Processes for the preparation of substituted bicyclic derivatives for the treatment of abnormal cell growth

A method for preparing a compound of formula 1

• 38
• pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein:
• m is an integer from 0 to 3;
• p is an integer from 0 to 4;
• each R1 and R2 is independently selected from H and C1-C6 alkyl;
• R3 is —(CR1R2)t(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5, said heterocyclic group is optionally fused to a benzene ring or a C5-C8 cycloalkyl group, the —(CR1R2)t— moiety of the foregoing R3 group optionally includes a carbon-carbon double or triple bond where t is an integer between 2 and 5, and the foregoing R3 groups, including any optional fused rings referred to above, are optionally substituted by 1 to 5 R8 groups;
• R4 is —C≡C—(CR16R17)tR9, —C═C—(CR16R17)t—R9, —C≡C—(CR16R17)kR13, or —C═C—(CR16R17)kR13, wherein the attachment point to R9 is through a carbon atom of the R9 group, each k is an integer from 1 to 3, each t is an integer from 0 to 5, and each m is an integer from 0 to 3;
• each R5 is independently selected from halo, hydroxy, —NR1R2, C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, trifluoromethoxy, —NR6C(O)R1, —C(O)NR6R7, —SO2NR6R7, —NR6C(O)NR7R1, and —NR6C(O)OR7;
• each R6, R6a and R7 is independently selected from H, C1-C6 alkyl, —(CR1R2)t(C6-C10 aryl), and —(CR1R2)t(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, the alkyl, aryl and heterocyclic moieties of the foregoing R6 and R7 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, —NR1R2, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, and C1-C6 alkoxy;
• or R6 and R7, or R6a and R7, when attached to a nitrogen atom (including the same nitrogen atom or two separate nitrogen atoms in proximity to each other through interconection by, for instance, —C(O) or —SO2—), can be taken together to form a 4 to 10 membered heterocyclic ring which may include 1 to 3 additional hetero moieties, in addition to the nitrogen to which said R6, R6a, and R7 are attached, selected from N, N(R1), O, and S, provided two O atoms, two S atoms or an O and S atom are not attached directly to each other;
• each R8 is independently selected from oxo (═O), halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C1-C6 alkoxy, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —C(O)R6, —C(O)OR6, —OC(O)R6, —NR6C(O)R7, —NR6SO2NR7R1, —NR6C(O)NR1R7, —NR6C(O)OR7, —C(O)NR6R7, —NR6R7, —NR6OR7, —SO2NR6R7, —S(O)j(C1-C6 alkyl) wherein j is an integer from 0 to 2, —(CR1R2)t(C6-C10 aryl), —(CR1R2)t(4 to 10 membered heterocyclic), —(CR1R2)qC(O)(CR1R2)t(C6-C10 aryl), —(CR1R2)qC(O)(CR1R2)t(4 to 10 membered heterocyclic), —(CR1R2)tO(CR1R2)q(C6-C10 aryl), —(CR1R2)tO(CR1R2)q(4 to 10 membered heterocyclic), —(CR1R2)qS(O)j(CR1R2)t(C6-C10 aryl), and —(CR1R2)qS(O)j(CR1R2)t(4 to 10 membered heterocyclic), wherein j is 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R8 groups are optionally substituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R8 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR6, —C(O)R6, —C(O)OR6, —OC(O)R6, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, —NR6OR7, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(CR1R2)t(C6-C10 aryl), and —(CR1R2)t(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5;
• R9 is a non-aromatic mono-cyclic ring, a fused or bridged bicyclic ring, or a spirocyclic ring, wherein said ring contains from 3 to 12 carbon atoms in which from 0 to 3 carbon atoms are optionally replaced with a hetero moiety independently selected from N, O, S(O)j wherein j is an integer from 0 to 2, and —NR1—, provided that two O atoms, two S(O)j moieties, an O atom and a S(O)j moiety, an N atom and an S atom, or an N atom and an O atom are not attached directly to each other within said ring, and wherein the carbon atoms of said ring are optionally substituted with 1 or 2 R8 groups;
• each R11 is independently selected from the substituents provided in the definition of R8, except R11 is not oxo(═O);
• R12 is R6, —OR6, —OC(O)R6, —OC(O)NR6R7, —OCO2R6, —S(O)jR6, —S(O)jNR6R7, —NR6R7, —NR6C(O)R7, —NR6SO2R7, —NR6C(O)NR6aR7, —NR6SO2NR6aR7, —NR6CO2R7, CN, —C(O)R6, or halo, wherein j is an integer from 0 to 2;
• R13 is —NR1R14 or 13 OR14;
• R14 is H, R15, —C(O)R15, —SO2R15, —C(O)NR15R7, —SO2NR15R7, or —CO2R15;
• R15 is R18, —(CR1R2)t(C6-C10 aryl), —(CR1R2)t(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, and the aryl and heterocyclic moieties of the foregoing R15 groups are optionally substituted with 1 to 3 R8 substituents;
• each R16 and R17 is independently selected from H, C1-C6 alkyl, and —CH2OH, or R16 and R17 are taken together as —CH2CH2— or —CH2CH2CH2—;
• R18 is C1-C6 alkyl wherein each carbon not bound to a N or O atom, or to S(O)j, wherein j is an integer from 0 to 2, is optionally substituted with R12;
• and wherein any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group, which is not attached to a halogeno, SO or SO2 group or to a N, O or S atom, is optionally subsituted with a group selected from hydroxy, halo, C1-C4 alkyl, C1-C4 alkoxy and —NR1R2, which comprises reacting a compound of formula 3
• 39
• wherein A is Cl or F and R4, R5 and m are as defined for formula 1 with a compound of formula 4
• 40
• wherein R1, R2, R3, R11 and p are as defined for formula 1.

A compound of formula H—C≡C—(CR16R17)tR9, wherein each R16 and R17 is independently selected from H, C1-C6 alkyl, and —CH2OH, or R16 and R17 are taken together as —CH2CH2— or —CH2CH2CH2—;

• wherein R9 is a non-aromatic mono-cyclic ring, a fused or bridged bicyclic ring, or a spirocyclic ring, wherein said ring contains from 3 to 12 carbon atoms in which from 0 to 3 carbon atoms are optionally replaced with a hetero moiety independently selected from N, O, S(O)j wherein j is an integer from 0 to 2, and —NR1—, provided that two O atoms, two S(O) moieties, an O atom and a S(O)j moiety, an N atom and an S atom, or an N atom and an O atom are not attached directly to each other within said ring, and wherein the carbon atoms of said ring are optionally substituted with 1 or 2 R8 groups, wherein each R1 and R2 is independently selected from H and C1-C6 alkyl, wherein each R8 is independently selected from oxo (═O), halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C1-C6 alkoxy, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —C(O)R6, —C(O)OR6, —OC(O)R6, —NR6C(O)R7, —NR6SO2NR7R1, —NR6C(O)NR1R7, —NR6C(O)OR7, —C(O)NR6R7, —NR6R7, —NR6OR7, —SO2NR6R7, —S(O)j(C1-C6 alkyl) wherein j is an integer from 0 to 2, —(CR1R2)t(C6-C10 aryl), —(CR1R2)t(4 to 10 membered heterocyclic), —(CR1R2)qC(O)(CR1R2)t(C6-C10 aryl), —(CR1R2)qC(O)(CR1R2)t(4 to 10 membered heterocyclic), —(CR1R2)tO(CR1R2)q(C6-C10 aryl), —(CR1R2)tO(CR1R2)q(4 to 10 membered heterocyclic), —(CR1R2)qS(O)j(CR1R2)t(C6-C10 aryl), and —(CR1R2)qS(O)j(CR1R2)t(4 to 10 membered heterocyclic), wherein j is 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R8 groups are optionally substituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R8 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR6, —C(O)R6, —C(O)OR6, —OC(O)R6, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, —NR6OR7, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(CR1R2)t(C6-C10 aryl), and —(CR1R2)t(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5;
• each R6 and R7 is independently selected from H, C1-C6 alkyl, —(CR1R2)t(C6-C10 aryl), and —(CR1R2)t(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, the alkyl, aryl and heterocyclic moieties of the foregoing R6 and R7 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, —NR1R2, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, and C1-C6 alkoxy;
• or R6 and R7, when attached to a nitrogen atom (including the same nitrogen atom or two separate nitrogen atoms in proximity to each other through interconection by, for instance, —C(O) or —SO2—), can be taken together to form a 4 to 10 membered heterocyclic ring which may include 1 to 3 additional hetero moieties, in addition to the nitrogen to which said R6, and R7 are attached, selected from N, N(R1), O, and S, provided two O atoms, two S atoms or an O and S atom are not attached directly to each other;
• and t is an integer from 0 to 5.

A compound of formula M-C═C—(CR16R17)t—R9, wherein M is selected from the group consisting of H, B(R19)2, Al(R20)2, Sn(R21)3, MgW, or ZnW, wherein R19 is selected from the group consisting of 9-BBN, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, and halo wherein R20 is selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, and halo, wherein R is C1-C10 alkyl and wherein W is Cl, Br or I;

• wherein each R16 and R17 is independently selected from H, C1-C6 alkyl, and —CH2OH, or R16 and R17 are taken together as —CH2CH2— or —CH2CH2CH2—;
• wherein R9 is a non-aromatic mono-cyclic ring, a fused or bridged bicyclic ring, or a spirocyclic ring, wherein said ring contains from 3 to 12 carbon atoms in which from 0 to 3 carbon atoms are optionally replaced with a hetero moiety independently selected from N, O, S(O)j wherein j is an integer from 0 to 2, and —NR1—, provided that two O atoms, two S(O)j moieties, an O atom and a S(O)j moiety, an N atom and an S atom, or an N atom and an O atom are not attached directly to each other within said ring, and wherein the carbon atoms of said ring are optionally substituted with 1 or 2 R8 groups, wherein each R1 and R2 is independently selected from H and C1-C6 alkyl, wherein each R8 is independently selected from oxo (═O), halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C1-C6 alkoxy, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —C(O)R6, —C(O)OR6, —OC(O)R6, —NR6C(O)R7, —NR6SO2NR7R1, —NR6C(O)NR1R7, —NR6C(O)OR7, —C(O)NR6R7, —NR6R7, —NR6OR7, —SO2NR6R7 —S(O)j(C1-C6 alkyl) wherein j is an integer from 0 to 2, —(CR1R2)t(C6-C10 aryl), —(CR1R2)t(4 to 10 membered heterocyclic), —(CR1R2)qC(O)(CR1R2)t(C6-C10 aryl), —(CR1R2)qC(O)(CR1R2)t(4 to 10 membered heterocyclic), —(CR1R2)tO(CR1R2)q(C6-C10 aryl), —(CR1R2)tO(CR1R2)q(4 to 10 membered heterocyclic), —(CR1R2)qS(O)j(CR1R2)t(C6-C10 aryl), and —(CR1R2)qS(O)j(CR1R2)t(4 to 10 membered heterocyclic), wherein j is 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R8 groups are optionally substituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R8 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR6, —C(O)R6, —C(O)OR6, —OC(O)R6, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, —NR6OR7, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(CR1R2)t(C6-C10 aryl), and —(CR1R2)t(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5;
• each R6, and R7 is independently selected from H, C1-C6 alkyl, —(CR1R2)t(C6-C10 aryl), and —(CR1R2)t(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, the alkyl, aryl and heterocyclic moieties of the foregoing R6 and R7 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, —NR1R2, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, and C1-C6 alkoxy;
• or R6 and R7, when attached to a nitrogen atom (including the same nitrogen atom or two separate nitrogen atoms in proximity to each other through interconection by, for instance, —C(O) or —SO2—), can be taken together to form a 4 to 10 membered heterocyclic ring which may include 1 to 3 additional hetero moieties, in addition to the nitrogen to which said R6, and R7 are attached, selected from N, N(R1), O, and S, provided two O atoms, two S atoms or an O and S atom are not attached directly to each other;
• and t is an integer from 0 to 5.

A compound of formula H—C≡C—(CR16R17)kR13, wherein each R16 and R17 is independently selected from H, C1-C6 alkyl, and —CH2OH, or R16 and R17 are taken together as —CH2CH2— or —CH2CH2CH2—;

• wherein R13 is —NR1R14 or —OR14, wherein R14 is H, R15, —C(O)R15, —SO2R15, —C(O)NR15R7, —SO2NR15R7, or —CO2R15, wherein R15 is R18, —(CR1R2)t(C6-C10 aryl), —(CR1R2),(4 to 10 membered heterocyclic), wherein each R1 and R2 is independently selected from H and C1-C6 alkyl, wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, and the aryl and heterocyclic moieties of the foregoing R15 groups are optionally substituted with 1 to 3 R8 substituents, wherein R18 is C1-C6 alkyl wherein each carbon not bound to a N or O atom, or to S(O)j, wherein j is an integer from 0 to 2, is optionally substituted with R12, wherein R12 is R6, OR6, —OC(O)R6, —OC(O)NR6R7, —OCO2R6, —S(O)jR6, —S(O)jNR6R7, —NR6R7, —NR6C(O)R7, —NR6SO2R7, —NR6C(O)NR6aR7, —NR6SO2NR6aR7, —NR6CO2R7, CN, —C(O)R6, or halo, wherein j is an integer from 0 to 2, each R6, R6a and R7 is independently selected from H, C1-C6 alkyl, —(CR1R2)t(C6-C10 aryl), and —(CR1R2)t(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, the alkyl, aryl and heterocyclic moieties of the foregoing R6 and R7 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, —NR1R2, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, and C1-C6 alkoxy;
• or R6 and R7, or R6a and R7, when attached to a nitrogen atom (including the same nitrogen atom or two separate nitrogen atoms in proximity to each other through interconection by, for instance, —C(O) or —SO2—), can be taken together to form a 4 to 10 membered heterocyclic ring which may include 1 to 3 additional hetero moieties, in addition to the nitrogen to which said R6, R6a, and R7 are attached, selected from N, N(R1), O, and S, provided two O atoms, two S atoms or an O and S atom are not attached directly to each other;
• each R8 is independently selected from oxo (═O), halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C1-C6 alkoxy, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —C(O)R6, —C(O)OR6, —OC(O)R6, —NR6C(O)R7, —NR6SO2NR7R1, —NR6C(O)NR1R7, —NR6C(O)OR7, —C(O)NR6R7, —NR6R7, —NR6OR7, —SO2NR6R7, —S(O)j(C1-C6 alkyl) wherein j is an integer from 0 to 2, —(CR1R2)t(C6-C10 aryl), —(CR1R2)t(4 to 10 membered heterocyclic), —(CR1R2)qC(O)(CR1R2)t(C6-C10 aryl), —(CR1R2)qC(O)(CR1R2)t(4 to 10 membered heterocyclic), —(CR1R2)tO(CR1R2)q(C6-C10 aryl), —(CR1R2)tO(CR1R2)q(4 to 10 membered heterocyclic), —(CR1R2)qS(O)j(CR1R2)t(C6-C10 aryl), and —(CR1R2)qS(O)j(CR1R2)t(4 to 10 membered heterocyclic), wherein j is 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R8 groups are optionally substituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R8 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR6, —C(O)R6, —C(O)OR6, —OC(O)R6, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, —NR6OR7, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(CR1R2)t(C6-C10 aryl), and —(CR1R2)t(4 to 10 membered heterocyclic), and wherein t is an integer from 0 to 5.

A compound of formula M-C═C—(CR16R17)kR13, wherein M is selected from the group consisting of H, B(R19)2, Al(R20)2, Sn(R21)3, MgW, or ZnW, wherein R19 is selected from the group consisting of 9-BBN, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, and halo wherein R20 is selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, and halo, and wherein R21 is C1-C10 alkyl and:

• wherein W is Cl, Br or I;
• wherein each R16 and R17 is independently selected from H, C1-C6 alkyl, and —CH2OH, or R16 and R17 are taken together as —CH2CH2— or —CH2CH2CH2—;
• wherein R13 is —NR1R14 or —OR14, wherein R14 is H, R15, —C(O)R15, —SO2R15, —C(O)NR15R7, —SO2NR15R7, or —CO2R15, wherein R15 is R18, —(CR1R2)t(C6-C10 aryl), —(CR1R2)t(4 to 10 membered heterocyclic), wherein each R1 and R2 is independently selected from H and C1-C6 alkyl, wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, and the aryl and heterocyclic moieties of the foregoing R15 groups are optionally substituted with 1 to 3 R8 substituents, wherein R18 is C1-C6 alkyl wherein each carbon not bound to a N or 0 atom, or to S(O)j, wherein j is an integer from 0 to 2, is optionally substituted with R12, wherein R12 is R6, —OR6, —OC(O)R6, —OC(O)NR6R7, —OCO2R6, —S(O)jR6, —S(O)jNR6R7, —NR6R7, —NR6C(O)R7, —NR6SO2R7, —NR6C(O)NR6aR7, —NR6SO2NR6aR7, —NR6CO2R7, CN, —C(O)R6, or halo, wherein j is an integer from 0 to 2, each R6, R6a and R7 is independently selected from H, C1-C6 alkyl, —(CR1R2)t(C6-C10 aryl), and —(CR1R2)t(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, the alkyl, aryl and heterocyclic moieties of the foregoing R6 and R7 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, —NR1R2, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, and C1-C6 alkoxy;
• or R6 and R7, or R6a and R7, when attached to a nitrogen atom (including the same nitrogen atom or two separate nitrogen atoms in proximity to each other through interconection by, for instance, —C(O) or —SO2—), can be taken together to form a 4 to 10 membered heterocyclic ring which may include 1 to 3 additional hetero moieties, in addition to the nitrogen to which said R6, R6a, and R7 are attached, selected from N, N(R1), O, and S, provided two O atoms, two S atoms or an O and S atom are not attached directly to each other;
• each R8 is independently selected from oxo (═O), halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C1-C6 alkoxy, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —C(O)R6, —C(O)OR6, —OC(O)R6, —NR6C(O)R7, —NR6SO2NR7R1, —NR6C(O)NR1R7, —NR6C(O)OR7, —C(O)N R6R7, —NR6R7, —NR6OR7, —SO2NR6R7, —S(O)j(C1-C6 alkyl) wherein j is an integer from 0 to 2, —(CR1R2)j(C6-C10 aryl), —(CR1R2)t(4 to 10 membered heterocyclic), —(CR1R2)qC(O)(CR1R2)t(C6-C10 aryl), —(CR1R2)qC(O)(CR1R2)t(4 to 10 membered heterocyclic), —(CR1R2)tO(CR1R2)q(C6-C10 aryl), —(CR1R2)tO(CR1R2)q(4 to 10 membered heterocyclic), —(CR1R2)qS(O)j(CR1R2)t(C6-C10 aryl), and —(CR1R2)qS(O)j(CR1R2)t(4 to 10 membered heterocyclic), wherein j is 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R8 groups are optionally substituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R8 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR6, —C(O)R6, —C(O)OR6, —OC(O)R6, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, —NR6OR7, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(CR1R2)t(C6-C10 aryl), and —(CR1R2)t(4 to 10 membered heterocyclic), and wherein t is an integer from 0 to 5.