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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Cirtociclib
Cirtociclib
CAS 2888704-84-3
MF C15H17F2N7O2 MW365.34 g/mol
N-[3-(difluoromethoxy)-1H-pyrazol-5-yl]-1-(oxan-4-ylmethyl)pyrazolo[3,4-b]pyrazin-6-amine
N-[5-(difluoromethoxy)-1H-pyrazol-3-yl]-1-[(oxan-4-yl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-amine
cyclin-dependent kinase inhibitor, antineoplastic, BLU-222, BLU 222, BLU 170298, U93X72ED47, CDK2 Inhibitor BLU-222
Cirtociclib (also known as BLU-222) is an investigational drug that acts as a highly selective inhibitor of cyclin-dependent kinase 2 (CDK2). It is being developed by Blueprint Therapeutics for the treatment of advanced solid tumours, particularly those with genetic drivers like CCNE1 amplification, which are common in certain ovarian and breast cancers
Certociclib is a small molecule drug. Certociclib is under investigation in clinical trial NCT05252416 ((VELA) Study of BLU-222 in Advanced Solid Tumors). Certociclib has a monoisotopic molecular weight of 365.14 Da.
Certociclib is an orally bioavailable inhibitor of cyclin-dependent kinase 2 (CDK2), with potential antineoplastic activity. Upon administration, certociclib selectively targets, binds to and inhibits the activity of CDK2. This may lead to cell cycle arrest, the induction of apoptosis, and the inhibition of tumor cell proliferation. CDK2, a serine/threonine kinase that plays an important role in the regulation of cell cycle progression and cellular proliferation, is overexpressed in certain tumor cells.
How It Works
- Targeting CDK2: It binds to CDK2, a protein that regulates the cell cycle.
- Cell Cycle Arrest: By inhibiting CDK2, the drug causes G1 arrest, preventing cancer cells from replicating.
- Selectivity: It is designed to be “best-in-class” for its high selectivity for CDK2 over other kinases like CDK1, CDK4, or CDK6.
Therapeutic Potential
- Ovarian Cancer: Specifically targets high-grade serous ovarian cancer where CCNE1 is amplified.
- Breast Cancer: Shows promise in treating hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer, especially when the cancer has become resistant to existing CDK4/6 inhibitors.
- Combination Therapy: Researchers are testing it alongside other drugs, such as palbociclib, ribociclib, or chemotherapy agents like carboplatin, to enhance efficacy.
Current Status
- Clinical Trials: It is currently being evaluated in a Phase 1/2 clinical trial known as the VELA study (NCT05252416) for patients with advanced solid tumours.
- Research Status: It is not yet approved for general medical use and is primarily available for research and clinical trial participants.
(VELA) Study of BLU-222 in Advanced Solid Tumors
CTID: NCT05252416
Phase: Phase 1
Status: Terminated
Date: 2025-11-28
🌟 Key Point: Cirtociclib represents a new generation of precision medicine aimed at overcoming resistance to standard cancer therapies by specifically targeting the CDK2 pathway
PAT
The structure of one CDK2 inhibitor, referred to herein as “a compound of formula (I)” or N-(5-(difluoromethoxy)-lH-pyrazol-3-yl)-l-((tetrahydro-2H-pyran-4-yl)methyl)-lH-pyrazolo[3,4-b]pyrazin-6-amine is shown below:
PAT
Example 2
N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine
A mixture of 6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 87, 780 mg, 3.09 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (554 mg, 3.72 mmol), tBuXphos Pd G3 (150 mg, 0.19 mmol) and KOAc (892 mg, 9.08 mmol) in dioxane (15 mL) was stirred at 90° C. for 6 h under N 2. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by prep-HPLC-4 to afford the title compound as a white solid (361.4 mg, 32%). LCMS m/z=366 [M+H] +; 1H NMR (400 MHz, DMSO-d 6) δ: 12.21 (s, 1H), 10.82 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.32 (t, 1H), 5.98 (d, 1H), 4.40 (d, 2H), 3.87-3.75 (m, 2H), 3.29-3.16 (m, 2H), 2.24-2.11 (m, 1H), 1.46-1.29 (m, 4H).
PAT
- The cdk2 inhibitor blu-222 for treatment of cancerPublication Number: WO-2024168298-A1Priority Date: 2023-02-10
- Solid forms of a cdk2 inhibitorPublication Number: WO-2024148083-A1Priority Date: 2023-01-04
- Cdk2 inhibitorsPublication Number: US-2023322791-A1Priority Date: 2021-06-28
- Cdk2 inhibitorsPublication Number: US-2023159535-A1Priority Date: 2021-06-28
- CDK2 inhibitorsPublication Number: US-11970498-B2Priority Date: 2021-06-28Grant Date: 2024-04-30
- Cdk2 inhibitorsPublication Number: US-2024383902-A1Priority Date: 2021-06-28
- CDK2 inhibitorsPublication Number: US-11932648-B2Priority Date: 2021-06-28Grant Date: 2024-03-19
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References
/////////cirtociclib, cyclin-dependent kinase inhibitor, antineoplastic, BLU-222, BLU 222, BLU 170298, U93X72ED47, CDK2 Inhibitor BLU-222
Catadegbrutinib
Catadegbrutinib
CAS 2736508-60-2
MF C47H54N12O4 MW851.0 g/mol
3-tert-butyl-N-[(1R)-1-[4-[6-[6-[4-[[1-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-pyridinyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide
3-tert-butyl-N-{(1R)-1-[13-methyl-82,84-dioxo-27H-2(4,6)-pyrrolo[2,3-d]pyrimidina-8(1)-[1,3]diazinana-4(1,4)-piperazina3(5,2)-pyridina-6(4,1)-piperidina-1(1),7(1,4)-dibenzenaoctaphan-14-yl]ethyl}-1,2,4-oxadiazole-5-carboxamide
Bruton tyrosine kinase degrader, antineoplastic, BGB-16673, BGB 16673, PF6GPZ4DYT, BTK-IN-29, Tacabrutideg
Catadegbrutinib (BGB-16673) is an orally active, potent Bruton’s tyrosine kinase (BTK) degrader, or chimeric degradation activator compound (CDAC). It works by targeting BTK for proteasomal degradation, showing high efficacy against wild-type and mutated forms (including C481S) in B-cell malignancies. It is under investigation for cancers such as CLL, SLL, and MCL.
Key Details About Catadegbrutinib
- Mechanism of Action: As a PROTAC-class molecule, it binds to BTK and recruits E3 ubiquitin ligase, causing polyubiquitination and degradation of the protein.
- Target Potency: It shows strong degradation activity, with a
of
(concentration required for 50% degradation) and a
binding
of
.
- Clinical Potential: Developed for B-cell malignancies (chronic lymphocytic leukemia, mantle cell lymphoma) that have developed resistance to covalent and non-covalent BTK inhibitors.
- Synonyms/Codes: BGB-16673, BGB-116673, BTK-IN-29, and recently listed in WHO proposed INN as tacabrutideg.
- Status: Used primarily in research for treating B-cell malignancies, lymphomas, and potentially autoimmune diseases.
Catadegbrutinib is designed to overcome resistance mechanism challenges seen with existing BTK inhibitors.
SYN
Example 14: (R) -3- (tert-butyl) -N- (1- (4- (6- (6- (4- ( (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) -2-methylphenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide
[0357]
Step 1: tert-butyl 4- (5- (4-chloro-7H-pyrrolo [2, 3-d] pyrimidin-6-yl) pyridin-2-yl) piperazine-1- carboxylate
A mixture of 4-chloro-6-iodo-7H-pyrrolo [2, 3-d] pyrimidine (3 g, 10.73 mmol) , tert-butyl 4- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate (4.18 g, 10.73 mmol) , Na 2CO 3(1.25 g, 11.80 mmol) and Pd (dppf) Cl 2(0.39 g, 0.537 mmol) in dioxane (120 mL) and H 2O (20 mL) was stirred in a sealed tube at 85 ℃ overnight. After cooling, the reaction mixture was filtered and the solid was washed with 20 mL of MeOH and dried under vacuum to afford the product (4.05 g, 91%) . [M+H] += 415.0.
[0360]
Step 2: tert-butyl (R) -4- (5- (4- (4- (1- (3- (tert-butyl) -1, 2, 4-oxadiazole-5-carboxamido) ethyl) -3- methylphenyl) -7H-pyrrolo [2, 3-d] pyrimidin-6-yl) pyridin-2-yl) piperazine-1-carboxylate
A mixture of tert-butyl 4- (5- (4-chloro-7H-pyrrolo [2, 3-d] pyrimidin-6-yl) pyridin-2-yl) piperazine-1-carboxylate (0.9 g, 2.17 mmol) , (R) -3- (tert-butyl) -N- (1- (2-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide (0.94 g, 2.28 mmol) , Na 2CO 3(0.46 g, 4.34 mmol) and Pd (dppf) Cl 2(79.3 mg, 0.108mmol) in dioxane (60 mL) and H 2O (10 mL) was stirred in a sealed tube at 100 ℃ overnight. After cooling, the reaction mixture was filtered and the solid was washed with 5 mL of MeOH and dried under vacuum to afford the product (1.02 g, 70.6%) . [M+H] += 666.0.
[0363]
Step 3: (R) -3- (tert-butyl) -N- (1- (2-methyl-4- (6- (6- (piperazin-1-yl) pyridin-3-yl) -7H- pyrrolo [2, 3-d] pyrimidin-4-yl) phenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide, hydrogen chloride salt
To a solution of tert-butyl (R) -4- (5- (4- (4- (1- (3- (tert-butyl) -1, 2, 4-oxadiazole-5-carboxamido) ethyl) -3-methylphenyl) -7H-pyrrolo [2, 3-d] pyrimidin-6-yl) pyridin-2-yl) piperazine-1-carboxylate (1.02 g, 1.53 mmol) in DCM (50 mL) in a round bottom flask was added HCl in dioxane (4 N, 35 mL) at 0 ℃. The mixture was stirred for 2 h at 20 ℃. The precipitate was collected with filtration and dried in vacuum to afford the product (0.92 g, 100%) . 1H NMR (400 MHz, DMSO) δ H13.53 (s, 1H) , 10.06 (d, J = 7.5 Hz, 1H) , 9.33 (s, 2H) , 9.00 (s, 1H) , 8.93 (s, 1H) , 8.35 (d, J = 8.7 Hz, 1H) , 8.05 (d, J = 8.1 Hz, 1H) , 7.99 (s, 1H) , 7.75 (d, J = 8.0 Hz, 1H) , 7.55 (s, 1H) , 7.12 (d, J = 8.9 Hz, 1H) , 5.50-5.28 (m, 1H) , 3.89 (s, 4H) , 3.20 (s, 4H) , 2.57 (s, 3H) , 1.56 (d, J = 6.9 Hz, 3H) , 1.38 (s, 9H) . [M+H] += 566.3.
[0366]
Step 4: (R) -3- (tert-butyl) -N- (1- (4- (6- (6- (4- ( (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) – yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) -2- methylphenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide
A mixture of (R) -3- (tert-butyl) -N- (1- (2-methyl-4- (6- (6- (piperazin-1-yl) pyridin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) phenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide, hydrogen chloride salt (0.06 g, 0.1 mmol) , 1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (0.033 g, 0.11 mmol) and NaOAc (8.2 mg, 0.1 mmol) in DCM/EtOH (30 mL/10 mL) was stirred in a round bottom flask for 1 h at 20 ℃. Then NaBH 3CN (12.6 mg, 0.2 mmol) was added. The mixture was stirred overnight at 20 ℃. The mixture was concentrated to dryness and purified with silica gel column chromatography (MeOH in DCM from 0%to 12%gradient elution) to give the product (0.049 g, 57.8%) . 1H NMR (400 MHz, DMSO) δ H12.60 (s, 1H) , 10.27 (s, 1H) , 9.97 (d, J =6.1 Hz, 1H) , 8.79 (d, J = 18.7 Hz, 2H) , 8.18 (d, J = 7.8 Hz, 1H) , 8.09 (d, J = 7.0 Hz, 1H) , 8.04 (s, 1H) , 7.67 (d, J = 7.7 Hz, 1H) , 7.30 (s, 1H) , 7.13 (d, J = 6.9 Hz, 2H) , 6.97-6.92 (m, 3H) , 5.41-5.34 (m, 1H) , 3.71-3.68 (m, 4H) , 3.64-3.56 (m, 4H) , 2.70-2.64 (m, 4H) , 2.53 (s, 3H) , 2.47-2.43 (m, 4H) , 2.25-2.19 (m, 2H) , 1.84-1.81 (m, 2H) , 1.75-1.70 (m, 1H) , 1.56 (t, J = 9.1 Hz, 3H) , 1.37 (s, 9H) , 1.28-1.18 (m, 2H) .
PAT
PAT
- Degradation of bruton’s tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of usePublication Number: WO-2021219070-A1Priority Date: 2020-04-30
- Degradation of Bruton’s tyrosine kinase (BTK) by conjugation of BTK inhibitors to E3 ligase ligands and methods of use thereofPublication Number: CN-115485278-APriority Date: 2020-04-30
- Degradation of bruton’s tyrosine kinase (btk) by conjugation of btk inidbitors with e3 ligase ligand and methods of usePublication Number: US-2023167118-A1Priority Date: 2020-04-30
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References
- [1]. Wang H, et al. BGB-16673, a selective BTK degrader, exhibits deeper inhibition of cancer cell signaling pathways and better efficacy in MCL models. Blood, 2024, 144: 5833.[2]. Wu Y, et al. Translational modeling to predict human pharmacokinetics and pharmacodynamics of a Bruton’s tyrosine kinase-targeted protein degrader BGB-16673. Br J Pharmacol. 2024 Dec;181(24):4973-4987. [Content Brief][3]. Hexiang Wang, et al. Degradation of bruton’s tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use. WO2021219070A1. 2021-11-04.
/////////catadegbrutinib, Bruton tyrosine kinase degrader, antineoplastic, BGB-16673, BGB 16673, PF6GPZ4DYT, BTK-IN-29, Tacabrutideg
Birelentinib
Birelentinib
CAS 2662512-15-2
MF C23H21F2N5O3 MW453.4 g/mol
[(2S,5S)-5-[4-amino-5-[4-(2,3-difluorophenoxy)phenyl]imidazo[5,1-f][1,2,4]triazin-7-yl]oxan-2-yl]methanol
[(2S,5S)-5-{4-amino-5-[4-(2,3-difluorophenoxy)phenyl]imidazo[5,1-f][1,2,4]triazin-7-yl}oxan-2-yl]methanol
tyrosine kinase inhibitor, antineoplastic, DZD8586, DZD 8586, Fast Track designation, BTK-IN-30, Z2F599L9GD
Birelentinib (also known as DZD8586) is a first-in-class, non-covalent dual inhibitor of LYN (lymphocyte-specific protein tyrosine kinase) and BTK (Bruton’s tyrosine kinase).
It is currently being developed by Dizal Pharmaceutical as an oral therapy for various B-cell malignancies.
Clinical Status and FDA Designations
As of late 2025, birelentinib has received significant attention for its potential in treating resistant blood cancers:
- Fast Track Designation: In August 2025, the U.S. FDA granted Fast Track designation to birelentinib for adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
- Target Population: It is specifically intended for those who have failed at least two prior therapies, including a covalent BTK inhibitor and a BCL-2 inhibitor.
- Key Trials: It is being evaluated in multiple studies, including the Phase 3 Tai-Shan6 trial comparing it against standard treatments like bendamustine and rituximab.
Unique Therapeutic Properties
Birelentinib is designed to overcome common drug resistance mechanisms found in existing treatments:
- Overcoming Resistance: It targets both BTK-dependent pathways (including the common C481X mutation) and BTK-independent B-cell receptor (BCR) signaling pathways.
- Blood-Brain Barrier (BBB) Penetration: A notable feature is its ability to fully penetrate the blood-brain barrier, which may offer therapeutic benefits for patients with central nervous system (CNS) involvement.
- Efficacy: Early Phase 1/2 data presented at the ASH Annual Meeting and EHA Congress in 2025 showed an Objective Response Rate (ORR) of 84.2% in heavily pretreated patients
Birelentinib is an orally bioavailable non-covalent dual inhibitor of tyrosine-protein kinases Lyn (LYN) and BTK (Bruton’s tyrosine kinase; Bruton agammaglobulinemia tyrosine kinase), with potential antineoplastic activity. Upon oral administration, birelentinib targets and inhibits both LYN and BTK, thereby blocking both BTK-dependent and BTK-independent B-cell antigen receptor (BCR) signaling pathways. This prevents the proliferation of malignant B-cells in which the BCR signaling pathway is overactivated. Birelentinib is able to cross the blood-brain barrier (BBB) and thus potentially useful in the treatment of central nervous system (CNS) metastases
SYN’
SYN
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References
Publication Number: WO-2021136219-A1
Priority Date: 2020-01-02
/////////birelentinib, tyrosine kinase inhibitor, antineoplastic, DZD8586, DZD 8586, Fast Track designation, BTK-IN-30, Z2F599L9GD
Balomenib
Balomenib
CAS 2939850-17-4
MF C33H34F3N7O2 MW617.7 g/mol
4-methyl-1-[[(2S)-5-oxomorpholin-2-yl]methyl]-5-[[2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl]indole-2-carbonitrile
- 1H-Indole-2-carbonitrile, 4-methyl-1-[[(2S)-5-oxo-2-morpholinyl]methyl]-5-[[2-[6-(2,2,2-trifluoroethyl)-4-quinazolinyl]-2,7-diazaspiro[3.5]non-7-yl]methyl]-
- 4-methyl-1-[(2S)-5- oxomorpholin-2- yl]methyl]-5- [[2-[6-(2,2,2- trifluoroethyl) quinazolin-4-yl]-2,7- diazaspiro[3.5]nonan- 7-yl]methyl]indole-2- carbonitrile
4-methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-7-
yl}methyl)-1H-indole-2-carbonitrile
menin inhibitor, antineoplastic, ZE63-0302, 3BEG4BWN8E
Balomenib (also known as ZE63-0302) is an oral, small-molecule menin inhibitor currently in clinical development for metabolic and oncological conditions. It works by disrupting the protein-protein interaction between menin and KMT2A (formerly MLL), a mechanism that plays a critical role in both pancreatic beta-cell function and certain types of leukemia.
Key Therapeutic Areas
- Type 2 Diabetes (T2D): Balomenib is being investigated as a potentially disease-modifying treatment to improve pancreatic beta-cell function and survival. As of late 2025, it has advanced into Phase 1b clinical trials specifically for adults with T2D to evaluate its effects on fasting glucose, insulin dynamics, and HbA1c.
- Oncology (AML): It is also a candidate for treating acute myeloid leukemia (AML) with KMT2A rearrangements or NPM1 mutations. Preclinical data suggests it may be more effective against resistance mutations than earlier menin inhibitors.
Development and Safety
- Corporate Development: The drug was originally developed by Eilean Therapeutics. It is now the lead program for Clywedog Therapeutics, which is merging with Barinthus Biotherapeutics to focus on metabolic diseases.
- Safety Profile: Early trial results indicate a favorable safety profile. Notably, it was designed to minimize QTc prolongation (heart rhythm issues), a side effect common in other menin inhibitors.
- Сlinical Study Aiming to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of ZE63-0302 in Healthy VolunteersCTID: NCT06780124Phase: Phase 1Status: CompletedDate: 2026-01-22
- Study to Assess Safety, Tolerability, PK, and PD of Multiple Doses of ZE63-0302 Administrated Orally in T2DM Patients.CTID: NCT07234864Phase: Phase 1Status: RecruitingDate: 2026-01-22
SYN
Example 46. 4-Methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (Compound 102)
Compound was prepared using procedure described in the Example 45 and 5-formyl-4-methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-1H-indole-2-carbonitrile P177 instead of 5-formyl-4-methyl-1-{[(2R)-5-oxomorpholin-2-yl]methyl}-1H-indole-2-carbonitrile P176. Compound 102 was obtained with yield 49%. 1H NMR (400 MHz, DMSO-d 6), δ: 8.46 (s, 1H), 7.99 (m, 2H), 7.73 (m, 2H), 7.52 (m, 1H), 7.46 (d, J=5.6 Hz, 1H), 7.31 (d, J=4.8 Hz, 1H), 4.54 (m, 1H), 4.20 (m, 2H), 4.05 (m, 1H), 3.90 (m, 4H), 3.52 (m, 2H), 3.35 (m, 1H), 3.17 (m, 1H), 2.39 (m, 2H), 1.79 (m, 4H). LCMS (ESI) [MH] +: 618.
PAT
Example 46. 4-Methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (Compound 102)
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References
- Inhibitors of menin-mll interactionPublication Number: WO-2023107696-A2Priority Date: 2021-12-09
- Inhibitors of menin-mll interactionPublication Number: US-2025163061-A1Priority Date: 2021-12-09
- Inhibitors of menin-mll interactionPublication Number: EP-4444300-A2Priority Date: 2021-12-09
///////////balomenib, menin inhibitor, antineoplastic, ZE63-0302, 3BEG4BWN8E
Atebimetinib
Atebimetinib
CAS 2669009-92-9
MF C23H27FN4O6S MW506.5 g/mol
[4-[(dimethylamino)methyl]-3-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-2-oxochromen-7-yl] N,N-dimethylcarbamate
4-[(dimethylamino)methyl]-3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-2-oxo-2H-1-benzopyran-7-yl
dimethylcarbamate
MEK tyrosine kinase inhibitor, antineoplastic, IMM-104, IMM 104, Fast Track designation, TEL9243A3N
Atebimetinib (IMM-104) is an investigational oral, deep cyclic inhibitor (DCI) that targets the MAP kinase (MAPK) pathway in solid tumors, particularly RAS-mutant pancreatic cancer. Designed for rapid, pulsatile inhibition to minimize resistance and side effects, it is currently in Phase 2a trials, having shown promising, durable tumor shrinkage and high 1-year survival rates.
Key Aspects of Atebimetinib:
- Mechanism of Action: As a DCI, it works differently from standard inhibitors by targeting MAPK with a short half-life, allowing for rapid “pulsing” that suppresses tumor growth while permitting healthy cells to recover, thus improving tolerability.
- Targeted Cancers: Primarily aimed at RAS-mutant advanced or metastatic solid tumors, including pancreatic ductal adenocarcinoma (PDAC).
- Clinical Trial Results: In a Phase 2a study (NCT05585320), the combination of atebimetinib with modified chemotherapy showed a 64% overall survival (OS) rate at 12 months for first-line pancreatic cancer patients.
- Fast Track Designation: In 2024, the FDA granted fast track designation for atebimetinib to treat patients with pancreatic adenocarcinoma who have progressed after one line of therapy.
- Advantage over Traditional Inhibitors: It is designed to avoid typical MAP kinase inhibitor adverse events like pyrexia (fever) while overcoming the rapid resistance often seen in other therapies.
Atebimetinib is being developed by Immuneering Corporation.
Development Status
- FDA Designations: In 2024, the FDA granted atebimetinib Fast Track designation for patients with pancreatic adenocarcinoma (PDAC) who have progressed after one line of treatment.
- Future Plans: A global registrational Phase 3 trial, named MAPKeeper 301, is planned to begin dosing patients in mid-2026.
Clinical Trial Results (Phase 2a)
Recent data from the Phase 2a trial (as of early 2026) showed significant survival benefits when combined with modified chemotherapy (gemcitabine and nab-paclitaxel) for first-line pancreatic cancer:
- Overall Survival (OS): Reported at 94% at 6 months, 86% at 9 months, and 64% at 12 months. This is roughly double the 1-year survival rate typically seen with standard chemotherapy alone (~35%).
- Progression-Free Survival (PFS): Median PFS reached 8.5 months.
- Disease Control Rate: Approximately 81% of patients achieved disease control.
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WO2023076991 COMBINATION THERAPY FOR TREATING ABNORMAL CELL GROWTH
SYN
WO2025010293 MEK IMMUNE ONCOLOGY INHIBITOR PHARMACEUTICAL COMPOSITIONS
EXAMPLE 1A
Synthesis of Compound A
[0198] Compound A was prepared in 1 step:
[0199] 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (22.22 g, 34.79 mmol) was suspended in methanol. Dimethylamine 2M was added and the formed reaction mixture was stirred until full conversion was observed. After full conversion the reaction was concentrated under reduced pressure. IM HC1 was added to the residue and the water layer was extracted with CH2CI2. The water layer was made basic with solid Na CCE. The basic water layer was extracted with CH2CI2. The organic layer from the basic extraction was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound (13.23 g, 25.7 mmol, yield: 74%) as a light yellow amorphous solid.
[0200] Yield: Compound A was isolated as a light yellow solid (74% over 1 step). Analysis: LCMS (Method T): tR = 1.53 min; m/z calculated for [M+H]+ = 507.2, found = 507.2; 1H NMR (400 MHz, DMSO) d 9.38 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.28 (td, J = 8.0, 1.6 Hz, 1H), 7.25 – 7.18 (m, 2H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.90 – 6.77 (m, 1H), 4.04 (s, 2H), 3.64 (s, 2H), 3.06 (s, 3H), 2.93 (s, 3H), 2.52 (d, J = 4.9 Hz, 3H), 2.19 (s, 6H).
ADVT
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References
- Mek immune oncology inhibitor pharmaceutical compositionsPublication Number: WO-2025010293-A2Priority Date: 2023-07-03
- Inhibiting mitogen-activated protein (map)/erk kinase (mek)1 and mek2 and related methods of treatmentPublication Number: WO-2024220440-A1Priority Date: 2023-04-17
- Methods of treating cancer with a ras mutationPublication Number: WO-2024186693-A1Priority Date: 2023-03-03
- Combination therapy for treating abnormal cell growthPublication Number: WO-2023235356-A1Priority Date: 2022-06-03
- Combination therapy for treating abnormal cell growthPublication Number: WO-2023147297-A2Priority Date: 2022-01-25
- Methods of treating abnormal cell growthPublication Number: WO-2023081676-A1Priority Date: 2021-11-02
- Combination therapy for treating abnormal cell growthPublication Number: WO-2023076991-A1Priority Date: 2021-10-28
- Mek inhibitors and therapeutic uses thereofPublication Number: US-2023119327-A1Priority Date: 2020-01-10
//////atebimetinib, FLAX LAB, antineoplastic, IMM-104, IMM 104, Fast Track designation, TEL9243A3N
Anvumetostat
Anvumetostat
CAS 2790567-82-5
MF C22H19F3N4O3 MW444.4 g/mol
(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone
(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl){(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl}methanone
antineoplastic, AMG 193, QAT649EJ5E, PRMT5-IN-27,
Anvumetostat (also known as AMG 193) is an orally available, small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5), primarily being developed for the treatment of advanced solid tumours with MTAP-null (methylthioadenosine phosphorylase-deficient) mutations.
Mechanism of Action
- Targeting PRMT5: It is a potent and selective MTA-cooperative inhibitor of PRMT5.
- Synthetic Lethality: In cells where the MTAP gene is deleted (a common occurrence in various cancers), a metabolite called MTA (methylthioadenosine) accumulates. Anvumetostat selectively binds to the PRMT5-MTA complex, inhibiting its methyltransferase activity.
- Cellular Impact: By blocking PRMT5, the drug reduces the methylation of arginine residues in histones (H2A, H3, and H4), which can lead to decreased growth or death of cancer cells.
Clinical Development
Anvumetostat was initially developed by Amgen, Inc. and is currently in clinical trials. Institute (.gov) +1
- Current Status: As of early 2026, it is in Phase 2 of global research and development.
- Study Focus: Trials are evaluating its efficacy both as a monotherapy and in combination with other treatments for adult patients with metastatic or locally advanced MTAP-null cancers.
Key Identifiers
- Alternate Names: AMG 193, AMG-193.
- Chemical Class: Orally bioavailable small molecule.
- Genetic Biomarker: Specifically targets cancers with MTAP-null status
Anvumetostat is an orally available small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5), with potential antiproliferative and antineoplastic activities. Upon oral administration, anvumetostat selectively binds to PRMT5 and inhibits its function. By inhibiting its methyltransferase activity, levels of both monomethylated and dimethylated arginine residues in histones H2A, H3 and H4 are decreased. This modulates the expression of genes involved in several cellular processes, including cellular proliferation. This may increase the expression of antiproliferative genes and/or decrease the expression of genes that promote cell proliferation, which may lead to decreased growth of rapidly proliferating cells, including cancer cells. PRMT5, a type II methyltransferase that catalyzes the formation of both omega-N monomethylarginine (MMA) and symmetric dimethylarginine (sDMA) on histones and a variety of other protein substrates involved in signal transduction and cellular transcription, is overexpressed in several neoplasms. Elevated levels are associated with decreased patient survival. Methylthioadenosine phosphorylase (MTAP) is deleted in certain cancer cells leading to an accumulation of methylthioadenosine (MTA). As MTA inhibits PRMT5, MTAP-null cancer cells are specifically sensitive to PRMT5 inhibitors.
SYN
[0163] Examples 481 and 482: (4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4- (trifluoromethyl)phenyl)morpholino)methanone
[0164] Step 1: To a solution of 3-(4-(trifluoromethyl)phenyl)morpholine (0.100 g, 0.432 mmol, Enamine), 4-((2,4-dimethoxybenzyl)amino)-l,3-dihydrofuro[3,4-c][l,7]naphthyridine-8-carboxylic acid hydrochloride (138) (0.271 g, 0.649 mmol) and l,l’-dimethyltriethylamine (0.559 g, 0.755 mL, 4.32 mmol, Sigma- Aldrich Corporation) in DMF (4 mL) was added bromotripyrrolidinophosphonium hexafluorophosphate (0.202 g, 0.432 mmol, Sigma-Aldrich Corporation) and the resulting mixture was heated at 50 °C for 30 min. The reaction was brought to rt, diluted with water, sat.NaHCCh and extracted with EtOAc (3x). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was then chromatographed on silica gel using 0-50% 3:1 EtOAc/EtOH in heptane to afford (4-((2,4-dimethoxybenzyl)amino)- 1 ,3 -dihy drofuro [3 ,4-c] [ 1 ,7]naphthyridin-8-y 1) (3 – (4 -(trifluoromethyl)phenyl)morpholino)methanone (0.160 g, 0.269 mmol, 62.2% yield) as a light yellow solid, m/z (ESI): 595 (M+H)+.
[0165] To a solution of (4-((2,4-dimethoxybenzyl)amino)-l,3-dihydrofuro[3,4-c] [l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (0.160 g, 0.269 mmol, 62.2 % yield) in DCM (2 mL) was added TFA (14.80 g, 10 mL, 130 mmol, Aldrich) and the resulting mixture was heated at 50 °C for 1 h. The reaction was concentrated, washed with 10% Na2CO3 and extracted with DCM. The combined organics were concentrated and chromatographed on silica gel using 0-50% 3:1 EtOAc/EtOH in heptane to afford (4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone as the TFA salt (0.078 g, 0.140 mmol, 32.3% yield) as an off-white solid, m/z (ESI): 445 (M+H)+.
[0166] Step 2: (S)-(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4- (trifluoromethy l)phenyl)morpholino)methanone and (R)-(4-amino- 1 ,3 -dihy drofuro [3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone
(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 2,2,2-trifluoroacetate were separated via preparative SFC using a Chiral Technologies AD column (150 x 21 mm, 5mm) with a mobile phase of 60% Liquid CO2 and 40% MeOH with 0.2% TEA using a flowrate of 80 mL/min to generate peak 1, (S)-(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone with an ee of >99%, and peak 2, (R)-(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone with an ee of 99.28%. Peak assignment determined by
SFC with AD column with 60% Liquid CO2 and 40% MeOH with 0.2% TEA and absolute
stereochemistry was arbitrarily assigned.
Peak 1: (S)-(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (481) as a white solid . m/z (ESI): 445 (M+H)+. NMR 1H (400 MHz, DMSO-d6) 5 ppm 8.67 – 9.03 (m, 1 H), 7.85 (s, 1 H), 7.77 (br s, 4 H), 7.07 (br s, 2 H), 5.75 (s, 1 H), 5.37 (br s, 2 H), 5.04 (br s, 2 H), 4.46 – 4.61 (m, 1 H), 3.89 (br dd, J=12.2, 3.3 Hz, 4 H), 3.58 (br d, ./=5,8 Hz, 1 H). 19F NMR (377 MHz, DMSO-d6 ) 5 ppm -60.90 (br s, 3 F).
Peak 2: (R)-(4-amino- 1 ,3 -dihy drofuro [3 ,4-c] [ 1 ,7]naphthyridin-8-yl)(3 -(4-(trifluoromethyl)phenyl)morpholino)methanone (482) as a white solid, m/z (ESI): 445 (M+H)+. NMR 1H (400 MHz, DMSO-d6) 5 ppm 8.88 (br s, 1 H), 7.85 (s, 1 H), 7.77 (br d, J=1.7 Hz, 4 H), 7.07 (br s, 2 H),
5.69 – 5.78 (m, 1 H), 5.37 (br s, 2 H), 5.04 (br s, 2 H), 4.45 – 4.61 (m, 1 H), 3.89 (br dd, J=12.4, 3.3 Hz, 4 H), 3.51 – 3.64 (m, 1 H). 19F NMR (DMSO-d6, 377 MHz) 5 -60.90 (s, 3 F).
SYN
Example 4. Synthesis of Compound I – (4-amino-1 ,3-di hydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone
Reaction Scale 1
[0137] 4-Amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridine-8-carboxylic acid (1.0 kg, 4.3 mol, 1.0 equiv), (3S)-3-[4-(trifluoromethyl)phenyl]morpholine (1.2 kg, 5.2 mmol, 1.2- equiv), and DMF, (6.6 kg, 7.0 V) were charged to a clean, dry reactor. To the mixture was added triethylamine (1.1 Kg, 13.8 mol, 2.6 equiv). The mixture was cooled to 10 ± 5 °C and O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU) (1.67 kg, 5.2 mol, 1.2 equiv) was added slowly. Next, an additional amount of DMF (0.94 Kg, 1 V) was added. The reaction mixture was warmed to 25 ± 5 °C and stirred over 18 hours. Water (1 .0 kg, 1 V) was charged followed by MeCN (1 .6 kg, 2 V) and the reaction mass was warmed to 45 °C. Next, water (7.0 Kg, 7 V) was added over 30 min. A seed lot of 4-amino-1 ,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (10 g, 22 mmol, 0.01 equiv), was charged and the mixture was stirred at 45 °C for over 2 hours before being cooled to 20 °C over 10 hours. Water (12.0 kg, 12 V) was added over 2 hours at 20 °C and further stirred for over 4 hours before being filtered. The reactor was rinsed with a mixture of 10% DMF in water (9.83 kg, 10 V) and the resulting rinse mixture was used to wash the cake. The reactor was rinsed with a mixture of water (10.0k kg, 10 V) and the resulting rinse mixture was used to wash the cake. This rinsing and washing protocol was repeated once more with water (10.0k kg, 10V). The cake was dried under vacuum with a stream of nitrogen to afford (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-
(trifluoromethyl)phenyl]morpholin-4-yl]methanone. LCMS: 445.20 1H NMR (400 MHz, DMS0-d6 at 130 °C): 8.87 (s, 1 H), 7.80 (s, 1 H), 7.73 (d, 0=8.7 Hz, 2H), 7.71 (d, 0=8.7 Hz, 2H), 6.58 (br s, 2H), 5.72 (br s, 1 H), 5.38 (m, 2H), 5.09 (t, 0=3.5 Hz, 2H), 4.44 (br d, 0=12.3 Hz, 1 H), 4.08 (br d, 0=13.4 Hz, 1 H), 3.96 (dd, 0=12.3, 3.7 Hz, 1 H), 3.86 (br dd, 0=11 .4, 3.0 Hz, 1 H), 3.66 (td, 0=11 .4, 3.0 Hz, 1 H), 3.28 (m, 1 H).
Reaction Scale 2
[0138] 4-Amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridine-8-carboxylic acid (85.0 g, 352.2 mmol, 1.0 equiv), (3S)-3-[4-(trifluoromethyl)phenyl]morpholine (99.6 g, 422.6 mmol, 1.2- equiv), and DMF, (674 mL, 8.7 mol, 7.9 V) were charged to a clean, dry 5 L reactor. To the mixture was added 1 -methylimidazole (75.2 g, 916.2 mmol, 2.6 equiv). The mixture was cooled to 0 °C and N,N,N’,N’-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (118.6 g, 422.6 mmol, 1.2 equiv) was added slowly. Next, an additional amount of DMF (170 mL, 2 V) was added at 0 °C. The reaction mixture was warmed to 25 °C and stirred overnight. Next, the reaction mass was warmed to 45 °C and 2-methyltetrahydrofuran, (169.2 mL, 2 V) was added followed by slow addition of water (850 mL, 10 V) over 30 min by addition funnel. A seed lot of 4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (1.6 g, 3.5 mmol, 0.1 equiv), was charged as a slurry in a 1 :1 v/v of DMF and water (31 .3 mL) and the mixture was stirred at 45 °C for approximately 12 hrs. Water (510 mL, 6 V) was added over 1 h 10 min by addition funnel and the mixture was further stirred at 45°C for 30 min before being filtered. The reactor was rinsed with water (340 mL, 4 V) and the resulting rinse mixture was used to wash the cake. This rinsing and washing protocol was repeated twice more. The cake was dried under vacuum with a stream of nitrogen to afford (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone. LCMS: 445.20 1H NMR (400 MHz, DMSO-d6 at 130 °C): 8.87 (s, 1 H), 7.80 (s, 1 H), 7.73 (d, J=8.7 Hz, 2H), 7.71 (d, J=8.7 Hz, 2H), 6.58 (br s, 2H), 5.72 (br s, 1 H), 5.38 (m, 2H), 5.09 (t, J=3.5 Hz, 2H), 4.44 (br d, J=12.3 Hz, 1 H), 4.08 (br d, J=13.4 Hz, 1 H), 3.96 (dd, J=12.3, 3.7 Hz, 1 H), 3.86 (br dd, J=11.4, 3.0 Hz, 1 H), 3.66 (td, J=11.4, 3.0 Hz, 1 H), 3.28 (m, 1 H).
Reaction Scale 3:
[0139] 4-Amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridine-8-carboxylic acid (Compound A’) (20.0 g, 86.5 mmol, 1.0 equiv) was added to dimethylsulfoxide (400 mL) at 20 °C. To the mixture was added 1 ,T-carbonyldiimidazole (15.4 g, 95.2 mmol, 1.1 equiv) and the mixture was heated to 60 °C for 1 hour. A solution of (S)-3-(4-(trifluoromethyl)phenyl)morpholin-4-ium chloride (25.5 g, 95.2 mmol, 1.1 equiv) and dimethylsulfoxide (40 mL) was added, and the mixture was heated to 80 °C for 11 hours. The reaction mixture was cooled to 35 °C, then water (265 mL) was added, then the batch was cooled to 20 °C. The reaction was filtered, washed with 40% water:DMSO (80 mL), then washed with water (100 mL). The cake was dried under vacuum with a stream of nitrogen to afford (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (Compound I). LCMS: 445.20 1H NMR (400 MHz, DMSO-d6 at 130 °C): 8.87 (s, 1 H), 7.80 (s, 1 H), 7.73 (d, J=8.7 Hz, 2H), 7.71 (d, J=8.7 Hz, 2H), 6.58 (br s, 2H), 5.72 (br s, 1 H), 5.38 (m, 2H), 5.09 (t, >3.5 Hz, 2H), 4.44 (br d, >12.3 Hz, 1H), 4.08 (br d, >13.4 Hz, 1 H), 3.96 (dd, >12.3, 3.7 Hz, 1 H), 3.86 (br dd, >11 .4, 3.0 Hz, 1 H), 3.66 (td, >11 .4, 3.0 Hz, 1 H), 3.28 (m, 1 H).
Recrystallization of Compound I
[0140] A clean, dry 5 L reactor was charged with (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (279.7 g, 0.6 mol, 1.0 equiv) followed by acetone (6.2 L,
22 V). The mixture was stirred at 40 °C for 15 minutes before cooling to 25 °C. The reactor was discharged into a flask and the reactor was rinsed with acetone and the process stream was polish-filtered back into the reactor.
The reactor jacket was set to 65 °C and the reaction volume was reduced to approximately 6 V by distillation at atmospheric pressure, crystallization was observed. The reaction temperature was set to cool to 20 °C over two hours. Heptane (2.8 L, 10 V) was added over two hours. The slurry was filtered and the cake was washed twice with a 4:1 Heptane/acetone mix (750 mL, 3 V each) and dried under vacuum with a nitrogen purge to afford (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methanone.
ADVT
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References
- Process for synthesizing naphthyridine derivatives and intermediates thereofPublication Number: EP-4396170-A1Priority Date: 2021-08-30
- PRMTS inhibitorsPublication Number: CN-116888120-APriority Date: 2020-12-16
- Prmts inhibitorsPublication Number: WO-2022132914-A1Priority Date: 2020-12-16
- Prmts inhibitorsPublication Number: EP-4263545-A1Priority Date: 2020-12-16
- Mta-cooperative prmt5 inhibitors for use in the treatment of cancerPublication Number: EP-4572760-A1Priority Date: 2022-08-15
- Cancer treatments using mta-cooperative prmt5 inhibitorsPublication Number: WO-2023196545-A1Priority Date: 2022-04-08
- Process for the synthesis of naphthyridine derivatives and intermediates thereofPublication Number: CN-117897379-APriority Date: 2021-08-30
- Process for synthesizing naphthyridine derivatives and intermediates thereofPublication Number: WO-2023034786-A1Priority Date: 2021-08-30
- Process for Synthesizing Naphthyridine Derivatives and Intermediates ThereofPublication Number: US-2024360147-A1Priority Date: 2021-08-30
- Prmt5 inhibitor for use in cancer therapyPublication Number: WO-2024170488-A1Priority Date: 2023-02-13
- Cancer treatments using a prmt5 inhibitor and a mat2a inhibitorPublication Number: WO-2024118897-A1Priority Date: 2022-11-30
- Cancer treatments using a prmt5 inhibitor and a mat2a inhibitorPublication Number: EP-4626435-A1Priority Date: 2022-11-30
- MTA synergizes with PRMT5 inhibitors for cancer treatmentPublication Number: CN-119730853-APriority Date: 2022-08-15
- Mta-cooperative prmt5 inhibitors for use in the treatment of cancerPublication Number: WO-2024038004-A1Priority Date: 2022-08-15
////////anvumetostat, ANAX LAB, antineoplastic, AMG 193, QAT649EJ5E, PRMT5-IN-27,
Andamertinib
Andamertinib
CAS 2254145-43-0
MF C31H36N8O3 MW568.7 g/mol
N-[4-methoxy-2-[4-(3-methoxyazetidin-1-yl)piperidin-1-yl]-5-[[6-(1-methylindazol-5-yl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide
N-(4-methoxy-2-[4-(3-methoxyazetidin-1-yl)piperidin-1-yl]-5-{[6-(1-methyl-1H-indazol-5-yl)pyrimidin-4-yl]amino}phenyl)prop-2-enamide
epidermal growth factor receptor tyrosine kinase inhibitor, antineoplastic, PLB 1004, 5X3KAG7ZBW
Andamertinib (also known as PLB1004) is an investigational, orally bioavailable, and irreversible small-molecule inhibitor of the epidermal growth factor receptor (EGFR). It is primarily being developed to treat non-small cell lung cancer (NSCLC) with specific genetic mutations.
Key Clinical & Therapeutic Features
- Target Mutations: It specifically targets EGFR exon 20 insertion (ex20ins) mutations, which are often resistant to standard first- and second-generation EGFR inhibitors.
- Broad Selectivity: Beyond ex20ins, it also shows activity against classical mutations like Del19, L858R, and the resistance mutation T790M.
- Brain Penetration: Andamertinib is designed to cross the blood-brain barrier, making it potentially effective for patients with brain metastases.
- Clinical Performance: In phase 2 studies (e.g., the KANNON study), it demonstrated a confirmed objective response rate (ORR) of 42.7% and a median progression-free survival of 6.2 months in pretreated patients.
Regulatory Status (as of Early 2026)
- China: A New Drug Application (NDA) was accepted by the National Medical Products Administration (NMPA) in May 2025 and granted priority review for treating NSCLC with EGFR ex20ins mutations.
- Global: It remains in various stages of clinical trials globally, including studies for first-line treatment and combination therapies with other agents like vebreltinib.
Andamertinib is an orally bioavailable, mono-anilino-pyrimidine, mutant-selective epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, andamertinib targets, binds to and irreversibly inhibits the activity of various EGFR mutations, including exon 20 insertion (Ex20ins) activating mutations, the gatekeeper mutation T790M, ExDel19, and L858R. This prevents EGFR-mediated signaling, induces cell death and inhibits tumor growth in tumor cells expressing these EGFR mutations. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.
SYN
SYN
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References
- Aminopyrimidine compound, preparation method therefor and use thereofPublication Number: US-11352352-B2Priority Date: 2017-06-13Grant Date: 2022-06-07
- Aminopyrimidine compound, preparation method therefor and use thereofPublication Number: EP-3640248-A1Priority Date: 2017-06-13
- Aminopyrimidine compound, preparation method therefor and use thereofPublication Number: US-2020087296-A1Priority Date: 2017-06-13
- Aminopyrimidine derivatives, preparation method therefor and use thereofPublication Number: EP-3640248-B1Priority Date: 2017-06-13Grant Date: 2023-08-23
//////////andamertinib, FLAX LAB, antineoplastic, PLB 1004, 5X3KAG7ZBW
Amezalpat
Amezalpat
CAS 1616372-41-8
MF C34H41N3O4 MW555.7 g/mol
- [1,1′-Biphenyl]-3-acetic acid, 3′-[3-[1-[[4-(1,1-dimethylethyl)phenyl]methyl]-4-ethyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl]propyl]-4-ethoxy-
- 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetic acid
- 3′-(3-(1-((4-(1,1-DIMETHYLETHYL)PHENYL)METHYL)-4-ETHYL-4,5-DIHYDRO-5-OXO-1H-1,2,4-TRIAZOL-3-YL)PROPYL)-4-ETHOXY(1,1′-BIPHENYL)-3-ACETIC ACID
2-[5-[3-[3-[1-[(4-tert-butylphenyl)methyl]-4-ethyl-5-oxo-1,2,4-triazol-3-yl]propyl]phenyl]-2-ethoxyphenyl]acetic acid
peroxisome proliferator-activated receptor alpha (PPARα) antagonist, antineoplastic, TPST 1120, FDA Fast Track, Orphan Drug, 1EQ4LQN9N3
Amezalpat (formerly TPST-1120) is an investigational, oral, small-molecule inhibitor targeting peroxisome proliferator-activated receptor alpha (PPAR being developed by Tempest Therapeutics. It works by directly targeting tumor cells and reducing immune suppression in the tumor microenvironment. In combination with atezolizumab and bevacizumab, it has shown improved survival in hepatocellular carcinoma (HCC) patients, receiving FDA Fast Track and Orphan Drug designations.
Key Details on Amezalpat
- Indication: Primarily being studied for unresectable or metastatic hepatocellular carcinoma (liver cancer).
- Mechanism: A selective, competitive antagonist of PPAR
, which plays a role in fatty acid metabolism in cancer cells.
- Clinical Efficacy: A phase 1b/2 study indicated that adding amezalpat to standard-of-care (atezolizumab + bevacizumab) improved median overall survival to 21 months compared to 15 months for the control, according to Tempest Therapeutics.
- Trial Status: A pivotal Phase 3 study (NCT06680258) to evaluate this combination as a first-line treatment is planned for 2025.
- Other Potential Uses: Preclinical data suggests potential activity in other advanced solid tumors, including renal cell carcinoma.
Disclaimer: Amezalpat is an investigational agent and is not yet approved by the FDA for widespread clinical use.
Amezalpat is an orally bioavailable, small molecule, selective and competitive antagonist of peroxisome proliferator activated receptor alpha (PPARa), with potential immunomodulating and antineoplastic activities. Upon oral administration, amezalpat targets, binds to and blocks the activity of PPARa, thereby blocking transcription of PPARa target genes leading to an intracellular metabolism shift from fatty acid oxidation (FAO) to glycolysis in FAO-dependent tumors and reducing the production of fatty acids in the tumor microenvironment (TME). As fatty acids are essential for tumor cell growth in FAO-dependent tumor cells and are needed for the metabolism of suppressive immune cells in the TME, including regulatory T-cells (Tregs), reducing the amount of fatty acids leads to a direct killing of FAO-dependent tumor cells. It also skews macrophages from the immune suppressive M2 phenotype to an effector M1 phenotype and facilitates the cytotoxicity of immune effector cells, thereby stimulating an anti-tumor immune response and further killing tumor cells. Amezalpat also restores the natural inhibitor of angiogenesis thrombospondin-1 (TSP-1) and stimulator of interferon genes (STING) in the TME. PPARa, a ligand-activated nuclear transcription factor and metabolic checkpoint, regulates the expression of FAO genes and lipid metabolism. It plays a key role in immunosuppression in the TME. FAO is a metabolic pathway essential to tumor growth, survival and immunosuppression.
SYN
Example 6: 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetic acid
SYN
SYN
WO2014099503 TRIAZOLONE COMPOUNDS AND USES THEREOF
Example 6: 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1, 1′-biphenyl]-3-yl)acetic acid
Pat
WO2025235527 CRYSTALLINE FORMS OF A PPAR ALPHA ANTAGONIST
2-(3′-(3-(l-(4-(tertbutyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,T-biphenyl]-3-yl)acetic acid, depicted below as Compound A
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References
- Triazolone compounds and uses thereofPublication Number: US-2017239223-A1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: WO-2014099503-A1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: US-10568871-B2Priority Date: 2012-12-20Grant Date: 2020-02-25
- Triazolone compounds and uses thereofPublication Number: US-2024041837-A1Priority Date: 2012-12-20
- Compound or pharmaceutically acceptable salt thereof, pharmaceutical composition and uses thereofPublication Number: BR-112015013350-B1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: US-2015344446-A1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: US-11666557-B2Priority Date: 2012-12-20Grant Date: 2023-06-06
- Triazolone compounds and uses thereofPublication Number: US-2020138790-A1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: US-9676754-B2Priority Date: 2012-12-20Grant Date: 2017-06-13
- Triazolone compounds and uses thereofPublication Number: CA-2894281-CPriority Date: 2012-12-20Grant Date: 2021-04-20
- Triazolone compounds and uses thereofPublication Number: WO-2024102620-A2Priority Date: 2022-11-09
- Triazolone compounds and uses thereofPublication Number: AU-2013363398-B2Priority Date: 2012-12-20Grant Date: 2017-06-01
- Triazolone compounds and uses thereofPublication Number: EP-2935228-B9Priority Date: 2012-12-20Grant Date: 2017-12-06
- Triazolone compounds and uses thereofPublication Number: CA-2894281-A1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: EP-2935228-B1Priority Date: 2012-12-20Grant Date: 2017-08-02
/////////////amezalpat, ANAX LAB, antineoplastic, TPST 1120, FDA Fast Track, Orphan Drug, 1EQ4LQN9N3
Alnodesertib
Alnodesertib
CAS 2267316-76-5
MF C18H24N6O2S MW388.49
4-[4-[(cyclopropyl-methyl-oxo-λ6-sulfanylidene)amino]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-amine
4-[4-[(cyclopropyl-methyl-oxo-lambda6-sulfanylidene)amino]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-amine
(S)-({2-(2-aminopyridin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}imino)(cyclopropyl)(methyl)-λ6
-sulfanone
serine/threonine kinase inhibitor, antineoplastic, ART 0380, EX-A9085
Alnodesertib (formerly known as ART0380) is an investigational, orally administered drug designed to treat various types of cancer. It is a selective inhibitor of ATR (Ataxia-Telangiectasia and Rad3-related protein), a key kinase involved in DNA repair and cell cycle progression.
Mechanism of Action
Alnodesertib works by disrupting the DNA Damage Response (DDR):
- Targets ATR Kinase: It selectively inhibits ATR, which cancer cells rely on to fix DNA damage caused by rapid replication.
- Blocks Signaling: By blocking the phosphorylation of CHK1, it prevents the activation of DNA damage checkpoints.
- Induces Apoptosis: Inhibiting these repair pathways prevents cancer cells from surviving replication stress, ultimately leading to cell death (apoptosis).
Clinical Status and Indications
As of early 2026, alnodesertib is undergoing several clinical trials:
- Metastatic Colorectal Cancer (mCRC): The FDA granted Fast Track designation in September 2025 for alnodesertib in combination with irinotecan for adult patients with ATM-negative mCRC in the third-line setting.
- Ovarian Cancer: In March 2026, Artios Pharma reported that a Phase 2a study reached its primary endpoint, showing that adding a low dose of alnodesertib to gemcitabine improved progression-free survival in patients with platinum-resistant high-grade serous ovarian carcinoma (HGSOC).
- Other Solid Tumours: It is being evaluated in the ongoing STELLA Phase 1/2a study for its potential across multiple solid tumour types characterized by high replication stress.
Key Facts
| Feature | Details |
|---|---|
| Developer | Artios Pharma Limited |
| Drug Class | ATR Kinase Inhibitor |
| Administration | Oral |
| Current Phase | Phase 2 clinical trials |
| FDA Status | Fast Track Designation (for ATM-negative mCRC) |
SYN
EXAMPLES 39a and 39b
(R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4- yl)imino)(cyclopropyl)(methyl)-λ6-sulfanone
and
(S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4- yl)imino)(cyclopropyl)(methyl)-λ6-sulfanone
[0648] Synthesis is similar to that described for Example 24. The mixture of diastereomers (26.8 mg, 0.069 mmol) was separated by Chiral SFC (Mobile phase: n-hexane (0.1% DEA):EtOH(0.1% DEA) = 70:30; Flow rate: 80 g / min; 20 min; Column temperature: 35 °C; Back pressure: 100 bar; Column: Gilson-281, AY 20 x 250mm, 10 μm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 39a (6.6mg, 25% yield, >99% ee) as a white solid and 39b (7.1mg, 27% yield, >99% ee) as a white solid.
[0649] 39a ((R)-cyclopropyl(methyl)-λ6-sulfanone or (S)-cyclopropyl(methyl)-λ6-sulfanone): 1H NMR (500 MHz, CD3OD) δ 8.03 – 7.91 (m, 1H), 7.53 (s, 1H), 7.49 (dd, J =5.5, 1.4 Hz, 1H), 5.97 (s, 1H), 4.48 (d, J = 4.6 Hz, 1H), 4.11 (d, J = 12.0 Hz, 1H), 4.02 (dt, J = 11.3, 3.6 Hz, 1H), 3.82 (d, J = 11.4 Hz, 1H), 3.75 (dt, J = 11.5, 3.0 Hz, 1H), 3.65 – 3.56 (m, 4H), 3.25 (tdJ, = 12.8, 3.8 Hz, 1H), 3.01 (td, J = 7.9, 4.0 Hz, 1H), 1.42 (dd, J = 10.2, 5.4 Hz, 1H), 1.31 (dt, J = 11.1, 6.2 Hz, 4H), 1.20 (dt,J = 11.3, 5.7 Hz, 2H); MS (ES+) C18H24N6O2S requires: 388, found: 389 [M+H]+; Rt = 11.35 min.
[0650] 39b ((R)-cyclopropyl(methyl)-λ6-sulfanone or (S)-cyclopropyl(methyl)-λ6-sulfanone): 1H NMR (500 MHz, CD3OD) δ 7.97 (d, J = 5.4 Hz, 1H), 7.53 (s, 1H), 7.49 (dt, J = 5.5, 1.3 Hz, 1H), 5.97 (s, 1H), 4.50 (s, 1H), 4.08 (d, J = 12.7 Hz, 1H), 4.02 (dd, J = 11.4, 3.7 Hz, 1H), 3.82 (d, J = 11.3 Hz, 1H), 3.75 (dt, J = 11.4, 3.0 Hz, 1H), 3.66 – 3.55 (m, 4H), 3.25 (tdJ, = 12.9, 3.9 Hz, 1H), 3.05 – 2.97 (m, 1H), 1.41 (dt, J = 10.6, 5.2 Hz, 1H), 1.31 (dd, J = 11.8, 5.8 Hz, 4H), 1.20 (dt, J = 11.1, 5.6 Hz, 2H); MS (ES+) C18H24N6O2S requires: 388, found: 389 [M+H]+; Rt = 15.22 min.
[0651] Alternatively, Example 39a can also be prepared from Int. CC, Isomer lb.
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References
- HETEROCYCLIC INHIBITORS OF KINASE ATRPublication Number: WO-2019014618-A1Priority Date: 2017-07-13
- Heterocyclic inhibitors of ATR kinasePublication Number: US-11434233-B2Priority Date: 2017-07-13Grant Date: 2022-09-06
- Heterocyclic inhibitors of ATR kinasePublication Number: US-10800769-B2Priority Date: 2017-07-13Grant Date: 2020-10-13
- Heterocyclic inhibitors of ATR kinasePublication Number: US-10392376-B2Priority Date: 2017-07-13Grant Date: 2019-08-27
- Heterocyclic inhibitors of atr kinasePublication Number: US-2019016713-A1Priority Date: 2017-07-13
- Heterocyclic inhibitors of atr kinasePublication Number: US-2020102296-A1Priority Date: 2017-07-13
- Heterocyclic inhibitors of atr kinasePublication Number: US-2021047311-A1Priority Date: 2017-07-13
///////alnodesertib, ANAX LAB, serine/threonine kinase inhibitor, antineoplastic, ART 0380, EX-A9085
Zeprumetostat
Zeprumetostat
CAS 2098545-98-1
MF C32H44N4O4 MW 548.7 g/mol
CHINA 2025, APPROVALS 2025
- 4-Benzofurancarboxamide, N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-ethyl-6-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-2-(1-piperidinylmethyl)-
- N-[(1,2-Dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-ethyl-6-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-2-(1-piperidinylmethyl)-4-benzofurancarboxamide
N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-ethyl-6-[ethyl(oxan-4-yl)amino]-2-[(piperidin-1-yl)methyl]-1-benzofuran-4-carboxamide
enhancer of zeste homolog 2 (EZH2) inhibitor, antineoplastic, Airijing® (China), EZH2-IN-15, SHR 2554
The chemical structure for zeprumetostat was obtained from WHO proposed INN list 131 (August 2024). The INN record describes the compound as an enhancer of zeste homolog 2 (EZH2) inhibitor and antineoplastic. The chemical structure is claimed in patent WO2017084494A1 [3]. Based on Hengrui’s declared development pipeline, we predicted at that time that zeprumetostat was likely the INN for their EZH2 inhibitor clinical lead SHR2554.
Zeprumetostat is an orally available selective inhibitor of the histone lysine methyltransferase (HMT) enhancer of zeste homolog 2 (EZH2), with potential antineoplastic activity. Upon oral administration, zeprumetostat selectively targets, binds to and inhibits the activity of EZH2. Inhibition of EZH2 specifically prevents the methylation of histone H3 on lysine 27 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways and results in decreased proliferation of EZH2-expressing cancer cells. EZH2, an HMT class enzyme and the catalytic subunit of the polycomb repressive complex 2 (PRC2), is overexpressed or mutated in a variety of cancer cells and plays a key role in tumor cell proliferation; its expression is correlated with tumor initiation, progression, stem cell self-renewal, migration and angiogenesis.
Zeprumetostat is a small molecule drug. The usage of the INN stem ‘-metostat’ in the name indicates that Zeprumetostat is a histone N-methyltransferase inhibitor. Zeprumetostat has a monoisotopic molecular weight of 548.34 Da.
- Zeprumetostat, Azacitidine Combined With Lipo-MIT in R/R PTCLCTID: NCT07372352Phase: Phase 2Status: RecruitingDate: 2026-01-28
- EZH2 Inhibitor Zeprumetostat in Combination Therapy for Patients With Relapsed or Refractory Mature T-cell and NK-cell LymphomasCTID: NCT07339527Phase: Phase 1/Phase 2Status: Not yet recruitingDate: 2026-01-14
PAT
WO2017084494
[0234]N-((4,6-dimethyl-2-carbonyl-1,2-dihydropyridin-3-yl)methyl)-5-ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxamide
5-Ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxylic acid 1n (1.0 g, 2.4 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and 1-ethyl-3-(3-dimethylpropylamine)carbodiimide (696 mg, 3.6 mmol), 1-hydroxybenzotriazole (490 mg, 3.6 mmol), and N,N-diisopropylethylamine (1.56 g, 12.1 mmol) were added. The mixture was stirred for 1 hour, and then 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride 2a (593 mg, 3.0 mmol, prepared by the method disclosed in patent application “WO2014097041”) was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, excess water was added, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (V:V = 8:1). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product N-((4,6-dimethyl-2-carbonyl-1,2-dihydropyridin-3-yl)methyl)-5-ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxamide 2 (750 mg, white solid), yield: 57%.
[0238]
1H NMR(400MHz,DMSO-d 6):δ11.48(s,1H),8.15(t,1H),7.39(s,1H),6.46(s,1H),5.86(s,1H),4.32(d,2H),3.83(d,2H),3.54(s,2H),3.21(t,2H),3.01-3.07(m,2H),2.92-2.97(m,1H),2.77-2.82(m,2H),2.39(brs,4H),2.23(s,3H),2.11(s,3H),1.64-1.67(brd,2H),1.47-1.55(m,6H),1.36-1.37(brd,2H),1.02(t,3H),0.82(t,3H).
PAT
WO2019091450]
The method for preparing compounds from Formula IIa to Formula Ia provided by this invention can be specifically referred to in the methods for preparing amides disclosed in PCT applications WO2017084494A, WO2012142513, WO2013039988, WO2015-141616, and WO2011140325.
In a 25 mL three-necked flask, starter IIa (50 mg, 0.12 mmol), 1-ethyl-3-(3-dimethylpropylamine)carbodiimide (34.5 mg, 0.18 mmol), 1-hydroxybenzotriazole (23.67 mg, 0.18 mmol), and N,N-diisopropylethylamine (77.89 mg, 0.6 mmol) were mixed and dissolved in 3 mL of N,N-dimethylformamide and stirred until homogeneous. Then, starter 3-(aminomethyl)-4,6-dimethylpyridine-2(1H)-one hydrochloride (24.9 mg, 0.13 mmol) was added and the mixture was stirred at room temperature until the thin-layer chromatography showed that starter IIa had disappeared. The reaction was then terminated. Excess water was added to the reaction solution, and the mixture was extracted with a mixed solvent of dichloromethane and methanol. The organic phases were combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a dichloromethane-methanol eluent system to give 30.1 mg of white solid, yield 47.0%. [0151]m/z[M+H]
1H NMR(400MHz,DMSO-d6)ppm 11.51(s,1H)8.17(t,1H)7.39(s,1H)6.47(s,1H)5.86(s,1H)4.32(d,2H)3.83(d,2H)3.53(s,2H)3.21(t,2H)3.04(d,2H)2.94(br.s .,1H)2.79(d,2H)2.38(br.s.,4H)2.23(s,3H)2.08-2.14(m,3H)1.65(d,2H)1.44-1.56(m,6H)1.36(d,2H)1.02(t,3H)0.81(t,3H).
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References
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-11059811-B2Priority Date: 2015-11-19Grant Date: 2021-07-13
- Derived from benzofuran, method of preparing it and using it in medicinePublication Number: ES-2760510-T3Priority Date: 2015-11-19Grant Date: 2020-05-14
- Benzofuran derivative, a method for production thereof and use thereof in medicinePublication Number: RU-2727198-C2Priority Date: 2015-11-19Grant Date: 2020-07-21
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-2020354349-A1Priority Date: 2015-11-19
- BENZOFURAN DERIVATIVE, ITS USES AND ITS PREPARATION PROCESS, AND PHARMACEUTICAL COMPOSITIONPublication Number: BR-112018007876-B1Priority Date: 2015-11-19
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-2018327394-A1Priority Date: 2015-11-19
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: EP-3378859-B1Priority Date: 2015-11-19Grant Date: 2019-10-30
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-10759787-B2Priority Date: 2015-11-19Grant Date: 2020-09-01
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: EP-3378859-A1Priority Date: 2015-11-19
- Crystal of benzofuran derivative free base and preparation methodPublication Number: US-11155537-B2Priority Date: 2017-05-18Grant Date: 2021-10-26
- Use of ezh2 inhibitor combined with btk inhibitor in preparing drug for treating tumorPublication Number: US-2021030736-A1Priority Date: 2017-05-18
- Use of EZH2 inhibitor combined with BTK inhibitor in preparing drug for treating tumorPublication Number: US-11065239-B2Priority Date: 2017-05-18Grant Date: 2021-07-20
- Crystal of benzofuran derivative free base and preparation methodPublication Number: US-2021130333-A1Priority Date: 2017-05-18
- Determination and preparation method of benzofuran derivative free basePublication Number: KR-102612379-B1Priority Date: 2017-05-18Grant Date: 2023-12-12
//////////zeprumetostat, ANAX LAB, CHINA 2025, APPROVALS 2025, antineoplastic, Airijing® (China), EZH2-IN-15, SHR 2554
New Drug Approvals 
