# US 10,117,945 B2 · mTORC1 inhibitors

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- Number: US 10,117,945 B2
- Document ID: US10117945B2
- Status: Granted
- Kind: B2
- Application number: 15/455,727
- Filed: 2017-03-10
- Published: 2017-08-31
- Granted: 2018-11-06
- Earliest claimed: 2014-09-11
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Kevan Shokat; Masanori Okaniwa
- Web page: https://patentgrep.com/patent/US10117945B2

## CPC

- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/10: Antimycotics
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein, inter alia, are compounds and methods of using the same for modulating the activity of mTORC1.

## Claims

### Claim 1

A compound having the formula:
wherein
Y is O or NR13;
R13 is independently hydrogen,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R56-substituted or unsubstituted alkyl, R56 substituted or unsubstituted heteroalkyl, R56-substituted or unsubstituted cycloalkyl, R56-substituted or unsubstituted heterocycloalkyl, R56-substituted or unsubstituted aryl, or R56-substituted or unsubstituted heteroaryl;
R56 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R57-substituted or unsubstituted alkyl, R57- substituted or unsubstituted heteroalkyl, R57-substituted or unsubstituted cycloalkyl, R57-substituted or unsubstituted heterocycloalkyl, R57-substituted or unsubstituted aryl, or R57-substituted or unsubstituted heteroaryl;
R57 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R58-substituted or unsubstituted alkyl, R58-substituted or unsubstituted heteroalkyl, R58-substituted or unsubstituted cycloalkyl, R58-substituted or unsubstituted heterocycloalkyl, R58-substituted or unsubstituted aryl, or R58-substituted or unsubstituted heteroaryl;
R100 is
or a monovalent form of INK128, PP242, PP121, MLN0128, AZD8055, AZD2014, NVP-BEZ235, BGT226, SF1126, Torin 1, Torin 2, WYE 687, WYE 687, PF04691502, PI-103, CC-223, OSI-027, XL388, KU-0063794, GDC-0349, or PKI-587;
W1 is N or CR11;
R11 is independently hydrogen,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R50-substituted or unsubstituted alkyl, R50-substituted or unsubstituted heteroalkyl, R50-substituted or unsubstituted cycloalkyl, R50-substituted or unsubstituted heterocycloalkyl, R50-substituted or unsubstituted aryl, or R50-substituted or unsubstituted heteroaryl;
R50 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R51-substituted or unsubstituted alkyl, R51-substituted or unsubstituted heteroalkyl, R51-substituted or unsubstituted cycloalkyl, R51- substituted or unsubstituted heterocycloalkyl, R51-substituted or unsubstituted aryl, or R51-substituted or unsubstituted heteroaryl;
R51 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R52-substituted or unsubstituted alkyl, R52-substituted or unsubstituted heteroalkyl, R52-substituted or unsubstituted cycloalkyl, R52-substituted or unsubstituted heterocycloalkyl, R52-substituted or unsubstituted aryl, or R52-substituted or unsubstituted heteroaryl;
W2 is N and W3 is C or W2 is C and W3 is N;
W4 is N or CR12;
R12 is independently hydrogen,
halogen, —CF3, —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, —NHOH, —OCF3 —OCHF2, R53-substituted or unsubstituted alkyl, R53-substituted or unsubstituted heteroalkyl, R53-substituted or unsubstituted cycloalkyl, R53-substituted or unsubstituted heterocycloalkyl, R53-substituted or unsubstituted aryl, or R53-substituted or unsubstituted heteroaryl;
R53 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R54-substituted or unsubstituted alkyl, R54-substituted or unsubstituted heteroalkyl, R54-substituted or unsubstituted cycloalkyl, R54-substituted or unsubstituted heterocycloalkyl, R54-substituted or unsubstituted aryl, or R54-substituted or unsubstituted heteroaryl;
R54 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R55-substituted or unsubstituted alkyl, R55-substituted or unsubstituted heteroalkyl, R55-substituted or unsubstituted cycloalkyl, R55-substituted or unsubstituted heterocycloalkyl, R55-substituted or unsubstituted aryl, or R55-substituted or unsubstituted heteroaryl;
R3 is hydrogen, oxo, halogen, —CX3, —CN, —SO2Cl, —SOnR10, —SOvNR7R8, —NHNH2, —ONR7R8, —NHC═(O)NHNH2,
—NHC═(O)NR7R8, —N(O)m, —NR7R8, —C(O)R9, —C(O)—OR9,—C(O)NR7R8, —OR10, —NR7SO2R10, —NR7C═(O)R9, —NR7C(O)OR9, —NR7OR9, —OCX3, —OCHX2, R20-substituted or unsubstituted alkyl, R20-substituted or unsubstituted heteroalkyl, R20-substituted or unsubstituted cycloalkyl, R20-substituted or unsubstituted heterocycloalkyl, R20-substituted or unsubstituted aryl, or R20-substituted or unsubstituted heteroaryl;
m and v are independently 1 or 2;
n is independently an integer from 0 to 4;
X is independently —Cl, —Br, —I, or —F;
R20 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R21-substituted or unsubstituted alkyl, R21-substituted or unsubstituted heteroalkyl, R21-substituted or unsubstituted cycloalkyl, R21-substituted or unsubstituted heterocycloalkyl, R21-substituted or unsubstituted aryl, or R21-substituted or unsubstituted heteroaryl;
R21 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R22-substituted or unsubstituted alkyl, R22-substituted or unsubstituted heteroalkyl, R22-substituted or unsubstituted cycloalkyl, R22-substituted or unsubstituted heterocycloalkyl, R22-substituted or unsubstituted aryl, or R22substituted or unsubstituted heteroaryl;
R7 is independently hydrogen,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R38-substituted or unsubstituted alkyl, R38-substituted or unsubstituted heteroalkyl, R38-substituted or unsubstituted cycloalkyl, R38-substituted or unsubstituted heterocycloalkyl, R38-substituted or unsubstituted aryl, or R38substituted or unsubstituted heteroaryl;
R38 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, —S(O)2CHCH2, —NHS(O)2CHCH2, R39-substituted or unsubstituted alkyl, R39-substituted or unsubstituted heteroalkyl, R39-substituted or unsubstituted cycloalkyl, R39substituted or unsubstituted heterocycloalkyl, R39-substituted or unsubstituted aryl, or R39-substituted or unsubstituted heteroaryl;
R39 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, —S(O)2CHCH2, —NHS(O)2CHCH2, R40-substituted or unsubstituted alkyl, R40-substituted or unsubstituted heteroalkyl, R40substituted or unsubstituted cycloalkyl, R40-substituted or unsubstituted heterocycloalkyl, R40-substituted or unsubstituted aryl, or R40-substituted or unsubstituted heteroaryl;
R8 is independently hydrogen,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R41-substituted or unsubstituted alkyl, R41-substituted or unsubstituted heteroalkyl, R41-substituted or unsubstituted cycloalkyl, R41-substituted or unsubstituted heterocycloalkyl, R41-substituted or unsubstituted aryl, or R41-substituted or unsubstituted heteroaryl;
R41 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, —S(O)2CHCH2, —NHS(O)2CHCH2, R42-substituted or unsubstituted alkyl, R42-substituted or unsubstituted heteroalkyl, R42-substituted or unsubstituted cycloalkyl, R42substituted or unsubstituted heterocycloalkyl, R42-substituted or unsubstituted aryl, or R42-substituted or unsubstituted heteroaryl;
R42 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, —S(O)2CHCH2, —NHS(O)2CHCH2, R43-substituted or unsubstituted alkyl, R43-substituted or unsubstituted heteroalkyl, R43-substituted or unsubstituted cycloalkyl, R43-substituted or unsubstituted heterocycloalkyl, R43-substituted or unsubstituted aryl, or R43-substituted or unsubstituted heteroaryl;
R9 is independently hydrogen,
halogen, —CF3, —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, —NHOH, —OCF3 —OCHF2, R44-substituted or unsubstituted alkyl, R44-substituted or unsubstituted heteroalkyl, R44-substituted or unsubstituted cycloalkyl, R44-substituted or unsubstituted heterocycloalkyl, R44-substituted or unsubstituted aryl, or R44-substituted or unsubstituted heteroaryl;
R44 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R45-substituted or unsubstituted alkyl, R45-substituted or unsubstituted heteroalkyl, R45-substituted or unsubstituted cycloalkyl, R45substituted or unsubstituted heterocycloalkyl, R45-substituted or unsubstituted aryl, or R45-substituted or unsubstituted heteroaryl;
R45 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, OCHF2, R46-substituted or unsubstituted alkyl, R46-substituted or unsubstituted heteroalkyl, R46-substituted or unsubstituted cycloalkyl, R46-substituted or unsubstituted heterocycloalkyl, R46-substituted or unsubstituted aryl, or R46-substituted or unsubstituted heteroaryl;
R10 is independently hydrogen,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R47-substituted or unsubstituted alkyl, R47-substituted or unsubstituted heteroalkyl, R47-substituted or unsubstituted cycloalkyl, R47-substituted or unsubstituted heterocycloalkyl, R47-substituted or unsubstituted aryl, or R47-substituted or unsubstituted heteroaryl;
R47 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R48-substituted or unsubstituted alkyl, R48-substituted or unsubstituted heteroalkyl, R48-substituted or unsubstituted cycloalkyl, R48substituted or unsubstituted heterocycloalkyl, R48-substituted or unsubstituted aryl, or R48-substituted or unsubstituted heteroaryl;
R48 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R49-substituted or unsubstituted alkyl, R49-substituted or unsubstituted heteroalkyl, R49-substituted or unsubstituted cycloalkyl, R49-substituted or unsubstituted heterocycloalkyl, R49-substituted or unsubstituted aryl, or R49-substituted or unsubstituted heteroaryl;
L1 is L2-L3-L4-L5;
L2 is connected directly to a monovalent rapamycin or a monovalent rapamycin analog;
L2 is a
bond, —NH—, —NR26—, —S—, —O—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R26-substituted or unsubstituted alkylene, R26-substituted or unsubstituted heteroalkylene, R26-substituted or unsubstituted cycloalkylene, R26-substituted or unsubstituted heterocycloalkylene, R26-substituted or unsubstituted arylene, or R26-substituted or unsubstituted heteroarylene;
R26 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R27-substituted or unsubstituted alkyl, R27-substituted or unsubstituted heteroalkyl, R27-substituted or unsubstituted cycloalkyl, R27substituted or unsubstituted heterocycloalkyl, R27-substituted or unsubstituted aryl, or R27-substituted or unsubstituted heteroaryl;
R27 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R28-substituted or unsubstituted alkyl, R28-substituted or unsubstituted heteroalkyl, R28-substituted or unsubstituted cycloalkyl, R28-substituted or unsubstituted heterocycloalkyl, R28-substituted or unsubstituted aryl, or R28-substituted or unsubstituted heteroaryl;
L3 is a
bond, —NH—, —NR29—, —S—, —O—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R29-substituted or unsubstituted alkylene, R29-substituted or unsubstituted heteroalkylene, R29-substituted or unsubstituted cycloalkylene, R29-substituted or unsubstituted heterocycloalkylene, R29-substituted or unsubstituted arylene, or R29-substituted or unsubstituted heteroarylene;
R29 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R30-substituted or unsubstituted alkyl, R30-substituted or unsubstituted heteroalkyl, R30-substituted or unsubstituted cycloalkyl, R30substituted or unsubstituted heterocycloalkyl, R30-substituted or unsubstituted aryl, or R30-substituted or unsubstituted heteroaryl;
R30 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R31-substituted or unsubstituted alkyl, R31-substituted or unsubstituted heteroalkyl, R31-substituted or unsubstituted cycloalkyl, R31-substituted or unsubstituted heterocycloalkyl, R31-substituted or unsubstituted aryl, or R31-substituted or unsubstituted heteroaryl;
L4 is a
bond, —NH—, —NR32—, —S—, —O—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R32-substituted or unsubstituted alkylene, R32-substituted or unsubstituted heteroalkylene, R32-substituted or unsubstituted cycloalkylene, R32-substituted or unsubstituted heterocycloalkylene, R32-substituted or unsubstituted arylene, or R32-substituted or unsubstituted heteroarylene;
R32 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R33-substituted or unsubstituted alkyl, R33-substituted or unsubstituted heteroalkyl, R33-substituted or unsubstituted cycloalkyl, R33substituted or unsubstituted heterocycloalkyl, R33-substituted or unsubstituted aryl, or R33-substituted or unsubstituted heteroaryl;
R33 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R34-substituted or unsubstituted alkyl, R34-substituted or unsubstituted heteroalkyl, R34-substituted or unsubstituted cycloalkyl, R34-substituted or unsubstituted heterocycloalkyl, R34-substituted or unsubstituted aryl, or R34-substituted or unsubstituted heteroaryl;
L5 is a
bond, —NH—, —NR35—, —S—, —O—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R35-substituted or unsubstituted alkylene, R35-substituted or unsubstituted heteroalkylene, R35-substituted or unsubstituted cycloalkylene, R35-substituted or unsubstituted heterocycloalkylene, R35-substituted or unsubstituted arylene, or R35-substituted or unsubstituted heteroarylene;
R35 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R36-substituted or unsubstituted alkyl, R36-substituted or unsubstituted heteroalkyl, R36-substituted or unsubstituted cycloalkyl, R36substituted or unsubstituted heterocycloalkyl, R36-substituted or unsubstituted aryl, or R36-substituted or unsubstituted heteroaryl;
R36 is independently oxo,
halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, R37-substituted or unsubstituted alkyl, R37-substituted or unsubstituted heteroalkyl, R37-substituted or unsubstituted cycloalkyl, R37-substituted or unsubstituted heterocycloalkyl, R37-substituted or unsubstituted aryl, or R37-substituted or unsubstituted heteroaryl; and
R22, R28, R31, R34, R37, R40, R43, R46, R49, R52, R55, and R58, are independently oxo, halogen, —CF3, —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, —NHOH, —OCF3, —OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein L1 is at least 17 Å in length.

### Claim 3 (depends on 1)

The compound of claim 1, having the formula:

### Claim 4 (depends on 1)

The compound of claim 1, having the formula:

### Claim 5 (depends on 3)

The compound of claim 3, wherein R3 is R20-substituted or unsubstituted aryl or R20-substituted or unsubstituted heteroaryl.

### Claim 6 (depends on 3)

The compound of claim 3, wherein R3 is R20-substituted or unsubstituted fused ring heteroaryl.

### Claim 7 (depends on 3)

The compound of claim 3, wherein R3 is R20-substituted benzoxazolyl, R20-substituted pyrimidinyl, R20-substituted thiophenyl, R20-substituted furanyl, R20-substituted indolyl, R20-substituted benzoxadiazolyl, R20-substituted benzodioxolyl, R20-substituted benzodioxanyl, R20-substituted thianaphthanyl, R20-substituted pyrrolopyridinyl, R20-substituted indazolyl, R20-substituted quinolinyl, R20-substituted quinoxalinyl, R20-substituted pyridopyrazinyl, R20-substituted quinazolinonyl, R20-substituted benzoisoxazolyl, R20-substituted imidazopyridinyl, R20-substituted benzofuranyl, R20-substituted benzothiophenyl, R20-substituted phenyl, R20-substituted naphthyl, R20-substituted biphenyl, R20-substituted pyrrolyl, R20-substituted pyrazolyl, R20-substituted imidazolyl, R20-substituted pyrazinyl, R20-substituted oxazolyl, R20-substituted isoxazolyl, R20-substituted thiazolyl, R20-substituted furylthienyl, R20-substituted pyridyl, R20-substituted pyrimidyl, R20-substituted benzothiazolyl, R20-substituted purinyl, R20-substituted benzimidazolyl, R20-substituted isoquinolyl, R20-substituted thiadiazolyl, R20-substituted oxadiazolyl, R20-substituted pyrrolyl, R20-substituted diazolyl, R20-substituted triazolyl, R20-substituted tetrazolyl, R20-substituted benzothiadiazolyl, R20-substituted isothiazolyl, R20-substituted pyrazolopyrimidinyl, R20-substituted pyrrolopyrimidinyl, R20-substituted benzotriazolyl, or R20-substituted quinolyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein
L2 is R26-substituted or unsubstituted 2 to 8 membered heteroalkylene;
L3 is a R29-substituted or unsubstituted 5 to 10 membered heteroarylene;
L4 is a R32-substituted or unsubstituted 2 to 15 membered heteroalkylene; and
L5 is a R35-substituted or unsubstituted 2 to 15 membered heteroalkylene.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1.

### Claim 10 (depends on 1)

A method of treating a disease in a subject, said method comprising administering to said subject an effective amount of a compound of claim 1, wherein said disease is a cancer.

### Claim 11 (depends on 10)

The method of claim 10, wherein said administering is through a drug-eluting stent.

### Claim 12 (depends on 1)

The compound of claim 1, wherein
L2 is 2 to 8 membered heteroalkylene comprising at least one NH or O;
L3 is 5 to 10 membered heteroarylene;
L4 is —[(CH2)b11O]b12—;
L5 is CH2CH2C═(O)NH(CH2)b10;
b10 is an integer from 1 to 6;
b11 is an integer from 1 to 3; and
b12 is an integer from 1 to 8.

### Claim 13 (depends on 1)

The compound of claim 1, wherein
L2 is —CH2CH2OCH2—;
L3 is triazolylene;
L4 is —(CH2CH2O)b—;
L5 is —CH2CH2C═(O)NH(CH2)4; and
b is an integer from 4 to 8.

### Claim 14 (depends on 3)

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 3.

### Claim 15 (depends on 3)

A method of treating a disease in a subject, said method comprising administering to said subject an effective amount of a compound of claim 3, wherein said disease is a cancer.

### Claim 16 (depends on 15)

The method of claim 15, wherein said administering is through a drug-eluting stent.

### Claim 17 (depends on 1)

The compound of claim 1, having the formula:

### Claim 18 (depends on 1)

The compound of claim 1, wherein
each alkyl is a C1-C20 alkyl;
each heteroalkyl is a 2 to 20 membered heteroalkyl;
each cycloalkyl is a C3-C8 cycloalkyl;
each heterocycloalkyl is a 3 to 8 membered heterocycloalkyl;
each aryl is a C6-C10 aryl;
each heteroaryl is a 5 to 10 membered heteroaryl;
each alkylene is a C1-C20 alkylene;
each heteroalkylene is a 2 to 20 membered heteroalkylene;
each cycloalkylene is a C3-C8 cycloalkylene;
each heterocycloalkylene is a 3 to 8 membered heterocycloalkylene;
each arylene is a C6-C10 arylene; and
each heteroarylene is a 5 to 10 membered heteroarylene.

### Claim 19 (depends on 1)

The compound of claim 1, wherein each alkyl is a C1-C8 alkyl;
each heteroalkyl is a 2 to 8 membered heteroalkyl;
each cycloalkyl is a C3-C7 cycloalkyl;
each heterocycloalkyl is a 3 to 7 membered heterocycloalkyl;
each aryl is a C6-C10 aryl;
each heteroaryl is a 5 to 9 membered heteroaryl;
each alkylene is a C1-C8 alkylene;
each heteroalkylene is a 2 to 8 membered heteroalkylene;
each cycloalkylene is a C3-C7 cycloalkylene;
each heterocycloalkylene is a 3 to 7 membered heterocycloalkylene;
each arylene is a C6-C10 arylene; and
each heteroarylene is a 5 to 9 membered heteroarylene.