RAF inhibitor compounds and methods

A compound selected from Formulas Ia and Ib:

• and stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein:
• the A-ring is:
• (i) a 5 or 6 membered heterocyclic ring having one or two heteroatoms independently selected from O, N, and S, (ii) a 5 or 6 membered carbocyclic ring optionally fused to a 5 or 6 membered heterocycle, or (iii) a phenyl ring, wherein said heterocyclic, carbocyclic and phenyl rings are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R20, —C(═Y)OR20, —C(═Y)NR20R21, NR20R21, —NR20C(═Y)R21, —NR20C(═Y)OR21, —NR23C(═Y)NR20R21, ═NOR20, ═NR20, ═N+(O)OR20, ═NNR20R21, ═O, —OR20, —OC(═Y)R20, OC(═Y)OR20, OC(═Y)NR20R21, —OS(O)2(OR20), —OP(═Y)(OR20)(OR21), —OP(OR20)(OR21), —P(═Y)(OR20)(OR21), —P(═Y)(OR)NR20R21, ═S, —SR20, —S(O)R20, —S(O)2R20, —S(O)2NR20R21, —S(O)(OR20), —S(O)2(OR20), —SC(═Y)R20, —SC(═Y)OR20, ——SC(═Y)NR20R21, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, and a protecting group, and wherein said alkyl, alkenyl, alkynyl, aryl, carbocyclyl and heterocyclyl are optionally and independently substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R20, —C(═Y)OR20, —C(═Y)NR20R21, NR20R21—NR20C(═Y)R21, —NR20C(═Y)OR21, —NR21C(═Y)NR20R21, —OR20, —OC(═Y)R20, —OC(═Y)OR20, —C(═Y)NR20R21, —OS(O)2(OR20), —OP(═Y)(OR20)(OR21), —OP(OR20)(OR21), —P(═Y)(OR20)(O21), —P(═Y)(OR)NR20R21, —SR20, —S(O)R20, —S(O)2R20, —S(O)2NR20R21, —S(O)(OR20), —S(O)2(OR20), —SC(═Y)R20, —SC(═Y)OR20, —SC(═Y)NR20R21, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C3-C12 carbocyclyl, C2-C20 heterocyclyl;
• X is selected from a C2-C20 heterocyclyl, a C3-C12 carbocyclyl, and a C6-C20 aryl, wherein said heterocycle, carbocyclyl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R20, —C(═Y)OR20, —C(═Y)NR20R21, —NR20R21, —NR20C(═Y)R21, —NR20C(═Y)OR21, —NR23C(═Y)NR20R21, —OR20, —OC(═Y)R20, —OC(═Y)OR20, —OC(═Y)NR20R21, —OS(O)2(OR20), —OP(═Y)(OR20)(OR21), —OP(OR20)(OR21)—P(═Y)(OR20)(OR21), —P(═Y)(OR23)NR20R21, —SR20, —S(O)R20, —S(O)2R20, —S(O)2NR20R21, —S(O)(OR20), —S(O)2(OR21), —SC(═Y)R20, —SC(═Y)OR20, —SC(═Y)NR20R21, 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C6-C20 aryl, and C2-C20 heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR20, NR20R21 —SR20, —S(O)R20, —S(O)2R20, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl;
• R1 is selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (C1-C8 alkyl)NR20R21, a C2-C20 heterocyclyl, a C3-C12 carbocyclyl, and a C6-C20 aryl, wherein said alkyl, alkenyl, alkynyl, heterocycle, carbocyclyl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R20, —C(═Y)OR20, —C(═Y)NR21R21, —NR20R21, OR20, CN, —C(═O)NR20R21, —C(═O)OR20, alkyl, (C1-C8 alkyl)NR20R21, and heterocyclyl;
• R2 is selected from H, F, Cl, Br, I, —C(═Y)R20, —C(═Y)OR20, —C(═Y)NR20R21, —OR20, —OC(═Y)R20, —OC(═Y)OR20, —OC(═Y)NR20R21, —OS(O)2(OR20), —OP(═Y)(OR20)(OR21), —OP(OR20)(OR21), —P(═Y)(OR20)(OR21), —P(═Y)(OR)NR20R21, —SR20, —S(O)R20, —S(O)2R20, —S(O)2NR20R21, —S(O)(OR20), —S(O)2(OR20), —SC(═Y)R20, —SC(═Y)OR20, —SC(═Y)NR20R21, 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C6-C20 aryl, and C2-C20 heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR20, NR20R21 —SR20, —S(O)R20, —S(O)2R20, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl,
• or R1 and R2 of Formula Ia together with the atoms to which they are attached optionally form a saturated, partially unsaturated or aromatic 5 or 6 membered fused heterocycle ring having at least two heteroatoms independently selected from O, N and S, wherein said heterocycle ring is optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R20, —C(═Y)OR20, —C(═Y)NR20R21, —NR20R21, —NR20C(═Y)R21, —NR20C(═Y)OR21, —NR23C(═Y)NOR21, —OR20, —OC(═Y)R20, —OC(═Y)OR20, —OC(═Y)NR20R21, —OS(O)2(OR20), —OP(═Y)(OR20)(OR21), —OP(OR21)(OR21), —P(═Y)(OR20)(OR21), —P(═Y)(OR23)NR20R21, —SR20, —S(O)R20, —S(O)2R21, —S(O)2NR20R21, —S(O)(OR20), —S(O)2(OR20), —SC(═Y)R20, —SC(═Y)OR20, —SC(═Y)NR20R21, 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C6-C20 aryl, and C2-C20 heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR20, NR20R21—SR20, —S(O)R20, —S(O)2R20, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl;
• R3, R4, and R5 are independently selected from H, F, Cl, Br, I, —C(═Y)R20, —C(═Y)OR20, —C(═Y)NR20R21, —NR20R21, —NR20C(═Y)R21, —NR20C(═Y)OR21 NR23C(═Y)NR20R21, —OR20, —OC(═Y)R20, —OC(═Y)OR20, —OC(═Y)NR20R21, —OS(O)2(OR20), —OP(═Y)(OR20)(OR21), —OP(OR20)(OR21), —P(═Y)(OR20)(OR21), —P(═Y)(OR23)NR20R21, SR20, —S(O)R20, —S(O)2R20, —S(O)2NR20R21, —S(O)(OR20), —S(O)2(OR20), —SC(═Y)R20, —SC(═Y)OR20, —SC(═Y)NR20R21, 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C6-C20 aryl, and C2-C20 heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR21, NR21R21 —SR20, —S(O)R20, —S(O)2R20, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl;
• R20 and R21 are independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C2-C20 heterocyclyl, and a protecting group, wherein said alkyl, alkenyl, alkynyl, aryl, and heterocyclyl are optionally and independently substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)Ra, —C(═Y)ORa, —C(═Y)NRaRb, —ORa, —OC(═Y)Ra, —OC(═Y)ORa, —OC(═Y)NRaRb, —OS(O)2(ORa), —OP(═Y)(ORa)(ORb), —OP(ORa)(ORb), —P(═Y)(ORa)(ORb), —P(═Y)(OR)NRaRb, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)2NRaRb, —S(O)(ORa), —S(O)2(ORa), —SC(═Y)Ra, —SC(═Y)ORa, and —SC(═Y)NRaRb,
• or R20 and R21 together with the atoms to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from F, Cl, Br, I, alkyl, alkenyl and alkynyl;
• R23 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C2-C20 heterocyclyl, or a protecting group;
• Ra and Rb are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, or C2-C20 heterocyclyl;
• Y is independently O, S, NR20, +N(O)R20, N(OR20), +N(O)(OR20), or N—NR20R21;
• and
• protecting group is selected from trialkylsilyl, dialkylphenylsilyl, benzoate, benzyl, benzyloxymethyl, methyl, methoxymethyl, triarylmethyl, phthalimido, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethylenoxycarbonyl (Fmoc), and tetrahydropyranyl.