MCL-1 inhibitors and methods of use thereof
Disclosed is a compound which is 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 4,7 .0 11,15 ,0 16,21 .0 20,24 .0 30,35 ]octatriaconta-1(37),4(38),6,11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylic acid (Formula I) and enantiomers and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions of 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 4,7 .0 11,15 .0 16,21 .0 20,24 .0 30,35 ]octatriaconta-1(37),4(38),6,11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylic acid, and enantiomers and pharmaceutically acceptable salts thereof, and methods of treating cancer with such compounds and compositions.
1. A compound which is Form A (R a )-17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 4,7 .0 11,15 .0 16,21 .0 20,24 .0 30,35 ]octatriaconta-1(37),4(38),6,11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylic acid monohydrate.
2. The compound of claim 1 , wherein said compound has an XRPD pattern comprising at least one peak expressed as 2θ (±0.2°) at about 7.0°.
3. The compound of claim 1 , wherein said compound has an XRPD pattern comprising at least one peak expressed as 2θ (±0.2°) at about 8.4°.
4. The compound of claim 1 , wherein said compound has an XRPD pattern comprising at least one peak expressed as 2θ (±0.2°) at about 12.5°.
5. The compound of claim 1 , wherein said compound has an XRPD pattern comprising at least one peak expressed as 2θ (±0.2°) selected from about 7.0°, 8.4° and 12.5°.
6. The compound of claim 1 , wherein said compound has an XRPD pattern comprising at least one peak expressed as 2θ (±0.2°) selected from about 5.4°, 7.0°, 8.4°, 10.7°, 12.5°, 13.1°, 14.4°, 15.1°, 15.6°, 17.1° and 18.2°.
7. The compound of claim 1 , wherein the compound has a DSC thermogram comprising an endotherm with a desolvation onset at about 121° C. and a peak at about 152° C.
8. The compound of claim 1 , wherein the compound has a DSC thermogram comprising an endotherm with a melting/decomposition onset at about 181° C. and a peak at about 194° C.
9. The compound of claim 1 , wherein the compound has a TGA thermogram exhibiting a mass loss of about 4.0% upon heating from about 25° C. to about 160° C.
10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.