Heteroaryl compounds useful as inhibitors of SUMO activating enzyme
Disclosed are chemical entities which are compounds of formula (I): or pharmaceutically acceptable salts thereof; wherein Y, R a , R a ′, R b , R c , X 1 , X 2 , X 3 , R d , Z 1 , and Z 2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. Chemical entities according to the disclosure can be useful as inhibitors of Sumo Activating Enzyme (SAE). Further provided are pharmaceutical compositions comprising a compound of the disclosure and methods of using the compositions in the treatment of proliferative, inflammatory, cardiovascular, and neurodegenerative diseases or disorders.
1. A compound chosen from:
or a pharmaceutically acceptable salt thereof;
wherein R is an amine protecting group.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R is tert-butoxycarbonyl (Boc).
3. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is:
4. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is:
5. A method for preparing [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a or a pharmaceutically acceptable salt thereof,
the method comprising:
a) providing a Compound 1;
wherein R is an amine protecting group;
b) converting Compound 1 to [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a, or a pharmaceutically acceptable salt thereof; and
c) isolating [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a, or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 , wherein converting Compound 1 to [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a, or a pharmaceutically acceptable salt thereof, comprises:
reacting Compound 1 with Int-259
to obtain a Compound 2
wherein R is an amine protecting group; and
converting Compound 2 to [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a, or a pharmaceutically acceptable salt thereof.
7. The method of claim 6 , wherein converting Compound 2 to [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a, or a pharmaceutically acceptable salt thereof comprises:
removing R and the triisopropylsilyloxy (TIPS) groups to obtain [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a, or a pharmaceutically acceptable salt thereof.
8. The method of claim 6 , wherein Compound 1 is reacted with Int-259 in the presence of a base.
9. The method of claim 7 , wherein R is removed in the presence of an acid.
10. The method of claim 7 , wherein the triisopropylsilyloxy (TIPS) group is removed in the presence of an acid.
11. The method of claim 7 , wherein R and the triisopropylsilyloxy (TIPS) group are removed in separate steps.
12. The method of claim 7 , wherein R and the triisopropylsilyloxy (TIPS) group are removed concurrently in one step.
13. The method of claim 5 , wherein [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a, or a pharmaceutically acceptable salt thereof, is isolated by a process selected from the group consisting of crystallization, filtration, trituration, evaporation, chromatography, and combinations thereof.
14. The method of claim 13 , wherein [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a, or a pharmaceutically acceptable salt thereof, is isolated by chromatography.
15. The method of claim 5 , further comprising crystallizing the isolated [(1R,2S,4R)-4-{([5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a, or a pharmaceutically acceptable salt thereof.
16. The method of claim 5 , further comprising crystallizing the isolated [(1R,2S,4R)-4-{([5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a, or a pharmaceutically acceptable salt thereof to obtain a compound or pharmaceutically acceptable salt selected from:
a) crystalline Form 1 of [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a;
b) crystalline Form 2 of [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a; and
c) crystalline Form 3 of [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-263a.