Tricyclic necrostatin compounds

A Nec-3 compound of formula (VI):

• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
• Z is CH2;
• the bond indicated by (a) can be a single or double bond;
• R1 is hydrogen, alkanoyl of one to six carbon atoms;
• alkoxy of one to six carbon atoms;
• alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms;
• alkylsulfinyl of one to six carbon atoms;
• alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of from one to six carbon atoms;
• alkylsulfonyl of one to six carbon atoms;
• alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms;
• C7-16 aralkyl;
• amino;
• aminoalkyl of one to six carbon atoms;
• C6 or C10 aryl;
• C7 or C11 aryloyl;
• azido;
• azidoalkyl of one to six carbon atoms;
• carboxaldehyde;
• (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms;
• cycloalkyl of three to eight carbon atoms;
• cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms;
• halo;
• haloalkyl of one to six carbon atoms;
• C2-9 heterocyclyl;
• C2-9 (heterocyclyl)oxy;
• C3-10 (heterocyclyl)oyl;
• hydroxyl;
• hydroxyalkyl of one to six carbon atoms;
• nitro;
• nitroalkyl of one to six carbon atoms;
• N-protected amino;
• N-protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms;
• thioalkoxy of one to six carbon atoms;
• thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of from one to six carbon atoms;
• —(CH2)qCO2RA, wherein q is zero to four and RA is selected from the group consisting of (a) C1-6 alkyl, (b) C6 or C10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
• —(CH2)qCONRBRC, wherein RB and RC are independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6 or C10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
• —(CH2)qSO2RD, wherein RD is selected from the group consisting of (a) C1-6 alkyl, (b) C6 or C10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
• —(CH2)qSO2NRERF, wherein RE and RF are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) C6 or C10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
• —(CH2)qNRGRH, wherein RG and RH are independently selected from the group consisting of (a) hydrogen;
• (b) an N-protecting group;
• (c) alkyl of one to six carbon atoms;
• (d) alkenyl of two to six carbon atoms;
• (e) alkynyl of two to six carbon atoms;
• (f) C6 or C10 aryl;
• (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
• (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group;
• C1-6 perfluoroalkyl;
• C1-6 perfluoroalkoxy;
• C6 or C10 aryloxy;
• C3-8 cycloalkoxy;
• C9-14 cycloalkylalkoxy;
• or C7-16 arylalkoxy;
• each of R2, R4, R7, R8, R10, and R11, independently, represents hydrogen, alkanoyl of one to six carbon atoms;
• alkyl of one to six carbon atoms;
• alkoxy of one to six carbon atoms;
• alkoxyalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms;
• alkylsulfinyl of one to six carbon atoms;
• alkylsulfinylalkyl, wherein the alkyl and alkylene groups are independently of from one to six carbon atoms;
• alkylsulfonyl of one to six carbon atoms;
• alkylsulfonylalkyl, wherein the alkyl and alkylene groups are independently of one to six carbon atoms;
• C7-16 aralkyl;
• amino;
• aminoalkyl of one to six carbon atoms;
• C6 or C10 aryl;
• C7 or C11 aryloyl;
• azido;
• azidoalkyl of one to six carbon atoms;
• carboxaldehyde;
• (carboxaldehyde)alkyl, wherein the alkylene group is of one to six carbon atoms;
• cycloalkyl of three to eight carbon atoms;
• cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms and the alkylene group is of one to ten carbon atoms;
• halo;
• haloalkyl of one to six carbon atoms;
• C2-9 heterocyclyl;
• C2-9 (heterocyclyl)oxy;
• C3-10 (heterocyclyl)oyl;
• hydroxyl;
• hydroxyalkyl of one to six carbon atoms;
• nitro;
• nitroalkyl of one to six carbon atoms;
• N-protected amino;
• N-protected aminoalkyl, wherein the alkylene group is of one to six carbon atoms;
• thioalkoxy of one to six carbon atoms;
• thioalkoxyalkyl, wherein the alkyl and alkylene groups are independently of from one to six carbon atoms;
• —(CH2)qCO2RA, wherein q is zero to four and RA is selected from the group consisting of (a) C1-6 alkyl, (b) C6 or C10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
• —(CH2)qCONRBRC, wherein RB and RC are independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6 or C10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
• —(CH2)qSO2RD, wherein RD is selected from the group consisting of (a) C1-6 alkyl, (b) C6 or C10 aryl and (c) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
• —(CH2)qSO2NRERF, wherein RE and RF are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) C6 or C10 aryl and (d) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
• —(CH2)qNRGRH, wherein RG and RH are independently selected from the group consisting of (a) hydrogen;
• (b) an N-protecting group;
• (c) alkyl of one to six carbon atoms;
• (d) alkenyl of two to six carbon atoms;
• (e) alkynyl of two to six carbon atoms;
• (f) C6 or C10 aryl;
• (g) arylalkyl, wherein the alkylene group is of one to six carbon atoms;
• (h) cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of three to eight carbon atoms, and the alkylene group is of one to ten carbon atoms, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group;
• C1-6 perfluoroalkyl;
• C1-6 perfluoroalkoxy;
• C6 or C10 aryloxy;
• C3-8 cycloalkoxy;
• C9-14 cycloalkylalkoxy;
• or C7-16 arylalkoxy;
• R3 is alkyl of one to six carbon atoms;
• alkoxy of one to six carbon atoms;
• halo;
• or amino;
• R9 is alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms;
• R5 is C(O)R13, C(S)R13, C(O)OR13, C(O)NR13R14, C(S)NR13R14, C(NH)R13, or S(O2)R13, wherein each of R13 and R14, independently, represents hydrogen, an optionally substituted C1-12 alkyl, an optionally substituted C1-7 heteroalkyl, an optionally substituted C6 or C10 aryl, an optionally substituted C2-9 heteroaryl, an optionally substituted C7-16 aralkyl, or an optionally substituted C2-15 heteroaralkyl;
• and
• R6 is hydrogen, C1-6 alkyl, an optionally substituted C6 or C10 aryl, an optionally substituted C7-16 aralkyl, an optionally substituted C2-9 heteroaryl, or an optionally substituted C2-15 heteroaralkyl, wherein when each of R1, R2, R4, and R6 through R11 is selected from the group consisting of hydrogen, amino, halide, and hydroxyl and Z is CH2, R3 is not hydroxyl or methoxyl.