Inhibitors of E1 activating enzymes

1. A compound of formula (VIIIa):

or a pharmaceutically acceptable salt thereof, wherein:

stereochemical configurations depicted at asterisked positions indicate relative stereochemistry;

Q is C(R k );

R a is —OH;

R b is hydrogen, fluoro, or C 1-4 aliphatic;

R c is hydrogen, —OH, or —OCH 3 ;

R d is hydrogen;

R 8 is hydrogen or C 1-4 aliphatic;

R k is hydrogen;

each R P independently is fluoro; —OR 5x ; —N(R 4x )(R 4y ); —CO 2 R 5x ; —C(O)N(R 4x )(R 4y ); C 1-4 aliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); or C 1-4 fluoroaliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y );

each R 8p independently is fluoro; —OR 5x , —N(R 4x )(R 4y ); —CO 2 R 5x ; —C(O)N(R 4x )(R 4y ); C 1-4 aliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); or C 1-4 fluoroaliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); provided that when two R 8p are attached to the same carbon atom, one must be selected from the group consisting of fluoro; —CO 2 R 5x ; —C(O)N(R 4x )(R 4y ); C 1-4 aliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); and C 1-4 fluoroaliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); or two R 8p on the same carbon atom together form ═O or ═C(R 5x ) 2 ;

R 4x is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 6-10 ar(C 1-4 )alkyl, the aryl portion of which is optionally substituted;

R 4y is hydrogen; C 1-4 alkyl; C 1-4 fluoroalkyl; C 6-10 ar(C 1-4 )alkyl, the aryl portion of which is optionally substituted; optionally substituted 5- or 6-membered aryl; optionally substituted heteroaryl; or optionally substituted heterocyclyl ring; or

R 4x and R 4y , taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from the group consisting of N, O, and S;

each R 5x independently is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or an optionally substituted C 6-10 aryl, or optionally substituted C 6-10 ar(C 1-4 )alkyl;

wherein:

in each recitation of optionally substituted aryl, the aryl group, when substituted, contains on one or more unsaturated carbon atoms a substituent independently selected from the group consisting of

halo, —NO 2 , —CN, —R*, —C(R*)═C(R*) 2 , —C≡C—R*, —OR*, —SR o , —S(O)R o , —SO 2 R o , —SO 2 N(R + ) 2 , —N(R + ) 2 , —NR + C(O)R*, —NR + C(O)N(R + ) 2 , —NR + CO 2 R o , —O—CO 2 R*, —OC(O)N(R + ) 2 , —O—C(O)R*, —CO 2 R*, —C(O)—C(O)R*, —C(O)R*, —C(O)N(R + ) 2 , —C(═NR + )—N(R + ) 2 , —C(═NR + )—OR*, —N(R + )—N(R + ) 2 , —N(R + )C(═NR + )—N(R + ) 2 , —NR + SO 2 R o , —NR + SO 2 N(R + ) 2 , —P(O)(R*) 2 , —P(O)(OR*) 2 , —O—P(O)—OR*, and —P(O)(NR + )—N(R + ) 2 ;

in each recitation of optionally substituted heteroaryl, the heteroaryl group, when substituted, if on an unsaturated carbon atom, contains on one or more unsaturated carbon atoms, a substituent independently selected from the group consisting of

halo, —NO 2 , —CN, —R*, —C(R*)═C(R*) 2 , —C≡C—R*, —OR*, —SR o , —S(O)R o , —SO 2 R o , —SO 2 N(R + ) 2 , —N(R + ) 2 , —NR + C(O)R*, —NR + C(O)N(R + ) 2 , —NR + CO 2 R o , —O—CO 2 R*, —OC(O)N(R + ) 2 , —O—C(O)R*, —CO 2 R*, —C(O)—C(O)R*, —C(O)R*, —C(O)N(R + ) 2 , —C(═NR + )—N(R + ) 2 , —C(═NR + )—OR*, —N(R + )—N(R + ) 2 , —N(R + )C(═NR + )—N(R + ) 2 , —NR + SO 2 R o , —NR + SO 2 N(R + ) 2 , —P(O)(R*) 2 , —P(O)(OR*) 2 , —O—P(O)—OR*, and —P(O)(NR + )—N(R + ) 2 , and, if on a substitutable nitrogen atom, contains on one or more substitutable nitrogen atoms, a substituent independently selected from the group consisting of —R*, —N(R*) 2 , —C(O)R*, —CO 2 R*, —C(O)—C(O)R*, —C(O)CH 2 C(O)R*, —SO 2 R*, —SO 2 N(R*) 2 , —C(═S)N(R*) 2 , —C(═NH)—N(R*) 2 , and —NR*SO 2 R*; and

in each recitation of optionally substituted heterocyclyl, the heterocyclyl group, when substituted, if on a saturated carbon atom, contains on one or more saturated carbon atoms, a substituent independently selected from the group consisting of

halo, —NO 2 , —CN, —R*, —C(R*)═C(R*) 2 , —C≡C—R*, —OR*, —SR o , —S(O)R o , —SO 2 R o , —SO 2 N(R + ) 2 , —N(R + ) 2 , —NR + C(O)R*, —NR + C(O)N(R + ) 2 , —NR + CO 2 R o , —O—CO 2 R*, —OC(O)N(R + ) 2 , —O—C(O)R*, —CO 2 R*, —C(O)—C(O)R*, —C(O)R*, —C(O)N(R + ) 2 , —C(═NR + )—N(R + ) 2 , —C(═NR + )—OR*, —N(R + )—N(R + ) 2 , —N(R + )C(═NR + )—N(R + ) 2 , —NR + SO 2 R o , —NR + SO 2 N(R + ) 2 , —P(O)(R*) 2 , —P(O)(OR*) 2 , —O—P(O)—OR*, and —P(O)(NR + )—N(R + ) 2 , ═O, ═S, ═C(R*) 2 , ═N—N(R + ) 2 , ═N—OR*, ═N—NHC(O)R*, ═N—NHCO 2 R o , ═N—NHSO 2 R o , and ═N—R*, and, if on a substitutable nitrogen atom, contains on one or more substitutable nitrogen atoms, a substituent independently selected from the group consisting of —R*, —N(R*) 2 , —C(O)R*, —CO 2 R*, —C(O)—C(O)R*, —C(O)CH 2 C(O)R*, —SO 2 R*, —SO 2 N(R*) 2 , —C(═S)N(R*) 2 , —C(═NH)—N(R*) 2 , and —NR*SO 2 R*;

wherein:

each occurrence of R o is independently an aliphatic or aryl group;

each occurrence of R + is independently hydrogen or an aliphatic, aryl, heteroaryl, or heterocyclyl group, or two R + on the same nitrogen atom, taken together with the nitrogen atom, form a five to eight membered aromatic or non-aromatic ring having, in addition to the nitrogen atom, zero to two ring heteroatoms independently selected from the group consisting of N, O, and S; and

each occurrence of R* is independently hydrogen, aliphatic, aryl, heteroaryl, or heterocyclyl group;

s is 0, 1, or 2; and

t is 0, 1, or 2.

2. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2 , formulated for administration to a human patient.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R b and R c are each hydrogen;

R 8 is hydrogen;

R 8p is fluoro, —OR 5x , C 1-4 aliphatic optionally substituted with —OR 5x , or C 1-4 fluoroaliphatic optionally substituted with —OR 5x ;

s is 0 or 1; and

t is 0.

5. A pharmaceutical composition comprising a compound of claim 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. [(1S,2S,4R)-2-Hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate, or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound of claim 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. ((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulfamate, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound of claim 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.