Methods for the synthesis of complement factor d inhibitors

A method of preparing a compound of formula (I), comprising reacting a compound of formula (II) with a weak base in a water-miscible organic solvent:

• wherein
• R1 is H;
• halo;
• OH;
• NH2;
• cyano;
• optionally substituted C1-C6 alkyl;
• optionally substituted C2-C6 alkenyl;
• optionally substituted 3- to 8-membered heterocyclyl;
• —C(O)NRaRa′, wherein each of Ra and Ra′ is, independently, H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C3-C8 cycloalkyl;
• —C(O)Rb;
• —OC(O)Rb;
• or —C(O)ORb;
• wherein Rb, in each instance, is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted C3-C8 carbocyclyl;
• each of R2 and R3 is, independently, H or optionally substituted C1-C6 alkyl;
• X1 is N or CRc, wherein Rc is H, halo, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy;
• each of X2 and X5 is independently N or CRd, wherein each Rd is independently selected from H, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 carbocyclyl, and optionally substituted 5- to 8-membered heteroaryl;
• and
• each of X3 and X4 is independently selected from N, CRe, and CRf, wherein Re is selected from H, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and —C(O)ORg, wherein Rg is H or optionally substituted C1-C6 alkyl;
• and Rf is selected from optionally substituted C4-C10 aryl, optionally substituted 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally substituted 4- to 10-membered saturated or unsaturated non-aromatic heterocyclyl containing 1-4 heteroatoms selected from N, O, and S;
• wherein at least one of X3 and X4 is CRf.