US 11,807,624 B2
Substituted pyrimidinones as agonists of the APJ receptor
Vatee Pattaropong, Bedford, MA (US); and Philip Dean Ramsden, Acton, MA (US)
Assigned to Amgen Inc., Thousand Oaks, CA (US)
Appl. No. 17/051,212
Filed by AMGEN INC., Thousand Oaks, CA (US)
PCT Filed Apr. 30, 2019, PCT No. PCT/US2019/029780
§ 371(c)(1), (2) Date Oct. 28, 2020,
PCT Pub. No. WO2019/213006, PCT Pub. Date Nov. 7, 2019.
Claims priority of provisional application 62/665,244, filed on May 1, 2018.
Prior Publication US 2021/0246118 A1, Aug. 12, 2021
Int. Cl. C07D 239/545 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 403/12 (2006.01); C07D 405/14 (2006.01)
CPC C07D 401/14 (2013.01) [C07D 239/545 (2013.01); C07D 401/12 (2013.01); C07D 403/12 (2013.01); C07D 405/14 (2013.01)] 35 Claims
 
1. A compound of Formula I or Formula II:

OG Complex Work Unit Chemistry
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 selected from R1a, R1b, R1c, R1d, R1e, R1f, or R1g;
R1a is an unsubstituted C1-C8 straight or branched chain alkyl or R1a is a C1-C8 straight or branched chain alkyl substituted with 1, 2, or 3 R1a′ substituents;
R1b 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 R1b′ substituents, a C5-C8 polycyclic cycloalkyl substituted with 1, 2, or 3 R1b′ substituents, or a monocyclic C4-C8 cycloalkenyl substituted with 1, 2, or 3 R1b′ substituents;
R1c 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 R1c′ substituents;
R1d is a phenyl group that is unsubstituted or is substituted with 1, 2, or 3 R1d′ substituents;
R1e is an unsubstituted furanyl, or is a furanyl substituted with 1, 2, or 3 R1e′ substituents;
R1f is a 5- or 6-membered heteroaryl group that is unsubstituted or is substituted with 1, 2, or 3 R1f substituents, wherein the 5-membered heteroaryl group includes 1, 2, or 3 heteroatoms independently selected from N, O, and S and the 6-membered heteroaryl group includes 2 or 3 N heteroatoms; and further wherein if the 5-membered heteroaryl includes only 1 hetero atom, then it is selected from N or S;
R1g is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R1g′ substituents;
R1a′ in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —C2-C4 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), —S(═O)2—(C1-C6 alkyl), a monocyclic or bicyclic C6-C10 aryl group, —O-(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, —O-(monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S), C3-C8 cycloalkyl, —O—(C3-C8 cycloalkyl), —O—(C1-C6 alkyl)-(C3-C8 cycloalkyl), —O—(C1-C6 alkyl)-(monocyclic or bicyclic C6-C10 aryl group), O—(C1-C6 alkyl)-(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 3 to 8 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, —O-(heterocyclyl group containing 3 to 8 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, or S), or an —O—(C1-C6 alkyl)-(heterocyclyl group containing 3 to 8 ring members and 1, 2, or 3 heteroatoms independently selected from N, O, or S), wherein the C6-C10 aryl of any of the R1a′ groups that include a C6-C10 aryl group, the heteroaryl of any of the R1a′ groups that include a heteroaryl group, the C3-C8 cycloalkyl of any of the R1a′ groups that include a —C3-C8 cycloalkyl group, and the heterocyclyl of any of the R1a′ groups that include a heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R1a″ substituents; and further wherein the C3-C8 cycloalkyl of any of the R1a′ groups that include a —C3-C8 cycloalkyl group, and the heterocyclyl of any of the R1a′ groups that include a heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the S atom of the heterocyclyl of any of the R1a′ groups that include a heterocyclyl group may contain one or two oxo substituents, and still further wherein, the heteroaryl of any of the R1a′ groups that include a heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;
R1a′″ is in each instance 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), —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, or —S(═O)2—(C1-C6 alkyl);
R1b′ in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH, ═O, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), perhaloalkyl), —C1-C6 alkyl, —C1-C6 haloalkyl, perhaloalkyl, alkenyl, ═CH2, ═CH—(C1-C6 alkyl), —(C1-C6 alkyl)-OH, alkyl)-O—(C1-C6 alkyl), —(C1-C6 haloalkyl)-OH, haloalkyl)-O—(C1-C6 alkyl), —(C1-C6 perhaloalkyl)-OH, perhaloalkyl)-O—(C1-C6 alkyl), —O—(C1-C6 alkyl)-OH, alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl)-OH, 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, —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 R1b′ phenyl and R1b′ heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3, R1b″ substituents; and further wherein two R1b′ groups on a single carbon atom of a monocyclic C3-C8 cycloalkyl R1b 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;
R1b″ is in each instance, independently selected from —F, —Cl, —Br, —I, —CN, —OH, O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), perhaloalkyl), —C1-C6 alkyl, —C1-C6 haloalkyl, perhaloalkyl, alkenyl, alkyl)-OH, alkyl)-O—(C1-C6 alkyl), —(C1-C6 haloalkyl)-OH, haloalkyl)-O—(C1-C6 alkyl), —(C1-C6 perhaloalkyl)-OH, perhaloalkyl)-O—(C1-C6 alkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl)-OH, 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, —NHS(═O)2—(C1-C6 alkyl), or —S(═O)2—(C1-C6 alkyl);
R1c′ in each instance is independently selected from —F, —Cl, —Br, —I, —C1-C6 alkyl, —C1-C6 haloalkyl, perhaloalkyl, alkyl)-O—(C1-C6 alkyl), —CN, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), perhaloalkyl), alkenyl, alkyl)-OH, alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl)-OH, 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, —NHS(═O)2—(C1-C6 alkyl), or —S(═O)2—(C1-C6 alkyl), wherein R1c′ may also be oxo unless R1c is a 6-membered heterocyclic group that includes one N atom and includes at least one double bond, and further wherein two R1c′ substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of a 5- or 6-membered heterocyclic R1c 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 R1c″ substituent and may include an oxo substituent if the ring is not an aromatic ring and further wherein two R1c′ substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of a 5- or 6-membered heterocyclic R1c 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 R1c″ substituent and may include an oxo substituent if the ring is not an aromatic ring;
R1c″ 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), perhaloalkyl), —C2-C6 alkenyl, alkyl)-OH, 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);
R1d′ in each instance is independently selected from —F, —Cl, —Br, —I, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, alkyl)-OH, haloalkyl)-OH, perhaloalkyl)-OH, alkyl)-O—(C1-C6 alkyl), —CN, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), perhaloalkyl), —C2-C6 alkenyl, alkyl)-OH, 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, -Q=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), —S(═O)2NH2, —S(═O)2NH(C1-C6 alkyl), —S(═O)2N(C1-C6 alkyl)2, or —O— phenyl, wherein the phenyl of the —O-phenyl R1d′ group may optionally be substituted with 1 or 2 R1d″ substituents; and further wherein two R1d′ substituents on adjacent carbon atoms of the phenyl R1d group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S and may further optionally be substituted with 1 or 2 R1d′″ substituent and may include an oxo substituent if the ring is not an aromatic ring;
R1d″ 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, —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl)-OH, 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 or —S(═O)2—(C1-C6 alkyl);
R1d″′ is in each instance 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, or —S(═O)2—(C1-C6 alkyl);
R1e′ 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), or —C(═O)N(C1-C6 alkyl)2;
R1f 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, —S(═O)2—(C1-C6 alkyl), or —CH(OH)-phenyl, wherein the phenyl of the —CH(OH)-phenyl may optionally be substituted with one or two R1f″ substituents; and further wherein two R1f′ substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of the 5- or 6-membered heteroaryl R1f group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S and may further optionally be substituted with 1 or 2 R1f′ substituent and may include an oxo substituent if the ring is not an aromatic ring;
R1f′ is in each instance independently selected from —F, —Cl, —Br, —I, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, C3-C8 cycloalkyl —(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 or —S(═O)2—(C1-C6 alkyl);
R1f″ is in each instance 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, or —S(═O)2—(C1-C6 alkyl);
R1g′ 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 haloalkyl-OH, —C1-C6 perhaloalkyl-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, phenyl, —C(═O)-(heterocyclyl), a C3-C6 cycloalkyl group or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, or S;
R2 is selected from —H, or C1-C4 alkyl;
R3 is selected from an unsubstituted C1-C10 alkyl, a C1-C10 alkyl substituted with 1, 2, or 3 R3a substituents, an unsubstituted C3-C8 cycloalkyl, a C3-C8 cycloalkyl 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 —(CR3b═CR3c)-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, -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;
R3a in each instance is independently selected from —F, —Cl, —CN, —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), 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, —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 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), —(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 R3h—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, 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, —Br, —I, —CN, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, alkyl)-OH, alkyl)-O—(C1-C6 alkyl), —OH, —O—(C1-C6 alkyl), haloalkyl), 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, oxo, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), perhaloalkyl), —S—(C1-C6 alkyl), —S—(C1-C6 haloalkyl), 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 3 to 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 3 to 6 membered cycloalkyl R4b group, the 3 to 6 membered heterocyclyl R4b group, the phenyl R4b group, and the a 5 or 6 membered heteroaryl R4b ring are unsubstituted or are substituted with 1 or 2 R4c substituents; and further wherein the 3 to 6 membered cycloalkyl R4b group and the 3 to 6 membered heterocyclyl R4b group may optionally be additionally substituted with an oxo substituent; and
R4c 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), or —C(═O)N(C1-C6 alkyl)2.