 5 of U.S. Application Publication No. 2020/0062765) was dissolved in ethanol (604 mL) at 50℃. Sodium hydroxide (68.1 g) was added to the above solution. The mixture was cooled to 1℃ in 1.5 hours and stirred for 18.5 hours. The mixture was then filtered, and the solid thus obtained was washed with a cooled mixture of ethanol (151 mL) and water (151 mL) and dried. The solid thus obtained was confirmed to be the crystalline form A of Compound 1 free base.

[0213]

The NMR data for the crystalline form A of Compound 1 free base are as follows: 1H NMR (500 MHz, DMSO) δ 1.09-1.10 (d, J=5.0 Hz, 3H) , 1.48-1.49 (d, J=5.0 Hz, 3H) , 3.16-3.20 (m, 1H) , 3.75-3.79 (m, 2H) , 4.82-4.86 (m, 1H) , 6.76-6.78 (d, J=10.0 Hz, 1H) , 6.92-6.94 (m, 2H) , 7.01-7.05 (m, 1H) , 7.23-7.28 (m, 2H) , 7.37-7.42 (m, 1H) , 7.62-7.63 (d, J=5.0 Hz, 1H) , 7.72-7.75 (m, 4H) .

[0214]

The IR data for the crystalline form A of Compound 1 free base are as follows: IR (cm ^-1) : 3350, 3247, 3055, 2961, 2923, 2864, 1611, 1586, 1349, 829, 819.

SYN

European Journal of Medicinal Chemistry 291 (2025) 117643

Taletrectinib is an oral, next-generation ROS1 TKI developed by Nuvation Bio Inc. for the treatment of ROS1-positive NSCLC. In 2024, the NMPA approved taletrectinib for adult patients with locally advanced or metastatic ROS1-positive NSCLC, regardless of prior ROS1TKI treatment [47]. Under an exclusive license agreement, Innovent Biologics will commercialize taletrectinib in China under the brand
name DOVBLERON®. Taletrectinib exerts its pharmacological action through the mechanism of selectively impeding the ROS1 receptor tyrosine kinase, which effectively disrupts the signaling cascades which are responsible for facilitating the growth and survival of cancer cells in ROS1-positive NSCLC. This inhibition of the ROS1 receptor tyrosine kinase is a key event in the drug’s mode of action, as it specifically targets the molecular processes that drive the progression of the disease in ROS1-positive NSCLC cases [48]. The NMPA granted approval founded on the data sourced from the crucial Phase 2 TRUST – I study. This study substantiated that patients administered with taletrectinib achieved sustained responses and extended PFS. Regarding safety, taletrectinib boasted a generally good tolerability. It presented an advantageous safety profile and favorable tolerability characteristics, as evidenced by the low incidences of dose reduction and treatment discontinuation triggered by adverse effects. [49]. Overall, taletrectinib represents a promising therapeutic option for patients with advanced ROS1-positive NSCLC, offering efficacy in both TKI-naïve and TKI-pretreated populations, including those with CNS metastases [50–52].
The synthesis of Taletrectinib, illustrated in Scheme 12, commences with Mitsunobu coupling of Tale-001 and Tale-002 to afford Tale-003, which then undergoes Suzuki coupling with Tale-004 constructing
Tale-005 [53]. Sequential acidolysis/deprotection of Tale-005 ultimately delivers Taletrectinib

[47] M. P´ erol, N. Yang, C.M. Choi, Y. Ohe, S. Sugawara, N. Yanagitani, G. Liu, F.G.M.
D. Braud, J. Nieva, M. Nagasaka, 1373P efficacy and safety of taletrectinib in
patients (pts) with ROS1+ non-small cell lung cancer (NSCLC): interim analysis of
global TRUST-II study, Ann. Oncol. 34 (2023) S788–S789.
[48] G. Harada, F.C. Santini, C. Wilhelm, A. Drilon, NTRK fusions in lung cancer: from
biology to therapy, Lung Cancer 161 (2021) 108–113.
[49] W. Li, A. Xiong, N. Yang, H. Fan, Q. Yu, Y. Zhao, Y. Wang, X. Meng, J. Wu, Z. Wang,
Y. Liu, X. Wang, X. Qin, K. Lu, W. Zhuang, Y. Ren, X. Zhang, B. Yan, C.M. Lovly,
C. Zhou, Efficacy and safety of taletrectinib in Chinese patients with ROS1+ non-
small cell lung cancer: the phase II TRUST-I study, J. Clin. Oncol. 42 (2024)
2660–2670.
[50] M. Nagasaka, D. Brazel, S.I. Ou, Taletrectinib for the treatment of ROS-1 positive
non-small cell lung cancer: a drug evaluation of phase I and II data, Expert Opin
Investig Drugs 33 (2024) 79–84.
[51] S. Waliany, J.J. Lin, Taletrectinib: TRUST in the continued evolution of treatments
for ROS1 fusion-positive lung cancer, J. Clin. Oncol. 42 (2024) 2622–2627.
[52] M. Nagasaka, Y. Ohe, C. Zhou, C.M. Choi, N. Yang, G. Liu, E. Felip, M. P´ erol,
B. Besse, J. Nieva, L. Raez, N.A. Pennell, A. Dimou, F. Marinis, F. Ciardiello,
T. Seto, Z. Hu, M. Pan, W. Wang, S. Li, S.I. Ou, TRUST-II: a global phase II study of
taletrectinib in ROS1-positive non-small-cell lung cancer and other solid tumors,
Future Oncol. 19 (2023) 123–135.
[53] Y. Takeda, K. Yoshikawa, Y. Kagoshima, Y. Yamamoto, R. Tanaka, Y. Tominaga,
M. Kiga, Y. Hamada, Preparation of imidazo[1,2-b]pyridazine Derivatives as
Potent Inhibitors of ROS1 Kinase and NTRK Kinase, 2013. WO2013183578A1.

Medical uses

Taletrectinib is indicated for the treatment of adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer.^[1]^[2]

Adverse effects

The FDA prescribing information for taletrectinib includes warnings and precautions for hepatotoxicity, interstitial lung disease/pneumonitis, QTc interval prolongation, hyperuricemia, myalgia with creatine phosphokinase elevation, skeletal fractures, and embryo-fetal toxicity.^[1]^[3]

History

The efficacy of taletrectinib to treat ROS1-positive non-small cell lung cancer was evaluated in participants with locally advanced or metastatic, ROS1-positive non-small cell lung cancer enrolled in two multi-center, single-arm, open-label clinical trials, TRUST-I (NCT04395677) and TRUST-II (NCT04919811).^[3] The efficacy population included 157 participants (103 in TRUST-I; 54 in TRUST-II) who were naïve to treatment with a ROS1 tyrosine kinase inhibitor (TKI) and 113 participants (66 in TRUST-I; 47 in TRUST-II) who had received one prior ROS1 tyrosine kinase inhibitor.^[3] Participants may have received prior chemotherapy for advanced disease.^[3] The US Food and Drug Administration (FDA) granted the application for taletrectinib priority review, breakthrough therapy, and orphan drug designations.^[3]

Society and culture

Legal status

Taletrectinib was approved for medical use in the United States in June 2025.^[3]^[4]

Names

Taletrectinib is the international nonproprietary name.^[5]

Taletrectinib is sold under the brand name Ibtrozi.^[3]^[4]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Prescribing Information for NDA 219713, Supplement 000” (PDF). Drugs@FDA. U.S. Food and Drug Administration. April 2025. Retrieved 14 June 2025.
^ Jump up to:^a ^b Khan I, Sahar A, Numra S, Saha N, Nidhi, Parveen R (April 2025). “Efficacy and safety of taletrectinib for treatment of ROS1 positive non-small cell lung cancer: A systematic review”. Expert Opinion on Pharmacotherapy. 26 (6): 765–772. doi:10.1080/14656566.2025.2487150. PMID 40170301.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “FDA approves taletrectinib for ROS1-positive non-small cell lung cancer”. U.S. Food and Drug Administration (FDA). 11 June 2025. Retrieved 13 June 2025. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b “U.S. Food and Drug Administration Approves Nuvation Bio’s Ibtrozi (taletrectinib), a Next-Generation Oral Treatment for Advanced ROS1-Positive Non-Small Cell Lung Cancer”. Nuvation Bio (Press release). 12 June 2025. Retrieved 13 June 2025.
^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85”. WHO Drug Information. 35 (1). hdl:10665/340684.

External links

Clinical trial number NCT04395677 for “A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene” at ClinicalTrials.gov
Clinical trial number NCT04919811 for “Taletrectinib Phase 2 Global Study in ROS1 Positive NSCLC (TRUST-II)” at ClinicalTrials.gov

Clinical data

Trade names	Ibtrozi
License data	US DailyMed: Taletrectinib
Routes of administration	By mouth
Drug class	Antineoplastic
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	1505514-27-1as salt: 1505515-69-4
PubChem CID	72202474as salt: 72694302
DrugBank	DB18711
ChemSpider	114934673as salt: 88297530
UNII	W4141180YDas salt: 6KLL51GNBG
KEGG	D12363as salt: D12364
ChEMBL	ChEMBL4650989as salt: ChEMBL4650361
Chemical and physical data
Formula	C₂₃H₂₄FN₅O
Molar mass	405.477 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

/////////Taletrectinib, FDA 2025, APPROVALS 2025, Ibtrozi, CANCER, AB-106, DS-6051a, UNII-W4141180YD, DS 6051B, APPROVALS 2024, CHINA 2024, Nuvation Bio Inc

Alflutinib, Furmonertinib, Firmonertinib

June 3, 2025 3:09 am / Leave a comment

FIRMOMERTINIB, Furmonertinib, Alflutinib

CAS 1869057-83-9

, AST 2818, UNII-A49A7A5YN4

N-[2-[[2-(Dimethylamino)ethyl]methylamino]-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-2-propenamide

N-[2-[2-(dimethylamino)ethyl-methylamino]-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]prop-2-enamide

C₂₈H₃₁F₃N₈O₂ 568.6 g/mol

2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-

Alflutinib is under investigation in clinical trial NCT03452592 (Efficacy and Safety of Alflutinib in Locally Advanced or Metastatic Non-small Cell Lung Cancer Patients With T790M).

Firmonertinib is an orally available selective inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. Upon administration, firmonertinib specifically binds to and inhibits the tyrosine kinase activity of EGFR T790M, a secondarily acquired resistance mutation. This prevents EGFR T790M-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. EGFR, a receptor tyrosine kinase that is mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. Compared to some other EGFR inhibitors, alflutinib may have therapeutic benefits in tumors with T790M-mediated drug resistance.

FIRMONERTINIB is a small molecule drug with a maximum clinical trial phase of III (across all indications) and has 4 investigational indications.

SCHEME

CONTD……..

REF

[US10072002B2]

https://patentscope.wipo.int/search/en/detail.jsf?docId=US201062358&_cid=P22-MBFXFH-62339-1

Example 3: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide

Step 1: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N⁵-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine

The compound was synthesized in the same manner as those in Step 1 of Example 1 with a yield of 86%. MS m/z: 545 [M+1].

Step 2: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N⁵-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine

The compound was synthesized in the same manner as those in Step 2 of Example 2 with a yield of 56%. MS m/z: 515 [M+1].

Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide

The compound was synthesized in the same manner as those in Step 3 of Example 1 with a yield of 23%. MS m/z: 569 [M+1].

¹H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 10.27 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 8.28 (t, J=8.5 Hz, 2H), 8.18 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.29-7.14 (m, 3H), 6.98 (s, 1H), 6.28 (d, J=17.1 Hz, 1H), 5.76 (d, J=10.4 Hz, 1H), 5.00 (q, J=9.0 Hz, 2H), 3.89 (s, 3H), 3.61 (s, 2H), 3.28 (s, 2H), 2.80 (s, 3H), 2.73 (s, 6H).

PATENT

CN110606842

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN280196686&_cid=P22-MBFXJY-67679-1

Patent application CN105315259A protects the compound of formula I and discloses its preparation method as follows:

Example 1: Preparation of 6-chloro-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (XI-1)

Add toluene (24.0L) to the reactor, then add 2,6-dichloro-3-nitropyridine (3000g, 15.54mol), adjust the internal temperature between -20℃ and -10℃, and add sodium hydrogen (933g, 23.33mol) in batches. Add 2,2,2-trifluoroethanol (1586g, 16.00mol) toluene (6.0L) solution dropwise. React for 2h, and monitor the reaction end point by TLC and HPLC. After the reaction is completed, add 10% ammonium chloride solution (6.0L) dropwise. Let stand and separate. Wash the organic phase with water (6.0L) and concentrate under reduced pressure. Add ethyl acetate (0.3L), heat to 40-50℃, add n-heptane (2.7L) dropwise, cool to -15 to -5℃ after dripping, and continue crystallization for 3 hours, and filter with suction. Obtain 3017g of product solid, with a yield of 75.65%.

¹H NMR(500MHz，DMSO-d6)δ8.60(d，J＝8.0Hz，1H)，7.50(d，J＝8.5Hz，lH)，5.13(q，J＝9.0Hz，2H)；

¹³C NMR(126MHz，DMSO-d6)δ153.20，151.09，139.34，132.67，123.38(q，J＝277.2Hz)，119.14，63.34(q，J＝36Hz)；

MS m/z：256.99[M+1]。

Example 2: Preparation of 6-chloro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (X-1)

At room temperature, add acetonitrile (21.0L) and water (21.0L) to the reactor, start stirring, add 6-chloro-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (3017.0g, 11.76mol) obtained in Example 1, and add hydrosulfite (15.1Kg, 70.54mol). Control the temperature at 27-33°C to react for 2 hours. Add 36% concentrated hydrochloric acid (11.9Kg, 117.60mol) dropwise, and continue to react for 1.5 hours. Add solid sodium bicarbonate (12.8Kg, 12.96mol). Filter, separate the mother liquor, wash the organic phase with saturated brine (21.0L), and concentrate under reduced pressure to obtain an oily substance. Theoretically calculated for the next step reaction.

¹H NMR(500MHz，DMSO-d6)δ7.03(d，J＝8.0Hz，1H)，6.90(d，J＝8.0Hz，1H)，5.21(s，2H)，4.93(q，J＝9.0Hz，2H)；

¹³C NMR(126MHz，DMSO-d6)δ148.16，131.72，130.55，123.93(q，J＝278.5Hz)，121.02，118.42，61.72(q，J＝34.0Hz)；

MS m/z：227.01[M+1]。

Example 3: Preparation of 6-chloro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (IX-1)

At room temperature, dichloromethane (10.4 L) was added to the reaction kettle, stirring was started, 6-chloro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (2664 g, 11.76 mol) obtained in Example 2 was added, diisopropylethylamine (2279 g, 17.64 mol) was added, the temperature was controlled at -15 to -10°C, a dichloromethane (5.2 L) solution of trifluoroacetic anhydride (2963 g, 14.11 mol) was added dropwise, and stirring was continued for 20 minutes after the addition was completed. Water (13.0 L) was added dropwise, the layers were separated, the organic phase was concentrated under reduced pressure, and the next step reaction was theoretically calculated.

¹ H NMR(400MHz,DMSO-d6)δ11.23(s,7H),7.95(d,J8.0Hz,1H),7.34(d,J8.0Hz,1H),5.03(q,J8.9Hz,2H)

¹³C NMR(101MHz，DMSO-d6)δ155.74(q，J＝46.6Hz)，155.60，145.37，140.24，124.01(q，J＝278.8Hz)，119.07，118.30，116.19(q，J＝289.9Hz)，62.99(q，J＝35.4Hz)；

MS m/z.322.99[M+1]。

Example 4: Preparation of 6-chloro-5-nitro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (VIII-1)

At room temperature, concentrated sulfuric acid (11.7 L) was added to the reaction kettle, stirring was started, 6-chloro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (3.9 Kg, 11.76 mol) obtained in Example 3 was added, and potassium nitrate solid (1783.4 g, 17.64 mol) was added in batches. After the addition, stirring was continued for about 40 minutes. After monitoring the reaction, the temperature was lowered to control the internal temperature at 10-25°C, and dichloromethane (27.3 L) was added dropwise. Stirring was continued, stirring was continued for 45 minutes, and the layers were separated. The organic phase was taken and washed once with water (11.7 L). The organic phase was concentrated under reduced pressure and theoretically calculated for the next step reaction.

¹H NMR(500MHz，DMSO-d6)δ11.58(s，1H)，8.78(s，1H)，5.17(q，J＝8.7Hz，2H)；

¹³C NMR(126MHz，DMSO-d6)δ155.89，155.43(q，J＝37.8Hz)，138.84，138.57，135.05，123.22(q，J＝273.4Hz)，118.47，115.51(q，J＝278.5Hz)，63.65(q，J＝35.3Hz)；

MS m/z：367.98[M+1]。

Example 5: Preparation of 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (VII-1)

At room temperature, methanol (13.0 L) was added to the reactor, 6-chloro-5-nitro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (4322 g, 11.76 mol) obtained in Example 4 was added, p-toluenesulfonic acid monohydrate (3355 g, 17.64 mol) was added, the temperature was controlled at 60-65°C for 15 hours, and the methanol was removed under reduced pressure. Methyl tert-butyl ether (13.0 L) and water (6.5 L) were added, and the pH was adjusted to 7-8 with potassium carbonate. Layering was performed, the organic phase was washed once with water (8.6 L), separated, and concentrated under reduced pressure. n-heptane (21.5 L) was added, the temperature was controlled at 60-65°C and stirred for 1 hour, cooled to room temperature, filtered, and the filter cake was dried with air at 50°C for 18 hours to obtain 1475 g of the product.

The total yield of the five-step reaction from Example 1 to Example 5 is 34.9%.

¹H NMR(500 MHz，DMSO-d6)δ7.62(s，1H)，5.92(s，2H)，5.05(q，J＝8.9Hz，2H).

¹³C NMR(126MHz，DMSO-d6)δ149.30，139.53，132.84，123.46，123.44(q，J＝278.5Hz)，116.25，62.52(q，J＝35.3Hz)；

MS m/z：272.00[M+1]。

Example 6: Preparation of 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (V-1)

Toluene (50 mL) was added to a 100 mL reaction bottle, and the compound of formula VII-1, 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (5.0 g, 18.4 mmol), the compound of formula VI, 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (5.8 g, 23.8 mmol), p-toluenesulfonic acid monohydrate (1.8 g, 9.2 mmol) were added in sequence, and the reaction mixture was heated to 110-115°C and reacted for 24 hours. The temperature was lowered to 22°C, filtered by suction, and the filter cake was dried at 50°C for 20 hours to obtain the compound of formula V-1, 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (10.4 g, 74.7 HPLC area% purity). According to the HPLC purity conversion, the next step reaction was carried out.

¹H NMR(400MHz，DMSO-d6)δ9.43(s，1H)，8.76(s，1H)，8.46-8.45(d，J＝5.4Hz，1H)，8.39(s，1H)，8.38-8.36(d，J＝7.8Hz，1H)，7.57-7.55(d，J＝8.2Hz，1H)，7.41-7.40(d，J＝5.4Hz，1H)，7.31-7.27(t，J＝7.5Hz，1H)，7.20-7.16(t，J＝7.5Hz，1H)，5.23-5.16(q，J＝8.8Hz，2H)，3.90(s，3H)；

MS m/z：479.08[M+1]。

Example 7: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV)

Add N,N-dimethylformamide (30 mL) to a 250 mL reaction bottle, add the compound of formula V-1 obtained in Example 6, 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (10.4 g, 16.22 mmol), stir, add potassium carbonate (4.48 g, 32.44 mol), N,N,N’-trimethylethylenediamine (2.48 g, 24.33 mol) in sequence, heat the reaction mixture to 77-82°C, keep warm for 1-1.5 hours. Add water (60 mL), and cool to room temperature after addition. Filter by suction, transfer the filter cake to a 50 L reactor, add acetonitrile (40 mL), and heat to reflux for 2 hours. The mixture was cooled to room temperature and filtered with suction. The filter cake was dried at 50°C for 18 hours to give a compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (6.7 g). The total yield of the two-step reaction with Example 6 was 66.8%.

¹H NMR(500MHz，DMSO-d6)δ8.62(s，1H)，8.41(s，1H)，8.26(s，2H)，8.24(s，1H)，7.48(d，J＝8.2Hz，1H)，7.21(t，J＝7.6Hz，1H)，7.16(d，J＝5.3Hz，1H)，7.05(t，J＝7.3Hz，1H)，5.04(q，J＝8.9Hz，2H)，3.84(s，3H)，3.69(t，J＝6.9Hz，2H)，2.89(s，3H)，2.55(t，J＝6.9Hz，2H)，2.17(s，6H)；

¹³C NMR(126MHz，DMSO-d6)δ162.15，160.55，156.99，154.98，148.42，137.53，132.83，132.68，125.50，123.58(q，J＝279.7Hz)，124.38，122.11，122.06，120.67，113.38，112.27，110.30，107.11，62.14(q，J＝35.3Hz)，56.10，49.51，45.34，45.33，39.35，32.98。

MS m/z.：545.22[M+1]。

Example 8: Preparation of 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (V-1′)

Toluene (7.43 L) was added to a 20 L reactor, and compound VII-1 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (743.0 g, 2.74 mol), compound VI 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (866.7 g, 3.56 mol), p-toluenesulfonic acid monohydrate (780.7 g, 4.10 mol) were added in sequence, stirred, and the reaction mixture was heated to 110-115°C and reacted for 36 hours. The temperature was controlled at 15-30°C, tetrahydrofuran (3.72 L) was added and stirred for 30 minutes. Filtered by suction, the filter cake was transferred to a 50 L reactor, tetrahydrofuran (4.46 L) was added, and heated to reflux for 3 hours. The temperature was lowered to 15-25°C, filtered, and the filter cake was dried at 50°C for 17 hours to obtain 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1719 g, 85.96 HPLC area% purity). The purity was calculated according to HPLC and used for the next step reaction.

Melting point: 216.0-218.3℃

¹H NMR(500MHz，DMSO-d6)δ9.70(s，1H)，9.21(s，1H)，8.62(s，1H)，8.40(d，J＝6.2Hz，1H)，8.24(d，J＝7.8Hz，1H)，7.59(d，J＝8.3Hz，1H)，7.50(d，J＝6.5Hz，1H)，7.49(d，J＝8.3Hz，2H)，7.32(t，J＝7.6Hz，1H)，7.18(t，J＝7.5Hz，1H)，7.12(d，J＝7.9Hz，2H)，5.17(q，J＝8.8Hz，2H)，3.91(s，3H)，2.29(d，J＝5.2Hz，3H)；

¹³C NMR(126MHz，DMSO-d6)δ166.66，157.35，155.72，147.40，140.87，139.90，139.72，138.59，135.83，130.09，129.99，129.98，129.97，127.39，127.38，127.37，127.15，125.22(q，J＝278.5Hz)，124.97，123.85，123.69，113.63，112.97，110.27，63.58(q，J＝35.3Hz)，35.57，22.81。

Example 9: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV)

Add N,N-dimethylformamide (5.14L) to a 50L reactor, add 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1714.0g, 2.261mol) obtained in Example 8, stir, add potassium carbonate (624.7g, 4.52mol), N,N,N’-trimethylethylenediamine (346.2g, 3.39mol) in sequence, heat the reaction mixture to 77-82°C, keep warm for 1-1.5 hours. Add water (10.28L), and cool to room temperature after adding. Filter by suction, transfer the filter cake to a 50L reactor, add acetonitrile (6.86L), and heat to reflux for 2 hours. The temperature was lowered to 15-25°C, filtered with suction, and the filter cake was dried at 50°C for 18 hours to obtain the compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1142 g). The total yield of the two-step reaction with Example 8 was 76.54%.

MS m/z：545.22[M+1]。

Example 10: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV)

Acetonitrile (10 mL) was added to a 50 L reactor, and 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1.0 g, 1.5 mmol) obtained in Example 8 was added, and stirred. Potassium carbonate (577 mg, 3 mmol) and N,N,N’-trimethylethylenediamine (320 mg, 2.25 mmol) were added in sequence. The reaction mixture was heated to 77-82°C and kept for 1-2 hours. Water (10 mL) was added and the temperature was cooled to room temperature after the addition. The product was filtered to give a compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (629 mg) with a purity of 95.94%. The total yield of the two-step reaction with Example 8 was 77%.

Example 11: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)

Add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0 g, 7.34 mmol) to a 100 mL reaction bottle at room temperature, add tetrahydrofuran (27 mL) and water (13 mL), and stir for 10 to 20 minutes. Add hydrosulfite (9.6 g, 44.1 mmol) to the reactor in batches. After addition, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 30 to 35 ° C for reaction. The purity of the product compound of formula III’ was 64.68% after sampling the liquid phase after 2 hours of reaction. The reaction was continued until 17 hours after the reaction. 40 mL of water was added to the reaction solution, and the layers were separated by standing. The tetrahydrofuran phase was taken, and the aqueous phase was extracted twice with 100 mL of dichloromethane. The organic phases were combined, washed with saturated brine, separated by standing, and concentrated under reduced pressure to obtain 3.2 g of solid with a purity of 62.32%.

¹H NMR(500MHz，DMSO)δ10.67(s，1H)，10.36(s，1H)，8.82(s，1H)，8.18(s，1H)，8.01(s，1H)，7.59(d，J＝8.2Hz，1H)，7.45(d，J＝6.8Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.24(s，1H)，4.97(q，J＝8.7Hz，2H)，3.93(s，3H)，3.75(s，2H)，3.41(s，2H)，3.10(s，3H)，2.78(s，6H)；

MS m/z：515.24[M+1]。

Example 12: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)

In a 100mL single-mouth bottle, there is 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (2.0g, 3.67mmol), palladium carbon (200mg), ethanol (20mL), hydrogen balloon replacement twice, hydrogen gas, magnetic stirring, room temperature overnight (17 hours). After the reaction is completed, suction filtration, the filtrate is taken, and it is concentrated to dryness under reduced pressure to obtain 2.1g of product with a purity of 56.93%.

Example 13: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)

At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1317.0 g, 2.42 mol) to a 50 L reactor, add tetrahydrofuran (8.8 L) and water (4.3 L), and stir for 10 to 20 minutes. Add hydrosulfite (2970.0 g, 14.52 mol) to the reactor in batches. After adding, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 40-45 ° C and react for 2 hours. Add concentrated hydrochloric acid (5882.2 g, 58.08 mol) to the reactor. After the addition is complete, heat to 42 to 47 ° C and react for 15 hours. Add 30% sodium hydroxide (2323.2g, 58.08mol) aqueous solution dropwise, and then add solid sodium bicarbonate (1219.7g, 14.52mol) in batches to adjust the pH value to 6-8. After stirring for 20 minutes, filter with suction, let the filtrate stand and separate. The organic phase is concentrated under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine, with a purity of 97.1%. Calculated based on the theoretical yield of 100%, it is directly used in the next step reaction.

MS m/z：515.24[M+1]。

Example 14: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (III-1)

To the 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine obtained in Example 13, THF (5.3 L) and ethanol (4.0 L) were added, the temperature was raised to 50-70°C, and concentrated hydrochloric acid (617.8 g, 6.1 mol) was added dropwise. After the addition was completed, the mixture was cooled to room temperature and stirred for 12 hours. Filtered by suction, the filter cake was dried by air at 50°C to obtain 1507.4 g of a crude product. Methanol (6.0 L) and ethanol (4.5 L) were added to a 20 L reaction bottle, and the above crude product was added, the temperature was raised to 55-60 ° C, hot slurry was added for 1-2 hours, the temperature was lowered to room temperature, and suction was filtered to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (1335.6 g), the liquid phase purity was 99.80%, and the total yield of the two-step reaction with Example 13 was 94.0%. Melting point: 236.6-240.8 ° C.

¹H NMR(500MHz，DMSO-d6)δ10.67(s，1H)，10.36(s，1H)，8.82(s，1H)，8.18(s，1H)，8.01(s，1H)，7.59(d，J＝8.2Hz，1H)，7.45(d，J＝6.8Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.24(s，1H)，4.97(q，J＝8.7Hz，1H)，3.93(s，3H)，3.75(s，2H)，3.41(s，2H)，3.10(s，3H)，2.78(s，6H)；

¹³C NMR(126MHz，DMSO-d6)δ166.81，153.27，152.17，150.76，138.61，138.16，138.15，125.46，124.94，123.83(q.J＝278.5Hz)，123.42，123.41，122.60，122.59，120.52，111.34，111.17，106.29，62.14(q，J＝35.3Hz)，53.53，46.28，42.27，42.26，40.92，33.67。

Example 15: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (III-1)

At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1136.0 g, 2.09 mol) to a 50 L reactor, add acetonitrile (7.95 L) and water (7.95 L), and stir for 10 to 20 minutes. Add hydrosulfite (2563.9 g, 12.50 mol) to the reactor in batches. After adding, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 35 to 40 ° C and react for 3 hours. Add concentrated hydrochloric acid (2505.3 g, 25.08 mol) to the reactor. After the addition is complete, heat to 35 to 45 ° C and react for 18 hours. 30% sodium hydroxide (1003.2 g, 25.08 mol) aqueous solution was added dropwise to adjust the pH value to 6-8. Solid sodium bicarbonate (1053.5 g, 12.54 mol) was added to adjust the pH value to 7-8. After stirring for 40 minutes, the mixture was filtered, the filtrate was allowed to stand, the layers were separated, and the organic phase was concentrated under reduced pressure. The purity of the liquid phase was detected to be 97.60%.

Add ethanol (5.68 L) to the product of the previous step, raise the temperature to 50-70°C, and drop concentrated hydrochloric acid (522 g, 5.23 mol). After the dropwise addition is completed, cool to room temperature and stir for 15 hours. Filter by suction, and air dry the filter cake at 50°C to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (780 g), with a liquid phase purity of 98.74%.

Example 16: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (II-1)

2-[2-(Dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (1543.5 g, 2.63 mol) was added to a 50 L reactor, and dichloromethane (13.1 L) and triethylamine (532.2 g, 5.26 mol) were added. The mixture was stirred and cooled to -10 to -5 °C, and a solution of 3-chloropropionyl chloride (501.5 g, 3.95 mol) in dichloromethane (10.0 L) was added dropwise. After the addition is completed, keep warm and stir for 10 to 20 minutes, filter with suction, and the filter cake is formula II-12-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride wet product (2683.5g), which is calculated based on the theoretical yield of 100% and is directly used in the next reaction.

Melting point: 233.2-238.7℃

¹H NMR(500MHz，DMSO-d6)δ10.18(s，1H)，8.57(s，1H)，8.42(s，1H)，8.27(t，J＝6.6Hz，2H)，8.17(s，1H)，7.51(d，J＝8.1Hz，1H)，7.26-7.22(m，1H)，7.22-7.17(m，2H)，4.99(q，J＝9.1Hz，2H)，3.91(d，J＝6.3Hz，2H)，3.89(s，3H)，3.55(s，2H)，3.13(s，2H)，3.02(t，J＝6.1Hz，2H)，2.85(s，3H)，2.64(s，6H)；

¹³C NMR(126MHz，DMSO-d6)δ168.41，161.88，160.22，157.34，148.05，146.73，137.62，133.25，130.86，125.43，124.09(q，J＝279.2Hz)，122.04，121.74，120.88，118.51，116.60，112.33，110.40，107.09，61.65(q，J＝35.3Hz)，54.90，40.96，40.95，40.60，38.71，32.96，32.95，32.94。

Example 17: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)

The wet product (2683.5 g) of Formula II 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride obtained in Example 16 was added to a 20L reactor, and acetonitrile (16.8L) and triethylamine (1329.3g, 13.15mol) were added, stirred, and heated to reflux for 4 hours. Cooled to room temperature, purified water (4.20L) was added, stirred at room temperature for 3-4 hours, and filtered. The filter cake was transferred to a 50L reactor, dichloromethane (17L) was added, and the pH value was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution (17L). Liquid separation, the organic phase was transferred to a 20L reactor, activated carbon (84.3g) was added, refluxed for 1 hour, cooled to 20-30°C, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the compound of formula I 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1390g), with a total yield of 92.9% and a purity of 99.21% for the two-step reaction with Example 16.

¹H NMR(500MHz，DMSO-d6)δ9.96(s，1H)，8.71(s，1H)，8.44(s，1H)，8.29(d，J＝5.3Hz，1H)，8.26(d，J＝7.7Hz，1H)，8.13(s，1H)，7.51(d，J＝8.2Hz，1H)，7.24(t，J＝7.2Hz，1H)，7.20(d，J＝5.3Hz，1H)，7.15(t，J＝7.2Hz，1H)，6.51(dd，J＝17.0，10.2Hz，1H)，6.28(dd，J＝17.0，1.8Hz，1H)，5.78(dd，J＝10.2，1.8Hz，1H)，5.00(q，J＝9.1Hz，2H)，3.89(s，3H)，3.18(t，J＝6.5Hz，2H)，2.87(s，3H)，2.48(t，J＝6.5Hz，2H)，2.22(s，6H)；

¹³C NMR(126MHz，DMSO-d6)δ163.40，161.84，160.26，157.35，148.07，147.15，137.60，133.23，131.61，130.07，126.67，125.41，124.03(q，J＝278.5Hz)，122.00，121.68，120.80，118.39，116.13，112.36，110.37，107.02，61.29(q，J＝35.3Hz)，56.57，52.44，45.60，45.59，38.54，32.93；

MS m/z：569.25[M+1]。

Example 18: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’)

At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (20.0 g, 36.73 mmol) to a 1L reaction bottle, add tetrahydrofuran (134 mL) and water (66 mL), and stir for 10 to 20 minutes. Add hydrosulfite (47.9 g, 220.38 mmol) to the reaction bottle in batches. After addition, continue stirring for 10 to 20 minutes. Control the internal temperature to 35-40°C and react for 3 hours. Add concentrated hydrochloric acid (89.3 g, 881.52 mmol) to the reaction bottle. After the addition is complete, heat to 42 to 47°C and react for 17 hours. 30% sodium hydroxide (35.26 g, 881.52 mmol) aqueous solution was added dropwise, and solid sodium bicarbonate (18.5 g, 220.38 mmol) was added in batches to adjust the pH value to 6-8. After stirring for 30 minutes, the mixture was filtered, and the filtrate was allowed to stand and separated. The organic phase was concentrated to dryness under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (19.2 g) with a purity of 95.8% and a yield of 97.12%.

Example 19: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (II-1)

Add 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5 g, 9.72 mmol) to a 250 mL reaction bottle, add dichloromethane (42 mL), stir, protect with argon, cool to -5 to 0°C, and add 3-chloropropionyl chloride (1.851 g) and dichloromethane (33 mL) dropwise. After the addition is complete, the mixture is stirred for 10-20 minutes at a temperature maintained at room temperature. After the reaction is complete, the mixture is concentrated under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (7.0 g) with a purity of 85.67%. Melting point: 233.5-238.9°C.

Example 20: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)

The 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride obtained in Example 19 was added to a 250 mL reaction bottle, and acetonitrile (45 mL) and triethylamine (4.9 g) were added. The mixture was stirred magnetically and protected by argon. The temperature was raised to reflux in an oil bath. The reaction was allowed to react for 6 h. Water (23 mL) was added dropwise, and the mixture was naturally cooled to room temperature in an oil bath. The mixture was filtered with suction, and the filter cake was transferred to a 500 mL reaction bottle. Dichloromethane (100 mL) was added, and the pH value was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution (100 mL). The liquids were separated and the organic phase was concentrated under reduced pressure. The solid was dried in an oven at 50°C to give 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.1 g) with a purity of 97.7%. The total yield of the two-step reaction with Example 19 was 74.17%.

Comparative Example 1: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)

2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1 g, 1.94 mmol) was added to a 50 mL multi-necked flask, tetrahydrofuran (10 mL) was used as the solvent, argon was replaced three times, and stirring was maintained at 0-5°C under argon protection, and 3-chloropropionyl chloride (0.37 g, 2.92 mmol), the addition was completed in 15 minutes, and the mixture was stirred at 0-5°C for 1 hour. Sodium hydroxide (0.31 g, 7.77 mmol) and water (1 mL) were added to the reaction solution, and the temperature was raised to 65°C and stirred for 15 hours. Saturated ammonium chloride solution (10 mL) was added, and the liquids were separated. The organic phase was washed with saturated sodium bicarbonate solution (10 mL). The liquids were separated and the organic phase was concentrated to dryness to obtain 1.04 g of a yellow solid with a yield of 94.9% and a purity of 87.35%.

Comparative Example 2: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product)

Add 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g) to a 250 mL reaction bottle, add acetone (50 mL) and potassium carbonate (940 mg), stir, protect with argon, cool to -50°C, and add 3-chloropropionyl chloride (1.481 g) dropwise. After the addition is completed, the temperature is raised to -20°C and stirred for 30 minutes. A solution of sodium hydroxide (350 mg) and water (60 ml) is added dropwise over 10 minutes. The mixture is stirred at room temperature for 3 to 4 hours. The mixture is filtered and the filter cake is dried in an oven at 50°C to obtain a compound of formula II-1′, 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.28 g) with a purity of 64.18%.

¹H NMR(400MHz，DMSO-d₆)δ10.32(s，1H)，10.21(s，1H)，8.54(s，1H)，8.43(s，1H)8.29-8.28(d，J＝5.1Hz，1H)，8.28-8.26(d，J＝6.2Hz，1H)，8.19(s，1H)，7.54-7.52(d，J＝8.0Hz，1H)，7.27-7.18(m，3H)，5.77(s，2H)，5.00(q，J＝9.1Hz，1H)，3.92(t，J＝6.2Hz，1H)，3.63(t，J＝5.7Hz，2H)，3.28(t，J＝5.7Hz，2H)，3.06-3.03(t，J＝6.2Hz，2H)，2.85(s，3H)，2.74(s，6H).

MS m/z：605.23[M+1]。

Add 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.28 g) to a 250 mL reaction bottle, add acetonitrile (45 ml) and triethylamine (3.606 g), stir magnetically, protect with argon, heat in an oil bath to reflux, and react for 6 h. Water (23 ml) was added dropwise, the temperature was naturally lowered in an oil bath and stirring was continued overnight (16 h), filtered with suction, and the solid was dried to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.3 g) with a purity of 95.13% and a two-step yield of 59.42%.

Example 21: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

The crude product (1390 g) of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine was transferred to a 50L reactor, acetone (25.0L) was added, argon was replaced 3 times, the temperature was raised to 45-50°C, all the solids were dissolved, and purified water (6.95L) was added dropwise. After the addition was completed, the mixture was cooled to 20-25°C and stirred for 2 hours. The mixture was filtered and the filter cake was vacuum dried at 50°C for 24 hours to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (895g). The reaction yield is 66.7% and the purity is 99.89%.

Example 22: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add ethyl acetate 100mL, heat to 70-75°C in an oil bath to dissolve all the solids, then cool naturally to 25°C in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.1g) with a purity of 99.73% and a yield of 62.0%.

Example 23: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add ethyl acetate 100mL, heat to 70-75°C in an oil bath, dissolve all the solids, continue to stir for 30min, and drop 150mL of n-heptane. After the drop is complete, cool to 25°C in an oil bath, filter by suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0g), with a purity of 99.32% and a yield of 80%.

Example 24: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add acetonitrile 75mL, heat in an oil bath to 77-82°C, dissolve all the solids, and drop 25mL of water. After dripping, naturally cool to 25°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.3g), with a purity of 99.64% and a yield of 86%.

Example 25: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add acetonitrile 75mL, heat in an oil bath to 77-82°C, dissolve all the solids, and continue to stir for 30min. Cool naturally to 25°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0g), with a purity of 99.45% and a yield of 80%.

Example 26: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g), add 20mL of tetrahydrofuran, heat in an oil bath to 45-50°C to dissolve all the solids, continue to stir and maintain the temperature for 30 minutes, and add 40mL of n-heptane dropwise. After the addition was completed, the mixture was naturally cooled to 25°C in an oil bath, filtered and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.23 g) with a purity of 99.51% and a yield of 84.6%.

Example 27: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 100mL of isopropanol, heat to 50°C in an oil bath, dissolve all the solids, and continue to stir for 30 minutes. Cool naturally to 22°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.25g), with a purity of 99.51% and a yield of 85%.

Example 28: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 75mL of methanol, and heat to 55-60°C in an oil bath to dissolve all the solids. Cool naturally to 17°C in the oil bath, stir overnight, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.55g), with a purity of 99.63% and a yield of 71%.

Example 29: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g), add 50mL of dichloromethane, heat in an oil bath to 40°C to dissolve all the solids, continue to stir and maintain the temperature for 30 minutes, and add 100mL of n-heptane dropwise. The mixture was naturally cooled to 15°C in an oil bath, stirred overnight, filtered and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.78 g) with a purity of 99.56% and a yield of 75.6%.

Example 30: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 100mL of toluene, heat to 65°C in an oil bath, dissolve all the solids, and continue to stir for 30 minutes. Cool naturally to 20°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.27g), with a purity of 99.57% and a yield of 65.4%.

Example 31: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add DMF50mL, heat to 80°C in an oil bath, dissolve all the solids, continue to stir for 30min, and drop 25mL of water. Naturally cool to 20°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.84g), with a purity of 99.77% and a yield of 76.8%.

Example 32: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 25 mL single-necked bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add tetrahydrofuran (6 mL), protect with argon, heat in an oil bath to 40-45°C until all the solution is dissolved, continue to stir and keep warm for 30 min, cool naturally to 22°C in an oil bath, filter and obtain a solid. The solid was transferred to a crystallization dish and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (622 mg) with a purity of 99.83% and a yield of 62.2%.

Example 33: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add acetone (15 mL), protect with argon, heat in an oil bath to 45-50° C. until all the solution is dissolved, and then continue to stir and keep warm for 30 min, cool naturally to 22° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (537 mg) with a purity of 99.83% and a yield of 53.7%.

Example 34: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add tetrahydrofuran (8 mL), protect with argon, heat in an oil bath to 40-45° C. until all the solution is dissolved, and continue to stir and keep warm for 30 min. Add water (16 mL) dropwise, cool naturally to 21° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (880 mg) with a purity of 99.68% and a yield of 88.0%.

Example 35: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 100 mL single-mouth bottle, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1.0 g), add ethanol (35 mL), protect with argon, heat in an oil bath to 75-80° C. until all the solution is dissolved, add water (10 mL) dropwise over 10 min, cool naturally to 20° C. in an oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (915 mg), with a yield of 91.5% and a purity of 99.49%.

Example 36: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add xylene (20 mL), protect with argon, heat in an oil bath to 80° C. until all the solution is dissolved, cool naturally to 20° C. in an oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (798 mg), with a yield of 79.8% and a purity of 99.48%.

Example 37: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add ethanol 125mL, heat in an oil bath to 75-80°C to dissolve all the solids, continue to stir and keep warm for 30min, then cool naturally to 25°C in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.7g) with a purity of 99.66% and a yield of 74%.

Example 38: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I)

To a 100 mL single-mouth bottle, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1.0 g), add methanol (35 mL), protect with argon, heat in an oil bath to 80° C. until all the solution is dissolved, add water (10 mL) dropwise over 10 min, cool naturally to 20° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (912 mg), with a yield of 91.2% and a purity of 99.53%.

PATENT

CN110606842

WO2019238103

PAPER

https://www.nature.com/articles/s41401-020-0389-3

NCT Number	Sponsor	Condition	Start Date	Phase
NCT02973763	Allist Pharmaceuticals, Inc.	NSCLC	December 30, 2016	Phase 1
NCT03787992	Allist Pharmaceuticals, Inc.	Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non-small Cell Lung Cancer	May 30, 2019	Phase 3
NCT03452592	Allist Pharmaceuticals, Inc.	Advanced NSCLC Patients With T790M	April 30, 2018	Phase 2

[1]. Y. Shi, et al. P2.03-028 Third Generation EGFR Inhibitor AST2818 (Alflutinib) in NSCLC Patients with EGFR T790M Mutation: A phase1/2 Multi-Center Clinical Trial.[2]. Alexander I. Spira, et al. FURVENT: Phase 3 trial of furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertion mutations (FURMO-004). Journal of Clinical Oncology. Volume 42, Number 16_suppl.

/////////FIRMOMERTINIB, Furmonertinib, Alflutinib, AST 2818, UNII-A49A7A5YN4, PHASE 2, CANCER

Tibremciclib

April 11, 2025 8:47 am / Leave a comment

Tibremciclib

cas 2397678-18-9, GTPL12881

CRB7BT5JDQ

518.6 g/mol, C₂₈H₃₂F₂N₈

N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-[(1R)-6-fluoro-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-8-yl]pyrimidin-2-amine

Tibremciclib is a CDK4 inhibitor with antineoplastic activity^[1].

Originator Betta Pharmaceuticals Co Ltd
Class Antineoplastics; Small molecules
Mechanism of Action Cyclin-dependent kinase 4 inhibitors; Cyclin-dependent kinase 6 inhibitors

Phase III Breast cancer; Solid tumours

13 Sep 2024 Efficacy and adverse event data from a phase III trial in Breast cancer presented at the 49th European Society for Medical Oncology Congress 2024 (ESMO-2024)

30 Jun 2023Phase-III clinical trials in Breast cancer (Metastatic disease, Late-stage disease, Combination therapy, Second-line therapy or greater) in China (PO) (NCT05433480)
02 Jun 2023Efficacy, adverse events and PK data from a phase I trial in Solid tumours presented at the 59th Annual Meeting of the American Society of Clinical Oncology (ASCO-2023)

Cyclin-dependent kinases (CDKs) are a class of serine / threonine protein kinases that participate in the regulation of the cell cycle, transcription initiation, and control of certain specific metabolic cascades. Different CDKs and cyclins form CDK-cyclin complexes. If the CDK activity is dysregulated, it will directly or indirectly cause uncontrolled cell proliferation, genomic instability (increased DNA mutation, chromosome deletion, etc.) and chromosomal instability (change in chromosome number). )Wait.

The CDKs family has identified more than 20 subtypes. CDK1, CDK2, CDK4, and CDK6 are involved in cell cycle regulation; CDK7, CDK8, CDK9, and CDK11 are involved in transcription regulation; and other kinases include CDK3 and CDK5. Among them, CDK4 / 6 (cyclin-dependent kinases 4 and 6) is a key factor in regulating the cell cycle. Cancer-related cell cycle mutations mainly exist in the G1 and G1 / S phase transformation. CDK4 / 6 binds to CyclinD A complex with kinase activity is formed and phosphorylation of the tumor suppressor gene Rb product pRb releases the bound transcription factor E2F to initiate transcription of genes related to the S phase, prompting cells to pass the checkpoint and transfer from the G1 phase to the S phase. The specific activation of CDK4 / 6 is closely related to the proliferation of some tumors. About 80% of human tumors have abnormalities in the cyclin D-CDK4 / 6-INK4-Rb pathway. CDK4 / 6 inhibitors block the cell cycle in the G1 phase, thereby inhibiting tumor proliferation.

The development of drugs targeting CDK4 / 6 kinases is a significant area. The advantages of anti-tumor targets are: (1) Most proliferating cells rely on CDK2 or CDK4 / 6 to proliferate, but CDK4 / 6 inhibitors do not show Cytotoxicity of “pan-CDK inhibitors”, such as bone marrow suppression and intestinal response; (2) Preclinical experiments show that if the level of cyclin D or the inactivation of P16INK4a can increase the sensitivity of cells to drugs, due to tumors Compared with normal cells, cells have the above phenomenon, so the targeting of drugs is increased to a certain extent.

PCT International Application PCT / CN2017 / 117950 describes a class of benzimidazole derivatives that are used as CDK4 / 6 protein kinase inhibitors, and most of these compounds effectively inhibit CDK4 and CDK6. Because there are still unmet needs in the treatment options for kinase-mediated diseases, here we further screen the salt forms and crystal forms of benzimidazole derivatives to meet the medical needs of patients.

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Patent

Betta Pharmaceuticals Co., Ltd., WO2019242719

https://patents.google.com/patent/WO2019242719A1/en

Synthesis of 1-A1-01 (Step 1)

In a 50L reactor, add 20L of dichloromethane (DCM), 1-A1-S1 (300g), and triethylamine (390g). While stirring, lower the temperature to below -5 ° C, and add benzyl chloroformate / Cbz- Cl (570 g) was added dropwise for 5 hours, and the temperature was naturally raised to room temperature. TLC (ethyl acetate: n-hexane = 1: 3) was monitored until the reaction was completed. Water (1.5 L) was added, and concentrated hydrochloric acid (80 mL) was slowly added dropwise to control the pH to 1-2. The solution was allowed to stand and separate. The organic phase was washed with 15 L of water, dried over anhydrous sodium sulfate for 0.5 hours, filtered to remove the desiccant, and collected the filtrate. And concentrated to obtain 730 g of light yellow oily liquid, which is crude 1-A1-01, yield 95.4%

Synthesis of 1-A1-02 (Step 2)

720mL of DCM, N, N-dimethylsulfoxide (90g) was added to a 20L reaction flask, protected by nitrogen, and the temperature was lowered below -65 ° C under stirring, and oxalyl chloride (106g) was added dropwise. The addition was completed in 2 hours. Stir for 20 minutes under heat preservation; add 1-A1-01’s dichloromethane solution (143g / 500mL DCM) dropwise. After 40 minutes, the addition is complete and the reaction is held for 15 minutes. Controlled at this temperature, TEA was added dropwise. After the addition was completed for 2 hours, the temperature was naturally raised to -20 ° C. 250 L of water was added to the system. The pH of the system was adjusted to 1-2 with hydrochloric acid. × 2) Washed, dried over anhydrous sodium sulfate, filtered to remove the desiccant, collected the filtrate and concentrated to obtain 432 g of a yellow oily liquid, which is the crude product 1-A1-02, which was directly used in the next reaction.

Synthesis of 1-A1-03 (Step 3)

In a stirred state, 400 mL of tetrahydrofuran (THF) and potassium tert-butoxide (215 g) were sequentially added to a 1 L reaction kettle, the temperature was lowered to 5-15 ° C., and triethyl phosphoryl acetate (430 g) was added dropwise. The dropwise addition was completed in 50 minutes. At a controlled temperature of 15 ° C, a tetrahydrofuran solution of 1-A1-02 (431 g / 100 mL of THF) was added dropwise. After the dropwise addition was completed for 1 hour, TLC (ethyl acetate: n-hexane = 1: 3) was monitored to complete the reaction, and the system was added. Saturated aqueous sodium chloride solution (1.5L), allowed to stand and separate, and collected the tetrahydrofuran phase; the aqueous phase was extracted with dichloromethane (2L), and the organic phases were combined and dried over anhydrous sodium sulfate for 0.5 hours, and the drying agent was removed by filtration. The filtrate was collected and concentrated, and the concentrate was purified by column chromatography to obtain 390 g of a pale yellow oily liquid, which was 1-A1-03 product.

Synthesis of 1-A1-041 (step 4)

In a 5L reactor, an aqueous solution of sodium hydroxide (301 g / 1.5 L of water) was added to a tetrahydrofuran (601 g / 2.3 L of THF) solution of 1-A1-03, and the mixture was heated to reflux for 3-4 hours to stop the reaction. The temperature was lowered to 40-50 ° C, and the layers were left to stand. The organic phase (THF) was collected and concentrated to a large amount of solids; the solids were dissolved by adding water (20L), and the aqueous phase was sequentially treated with methyl tert-butyl ether (2L) and ethyl acetate. Ester (2L), methyl tert-butyl ether (2L) washing; the aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid, extracted twice with ethyl acetate (1.5L, 3L), the organic phases were combined, and anhydrous sulfuric acid was used Sodium was dried for 0.5 hours; the desiccant was removed by filtration, and the filtrate was collected and concentrated to a large amount of solids. The solids were added with isopropyl ether (3L) and slurried for 2 hours. The solids were collected by filtration and the solids were rinsed with isopropyl ether (1L). The solid was air-dried at 50 ° C for 3-4 hours to obtain 331 g of a pale yellow solid, which is a 1-A1-041 product with a yield of 52.7%.

Synthesis of 1-051 (step 5)

In a stirred state, 1-A1-041 (600g), methanol (25L), and concentrated sulfuric acid were added to a 50L reactor, and the reaction was heated under reflux for 3-4 hours. After the reaction was completed, the temperature was reduced to room temperature. Dichloromethane (15L) was added to the concentrate, and the pH was adjusted to 9-10 with an aqueous solution of potassium carbonate. The organic phase was collected by stirring, standing, and separating. The organic phase was dried over anhydrous sodium sulfate for 0.5 hours. The desiccant was removed by filtration and the filtrate was collected. And concentrated to obtain 6.37 kg of off-white solid, which is 1-A1-051 product, with a yield of 97.3%.

Synthesis of 1-A1 (step 6)

In a 2L hydrogenation kettle, add 1-A1-051 (500g), methanol (1.8L), and palladium on carbon. The system replaces nitrogen 3 times and hydrogen 3 times in sequence. The system maintains a hydrogen atmosphere, and the temperature is increased to 85 ° C and the pressure is 3.0. The reaction was carried out at Mpa for 3 hours, and the reaction was completed. The temperature was lowered to room temperature, the palladium on carbon was removed by filtration, and the organic phase was collected and concentrated until a large amount of light yellow solid appeared. Isopropyl ether (3L) was added to freeze (-20 ° C) for crystallization, and the solid product was collected by filtration. Ether (500 mL) was rinsed to obtain 234 g of a pale yellow solid, which was a 1-A1 product with a yield of 90.5%.

Synthesis of 1-A2 (Step 7)

In a stirred state, 1-A1 (200g), 4-bromo-2,6-difluoroaniline (410g), and toluene (1.2L) were added to a 50L reactor, and phosphorus oxychloride (413g) was added dropwise to the system. The addition was completed in 1 hour. Triethylamine was added dropwise under an ice bath, and the addition was completed in 1 hour. The temperature was raised to 110 ° C, and the reaction was performed for 1 hour. Reduce the temperature of the system to 2-10 ° C, add 1L of water, adjust the pH = 9-10 with saturated potassium carbonate aqueous solution, extract twice with ethyl acetate (1.5L, 1L), and combine the organic phases with 2L saturated sodium chloride aqueous solution. Wash, dry with anhydrous sodium sulfate for 0.5 hours, remove the desiccant by filtration, collect the filtrate and concentrate to the appearance of a solid product, add isopropyl ether (1L) to beat the solid for 10 minutes, filter, and collect 460 g of a yellow solid as a 1-A2 product.

Synthesis of 1-A3 (step eight)

Under stirring, 1-A2 (450g), N, N-dimethylformamide (2L), and cesium carbonate (700g) were added to the reaction kettle, and the reaction was heated to 110 ° C for 24 hours, and the reaction was detected by TLC. Ethyl acetate (3L) was added to the system, and solid impurities were removed by filtration. The filtrate was washed with a saturated sodium chloride aqueous solution (1L × 5), and the organic phase was dried over anhydrous sodium sulfate for 0.5 hours, concentrated to the appearance of a large amount of solid, Butyl ether (1L × 2) was beaten for 30 minutes, and 382 g of pale yellow solid product was obtained by filtration, that is, 1-A3, and the yield was 90.10%.

Synthesis of 1-01 (step 9)

With stirring, 1-A3 (380 g), pinacol diborate (400 g), potassium acetate (340 g), palladium acetate (6 g), tricyclohexyl phosphorus (7 g), and 1,4-dioxane were sequentially added. The ring was added to the reaction kettle, protected by nitrogen, and heated to 90 ° C for 2 hours. TLC was monitored until the reaction was complete. The temperature was reduced to room temperature, and the filtrate was concentrated to remove a large amount of 1,4-dioxane. The concentrate was purified by n-hexane and dichloromethane column chromatography, and n-hexane (1.2 L) was slurried for 1 hour to obtain 334 g of a gray solid. That is 1-01, and the yield is 70.10%.

Synthesis of 1-02 (step 10)

Under stirring, take 1-01 (128g), 1,4-dioxane (1L), 1-S3 (85g), potassium carbonate (110g), and purified water and add them to a 2L three-necked flask in sequence. [1,1′-Bis (diphenylphosphine) ferrocene] palladium dichloromethane complex (Pd (dppf) Cl ₂ .DCM) was added. The temperature was raised to 60 ° C. After 4 hours of reaction, the reaction was complete. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove most of 1,4-dioxane. Dichloromethane (1.5 L) and purified water (1.1 L) were added, stirred, and allowed to stand and separate. The layers were separated, and water was added. The phases were extracted with dichloromethane (10 L), the organic phases were combined, washed with 0.5% dilute hydrochloric acid (1 L x 2), saturated aqueous sodium chloride solution (1 L), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate (500 g), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. Ethyl acetate (0.5 L) was added to the concentrate and the mixture was stirred for 30 minutes to precipitate a solid. After filtration, the obtained solid was rinsed with ethyl acetate (0.5 L) and dried under vacuum at 45 ° C for 3 hours to obtain 120 g of a yellow solid.

Synthesis of 1-03 (step 11)

Under stirring, take 1-02 (100g), 1,4-dioxane (1L), 1-C2 (80g), and cesium carbonate (163g) into a 2L three-necked bottle in sequence, protected by nitrogen, and add palladium acetate ( 2g) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthracene (Xantphos) (4g), heated to 85 ° C. until the reaction was complete. The reaction solution was cooled to room temperature and filtered to obtain a solid product. The solid was rinsed with ethyl acetate, and then added to a mixed system of dichloromethane (1.5 L) and purified water (1.1 L), stirred, allowed to stand, and separated into layers. The aqueous phase was extracted with dichloromethane (700 mL). The organic phases were combined and washed with purified water (700 mL x 2). The organic phase was dried by adding anhydrous sodium sulfate (700 g), filtered to remove the desiccant, and the filtrate was concentrated. Methanol (0.5 L) was added, heated to 55-65 ° C. and stirred for 0.5 hours, lowered to room temperature, and filtered. The solid product was filtered and rinsed with 500 mL of ethyl acetate. The solid was dried under vacuum at 45 ° C for 8 hours to obtain 111.79 g of a pale yellow solid 1-03.

Synthesis of compound II (step twelve)

Under stirring, take 1-03 (500g) and anhydrous methanol (3.8L), add them to a 10L reactor in sequence, and heat to 65 ° C. After the reaction system is clarified for 0.5 hours, add L-tartaric acid in methanol (150.89) dropwise. g of tartaric acid is dissolved in 500mL of anhydrous methanol), and the dropping time is controlled to be 45 to 60 minutes. After the addition is complete, the reaction is kept at 65 ° C for 4 hours. ), Control the dropwise addition time to 30 to 45 minutes. After the dropwise addition is complete, hold the reaction at 65 ° C for 1 hour. Continue to dropwise add L-tartaric acid in methanol (36.55g of tartaric acid dissolved in 250mL of anhydrous methanol) and control the dropwise addition time to 30. To 45 minutes, the dropwise addition was completed. The temperature was kept at 65 ° C for 1.5 hours, and the heating was stopped. The temperature was naturally lowered to 20-30 ° C, filtered, the filter cake was rinsed with methanol (400mL × 2), and dried at 45 ° C under vacuum for 36 hours. 530.64 g of crystalline powder was Compound II, which was identified by X-ray powder diffraction, and showed that the crystal form was Form A of Compound II.

WO2022199656

WO2023131179

[1]. Wang Yiqian, et al. Crystal form of compound useful as CDK4/6 inhibitors for the treatment of cancer. World Intellectual Property Organization, WO2019242719 A1. 2019-12-26.

///Tibremciclib, GTPL12881, BETTA, PHASE 3, CANCER

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Example 1A

Alternate Preparation Example 1B

Crystalline 5-(4-{2-[3-(Fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol, Isomer 2

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Example 27: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine

General Synthetic Methods:

Step 1: (S)-tert-butyl 4-(6′-amino-5′-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4-methoxy-[3,3′-bipyridin]-6-yl)-3-methylpiperazine-1-carboxylate

Step 2: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine

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Example 5

Compound I-5: N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide

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Example 1

tert-Butyl [(2R)-1-(4-bromophenoxy)propan-2-yl]carbamate (1)

Example 2

6-Fluoroimidazo[1,2-b]pyridazine methanesulfonate (2)

Example 3

tert-Butyl {(2R)-1-[4-(6-fluoroimidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate (3)

Example 4

tert-Butyl {(2R)-1-[4-(6-{[(1R)-1-(3-fluorophenyl)ethyl]amino}imidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate hydrochloride (4)

Example 5

3-{4-[(2R)-2-Aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethylimidazo[1,2-b]pyridazin-6-amine dihydrochloride (5)

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Example 3: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide

Step 1: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine

Step 2: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine

Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide

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Step 1: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N⁵-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine

Step 2: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N⁵-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine