Methods of Using PI3K and MEK Modulators

A method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a compound of Formula Ia, Ic, Id, II, or V or a pharmaceutically acceptable composition, thereof, in combination with a compound(s) selected from the group consisting of a compound of Formula VIa, VIb, VII, VIIIa, and VIIIb, or a pharmaceutically acceptable composition thereof,

• where Formula Ia is as follows:
• and optionally as a pharmaceutically acceptable salt or solvate thereof, wherein
• the A ring represents an arylene or heteroarylene group and the A ring is optionally substituted with one, two, three or four groups selected from R10, R12, R14, and R16 where R10, R12, R14, and R16 are independently hydrogen, lower alkanyl, lower alkenyl, lower alkynyl, halo, haloalkoxy, hydroxy, lower alkoxy, amino, alkylamino, dialkylamino, haloalkyl, —NHS(O)2R8, —CN, —C(O)R8, —C(O)OR8, —C(O)NR8R8′ or —NR8C(O)R8′;
• X is lower alkyl, halo, haloalkyl, or haloalkoxy;
• R1, R2, R3, R4, R5 and R6 are independently hydrogen, halo, nitro, —NR8R8′, —OR8, —NHS(O)2R8, —CN, —S(O)mR8, —S(O)2NR8R8′, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)OR8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′, —NR8C(O)R8′, lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl;
• where the lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, lower alkanyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, —OR8, —NR8R8′, —NHS(O)2R9, —CN, —S(O)mR9, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′, and —NR8C(O)R8′;
• or
• one of R1 and R2 together with the carbon to which they are attached, R3 and R4 together with the carbon to which they are attached, and R5 and R6 together with the carbon to which they are attached form C(O) or C(═NOH);
• m is 1 or 2;
• R7 is hydrogen, halo or lower alkyl;
• R8, R8′ and R8″ are independently hydrogen, hydroxy, alkoxy, substituted alkoxy, lower alkanyl, haloalkyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;
• where the lower alkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from lower alkanyl, halo, hydroxy, hydroxyalkyl, lower alkoxy, substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano, —S(O)nR31 (where n is 0, 1, or 2 and R31 is alkyl, substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), —NR34SO2R34a (where R34 is hydrogen or lower alkyl and R34a is lower alkyl, lower alkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl), —SO2NR35R35a (where R35 is hydrogen or alkyl and R35a is lower alkyl, lower alkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, aryloxy, arylalkyloxy, optionally substituted heteroaryl, —NHC(O)R32 (where R32 is lower alkanyl, lower alkenyl, alkoxy, or cycloalkyl) and —NR30R30′ (where R30 and R30′ are independently hydrogen, lower alkyl, or hydroxyalkyl), and —C(O)NHR33 (where R33 is lower alkanyl, lower alkenyl, lower alkynyl, or cycloalkyl);
• and
• R9 is lower alkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;
• where the lower alkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally susbstituted with one, two, three, four, or five groups selected from lower alkanyl, halo, hydroxy, haloalkoxy, haloalkyl, amino, alkylamino, and dialkylamino;
• where Formula Ic is as follows:
• and optionally as a pharmaceutically acceptable salt or solvate thereof, wherein
• R10, R12, R14, and R16 are independently hydrogen, lower alkanyl, halo, haloalkoxy, hydroxy, lower alkoxy, or haloalkyl;
• X is halo;
• R3 is hydrogen, halo, nitro, —NR8R8′, —OR8, —NHS(O)2R8, —CN, —S(O)mR8, —S(O)2NR8R8′, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)OR8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′, —NR8C(O)R8′, lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl;
• where the lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, lower alkanyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, —OR8, —NR8R8′, —NHS(O)2R9, —CN, —S(O)mR9, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′, and —NR8C(O)R8′;
• R7 is hydrogen, halo or lower alkyl;
• R8, R8′ and R8″ are independently hydrogen, hydroxy, alkoxy, substituted alkoxy, lower alkanyl, haloalkyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;
• where the lower alkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from lower alkanyl, halo, hydroxy, hydroxyalkyl, lower alkoxy, substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano, —S(O)nR31 (where n is 0, 1, or 2 and R31 is alkyl, substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), —NR34SO2R34a (where R34 is hydrogen or lower alkyl and R34a is lower alkyl, lower alkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl), —SO2NR35R35a (where R35 is hydrogen or alkyl and R35a is lower alkyl, lower alkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, aryloxy, arylalkyloxy, optionally substituted heteroaryl, —NHC(O)R32 (where R32 is lower alkanyl, lower alkenyl, alkoxy, or cycloalkyl) and —NR30R30′ (where R30 and R30′ are independently hydrogen, lower alkyl, or hydroxyalkyl), and —C(O)NHR33 (where R33 is lower alkanyl, lower alkenyl, lower alkynyl, or cycloalkyl);
• and
• R9 is lower alkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;
• where the lower alkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally susbstituted with one, two, three, four, or five groups selected from lower alkanyl, halo, hydroxy, haloalkoxy, haloalkyl, amino, alkylamino, and dialkylamino;
• where Formula Id is as follows:
• and optionally as a pharmaceutically acceptable salt or solvate thereof, wherein X, R7, R10, R12, R14, R16, R3, R8, and R8′ are as defined above for Formula Ic;
• where Formula II is as follows:
• and optionally as a pharmaceutically acceptable salt or solvate thereof, wherein X, R1, R2, R3, R4, R5, R6, and R7 are as defined above for Formula Ia;
• where Formula V is as follows:
• and optionally as a pharmaceutically acceptable salt or solvate thereof, wherein the A ring, R3, R4, and R4 are as defined above for Formula Ia;
• where Formula VIa is as follows:
• and optionally as a pharmaceutically acceptable salt or hydrate thereof, wherein
• R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted heteroalicyclic, optionally substituted heteroalicyclicalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
• X is —NR3—;
• R2 is hydrogen, optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aryl-C1-6 alkyl, heteroalicyclic, heterocyclylalkyl, heterocyclyl-aryl- or heteroaryl;
• where the cycloalkyl, aryl, aryl-C1-6 alkyl, heteroalicyclic, heterocyclylalkyl, heterocyclyl-aryl-, and heteroaryl groups in R2 are optionally substituted with 1, 2, 3, or 4 R8 groups;
• R3 is hydrogen;
• R4 is optionally substituted C1-C6 alkyl;
• R6 is hydrogen, acyl, phenyl, heteroalicyclic, or heteroaryl;
• where the phenyl, heteroalicyclic, and heteroaryl in R6 are optionally substituted with 1, 2, 3, or 4 R9 groups;
• R8 at each occurrence is independently hydroxy, halo, haloalkyl, C1-C6 alkyl, optionally substituted C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 alkoxyalkylaminoalkyl, C1-C6 alkylcarboxyheterocyclyl, —O—C1-C6alkylheterocyclyl, aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl, optionally substituted heteroalicyclic, optionally substituted heteroalicyclicalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
• and
• R9 at each occurrence is independently halo, haloalkyl, haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 carboxyalkyl, alkoxycarbonyl, aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl, optionally substituted aryloxy, optionally substituted heteroalicyclic, or optionally substituted heteroaryl;
• where Formula VIb is as follows:
• and optionally a pharmaceutically acceptable salt or solvate thereof, wherein
• R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted heteroalicyclic, optionally substituted heteroalicyclicalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
• R6 is phenyl, acyl, or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with 1, 2, 3, or 4 R9 groups;
• and
• R9 at each occurrence is independently halo, haloalkyl, haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 carboxyalkyl, alkoxycarbonyl, aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl, aryloxy, optionally substituted heteroalicyclic, or optionally substituted heteroaryl;
• where Formula VII is as follows:
• R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted heteroalicyclic, optionally substituted heteroalicyclicalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
• X is —NR3—;
• R3 is hydrogen;
• R4 is optionally substituted C1-C6 alkyl;
• R5 is hydrogen;
• R6 is acyl and R2 is heterocyclyl-aryl-optionally substituted with 1, 2, 3, or 4 R8 groups;
• or
• R6 is halo and R2 is optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, aryl-C1-6 alkyl, heteroalicyclicalkyl, or heterocyclyl-aryl-;
• where the C3-C7 cycloalkyl, phenyl, phenyl, aryl-C1-6 alkyl, heteroalicyclicalkyl, and heterocyclyl-aryl-groups in R2 are optionally substituted with 1, 2, 3, or 4 R8 groups;
• or
• R6 is phenyl optionally substituted with 1, 2, or 3 halo;
• and R2 is phenyl or heterocyclyl-aryl-;
• where the phenyl and heterocyclyl-aryl-groups in R2 are optionally substituted with 1, 2, 3, or 4 R8 groups;
• or
• R6 is heteroaryl optionally substituted with 1, 2, or 3 halo;
• and R2 is heterocyclyl-aryl-optionally substituted with 1, 2, 3, 4, or 5 R8 groups;
• each R8 at each instance is independently hydroxy, halo, C1-C6 alkyl, haloalkyl, optionally substituted C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxyalkylaminoalkyl, —O—C1-C6alkylheterocyclyl, aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl, optionally substituted heteroalicyclic, optionally substituted heteroalicyclicalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
• where Formula VIIIa is as follows:
• or a pharmaceutically acceptable salt or solvate thereof, wherein
• W1, W2, W3, and W4 are —C(R1)— or W2 and W3 are —C(R1)— and one of W1 and W4 is —N— and the other is —C(R1)—;
• X is —N(R5)—;
• A is aryl, heteroaryl, or heterocycloalkyl where the aryl, heteroaryl, and heterocycloalkyl are optionally substituted with (R2)n1;
• or
• B is aryl, —C1-C6 alkylaryl, heteroaryl, or heterocycloalkyl, where the aryl, C1-C6-alkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with (R3)n2;
• n1 is 0, 1, 2, or 3;
• n2 is or an integer from 1 to 5;
• each R1 is independently hydrogen, C1-C6-alkyl, haloalkyl, C1-C6-alkoxy, haloalkoxy, or —NO2;
• each R2 (when R2 is present) is independently —C1-C6-alkanyl, —C1-C6-alkenyl, —OR6, —N(R7)—C(O)—R6, —N(R7)—C(O)—C0-C6 alkyl-N(R7b)R7a, —OC(O)—C0-C6 alkyl-N(R7)R7a, —C0-C6alkyl-C(O)R6, heterocycloalkyl, aryl, halo, —NO2, or —C0-C6-alkyl-N(R7)R7a, wherein each alkyl, aryl, and heterocycloalkyl groups, each either alone or as part of another group within R2, is independently optionally substituted with one, two, three, four, or five groups selected from C1-C6-alkyl, C1-C6-alkoxy, halo, haloalkyl, and haloalkoxy;
• each R3 (when R3 is present) is independently hydroxy, —NO2, halo, —CN, C1-C6-alkanyl, C2-C6-alkenyl, C1-C6 alkoxy, —C0-C6 alkyl-N(R7)C(O)—C0-C6-alkyl-N(R7b)R7a, —C0-C6-alkyl-N(R7)C(O)—C0-C6-alkyl-N(R7b)C(O)R7a, —C0-C6 alkyl-C(O)N(R7)—C0-C6-alkyl-N(R7)R7a, —C0-C6-alkyl-C(O)N(R7)—C1-C6-alkyl-C(O)OR7a, —C0-C6-alkyl-N(R7)—C(O)—C0-C6-alkyl-(R7), —C0-C6-alkyl-N(R7)—C0-C6-alkyl-N(R7)R7a, —C0-C6-alkyl-N(R7)C(O)—C0-C6-alkyl-N(R7b)—C0-C6-alkyl-N(R7c)R7a, —C0-C6-alkyl-N(R7)C(O)O—C0-C6-alkyl-N(R7b)R7a, —C0-C6-alkyl-N(R7)—C0-C6 alkyl-C(═N(R7b)(R7a))(NR7cR7d), —C0-C6-alkyl-heteroaryl, —C0-C6-alkyl-OR6, —CO0C6-alkyl-C(O)OR6, —C0-C6-alkyl-N(R7)R7a, —C0-C6-alkyl-C(O)—NR7R7a, —C0-C6-alkyl-C(O)—R7, —S(O)2R7, —SO2N(R7)—C0-C6-alkyl-N(R7)R7a, —C0-C6-alkyl-C(O)-heterocycloalkyl (dupe of C(O)R7), —C0-C6-alkyl-C(O)N(R7)—C0-C6-alkyl-heterocycloalkyl, —C0-C6-alkyl-N(R7)C(O)—C0-C6-alkyl-cycloalkyl, —C0-C6-alkyl-N(R7)—C(O)—C0-C6-alkyl-aryl, —C0-C6-alkyl-N(R7)—C(O)—C0-C6-alkyl-heteroaryl, —C0-C6-alkyl-N(R7)C(O)—C0-C6-alkyl-heterocycloalkyl, —C0-C6-alkyl-N(R7)C(O)—C0-C6-alkyl-heterocycloalkyl-aryl, or —N(R7)C(O)R7a, wherein each of the alkyl, alkanyl, alkenyl, cycloalkyl, aryl, alkoxy, heterocycloalkyl, and heteroaryl groups, either alone or as part of another group within R3, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from C1-C6-alkanyl, C1-C6 alkenyl, cycloalkyl, halo, —C(O)—R6, oxo, hydroxy, —C0-C6-alkyl-N(R8)R8a, —C0-C6-alkyl-heterocycloalkyl, —C0-C6-alkyl-aryl, —C0-C6-alkyl-heteroaryl, —C(O)OR6, and hydroxyalkyl;
• R4 is hydrogen;
• R5 is hydrogen;
• R6 and R9 are independently hydrogen, C1-C6-alkyl, aryl, arylalkyl, or cycloalkyl, where each of the —C1-C6-alkyl, aryl, arylalkyl, and cycloalkyl, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from C1-C6-alkoxy, C1-C6-alkyl, and halo;
• and
• R7, R7a R7b, R7c, and R7d are independently hydrogen, —C1-C6-alkanyl, —C1-C6-alkenyl, —OH, —O—C1-C6 alkanyl, —O—C1-C6 alkenyl, —O—C0-C6-alkyl-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl, either alone or part of another group within R7, R7a R7b, R7c, and R7d, is independently optionally substituted with 1, 2, 3, 4, or 5 —NH2, alkylamino, dialkylamino, —S—C1-C6-alkyl, —CN, hydroxy, oxo, C1-C6 alkoxy, C1-C6 alkyl, or halo;
• and where Formula VIIIb is as follows:
• or a pharmaceutically acceptable salt or solvate thereof, wherein
• n1 is one or two;
• and n2 is one or two;
• n3 is 0, 1, or two;
• each R1 is independently hydrogen, C1-C6-alkyl, haloalkyl, C1-C6-alkoxy, haloalkoxy, —NO2, halo, hydroxy, hydroxyalkyl, —CN, cyanoalkyl, or —C0-C6 alkyl-N(R10)R10a where R10 and R10a are independently hydrogen, —C1-C6-alkyl, —OH, —O—C1-C6 alkyl, haloalkyl, or haloalkoxy;
• each R2 (when R2 is present) is independently C1-C6-alkanyl, C1-C6-alkenyl, —OR6, —N(R7)—C(O)—R6, —N(R7)—C(O)—C0-C6 alkyl-N(R7b)R7a, —OC(O)—C0-C6 alkyl-N(R7)R7a, —C0-C6alkyl-C(O)R6, heterocycloalkyl, aryl, halo, —NO2, or —C0-C6-alkyl-N(R7)R7a, wherein each alkyl, aryl, and heterocycloalkyl groups, each either alone or as part of another group within R2, is independently optionally substituted with one, two, three, four, or five groups selected from C1-C6-alkyl, C1-C6-alkoxy, halo, haloalkyl, and haloalkoxy;
• each R3 (when R3 is present) is independently hydroxy, —NO2, halo, —CN, C1-C6-alkanyl, C2-C6-alkenyl, C1-C6 alkoxy, —C0-C6 alkyl-N(R7)C(O)—C0-C6-alkyl-N(R7b)R7a, —C0-C6-alkyl-N(R7)C(O)—C0-C6-alkyl-N(R7b)C(O)R7a, —C0-C6 alkyl-C(O)N(R7)—C0-C6-alkyl-N(R7)R7a, —C0-C6-alkyl-C(O)N(R7)—C1-C6-alkyl-C(O)OR7a, —C0-C6-alkyl-N(R7)—C(O)—C0-C6-alkyl-(R7), —C0-C6-alkyl-N(R7)—C0-C6-alkyl-N(R7)R7a, —C0-C6-alkyl-N(R7)C(O)—C0-C6-alkyl-N(R7b)—C0-C6-alkyl-N(R7c)R7a, —C0-C6-alkyl-N(R7)C(O)O—C0-C6-alkyl-N(R7b)R7a, —C0-C6-alkyl-N(R7)—C0-C6 alkyl-C(═N(R7b)(R7a))(NR7cR7d), —C0-C6-alkyl-heteroaryl, —C0-C6-alkyl-OR6, —C0-C6-alkyl-C(O)OR6, —C0-C6-alkyl-N(R7)R7a, —C0-C6-alkyl-C(O)—NR7R7a, —C0-C6-alkyl-C(O)—R7, —S(O)2R7, —SO2N(R7)—C0-C6-alkyl-N(R7)R7a, —C0-C6-alkyl-C(O)-heterocycloalkyl (dupe of C(O)R7), —C0-C6-alkyl-C(O)N(R7)—C0-C6-alkyl-heterocycloalkyl, —C0-C6-alkyl-N(R7)C(O)—C0-C6-alkyl-cycloalkyl, —C0-C6-alkyl-N(R7)—C(O)—C0-C6-alkyl-aryl, —C0-C6-alkyl-N(R7)—C(O)—C0-C6-alkyl-heteroaryl, —C0-C6-alkyl-N(R7)C(O)—C0-C6-alkyl-heterocycloalkyl, —C0-C6-alkyl-N(R7)C(O)—C0-C6-alkyl-heterocycloalkyl-aryl, or —N(R7)C(O)R7a, wherein each of the alkyl, alkanyl, alkenyl, cycloalkyl, aryl, alkoxy, heterocycloalkyl, and heteroaryl groups, either alone or as part of another group within R3, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from C1-C6-alkanyl, C1-C6 alkenyl, cycloalkyl, halo, —C(O)—R6, oxo, hydroxy, —C0-C6-alkyl-N(R8)R8a, —C0-C6-alkyl-heterocycloalkyl, —C0-C6-alkyl-aryl, —C0-C6-alkyl-heteroaryl, —C(O)OR6, and hydroxyalkyl;
• R4 is hydrogen;
• R5 is hydrogen;
• R6 is hydrogen, C1-C6-alkyl, aryl, arylalkyl, or cycloalkyl, where each of the —C1-C6-alkyl, aryl, arylalkyl, and cycloalkyl, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from C1-C6-alkoxy, C1-C6-alkyl, and halo;
• and
• R7, R7a R7b, R7c, and R7d are independently hydrogen, —C1-C6-alkanyl, —C1-C6-alkenyl, —OH, —O—C1-C6 alkanyl, —O—C1-C6 alkenyl, —O—C0-C6-alkyl-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl, either alone or part of another group within R7, R7a R7b, R7c, and R7d, is independently optionally substituted with 1, 2, 3, 4, or 5 —NH2, alkylamino, dialkylamino, —S—C1-C6-alkyl, —CN, hydroxy, oxo, C1-C6 alkoxy, C1-C6 alkyl, or halo.