Istisociclib

KB 130742

CAS 2416873-83-9

MF C16H25N5, 287.40 g/mol

trans-(1S,3S)-3-N-(5-pentan-3-ylpyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diamine

• (1S,3S)-N1-[5-(1-Ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]-1,3-cyclopentanediamine
• 1,3-Cyclopentanediamine, N1-[5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]-, (1S,3S)-

(1S,3S)-N1-[5-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]cyclopentane-1,3-diamine
cyclin-dependent kinase (CDK) inhibitor, antineoplastic, KB-0742, 2416873-83-9, KB 0742, F7J6KSY5I8, UB-18422, KB-130742, KB 00130742

Istisociclib is a small molecule drug. The usage of the INN stem ‘-ciclib’ in the name indicates that Istisociclib is a cyclin dependant kinase inhibitor. Istisociclib is under investigation in clinical trial NCT04718675 (A Study of KB-0742 in Participants With Relapsed or Refractory Solid Tumors Including Platinum Resistant High Grade Serous Ovarian Cancer (HGSOC)). Istisociclib has a monoisotopic molecular weight of 287.21 Da.

Istisociclib is an orally bioavailable, selective inhibitor of the serine/threonine cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the RNA polymerase II (RNA Pol II) elongation factor positive transcription elongation factor b (PTEF-b; PTEFb), with potential antineoplastic activity. Upon oral administration, istisociclib targets, binds to and blocks the phosphorylation and kinase activity of CDK9, thereby preventing PTEFb-mediated activation of RNA Pol II, leading to the inhibition of gene transcription of various anti-apoptotic proteins and oncogenic transcription factors including MYC and androgen receptor (AR). This induces cell cycle arrest and apoptosis and prevents tumor cell proliferation. CDK9 regulates elongation of transcription through phosphorylation of RNA Pol II at serine 2 (p-Ser2-RNAPII), and is an important cofactor for various oncogenic transcription factors. It is upregulated in various tumor cell types and plays a key role in the regulation of Pol II-mediated transcription of anti-apoptotic proteins. Tumor cells are dependent on anti-apoptotic proteins for their survival.

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

A Study of KB-0742 in Participants With Relapsed or Refractory Solid Tumors Including Platinum Resistant High Grade Serous Ovarian Cancer (HGSOC)

CTID: NCT04718675

Phase: Phase 1/Phase 2

Status: Terminated

Date: 2025-02-17

REF

• Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent CancersPublication Name: Journal of Medicinal ChemistryPublication Date: 2023-11-15PMCID: PMC10726352PMID: 37967851DOI: 10.1021/acs.jmedchem.3c01233
• CDK9 inhibitors in cancer researchPublication Name: RSC Medicinal ChemistryPublication Date: 2022-06-22PMCID: PMC9215160PMID: 35814933DOI: 10.1039/d2md00040g
• From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer TherapyPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-04-29PMID: 35485642DOI: 10.1021/acs.jmedchem.1c02064
• Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery EffortsPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-03-02PMID: 35235745DOI: 10.1021/acs.jmedchem.1c02190

PAT

WO-2023096922-A1

 (lS,3S)-N¹-(5-(pentan-3-yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diamine is a pharmaceutically active compound that has been studied for various uses, such as for the treatment of cancer. As used herein, the term “Compound A” is used to refer to both the free base and salt forms of (lS,3S)-N¹-(5-(pentan-3-yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diamine. The free base of Compound A has the CAS number of 2416873-83-9 and structure of formula (I):

SYN

Example 35: (1S,3S)-N3-[5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]cyclopentane-1,3-diamine (35)

2-Ethylbutanoic acid (7.5 g, 64.57 mmol) was dissolved in THF (150 mL) and cooled to 0 °C. Within 20 min CDI (16.23 g, 100.08 mmol) was added portion-wise. The reaction warmed to room temp (rt) and the mixture was stirred at rt overnight (Solution A). In another flask MgCl₂ (6.14 g, 64.57 mmol) and potassium 3-ethoxy-3-oxo-propanoate (17 g, 100.1 mmol) were mixed with THF (150 mL) and stirred under argon overnight at 50 °C. The resultant white suspension was cooled to rt and solution A was added dropwise over 10 min and the reaction mixture (RM) was stirred for 16h at room temperature. After several minutes a sticky, amorphous solid appeared whereupon after several hours the reaction mixture became homogenous in appearance. The RM was concentrated to about a third, taken up in half sat. potassium bisulphate solution and extracted twice with ethyl acetate. The organic layers were subsequently washed with a sat. sodium bicarbonate solution, combined, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by column chromatography gave ethyl 4-ethyl-3-oxo-hexanoate (4.3 g, 23.087 mmol, 35.8% yield) as a transparent liquid. The RM was monitored by TLC (10% EA in Hex, Product Rf=0.6, SM Rf=0.1).

Step 2

To a suspension of ethyl 4-ethyl-3-oxo-hexanoate (4.4 g, 23.62 mmol) in acetic acid (11 mL) at 70 °C was added 1H-pyrazol-5-amine (4.71 g, 56.7 mmol) in two portions (the second portion was added after 2 hours of stirring the first portion) over a 4 hour period. Upon consumption of SM as indicated by TLC, the reaction was cooled to rt and the solvent was evaporated in a rotary evaporator. The residue was treated with ethyl acetate and filtered to give 5-(1-ethylpropyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (3.7 g, 17.7 mmol, 74.9% yield) as an off-white solid. The reaction mixture was monitored by TLC (5% MeOH in DCM, Product Rf=0.3, SM Rf=0.8).

Step 3

A stirred solution of 5-(1-ethylpropyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (3.7 g, 18.03 mmol) in POCl3 (33.7 mL, 360.52 mmol) was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, excess reagent was evaporated in a rotary evaporator, and the residue was treated with ice-water. The chlorinated product was extracted from aqueous mixture by DCM. The organic layer was separated, dried ^{over anhydrous Na}₂^SO₄^{, filtered and purified by column chromatography to give 7-} chloro-5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidine (3.1 g, 13.9 mmol, 76.9% yield) as a light yellow liquid. The reaction mixture was monitored by TLC (20% EA in Hex, Product Rf=0.6, SM Rf=0.1).

To a stirred solution 7-chloro-5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidine (2.3 g, 10.28 mmol), tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (2.27 g, 11.31 mmol) and K2CO3 (4.26 g, 30.84 mmol) in MeCN (20 mL) were heated to reflux for 16 hours. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography, eluent 30% EA in hexane to give tert-butyl N-[(1S,3S)-3-[[5-(1-ethylpropyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino]cyclopentyl]carbamate (4.5 g, 11.6 mmol, 112.8% yield) as an off-white solid. The reaction mixture was monitored by TLC (40% EA in Hex, Product Rf=0.5, SM Rf=0.7).

Step 5

To tert-butyl N-[(1 S,3S)-3-[[5-(l-ethylpropyl)pyrazolo[l,5-a]pyrimidin-7-yl]amino]cyclopentyl]carbamate (1.0 g, 2.58 mmol) in l,4-Dioxane (0.2 mL), 4 M HC1 in Dioxane (3.22 mL, 12.9 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo, triturated with pentane and lyophilized from MeCN:H20 to give [(lS,3S)-3-[[5-(l-ethylpropyl)pyrazolo[l,5-a]pyrimidin-4-ium-7-yl]amino]cyclopentyl]ammonium dichloride (0.9 g, 2.5 mmol, 96.8% yield) as a pale-yellow sticky solid. The reaction mixture was monitored by TLC ( 100% EA, Product Rf=0.l, SM Rf=0.8). 1H NMR (400 MHz, DMSO-d6) d 15.00 (s, 1H), 9.93-9.86 (m, 1H), 8.51 (s, 3H), 8.30 (s, 1H), 6.84 (s, 1H), 6.58 (s, 1H), 4.95 (q, J = 7.8 Hz, 1H), 3.77- 3.66 (m, 1H), 2.84-2.71 (m, 1H), 2.29-2.05 (m, 4H), 1.94-1.63 (m, 6H), 0.81 (t, J = 7.4 Hz, 6H). LC-MS (m/z 287.21, found 288.0 [M+H+])

Step 6

To [(1S,3S)-3-[[5-(l-ethylpropyl)pyrazolo[I,5-a]pyrimidin-4-ium-7-yl]amino]cyclopentyl]ammonium-di chloride (0.2 g, 0.5600 mmol) in aq. NH3 (4.0 mL, 0.56 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo, triturated with pentane and lyophilized from MeCN:H20 to give (lS,3S)-N3-[5-(l-ethylpropyl)pyrazolo[l,5-a]pyrimidin-7-yl]cyclopentane-l,3-diamine (140 mg, 0.49 mmol, 87.8% yield) as a pale-yellow sticky solid. The reaction mixture was monitored by TLC (100% EA, Product Rf=0.1, SM Rf=0.8). 1H NMR (400 MHz, DMSO-d6) d 7.95 (d, J = 2.2 Hz, 1H), 6.86 (s, 1H), 6.29 (d, J = 2.2 Hz, 1H), 5.95 (s, 1H), 4.31-4.19 (m, 1H), 3.57-3.44 (m, 1H), 2.52-2.44 (m, 1H), 2.36-2.22 (m, 1H),

2.09–1.79 (m, 3H), 1.80–1.59 (m, 5H), 1.58–1.24 (m, 3H), 0.83 (t, J = 7.4 Hz, 6H). LC-MS (m/z 287.21, found 288.5 [M+H+]).

PAT

• Compounds, compositions and methods for modulating CDK9 activityPublication Number: CN-112996790-BPriority Date: 2018-10-30Grant Date: 2023-11-03
• Compounds, compositions, and methods for modulating cdk9 activityPublication Number: US-2024132506-A1Priority Date: 2018-10-30
• Compounds, Compositions, and Methods for Modulating CDK9 ActivityPublication Number: US-2020131189-A1Priority Date: 2018-10-30
• Compounds, compositions, and methods for modulating cdk9 activityPublication Number: US-2022002305-A1Priority Date: 2018-10-30
• Compounds, compositions, and methods for modulating cdk9 activityPublication Number: EP-3873911-A1Priority Date: 2018-10-30
• Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activityPublication Number: US-11845754-B2Priority Date: 2018-10-30Grant Date: 2023-12-19
• Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activityPublication Number: US-11155560-B2Priority Date: 2018-10-30Grant Date: 2021-10-26
• Compounds and methods for modulating cdk9 activityPublication Number: EP-4240422-A1Priority Date: 2020-11-05
• Compounds and methods for modulating cdk9 activityPublication Number: WO-2022098843-A1Priority Date: 2020-11-05
• Compounds and methods for modulating cdk9 activityPublication Number: US-2025188084-A1Priority Date: 2020-11-05
• Chimeric degraders of cyclin-dependent kinase 9 and uses thereofPublication Number: WO-2021216828-A1Priority Date: 2020-04-24
• Chimeric degraders of cyclin-dependent kinase 9 and uses thereofPublication Number: US-2023158159-A1Priority Date: 2020-04-24
• Polymorphic and salt forms of (ls,3s)-n-(5-(pentan-3- yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diaminePublication Number: EP-4436569-A1Priority Date: 2021-11-24
• Polymorphs and salt forms of (1S,3S)-N1-(5-(pentan-3-yl)pyrazolo[1,5-A]pyrimidin-7-yl)cyclopentane-1,3-diaminePublication Number: KR-20240110634-APriority Date: 2021-11-24
• Compositions and methods for enhanced protein productionPublication Number: EP-4412621-A2Priority Date: 2021-09-22
• Compositions and methods for enhanced protein productionPublication Number: US-2024252688-A1Priority Date: 2021-09-22
• Compositions and methods for enhanced protein productionPublication Number: WO-2023056202-A2Priority Date: 2021-09-22
• A cdk9 inhibitor for use in the treatment of cancer in a subject having an asxl1 mutationPublication Number: WO-2025217597-A1Priority Date: 2024-04-12
• Polymorphic and salt forms of (1s,3s)-n1-(5-(pentan-3- yl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diaminePublication Number: WO-2023096922-A8Priority Date: 2021-11-24
• Polymorphic and salt forms of (ls,3s)-n1-(5-(pentan-3- yl)pyrazolo[l,5-a]pyrimidin-7-yl)cyclopentane-l,3-diaminePublication Number: WO-2023096922-A1Priority Date: 2021-11-24
• Polymorphic and salt forms of (1s,3s)-n1-(5-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl) cyclopentane-1,3-diaminePublication Number: US-2025059193-A1Priority Date: 2021-11-24
• Polymorphic forms and salt forms of (1S,3S)-N1-(5-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diaminePublication Number: CN-118678952-APriority Date: 2021-11-24

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//////istisociclib, cyclin-dependent kinase (CDK) inhibitor, antineoplastic, KB-0742, 2416873-83-9, KB 0742, F7J6KSY5I8, UB-18422, KB-130742, KB 00130742