Cycloalkyl substituted triazole compounds as agonists of the apj receptor

A compound of Formula I or Formula II:

• or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof,
• wherein:
• R1 is an unsubstituted monocyclic C3-C8 cycloalkyl, an unsubstituted C5-C8 polycyclic cycloalkyl, an unsubstituted monocyclic C4-C8 cycloalkenyl, a monocyclic C3-C8 cycloalkyl substituted with 1, 2, 3, or 4 R1a substituents, a C5-C8 polycyclic cycloalkyl substituted with 1, 2, or 3 R1a substituents, or a monocyclic C4-C8 cycloalkenyl substituted with 1, 2, or 3 R1a substituents;
• R1a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH, ═O, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —C2-C4 alkenyl, ═CH2, ═CH—(C1-C6 alkyl), —(C1-C6 alkyl)-OH, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 haloalkyl)-OH, —(C1-C6 haloalkyl)-O—(C1-C6 alkyl), —(C1-C6 perhaloalkyl)-OH, —(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl)-OH, —O—(C1-C6 haloalkyl)-O—(C1-C6 alkyl), —O—(C1-C6 perhaloalkyl)-OH, —O—(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1-C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, —NHS(═O)2—(C1-C6 alkyl), —S(═O)2—(C1-C6 alkyl), a phenyl group, or a monocyclic heteroaryl group with 5 or 6 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the R1a phenyl and R1a heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3, R1a′ substituents;
• and further wherein two R1a groups on a single carbon atom of a monocyclic C3-C8 cycloalkyl R1 group may join together with the carbon atom to which they are attached to form a heterocyclic ring having 3 to 6 members of which 1 or 2 are heteroatoms independently selected from O, N, and S;
• R1a′ is in each instance, independently selected from —F, —Cl, —Br, —I, —CN, —OH, O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —C2-C4 alkenyl, —(C1-C6 alkyl)-OH, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 haloalkyl)-OH, —(C1-C6 haloalkyl)-O—(C1-C6 alkyl), —(C1-C6 perhaloalkyl)-OH, —(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl)-OH, —O—(C1-C6 haloalkyl)-O—(C1-C6 alkyl), —O—(C1-C6 perhaloalkyl)-OH, —O—(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1-C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, —NHS(═O)2—(C1-C6 alkyl), or —S(═O)2-(C1-C6 alkyl);
• R2 is selected from —H, or C1-C4 alkyl or is absent in the compounds of Formula II;
• R3 is selected from a group of formula —(CR3bR3c)-Q, a group of formula —(CR3dR3e)—(CR3fR3g)-Q, a group of formula —(CR3dR3e)—(CR3fR3g)—C(═O)-Q a group of formula —(CR3dR3e)—(CR3fR3g)—CH(OH)-Q, a group of formula —(CR3dR3e)—(CR3fR3g)—(CR3fR3g)-Q, a group of formula —(C3-C8 cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R3h substituents, and further wherein the C3-C8 cycloalkyl of the —(C3-C8 cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R3h substituents;
• R3b and R3c are independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2;
• R3d and R3e are independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —(C1-C6 alkyl)-OH, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-phenyl, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2;
• R3f and R3g are independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —(C1-C6 alkyl)-OH, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C2-C6 alkenyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2;
• R3h in each instance is independently selected from —F, —Cl, —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)—(C1-C6 alkyl), —C(═O)—(C3-C6 cycloalkyl), —C(═O)—O—(C1-C6 alkyl), oxo, or —C(═O)-(heterocyclyl), wherein the heterocyclyl group of the Rh—C(═O)-(heterocyclyl) has 5 or 6 ring members of which 1 or 2 are heteroatoms independently selected from N, or S or has 3 or 4 ring members of which 1 is a heteroatom selected from N, O, or S;
• Q is a monocyclic or bicyclic C6-C00 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C3-C8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C6-C10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 RQ substituents;
• and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;
• RQ in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(═O)(C1-C6 alkyl), —C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1-C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, —S(═O)2—(C1-C6 alkyl), —(C1-C6 alkyl)-OH, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NH2, —(C1-C6 alkyl)-NH—(C1-C6 alkyl), —(C1-C6 alkyl)-N—(C1-C6 alkyl)2, phenyl, a heterocyclyl group, a —(C1-C6 alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the RQ heterocyclyl and —(C1-C6 alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the —(C1-C6 alkyl)heterocyclyl RQ groups may be further substituted with one or two oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C1-C6 alkyl, or —C(═O)—(C1-C6 alkyl);
• R4 is selected from a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C1-C6 alkyl group, wherein the C6-C10 aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R4a substituents, and further wherein the straight or branched chain C1-C6 alkyl R4 group is unsubstituted or is substituted with 1, 2, or 3 R4b substituents;
• R4a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —(C1-C6 alkyl)-OH, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, NH(C1-C6 alkyl-OH), —N(C1-C6 alkyl-OH)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1-C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, phenyl, —S(═O)2—(C1-C6 alkyl), —(C1-C6 alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the —(C1-C6 alkyl)-heterocyclyl and heterocyclyl R4a groups is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S, and is unsaturated or partially unsaturated and is optionally substituted with 1 or 2 oxo substituents, and further wherein the heterocyclyl of the R4 group may be further substituted with 1 oxo substituent;
• and
• R4b in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, NH(C1-C6 alkyl-OH), —N(C1-C6 alkyl-OH)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1-C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, or, —S(═O)2—(C1-C6 alkyl);
• wherein if R1 is an unsubstituted cyclopropyl, if R4 is an unsubstituted cyclopropyl group, or if R4 is a substituted or unsubstituted straight or branched chain C1-C6 alkyl group, then at least one of the following is true:
• (a) if R4 is an unsubstituted cyclopropyl group, then R3 is a group of formula -(heterocyclyl)-Q or R3 is a group of formula —(CR3dR3e)—(CR3fR3g)-Q and at least one of R3d, R3e, R3f, or R3g is not —H;
• (b) if R1 is an unsubstituted cyclopropyl, then R4 is a substituted or unsubstituted monocyclic or bicyclic C6-C10 aryl group, a substituted or unsubstituted monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, or is a substituted or unsubstituted monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group;
• or
• (c) if R4 is a substituted or unsubstituted straight or branched chain C1-C6 alkyl group, then R3 is a group of formula -(heterocyclyl)-Q or R3 is a group of formula —(CR3dR3e)—(CR3fR3g)-Q and at least one of R3d, R3e, R3f, or R3g is not —H.