Preparation and methods of use for ortho-aryl 5-membered heteroaryl-carboxamide containing multi-targeted kinase inhibitors

A compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• wherein
• A is C or N;
• B, D, and E are each independently selected from CR0, N, O, and S;
• R0 is selected from H, —F, —Cl, —CH3, —C2-C4 linear or branched alkyl, —C2-C4 alkenyl, —C2-C4 alkynyl, —CHRARB, —Y, —CO(CH2)nY, —(CH2)n—, NRARB, —[O—(CH2)2]nY, —(CH2)nSO2NRARB, —S(O)m—(CH2)m—R1, —S(O)mR1, —NRARB, —OR2, —CH2—F, —CH2[18]F, —CHF2, —CHF[18]F, —CH[18]F2, —CF3, —CF2[18]F, —CF[18]F2, and —C[18]F3;
• provided that Ro is not CF3 when A, B, D, and E form a 1H-imidazole ring;
• Ar is a 6-membered substituted aryl, a 6-membered optionally substituted heteroaryl, a 5 membered optionally substituted heteroaryl, or a 5,6-fused bicyclic optionally substituted heteroaryl ring system;
• R1 is independently H, CH3, —CH2CH3, or cyclopropyl;
• R2 is independently H, —CH3, —(CH2)n—CH3, or —(CH2)n—NRARB;
• RA and RB are each independently H, CH3, —CH2CH3, or cyclopropyl;
• RA and R taken together form a 3-6 membered carbocyclic ring system or 5-7 membered saturated heterocyclic ring system;
• Y is —CHR1R2, —CN, —COR1, CONRARB, —OR1, —NRARB, —NR1COR2, —S(O)mR1, —SO2NRARB, —[O—(CH2)2]n—CH2F, —S(O)m[11]CH3, —[O—(CH2)2]n—CH218F, —CH2—F;
• —CH2[18]F, —CHF2, —CHF[18]F, —CH[18]F2, —CF3, —CF2[18]F, —CF[18]F2, or —C[18]F3;
• m is 0, 1, or 2;
• n is 1, 2, or 3;
• G is an appropriate group that interacts with the Gatekeeper region in the ATP binding site of a specific kinase or profile of kinases of interest;
• L is a linker group or ring system;
• and
• (H) is an appropriate group that interacts with the Hinge—region in the ATP binding site of a specific kinase or profile of kinases of interest.