Inhibitors of e1 activating enzymes

A compound of formula (I-A):

• or a pharmaceutically acceptable salt thereof, wherein:
• stereochemical configurations depicted at asterisked positions indicate relative stereochemistry;
• Ring A is selected from the group consisting of:
• wherein one ring nitrogen atom in Ring A optionally is oxidized;
• X is —CH2—, —CHF—, —CF2—, —NH—, or —O—;
• Y is —C(Rm)(Rn)—;
• Ra is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R4)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
• or Ra and Rc together form a bond;
• Rb is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
• Rc is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R4)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
• or Ra and Rc together form a bond;
• Rd is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
• Re is hydrogen, or C1-4 aliphatic;
• or Re, taken together with one Rf and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
• Re′ is hydrogen or C1-4 aliphatic;
• each Rf is independently hydrogen, fluoro, C1-4 aliphatic, or C1-4 fluoroaliphatic, provided that if X is —O— or —NH—, then Rf is not fluoro;
• or two Rf taken together form ═O;
• or two Rf, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring;
• or one Rf, taken together with Re and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
• Rg is hydrogen, halo, —NO2, —CN, —C(R5)═C(R5)2, —C≡C—R5, —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R4)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)N(R4)2, —N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—R6, —NR4CO2R6, —N(R4)SO2R6, —N(R4)SO2N(R4)2, —O—C(O)R5, —OCO2R6, —OC(O)N(R4)2, —C(O)R5, —CO2R5, —C(O)N(R4)2, —C(O)N(R4)—OR5, —C(O)N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—N(R4)—C(O)R5, —C(═NR4)—N(R4)2, —C(═NR4)—OR5, —N(R4)—N(R4)2, —N(R4)—OR5, —C(═NR4)—N(R4)—OR5, —C(R6)═N—OR5, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl;
• each Rh independently is hydrogen, halo, —CN—, —N(R4)2, —SR6, or an optionally substituted C1-4 aliphatic group;
• Rj is hydrogen, —OR5, —SR6, —N(R4)2, or an optionally substituted aliphatic, aryl, or heteroaryl group;
• Rk is hydrogen, halo, —OR5, —SR6, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
• Rm is hydrogen, fluoro, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
• and
• Rn is hydrogen, fluoro, or an optionally substituted C1-4 aliphatic group;
• or
• Rm and Rn together form ═O or ═C(R5)2;
• each R4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
• or two R4 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;
• R4x is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted;
• R4y is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl ring;
• or
• R4x and R4y, 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 R5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
• each R5x independently is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or an optionally substituted C6-10 aryl or C6-10 ar(C1-4)alkyl;
• each R6 independently is an optionally substituted aliphatic, aryl, or heteroaryl group;
• and
• m is 1, 2, or 3.

A pharmaceutical composition, comprising a compound of formula (I-A):

• or a pharmaceutically acceptable salt thereof, wherein:
• stereochemical configurations depicted at asterisked positions indicate relative stereochemistry;
• Ring A is selected from the group consisting of:
• wherein one ring nitrogen atom in Ring A optionally is oxidized;
• X is —CH2—, —CHF—, —CF2—, —NH—, or —O—;
• Y is —C(Rm)(Rn)—;
• Ra is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R4)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
• or Ra and Rc together form a bond;
• Rb is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
• Rc is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R4)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
• or Ra and Rc form a bond;
• Rd is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
• Re is hydrogen, or C1-4 aliphatic;
• or Re, taken together with one Rf and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
• Re′ is hydrogen or C1-4 aliphatic;
• each Rf is independently hydrogen, fluoro, C1-4 aliphatic, or C1-4 fluoroaliphatic, provided that if X is —O— or —NH—, then Rf is not fluoro;
• or two Rf taken together form ═O;
• or two Rf, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring;
• or one Rf, taken together with Re and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
• Rg is hydrogen, halo, —NO2, —CN, —C(R5)═C(R5)2, —C≡C—R5, —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R4)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)N(R4)2, —N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—R6, —NR4CO2R6, —N(R4)SO2R6, —N(R4)SO2N(R4)2, —O—C(O)R5, —OCO2R6, —OC(O)N(R4)2, —C(O)R5, —CO2R5, —C(O)N(R4)2, —C(O)N(R4)—OR5, —C(O)N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—N(R4)—C(O)R5, —C(═NR4)—N(R4)2, —C(═NR4)—OR5, —N(R4)—N(R4)2, —N(R4)—OR5, —C(═NR4)—N(R4)—OR5, —C(R6)═N—OR5, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl;
• each Rh independently is hydrogen, halo, —CN—, —N(R4)2, —SR6, or an optionally substituted C1-4 aliphatic group;
• Rj is hydrogen, —OR5, —SR6, —N(R4)2, or an optionally substituted aliphatic, aryl, or heteroaryl group;
• Rk is hydrogen, halo, —OR5, —SR6, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
• Rm is hydrogen, fluoro, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
• and
• Rn is hydrogen, fluoro, or an optionally substituted C1-4 aliphatic group;
• or
• Rm and R together form ═O or ═C(R5)2;
• each R4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
• or two R4 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;
• R4x is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted;
• R4y is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl ring;
• or
• R4x and R4y, 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 R5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
• each R5x independently is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or an optionally substituted C6-10 aryl or C6-10 ar(C1-4)alkyl;
• each R6 independently is an optionally substituted aliphatic, aryl, or heteroaryl group;
• and
• m is 1, 2, or 3;
• and
• a pharmaceutically acceptable carrier.