SELECTIVE CASPASE INHIBITORS AND USES THEREOF

摘要

The present invention relates to compounds of Formula I, IA, II, HA, III, or IHA and their pharmaceutical uses. Particular aspects of the invention relate to the use of those compounds for the selective inhibition of one or more caspases. Also described are methods where the compounds of Formula I, IA, II, IIA, III, or IIIA are used in the prevention and/or treatment of various diseases and conditions in subjects, including caspase-mediated diseases such as sepsis, myocardial infarction, ischemic stroke, spinal cord injury (SCI), traumatic brain injury (TBI) and neurodegenerative disease (e.g. multiple sclerosis (MS) and Alzheimer's, Parkinson's, and Huntington's diseases).

主权项

1. A compound of Formula I: wherein a is 0 or 1; b is 0 or 1 provided that when b is 0, a is 0; A is
1) H,2) C1-C6 alkyl,3) aryl,4) heteroaryl,5) heterocyclyl,6) R3—C(O)—,7) R3—OC(O)—;8) R3—C(O)O—, or9) R3—S(O)2—; P2, P3, P4, P5, when present, and PX, when present, are any (D) or (L) amino acid residue; the line “−” when located between P2, P3, P4, P5 or PX represents a peptide bond or a peptidomimetic bond; the wavy line represents either cis or trans orientation of R1 and R2; R1 is
1) aryl,2) heteroaryl,3) heterocyclyl,4) C2-C6 alkene-R20,5) SO2R5,6) SO3R5,7) SOR5,8) SONHR5,9) SO2NHR5,10) CN,11) CO2R5,12) COR5,13) PO3R5,14) PO(OR5)2, or15) PO(OR5), wherein the aryl, the heteroaryl, or the heterocyclyl are optionally substituted with one or more R30; R2 is
1) R1; or2) H,3) halogen,4) haloalkyl,5) C1-C6 alkyl,6) C2-C6 alkene,7) C3-C7 cycloalkyl,8) OR9;9) OCOR6,10) OCO2R6,11) NR7R8,12) NHSO2R6,13) NHCOR6,14) aryl,15) heteroaryl, or16) heterocyclyl; R3 is
1) C1-C6 alkyl,2) aryl,3) heteroaryl, or4) heterocyclyl; R4 is
1) H, or2) C1-C6 alkyl; R5 is
1) H,2) C1-C6 alkyl,3) C2-C6 alkene,4) C3-C7 cycloalkyl,5) aryl,6) heteroaryl,7) heterocyclyl, or8) any optionally protected (D) or (L) amino acid residue; R6 is
1) any (D) or (L) amino acid residue,2) C1-C6 alkyl,3) C3-C7 cycloalkyl,4) aryl,5) heteroaryl, or6) heterocyclyl,in which the alkyl or the cycloalkyl are optionally substituted with one or more R10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R20 substituents; R7 and R8 are independently selected from:
1) H,2) C1-C6 alkyl,3) C3-C7 cycloalkyl,4) haloalkyl,5) aryl,6) heteroaryl, or7) heterocyclyl, wherein the alkyl and the cycloalkyl are optionally substituted with one or more R10 substituents, and the aryl, the heteroaryl and the heterocyclyl are optionally substituted with one or more R20 substituents; R9 is
1) H,2) C1-C6 alkyl,3) C3-C7 cycloalkyl,4) aryl,5) heteroaryl, or6) heterocyclyl, in which the alkyl or the cycloalkyl are optionally substituted with one or more R10 substituents; and in which the aryl, heteroaryl or heterocyclyl are optionally substituted with one or more R20 substituents; R10 is independently selected from:
1) halogen,2) C1-C6 alkyl,3) C3-C7 cycloalkyl,4) haloalkyl,5) aryl,6) heteroaryl,7) heterocyclyl,8) OR9,9) S(O)mR9,10) NR7R8,11) COR9,12) C(O)OR9,13) OC(O)R9,14) SC(O)R9,15) CONR7R8, or16) S(O)2NR7R8; R20 is independently selected from:
1) halogen,2) NO2,3) CN,4) C1-C6 alkyl,5) haloalkyl,6) C3-C7 cycloalkyl,7) OR7,8) NR7R8,9) SR7,10) aryl,11) heteroaryl,12) heterocyclyl,13) SO2R5,14) SO3R5,15) SOR5,16) SONHR5,17)SO2NHR5,18) PO3R5,19) PO(OR5)2,20) PO(OR5),21) COR7,22) CO2R7,23) S(O)mR7,24) CONR7R8, or25) S(O)2NR7R8, wherein the alkyl and the cycloalkyl are optionally substituted with one or more R6 substituents; and wherein the aryl, the heteroaryl, or the heterocyclyl are optionally substituted with one or more R30; R30 is
1) NO2,2) C2-C6 alkene-R20,3) SO2R5,4) SOR5,5) SONHR5,6) SO2NHR5,7) CN,8) CO2R5,9) COR5,10) PO3R5,11) PO(OR5)2, or12) PO(OR5); or a prodrug, or a pharmaceutically acceptable salt, or the compound is labeled with a detectable label or an affinity tag thereof.