Processes for the preparation of isothiazole derivatives

A process for the preparation of a compound of Formula II

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —C(O)(C1-C10 alkyl), —(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), —C(O)(CH2)t(C6-C10 aryl), or —C(O)(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• and the foregoing R1 groups, except H, are optionally substituted by 1 to 3 R4 groups;
• R2 is selected from the list of substituents provided in the definition of R1, —SO2(CH2)t(C6-C10 aryl), —SO2(CH2)t(4-10 membered heterocyclic), and —OR5, t is an integer ranging from 0 to 5, and the foregoing R2 groups are optionally substituted by 1 to 3 R4 groups;
• or R1 and R2 may be taken together with the nitrogen to which each is attached to form a 4-10 membered saturated monocyclic or polycyclic ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R6)— in addition to the nitrogen to which R1 and R2 are attached, said —N(R6)— is optionally ═N— or —N═ where R1 and R2 are taken together as said heteroaryl group, said saturated ring optionally may be partially unsaturated by including 1 or 2 carbon-carbon double bonds, and said saturated and heteroaryl rings, including the R6 group of said —N(R6)—, are optionally substituted by 1 to 3 R4 groups;
• R3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)t(C6-C10 aryl), or —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• the —(CH2)t— moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4 groups;
• each R4 is independently selected from halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR5, —NR6C(O)OR5, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —S(O)jR7 wherein j is an integer ranging from 0 to 2, —NR5(CR6R7)tOR6, —(CH2)t(C6-C10 aryl), —SO2(CH2)t(C6-C10 aryl), —S(CH2)t(C6-C10 aryl), —O(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), and —(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5;
• said alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• and the alkyl, aryl and heterocyclic moieties of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —(CR6R7)mOR6 wherein m is an integer from 1 to 5, —OR5 and the substituents listed in the definition of R5;
• each R5 is independently selected from H, C1-C10 alkyl, —(CH2)t(C6-C10 aryl), and —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R5 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
• each R6 and R7 is independently H or C1-C6 alkyl;
• R8 is H, C1-C10 alkyl, —C(O)(C1-C10 alkyl), —C(O)(C6-C10 aryl), —C(O)(4-10 membered heterocyclic), —(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), —C(O)O(C1-C10 alkyl);
• —C(O)O(C6-C10 aryl), —C(O)O(4-10 membered heterocyclic) wherein t is an integer from 0 to 5;
• said aryl and heterocyclic R8 groups are optionally fused to a C6-C10 aryl group;
• and the foregoing aryl and heterocyclic R8 groups are optionally substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, and nitro groups;
• comprising (1) reacting a compound of Formula IV
• wherein R3, R4, R5, R6, R7 and R8 are as defined above for Formula II with a source of carbonyl, with or without an added base, and then adding a compound of Formula III
• HNR1R2 III
• wherein R1 and R2 are as defined above for Formula II in a solvent to give a compound of the Formula II or (2) reacting a compound of Formula III with a source of carbonyl, with or without an added base, and then adding a compound of Formula IV in a solvent to give a compound of the Formula II.

A process for the preparation of a compound of Formula IV

• or a pharmaceutically acceptable salt thereof;
• wherein
• R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)t(C6-C10 aryl), or —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• the —(CH2)t— moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4 groups;
• each R4 is independently selected from halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR5, —NR6C(O)OR5, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —S(O)jR7 wherein j is an integer ranging from 0 to 2, —NR5(CR6R7) OR6, —(CH2)t(C6-C10 aryl), —SO2(CH2)t(C6-C10 aryl), —S(CH2)t(C6-C10 aryl), —O(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), and —(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5;
• said alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• and the alkyl, aryl and heterocyclic moieties of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —(CR6R7)mOR6 wherein m is an integer from 1 to 5, —OR5 and the substituents listed in the definition of R5;
• each R5 is independently selected from H, C1-C10 alkyl, —(CH2)t(C6-C10 aryl), and —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R5 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
• each R6 and R7 is independently H or C1-C6 alkyl;
• R8 is H, C1-C10 alkyl, —C(O)(C1-C10 alkyl), —C(O)(C6-C10 aryl), —C(O)(4-10 membered heterocyclic), —(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), —C(O)O(C1-C10 alkyl);
• —C(O)O(C6-C10 aryl), —C(O)O(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said aryl and heterocyclic R8 groups are optionally fused to a C6-C10 aryl group;
• and the foregoing aryl and heterocyclic R8 groups are optionally substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, and nitro groups;
• comprising reacting a compound of the Formula V
• wherein R3, R4, R5, R6, R7 and R8 are as defined above;
• R9 is C1-C10 alkyl, C6-C10 aryl, 4-10 membered heterocyclic, said aryl and heterocyclic R9 groups are optionally fused to a C6-C10 aryl group;
• and the foregoing aryl and heterocyclic R9 groups are optionally substituted independently with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, and nitro groups;
• and n is 0, 1 or 2, with an ammonia source in a solvent to give a compound of the Formula IV.

A process for the preparation of a compound of Formula V

• or a pharmaceutically acceptable salt thereof;
• wherein
• R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)t(C6-C10 aryl), or —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• the —(CH2)t— moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4 groups;
• each R4 is independently selected from halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR5, —NR6C(O)nR5, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —S(O)jR7 wherein j is an integer ranging from 0 to 2, —NR5(CR6R7)tOR6, —(CH2)t(C6-C10 aryl), —SO2(CH2)t(C6-C10 aryl), —S(CH2)t(C6-C10 aryl), —O(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), and —(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5;
• said alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• and the alkyl, aryl and heterocyclic moieties of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —(CR6R7)mOR6 wherein m is an integer from 1 to 5, —OR5 and the substituents listed in the definition of R5;
• each R5 is independently selected from H, C1-C10 alkyl, —(CH2)t(C6-C10 aryl), and —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R5 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
• each R6 and R7 is independently H or C1-C6 alkyl;
• R8 is H, C1-C10 alkyl, —C(O)(C1-C10 alkyl), —C(O)(C6-C10 aryl), —C(O)(4-10 membered heterocyclic), —(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), —C(O)O(C1-C10 alkyl);
• —C(O)O(C6-C10 aryl), —C(O)O(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said aryl and heterocyclic R8 groups are optionally fused to a C6-C10 aryl group;
• and the foregoing aryl and heterocyclic R8 groups are optionally substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, and nitro groups;
• R9 is C1-C10 alkyl, C6-C10 aryl, 4-10 membered heterocyclic, said aryl groups and heterocyclic R9 groups are optionally fused to a C6-C10 aryl group;
• and the foregoing aryl and heterocyclic R9 groups are optionally substituted independently with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, and nitro groups;
• and
• n is 0, 1, or 2;
• comprising reacting a compound of the Formula VII
• wherein n, R8, and R9 are as defined above, with a compound of Formula VI
• R3X VI
• wherein R3 is as defined above and X is halogen, hydroxyl, C1-C4 alkyl sulfonate ester, aryl sulfonate ester or an imidate, in the presence of an acid, a base, or R′3P and R″OC(O)N═NC(O)OR″ wherein each R′ and R″ is independently C1-C4 alkyl or a first C6-C10 aryl, and wherein said R′ and R″ alkyl and aryl groups are optionally substituted with C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, trifluoromethyl, trifluoromethoxy, —OR5, —NR6C(O)OR5, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5—S(O)jR7 wherein j is an integer ranging from 0 to 2, —NR5(CR6R7)tOR6, —(CH2)t(C6-C10 aryl), —SO2(CH2)t(C6-C10 aryl), —S(CH2)t(C6-C10 aryl), —O(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), and —(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5;
• said C1-C10 alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said —(CH2)t(C6-C10 aryl), —SO2(CH2)t(C6-C10 aryl), —S(CH2)t(C6-C10 aryl), —O(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic) groups are optionally fused to a second C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• and the alkyl, aryl and heterocyclic moieties of the foregoing groups are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —(CR6R7)mOR6 wherein m is an integer from 1 to 5, —OR5 and the substituents listed in the definition of R5 where R5, R6, and R7 are as defined above with the proviso that R5, R6, and R7 cannot be H, in a solvent, to give a compound of the Formula V.

A compound of the Formula IIa

• or a pharmaceutically acceptable salt thereof;
• wherein
• R1 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —C(O)(C1-C10 alkyl), —(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), —C(O)(CH2)t(C6-C10 aryl), or —C(O)(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• and the foregoing R1 groups, except H, are optionally substituted by 1 to 3 R4 groups;
• R2 is selected from the list of substituents provided in the definition of R1, —SO2(CH2)t(C6-C10 aryl), —SO2(CH2)t(4-10 membered heterocyclic), and —OR5, t is an integer ranging from 0 to 5, and the foregoing R2 groups are optionally substituted by 1 to 3 R4 groups;
• or R1 and R2 may be taken together with the nitrogen to which each is attached to form a 4-10 membered saturated monocyclic or polycyclic ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R6)— in addition to the nitrogen to which R1 and R2 are attached, said —N(R6)— is optionally ═N— or —N═ where R1 and R2 are taken together as said heteroaryl group, said saturated ring optionally may be partially unsaturated by including 1 or 2 carbon-carbon double bonds, and said saturated and heteroaryl rings, including the R6 group of said —N(R6)—, are optionally substituted by 1 to 3 R4 groups;
• R3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)t(C6-C10 aryl), or —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• the —(CH2)t— moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4 groups;
• each R4 is independently selected from halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR5, —NR6C(O)OR5, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —S(O)jR7 wherein j is an integer ranging from 0 to 2, —NR5(CR6R7)tOR6, —(CH2)t(C6-C10 aryl), —SO2(CH2)t(C6-C10 aryl), —S(CH2)t(C6-C10 aryl), —O(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), and —(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5;
• said alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• and the alkyl, aryl and heterocyclic moieties of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —(CR6R7)mOR6 wherein m is an integer from 1 to 5, —OR5 and the substituents listed in the definition of R5;
• each R5 is independently selected from H, C1-C10 alkyl, —(CH2)t(C6-C10 aryl), and —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R5 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
• each R6 and R7 is independently H or C1-C6 alkyl;
• and
• R8 is H, C1-C10 alkyl, —C(O)(C1-C10 alkyl), —C(O)(C6-C10 aryl),
• —C(O)(4-10 membered heterocyclic), —(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), —C(O)O(C1-C10 alkyl);
• —C(O)O(C6-C10 aryl), —C(O)O(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said aryl and heterocyclic R8 groups are optionally fused to a C6-C10 aryl group;
• and the foregoing aryl and heterocyclic R8 groups are optionally substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, and nitro groups with the proviso that R8 is not ethyl when simultaneously R1 is H, R2 is pyrrolidin-1-yl-butyl and R3 is C1-C3 alkyl.

A compound of the Formula IVa

• or a pharmaceutically acceptable salt thereof;
• wherein
• R3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)t(C6-C10 aryl), or —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• the —(CH2)t— moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4 groups;
• each R4 is independently selected from halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR5, —NR6C(O)OR5, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —S(O)jR7 wherein j is an integer ranging from 0 to 2, —NR5(CR6R7)tOR6, —(CH2)—(C6-C10 aryl), —SO2(CH2)t(C6-C10 aryl), —S(CH2)t(C6-C10 aryl), —O(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), and —(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5;
• said alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• and the alkyl, aryl and heterocyclic moieties of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6SO2R5, —SO2NR5R6, —NR60(O)R5, —C(O)NR5R6, —NR5R6, —(CR6R7)mOR6 wherein m is an integer from 1 to 5, —OR5 and the substituents listed in the definition of R5;
• each R5 is independently selected from H, C1-C10 alkyl, —(CH2)t(C6-C10 aryl), and —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R5 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
• each R6 and R7 is independently H or C1-C6 alkyl;
• and
• R8 is H, C1-C10 alkyl, —C(O)(C1-C10 alkyl), —C(O)(C6-C10 aryl), —C(O)(4-10 membered heterocyclic), —(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), —C(O)O(C1-C10 alkyl);
• —C(O)O(C6-C10 aryl), —C(O)O(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said aryl and heterocyclic R8 groups are optionally fused to a C6-C10 aryl group;
• and the foregoing aryl and heterocyclic R8 groups are optionally substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, and nitro groups with the proviso that R8 is not ethyl when R3 is C1-C3 alkyl.

A compound of the formula Va

• or a pharmaceutically acceptable salt thereof;
• wherein
• R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)t(C6-C10 aryl), or —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R3 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• the —(CH2)t— moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 5, and the foregoing R3 groups are optionally substituted by 1 to 5 R4 groups;
• each R4 is independently selected from halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR5, —NR6C(O)OR5, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5, —C(O)NR5R6, —NR5R6, —S(O)jR7 wherein j is an integer ranging from 0 to 2, —NR5(CR6R7)tOR6, —(CH2)t(C6-C10 aryl), —SO2(CH2)t(C6-C10 aryl), —S(CH2)t(C6-C10 aryl), —O(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), and —(CR6R7)mOR6, wherein m is an integer from 1 to 5 and t is an integer from 0 to 5;
• said alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R4 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• 1 or 2 carbon atoms in the foregoing heterocyclic moieties are optionally substituted by an oxo (═O) moiety;
• and the alkyl, aryl and heterocyclic moieties of the foregoing R4 groups are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6SO2R5, —SO2NR5R6, —NR6C(O)R5—C(O)NR5R6, —NR5R6, —(CR6R7)mOR6 wherein m is an integer from 1 to 5, —OR5 and the substituents listed in the definition of R5;
• each R5 is independently selected from H, C1-C10 alkyl, —(CH2)t(C6-C10 aryl), and —(CH2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R6)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R5 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R5 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from nitro, trifluoromethyl, trifluoromethoxy, azido, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
• each R6 and R7 is independently H or C1-C6 alkyl;
• R8 is H, C1-C10 alkyl, —C(O)(C1-C10 alkyl), —C(O)(C6-C10 aryl),
• —C(O)(4-10 membered heterocyclic), —(CH2)t(C6-C10 aryl), —(CH2)t(4-10 membered heterocyclic), —C(O)O(C1-C10 alkyl);
• —C(O)O(C6-C10 aryl), —C(O)O(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said aryl and heterocyclic R8 groups are optionally fused to a C6-C10 aryl group;
• and the foregoing aryl and heterocyclic R8 groups are optionally substituted with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, and nitro groups;
• R9 is C1-C10 alkyl, C6-C10 aryl, 4-10 membered heterocyclic, the aryl and heterocyclic R9 groups are optionally fused to a C6-C10 aryl group;
• and the foregoing aryl and heterocyclic R9 groups are optionally substituted independently with 1-2 substituents independently selected from halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, and nitro groups;
• and
• n is 1 or 2.