Optically active azabicyclo ring derivative
The compound of formula (1a) wherein p is 1 or 2, R 1 -R 4 are hydrogen atom or the like, and a-d are 1 or 2, or a pharmaceutically acceptable salt thereof, which has an antitumor effect by inhibiting the binding between a MLL fusion protein that is infused with AF4, AF9, or the like, which is a representative fusion partner gene causing MLL leukemia, and menin.
1. 2-[(4-{7-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide mono-L(+)-tartrate in crystal form of form I which is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 5.3°±0.2°, and 13.0°±0.2°.
2. The compound of claim 1 , wherein the crystal form is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 5.3°±0.2°, 11.2°±0.2°, 13.0°±0.2°, 15.9°±0.2°, 17.9°±0.2°, and 18.2°±0.2°.
3. The compound of claim 1 , wherein the crystal form is characterized by a powder x-ray diffraction pattern having diffraction angle (20°) peaks of 5.3°±0.2°, 8.0°±0.2°, 11.2°±0.2°, 13.0°±0.2°, 13.5°±0.2°, 15.9°±0.2°, 16.4°±0.2°, 17.5°±0.2°, 17.9°±0.2°, 18.2°±0.2°, and 20.0°±0.2°.
4. 2-[(4-{7-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide monohydrochloride in crystal form of form II which is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 10.6°±0.2°, 15.9°±0.2°.
5. The compound of claim 4 , wherein the crystal form is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 5.3°±0.2°, 9.9°±0.2°, 10.6°±0.2°, 15.9°±0.2°, 16.3°±0.2°, and 17.9°±0.2°.
6. The compound of claim 4 , wherein the crystal form is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 5.3°±0.2°, 9.9°±0.2°, 10.6°±0.2°, 11.9°±0.2°, 13.1°±0.2°, 13.6°±0.2°, 15.9°±0.2°, 16.3°±0.2°, 17.9°±0.2°, 18.9°±0.2°, and 21.2°±0.2°.
7. 2-[(4-{7-[(1S,3S,4R,6R)-6-(Cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N,N-di(propan-2-yl)benzamide dihydrochloride in crystal form of form III which is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 4.3°±0.2°, and 7.0°±0.2°.
8. The compound of claim 7 , wherein the crystal form is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 4.3°±0.2°, 7.0±0.2°, 10.6°±0.2°, 15.9°±0.2°, 16.5°±0.2°, 16.8°±0.2°.
9. The compound of claim 7 , wherein the crystal form is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 4.3°±0.2°, 7.0±0.2°, 9.9°±0.2°, 10.6°±0.2°, 11.8°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 15.9°±0.2°, 16.5°±0.2°, 16.8°±0.2°, and 17.9°±0.2°.
10. 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide mono-L(+)-tartrate in crystal form of form IV which is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 5.1°±0.2°, and 9.0±0.2°.
11. The compound of claim 10 , wherein the crystal form is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 5.1°±0.2°, 6.3°±0.2°, 9.0±0.2°, 15.3°+0.2°, 17.2°±0.2°, and 18.0°±0.2°.
12. The compound of claim 10 , wherein the crystal form is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 5.1°±0.2°, 6.3°±0.2°, 9.0°±0.2°, 10.5°±0.2°, 12.3°±0.2°, 12.6°±0.2°, 13.3°±0.2°, 15.3°±0.2°, 17.1°±0.2°, 17.2°±0.2°, and 18.0°±0.2°.
13. 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide disuccinate in crystal form of form V which is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 17.2°±0.2°, and 18.4°±0.2°.
14. The compound of claim 13 , wherein the crystal form is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks 8.1°±0.2°, 8.6°±0.2°, 9.8°±0.2°, 14.5°±0.2°, 17.2°±0.2°, 17.8°±0.2° and 18.4°±0.2°.
15. The compound of claim 13 , wherein the crystal form is characterized by a powder x-ray diffraction pattern having diffraction angle (2θ°) peaks of 4.9°±0.2°, 8.1°±0.2°, 8.6°±0.2°, 9.8°±0.2°, 13.9°±0.2°, 14.5°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 18.4°±0.2°, 19.0°±0.2°, and 20.5°±0.2°.