6-heteroaryloxy- or 6-aryloxy-quinoline-2-carboxamides and method of use

A compound of formula (I):

• or a pharmaceutically acceptable salt, ester, amide, or radiolabelled form thereof, wherein:
• R1 is selected from the group consisting of phenyl and monocyclic 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halogen, cyano, —NO2, —OR1a, —OC(O)R1a, —OC(O)N(Rb)(R3a), —SR1a, —S(O)R2a, —S(O)2R2a, —S(O)2N(Rb)(R3a), —C(O)R1a, —C(O)OR1a, —C(O)N(Rb)(R3a), —N(Rb)(R3a), —N(Ra)C(O)R1a, —N(Ra)C(O)O(R1a), —N(Ra)C(O)N(Rb)(R3a), —(CR4aR5a)m—NO2, —N(Rb)S(O)2(R2a), —(CR4aR5a)m—OR1a, —(CR4aR5a)m—OC(O)R1a, —(CR4aR5a)m—OC(O)N(Rb)(R3a), —(CR4aR5a)m—SR1a, —(CR4aR5a)m—S(O)R2a, —(CR4aR5a)m—S(O)2R2a, —(CR4aR5a)m—S(O)2N(Rb)(R3a), —(CR4aR5a)m—C(O)R1a, —(CR4aR5a)m—C(O)OR1a, —(CR4aR5a)m—C(O)N(Ra)(R3a), —(CR4aR5a)m—N(Rb)(R3a), —(CR4aR5a)m—N(Ra)C(O)R1a, —(CR4aR5a)m—N(Ra)C(O)O(R1a), —(CR4aR5a)m—N(Ra)C(O)N(Rb)(R3a), (CR4aR5a)m—N(Rb)S(O)2(R2a), cyano-C1-C6-alkyl, and halo-C1-C6-alkyl;
• Ra and Rb, at each occurrence, are each independently hydrogen, C1-C6-alkyl, or halo-C1-C6-alkyl;
• R1a and R3a, at each occurrence, are each independently hydrogen, C1-C6-alkyl, or halo-C1-C6-alkyl;
• R2a, at each occurrence, is independently C1-C6-alkyl or halo-C1-C6-alkyl;
• R4a and R5a, at each occurrence, are each independently hydrogen, halogen, C1-C6-alkyl, or halo-C1-C6-alkyl;
• m, at each occurrence, is independently 1, 2, 3, 4, or 5;
• R2 is selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, and -G2;
• R3 is selected from the group consisting of hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, —(CR4bR5b)n—NO2, —(CR4bR5b)n—OR1b, —CH[(CR4bR5b)n—OR1b]2, —(CR4bR5b)n—OC(O)R1b, —(CR4bR5b)n—OC(O)N(Rb)(R3b), —(CR4bR5b)n—SR1b, —(CR4bR5b)n—S(O)2R2b, —(CR4bR5b)n—S(O)2N(Rb)(R3b), —(CR4bR5b)n—C(O)R1b, —(CR4bR5b)n—C(O)OR1b, —(CR4bR5b)n—C(O)N(Rb)(R3b), —(CR4bR5b)n—C(O)N(Rb)(—(CR4bR5b)n—OR1b), —(CR4bR5b)n—C(O)N(Rb)(G4), —(CR4bR5b)n—C(O)N(Rb)(G3), —(CR4bR5b)n—C(O)G4, —(CR4bR5b)n—N(Rb)(R3b), —(CR4bR5b)n—N(Rb)(G3), —(CR4bR5b)n—N(Ra)C(O)R1b, —(CR4bR5b)n—N(Rb)S(O)2R2b, —S(O)2R2b, —(CR4bR5b)n—N(Ra)C(O)O(R1b), —(CR4bR5b)n—N(Ra)C(O)N(Rb)(R3b), -G2, —(CR4bR5b)n-G4, -G2-G6, -G1, —(CR4bR5b)n-G3, —CH[C(O)N(Rb)(R3b)][—(CR4bR5b)n-G3], cyano-C1-C6-alkyl, and halo-C1-C6-alkyl;
• R1b and R3b, at each occurrence, are each independently hydrogen, C1-C6-alkyl, or halo-C1-C6-alkyl;
• R2b, at each occurrence, is independently C1-C6-alkyl or halo-C1-C6-alkyl;
• R4b and R5b, at each occurrence, are each independently hydrogen, halogen, C1-C6-alkyl, or halo-C1-C6-alkyl;
• n, at each occurrence, is independently 1, 2, 3, 4, or 5;
• G1 and G3 are each independently aryl or heteroaryl;
• wherein G1 and G3 are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, cyano, halo-C1-C6-alkyl, halogen, nitro, —N(Rc)2, —N(Rc)C(O)Rc, —ORc, —C(O)Rc, —C(O)ORc, —C(O)N(Rc)2, —SO2Rd, and —SO2N(Rc)2;
• G2, G4 and G6 are each independently 3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or 4-10-membered-heterocycle;
• wherein G2, G4 and G6 are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, benzyl, cyano, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, halogen, nitro, oxo, —N(Rc)2, —N(Rc)C(O)Rc, —ORc, —C(O)Rc, —C(O)ORc, —C(O)N(Rc)2, —SO2Rd, —SO2N(Rc)2, and phenyl, wherein phenyl and the phenyl ring of benzyl are optionally substituted with 1, 2, 3, or 4 C1-C6-alkyl, halogen, or C1-C6-alkoxy;
• Rc at each occurrence, is independently hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, or halo-C1-C6-alkyl;
• wherein said aryl, the aryl of aryl-C1-C6-alkyl, the cycloalkyl, and the cycloalkyl of cycloalkyl-C1-C6-alkyl are independently unsubstituted or substituted with 1, 2 3, 4, or 5 substituents independently selected from the group consisting of C1-C6-alkyl, halo-C1-C6-alkyl, and halogen;
• Rd is C1-C6-alkyl or halo-C1-C6-alkyl;
• or
• R2, R3 and the nitrogen atom to which they are attached form a 4-8-membered-monocylic heterocycle, 6-11-membered-bicyclic heterocycle, 10-12-membered-tricyclic heterocycle, 7-11-membered-spirocyclic heterocycle or 8-11-membered-bicyclic heteroaryl comprised of a monocyclic heterocycle fused to a monocyclic heteroaryl, wherein said 4-8-membered monocyclic heterocycle, said 6-11-membered-bicyclic heterocycle, said, 10-12-membered-tricyclic heterocycle, said 7-11-membered-spirocyclic heterocycle and said 8-11-membered-bicyclic heteroaryl are unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halogen, cyano, —NO2, —OR1c, —O—(CR4cR5c)p—OR1c, —OG13, —OC(O)R1c, —OC(O)N(Rb)(R3c), —SR1c, —S(O)R2c, —S(O)2R2c, —S(O)2G13, —S(O)2G14, —S(O)2N(Rb)(R3c), —S(O)2—(CR4cR5c)p—C(O)OR1c, —S(O)2—(CR4cR5c)p-G14, —C(O)R1c, —C(O)G14, —C(O)OR1c, —C(O)N(Rb)(R3c), —N(Rb)(R3c), —N(Ra)C(O)R1c, —N(Ra)C(O)G14, —N(Ra)C(O)O(Rc), —N(Ra)C(O)N(Rb)(R3c), —(CR4cR5c)p—NO2, —N(Rb)S(O)2(R2c), —N(Rb)S(O)2(G13), —(CR4cR5c)p—OR1c, —(CR4cR5c)p—O—(CR4cR5c)p—OR1c, —(CR4cR5c)p—OC(O)R1c, —(CR4cR5c)p—OC(O)N(Rb)(R3c), —(CR4cR5c)p—SR1c, —(CR4cR5c)p—S(O)R2c, —(CR4cR5c)p—S(O)2R2c, —(CR4cR5c)p—S(O)2N(Rb)(R3c), —(CR4cR5c)p—C(O)R1c, —(CR4cR5c)p—C(O)OR1c, —(CR4cR5c)p—C(O)N(Ra)(R3c), —(CR4cR5c)p—N(Rb)(R3c), —(CR4cR5c)p—N(Ra)C(O)R1c, —(CR4cR5c)p—N(Ra)C(O)O(R1c), —(CR4cR5c)p—N(Ra)C(O)O(CH2G13), —(CR4cR5c)p—N(Ra)C(O)N(Rb)(R3c), —(CR4cR5c)p—N(Rb)S(O)2(R2c), -G11, —(CR4cR5c)p-G13, —(CR4cR5c)p—OG13, -G12, —(CR4cR5c)p-G14, cyano-C1-C6-alkyl, oxo, C1-C6-alkoxyimino and halo-C1-C6-alkyl;
• R1c and R3c, at each occurrence, are each independently hydrogen, C1-C6-alkyl, or halo-C1-C6-alkyl;
• R2c, at each occurrence, is independently C1-C6-alkyl or halo-C1-C6-alkyl;
• R4c and R5c, at each occurrence, are each independently hydrogen, halogen, C1-C6-alkyl, or halo-C1-C6-alkyl;
• p, at each occurrence, is independently 1, 2, 3, 4, or 5;
• G11 and G13 are each independently phenyl or 5-6-membered-heteroaryl;
• wherein G11 and G13 are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, cyano, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkyl, halogen, nitro, —N(Re)2, —N(Re)C(O)Re, —ORe, —C(O)Re, —C(O)ORe, —C(O)N(Re)2, —SO2Rf, and —SO2N(Re)2;
• G12, and G14 are each independently 3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or 4-10-membered-heterocycle, wherein G12 and G14 are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, benzyl, cyano, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, halogen, nitro, oxo, —N(Re)2, —N(Re)C(O)Re, —N(Re)S(O)2Rf, —ORe, —C(O)Re, —C(O)ORe, —C(O)N(Re)2, —SO2Rf, —SO2N(Re)2, and phenyl, wherein phenyl and the phenyl ring of benzyl are optionally substituted with C1-C6-alkyl, halogen, or C1-C6-alkoxy;
• Re at each occurrence, is independently hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, or halo-C1-C6-alkyl;
• wherein said aryl, the aryl of aryl-C1-C6-alkyl, the cycloalkyl, and the cycloalkyl of cycloalkyl-C1-C6-alkyl are independently unsubstituted or substituted with 1, 2 3, 4, or 5 substituents independently selected from the group consisting of C1-C6-alkyl, halo-C1-C6-alkyl, and halogen;
• and
• Rf is C1-C6-alkyl or halo-C1-C6-alkyl.