Zamzetoclax

CAS 2388470-64-0

MF C38H46ClN5O6S MW736.32

N-[(3′R,4S,6′R,7′S,8′E,11′S)-7-chloro-7′-methoxy-11′-methyl-13′,15′-dioxospiro[2,3-dihydro-1H-naphthalene-4,22′-20-oxa-13λ⁶-thia-1,14-diazatetracyclo[14.7.2.0^3,6.0^19,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13′-yl]-3-methoxy-1-methylpyrazole-4-carboxamide

• 1H-Pyrazole-4-carboxamide, N-[(1’S,10S,12S,14E,16S,16aR,18aR)-6′-chloro-3′,4′,8,11,12,13,16,16a,17,18,18a,19-dodecahydro-16-methoxy-12-methyl-10-oxido-8-oxospiro[5,7-etheno-1H-10lambda4-cyclobut[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecine-2(3H),1′(2’H)-naphthalen]-10-yl]-3-methoxy-1-methyl-
• N-[(1’S,10S,12S,14E,16S,16aR,18aR)-6′-Chloro-3′,4′,8,11,12,13,16,16a,17,18,18a,19-dodecahydro-16-methoxy-12-methyl-10-oxido-8-oxospiro[5,7-etheno-1H-10lambda4-cyclobut[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecine-2(3H),1′(2’H)-naphthalen]-10-yl]-3-methoxy-1-methyl-1H-pyrazole-4-carboxamide

B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, RRS8GZU2UN

Zamzetoclax (compound 1) is a potential Mcl-1 inhibitor.

REFDiscovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein–Protein Interaction Modulator with the Potential of Treating Hematological Malignancies

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2023-04-28

PMID: 37114951

DOI: 10.1021/acs.jmedchem.2c01953

SYN

WO 2019/222112

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019222112&_cid=P12-MJ7Z15-98773-1

Example 154

[0447] Example 154 was synthesized in the same manner as Example 18 using 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. Example 109 (620 mg, 1.04 mmol) was dissolved in dichloromethane (12 mL). 3-Methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (324 mg, 2.08 mmol, 2 equiv.) and N-(3-dimethylaminopropyl)-N¢-ethylcarbodiimide hydrochloride (400 mg, 2.08 mmol, 2 equiv.) were added. The reaction mixture was stirred for 5 minutes at room temperature before DMAP (253 mg, 2.08 mmol, 2 equiv.) was added in a single portion. The reaction mixture was stirred overnight at room temperature and the progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by Gilson reverse phase prep HPLC (60-100% ACN/H₂O with 0.1% TFA) to give Example 154.¹H NMR (400 MHz, methanol-d4) d 8.07 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.22– 7.10 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 6.20– 6.05 (m, 1H), 5.63 (dd, J = 15.5, 8.0 Hz, 1H), 4.10 (d, J = 12.0 Hz, 1H), 4.06 (s, 4H), 3.91– 3.83 (m, 1H), 3.82 (s, 3H), 3.79 (s, 1H), 3.72 (d, J = 14.4 Hz, 1H), 3.38 (d, J = 14.5 Hz, 1H), 3.30 (s, 3H), 3.09 (dd, J = 15.1, 10.0 Hz, 1H), 2.89– 2.72 (m, 2H), 2.51 (d, J = 26.7 Hz, 2H), 2.24 (dd, J = 10.9, 6.0 Hz, 2H), 2.12 (d, J = 13.7 Hz, 1H), 2.02– 1.70 (m, 4H), 1.54– 1.40 (m, 1H), 1.14 (d, J = 6.1 Hz, 3H). LCMS-ESI+ (m/z): calcd for C38H46ClN5O6S: 735.28; found: 735.94.

SYN

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=33B420439B8C0CFAAEE83F88092DF1B6.wapp1nC?docId=US413449521&_cid=P12-MJ7YW7-95600-1

WO 2019/222112 discloses novel 3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene] derivatives that are active against MCL-1. For example, Compound 1 (below) has been shown to be an effective MCL-1 inhibitor

SYN

US10703733,

SYN

WO2023215404

PAT

• Mcl-1 inhibitorsPublication Number: US-2019352271-A1Priority Date: 2018-05-14
• Mcl-1 inhibitorsPublication Number: US-2020331870-A1Priority Date: 2018-05-14
• MCL-1 inhibitorsPublication Number: US-10988451-B2Priority Date: 2018-05-14Grant Date: 2021-04-27
• MCL-1 inhibitorsPublication Number: US-11643400-B2Priority Date: 2018-05-14Grant Date: 2023-05-09
• Mcl-1 inhibitorsPublication Number: US-2023312490-A1Priority Date: 2018-05-14
• Processes and intermediates for preparing mcl1 inhibitorsPublication Number: US-2023013713-A1Priority Date: 2019-11-26
• Processes and intermediates for preparing MCL1 inhibitorsPublication Number: US-11760736-B2Priority Date: 2019-11-26Grant Date: 2023-09-19
• Mcl1 inhibitorsPublication Number: US-2021171543-A1Priority Date: 2019-11-12
• Mcl1 inhibitorsPublication Number: US-2023348494-A1Priority Date: 2019-11-12
• MCL-1 inhibitorsPublication Number: US-10703733-B2Priority Date: 2018-05-14Grant Date: 2020-07-07
• Salts and polymorphs of certain mcl-1 inhibitorsPublication Number: US-2023357274-A1Priority Date: 2022-05-04
• Combination mcl-1 inhibitors with anti-body drug conjugatesPublication Number: US-2022409736-A1Priority Date: 2021-06-11
• Processes and intermediates for preparing mcl1 inhibitorsPublication Number: US-2022177409-A1Priority Date: 2020-11-19
• Processes and intermediates for preparing mcl1 inhibitorsPublication Number: US-2021179570-A1Priority Date: 2019-11-26
• Processes and intermediates for preparing MCL1 inhibitorsPublication Number: US-11325891-B2Priority Date: 2019-11-26Grant Date: 2022-05-10

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[1]. Salts and polymorphs of certain MCL-1 inhibitors. World Intellectual Property Organization, WO2023215404 A1 2023-11-09.

///////////zamzetoclax, B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, RRS8GZU2UN