Immunophilin binding agents and uses thereof

A method of treating a CNS disease in a subject in need of such treatment, comprising co-administering outside the CNS of said subject an anti-CNS disease drug and a compound having the formula:

• AB-LB1-RB1, or a pharmaceutically acceptable salt thereof,
• wherein
• AB is an immunophilin-binding moiety;
• LB1-RB1 is a polar moiety;
• LB1 is a bond, a covalent linker, or a bioconjugate linker;
• RB1 is hydrogen, halogen, —CXB31, —CHXB21, —CH2XB1, —OCXB31, —OCH2XB1, —OCHXB21, —CN, —SOnB1RB1D, —SOvB1NRB1ARB1B, —NHC(O)NRB1ARB1B, —N(O)mB1, —NRB1ARB1B, —C(O)RB1C, —C(O)ORB1C, —C(O)NRB1ARB1B, —ORB1D, —NRB1ASO2RB1D, —NRB1AC(O)RB1C, —NRB1AC(O)ORB1C, —NRB1AORB1C, —NRB1AC(NRB1C) RB1D, —NRB1AC(NRB1C)NRB1ARB1B, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• RB1A, RB1B, RB1C, and RB1D are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —Cl3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHC(NH)H, —NHC(NH)NH2, —NHOH, —OCCl3, —OCBr3, —OCF3, —OCI3, —OCH2Cl, —OCH2Br, —OCH2F, —OCH2I, —OCHCl2, —OCHBr2, —OCHF2, —OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• or RB1A and RB1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• nB1 is an integer from 0 to 4;
• mB1 and vB1 are independently 1 or 2;
• XB1 is independently —F, —Cl, —Br, or —I;
• when LB1 is a bond, RB1 is not H;
• wherein the anti-CNS disease drug has the formula:
• A-L1-R1;
• wherein
• A is an immunophilin-binding moiety;
• L1 is a bond or a covalent linker;
• and
• R1 is a monovalent kinase inhibitor, a monovalent pseudokinase inhibitor, a monovalent GTPase inhibitor, a monovalent histone-modifying enzyme inhibitor, a monovalent anti-cancer agent, a monovalent anti-neurodegenerative disease agent, or a monovalent anti-viral agent;
• wherein the anti-CNS disease drug is capable of entering the central nervous system and the compound is incapable of entering the central nervous system following co-administration outside of the central nervous system of the subject.