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US 2006/0189636 A1Published application
Inhibitors of E1 activating enzymes
AssigneeMillennium Pharmaceuticals, Inc.
InventorsStephen Critchley, Thomas Gant, Steven Langston, Edward Olhava, Stephane Peluso
Life of this patent
Estimating the term…
Abstract
This invention relates to compounds that inhibit E1 activating enzymes, pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers, inflammatory and neurodegenerative disorders; and inflammation associated with infection and cachexia.
Claims30
A compound of formula (I-A):
- or a pharmaceutically acceptable salt thereof,
- wherein:
- 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—;
- each Rh independently is hydrogen, halo, —CN, —OH, —O—(C1-4 aliphatic), —NH2, —NH—(C1-4 aliphatic), —N(C1-4 aliphatic)2, —SH, —S—(C1-4 aliphatic), 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;
- R1 is hydrogen, chloro, bromo, fluoro, iodo, —N(R7R8, —R9, —SH, —SCH3, —S—R10, —OH, —OCH3, or —O—R11;
- R2 is hydrogen, chloro, bromo, fluoro, iodo, —N(R6)2, —CN, —O—(C1-4 aliphatic), —OH, —SR6, or an optionally substituted C1-4 aliphatic group;
- R3a is selected from the group consisting of hydrogen, fluoro, —CN, —N3, hydroxy, —OR21, —NH2, —NH(R21), —N(H)CO2R21, —N(H)C(O)R21, —CON(H)R21, —C(O)R5, —OC(O)N(H)R21, —OC(O)R21, —OC(O)OR21, —C1-4 fluoroaliphatic, or a —C1-4 aliphatic 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);
- R3b is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
- R3c is selected from the group consisting of hydrogen, fluoro, —CN, —N3, hydroxy, —OR21, —NH2, —NH(R21), —N(H)CO2R21, —N(H)C(O)R21, —CON(H)R21, —OC(O)N(H)R21, —OC(O)R21, —OC(O)OR21, —C1-4 fluoroaliphatic, or a —C1-4 aliphatic 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);
- R3d is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
- each R4 is independently hydrogen, fluoro, C1-4 aliphatic, or C1-4 fluoroaliphatic;
- or two R4, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring;
- or one R4, taken together with R5 and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
- or two R4 together form ═O;
- R5 is hydrogen, or C1-4 aliphatic;
- or R5, taken together with one R4 and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
- R5′ is hydrogen, or C1-4 aliphatic;
- each R6 is independently hydrogen or C1-4 aliphatic;
- R7 is an optionally substituted C1-10 aliphatic, aryl, heteroaryl, or heterocyclyl group;
- R8 is hydrogen or C1-4 aliphatic;
- R9 is —V-Z-R12a, —V-Z-R12b, —R12c, or an optionally substituted aliphatic, aryl, heterocyclyl, or heteroaryl group, wherein the heteroaryl group is attached at a carbon atom;
- R10 is an unsubstituted C2-10 aliphatic, a substituted C1-10 aliphatic, or an optionally substituted aryl, heteroaryl, or heterocyclyl;
- R11 is an unsubstituted C2-10 aliphatic, a substituted C1-10 aliphatic, or an optionally substituted aryl, heteroaryl, or heterocyclyl;
- 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;
- 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;
- V is —S(O)2—, —S(O)—, —C(O)O—, —C(O)—, —C(NR13)═N—, —C(═N(R13))—N(R13)—, —C(OR11)═N—, —CON(R13)—, —N(R13)C(O)—, —N(R13)C(O)N(R13)—, —N(R13)S(O)2—, —N(R13)SO2—N(R13)—, —N(R3)CO2—, —SO2N(R13)—, —OC(O)—, —OC(O)O—, —OC(O)N(R13)—, —N(R13)—N(R13)—;
- Z is an optionally substituted C1-6 alkylene chain, wherein the alkylene chain is optionally interrupted by —C(R13)═C(R13)—, —C≡C—, —O—, —S—, —N(R13)—, —N(R13)CO—, —N(R13)CO2—, —C(O)N(R13)—, —C(O)—, —C(O)—C(O)—, —CO2—, —OC(O)—, —OC(O)O—, —N(R13)C(O)N(R13)—, —N(R13)N(R13)—, —OC(O)N(R13)—, —S(O)—, —S(O)2—, —N(R13)S(O)2—, —S(O)2N(R13)—;
- R12a is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic group;
- R12b is halo, —NO2, —CN, —OR14, —SR15, —N(R16)2, —N(R16C(O)R15, —N(R16)C(O)N(R16)2, —N(R16)CO2R14, —O—CO2—R14, —OC(O)N(R16)2, —OC(O)R14, —N(R16)—N(R16)2, —N(R16)—OR15, —N(R16)S(O)2R15, or —N(R16)SO2—N(R16)2, —C(R14)═C(R14)2, —C≡C—R14, —S(O)R15, —SO2R15, —SO2—N(R16)2—C(R14)═N—OR14, —CO2R14, —C(O)—C(O)R14, —C(O)R14, —C(O)N(R16)2—C(═NR16)—N(R16)2, or —C(═NR16)—OR14;
- R12c is —NO2, —CN, —S(O)R15, —SO2R15, —SO2—N(R16)2, C(R14)═N—OR14, —N(R16)C(O)R15, —N(R16)C(O)N(R16)2, —O—CO2—R14, —OC(O)N(R16)2, —OC(O)R14, —CO2R14, —C(O)—C(O)R14, —C(O)R14, —C(O)N(R16)2, —C(═NR16)—N(R16)2, —C(═NR16)—OR14, —N(R16)—N(R16)2, —N(R16)—OR15, —N(R16)S(O)2R15, or —N(R16)SO2—N(R16)2;
- each R13 is independently hydrogen, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
- each R14 independently is hydrogen, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
- each R15 independently is an optionally substituted aliphatic, or aryl group;
- each R16 independently is an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
- or two R16 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted five to eight membered heterocylyl ring having, in addition to the nitrogen atom, zero to two additional ring heteroatoms selected from the group consisting of N, O, and S;
- each R21 independently is an optionally substituted C1-10 aliphatic, aryl, heteroaryl, or heterocyclyl group;
- and
- m is 1, 2, or 3;
- provided that:
- if Ring A is A-i, X is —O—, Y is —O— or —CH2—, R2 is hydrogen or chloro, R3a is hydroxyl or —OCOR21, R3b is hydrogen, R3c is hydroxyl or —OCOR21, R3d is hydrogen, R4 and R5 are each hydrogen, and m is 1;
- then R1 is bromo, fluoro, —NR7R8, —R9, —SR10, or —OR11, R7 is a substituted aliphatic, or an optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl, cycloaliphatic, heterocyclyl, (cycloaliphatic)alkyl, or (heterocyclyl)alkyl, and R9 is other than unsubstituted imidazole.
46 more elements
A compound of formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein:
- X is —CH2—, —NH—, or —O—;
- Y is —O—, or —CH2—;
- Q is ═N— or ═CH—;
- R1 is chloro, bromo, fluoro, iodo, —NR7R8, —R9, —S—R10, or —O—R11;
- R2 is hydrogen, chloro, bromo, fluoro, iodo, —N(R6)2, —CN, —O—(C1-4 aliphatic), —OH, —SR6, or an optionally substituted C1-4 aliphatic group;
- R3a is selected from the group consisting of hydrogen, hydroxy, —NH2, —C1-4 aliphatic, fluoro, —CN, —C1-4 fluoroaliphatic, —OR21, —NH(R21), —N(H)CO2R21, —N(H)C(O)R21, —CON(H)R21, —OC(O)N(H)R21, —OC(O)R21, and —OC(O)OR21;
- R3b is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
- R3c is selected from the group consisting of hydrogen, hydroxy, —NH2, —C1-4 aliphatic, fluoro, —CN, —C1-4 fluoroaliphatic, —OR21, —NH(R21), —N(H)CO2R21, —N(H)C(O)R21, —CON(H)R21, —OC(O)N(H)R21, —OC(O)R21, and —OC(O)OR21;
- R3d is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
- each R4 is independently hydrogen or C1-4 aliphatic;
- or two R4, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring;
- or one R4, taken together with R5 and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
- R5 is hydrogen, or C1-4 aliphatic;
- or R5, taken together with one R4 and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
- each R6 is independently hydrogen or C1-4 aliphatic;
- R7 is an optionally substituted C1-10 aliphatic, aryl, heteroaryl, or heterocyclyl group;
- R8 is hydrogen or C1-4 aliphatic;
- R9 is —V-Z-R12a, —V-Z-R12b, —R12c, or an optionally substituted aliphatic, aryl, heterocyclyl, or heteroaryl group, wherein the heteroaryl group is attached at a carbon atom;
- R10 is an optionally substituted C2-10 aliphatic, aryl, heteroaryl, or heterocyclyl;
- R11 is an optionally substituted C2-10 aliphatic, aryl, heteroaryl, or heterocyclyl;
- V is —S(O)2—, —S(O)—, —C(O)O—, —C(O)—, —C(NR13)═N—, —C(═N(R13))—N(R13)—, —C(OR11)═N—, —CON(R13)—, —N(R13)C(O)—, —N(R13)C(O)N(R13)—, —N(R13)S(O)2—, —N(R13)SO2—N(R13)—, —N(R13)CO2—, —SO2N(R13)—, —OC(O)—, —OC(O)O—, —OC(O)N(R13)—, —N(R13)—N(R13)—;
- Z is an optionally substituted C1-6 alkylene chain, wherein the alkylene chain is optionally interrupted by —C(R13)═C(R13)—, —C≡C—, —O—, —S—, —N(R13)—, —N(R13)CO—, —N(R13)CO2—, —C(O)N(R13)—, —C(O)—, —C(O)—C(O)—, —CO2—, —OC(O)—, —OC(O)O—, —N(R13)C(O)N(R13)—, —N(R13)N(R13)—, —OC(O)N(R13)—, —S(O)—, —S(O)2—, —N(R13)S(O)2—, —S(O)2N(R13)—;
- R12a is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic group;
- R12b is halo, —NO2, —CN, —OR14, —SR15, —N(R16)2, —N(R16)C(O)R15, —N(R16)C(O)N(R16)2, —N(R16)CO2R14, —O—CO2—R14, —OC(O)N(R16)2, —OC(O)R14, —N(R16)—N(R16)2, —N(R16)S(O)2R15, or —N(R16)SO2—N(R16)2—C(R14)═C(R14)2, —C≡C—R14, —S(O)R15, —SO2R15, —SO2—N(R16)2, —C(R14)═N—OR14, —CO2R14, —C(O)—C(O)R14, —C(O)R14, —C(O)N(R16)2, —C(═NR16)—N(R16)2, or —C(═NR16)—OR14;
- R12c is —NO2, —CN, —S(O)R15, —SO2R15, —SO2—N(R16)2, —C(R14)═N—OR14, —N(R16)C(O)R15, —N(R16)C(O)N(R16)2, —O—CO2—R14—, —OC(O)N(R16)2, —OC(O)R14, —CO2R14, —C(O)—C(O)R14, —C(O)R14, —C(O)N(R16)2, —C(═NR16)—N(R16)2, —C(═NR16)—OR14, —N(R16)—N(R16)2, —N(R16)S(O)2R15, or —N(R16)SO2—N(R16)2;
- each R13 is independently hydrogen, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
- each R14 independently is hydrogen, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
- each R15 independently is an optionally substituted aliphatic, or aryl group;
- each R16 independently is an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
- or two R16 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted five to eight membered heterocylyl ring having, in addition to the nitrogen atom, zero to two additional ring heteroatoms selected from the group consisting of N, O, and S;
- and
- each R21 independently is an optionally substituted C1-10 aliphatic, aryl, heteroaryl, or heterocyclyl group;
- provided that:
- if X is —O—, Y is —O— or —CH2—, Q is ═N—, R2 is hydrogen or chloro, R3a is hydroxyl or —OCOR21, R3b is hydrogen, R3c is hydroxyl or —OCOR21, R3d is hydrogen, and R4 and R5 are each hydrogen;
- then R1 is bromo, fluoro, —NR7R8, —R9, —SR10, or —OR11, and R7 is a substituted aliphatic, or an optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl, cycloaliphatic, heterocyclyl, (cycloaliphatic)alkyl, or (heterocyclyl)alkyl.
34 more elements
Dependencies are inferred from the claim text.