Medicinal Chemistry International

DRUG PATENTS INTERNATIONAL

Mobinitinib

CAS1402709-93-6

MF C22H23Cl2N7 MW456.37

6-chloro-7-{4-[(4-chlorophenyl)methyl]piperazin-1-yl}-2-(1,3-dimethyl-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

6-chloro-7-{4-[(4-chlorophenyl)methyl]piperazin-1-yl}-2-(1,3-dimethyl-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine
dual FMS-like tyrosine kinase-3 (FLT3)-Aurora kinase inhibitor, antineoplastic, CCT241736, CCT 241736, ZE94SP78UG, EP0042, EP 0042

Mobinitinib (CCT241736) is an investigational, orally bioavailable, small-molecule, dual inhibitor targeting Aurora kinase and FLT3 (including ITD and D835Y mutations). It shows potent antineoplastic activity in preclinical models, including acute myeloid leukemia (AML), by inhibiting tumor cell proliferation and disrupting mitotic spindle assembly. It is a distinct compound from similarly named drugs like Momelotinib or Binimetinib.

Key Details About Mobinitinib (CCT241736)

Mechanism of Action: Acts as a dual inhibitor of Aurora kinases (A and B) and FMS-related tyrosine kinase 3 (FLT3). By inhibiting these kinases, it interferes with mitotic spindle assembly and chromosome segregation, leading to cell cycle arrest.
Target Indications: Primarily studied for its potential to treat hematological malignancies and solid tumors that overexpress FLT3 or Aurora kinases. Preclinical studies show effectiveness in FLT3-ITD positive AML cell lines (e.g., MOLM-13, MV4-11).
Preclinical Activity: Demonstrates strong anti-proliferative activity with values in the sub-micromolar range (e.g., 0.1–0.3 M) in certain human tumor cell lines. It has shown significant tumor growth inhibition in mouse xenograft models at doses of 50-100 mg/kg.
Chemical Properties: It is a 1H-imidazo[5-b]pyridine derivative.

It is important to distinguish mobinitinib (CCT241736) from momelotinib, a JAK1/JAK2 inhibitor approved for myelofibrosis, and binimetinib, a MEK inhibitor for melanoma.

Mobinitinib is an orally bioavailable inhibitor of both the serine/threonine protein kinase Aurora kinase and FMS-related tyrosine kinase 3 (FLT3; STK1; CD135; FLK2), with potential antineoplastic activity. Upon oral administration, mobinitinib specifically binds to and inhibits Aurora kinase and FLT3, which interferes with the activation of Aurora kinase- and FLT3-mediated signal transduction pathways. This may result in the disruption of the assembly of the mitotic spindle apparatus, the disruption of chromosome segregation and the inhibition of cell proliferation in tumor cells that overexpress Aurora kinase and/or FLT3. Aurora kinase plays essential roles in mitotic checkpoint control during mitosis. Aurora kinase and FLT3 are overexpressed in a variety of cancers and play key roles in tumor cell proliferation.

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

Study to Evaluate the Safety and Tolerability of EP0042

CTID: NCT04581512

Phase: Phase 1/Phase 2

Status: Recruiting

Date: 2025-10-14

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013190319&_cid=P12-MLIU87-35242-1

5-Chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine

[00119] To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.152 g, 0.73 mmol) and isopropanol (22 mL) was added 1 -(4-chlorobenzyl)piperazine (0.165 g, 0.78 mmol) followed by diisopropylethylamine (0.17 mL, 0.97 mmol). The reaction mixture was heated at 45 °C for 18 h, then allowed to cool to room temperature, and diluted with isopropanol (5 mL). The precipitate was collected by filtration, washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.215 g, 77%); ¹H-NMR (500 MHz, DMSO-d₆) 2.48 (br s, obscured by DMSO peak, 4H, piperazine C-H), 3.06 (br t, J = 4.3 Hz, 4H, piperazine C-H), 3.52 (s, 2H, NCH₂C₆H₄Cl), 6.95 (s, 2H, NH₂), 7.35 (d, J = 8.5 Hz, 2H) and 7.38 (d, J = 8.5 Hz, 2H) (3,5-ArH and 2,6- ArH), 8.06 (s, 1 H, 6-H); LC - MS (ESI, m/z): Rt = 1 .70 min - 382, 384, 386 [(M+H)⁺, Cl₂ isotopic pattern].

6-Chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

[00120] To a mixture of 5-chloro-4-(4-(4-chlorobenzyl)piperazin-1 -yl)-3-nitropyridin-2-amine (0.076 g, 0.20 mmol) and EtOH (4.0 ml.) was added 1 ,3-dimethyl-1 H-pyrazole-4-carbaldehyde (0.027 g, 0.22 mmol) followed by a freshly prepared aqueous solution of Na₂S₂O₄ (1 M; 0.85 mL, 0.85 mmol). The reaction mixture was stirred at 80 °C for 24 h, it was then allowed to cool to room temperature, concentrated in vacuo, and the residue was absorbed on silica gel and placed on a 10 g isolute silica column. Elution with ethyl acetate / dichloromethane (v/v; 1 :1 ), and then 4% methanol in ethyl acetate / dichloromethane (v/v; 1 :1 ) afforded the title compound as a white solid after trituration with diethyl ether (0.023 g, 25%).

[00121 ] ¹ H-NMR (500 MHz, DMSO-d₆) 2.51 (s, obscured by solvent peak, pyrazole 3-CH₃), 2.57 (br s, 4H, piperazine C-H), 3.54 (s, 2H, N-CH₂C₆H₄Cl), 3.68 (br s, 4H, piperazine C-H), 3.84 (s, 3H, pyrazole N-Me), 7.37 (d, J = 8.5 Hz, 2H) and 7.40 (d, J = 8.5 Hz, 2H) (C₆H₄Cl), 8.02 (s, 1 H), and 8.18 (s, 1 H) (pyrazole 5-H, and imidazo[4,5-b]pyridine 5-H), 12.95 (br s, 1 H, imidazo[4,5-b]pyridine N-H); LC - MS (ESI, m/z): Rt = 1.97 min - 456, 458, 460 [(M+H)⁺, Cl₂ isotopic pattern].

[00122] HRMS: Found: 456.1457, calculated for C₂₂H₂₄Cl₂N₇ (M+H)⁺: 456.1465.

LIT

FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming ResistancePublication Name: Journal of Medicinal ChemistryPublication Date: 2021-03-10PMID: 33719439DOI: 10.1021/acs.jmedchem.0c01851
Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736Publication Name: Blood AdvancesPublication Date: 2020-04-13PMCID: PMC7160287PMID: 32282883DOI: 10.1182/bloodadvances.2019000986
Metabolism of the dual FLT-3/Aurora kinase inhibitor CCT241736 in preclinical and human in vitro models: Implication for the choice of toxicology speciesPublication Name: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical SciencesPublication Date: 2019-11-01PMCID: PMC6892276PMID: 30953752DOI: 10.1016/j.ejps.2019.04.004
Optimization of Imidazo[4,5-b]pyridine-Based Kinase Inhibitors: Identification of a Dual FLT3/Aurora Kinase Inhibitor as an Orally Bioavailable Preclinical Development Candidate for the Treatment of Acute Myeloid LeukemiaPublication Name: Journal of Medicinal ChemistryPublication Date: 2012-10-08PMCID: PMC3483018PMID: 23043539DOI: 10.1021/jm300952s

PAT

Pharmaceutically active compoundsPublication Number: WO-2013190319-A1Priority Date: 2012-06-21
Compound and, pharmaceutical compositionPublication Number: BR-112014032142-B1Priority Date: 2012-06-21
Pharmaceutically active compoundsPublication Number: US-9447092-B2Priority Date: 2012-06-21Grant Date: 2016-09-20
Pharmaceutically active compoundsPublication Number: CA-2876357-A1Priority Date: 2012-06-21
Pharmaceutically active compoundsPublication Number: US-2015266868-A1Priority Date: 2012-06-21
PHARMACEUTALLY ACTIVE COMPOUNDSPublication Number: RU-2015101702-APriority Date: 2012-06-21
Pharmaceutically active compoundsPublication Number: SI-2864328-T1Priority Date: 2012-06-21

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DRUG PATENTS INTERNATIONAL

Mocaciclib

CAS 2766124-39-2

MF C33H36FN9O2 MW609.71

2-fluoro-N-[1-[2-[[[2-[[(3R,4R)-3-hydroxypiperidin-4-yl]methylamino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]isoquinolin-6-yl]prop-2-enamide
2-Fluoro-N-[1-[2-[[[2-[[[(3R,4R)-3-hydroxy-4-piperidinyl]methyl]amino]-8-(1-methylethyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl]amino]methyl]phenyl]-6-isoquinolinyl]-2-propenamide
2-fluoro-N-[1-[2-[[[2-[[(3R,4R)-3-hydroxypiperidin-4-yl]methylamino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]isoquinolin-6-yl]prop-2-enamide

cyclin-dependent kinase (CDK) inhibitor, antineoplastic, Q 901, CDK7-IN-21,

OriginatorThe Lead Discovery Center; The Max Planck Institute of Biochemistry
DeveloperQurient Co
ClassAntineoplastics; Small molecules
Mechanism of ActionCyclin-dependent kinase-activating kinase inhibitors
Phase I/IISolid tumours
31 May 2024Preliminary efficacy, pharmacodynamics, pharmacokinetics and adverse events data from a phase I/II trial in Solid tumours presented at the 60th Annual Meeting of the American Society of Clinical Oncology (ASCO-2024)
21 May 2024Qurient Therapeutics enters into an Cooperative Research and Development Agreement (CRADA) with the US National Cancer Institute (NCI) for phase I/II trial in Small cell lung cancer (SCLC) and Solid tumours
21 May 2024Qurient Therapeutics plans phase I/II trial in Small cell lung cancer (SCLC) and Solid tumours

Mocaciclib (Q-901) is an orally bioavailable, selective cyclin-dependent kinase (CDK) inhibitor with potent activity against CDK2, CDK4, and CDK6. Preclinical data show that Mocaciclib inhibits CDK2/cyclin E with an IC₅₀ of 1.1 nM, CDK4/cyclin D1 with an IC₅₀ of 2.5 nM, and CDK6/cyclin D3 with an IC₅₀ of 4.1 nM, demonstrating high potency in enzymatic assays. In cancer cell lines, Mocaciclib suppresses retinoblastoma protein (Rb) phosphorylation, leading to G1 cell cycle arrest and growth inhibition in Rb-positive tumor models. It has shown antiproliferative effects in various preclinical models, including breast and lung cancers.

Mocaciclib is a selective inhibitor of cyclin-dependent kinase 7 (CDK7), with potential antineoplastic activity. Upon administration, mocaciclib selectively targets, covalently binds to and inhibits the activity of CDK7, thereby inhibiting CDK7-mediated signaling. The inhibition of CDK7 prevents phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II, thereby preventing transcription of important cancer-promoting genes. It prevents phosphorylation of the cell cycle kinases CDK1, 2, 4, and 6, thereby disrupting uncontrolled cell cycle progression. Altogether, this may induce apoptosis, cause cell cycle arrest, inhibit DNA damage repair and inhibit tumor cell proliferation in certain cancers that are dependent on CDK7-mediated transcriptional regulation and signaling. CDK7, a serine/threonine kinase, plays a role in controlling cell cycle progression and transcriptional regulation, and promotes the expression of key oncogenes through the phosphorylation of RNA polymerase II. It is overexpressed in multiple cancers.

SYN

[WO2019197546A1]

compound 64

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019197546&_cid=P20-MLKA3Y-79608-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022117504&_cid=P20-MLK9ZO-76153-1

This is compound 64, as disclosed in WO2O19/197546.

PAT

Compounds having cyclin-dependent kinase(cdk)-inhibitory functionPublication Number: WO-2022117504-A1Priority Date: 2020-12-02
Substituted pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines as CDK inhibitorsPublication Number: US-11858937-B2Priority Date: 2018-04-11Grant Date: 2024-01-02
Pharmaceutically active pyrazolo-triazine and/or pyrazolo-pyrimidine derivativesPublication Number: US-2021139483-A1Priority Date: 2018-04-11

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#mocaciclib, #cyclin-dependent kinase (CDK) inhibitor, #antineoplastic, #Q 901, #CDK7-IN-21,

DRUG PATENTS INTERNATIONAL

Mosperafenib

CAS 2649372-20-1

MF C20H17F2N5O4S MW 461.4 g/mol

(3R)-N-{2-cyano-4-fluoro-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]phenyl}-3-fluoropyrrolidine-1-sulfonamide
(3R)-N-(2-cyano-4-fluoro-3-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide

(3R)-N-{2-cyano-4-fluoro-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]phenyl}-3-fluoropyrrolidine-1-sulfonamide
B-Raf (BRAF) inhibitor, antineoplastic, RG6344, RO7276389, RG 6344, RO 7276389, 881-730-4, B-Raf IN 2

Mosperafenib is a small molecule drug. The usage of the INN stem '-rafenib' in the name indicates that Mosperafenib is a Raf (rapidly accelerated fibrosarcoma) kinase inhibitor. Mosperafenib has a monoisotopic molecular weight of 461.1 Da.

Mosperafenib (RG6344, RO7276389) is an investigational, oral, "paradox-breaker" BRAF inhibitor developed by Roche for treating BRAF-mutated cancers, particularly BRAF V600E-mutant metastatic colorectal cancer. It acts as a potent, selective inhibitor that avoids MAPK pathway overactivation in non-V600E contexts, showing superior preclinical activity and brain penetration compared to existing inhibitors like encorafenib.

Key Aspects of Mosperafenib:

Mechanism: As a "paradox-breaker" BRAF inhibitor, it avoids the paradoxical MAPK pathway activation seen with earlier inhibitors. It inhibits BRAF mutants () and is effective in RAF dimer-mediated resistant models.
Clinical Development: Currently in Phase I clinical trials for BRAF V600E-mutant colorectal cancer.
Preclinical Performance: In studies, it demonstrated higher antitumor activity than encorafenib/cetuximab combinations, even in BRAFi-naïve models.
Combination Potential: It is being evaluated in combination with cetuximab and FOLFOX.
Targeting: It targets BRAF V600E/K/A/D mutations.

OriginatorRoche
ClassAntineoplastics; Fluorinated hydrocarbons; Fluorobenzenes; Nitriles; Phenyl ethers; Pyridones; Pyrrolidines
Mechanism of ActionProto-oncogene protein b-raf inhibitors
Phase IMalignant melanoma; Solid tumours
18 Sep 2025Chemical structure information added.
30 May 2025Efficacy, pharmacokinetics and adverse events data from a phase I trial in Solid tumors presented at the 61st Annual Meeting of the American Society of Clinical Oncology (ASCO-2025)
25 Apr 2025Efficacy, pharmacokinetics and adverse events data from a phase I trial in Solid tumors presented at the 116th Annual Meeting of the American Association for Cancer Research (AACR-2025)

SYN

[WO2021116050]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021116050&_cid=P11-MLLPKF-91057-1

SYN

US20240174621,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US430558420&_cid=P11-MLLPRY-96230-1

3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (Example 1)

R)-3-Fluoropyrrolidine-1-sulfonamide (1.26 g, 7.51 mmol, Eq: 2.1) and cesium carbonate (2.56 g, 7.87 mmol, Eq: 2.2) were suspended in dry DMF (10.2 ml) under an argon atmosphere. The reaction was stirred at 50° C. for 30 min. The reaction mixture was cooled to rt and a solution of 3,6-difluoro-2-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)benzonitrile (1.12 g, 3.58 mmol, Eq: 1.0) in DMF (25.5 ml) was added. The reaction mixture was stirred at 100° C. for 15 h, then concentrated in vacuo. The residue was taken up in sat. aq. NH ₄Cl (100 mL) and EtOAc (100 mL). The phases were separated, and the aqueous layer was extracted further with 2×100 mL EtOAc. The combined organic layers were washed with water (200 mL) and brine (200 mL), dried (Na ₂SO ₄), filtered and concentrated in vacuo. The water layer was back-extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried (Na ₂SO ₄), filtered and concentrated in vacuo. The residue was diluted with DCM and MeOH, and concentrated onto silica. Purification by flash chromatography (120 g, 0.5-2% MeOH/DCM) gave an off-white solid which was triturated with 1:1 heptane/DCM (20 mL) with sonication, then dried in vacuo to give the title compound as a colourless solid (1.087 g, 66% yield). MS (ESI) m/z: 426.2 [M+H] ⁺. Chiral SFC: RT=4.594 min [Chiralpak IC column, 4.6×250 mm, 5 μm particle size (Daicel); gradient of 20-40% MeOH containing 0.2% NHEt ₂over 8 min; flow: 2.5 mL/min; 140 bar backpressure].

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021116055&_cid=P11-MLLPB3-84537-1

Refences compounds AR-25, AR-30 and AR-31 were prepared according to the synthesis disclosed in WO2012/118492 in example 25, example 30 and example 31 respectively.

6-hydroxy-3-methyl-quinazolin-4-one

2-Amino-5-hydroxybenzoic acid (10 g, 65.3 mmol, Eq: 1.0) and A-methylformamide (30 g, 29.9 mL, 503 mmol, Eq: 7.7) were heated at 145 °C for 21 h 45 min, then cooled to rt. The reaction mixture was diluted with 50 mL H₂O and stirred at rt for 20 min. The resulting precipitate was collected by filtration. The light brown solid was washed 3 × with 20 mL water. The solid was taken up in toluene and evaporated to dryness (3 ×). The solid was dried in vacuo at 40 °C overnight under high vacuum to give the title compound as a light brown solid (10.3 g, 89% yield). MS (ESI) mlz: 177.1 [M+H]⁺.

3.6-difluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile

Cesium carbonate (3.22 g, 9.79 mmol, Eq: 1.15) was added at rt to a solution of 6-hydroxy-3-methylquinazolin-4-one (1500 mg, 8.51 mmol, Eq: 1.0) in N,N-dimethylformamide (35 mL). The mixture was stirred for 30 min at rt then 2,3,6-trifluorobenzonitrile (1.47 g, 1.08 ml, 9.37 mmol, Eq: 1.1) was added. After 1 h, the reaction was cooled on ice and diluted with water (120 mL). The resultant solid was collected by filtration, washed with iced water (100 mL) and heptane (100 mL) and suction-dried. The solid was taken up in toluene and evaporated to dryness (3 ×) then dried overnight in vacuo to give the title compound as a light brown solid (2.58 g, 97% yield). MS (ESI) m/z: 314.1 [M+H]+.

(3R)-3 -fluoropyrrolidine- 1 -sulfonamide

(R)-3 -Fluoropyrrolidine hydrochloride (1.8 g, 14.3 mmol, Eq: 1.2) was added to a solution of sulfuric diamide (1.148 g, 11.9 mmol, Eq: 1.0) and triethylamine (2.42 g, 3.33 mL, 23.9 mmol, Eq: 2) in dioxane (10 mL). The reaction was stirred in a sealed tube at 115 °C for 15.5 h then cooled to rt and concentrated in vacuo. The residue was diluted with DCM, evaporated with silica gel to dryness and transferred to a column. Purification by flash chromatography (40 g silica, 80% EtOAc) gave the title compound as a white crystalline solid (1.82 g, 91% yield). MS (ESI) m/z: 169.1 [M+H]⁺.

(3S)-3 -fluoropyrrolidine- 1 -sulfonamide

Triethylamine (304 mg, 419 μl, 3.01 mmol, Eq: 2.0) was added to a suspension of sulfuric diamide (146 mg, 1.5 mmol, Eq: 1.0) and (S)-3 -fluoropyrrolidine hydrochloride (234 mg, 1.8 mmol, Eq: 1.2) in dioxane (1.3 ml). The reaction was stirred in a sealed tube at 115°C for 16 h 35 min, then concentrated in vacuo. The residue was diluted with MeOH and evaporated with silica gel to dryness and transferred to a column. Purification by flash chromatography (40 g silica, 0-8% MeOH/DCM) gave the title compound as a light yellow solid (193 mg, 75% yield). MS (ESI) m/z: 169.1 [M+H]⁺.

(3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1 -sulfonamide (Example 1)

(R)-3-Fluoropyrrolidine-1-sulfonamide (1.26 g, 7.51 mmol, Eq: 2.1) and cesium carbonate (2.56 g, 7.87 mmol, Eq: 2.2) were suspended in dry DMF (10.2 ml) under an argon atmosphere. The reaction was stirred at 50 °C for 30 min. The reaction mixture was cooled to rt and a solution of 3,6-difluoro-2-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)benzonitrile (1.12 g, 3.58 mmol, Eq: 1.0) in DMF (25.5 ml) was added. The reaction mixture was stirred at 100 °C for 15 h, then concentrated in vacuo. The residue was taken up in sat. aq. NH₄Cl (100 mL) and EtOAc (100 mL). The phases were separated, and the aqueous layer was extracted further with 2 x 100 mL EtOAc. The combined organic layers were washed with water (200 mL) and brine (200 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The water layer was back-extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was diluted with DCM and MeOH, and concentrated onto silica. Purification by flash chromatography (120 g, 0.5-2% MeOH/DCM) gave an off-white solid which was triturated with 1 : 1 heptane/DCM (20 mL) with sonication, then dried in vacuo to give the title compound as a colourless solid (1.087 g, 66% yield). MS (ESI) mlz: 426.2 [M+H]⁺. Chiral SFC: RT = 4.594 min [Chiralpak IC column, 4.6 x 250 mm, 5μm particle size (Daicel); gradient of 20 - 40% MeOH containing 0.2% NHEt₂ over 8 min; flow: 2.5 mL/min; 140 bar backpressure],

(3S)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1 -sulfonamide (Example 2)

(S)-3-Fluoropyrrolidine-1-sulfonamide (181 mg, 1.08 mmol, Eq: 2.1) was dissolved in DMF (1.6 ml). At rt cesium carbonate (368 mg, 1.13 mmol, Eq: 2.2) was added and the reaction mixture was stirred at 50 °C for 30 min. The reaction mixture was cooled to rt and a solution of 3,6-difluoro-2-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)benzonitrile (160.8 mg, 513 μmol, Eq: 1.0) in DMF (4 ml) was added. The reaction mixture was stirred at 105 °C for 2 h 50 min then concentrated in vacuo. The residue was taken up in DCM and washed with sat. aq. NH₄Cl. The aq. layer was back-extracted twice with DCM. The combined organic layers were dried over Na₂SO₄, filtrated and evaporated. The residue (brown oil) was diluted with DCM and transferred to a column. Purification by flash chromatography (80 g, 0-100% EtOAc in DCM) gave a solid which was further purified by SFC to give the title compound as a light yellow solid (119 mg, 50% yield). MS (ESI) m/z: 426.2 [M+H]⁺. Chiral SFC: RT = 4.411 min [Chiralpak IC column, 4.6 x 250 mm, 5μm particle size (Daicel); gradient of 20 - 40% MeOH containing 0.2% NHEt₂ over 8 min; flow: 2.5 mL/min; 140 bar backpressure].

PAT

New methylquinazolinone derivatives

Publication Number: AU-2020403443-A1

Priority Date: 2019-12-10

Methylquinazolinone derivativesPublication Number: US-2024174621-A1Priority Date: 2019-12-10
New methylquinazolinone derivativesPublication Number: EP-4073065-B1Priority Date: 2019-12-10Grant Date: 2025-02-19
Methylquinazolinone derivativesPublication Number: US-2022298119-A1Priority Date: 2019-12-10
Novel BRAF inhibitors as anomalous breakersPublication Number: CN-114746405-BPriority Date: 2019-12-10Grant Date: 2024-03-26
New BRAF inhibitors as paradox breakersPublication Number: AU-2020403082-A1Priority Date: 2019-12-10

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DRUG PATENTS INTERNATIONAL

Nacresertib

CAS 2629977-59-7

MF C22H26N4O4, 410.5 g/mol

N-[2-(4-hydroxy-4-methylcyclohexyl)-6-methoxyindazol-5-yl]-6-methyl-1-oxidopyridin-1-ium-2-carboxamide

2-({2-[(1r,4r)-4-hydroxy-4-methylcyclohexyl]-6-methoxy-2H-indazol-5-yl}carbamoyl)-6-methylpyridine
1-oxide
serine/threonine kinase inhibitor, MB3QBD4BE7,

SYN

compound 001 [WO2021057785]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021057785&_cid=P20-MLN614-09477-1

Example 1: Synthesis of Compound 001

ynthesis of compound 001, namely 2-((2-(trans-4-hydroxy-cis-4-methylcyclohexyl)-6-methoxy-2H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide [0133]

[0134]Cesium carbonate (985 mg) was added to 5 mL of a DMF solution containing compound 12 (300 mg) and compound 5 (344 mg) at 25°C. The reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was then added to 30 mL of water and extracted with ethyl acetate (10 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) using a column (CH3CN :

_H2O ( _{0.1 %} NH4HCO3 ₎ = 15-45%, UV: 214 nm, flow rate: 15 mL/min) to obtain compound 001 (70 mg, yield 17%).[0135]

¹ H NMR (400MHz, DMSO-d6): δ14.16(s,1H),8.78(s,1H),8.34(s,1H),8.32-8.30(m,1H),7.77(d,J＝7.6Hz,1H),7.58(t,J＝8.0Hz,1H),7.13(s,1 H),4.45(s,1H),4.43-4.40(m,1H),3.95(s,3H),2.53(s,3H),2.09-2.00(m,4H),1.68-1.58(m,4H),1.22(s,3H).LCMS: Rt＝3.646min,[M+H] ⁺ =411.1.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022194252&_cid=P20-MLN5V2-06374-1

2-((2-(trans-4-hydroxy-cis-4-methylcyclohexyl)-6-methoxy-2H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide as shown in the following formula:

[0257](1) Synthesis of compound 3

[0258]DMAP (42.5 g), compound 2 (63.4 g), and triethylamine (63.9 g) were added sequentially to a 500 mL solution of compound 1 (50 g) in dichloromethane at 15°C, and the mixture was stirred at 25°C for 18 hours. Dichloromethane (200 mL) was added to the reaction mixture, followed by washing with water (300 mL × 2), then with 1 M dilute hydrochloric acid (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 98 g of a yellow solid, yield: 99% (i.e., compound 3).

[0259](2) Synthesis of compound 4

[0260]1M dilute hydrochloric acid (300 mL) was added to a tetrahydrofuran solution (50 g) of compound 3 at 15°C, and the mixture was stirred at 25°C for 20 hours. The mixture was cooled to 0°C. The pH was adjusted to 9 with 1M sodium hydroxide solution. Extraction was performed with ethyl acetate (200 mL × 3). The extract was washed with saturated sodium chloride solution (300 mL). The solution was dried over anhydrous sodium sulfate. The mixture was filtered. The solution was concentrated under reduced pressure, and the residue was slurried with petroleum ether (150 mL) to give 39 g of a white solid, 91% yield (i.e., compound 4).

[0261](3) Synthesis of compounds 5 & 6

[0262]At -40°C, a tetrahydrofuran solution (200 mL) of compound 4 (34.5 g) was added dropwise to a tetrahydrofuran solution (500 mL) of methyl magnesium bromide (85.8 mL). The mixture was stirred at -40°C for 4 hours. The reaction was quenched with a saturated ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (500 mL × 3). The extract was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a colorless oily compound 5 (4.3 g, 10%), a colorless oily compound 6 (7.0 g, 17%), and a mixture of 12 g.

[0263]Compound 5

[0264]

^1H NMR (400MHz,CDCl3 ₎ : δ7.79(d,J＝8.0Hz,2H), 7.32(d,J＝8.4Hz,2H), 4.52-4.41(m,1H), 2.44(s,3H), 1.95-1.80(m,2H), 1.77-1.61(m,4H), 1.46-1.35(m,2H), 1.19(s,3H).

[0265]Compound 6

[0266]

^1H NMR (400MHz,CDCl3 ₎ : δ7.79(d,J＝8.4Hz,2H), 7.33(d,J＝8.0Hz,2H), 4.74-4.64(m,1H), 2.44(s,3H), 1.92-1.79(m,2H), 1.77-1.62(m,4H), 1.49-1.38(m,2H), 1.23(s,3H).

[0267](4) Synthesis of compound 8

[0268]A mixture of concentrated sulfuric acid (1.6 mL, 98%) and nitric acid (1.6 mL, 70%) was added dropwise to a solution of compound 7 (2.0 g) in concentrated sulfuric acid (12 mL, 98%) at -15°C. After the addition was complete, the mixture was stirred at -15°C for 2 hours. The reaction solution was then slowly poured into ice water and stirred for 5 minutes. The mixture was filtered, washed with water, and the solid was collected and dried under reduced pressure to give 2.5 g of a yellow solid, yield: 97% (i.e., compound 8).

[0269](5) Synthesis of compound 9

[0270]Hydrazine hydrate (2.4 mL, 98%) was added to a DMF (20 mL) solution of compound 8 (2.0 g) at room temperature. After the addition was complete, the mixture was heated to 120 °C and stirred for 16 hours. After cooling to room temperature, the mixture was slowly poured into ice water and stirred. The mixture was filtered, the solid was washed with water, and the solid was collected and concentrated under reduced pressure to obtain 1.3 g of yellow solid. Yield: 67% (i.e., compound 9).

[0271](6) Synthesis of compound 10

[0272]Compound 9 (12.4 g) and palladium on carbon (7 g, 10%) were added sequentially to 400 mL of ethyl acetate at 15°C. After the addition was complete, the mixture was stirred for 18 hours under hydrogen protection at 15°C. The palladium on carbon was filtered off from the reaction solution, and the filtrate was concentrated and evaporated to dryness to obtain 10.4 g of white solid product, with a yield of 99% (i.e., compound 10).

[0273](7) Synthesis of compound 12

[0274]EDCI.HCl (2.6 g) was added to a Py (15 mL) solution of compound 10 (1.5 g) and compound 11 (1.4 g) at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated and evaporated to dryness. The residue was slurried by passing MeOH/H₂O ₍ 20 mL/20 mL) to obtain 1.3 g of a yellow solid product, with a yield of 48% (i.e., compound 12).

[0275](8) Synthesis of compound A

[0276]

[0277]Cesium carbonate (985 mg) was added to 5 mL of a DMF solution containing compound 12 (300 mg) and compound 5 (344 mg) at 25°C. The reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was then added to 30 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) using a column (CH3CN :

_H2O (

_0.1_% NH4HCO3

₎ = 15-45%, UV: 214 nm, Flowrate: 15 mL/min) to obtain 70 mg of a yellow solid, with a yield of 17% (i.e., compound A).

[0278]

¹H NMR(400MHz,DMSO-d6):δ14.16(s,1H),8.78(s,1H),8.34(s,1H),8.32-8.30(m,1H),7.77(d,J＝7.6Hz,1H),7.58(t,J＝8.0Hz,1H),7.13(s,1H),4.45(s,1H),4.43-4.40(m,1H),3.95(s,3H),2.53(s,3H),2.09-2.00(m,4H),1.68-1.58(m,4H),1.22(s,3H).LCMS:Rt＝3.646min,[M+H] ⁺＝411.1.

PAT