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Soquelitinib

December 5, 2025 8:51 am / Leave a comment

Soquelitinib

CAS 2226636-04-8

MF C25H30N4O4S2, 514.7 g/mol

N-[5-({4-methoxy-2-methyl-5-[(3R)-3-methyl-4-(prop-2-enoyl)-1,4-diazepane-1-carbonyl]phenyl}sulfanyl)-1,3-thiazol-2-yl]cyclopropane-1-carboxamide
tyrosine kinase inhibitor, antineoplastic, CPI818, CPI-000818, CPI596, CP I818, CPI 000818, CP I596, 6I5H17AN3I,

N-[5-[4-methoxy-2-methyl-5-[(3R)-3-methyl-4-prop-2-enoyl-1,4-diazepane-1-carbonyl]phenyl]sulfanyl-1,3-thiazol-2-yl]cyclopropanecarboxamide

Soquelitinib (CPI-818) is an experimental drug which acts as a selective inhibitor of the enzyme interleukin-2-inducible T-cell kinase (ITK). It is in clinical trials for the treatment of T-cell lymphoma.^[1][2]

Soquelitinib is an orally available, small-molecule, irreversible inhibitor of interleukin-2 inducible T-cell kinase (ITK) with potential immunomodulatory and antineoplastic activities. Upon oral administration, soquelitinib selectively and covalently binds to the cysteine residue at position 442 (CYS-442) of ITK, thereby disrupting ITK-mediated signal transduction, while sparing tyrosine-protein kinase TXK (resting lymphocyte kinase, RLK) activity. This may abrogate T-cell receptor (TCR) signaling through ITK and inhibit TCR-induced proliferation of malignant T-cells. Additionally, inhibiting ITK activation may prevent the upregulation of GATA-3, a transcription factor that drives T-helper 2 (Th2) cell differentiation and is overexpressed in certain T-cell lymphomas. Thus, selective inhibition of ITK may inhibit Th2 responses without affecting T-helper 1 (Th1)-dependent immunity. ITK, a member of the Tec family of non-receptor protein tyrosine kinases plays a significant role in the T-cell development, differentiation and production of pro-inflammatory cytokines.

Safety, Tolerability, and Preliminary Efficacy of Soquelitinib in Participants With Moderate to Severe ADCTID: NCT06345404Phase: Phase 1Status: RecruitingDate: 2025-07-22
Study of the ITK Inhibitor Soquelitinib to Reduce Lymphoproliferation and Improve Cytopenias in Autoimmune Lymphoproliferative Syndrome (ALPS)-FAS PatientsCTID: NCT06730126Phase: Phase 2Status: RecruitingDate: 2025-05-31
Soquelitinib vs Standard of Care in Participants With Relapsed/Refractory Peripheral T-cell Lymphoma Not Otherwise Specified, Follicular Helper T-cell Lymphomas, or Systemic Anaplastic Large-cell LymphomaCTID: NCT06561048Phase: Phase 3Status: RecruitingDate: 2025-04-17
A Dose Escalation Study Evaluating CPI-818 in Relapsed/Refractory T-Cell LymphomaCTID: NCT03952078Phase: Phase 1Status: Active, not recruitingDate: 2025-04-16

Syn

Syn

SYN

WO-2023196278-A1

Embodiment B23. A method for an Th2/ITK-mediated disease in a patient in need thereof, the method comprising administering to the patient about 250 mg to about 1,000 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (A) is:

REF

https://www.nature.com/articles/s44386-024-00002-1

Pat

Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: US-2022363676-A1Priority Date: 2016-11-03
Compounds and methods for modulating Interleukin-2-inducible T-cell kinasePublication Number: US-11897874-B2Priority Date: 2016-11-03Grant Date: 2024-02-13
Itk inhibitors for increasing th1 cell activityPublication Number: WO-2023196278-A1Priority Date: 2022-04-05
Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: US-2019375743-A1Priority Date: 2016-11-03
Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: WO-2018089261-A2Priority Date: 2016-11-03
Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: US-11008314-B2Priority Date: 2016-11-03Grant Date: 2021-05-18
Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: EP-3534899-B1Priority Date: 2016-11-03Grant Date: 2022-06-01

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References

Khodadoust MS, Feldman TA, Yoon DH, Yannakou CK, Radeski D, Kim YH, et al. (November 2020). “Cpi-818, an oral interleukin-2-inducible T-cell kinase inhibitor, is well-tolerated and active in patients with T-cell lymphoma”. Blood. 136: 19–20. doi:10.1182/blood-2020-137782.
Hsu LY, Rosenbaum JT, Verner E, Jones WB, Hill CM, Janc JW, et al. (December 2024). “Synthesis and characterization of soquelitinib a selective ITK inhibitor that modulates tumor immunity”. npj Drug Discovery. 1 (1) 2: 1–4. doi:10.1038/s44386-024-00002-1.

Identifiers

IUPAC name
CAS Number	2226636-04-8
PubChem CID	134517711
DrugBank	DB18749
ChemSpider	129629996
UNII	6I5H17AN3I
KEGG	D12762
Chemical and physical data
Formula	C₂₅H₃₀N₄O₄S₂
Molar mass	514.66 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

//////////////Soquelitinib, tyrosine kinase inhibitor, antineoplastic, CPI818, CPI-000818, CPI596, CP I818, CPI 000818, CP I596, 6I5H17AN3I,

Setidegrasib

December 3, 2025 10:09 am / Leave a comment

Setidegrasib

CAS 2821793-99-9

MF C60H65FN12O7S MW1117.30

(2S,4R)-1-[(2S)-2-[4-[4-[[6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(oxan-4-yloxy)quinazolin-8-yl]oxymethyl]phenyl]triazol-1-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Kirsten rat sarcoma viral oncogene homologue (KRAS) degradation
inducer, antineoplastic, ASP-3082, ASP 3082, 3NQ4ME292X, KRAS G12D inhibitor 17

Setidegrasib (KRAS G12D inhibitor 17, ASP3082) is a PROTAC KRAS degrader (DC₅₀: 37 nM). Setidegrasib induces the degradation of G12D-mutation KRAS protein. Setidegrasib suppresses p-ERK, p-AKT, p-S6 levels in AsPC-1 cells. Setidegrasib exhibits anti-tumor activity in various cancer xenograft models in mice. Setidegrasib can be used for the study of KRAS(G12D)-mutated solid tumors. (Blue: VHL ligase ligand (HY-168699); Black: linker (HY-168698); Pink: G12D ligand (HY-168700)).

Setidegrasib is a small molecule drug. The usage of the INN stem ‘-rasib’ in the name indicates that Setidegrasib is a Ras protein inhibitor. Setidegrasib has a monoisotopic molecular weight of 1116.48 Da.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022173032&_cid=P21-MIPU3D-50779-1

PAT

Combination of anticancer agents comprising a bifunctional compound with g12d mutant kras inhibitory activityPublication Number: WO-2024033537-A1Priority Date: 2022-08-12
Combination of anticancer agents comprising a bifunctional compound with g12d mutant kras inhibitory activityPublication Number: WO-2024033538-A1Priority Date: 2022-08-12
Quinazoline compound for inducing degradation of g12d-mutation kras proteinPublication Number: WO-2022173032-A1Priority Date: 2021-02-15
Quinazoline compound for inducing degradation of g12d-mutation kras proteinPublication Number: EP-4293024-A1Priority Date: 2021-02-15
Quinazoline compound for inducing degradation of g12d mutant kras proteinPublication Number: US-2024182483-A1Priority Date: 2021-02-15

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[1]. Yoshinari, et al. Preparation of quinazoline-linked (4R)-4-hydroxy-L-prolinamide compounds for inducing degradation of G12D-mutation KRAS protein: World Intellectual Property Organization, WO2022173032[P]. 2022-08-18.[2]. Yoshinari T, et al. Discovery of KRAS(G12D) selective degrader ASP3082. Commun Chem. 2025 Aug 23;8(1):254. [Content Brief]

////////Setidegrasib, antineoplastic, ASP-3082, ASP 3082, 3NQ4ME292X, KRAS G12D inhibitor 17

Sendegobresib

December 2, 2025 2:59 am / Leave a comment

Sendegobresib

CAS 2704617-96-7

MFC37H45F3N6O5, 710.79

2,6-PIPERIDINEDIONE, 3-((4-(4-((4S)-1-((4-(1,6-DIHYDRO-1,4,5-TRIMETHYL-6-OXO-3-PYRIDINYL)-2,6-DIMETHOXYPHENYL)METHYL)-3,3-DIFLUORO-4-PIPERIDINYL)-1-PIPERAZINYL)-3-FLUOROPHENYL)AMINO)-, (3S)-

(3S)-3-[4-[4-[(4S)-1-[[2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridinyl)phenyl]methyl]-3,3-difluoropiperidin-4-yl]piperazin-1-yl]-3-fluoroanilino]piperidine-2,6-dione

bromodomain-containing protein 9 (BRD9) degradation inducer, antineoplastic, AW8PEP3VZ3, CFT 8634, ORPHAN DRUG

Sendegobresib is an orally bioavailable heterobifunctional protein degrader of bromodomain-containing protein 9 (BRD9; sarcoma antigen NY-SAR-29; rhabdomyosarcoma antigen MU-RMS-40.8), with potential antineoplastic activity. Sendegobresib is comprised of an E3 ligase-binding moiety and a BRD9-binding moiety. Upon oral administration, sendegobresib targets and binds to BRD9 with its BRD9-binding moiety. Upon BRD9 binding, the E3 ligase-binding moiety binds to cereblon (CRBN), a component of the CRL4-CRBN E3 ubiquitin ligase complex, which directs proteins for destruction, resulting in the proteasome-mediated degradation of BRD9. This leads to an inhibition of the growth of tumor cells that rely on BRD9 for survival. BRD9, a component of one form of the Brg/Brahma-Associated Factor (BAF) complex, is needed for the survival of certain cancer cells due to mutations.

A Study to Assess the Safety and Tolerability of CFT8634 in Locally Advanced or Metastatic SMARCB1-Perturbed Cancers, Including Synovial Sarcoma and SMARCB1-Null Tumors

CTID: NCT05355753

Phase: Phase 1

Status: Terminated

Date: 2024-12-17

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US355912448&_cid=P11-MINYJY-62955-1

Synthesis of Compound 172

Step-1: To a stirred solution of compound tert-butyl piperazine-1-carboxylate (85.40 g, 536.82 mmol) in DMF (500 mL) was added cesium carbonate (262.4 g, 805.4 mmol) and stirred for 15 min before adding 1,2-difluoro-4-nitro-benzene (100 g, 536.82 mmol). The reaction mixture stirred at RT for 16 h while monitoring by TLC. After completion, the reaction mass was quenched with ice flakes and the precipitated solid was filtered, dried under vacuum to afford tert-butyl 4-(2-fluoro-4-nitro-phenyl) piperazine-1-carboxylate 172-3 (152 g, 88.85% yield, 97.94% purity) as a yellow solid.

Step-2: To a stirred solution of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate 172-3 (50.0 g, 153.69 mmol) in 20 ml dioxane was added 4M dioxane HCl (30 ml) and reaction mixture stirred for 2 h at RT while monitoring by TLC. The solvent was evaporated to dryness under reduced pressure and crude solid was triturated with diethyl ether (75 ml) and n-pentane (100 ml) to afford HCl salt of 1-(2-fluoro-4-nitrophenyl) piperazine 172-4 (36.0 g, 136.2 mmol, 88.62% yield, 99% purity). LCMS (ES ⁺): m/z 226.10 [M+H] ⁺

Step-3: To stirred solution of 1-(2-fluoro-4-nitro-phenyl)piperazine 172-4 (8.0 g, 35.52 mmol) in toluene (200 ml) and ACN (100 ml) was added NaOAc (7.28 g, 88.80 mmol), followed by AcOH (8 ml) and molecular sieves 4 Å (10 g) and stirred for 15 min. After 15 min tert-butyl 3,3-difluoro-4-oxo-piperidine-1-carboxylate (11.49 g, 48.84 mmol, co-distilled with toluene before use) was added and the reaction mixture was allowed to reflux for 12 h, while monitoring by LCMS and TLC. After completion, reaction mixture was cooled to room temperature and filtered through Celite bed. The filtrate was concentrated under vacuum to dryness to afford crude residue 3,3-difluoro-4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate 172-6 (12.2 g, 98.89% purity) which was used for next step without any purification. LCMS (ES ⁺): m/z 443.75 [M+H] ⁺

Step-4: The compound 172-6 (8 g, 18.08 mmol) was dissolved in a mixture of methanol (20 mL), DCE (20 mL) and AcOH (2 ml), allowed to stir for 15 min, before adding sodium cyanoborohydride (5.68 g, 90.41 mmol). After addition, the reaction mixture was stirred for 24 h at room temperature, while monitoring by LCMS and TLC. The reaction mixture was filtered through Celite bed and filtrate was concentrated under vacuum. Crude compound purified by (silica gel mesh 100-200, and product eluted with 30% ethyl acetate in pet ether-neat ethyl acetate) column chromatography to afford tert-butyl-3,3-difluoro-4-[4-(2-fluoro-4-nitro-phenyl)piperazin-1-yl]piperidine-1-carboxylate 172-7 (7.2 g, 15.39 mmol, 85.11% yield, 98% purity). LCMS (ES ⁺): m/z 445.35 [M+H] ⁺

Step-5: To the stirred solution of tert-butyl 3,3-difluoro-4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidine-1-carboxylate 172-7 (5 g, 11.25 mmol) in ethyl acetate (100 mL) was added 10% Palladium on carbon wet (3.59 g, 33.75 mmol) at RT. The reaction mixture was stirred at RT under H ₂balloon pressure for 12 h was monitored by TLC. After the completion of the reaction, the reaction mixture was filtered-off through Celite and washed with ethyl acetate (200 mL). The filtrate was concentrated to obtain the crude product which was triturated with pentane, decanted the organic layer and the solidified product was filtered, dried well to afford tert-butyl 4-[4-(4-amino-2-fluoro-phenyl)piperazin-1-yl]-3,3-difluoro-piperidine-1-carboxylate 172-8 (3 g, 61.48% yield, 95.56% purity) as pale pink solid. LCMS (ES ⁺): m/z 415.56 [M+H] ⁺

Step-6: To a stirred solution of tert-butyl 4-[4-(4-amino-2-fluoro-phenyl)piperazin-1-yl]-3,3-difluoro-piperidine-1-carboxylate 172-8 (5 g, 12.06 mmol) in DMF (20 mL) taken in a seal tube was added 3-bromopiperidine-2,6-dione (6.95 g, 36.19 mmol) at rt followed by the addition of sodium bicarbonate (6.08 g, 72.38 mmol) and the reaction mixture was allowed to stir at 90° C. for 12 h. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and filtered off through Celite. The filtrate washed with water (2×100 mL), brine (1×25 mL), dried over anhydrous Na ₂SO ₄, filtered and concentrated to get the crude product. The crude product was purified by column chromatography using silica gel (100/200 mesh) and the product eluted at 2-3% MeOH/DCM) to afford (tert-butyl 4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate 172-9 (4.2 g, 56.31% yield, 91.08% purity) as a purple solid. LCMS (ES ⁺): m/z 526.48 [M+H] ⁺

Step-7: To the stirred solution of tert-butyl 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-1-yl]-3,3-difluoro-piperidine-1-carboxylate 172-9 (7 g, 13.32 mmol) in 1,4-dioxane (30 mL) was added 4M HCl in dioxane (30.35 mL, 665.95 mmol, 30.35 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, slowly warmed to RT and stirred at RT for 6 h. After the completion of the reaction, the reaction mixture was concentrated and the residual mass was triturated with diethyl ether (3×100 mL) and the solid precipitated out was dried well to afford 3-[4-[4-(3,3-difluoro-4-piperidyl)piperazin-1-yl]-3-fluoro-anilino]piperidine-2,6-dione 172-10 as HCl salt (5.54 g, 90.05% yield, 91.71% purity) as pale blue solid. LCMS (ES ⁺): m/z 426.22 [M+H] ⁺

Step 8: To a stirred solution of 3-[4-[4-(3,3-difluoro-4-piperidyl)piperazin-1-yl]-3-fluoro-anilino]piperidine-2,6-dione HCl 172-10 (5.65 g, 12.23 mmol) in DCE:MeOH (60:60 ml) were added 4 Å molecular sieves (3 g), acetic acid (0.797 g, 13.27 mmol) and sodium acetate (3.27 g, 39.82 mmol). The resulting solution was stirred for 10 min, then added 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)benzaldehyde 172-11 (4 g, 13.27 mmol) and heated the reaction mixture at 70° C. for 5 h then cooled it at RT and added Silia Bond Cyanoborohydride (3.85 g, 66.37 mmol). The stirring was continued at RT for 16 h, while monitoring the reaction by LCMS and TLC. After 16 h, the reaction mass was filtered through Celite, concentrated and purified by (Devisil silica gel, and product eluted with 1% to 5% MeOH in CH ₂C2) column flash chromatography to afford compound was dissolved in dry DCM (10 ml) and TFA (5 ml) was added at 0° C., stirred it for 30 min. After 30 min, reaction crude was concentrated to dryness and obtained crude was washed with diethyl ether (3×20 ml) to afford 3-[4-[4-[1-[[2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)phenyl]methyl]-3,3-difluoro-4-piperidyl]piperazin-1-yl]-3-fluoro-anilino]piperidine-2,6-dione TFA Compound 172 (3.21 g, 3.83 mmol, 28.85% yield, 98.40% purity) as a light green solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 10.78 (s, 1H), 9.97 (s, 1H), 7.52 (s, 1H), 6.84 (t, J=9.3 Hz, 1H), 6.66 (s, 2H), 6.51 (d, J=15.0 Hz, 1H), 6.42 (d, J=8.5 Hz, 1H), 4.28-4.24 (m, 3H), 3.86 (s, 7H), 3.47 (s, 6H), 2.90 (bs, 9H), 2.76-2.68 (m, 1H), 2.53-2.54 (m, 1H), 2.08 (d, J=10.7 Hz, 9H), 1.91-1.87 (m, 1H). LCMS (ES ⁺): m/z 711.20 [M+H] ⁺

PAT

WO-2021178920

PAT

WO-2022216765

PAT

Enhanced hyt-induced protein degradation using lipid nanoparticle deliveryPublication Number: US-2023414723-A1Priority Date: 2020-10-26
Compounds for targeted degradation of brd9Publication Number: WO-2021178920-A1Priority Date: 2020-03-05
Compounds for targeted degradation of brd9Publication Number: US-2022098194-A1Priority Date: 2020-03-05
Compounds for targeted degradation of brd9Publication Number: US-2023060334-A1Priority Date: 2020-03-05
Compounds for targeted degradation of BRD9Publication Number: US-11691972-B2Priority Date: 2020-03-05Grant Date: 2023-07-04
Selected compounds for targeted degradation of brd9Publication Number: US-2024245677-A1Priority Date: 2021-09-09
Exosome-based cancer assaysPublication Number: US-11938164-B2Priority Date: 2021-04-07Grant Date: 2024-03-26
Exosome-based cancer assaysPublication Number: US-2022331390-A1Priority Date: 2021-04-07
Exosome-based cancer assaysPublication Number: WO-2022216765-A1Priority Date: 2021-04-07
Enhanced hyt-induced protein degradation using lipid nanoparticle deliveryPublication Number: WO-2022093809-A1Priority Date: 2020-10-26
Directed degron molecules and applications thereofPublication Number: WO-2023081400-A1Priority Date: 2021-11-04
Directed degron molecules and applications thereofPublication Number: WO-2023081400-A9Priority Date: 2021-11-04
Directed degron molecules and applications thereofPublication Number: EP-4426687-A1Priority Date: 2021-11-04
Selected compounds for targeted degradation of brd9Publication Number: WO-2023039208-A1Priority Date: 2021-09-09
Selected compounds for targeted degradation of brd9Publication Number: EP-4398904-A1Priority Date: 2021-09-09

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/////////Sendegobresib, antineoplastic, AW8PEP3VZ3, CFT 8634, ORPHAN DRUG

Segigratinib, Ratangratinib

December 1, 2025 3:03 am / Leave a comment

Segigratinib, Ratangratinib

CAS 1882873-93-9

MF C27H28Cl2N6O3 MW 555.5 g/mol

N-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-(3,3-dimethylpiperazin-1-yl)benzamide

N-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[5,4-b]pyridin-3-yl]-4-(3,3-dimethylpiperazin-1-yl)benzamide
fibroblast growth factor receptor tyrosine kinase inhibitor, antineoplastic, 3D 185, Ratangratinib, 3D-185, G0Z5E4YTB4, HH 185

Ratangratinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3) and colony stimulating factor 1 receptor (CSF1R; CSF-1R; CD115; M-CSFR), with potential immunomodulatory and antineoplastic activities. Upon administration, ratangratinib binds to and inhibits FGFR1/2/3, which may result in the inhibition of FGFR1/2/3-mediated signal transduction pathways. This inhibits proliferation in FGFR1/2/3-overexpressing tumor cells. 3D185 also targets and binds to CSF1R, thereby blocking CSF1R activation and CSF1R-mediated signaling. This inhibits the activities of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), and prevents immune suppression in the tumor microenvironment (TME). This enhances antitumor T-cell immune responses and inhibits the proliferation of tumor cells. FGFR, a family of receptor tyrosine kinases (RTKs) upregulated in many tumor cell types, plays a key role in cellular proliferation, migration and survival. CSF1R, also known as macrophage colony-stimulating factor receptor (M-CSFR) and CD115 (cluster of differentiation 115), is a cell-surface receptor that plays major roles in tumor cell proliferation and metastasis.

Efficacy and Safety of 3D185 Monotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Cholangiocarcinoma

CTID: NCT05039892

Phase: Phase 2

Status: Not yet recruiting

Date: 2025-05-20

SYN

WO-2016026445-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016026445&_cid=P20-MIMK7T-68502-1

N-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6-(3,3-dimethylpiperazin-1-yl)nicotinamide

¹H NMR(DMSO-d6,400MHz)δppm 13.39(s,1H),10.86(s,1H),8.81(d,1H,J＝2.0Hz),8.40(d,1H,J＝8.0Hz),8.16(dd,1H,J ₁＝2.4Hz,J ₂＝2.4Hz),7.08(t,2H,J＝8.4Hz),6.90(d,1H,J＝9.2Hz),3.99(s,6H),3.60(t,2H,J＝4.0Hz),3.43(s,2H),2.82(t,2H,J＝4.4Hz),1.04(s,6H).LCMS:556.2[M+H] ⁺，RT＝1.21min。

SYN

US10562900,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US204149576&_cid=P20-MIMK4B-66027-1

¹H NMR (d-MeOD, 400 MHz) δ ppm 8.52 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.15-7.13 (m, 3H), 6.94 (s, 1H), 3.99 (s, 6H), 3.58-3.57 (m, 2H), 3.44-3.40 (m, 4H), 10.50 (s, 6H).

PAT

Indazole compounds as fgfr kinase inhibitor, preparation and use thereofPublication Number: EP-3184521-A1Priority Date: 2014-08-19
Indazole compounds as FGFR kinase inhibitor, preparation and use thereofPublication Number: US-10562900-B2Priority Date: 2014-08-19Grant Date: 2020-02-18
Indazole compounds as fgfr kinase inhibitor, preparation and use thereofPublication Number: US-2017275291-A1Priority Date: 2014-08-19
Indazole compounds as fgfr kinase inhibitor, preparation and use thereofPublication Number: WO-2016026445-A1Priority Date: 2014-08-19

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////////segigratinib, antineoplastic, 3D 185, Ratangratinib, 3D-185, G0Z5E4YTB4, HH 185

Rupitasertib

November 29, 2025 3:11 am / Leave a comment

Rupitasertib

CAS 1379545-95-5

MF C21H19ClF3N5O 449.9 g/mol

4-({(1S)-2-(azetidin-1-yl)-1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)quinazoline-8-carboxamide

4-[[(1S)-2-(azetidin-1-yl)-1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl]amino]quinazoline-8-carboxamide
serine/ threonine kinase inhibitor, antineoplastic, EMD SERONO, Gastric cancer; HER2 positive breast cancer; Solid tumours, M2698 HCl, M2698 hydrochloride, MSC2363318A, MSC 2363318A, MSC-2363318A, M2698, M-269, M 2698. Rupitasertib HCl, 0DXG50I4WD

OriginatorEMD Serono
DeveloperEMD Serono; Evexta Bio
ClassAntineoplastics; Small molecules
Mechanism of Action70 kDa ribosomal protein S6 kinase inhibitors; Proto-oncogene protein c-akt inhibitors
PreclinicalGlioblastoma; HER2 negative breast cancer
No development reportedGastric cancer; HER2 positive breast cancer; Solid tumours
28 Oct 2025No recent reports of development identified for preclinical development in Gastric-cancer in France (PO)
28 Jun 2025No recent reports of development identified for phase-I development in HER2-positive-breast-cancer(Combination therapy, Late-stage disease, Metastatic disease) in USA (PO)
28 Jun 2025No recent reports of development identified for phase-I development in Solid-tumours(Combination therapy, Late-stage disease) in USA (PO)
First-in-Human Dose Escalation Trial in Subjects With Advanced Malignancies
CTID: NCT01971515
Phase: Phase 1
Status: Completed
Date: 2018-09-19

Rupitasertib is an orally available inhibitor of the serine/threonine protein kinases ribosomal protein S6 Kinase (p70S6K) and Akt (protein kinase B), with potential antineoplastic activity. Upon administration, rupitasertib binds to and inhibits the activity of p70S6K and Akt. This prevents the activation of the PI3K/Akt/p70S6K signaling pathway and inhibits tumor cell proliferation in cancer cells that have an overactivated PI3K/Akt/p70S6K signaling pathway. Constitutive activation and dysregulated signaling of the PI3K/Akt/p70S6K pathway are frequently associated with tumorigenesis of many tumor types; targeting multiple kinases in this pathway is more efficacious than targeting a single kinase.

An optimized S6K inhibitor to overcome limitations of PAM pathway inhibitors

In just over 20 years, protein kinase inhibitors have changed the face of oncology and opened the new eras of targeted therapies and precision medicine. However, with few exceptions, no patient can be cured by one of these drugs alone. Today, scientists seek to develop novel kinase inhibitors[1] with improved efficacy and the potential to overcome resistances. The dual S6K AKT1/3 inhibitor rupitasertib (formerly DIACC3010, acquired from Merck KGaA, Darmstadt, Germany) has both of these characteristics and reaches brain metastases. After successfully completing a Phase I trial in patients with advanced/refractory solid tumors, including breast cancer, the drug candidate will be evaluated in a Phase 2/3 trial in ER+ HER2 breast cancer, which is expected to start in 2024.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012069146&_cid=P10-MIJPKI-12294-1

Example 4 was prepared following the general synthesis of A-E starting with (S)-2- amino-2-(3,4-di-fluoro-phenyl)-ethanol.LCMS [384.20 (M+1)]. ¹H NMR (DMSO-d₆, ppm) 1.92 (2H), 2.75 (1H), 2.93 (1H), 3.15 (4H), 5.43 (1H), 7.34 (2H), 7.53 (1H), 7.68 (1H), 7.81 (1H), 8.58 (4H), 10.30 (1H).

4-[(S)-2-Azetidin-1-yl-1-(4-chloro-3-trifluoromethylphenyl)-ethylamino]-guinazoline-8- carboxylic acid amide (5)

IC₅₀ P70S6K [nM]: 0.9

pS6 MDA-MB-468 [nM]: 11

Akt1 IC₅₀ [nM]: 1.4

Aurora B IC₅₀ [nM]: 100

PAT

Quinazoline carboxamide azetidinesPublication Number: SG-190318-A1Priority Date: 2010-11-24
Quinazoline carboxamide azetidinesPublication Number: US-2013252942-A1Priority Date: 2010-11-24
Quinazoline carboxamide azetidinesPublication Number: US-8946247-B2Priority Date: 2010-11-24Grant Date: 2015-02-03
SMAC Mimetic for Treating Myelodysplastic SyndromesPublication Number: US-2015158908-A1Priority Date: 2009-07-02
Methods of treating a ras protein-related disease or disorderPublication Number: US-2025049810-A1

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p70S6K/Akt dual inhibitor DIACC3010 is efficacious in preclinical models of gastric cancer alone and in combination with trastuzumabPublication Name: Scientific ReportsPublication Date: 2023-09-25PMCID: PMC10520030PMID: 37749105DOI: 10.1038/s41598-023-40612-9
TTD: Therapeutic Target Database describing target druggability informationPublication Name: Nucleic Acids ResearchPublication Date: 2023-09-15PMCID: PMC10767903PMID: 37713619DOI: 10.1093/nar/gkad751
Identification of Clinical Candidate M2698, a Dual p70S6K and Akt Inhibitor, for Treatment of PAM Pathway-Altered CancersPublication Name: Journal of Medicinal ChemistryPublication Date: 2021-10-01PMID: 34596404DOI: 10.1021/acs.jmedchem.1c01087
Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancerPublication Name: Journal of Hematology & OncologyPublication Date: 2021-08-18PMCID: PMC8371902PMID: 34407844DOI: 10.1186/s13045-021-01132-z
M2698 is a potent dual-inhibitor of p70S6K and Akt that affects tumor growth in mouse models of cancer and crosses the blood-brain barrierPublication Name: American journal of cancer researchPublication Date: 2016PMCID: PMC4859885PMID: 27186432

////////////Rupitasertib, antineoplastic, EMD SERONO, Gastric cancer; HER2 positive breast cancer; Solid tumours, M2698 HCl, M2698 hydrochloride, MSC2363318A, MSC 2363318A, MSC-2363318A, M2698, M-269, M 2698. Rupitasertib HCl, 0DXG50I4WD

Potrasertib

November 20, 2025 2:47 am / Leave a comment

Potrasertib

CAS 2226938-19-6

MFC28H30Cl2N8O MW 565.5 g/mol

6-(2,6-dichlorophenyl)-2-{3-methyl-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]anilino}-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one

7-(2,6-dichlorophenyl)-12-[3-methyl-4-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]anilino]-2,5,7,11,13-pentazatricyclo[7.4.0.02,6]trideca-1(13),5,9,11-tetraen-8-one
serine/ threonine kinase inhibitor, antineoplastic, IMP 7068, WEE1-IN-10, orb2664172, 621K13UG4B, Phase 1, Solid tumours

OriginatorIMPACT Therapeutics
ClassAntineoplastics; Small molecules
Mechanism of ActionWEE1 protein inhibitors
Phase ISolid tumours
28 Mar 2024No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease, Monotherapy) in Taiwan (PO)
28 Mar 2024No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease, Monotherapy) in USA (PO)
20 Oct 2023Efficacy, adverse events, pharmacodynamics and pharmacokinetics data from the phase I WEE1 trial in Solid tumours presented at the 48th European Society for Medical Oncology Congress (ESMO-2023)

Potrasertib is an investigational drug that is a selective inhibitor of WEE1 kinase, a protein crucial for the cell cycle. It is being studied for the treatment of various advanced solid tumors, including small cell lung cancer, ovarian, and colorectal cancers. By blocking the WEE1 kinase, potrasertib causes cancer cells with DNA damage to undergo premature, error-prone mitosis, which leads to cell death.

How it works

Potrasertib is a serine/threonine kinase inhibitor.
It works by targeting WEE1 kinase, which regulates the cell’s response to DNA damage.
By inhibiting WEE1, it prevents cancer cells from repairing DNA damage before dividing, forcing them into a state that leads to cell death.
This mechanism is particularly effective in tumors with a defective p53 gene, as these tumors rely more heavily on the WEE1 checkpoint for survival.

Potential uses

Combination therapy: It is being explored in combination with chemotherapy (like gemcitabine and cisplatin) or radiotherapy to enhance their effectiveness against cancer.
Monotherapy: It is also being studied as a standalone treatment for certain cancers, including ovarian, colorectal, and non-small cell lung cancer, especially those with high replication stress or WEE1 dependency.

Current status

Potrasertib is still an investigational drug and is not yet approved for widespread clinical use.
It is undergoing clinical trials to evaluate its safety and effectiveness in treating advanced cancers.

Potrasertib is an investigational new drug that is being evaluated by IMPACT Therapeutics for the treatment of advanced solid tumors. It is oral inhibitor of WEE1 kinase, a key regulator of cell cycle checkpoints.^[1][2]

SYN

WO2018090939

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018090939&_cid=P21-MI6TEY-70275-1

SYN

WO-2021073491-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021073491&_cid=P21-MI6TF3-70349-1

Example 1

SIMILAR NOT SAME

[0117]6-(2,6-dichlorophenyl)-2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one

SIMILAR NOT SAME

xample 2

[0128]6-(2,6-dichlorophenyl)-2-((4-((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one

[0130]a) Preparation of (2S,6R)-2,6-dimethyl-1-(methyl-d3)-4-(2-methyl-4-nitro)piperazine: Sodium hydride (385.03 mg, 9.63 mmol, 60% purity) was added to a solution of (3S,5R)-3,5-dimethyl-1-(2-methyl-4-nitro)piperazine (2 g, 8.02 mmol) in N,N-dimethylformamide (15 mL). The mixture was stirred at 0 °C for 25 hours, then trideuterated iodomethane (1.16 g, 8.02 mmol, 499.09 μL) was added, and the mixture was stirred at 0 °C for 2 hours. The reaction was quenched by adding an aqueous sodium bicarbonate solution (30 mL) at 0 °C, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target crude product (1.5 g, yellow-green solid). LC-MS(ESI): m/z(M+1) ⁺ 267.1. ¹ H NMR (400MHz, CDCl

₃ ): δ8.04-8.01 (m, 2H), 6.96 (d, J = 12.0Hz, 1H), 3.10 (d, J = 12Hz, 2H), 2.65 (t , J=12Hz, 2H), 2.45-2.43 (m, 2H), 2.36 (s, 3H), 1.16-1.15 (d, J=4.0Hz, 6H).

[0131]b) Preparation of 4-((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylaniline: Under nitrogen protection, palladium on carbon (281.58 μmol, 10% purity) was added to a methanol (5 mL) solution of (2S,6R)-2,6-dimethyl-1-(methyl-d3)-4-(2-methyl-4-nitro)piperazine (1.5 g, 5.63 mmol). The resulting suspension was purified multiple times under vacuum with hydrogen. The mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the target crude product (1.3 g, black solid). LC-MS (ESI): m/z (M+1) ⁺ 237.1.

[0132]c) Preparation of 6-(2,6-dichlorophenyl)-2-((4-(((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylphenyl)amino)-8,9-dihydroimidazo[1,2-a]pyrimidino[5,4-e]pyrimidin-5(6H)-one: 4-((3S,5R)-3,5-dimethyl-4-(methyl-d3)piperazin-1-yl)-3-methylaniline (459.32 mg, 1.94 mmol) and the prepared 6-(2,6-dichlorophenyl)-2- A mixture (700 mg, crude) of crude (methanesulfonyl)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one and 6-(2,6-dichlorophenyl)-2-(methanesulfonyl)-8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-one was dissolved in acetonitrile (5 mL) and trifluoroacetic acid (20.14 mg, 0.177 mmol, 13.08 μL) was added. The mixture was stirred at 20–25 °C for 2 hours, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by reversed-phase HPLC to give the target compound (56.89 mg, 100.00 μmol, yellow solid, 5.66% yield). LC-MS (ESI): m/z (M+1) ⁺ 568.0.

¹ H NMR (400MHz, CDCl ₃ ): δ8.81 (s, 1H), 7.49 (d, J=3.8Hz, 3H), 7.41-7.34 (m, 3H), 7.02 (d, J=4.2Hz, 1H), 4.25-4.21 (m, 2H), 4.02 (t, J=8.0Hz, 2H), 2.95 (d, J=6.0Hz 2H), 2.62 (t, J=6.0Hz, 2H), 2.46-2.41 (m, 2H), 2.34 (s, 6H), 1.15 (d, J=6.4Hz, 6H).

SYN

WO-2022188802-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022188802&_cid=P21-MI6TVM-79837-1

PAT

8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-onesPublication Number: US-11345711-B2Priority Date: 2016-11-16Grant Date: 2022-05-31
8,9-dihydroimidazole[1,2-a]pyrimido[5,4-e]pyrimidine-5(6h)-ketone compoundPublication Number: EP-3543242-B1Priority Date: 2016-11-16Grant Date: 2024-01-03
Compound 8,9-dihydroimidazole[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-ketonePublication Number: ES-2968252-T3Priority Date: 2016-11-16Grant Date: 2024-05-08
8,9-dihydroimidazole[1,2-a]pyrimido[5,4-e]pyrimidine-5(6h)-ketone compoundPublication Number: EP-3543242-A1Priority Date: 2016-11-16
8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-onesPublication Number: US-10703759-B2Priority Date: 2016-11-16Grant Date: 2020-07-07
8,9-DIHYDROIMIDAZO[1,2-a]PYRIMIDO[5,4-e]PYRIMIDIN-5(6H)-ONESPublication Number: US-2019308984-A1Priority Date: 2016-11-16
8,9-DIHYDROIMIDAZO[1,2-a]PYRIMIDO[5,4-e]PYRIMIDIN-5(6H)-ONESPublication Number: US-2020385394-A1Priority Date: 2016-11-16
8,9-Dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6H)-onesPublication Number: CN-109906227-BPriority Date: 2016-11-16Grant Date: 2022-03-11
Dihydroimidazo pyrimido pyrimidinone compoundPublication Number: WO-2021073491-A1Priority Date: 2019-10-16
DihydroimidazopyrimidopyrimidinonesPublication Number: CN-114502559-APriority Date: 2019-10-16
Dihydroimidazopyrimidopyrimidinone compoundsPublication Number: CN-114502559-BPriority Date: 2019-10-16Grant Date: 2024-02-02
Dihydroimidazo pyrimido pyrimidinone compoundPublication Number: US-2024010655-A1Priority Date: 2019-10-16
8,9-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidin-5(6h)-onesPublication Number: CA-3043945-A1Priority Date: 2016-11-16
Use of Wee1 kinase inhibitors in the treatment of cancerPublication Number: CN-118338905-APriority Date: 2021-11-26
Use of wee1 kinase inhibitors in the treatment of cancerPublication Number: WO-2023093840-A1Priority Date: 2021-11-26
Use of wee1 kinase inhibitors in the treatment of cancerPublication Number: WO-2022188802-A1Priority Date: 2021-03-10
The use of Wee1 kinase inhibitors in the treatment of cancer diseasesPublication Number: CN-117202908-APriority Date: 2021-03-10
Use of wee1 kinase inhibitors in the treatment of cancerPublication Number: US-2024091233-A1Priority Date: 2021-03-10

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Clinical data

Other names	IMP7068
Identifiers
IUPAC name
CAS Number	2226938-19-6
PubChem CID	139503236
UNII	621K13UG4B
Chemical and physical data
Formula	C₂₈H₃₀Cl₂N₈O
Molar mass	565.50 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

References

“IMP 7068”. AdisInsight. Springer Nature Switzerland AG.
Wang Z, Li W, Li F, Xiao R (January 2024). “An update of predictive biomarkers related to WEE1 inhibition in cancer therapy”. Journal of Cancer Research and Clinical Oncology. 150 (1): 13. doi:10.1007/s00432-023-05527-y. PMC 10794259. PMID 38231277.

///////potrasertib, antineoplastic, IMP 7068, WEE1-IN-10, orb2664172, 621K13UG4B, Phase 1, Solid tumours

Paluratide

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

Paluratide

CAS 2676177-63-0

MFC73H105F5N12O12 MW 1437.7 g/mol

1,11-anhydro[N-methyl-L-alanyl-(2S)-azetidine-2-carbonyl-N-ethyl-4-methyl-L-phenylalanyl-N-methylglycyl-3-{[3,5-difluoro-4-(trifluoromethyl)phenyl]methyl}-L-alanyl-L-prolyl-2-
aminocyclopentane-1-carbonyl-(2S)-N-methyl-3-cyclopentylglycyl-1-
(dimethylamino)-N-methyl-L-aspart-4-yl-N-methyl-L-leucyl-Lisoleucine]

(3S,9S,12S,17S,20S,23S,27S,30S,36S)-20-[(2S)-butan-2-yl]-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-N,N,7,17,18,24,28,31-octamethyl-9-[(4-methylphenyl)methyl]-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,29,32,35-undecaoxospiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1′-cyclopentane]-27-carboxamide
G-protein Ras (rat sarcoma virus) inhibitor, antineoplastic, LUNA 18, CHUGAI, AW3YP3CD9X

Paluratide (development code LUNA18) was an investigational cyclic peptide KRAS inhibitor developed by Chugai Pharmaceutical, a member of the Roche Group, for the treatment of cancers with KRAS mutations.^[1] The compound was notable as an orally bioavailable macrocyclic peptide that could target intracellular protein-protein interactions, a class of targets traditionally considered “undruggable.”^[2]

Development was discontinued in July 2025 due to a narrow therapeutic window compared to competing KRAS inhibitors.^[3]

Ras Inhibitor LUNA18 is an orally bioavailable cyclic peptide and Ras inhibitor, with potential antineoplastic activity. Upon oral administration, Ras inhibitor LUNA18 selectively targets, binds to and inhibits Ras, thereby inhibiting Ras-dependent signaling and inhibits proliferation of tumor cells in which Ras is overexpressed and/or mutated. Ras serves an important role in cell signaling, division and differentiation. Mutations of Ras may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis.

Paluratide (LUNA18 is synthesized using a novel liquid-phase peptide synthesis (LPPS) method, not traditional solid-phase methods, to overcome challenges with N-alkylated cyclic peptides. This process involves a convergent route of 24 telescoped chemical transformations, a final crystallization step, and a focus on specific strategies to manage side reactions like diketopiperazine formation and low reactivity of sterically hindered amino acids.

Key aspects of the synthesis

Liquid-phase synthesis: A novel, high-yielding LPPS process was developed to enable the large-scale production of paluratide. This is a departure from traditional solid-phase methods, which have limitations with solubility and waste.
Convergent synthetic route: The synthesis uses a convergent approach, meaning smaller fragments of the peptide are synthesized separately and then joined together. The overall process includes 24 telescoped chemical transformations followed by a final crystallization step.
Addressing synthesis challenges: Specific strategies were employed to overcome key difficulties:
- Low reactivity: Amino acids with N-alkylation are sterically hindered, so more reactive and stable protecting groups were used to ensure efficient coupling.
- Side reactions: The method was designed to prevent side reactions like diketopiperazine formation in intermediates and incomplete hydrolysis of active esters.
- Instability: The peptide backbone is sensitive to acidic conditions, so a mildly acidic aqueous medium was chosen for workup and purification to maintain stability.
Protecting group selection: Cbz-protected amino acid active esters were preferred over Boc-protected ones because they are less prone to forming N-carboxyanhydrides (NCA) under activating conditions, which can reduce yield and purity.
Purification: A final crystallization step is used for purification.

PAT

Method for producing eutectic of cyclic peptidePublication Number: WO-2024195801-A1Priority Date: 2023-03-20
Method for producing cyclic peptide crystalsPublication Number: WO-2024085235-A1Priority Date: 2022-10-20
Composition containing peptide, surfactant, and polymerPublication Number: WO-2024080308-A1Priority Date: 2022-10-12
Methods for producing cyclic compounds comprising n-substituted amino acid residuesPublication Number: EP-4086272-A1Priority Date: 2021-05-07
Methods for producing cyclic compounds comprising n-substituted amino acid residuesPublication Number: US-2022411462-A1Priority Date: 2021-05-07

SYN

https://pubs.acs.org/doi/10.1021/acs.oprd.5c00260?ref=PDF

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US383248369&_cid=P20-MI3YXS-80609-1

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Mechanism of action

Paluratide functions as a pan-RAS inhibitor, targeting multiple RAS isoforms including KRAS, NRAS, and HRAS.^[1] The compound binds with high affinity to KRAS^G12D, with a dissociation constant (K_d) of 0.043 nM, and blocks the interaction between KRAS^G12D and the guanine nucleotide exchange factor SOS1 with an IC₅₀ of less than 2.2 nM.^[4]

Unlike covalent KRAS inhibitors that target specific mutations (such as sotorasib for KRAS^G12C), paluratide was designed to inhibit RAS proteins through disruption of protein-protein interactions with guanine nucleotide exchange factors (GEFs).^[1] This mechanism allows the drug to affect RAS signalling regardless of the specific mutation, theoretically providing broader applicability across different KRAS-mutant cancers. The compound also demonstrates activity against downstream signalling pathways, affecting ERK and AKT phosphorylation.^[4]

Medical uses

Paluratide was being developed for the treatment of locally advanced or metastatic solid tumors harbouring RAS gene alterations.^[5] The drug demonstrated significant cellular activity against multiple cancer types with KRAS mutations in preclinical studies, including colorectal cancer, gastric cancer, non-small cell lung cancer, and pancreatic cancer.^[1]

Chemistry

Paluratide is an 11-member (11-mer) cyclic peptide with a molecular weight in the range of 1000–2000 g/mol, classified as a “middle-size” cyclic peptide.^[1] The compound features extensive N-alkylation, a modification that reduces hydrogen bond donors and improves oral absorption while maintaining cellular permeability.^[2] Its structure allows it to navigate the challenging boundary between small molecules and biologics, achieving properties of both classes. The compound demonstrated oral bioavailability ranging from 21% to 47% in preclinical animal studies without requiring special formulations.^[1]

Discovery

Paluratide was discovered through Chugai Pharmaceutical’s cyclic peptide platform using an mRNA display library screening approach.^[1] The initial hit compound, designated AP8747, was identified from the mRNA display library and subsequently underwent extensive chemical optimization without scaffold hopping (maintaining the basic cyclic peptide structure).^[1] The optimization focused on increasing plasma stability, improving absorption, reducing clearance, and reducing hydrogen bond donors to achieve oral bioavailability.

The final clinical compound, LUNA18, emerged after modifications to four amino acid positions (positions 5, 7, 10, and 11) from an intermediate compound (compound 40). Key structure-activity relationship findings included: the side chain at position 5 preferring aromatic over aliphatic groups; physicochemical properties being adjustable at position 11; and biological activity enhancement through modifications at positions 7 and 10.^[1]

Chugai also developed a novel synthetic methodology that enabled the broadly applicable synthesis of highly N-alkylated cyclic peptide-like drugs.^[6] This method overcame three major technical challenges: formation of diketopiperazine, insufficient reactivity of amidation due to steric hindrance, and instability of cyclic peptides under acidic conditions. Using this approach, more than 4,000 cyclic peptides were synthesized with a process yield of 31% and final product purity of 97%.^[6]

Clinical trials

A Phase 1 dose-escalation and cohort expansion study (NCT05012618) was initiated in August 2021 to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of paluratide administered as a single agent or in combination with other anti-cancer drugs.^[5] The study, in the United States and Japan, was designed to enrol approximately 195 patients with locally advanced or metastatic solid tumors positive for documented RAS alterations.^[5]

Paluratide was administered orally as capsules.^[5] The study also evaluated combination therapy with cetuximab, an EGFR inhibitor.^[5]

References

Tanada M, Tamiya M, Matsuo A, Chiyoda A, Takano K, Ito T, et al. (August 2023). “Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor”. Journal of the American Chemical Society. 145 (30): 16610–16620. Bibcode:2023JAChS.14516610T. doi:10.1021/jacs.3c03886. PMID 37463267.
Ohta A, Tanada M, Shinohara S, Morita Y, Nakano K, Yamagishi Y, et al. (November 2023). “Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets”. Journal of the American Chemical Society. 145 (44): 24035–24051. Bibcode:2023JAChS.14524035O. doi:10.1021/jacs.3c07145. PMID 37874670.
Taylor NP (24 October 2025). “Roche axes 4 Chugai solid tumor assets in early-phase clear-out”. Fierce Biotech.
“LUNA18 (Paluratide) – KRAS Inhibitor, ERK Inhibitor, RAS Inhibitor”. MedChemExpress.
“A Dose-escalation Study of LUNA18 in Patients With Locally Advanced or Metastatic Solid Tumors (With Expansion)”. ClinicalTrials.gov. 29 July 2025. NCT05012618.
Nomura K, Hashimoto S, Takeyama R, Tamiya M, Kato T, Muraoka T, et al. (October 2022). “Broadly Applicable and Comprehensive Synthetic Method for N-Alkyl-Rich Drug-like Cyclic Peptides”. Journal of Medicinal Chemistry. 65 (19): 13401–13412. doi:10.1021/acs.jmedchem.2c01296. PMID 36109865.
“Chugai Announces 2025 2nd Quarter Results” (Press release). Chugai Pharmaceutical. 24 July 2025.

External links

Phase 1 Clinical Trial Information at ClinicalTrials.gov
Development of LUNA18 at Journal of the American Chemical Society

Clinical data

Other names	LUNA18
Routes of administration	Oral administration
Legal status
Legal status	Development discontinued
Identifiers
IUPAC name
CAS Number	2676177-63-0
PubChem CID	166509683
ChemSpider	129321315
UNII	AW3YP3CD9X
Chemical and physical data
Formula	C₇₃H₁₀₅F₅N₁₂O₁₂
Molar mass	1437.707 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

//////Paluratide, antineoplastic, LUNA 18, CHUGAI, AW3YP3CD9X

Nuvisertib

November 13, 2025 2:57 am / Leave a comment

Nuvisertib

CAS 1361951-15-6

MF C22H26ClF3N4O MW418.5 g/mol

2-[(1r,4r)-4-({3-[3-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazin-6-yl}amino)cyclohexyl]propan-2-ol
serine/ threonine kinase inhibitor, antineoplastic, Orphan Drug, myelofibrosis, SGI-9481, SGI 9481, TP-3654, TP 3654, EOB0N7BOY4

The chemical structure for nuvisertib was obtained from proposed INN list 130 (Feb. 2024), in which the compound is described as a serine/ threonine kinase inhibitor with antineoplastic action. A structure match to clinical lead TP-3654 was made via PubChem. TP-3654 is declared as an orally available, second-generation pan-PIM kinase inhibitor [1-2].

References

1. Foulks JM, Carpenter KJ, Luo B, Xu Y, Senina A, Nix R, Chan A, Clifford A, Wilkes M, Vollmer D et al.. (2014)
A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas.
Neoplasia, 16 (5): 403-12. [PMID:24953177]

2. Wu CP, Li YQ, Chi YC, Huang YH, Hung TH, Wu YS. (2021)
The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs.
Int J Mol Sci, 22 (17). [PMID:34502348]

Nuvisertib is an orally available, second-generation and selective ATP-competitive inhibitor of proviral integration site for Moloney murine leukemia virus (PIM) kinases, with potential antineoplastic activity. Upon oral administration, nuvisertib selectively binds to and prevents the activation of the PIM kinases. This prevents the activation of PIM-mediated signaling pathways and inhibits proliferation in cells that overexpress PIM. PIMs, constitutively active proto-oncogenic serine/threonine kinases, are upregulated in various types of cancers and play key roles in tumor cell proliferation and survival.

Nuvisertib, also known as TP-3654, is an oral, investigational, and highly selective PIM1 kinase inhibitor being studied in a Phase 1/2 clinical trial for intermediate- or high-risk myelofibrosis (MF). It is not currently an approved medication.

Key Information

Mechanism of Action: Nuvisertib targets the PIM1 kinase pathway, which is often overactive in myelofibrosis and can promote cancer cell growth. By inhibiting this pathway, nuvisertib is being investigated for its potential to manage symptoms, reduce spleen size, improve blood counts, and slow the progression of bone marrow fibrosis.
Current Status: Nuvisertib is in ongoing Phase 1/2 clinical trials (NCT04176198) as a monotherapy and in combination with JAK inhibitors like ruxolitinib and momelotinib.
Designations: Nuvisertib has received Orphan Drug Designation for myelofibrosis

Study of TP-3654 in Patients With Advanced Solid Tumors

CTID: NCT03715504

Phase: Phase 1

Status: Completed

Date: 2023-11-14

SYN

WO2013013188

Example 31

SYN

US20240124469

https://patentscope.wipo.int/search/en/detail.jsf?docId=US427659372&_cid=P10-MHWTVL-76212-1

SYN

US9416132,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US130491286&_cid=P10-MHWU33-81462-1

31. 4-((3-(3-(Trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)-trans-cyclohexyl)propan-2-ol (EX. 8-31)

EX. 8-31 was prepared by similar procedures as in EX. 8-1 using 2-(trans-4-aminocyclohexyl)propan-2-ol.

¹H-NMR (CD ₃OD/400 MHz): δ 8.82 (s, 1H), 8.19 (m, 1H), 7.88 (s, 1H), 7.62 (m, 3H), 6.70 (d, J=9.6 Hz, 1H), 3.71 (m, 1H), 2.26 (m, 2H), 1.95 (m, 2H), 1.36 (m, 1H), 1.27 (m, 4H), 1.21 (s, 6H). MS (ES ⁺, m/z): (M+H) ⁺: 419.6.

Alternatively, EX. 8-31 was prepared in 50 g scale employing the following procedures.

To a solution of trans-4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (823 g, 3.38 mol) in EtOAc (4000 mL) was added EA/HCl (2500 mL). The mixture was stirred at 0° C. overnight. The reaction mixture was filtered and dried in vacuo to give a product of hydrochloride salt of trans-4-aminocyclohexanecarboxylic acid as white solid (604 g, 99.42% yield).

A mixture of hydrochloride salt of trans-4-aminocyclohexanecarboxylic acid (720 g), BnBr (1700 g, 2.5 eq) and K ₂CO ₃in DMF (8000 mL) was stirred at rt overnight. More BnBr (100 g) was added and the reaction mixture was heated to 50° C. and kept for 3 hrs. The reaction mixture was then poured into water and extracted with EtOAc and combined organic phase washed with brine and concentrated in vacuo to give crude trans-benzyl 4-(dibenzylamino)cyclohexanecarboxylate as white solid (1495 g, 93.9% yield).

To a solution of trans-benzyl 4-(dibenzylamino)cyclohexanecarboxylate (290 g×5, 3.6 mol) in 2 L of THF under N ₂at 0° C., MeMgBr (800 mL) was added. The mixture was stirred at room temperature overnight and then quenched with 1.5 L of saturated NH ₄Cl. The resulting mixture was extracted with EtOAc. The product was extracted with 1 M HCl to the aqueous phase, which was then wash with EtOAc. The aqueous phase was then neutralized with NaOH, extracted with EtOAc, washed with brine, dried with Na ₂SO ₄and concentrated in vacuo to give the 2-(trans-4-(dibenzylamino)cyclohexyl)propan-2-ol as white solid (950 g, 78.3% yield).

A mixture of 2-(trans-4-(dibenzylamino)cyclohexyl)propan-2-ol (120 g×8, 356 mmol) and Pd(OH) ₂(15 g×8) in methanol (1000 mL) and MeOH/NH ₃(100 mL) was stirred under H ₂(50 psi) at 50° C. for 72 hrs, then the catalyst was removed and the filtrate was concentrated in vacuo and The crude product was chromatographed on silica gel (DCM/MeOH 20:1-DCM/MeOH/NH ₃5:4:1) to give the 2-(trans-4-aminocyclohexyl)propan-2-ol as a pale yellow solid (210 g, 47.5% yield).

6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine was prepared according to procedure in EX. 8-29.

To a solution of 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (100 g, 337 mmol) and 2-(trans-4-aminocyclohexyl)propan-2-ol (55 g, 350 mmol) in 400 mL of DMSO was added DIEA (90 g, 900 mmol) and CsF (45 g, 30 mmol). The mixture was stirred at 180° C. for 4 hour. The solid was removed and the filtrate was poured into a stirred solution of water (4 L) and EA (1 L), The solid formed was collected and recrystallized from EA to give EX. 8-31 (Free Base) as off white solid (70.58 g, 48.34%). From the mother liquid and the filtrate, a second batch of product was obtained after column chromatography (EA).

¹H NMR (MeOD/400 MHz): δ 8.80 (s, 1H), 8.17 (d, J=6.8 Hz, 1H), 7.85 (s, 1H), 7.62-7.58 (m, 3H), 6.68 (d, J=9.6 Hz, 1H), 3.72-3.65 (m, 1H), 2.30-2.24 (m, 2H), 1.95-1.90 (m, 2H), 1.37-1.22 (m, 5H), 1.16 (s, 6H). MS (ES ⁺, m/z): (M+H) ⁺: 419.3. Melting Point: 216.7° C.-219.3° C.

To a production of EX. 8-31 (Free Base) (57 g, 136 mmol) in EA (10 L) was added HCl/EA until no further solid formed (about 100 mL of HCl/EA). The mixture was stirred at room temperature for half an hour and the solid was collected, washed with EA and dried under vacuo to give EX. 8-31 (HCl) (52.06 g, 91.33%) as off white solid.

¹H NMR (MeOD/400 MHz): δ 8.69 (s, 1H), 8.34 (s, 1H), 8.21 (d, J=7.6 Hz, 1H), 7.96 (d, J=9.6 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.75 (dd, J=7.6 Hz, 8.0 Hz, 1H), 7.23 (d, J=9.6 Hz, 1H), 3.73-3.66 (m, 1H), 2.24-2.20 (m, 2H), 1.97 (m, 2H), 1.37-1.25 (m, 5H), 1.16 (s, 6H). MS (ES ⁺, m/z): (M+H) ⁺: 419.2. Melting Point: 200.4° C.-201.6° C.

PAT

Heterocyclic protein kinase inhibitorsPublication Number: ES-2834093-T3Priority Date: 2011-07-21Grant Date: 2021-06-16
Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitorsPublication Number: US-2021238183-A1Priority Date: 2011-07-21
Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitorsPublication Number: US-2012058997-A1Priority Date: 2006-11-06
Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitorsPublication Number: US-9416132-B2Priority Date: 2011-07-21Grant Date: 2016-08-16
Heterocyclic protein kinase inhibitorsPublication Number: WO-2013013188-A1Priority Date: 2011-07-21
Heterocyclic protein kinase inhibitorsPublication Number: EP-3409278-B1Priority Date: 2011-07-21Grant Date: 2020-09-16
Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitorsPublication Number: US-10875864-B2Priority Date: 2011-07-21Grant Date: 2020-12-29
Heterocyclic protein kinase inhibitorsPublication Number: EP-3812387-A1Priority Date: 2011-07-21
Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitorsPublication Number: US-10392392-B2Priority Date: 2011-07-21Grant Date: 2019-08-27
Heterocyclic protein kinase inhibitorsPublication Number: US-2014329807-A1Priority Date: 2011-07-21
Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitorsPublication Number: US-2017002014-A1Priority Date: 2011-07-21
Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitorsPublication Number: US-2019071446-A1Priority Date: 2011-07-21
Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitorsPublication Number: US-2020102313-A1Priority Date: 2011-07-21
Heterocyclic protein kinase inhibitorsPublication Number: EP-2734205-B1Priority Date: 2011-07-21Grant Date: 2018-03-21
Heterocyclic protein kinase inhibitorsPublication Number: EP-3409278-A1Priority Date: 2011-07-21
Heterocyclic protein kinase inhibitorsPublication Number: JP-2014520898-APriority Date: 2011-07-21
Heterocyclic protein kinase inhibitorsPublication Number: JP-6105578-B2Priority Date: 2011-07-21Grant Date: 2017-03-29
Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitorsPublication Number: US-10047093-B2Priority Date: 2011-07-21Grant Date: 2018-08-14

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REF

https://news.us.sumitomo-pharma.com/2025-06-12-Sumitomo-Pharma-America-Announces-that-Nuvisertib-TP-3654-Has-Received-FDA-Fast-Track-Designation-for-the-Treatment-of-Myelofibrosis

– Nuvisertib (TP-3654), an investigational highly selective oral PIM1 kinase inhibitor, is being evaluated in patients with relapsed or refractory myelofibrosis (MF) –

– Nuvisertib demonstrated symptom and spleen responses correlating with cytokine modulation in the preliminary Phase 1/2 data recently presented at the European Hematology Association (EHA) 2025 Congress –

MARLBOROUGH, Mass., June 12, 2025 /PRNewswire/ — Sumitomo Pharma America, Inc. (SMPA) today announced that the U.S. Food and Drug Administration (FDA) granted Fast Track Designation to nuvisertib (TP-3654) for the treatment of patients with intermediate or high-risk myelofibrosis (MF). The FDA Fast Track Designation is granted to investigational therapies being developed to treat serious or life-threatening conditions that demonstrate the potential to address unmet medical needs. Nuvisertib is an oral, investigational, highly selective inhibitor of PIM1 kinase, which demonstrated clinical activity including symptom and spleen responses correlating with cytokine modulation in the updated preliminary Phase 1/2 data presented at the European Hematology Association (EHA) 2025 Congress in Milan, Italy.

MF, a serious and rare type of blood cancer, is characterized by the buildup of fibrous tissues in the bone marrow which is caused by dysregulation in the Janus-associated kinase (JAK) signaling pathway. The clinical manifestations of MF include an enlarged spleen, debilitating symptoms and reduction in hemoglobin and/or platelets. MF affects 1 in 500,000 people worldwide.¹

“This positive momentum for nuvisertib signals strong promise in our pipeline and reflects our dedication to addressing unmet medical needs on behalf of patients with myelofibrosis and their families,” said Tsutomu Nakagawa, Ph.D, President and Chief Executive Officer of SMPA. “Receiving FDA Fast Track Designation for nuvisertib in the treatment of myelofibrosis reinforces our confidence in its potential as a treatment option for patients facing a poor prognosis with limited treatment options. We are committed to working closely with the FDA to progress the clinical development of nuvisertib and bring an alternative treatment option to patients with myelofibrosis.”

Updated data from the ongoing Phase 1/2 study of nuvisertib in patients with relapsed/refractory MF were presented at the EHA Congress on June 12, 2025. Preliminary data showed that nuvisertib monotherapy appears to be well tolerated with no dose-limiting toxicities (DLTs). Evaluable patients showed clinical activity including a ≥25% spleen volume reduction (SVR25) in 22.2% of patients and a ≥50% reduction in total symptom score (TSS50) of 44.4% of patients, as well as improvement of bone marrow fibrosis (42.9% patients), hemoglobin (24% patients) and platelet count (26.7% patients). Data also showed that nuvisertib treatment led to significant cytokine modulation [reduction of pro-inflammatory cytokines (e.g. EN-RAGE, MIP-1β) and increase of anti-inflammatory cytokines (e.g. adiponectin)], which demonstrated significant (p<0.001) correlation with symptom and spleen responses. Preclinical² and emerging clinical data support the development of nuvisertib in combination with JAK inhibitors for the treatment of patients with MF.

“The data observed to date demonstrate promising clinical activity for nuvisertib and the strong potential for selective PIM1 inhibition to slow the progression of myelofibrosis,” said Jatin Shah, MD, Chief Medical Officer, Oncology. “Patients with myelofibrosis are in need of new therapeutic approaches, including combination treatment options, that can provide increased and durable response rates with limited hematologic adverse events. The FDA Fast Track Designation reinforces the potential of nuvisertib to provide clinical benefits for patients with myelofibrosis, an unmet medical need.”

About Nuvisertib (TP-3654)
Nuvisertib (TP-3654) is an oral investigational selective inhibitor of PIM1 kinase, which has shown potential antitumor and antifibrotic activity through multiple pathways, including induction of apoptosis in preclinical models.^2,3 Nuvisertib was observed to inhibit proliferation and increase apoptosis in murine and human hematopoietic cells expressing the clinically relevant JAK2 V617F mutation.³ Nuvisertib alone and in combination with ruxolitinib showed white blood cell and neutrophil count normalization, and also reduced spleen size and bone marrow fibrosis in JAK2 V617F and MPLW515L murine models of myelofibrosis.²The safety and efficacy of nuvisertib is currently being clinically evaluated in a Phase 1/2 study in patients with intermediate and high-risk myelofibrosis (NCT04176198). The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to nuvisertib for the indication of myelofibrosis in May 2022. The Japan Ministry of Health, Labour and Welfare (MHLW) granted Orphan Drug Designation to nuvisertib for the treatment of myelofibrosis in November 2024.

About Sumitomo Pharma
Sumitomo Pharma Co., Ltd., is a global pharmaceutical company based in Japan with key operations in the U.S. (Sumitomo Pharma America, Inc.), Canada (Sumitomo Pharma Canada, Inc.), and Europe (Sumitomo Pharma Switzerland GmbH) focused on addressing patient needs in oncology, urology, women’s health, rare diseases, psychiatry & neurology, and cell & gene therapies. With several marketed products in the U.S., Canada, and Europe, a diverse pipeline of early- to late-stage assets, we aim to accelerate discovery, research, and development to bring novel therapies to patients sooner. For more information on SMPA, visit our website https://www.us.sumitomo-pharma.com or follow us on LinkedIn.

The Sumitomo corporate symbol mark is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO PHARMA is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO is a registered trademark of Sumitomo Chemical Co., Ltd., used under license. Sumitomo Pharma America, Inc. is a U.S. subsidiary of Sumitomo Pharma Co., Ltd.

References

U.S. National Library of Medicine. (n.d.). Primary myelofibrosis: Medlineplus Genetics. MedlinePlus. https://medlineplus.gov/genetics/condition/primary-myelofibrosis/
Dutta A., Nath D, Yang Y, et al. Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models. Leukemia. 2022; 36 (3): 746-759. doi: 10.1038/s41375-021-01464-2.
Foulks JM, Carpenter KJ, Luo B, et al. A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas. Neoplasia. 2014;16(5):403-412.

SOURCE Sumitomo Pharma America

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancerPublication Name: Science Translational MedicinePublication Date: 2023-06-21PMCID: PMC10758289PMID: 37343085DOI: 10.1126/scitranslmed.add7872
The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer DrugsPublication Name: International Journal of Molecular SciencesPublication Date: 2021-08-30PMCID: PMC8431370PMID: 34502348DOI: 10.3390/ijms22179440
High-Throughput Screening to Identify Inhibitors of the Type I Interferon–Major Histocompatibility Complex Class I Pathway in Skeletal MusclePublication Name: ACS Chemical BiologyPublication Date: 2020-05-27PMCID: PMC7859889PMID: 32459468DOI: 10.1021/acschembio.0c00343
PIM kinase inhibitors: Structural and pharmacological perspectivesPublication Name: European Journal of Medicinal ChemistryPublication Date: 2019-06-15PMID: 30954777DOI: 10.1016/j.ejmech.2019.03.050
A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial CarcinomasPublication Name: Neoplasia (New York, N.Y.)Publication Date: 2014-05PMCID: PMC4198696PMID: 24953177DOI: 10.1016/j.neo.2014.05.004
BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancerPublication Name: Science Translational MedicinePublication Date: 2023-06-21PMCID: PMC10758289PMID: 37343085DOI: 10.1126/scitranslmed.add7872
The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer DrugsPublication Name: International Journal of Molecular SciencesPublication Date: 2021-08-30PMCID: PMC8431370PMID: 34502348DOI: 10.3390/ijms22179440
High-Throughput Screening to Identify Inhibitors of the Type I Interferon–Major Histocompatibility Complex Class I Pathway in Skeletal MusclePublication Name: ACS Chemical BiologyPublication Date: 2020-05-27PMCID: PMC7859889PMID: 32459468DOI: 10.1021/acschembio.0c00343
PIM kinase inhibitors: Structural and pharmacological perspectivesPublication Name: European Journal of Medicinal ChemistryPublication Date: 2019-06-15PMID: 30954777DOI: 10.1016/j.ejmech.2019.03.050
A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial CarcinomasPublication Name: Neoplasia (New York, N.Y.)Publication Date: 2014-05PMCID: PMC4198696PMID: 24953177DOI: 10.1016/j.neo.2014.05.004

///////Nuvisertib, serine/ threonine kinase inhibitor, antineoplastic, Orphan Drug, myelofibrosis, SGI-9481, SGI 9481, TP-3654, TP 3654, EOB0N7BOY4

Neladalkib

November 10, 2025 2:28 am / Leave a comment

Neladalkib

CAS 2739866-40-9

MF C23H22ClFN6O MW 452.9 g/mol

(19R)-5-chloro-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentazapentacyclo[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

anaplastic lymphoma kinase (ALK) inhibitor, antineoplastic, NVL-655, NVL 655, J32P26A6BC, ALK-IN-27

Neladalkib is a small molecule drug. The usage of the INN stem ‘-alkib’ in the name indicates that Neladalkib is a ALK (anaplastic lymphoma kinase) inhibitor. Neladalkib is under investigation in clinical trial NCT06765109 (Neladalkib (NVL-655) for TKI-naive Patients With Advanced ALK-Positive NSCLC). Neladalkib has a monoisotopic molecular weight of 452.15 Da.

ALK Inhibitor NVL-655 is an orally bioavailable, brain-penetrant, selective small molecule inhibitor of the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK), with potential antineoplastic activity. Upon oral administration, ALK inhibitor NVL-655 specifically targets, binds to and inhibits ALK fusion proteins and activating mutations, including the acquired resistance mutations solvent front mutation (SFM) G1202R and the compound mutations G1202R/L1196M and G1202R/G1269A. The inhibition of ALK leads to the disruption of ALK-mediated signaling and the inhibition of cell growth in ALK-expressing tumor cells. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK is not expressed in healthy adult human tissue but ALK dysregulation and gene rearrangements are associated with a variety of tumor cell types. NVL-655 is able to penetrate the blood-brain-barrier (BBB) and may therefore exert its activity against EGFR-driven central nervous system (CNS) primary tumors and CNS metastases.

Expanded Access Program of Neladalkib (NVL-655) for Patients With Advanced ALK+ NSCLC or Other ALK+ Solid TumorsCTID: NCT06834074Status: AvailableDate: 2025-09-22
Neladalkib (NVL-655) for TKI-naive Patients With Advanced ALK-Positive NSCLCCTID: NCT06765109Phase: Phase 3Status: RecruitingDate: 2025-08-29
A Study of Neladalkib (NVL-655) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1)CTID: NCT05384626Phase: Phase 1/Phase 2Status: RecruitingDate: 2025-07-24

SYN

WO2023196910

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023196910&_cid=P20-MHSIQF-58684-1

SYN

WO-2023196900

PAT

Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number: US-2022098212-A1Priority Date: 2020-05-05
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number: US-2022340586-A9Priority Date: 2020-05-05
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number: US-2023076627-A1Priority Date: 2020-05-05
Heteroaromatic macrocyclic ether chemotherapeutic agentsPublication Number: US-11667649-B2Priority Date: 2020-05-05Grant Date: 2023-06-06
Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compoundsPublication Number: US-2023322797-A1Priority Date: 2022-04-07
Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compoundsPublication Number: WO-2023196900-A1Priority Date: 2022-04-07
Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compoundsPublication Number: WO-2023196900-A9Priority Date: 2022-04-07
Methods of treating solid tumor using (19r)-5-chloro-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.02,6.08,12.013,18]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-aminePublication Number: WO-2023196910-A1Priority Date: 2022-04-07
Methods of treating solid tumor using (19r)-5-chloro-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.02,6.08,12.013,18]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-aminePublication Number: EP-4504189-A1Priority Date: 2022-04-07

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/////////neladalkib, antineoplastic, NVL-655, NVL 655, J32P26A6BC, ALK-IN-27

Nefextinib

November 9, 2025 8:27 am / Leave a comment

Nefextinib

CAS 2070931-57-4

MF C22H23FN6OS MW 438.52

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

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

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

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

SYN

example 31 [CN106366093A]

SYN

WO-2017012559

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

Example 31

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

Synthesis of compound 31-e

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

[0492]Synthesis of compound 31-d

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

[0494]Synthesis of compound 31-c

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

[0496]Synthesis of compound 31-b

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

[0498]Synthesis of compound 31-a

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

[0500]Synthesis of Compound 31

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

[0502]

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

PAT

Condensed ring pyrimidine compound, intermediate, its preparation method, composition and applicationPublication Number: CN-106366093-BPriority Date: 2015-07-21Grant Date: 2020-08-18
Condensation ring pyrimidine compounds, intermediates, methods for producing them, compositions and applicationsPublication Number: JP-6875372-B2Priority Date: 2015-07-21Grant Date: 2021-05-26
Condensed ring pyrimidine compounds, intermediates, preparation methods, compositions and applications thereofPublication Number: KR-102591886-B1Priority Date: 2015-07-21Grant Date: 2023-10-20
Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereofPublication Number: EP-3354653-B1Priority Date: 2015-07-21Grant Date: 2019-09-04
Fused ring pyrimidine compounds, intermediates, production methods, compositions and applications thereofPublication Number: JP-2018520202-APriority Date: 2015-07-21
Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereofPublication Number: US-10494378-B2Priority Date: 2015-07-21Grant Date: 2019-12-03
Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereofPublication Number: US-2018208604-A1Priority Date: 2015-07-21
Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereofPublication Number: WO-2017012559-A1Priority Date: 2015-07-21

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31. 4-((3-(3-(Trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)-trans-cyclohexyl)propan-2-ol (EX. 8-31)

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