US 2017/0320860 A1 · HETEROCYCLIC TRIAZOLE COMPOUNDS AS AGONISTS OF THE APJ RECEPTOR

Abstract

Compounds of Formula I and Formula II, pharmaceutically acceptable salts thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and may have use in treating cardiovascular and other conditions. Compounds of Formula I and Formula II have the following structures: where the definitions of the variables are provided herein.

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 a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S that is unsubstituted or is substituted with 1, 2, or 3 R1a substituents;
R1a in each instance is independently selected from —F, —Cl, —Br, —I, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —CN, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —C2-C6 alkenyl, —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), wherein R1a may also be oxo unless R1 is a 6-membered heterocyclic group that includes one N atom and includes at least one double bond, and further wherein two R1a substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of a 5- or 6-membered heterocyclic R1 group may join to form a 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, or 2 N atoms and may further optionally be substituted with 1 or 2 R1a′ substituent and may include an oxo substituent if the ring is not an aromatic ring and further wherein two R1a substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of a 5- or 6-membered heterocyclic R1 group may join to form a 5 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, or 2 heteroatoms selected from N, O, or S and may further optionally be substituted with 1 or 2 R1a′ substituent and may include an oxo substituent if the ring is not an aromatic ring;
R1a′ is in each instance independently selected from —F, —Cl, —Br, —I, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, C3-C8 cycloalkyl alkyl)-O—(C1-C6 alkyl), —CN, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —C2-C6 alkenyl, 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, 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 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 an unsubstituted C1-C10 alkyl, a C1-C10 alkyl substituted with 1, 2, or 3 R3a substituents, 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, a group of formula -(heterocyclyl)-Q, or -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;
R3a in each instance is independently selected from —F, —CN, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), alkyl)-OH, alkyl)-O—(C1-C6 alkyl), —C2-C6 alkenyl, —C2-C6 alkynyl, —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2;
R3b and R3c are independently selected from —H, —F, —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), perhaloalkyl), alkyl)-OH, 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, —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), (C1-C6 perhaloalkyl), alkyl)-OH, 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, —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), alkyl)-OH, 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, —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), (C1-C6 perhaloalkyl), alkyl)-OH, 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-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 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, and the heterocyclyl R4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R4a substituents, and further wherein the cycloalkyl R4 group is unsubstituted or is substituted with 1, 2, 3, or 4 R4b substituents, and further wherein the straight or branched chain C1-C6 alkyl R4 group is unsubstituted or is substituted with 1, 2, or 3 R4c 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;
R4b 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, oxo, —(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, heterocyclyl, a monocyclic 3-6 membered cycloalkyl group, or a 5 or 6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the heterocyclyl of the —(C1-C6 alkyl)-heterocyclyl and heterocyclyl R4b 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 phenyl and heteroaryl R4b groups are unsubstituted or are substituted with 1 or 2 R4aa substituents;
R4c in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH, oxo, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —S—(C1-C6 alkyl), —S—(C1-C6 haloalkyl), —S—(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, —C(═O)NH(C3-C6 cycloalkyl), —C(═O)N(C1-C6 alkyl)(C3-C6 cycloalkyl), —C(═O)N(C3-C6 cycloalkyl)2, —S(═O)—(C1-C6 alkyl), —S(═O)2—(C1-C6 alkyl), a monocyclic 3-6 membered cycloalkyl group, a 3 to 6 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, or S, a phenyl group, or a 5 or 6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the a monocyclic 3-6 membered cycloalkyl R4c group, the 3 to 6 membered heterocyclyl R4c group, the phenyl R4c group, or the a 5 or 6 membered heteroaryl R4c ring are unsubstituted or are substituted with 1 or 2 R4aa substituents;
and further wherein the 3 to 6 membered cycloalkyl R4c group and the 3 to 6 membered heterocyclyl R4c group may optionally be additionally substituted with an oxo substituent;
and
R4aa in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —S—(C1-C6 alkyl), —S—(C1-C6 haloalkyl), —S—(C1-C6 perhaloalkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, NH(C1-C6 alkyl-OH), —N(C1-C6alkyl-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, —C(═O)NH(C3-C6 cycloalkyl), —C(═O)N(C1-C6 alkyl)(C3-C6cycloalkyl), —C(═O)N(C3-C6 cycloalkyl)2, —S(═O)—(C1-C6 alkyl), or —S(═O)2—(C1-C6 alkyl).

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Heterocyclic triazole compounds as agonists of the apj receptor

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Heterocyclic triazole compounds as agonists of the apj receptor

Life of this patent

Abstract

Claims79