Dimer-selective RXR modulators and methods for their use

A compound of the formula:

• 35
• wherein,
• R1 through R4 each independently are hydrogen, a C1-C6 alkyl or a C7-C15 arylalkyl or heteroarylalkyl;
• R5 is a C5-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-C15 arylalkyl or heteroarylalkyl, N6R7, or OR8, where R6 and R7 each independently are a C7-C10 alkyl, heteroalkyl, a C7-C15 arylalkyl or heteroarylalkyl, a C3-C10 acyl, provided that only one of R6 or R7 can be acyl, or R6 and R7 taken together are C3-C6 cycloalkyl, and where R8 is a C7-C10 alkyl, heteroalkyl, aryl, heteroaryl, or a C7-C15 arylalkyl or heteroarylalkyl;
• R9 and R10 each independently are hydrogen, a C1-C10 alkyl, halogen, heteroalkyl, NR11R12, NO2 or OR13, where R11 and R12 each independently are hydrogen, a C1-C10 alkyl, heteroalkyl, a C7-C15 arylalkyl or heteroarylalkyl, a C1-C8 acyl, provided that only one of R11 or R12 can be acyl, or R11 and R12 taken together are a C3-C6 cycloalkyl, and where R13 is hydrogen or a C1-C10 alkyl, heteroalkyl or a C7-C15 arylalkyl or heteroarylalkyl;
• R14 and R15 each independently are hydrogen, a C1-C10 alkyl, a C1-C8 acyl, or OR16 where R16 is hydrogen or a C1-C10 alkyl;
• or R14 and R15 taken together are keto, methano, optionally substituted oxime, optionally substituted hydrazone, optionally substituted epoxy, 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, oxazolidine or:
• 36
• where R17 through R23 have the definitions given below and the dashed lines crossing the bonds indicate the attachment bonds to the rings adjacent to R14 and R15;
• R17 and R18 each independently are hydrogen, a C1-C10 alkyl, heteroalkyl, aryl, a C7-C15 arylalkyl or heteroarylalkyl or R17 and R18 taken together are a C3-C6 cycloalkyl;
• R19 is hydrogen, a C1-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-C15 arylalkyl or heteroarylalkyl;
• R20 through R23 each independently are hydrogen, halogen, a C1-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-C15 arylalkyl or heteroarylalkyl, NR24R25, NO2, or OR26, where R24 and R25 each independently are hydrogen, a C1-C10 alkyl, heteroalkyl, a C7-C15 arylalkyl or heteroarylalkyl or a C1-C8 acyl, provided that only one of R24 or R25 can be acyl, and where R26 is hydrogen or a C1-C10 alkyl, heteroalkyl, aryl, heteroaryl, or a C7-C15 arylalkyl or heteroarylalkyl;
• R27 through R31 each independently are hydrogen, a C1-C10 alkyl, heteroalkyl, halogen, NR32R33, NO2 or OR34, where R32 and R33 each independently are hydrogen, a C1-C10 alkyl, a C7-C15 arylalkyl or heteroarylalkyl, a C1-C8 acyl, provided that only one of R32 or R33 can be acyl, or R32 and R33 taken together are a C3-C6 cycloalkyl, and where R34 is hydrogen or a C1-C10 alkyl, heteroalkyl or a C7-C15 arylalkyl or heteroarylalkyl and can only exist when W is C;
• R35 through R38 each independently are hydrogen, a C1-C2 alkyl or OR39 where R39 is hydrogen or a C1-C10 alkyl, or R35 and R36 or R37 and R38 taken together are keto, or R35 and R36, R37 and R38, R35 and R37 or R36 and R38 taken together are epoxy;
• COR40 can originate from any W, when the originating W is C, and R40 is OR41 or NR42R43, with R41 being hydrogen, a C1-C6 alkyl or a C7-C15 arylalkyl or heteroarylalkyl, and with R42 and R43 each independently being hydrogen, a C1-C6 alkyl, a C7-C15 arylalkyl or heteroarylalkyl, aryl, ortho-, meta-, or para-substituted hydroxyaryl, or taken together are a C3-C6 cycloalkyl;
• R44 and R45 each independently-are hydrogen, a C1-C4 alkyl or CH2OR46, where R46 is hydrogen or a C1-C6 alkyl, or R44 and R45 taken together are a C3-C6 cycloalkyl or cycloheteroalkyl;
• R47 is hydrogen, a C1-C4 alkyl, or when n=1, R47 taken together with R44 or R45 are a C3-C6 cycloalkyl or cycloheteroalkyl;
• R48 and R49 each independently are C1-C4 alkyl;
• R50 is a C4-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-C15 arylalkyl or heteroarylalkyl, NR51R52, or OR53, where R51 and R52 each independently are a C2-C10 alkyl, heteroalkyl, a C7-C15 arylalkyl or heteroarylalkyl, a C3-C10 acyl, provided that only one of R51 or R52 can be acyl, or R51 and R52 taken together are C3-C6 cycloalkyl, and where R53 is a C7-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C3-C6 alkyl, heteroalkyl, aryl or heteroalkyl or a C7-C15 arylalkyl or heteroarylalkyl;
• R54 represents:
• 37
• where R9, R10, R14, R15 and R40 have the definitions given above;
• R55 through R58 each independently are hydrogen, halogen, a C1-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-C15 arylalkyl or heteroarylalkyl, NR59R60 or OR61, where R59 and R60 each independently are hydrogen, a C1-C10 alkyl or heteroalkyl, a C7-C15 arylalkyl or heteroarylalkyl, a C1-C8 acyl, provided that only one of R59 or R60 can be acyl, or R59 and R60 taken together are C3-C6 cycloalkyl, and where R61 is hydrogen or a C1-C 10 alkyl, heteroalkyl, aryl, heteroaryl, or a C7-C15 arylalkyl or heteroarylalkyl, or where R55 and R56 or R57 and R58 taken together are keto, methano, a C1-C10 alkyl methylene, a C1-C10 dialkylmethylene, C7-C15 arylalkyl or heteroarylalkylmethylene, oxime, O-alkyl oxime, hydrazone, 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, oxazolidine, or R55 and R57 or R56 and R58 taken together are epoxy;
• R62 through R64 each independently are hydrogen, aryl, heteroaryl, CF3, a C2 -C6 alkyl, C2-C6 heteroalkyl or NR51R52, where R51 and R52 have the definitions given above;
• R65 is hydrogen, a C1-C2 alkyl or OR66, where R66 is a C1-C2 alkyl;
• R67 is a C4-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-C15 arylalkyl or heteroarylalkyl, NR51R52, or OR68, where R51 and R52 have the definitions described above, and where R68 is a C3-C10 alkyl, heteroalkyl, aryl, heteroaryl, or a C7-C15 arylalkyl or heteroarylalkyl;
• X and Y each independently represent C, O, S, N, SO or SO2, provided, however, that when X or Y are O, S, SO or SO2, then either R1 and R2 or R3 and R4 respectively do not exist, and further provided, that when X or Y is N, then one each of R1 and R2 or R3 and R4 respectively, do not exist;
• M is N or C;
• Q is N or C;
• Z is O, S, SO, SO2, CR69R70 or NR71, where R69 through R71 each independently are hydrogen or a C1-C10 alkyl, heteroalkyl, aryl, heteroaryl, a C7-C15 arylalkyl or heteroarylalkyl, or R69 and R70 each independently are OR71, or R69 and R70 taken together are a cycloalkyl;
• each W is independently C, N, S or O, or a pharmaceutically acceptable salt, but is not O or S if attached by a double bond to another W or if attached to another such W which is O or S, and is not N if attached by a single bond to another such W which is N;
• m is 0, 1 or 2 carbon atoms;
• n is 0 or 1 carbon atoms;
• k is 1 to 5 carbon atoms;
• the dashed lines in the structures, other than at R14 and R15, represent optional double bonds, provided, however, that the double bonds cannot be contiguous, and further provided that when such optional double bonds exist then the substitution patterns around such bonds cannot violate double bond valency;
• and
• the wavy lines represent olefin geometry that is either cis (Z) or trans (E), and unless otherwise indicated, for substituents R1 through R71, all olefin geometric Isomers (i.e., cis (Z) or trans (E)) of the above compounds are included.