Heteroaryl compounds useful as inhibitors of sumo activating enzyme

1. A method of treating lung cancer, ovarian cancer, colon cancer, breast cancer, or lymphoma in a subject, comprising administering to a subject having lung cancer, ovarian cancer, colon cancer, breast cancer, or lymphoma a therapeutically effective amount of a chemical entity which is a compound or pharmaceutically acceptable salt of formula (I):

wherein:

stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry;

Y is —O—, —CH 2 —, or —N(H)—;

R a is hydrogen, fluoro, —NH 2 , or hydroxyl;

R a ′ is hydrogen or fluoro, provided that when R a is —NH 2 or hydroxyl, R a ′ is hydrogen;

R b is hydrogen or, together with the oxygen to which it is attached, forms a prodrug;

R c is hydrogen or C 1-4 alkyl;

R d is hydrogen, halogen, —CF 3 , or C 1-4 alkyl;

X 1 is N;

X 2 is S or O;

X 3 is C(R x3 ) or N;

R x3 is hydrogen, methyl, or halogen;

Z 1 is hydrogen, halogen, cyano, R z3 , —S—R z3 , —S(O)—R z3 , or —S(O) 2 —R z3 ;

R z3 is an optionally substituted phenyl, an optionally substituted 5- to 7-membered cycloaliphatic, an optionally substituted 5- to 7-membered heterocyclyl, or an optionally substituted C 1-4 aliphatic;

wherein Z 1 is not hydrogen, halogen, methyl, or cyano if Z 2 is hydrogen or methyl; and

(a) Z 2 is a ring system having an optionally substituted 5- to 7-membered heterocyclyl with 1-2 heteroatoms or an optionally substituted 5- to 7-membered cycloaliphatic fused to

(i) an optionally substituted 5-membered heteroaryl or an optionally substituted 6-membered aryl or heteroaryl to form a bicyclic group; or

(ii) an optionally substituted 9-membered heteroaryl or an optionally substituted 10-membered aryl or heteroaryl to form a tricyclic group;

or

(b) Z 2 is L-R e wherein L is L 1 -, —V 1 -L 2 -, or L 1 -V 1 -L 2 -;

L 1 is a C 1-3 alkylene chain wherein 1 or 2 saturated carbon atoms are optionally substituted by (R f )(R f ′) and in which there are optionally one or two degrees of unsaturation;

each R f is independently hydrogen; hydroxyl; —N(R h )(R h ′); C 1-4 aliphatic optionally substituted with hydroxyl, —OCH 3 , or cyclopropyl; —O—C 1-4 aliphatic optionally substituted with hydroxyl, —OCH 3 , or cyclopropyl; or, together with R f ′ and the carbon atom to which they are attached, form C═CH 2 , or a 3- to 6-membered carbocycle or 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C 1-4 alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle;

each R f ′ is independently hydrogen; C 1-4 aliphatic optionally substituted with hydroxyl, —OCH 3 , or cyclopropyl; —O—C 1-4 aliphatic optionally substituted with hydroxyl, —OCH 3 , or cyclopropyl; or, together with R f and the carbon atom to which they are attached, form C═CH 2 , or a 3- to 6-membered carbocycle or 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C 1-4 alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle; wherein if R f is hydroxyl, R f ′ is not —O—C 1-4 aliphatic optionally substituted with hydroxyl, —OCH 3 , or cyclopropyl;

R h and R h ′ are each independently hydrogen or C 1-4 alkyl;

V 1 is —S—, —O—, —S(O)—, —S(O) 2 —, —C(O)— or —N(R g )—;

L 2 is a C 0-2 alkylene chain wherein one saturated carbon atom is optionally substituted by (R f )(R f ′);

R g is hydrogen or C 1-4 alkyl; and

either (i) R e is hydrogen, hydroxyl, halogen, —CF 3 , or an optionally substituted C 1-4 aliphatic,

with the proviso that R e is not hydrogen if R f and R f ′ are present and form a ring; or

(ii) R e is a ring chosen from optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl, which is optionally fused to a second optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl;

or

(c) Z 2 is hydrogen.

2. The method of claim 1 , wherein the chemical entity chosen from:

and pharmaceutically acceptable salts thereof.

3. The method of claim 2 , wherein the chemical entity is chosen from:

I-256 [(1R,2S,4R)-4-{[5-({4-[1S)-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;

and

[(1R,2S,4R)-4-{[5-({4-[(1R)-3,4-Dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;

I-256a [(1R,2S,4R)-4-{[5-({4-[(1S)-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;

I-256b [(1R,2S,4R)-4-{[5-({4-[(1R)-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;

and pharmaceutically acceptable salts thereof.

4. The method of claim 3 , wherein the chemical entity is chosen from:

[(1R,2S,4R)-4-{[5-({4-[(1R)-3,4-Dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-256b and pharmaceutically acceptable salts thereof.

5. The method of claim 4 , wherein the chemical entity is crystalline Form 1 of:

[(1R,2S,4R)-4-{[5-({4-[(1R)-3,4-Dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-256b.

6. The method of claim 2 , wherein the chemical entity is chosen from:

I-257 [(1R,2S,4R)-4-{[5-({4-[(1S)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;

and

[(1R,2S,4R)-4-{[5-({4-[(1R)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;

I-257a [(1R,2S,4R)-4-{[5-({4-[(1S)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;

I-257b [(1R,2S,4R)-4-{[5-({4-[(1R)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;

and pharmaceutically acceptable salts thereof.

7. The method of claim 6 , wherein the chemical entity is chosen from:

[(1R,2S,4R)-4-{[5-({4-[(1R)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-257b

and pharmaceutically acceptable salts thereof.

8. The method of claim 7 , wherein the chemical entity is crystalline Form 1 of:

[(1R,2S,4R)-4-{[5-({4-[(1R)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-257b.

9. The method of claim 2 , wherein the chemical entity is chosen from:

I-263a [(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;

I-263b [(1R,2S,4R)-4-{[5-({4-[(1S)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;

and pharmaceutically acceptable salts thereof.

10. The method of claim 9 , wherein the chemical entity is chosen from:

[(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 pharmaceutically acceptable salts thereof.

11. The method of claim 10 , wherein the chemical entity is 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.

12. The method of claim 10 , wherein the chemical entity is 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.

13. The method of claim 10 , wherein the chemical entity is 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.

14. The method of claim 10 , wherein the chemical entity is chosen from:

[(1R,2S,4R)-4-{[5-({4-[(1S)-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-263b and pharmaceutically acceptable salts thereof.