Small molecule antagonists of the apelin receptor for the treatment of disease

A method of treating a disease mediated by apelin in a patient in need thereof, comprising administering to the patient therapeutically effective amount of a compound of formula (I):

• wherein:
• X1 is selected from the group consisting of —O— and —N(R5)—;
• A is selected from the group consisting of alkyl, phenyl and 5- or 6-membered heteroaryl, wherein each phenyl and heteroaryl is independently optionally substituted with from one to three R20;
• B is selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, wherein each phenyl and heteroaryl is independently optionally substituted with from one to three R20;
• Y1 and Y2 are each independently selected from the group consisting of a bond, —C(O)O—, —C(O)—, —CH2O—, —N(R1)—, —C(R2)(R3)— and —S(O)2—;
• Y3 and Y4 are each independently selected from the group consisting of a bond, —S—, —O—, —N(R1)—, —C(R2)(R3)—, —C(O)— and —S(O)2—;
• each R1 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl;
• wherein each alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and heteroaryl is independently optionally substituted with from one to three R21;
• each R2 and R3 is independently selected from the group consisting of hydrogen, halogen, —CN, —N(R4)(R5), alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl;
• wherein each alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and heteroaryl is independently optionally substituted with from one to three R21;
• each R4 and R5 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and heteroaryl;
• or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl;
• and wherein each alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and heteroaryl is independently optionally substituted with from one to three R21;
• each R20 is independently selected from the group consisting of halogen, —NO2, —CN, oxo, —N(R4)(R5), —C(O)—N(R4)(R5), —C(O)-alkyl, —C(O)-cycloalkyl, —C(O)-heterocycloalkyl, —C(O)-phenyl, —C(O)-heteroaryl, —C(O)O-alkyl, —C(O)β-cycloalkyl, —C(O)O-heterocycloalkyl, —C(O)O-phenyl, —C(O)O-heteroaryl, —S(O)2—N(R4)(R5), —S(O)2-alkyl, —S(O)2-cycloalkyl, —S(O)2-heterocycloalkyl, —S(O)2-phenyl, —S(O)2-heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl;
• wherein each alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl is independently optionally substituted with from one to three R21;
• and
• each R21 is independently selected from the group consisting of halogen, —CN, —NH2, —NO2, —C(O)—NH2, —C(O)-alkyl, —C(O)—O-alkyl, alkyl, alkoxy, haloalkyl, haloalkoxy and phenyl;
• or a pharmaceutically acceptable salt, polymorph, solvate, tautomer, or N-oxide thereof.

A compound of formula (II):

• wherein:
• B is selected from the group consisting of phenyl, heterocycloalkyl, and 5- or 6-membered heteroaryl, wherein each phenyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with from one to three R20;
• Y3 and Y4 are each independently selected from the group consisting of a bond, —S—, —O—, —N(R1)—, —C(R2)(R3)—, —C(O)— and —S(O)2—;
• n is 1, 2, or 3;
• each R1 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl;
• wherein each alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and heteroaryl is independently optionally substituted with from one to three R21;
• each R2 and R3 is independently selected from the group consisting of hydrogen, halogen, —CN, —N(R4)(R5), alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl;
• wherein each alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and heteroaryl is independently optionally substituted with from one to three R21;
• each R4 and R5 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and heteroaryl;
• or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl;
• and wherein each alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and heteroaryl is independently optionally substituted with from one to three R21;
• each R6 is independently selected from the group consisting of halogen, —CN, —NO2, —N(R4)(R5), —C(O)—N(R4)(R5), —C(O)-alkyl, —C(O)-cycloalkyl, —C(O)-heterocycloalkyl, —C(O)-phenyl, —C(O)-heteroaryl, —C(O)O-alkyl, —C(O)β-cycloalkyl, —C(O)O-heterocycloalkyl, —C(O)O-phenyl, —C(O)O-heteroaryl, —S(O)2—N(R4)(R5), —S(O)2-alkyl, —S(O)2-cycloalkyl, —S(O)2-heterocycloalkyl, —S(O)2-phenyl, —S(O)2-heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl;
• wherein each alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl is independently optionally substituted with from one to three R21;
• each R20 is independently selected from the group consisting of halogen, —NO2, —CN, oxo, —N(R4)(R5), —C(O)—N(R4)(R5), —C(O)-alkyl, —C(O)-cycloalkyl, —C(O)-heterocycloalkyl, —C(O)-phenyl, —C(O)-heteroaryl, —C(O)O-alkyl, —C(O)β-cycloalkyl, —C(O)O-heterocycloalkyl, —C(O)O-phenyl, —C(O)O-heteroaryl, —S(O)2—N(R4)(R5), —S(O)2-alkyl, —S(O)2-cycloalkyl, —S(O)2-heterocycloalkyl, —S(O)2-phenyl, —S(O)2-heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl;
• wherein each alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl is independently optionally substituted with from one to three R21;
• and
• each R21 is independently selected from the group consisting of halogen, —CN, —NH2, —NO2, —C(O)—NH2, —C(O)-alkyl, —C(O)—O-alkyl, alkyl, alkoxy, haloalkyl, haloalkoxy and phenyl;
• or a pharmaceutically acceptable salt, polymorph, solvate, tautomer, or N-oxide thereof;
• provided that:
• (A) when Y3 is —CH2—;
• Y4 is —S—;
• and B is unsubstituted pyrimidin-2-yl;
• then A is not phenyl, 3-NO2-4-Me-phenyl, 3-NO2-phenyl, 4-Cl-phenyl, 4-NO2-phenyl, 4-CF3-phenyl, 4-Br-phenyl, 4-Me-phenyl, 4-OMe-phenyl, 4-OEt-phenyl, 4-OiPr-phenyl, 4-OBu-phenyl, 4-tBu-phenyl, 4-F-phenyl, 4-SO2NMe2-phenyl, 4-SO2N(CH2)4-phenyl, 3,4-diMe-phenyl, 2-NO2-5-Cl-phenyl, 2-Cl-5-NO2-phenyl, 2-Me-3-NO2-phenyl, 4-Ph-phenyl, 4-SO2NEt2-phenyl, 4-SO2N(CH2)5-phenyl, 4-SO2-morpholine-phenyl, or 2-NO2-4,5-diOMe-phenyl;
• (B) when Y3 is —CH2—;
• Y4 is —S—;
• and B is 4-methyl-pyrimidin-2-yl;
• then A is not 3-NO2-4-Cl-phenyl, 4-SO2N(CH2)4-phenyl, 2-NO2-5-Cl-phenyl, or 2-Cl-5-NO2-phenyl;
• and
• (C) when Y3 is —CH2—;
• Y4 is —S—;
• and B is 4,6-dimethyl-pyrimidin-2-yl;
• then A is not 3-NO2-4-Cl-phenyl, 3-NO2-4-Me-phenyl, 4-SO2NMe2-phenyl, 2-NO2-5-Cl-phenyl, 2-Cl-5-NO2-phenyl, or 2-Me-3-NO2-phenyl.

A compound of formula (III):

• wherein:
• B is selected from the group consisting of phenyl, heterocycloalkyl, and 5- or 6-membered heteroaryl, wherein each phenyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with from one to three R20;
• R6 is selected from the group consisting of halogen, —CN, —NO2, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, and 5- or 6-membered heteroaryl;
• and
• each R20 is independently selected from the group consisting of halogen, oxo, —C(O)-phenyl, alkyl, alkoxy, haloalkoxy, and phenyl;
• or a pharmaceutically acceptable salt, polymorph, solvate, tautomer, or N-oxide thereof;
• provided that when B is unsubstituted pyrimidin-2-yl;
• then R6 is not —F, —Cl, —Br, —NO2, —CF3, -Me, —OMe, —OEt, -OiPr, —OBu, or -tBu.