Heteroaryl compounds useful as inhibitors of E1 activating enzymes

1. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

D is —N═;

E is —N═;

R g is hydrogen, halo,

cyano, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—R 6 , —NR 4 CO 2 R 6 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —O—C(O)R 5 , —OCO 2 R 6 , —OC(O)N(R 4 ) 2 , —C(O)R 5 , —CO 2 R 5 , —C(O)N(R 4 ) 2 , —C(O)N(R 4 )—OR 5 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 ) C(═NR 4 )—N(R 4 )—C(O)R 5 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —N(R 4 )—N(R 4 ) 2 , —N(R 4 )—OR 5 , —C(═NR 4 )—N(R 4 )—OR 5 , —C(R 6 )═N—OR 5 , or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl; and

each R h independently is hydrogen, halo, —CN—, —OR 5 , —N(R 4 ) 2 , —SR 6 , or an optionally substituted C 1-4 aliphatic group;

W is —CH 2 —, —CHF—, —CF 2 —, —CH(R 1 )—, —CF(R 1 )—, —NH—, —N(R 1 )—, —O—, —S—, or —NHC(O)—;

R 1 is C 1-4 aliphatic or C 1-4 fluoroaliphatic;

X is —CH 2 —, —CHF—, —CF 2 —, —NH—, or —O—;

Y is —O—, —S—, or —C(R m )(R n )—;

R a is hydrogen,

fluoro, —CN, —N 3 , —OR 5 , —N(R 4 ) 2 , —NR 4 CO 2 R 6 , —NR 4 C(O)R 5 , —C(O)N(R 4 ) 2 , —C(O)R 5 , —OC(O)N(R 4 ) 2 , —OC(O)R 5 , —OCO 2 R 6 , or a C 1-4 aliphatic or C 1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); or R a and R c together form a bond;

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

R c is hydrogen,

fluoro, —CN, —N 3 , —OR 5 , —N(R 4 ) 2 , —NR 4 CO 2 R 6 , —NR 4 C(O)R 5 , —C(O)N(R 4 ) 2 , —C(O)R 5 , —OC(O)N(R 4 ) 2 , —OC(O)R 5 , —OCO 2 R 6 , or a C 1-4 aliphatic or C 1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); or R a and R c together form a bond;

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

R e is hydrogen, or C 1-4 aliphatic; or R e , taken together with one R f and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring; or R e , taken together with R m and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4 aliphatic;

R e is hydrogen or C 1-4 aliphatic; or R e′ , taken together with R m and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4 aliphatic;

each R f is independently hydrogen, fluoro, C 1-4 aliphatic, or C 1-4 fluoroaliphatic; or two R f taken together form ═O; or two R f , taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring; or one R f , taken together with R e and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;

R m is hydrogen, fluoro, —N(R 4 ) 2 , or an optionally substituted C 1-4 aliphatic group; or R m and R n together form ═O or ═C(R 5 ) 2 ; or R m and R e , taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4 aliphatic; or R m and R e′ , taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4 aliphatic;

R n is hydrogen, fluoro, or an optionally substituted C 1-4 aliphatic group; or R m and R n together form ═O or ═C(R 5 ) 2 ;

each R 4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;

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 may be 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 may be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl, or 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 N, O, and S; and

each R 5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;

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

each R 6 independently is an optionally substituted aliphatic, aryl, or heteroaryl group; and

m is 1, 2, or 3.

2. The compound of claim 1 , wherein:

R g is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic,

halo, —R 1g , —R 2g , -T 1 -R 1g , -T 1 -R 2g , —V 1 -T 1 -R 1g , —V 1 -T 1 -R 2g , —V 1 —R 1g , or -T 1 -V 1 —R 1g ;

T 1 is a C 1-6 alkylene chain substituted with 0-2 independently selected R 3a or R 3b , wherein the alkylene chain optionally is interrupted

by —C(R 5 )═C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )C(═NR 4 )—N(R 4 )—, —N(R 4 )—C(═NR 4 )—, —N(R 4 )CO 2 —, —N(R 4 )SO 2 —, —N(R 4 )SO 2 N(R 4 )—, —OC(O)—, —OC(O)N(R 4 )—, —C(O)—, —CO 2 —, —C(O)N(R 4 )—, —C(═NR 4 )—N(R 4 )—, —C(NR 4 )═N(R 4 )—, —C(═NR 4 )—O—, or —C(R 6 )═N—O—, and wherein T 1 or a portion thereof optionally forms part of a 3-7 membered ring;

V 1 is —C(R 5 )═C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )C(═NR 4 )—N(R 4 )—, —N(R 4 )C(═NR 4 )—, —N(R 4 )CO 2 —, —N(R 4 )SO 2 —, —N(R 4 )SO 2 N(R 4 )—, —OC(O)—, —OC(O)N(R 4 )—, —C(O)—, —CO 2 —, —C(O)N(R 4 )—, —C(O)N(R 4 )—O—, —C(O)N(R 4 )C(═NR 4 )—N(R 4 )—, —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)—, —C(═NR 4 )—N(R 4 )—, —C(NR 4 )═N(R 4 )—, —C(═NR 4 )—O—, or —C(R 6 )═N—O—;

each R 1g independently is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;

each R 2g independently is —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—R 6 , —NR 4 CO 2 R 6 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —O—C(O)R 5 , —OCO 2 R 6 , —OC(O)N(R 4 ) 2 , —C(O)R 5 , —CO 2 R 5 , —C(O)N(R 4 ) 2 , —C(O)N(R 4 )—OR 5 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —N(R 4 )—N(R 4 ) 2 , —N(R 4 )—OR 5 , —C(═NR 4 )—N(R 4 )—OR 5 , or —C(R 6 )═N—OR 5 ;

each R 3a independently is —F, —OH, —O(C 1-4 alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-4 alkyl)-, —CO 2 H, —CO 2 (C 1-4 alkyl), —C(O)NH 2 , or —C(O)NH(C 1-4 alkyl);

each R 3b independently is a C 1-3 aliphatic optionally substituted with R 3a or R 7 , or two substituents R 3b on the same carbon atom, taken together with the carbon atom to which they are attached, form a 3- to 6-membered cycloaliphatic ring; and

each R 7 independently is an optionally substituted aryl or heteroaryl ring.

3. The compound of claim 2 , characterized by formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

Q is -T 1 - or —V 1 -T 1 -;

V 1 is —N(R 8 )—, —O—, or —S—;

R 8 is hydrogen or C 1-4 aliphatic;

T is a C 1-4 alkylene chain optionally substituted with one or two groups independently selected from fluoro, C 1-4 aliphatic, and C 1-4 fluoroaliphatic; and

Ring C is a 3- to 8-membered heterocyclyl or cycloaliphatic ring, or a 5- or 6-membered aryl or heteroaryl ring, any of which rings is substituted with 0-2 R o and 0-2 R 8o ;

each R o independently is

halo, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—R 6 , —NR 4 CO 2 R 6 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —O—C(O)R 5 , —OCO 2 R 6 , —OC(O)N(R 4 ) 2 , —C(O)R 5 , —CO 2 R 5 , —C(O)N(R 4 ) 2 , —C(O)N(R 4 )—OR 5 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —C(═NR 4 )—N(R 4 )—OR 5 , —C(R 6 )═N—OR 5 , or an optionally substituted aliphatic, or an optionally substituted aryl, heterocyclyl, or heteroaryl group; or two R o on the same saturated ring carbon atom, taken together with the carbon atom, form an optionally substituted 3- to 8-membered spirocyclic cycloaliphatic or heterocyclyl ring; or two adjacent R o , taken together with the intervening ring atoms, form an optionally substituted fused 4- to 8-membered aromatic or non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S;

each R 8o independently is C 1-4 aliphatic, C 1-4 fluoroaliphatic, halo, —OR 5x , —N(R 4x )(R 4y ), or a C 1-4 aliphatic 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 );

R 4 is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 6-10 ar(C 1-4 )alkyl, the aryl portion of which may be 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 may be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl, or 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 N, O, and S; and each R 5x independently is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or an optionally substituted C 6-10 aryl or C 6-10 ar(C 1-4 )alkyl.

4. The compound of claim 3 , wherein Ring C is a C 3-6 cycloaliphatic, phenyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or tetrahydropyrimidinyl ring, any of which is substituted with 0-2 R o and 0-2 R 8o .

5. The compound of claim 3 , wherein Ring C is a C 3-6 cycloaliphatic, phenyl, oxazolyl, or isoxazolyl ring, any of which is substituted with 0-2 R 8o and optionally is fused to an optionally substituted benzene, dioxolane, or dioxane ring.

6. The compound of claim 2 , characterized by formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

V 1 is —N(R 8 )—, —O—, or —S—;

R 8 is hydrogen or C 1-4 aliphatic; and

Ring D is an optionally substituted mono- or bicyclic ring system.

7. The compound of claim 6 , wherein Ring D is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl, benzodioxolyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, bicycloheptanyl or bicyclooctanyl, any of which groups is optionally substituted.

8. The compound of claim 7 , wherein:

each substitutable saturated ring carbon atom in Ring D is unsubstituted or substituted with ═O, ═S, ═C(R 5 ) 2 , ═N—N(R 4 ) 2 , ═N—OR 5 , ═N—NHC(O)R 5 , ═N—NHCO 2 R 6 , ═N—NHSO 2 R 6 , ═N—R 5 or —R p ;

each substitutable unsaturated ring carbon atom in Ring D is unsubstituted or substituted with —R p ;

each substitutable ring nitrogen atom in Ring D is unsubstituted or substituted with —R 9p ;

each R p independently is

halo, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—R 6 , —NR 4 CO 2 R 6 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —O—C(O)R 5 , —OCO 2 R 6 , —OC(O)N(R 4 ) 2 , —C(O)R 5 , —CO 2 R 5 , —C(O)N(R 4 ) 2 , —C(O)N(R 4 )—OR 5 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —C(═NR 4 )—N(R 4 )—OR 5 , —C(R 6 )═N—OR 5 , or an optionally substituted aliphatic, or an optionally substituted aryl, heterocyclyl, or heteroaryl group; or two R p on the same saturated carbon atom, taken together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered spirocyclic cycloaliphatic ring; and

each R 9p independently is —C(O)R 5 , —C(O)N(R 4 ) 2 , —CO 2 R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , or a C 1-4 aliphatic optionally substituted with R 3 or R 7 .

9. The compound of claim 8 , wherein:

each R p independently is halo, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —R 1p , —R 2p , -T 2 -R 1p , or -T 2 -R 2p ; or two R p on the same saturated carbon atom, taken together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered spirocyclic cycloaliphatic ring;

T 2 is a C 1-6 alkylene chain substituted with 0-2 independently selected R 3a or R 3b ;

each R 1p independently is an optionally substituted aryl, heteroaryl, or heterocyclyl group; and

each R 2p independently is —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—R 6 , —NR 4 CO 2 R 6 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —O—C(O)R 5 , —OCO 2 R 6 , —OC(O)N(R 4 ) 2 , —C(O)R 5 , —CO 2 R 5 , —C(O)N(R 4 ) 2 , —C(O)N(R 4 )—OR 5 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —C(═NR 4 )—N(R 4 )—OR 5 , or —C(R 6 )═N—OR 5 .

10. The compound of claim 9 , wherein Ring D is an optionally substituted indanyl, tetrahydronaphthyl, or chromanyl.

11. The compound of claim 9 , wherein:

V 1 is —N(R 8 )—;

Ring D is

each R p independently is halo, —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ), or is a C 1-4 aliphatic 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 , or —C(O)N(R 4x )(R 4y ), or is a C 1-4 aliphatic 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 ); or two R 8p on the same carbon atom together form ═O or ═C(R 5x ) 2 ; 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 ), or a C 1-4 aliphatic 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 ); and further provided that R 8p is other than —OR 5x or —N(R 4x )(R 4y ) when located at a position adjacent to a ring oxygen atom;

s is 0, 1, 2, 3, or 4; and

t is 0, 1, or 2.

12. The compound of claim 2 , wherein:

R g is —N(R 8 )(R 9 );

R 8 is hydrogen or C 1-4 aliphatic;

R 9 is hydrogen, C 1-4 aliphatic, -T 3 -R 9a or -T 4 -R 9b ;

T 3 is a C 1-6 alkylene chain substituted with 0-2 independently selected R 3a or R 3b ;

T 4 is a C 2-6 alkylene chain substituted with 0-2 independently selected R 3a or R 3b ;

R 9a is —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —S(O)R 6 , —SO 2 R 6 , —SO 2 —N(R 4 ) 2 , —C(R 5 )═N—OR 5 , —CO 2 R 5 , —C(O)—C(O)R 5 , —C(O)R 5 , —C(O)N(R 4 ) 2 , —C(═NR 4 )—N(R 4 ) 2 , or —C(═NR 4 )—OR 5 ; and

R 9b is halo, —NO 2 , —CN, —OR 5 , —SR 6 , —N(R 4 ) 2 , —N(R 4 )C(O)R 5 , —N(R 4 )C(O)N(R 4 ) 2 , —N(R 4 )CO 2 R 5 , —O—CO 2 —R 5 , —OC(O)N(R 4 ) 2 , —OC(O)R 5 , —N(R 4 )—N(R 4 ) 2 , —N(R 4 )S(O) 2 R 6 , or —N(R 4 )SO 2 —N(R 4 ) 2 .

13. The compound of claim 12 , wherein R 9 is hydrogen or a C 1-6 aliphatic or C 1-6 fluoroaliphatic optionally substituted with one or two substituents independently selected from of —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ).

14. The compound of claim 1 , characterized by formula (IX-A):

or a pharmaceutically acceptable salt thereof, wherein stereochemical configurations at asterisked positions indicate absolute configuration;

each R p independently is halo, —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ), or is a C 1-4 aliphatic 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 , or —C(O)N(R 4x )(R 4y ), or is a C 1-4 aliphatic 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 ); or two R 8p on the same carbon atom together form ═O or ═C(R 5x ) 2 ; provided that when two R 8p are attached to the same carbon atom, one must be selected from fluoro, —CO 2 R 5x , —C(O)N(R 4x )(R 4y ), or a C 1-4 aliphatic 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 ); and further provided that R 8p is other than —OR 5x or —N(R 4x )(R 4y ) when located at a position adjacent to a ring oxygen atom;

s is 0, 1, 2, 3, or 4; and

t is 0, 1, or 2.

15. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15 , formulated for administration to a human patient.

17. The compound of claim 1 , wherein W is —CH 2 —, —CHF—, —CF 2 —, —NH—, —O—, —S—, or —NHC(O)—.

18. The compound of claim 1 , characterized by one or more of the following features:

(a) X is —O—;

(b) Y is —CH 2 —;

(c) W is —NH—

(d) R a is —OH;

(e) R b and R d are each independently hydrogen or C 1-4 aliphatic;

(f) R c is hydrogen, fluoro, or —OR 5 ;

(g) R e and R e′ are each hydrogen;

(h) each R f is hydrogen; and

(i) m is 1.

19. The compound of claim 1 , which is

I-26 [(1R,2R,3S,4R)-4-({4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}amino)-2,3-dihydroxycyclopentyl]methyl sulfamate

I-45 [(1R,2R,3S,4R)-4-({4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-6-methyl-1,3,5-triazin-2-yl}amino)-2,3-dihydroxycyclopentyl]methyl sulfamate

I-55 {(1R,2R,3S,4R)-2,3-dihydroxy-4-[(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methyl sulfamate

I-125 {(1S,2S,4R)-2-hydroxy-4-[(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methyl sulfamate

I-134 {(1S,2S,4R)-4-[(4-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]-2-hydroxycyclopentyl}methyl sulfamate

I-147 {(1S,2S,4R)-4-[(4-{[(1R)-2,2-difluoro-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]-2-hydroxycyclopentyl}methyl sulfamate

I-153 [(1S,2S,4R)-4-({4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}amino)-2-hydroxycyclopentyl]methyl sulfamate

or a pharmaceutically acceptable salt thereof.