IP Library › Granted Patent US 10,117,945

Granted Patent B2

US 10,117,945 · App. 15/455,727 · Granted Nov 6, 2018

mTORC1 inhibitors

Inventors: Kevan Shokat (San Francisco, CA); Masanori Okaniwa (Kanagawa, JP)

Assignee: The Regents of the University of California

A61K47/481 A61K31/436 A61K31/519

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Quick Facts

Patent No.: US 10,117,945
App. No.: 15/455,727
Granted: Nov 6, 2018
Kind: B2

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Abstract

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

Claims (143)

1. A compound having the formula:

wherein

Y is O or NR 13 ;

R 13 is independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —, NHSO 2 H, —NHC═(O)H—NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 56 -substituted or unsubstituted alkyl, R 56 substituted or unsubstituted heteroalkyl, R 56 -substituted or unsubstituted cycloalkyl, R 56 -substituted or unsubstituted heterocycloalkyl, R 56 -substituted or unsubstituted aryl, or R 56 -substituted or unsubstituted heteroaryl;

R 56 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 57 -substituted or unsubstituted alkyl, R 57 - substituted or unsubstituted heteroalkyl, R 57 -substituted or unsubstituted cycloalkyl, R 57 -substituted or unsubstituted heterocycloalkyl, R 57 -substituted or unsubstituted aryl, or R 57 -substituted or unsubstituted heteroaryl;

R 57 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 58 -substituted or unsubstituted alkyl, R 58 -substituted or unsubstituted heteroalkyl, R 58 -substituted or unsubstituted cycloalkyl, R 58 -substituted or unsubstituted heterocycloalkyl, R 58 -substituted or unsubstituted aryl, or R 58 -substituted or unsubstituted heteroaryl;

R 100 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;

W 1 is N or CR 11 ;

R 11 is independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 50 -substituted or unsubstituted alkyl, R 50 -substituted or unsubstituted heteroalkyl, R 50 -substituted or unsubstituted cycloalkyl, R 50 -substituted or unsubstituted heterocycloalkyl, R 50 -substituted or unsubstituted aryl, or R 50 -substituted or unsubstituted heteroaryl;

R 50 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 51 -substituted or unsubstituted alkyl, R 51 -substituted or unsubstituted heteroalkyl, R 51 -substituted or unsubstituted cycloalkyl, R 51 - substituted or unsubstituted heterocycloalkyl, R 51 -substituted or unsubstituted aryl, or R 51 -substituted or unsubstituted heteroaryl;

R 51 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 52 -substituted or unsubstituted alkyl, R 52 -substituted or unsubstituted heteroalkyl, R 52 -substituted or unsubstituted cycloalkyl, R 52 -substituted or unsubstituted heterocycloalkyl, R 52 -substituted or unsubstituted aryl, or R 52 -substituted or unsubstituted heteroaryl;

W 2 is N and W 3 is C or W 2 is C and W 3 is N;

W 4 is N or CR 12 ;

R 12 is independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 —OCHF 2 , R 53 -substituted or unsubstituted alkyl, R 53 -substituted or unsubstituted heteroalkyl, R 53 -substituted or unsubstituted cycloalkyl, R 53 -substituted or unsubstituted heterocycloalkyl, R 53 -substituted or unsubstituted aryl, or R 53 -substituted or unsubstituted heteroaryl;

R 53 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 54 -substituted or unsubstituted alkyl, R 54 -substituted or unsubstituted heteroalkyl, R 54 -substituted or unsubstituted cycloalkyl, R 54 -substituted or unsubstituted heterocycloalkyl, R 54 -substituted or unsubstituted aryl, or R 54 -substituted or unsubstituted heteroaryl;

R 54 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 55 -substituted or unsubstituted alkyl, R 55 -substituted or unsubstituted heteroalkyl, R 55 -substituted or unsubstituted cycloalkyl, R 55 -substituted or unsubstituted heterocycloalkyl, R 55 -substituted or unsubstituted aryl, or R 55 -substituted or unsubstituted heteroaryl;

R 3 is hydrogen, oxo, halogen, —CX 3 , —CN, —SO 2 Cl, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 ,

—NHC═(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 ,—C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , R 20 -substituted or unsubstituted alkyl, R 20 -substituted or unsubstituted heteroalkyl, R 20 -substituted or unsubstituted cycloalkyl, R 20 -substituted or unsubstituted heterocycloalkyl, R 20 -substituted or unsubstituted aryl, or R 20 -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;

R 20 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 21 -substituted or unsubstituted alkyl, R 21 -substituted or unsubstituted heteroalkyl, R 21 -substituted or unsubstituted cycloalkyl, R 21 -substituted or unsubstituted heterocycloalkyl, R 21 -substituted or unsubstituted aryl, or R 21 -substituted or unsubstituted heteroaryl;

R 21 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 22 -substituted or unsubstituted alkyl, R 22 -substituted or unsubstituted heteroalkyl, R 22 -substituted or unsubstituted cycloalkyl, R 22 -substituted or unsubstituted heterocycloalkyl, R 22 -substituted or unsubstituted aryl, or R 22 substituted or unsubstituted heteroaryl;

R 7 is independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 38 -substituted or unsubstituted alkyl, R 38 -substituted or unsubstituted heteroalkyl, R 38 -substituted or unsubstituted cycloalkyl, R 38 -substituted or unsubstituted heterocycloalkyl, R 38 -substituted or unsubstituted aryl, or R 38 substituted or unsubstituted heteroaryl;

R 38 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , —S(O) 2 CHCH 2 , —NHS(O) 2 CHCH 2 , R 39 -substituted or unsubstituted alkyl, R 39 -substituted or unsubstituted heteroalkyl, R 39 -substituted or unsubstituted cycloalkyl, R 39 substituted or unsubstituted heterocycloalkyl, R 39 -substituted or unsubstituted aryl, or R 39 -substituted or unsubstituted heteroaryl;

R 39 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , —S(O) 2 CHCH 2 , —NHS(O) 2 CHCH 2 , R 40 -substituted or unsubstituted alkyl, R 40 -substituted or unsubstituted heteroalkyl, R 40 substituted or unsubstituted cycloalkyl, R 40 -substituted or unsubstituted heterocycloalkyl, R 40 -substituted or unsubstituted aryl, or R 40 -substituted or unsubstituted heteroaryl;

R 8 is independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 41 -substituted or unsubstituted alkyl, R 41 -substituted or unsubstituted heteroalkyl, R 41 -substituted or unsubstituted cycloalkyl, R 41 -substituted or unsubstituted heterocycloalkyl, R 41 -substituted or unsubstituted aryl, or R 41 -substituted or unsubstituted heteroaryl;

R 41 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , —S(O) 2 CHCH 2 , —NHS(O) 2 CHCH 2 , R 42 -substituted or unsubstituted alkyl, R 42 -substituted or unsubstituted heteroalkyl, R 42 -substituted or unsubstituted cycloalkyl, R 42 substituted or unsubstituted heterocycloalkyl, R 42 -substituted or unsubstituted aryl, or R 42 -substituted or unsubstituted heteroaryl;

R 42 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , —S(O) 2 CHCH 2 , —NHS(O) 2 CHCH 2 , R 43 -substituted or unsubstituted alkyl, R 43 -substituted or unsubstituted heteroalkyl, R 43 -substituted or unsubstituted cycloalkyl, R 43 -substituted or unsubstituted heterocycloalkyl, R 43 -substituted or unsubstituted aryl, or R 43 -substituted or unsubstituted heteroaryl;

R 9 is independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 —OCHF 2 , R 44 -substituted or unsubstituted alkyl, R 44 -substituted or unsubstituted heteroalkyl, R 44 -substituted or unsubstituted cycloalkyl, R 44 -substituted or unsubstituted heterocycloalkyl, R 44 -substituted or unsubstituted aryl, or R 44 -substituted or unsubstituted heteroaryl;

R 44 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 45 -substituted or unsubstituted alkyl, R 45 -substituted or unsubstituted heteroalkyl, R 45 -substituted or unsubstituted cycloalkyl, R 45 substituted or unsubstituted heterocycloalkyl, R 45 -substituted or unsubstituted aryl, or R 45 -substituted or unsubstituted heteroaryl;

R 45 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , OCHF 2 , R 46 -substituted or unsubstituted alkyl, R 46 -substituted or unsubstituted heteroalkyl, R 46 -substituted or unsubstituted cycloalkyl, R 46 -substituted or unsubstituted heterocycloalkyl, R 46 -substituted or unsubstituted aryl, or R 46 -substituted or unsubstituted heteroaryl;

R 10 is independently hydrogen,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 47 -substituted or unsubstituted alkyl, R 47 -substituted or unsubstituted heteroalkyl, R 47 -substituted or unsubstituted cycloalkyl, R 47 -substituted or unsubstituted heterocycloalkyl, R 47 -substituted or unsubstituted aryl, or R 47 -substituted or unsubstituted heteroaryl;

R 47 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 48 -substituted or unsubstituted alkyl, R 48 -substituted or unsubstituted heteroalkyl, R 48 -substituted or unsubstituted cycloalkyl, R 48 substituted or unsubstituted heterocycloalkyl, R 48 -substituted or unsubstituted aryl, or R 48 -substituted or unsubstituted heteroaryl;

R 48 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 49 -substituted or unsubstituted alkyl, R 49 -substituted or unsubstituted heteroalkyl, R 49 -substituted or unsubstituted cycloalkyl, R 49 -substituted or unsubstituted heterocycloalkyl, R 49 -substituted or unsubstituted aryl, or R 49 -substituted or unsubstituted heteroaryl;

L 1 is L 2 -L 3 -L 4 -L 5 ;

L 2 is connected directly to a monovalent rapamycin or a monovalent rapamycin analog;

L 2 is a

bond, —NH—, —NR 26 —, —S—, —O—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R 26 -substituted or unsubstituted alkylene, R 26 -substituted or unsubstituted heteroalkylene, R 26 -substituted or unsubstituted cycloalkylene, R 26 -substituted or unsubstituted heterocycloalkylene, R 26 -substituted or unsubstituted arylene, or R 26 -substituted or unsubstituted heteroarylene;

R 26 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 27 -substituted or unsubstituted alkyl, R 27 -substituted or unsubstituted heteroalkyl, R 27 -substituted or unsubstituted cycloalkyl, R 27 substituted or unsubstituted heterocycloalkyl, R 27 -substituted or unsubstituted aryl, or R 27 -substituted or unsubstituted heteroaryl;

R 27 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 28 -substituted or unsubstituted alkyl, R 28 -substituted or unsubstituted heteroalkyl, R 28 -substituted or unsubstituted cycloalkyl, R 28 -substituted or unsubstituted heterocycloalkyl, R 28 -substituted or unsubstituted aryl, or R 28 -substituted or unsubstituted heteroaryl;

L 3 is a

bond, —NH—, —NR 29 —, —S—, —O—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R 29 -substituted or unsubstituted alkylene, R 29 -substituted or unsubstituted heteroalkylene, R 29 -substituted or unsubstituted cycloalkylene, R 29 -substituted or unsubstituted heterocycloalkylene, R 29 -substituted or unsubstituted arylene, or R 29 -substituted or unsubstituted heteroarylene;

R 29 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 30 -substituted or unsubstituted alkyl, R 30 -substituted or unsubstituted heteroalkyl, R 30 -substituted or unsubstituted cycloalkyl, R 30 substituted or unsubstituted heterocycloalkyl, R 30 -substituted or unsubstituted aryl, or R 30 -substituted or unsubstituted heteroaryl;

R 30 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 31 -substituted or unsubstituted alkyl, R 31 -substituted or unsubstituted heteroalkyl, R 31 -substituted or unsubstituted cycloalkyl, R 31 -substituted or unsubstituted heterocycloalkyl, R 31 -substituted or unsubstituted aryl, or R 31 -substituted or unsubstituted heteroaryl;

L 4 is a

bond, —NH—, —NR 32 —, —S—, —O—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R 32 -substituted or unsubstituted alkylene, R 32 -substituted or unsubstituted heteroalkylene, R 32 -substituted or unsubstituted cycloalkylene, R 32 -substituted or unsubstituted heterocycloalkylene, R 32 -substituted or unsubstituted arylene, or R 32 -substituted or unsubstituted heteroarylene;

R 32 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 33 -substituted or unsubstituted alkyl, R 33 -substituted or unsubstituted heteroalkyl, R 33 -substituted or unsubstituted cycloalkyl, R 33 substituted or unsubstituted heterocycloalkyl, R 33 -substituted or unsubstituted aryl, or R 33 -substituted or unsubstituted heteroaryl;

R 33 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 34 -substituted or unsubstituted alkyl, R 34 -substituted or unsubstituted heteroalkyl, R 34 -substituted or unsubstituted cycloalkyl, R 34 -substituted or unsubstituted heterocycloalkyl, R 34 -substituted or unsubstituted aryl, or R 34 -substituted or unsubstituted heteroaryl;

L 5 is a

bond, —NH—, —NR 35 —, —S—, —O—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R 35 -substituted or unsubstituted alkylene, R 35 -substituted or unsubstituted heteroalkylene, R 35 -substituted or unsubstituted cycloalkylene, R 35 -substituted or unsubstituted heterocycloalkylene, R 35 -substituted or unsubstituted arylene, or R 35 -substituted or unsubstituted heteroarylene;

R 35 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 36 -substituted or unsubstituted alkyl, R 36 -substituted or unsubstituted heteroalkyl, R 36 -substituted or unsubstituted cycloalkyl, R 36 substituted or unsubstituted heterocycloalkyl, R 36 -substituted or unsubstituted aryl, or R 36 -substituted or unsubstituted heteroaryl;

R 36 is independently oxo,

halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , R 37 -substituted or unsubstituted alkyl, R 37 -substituted or unsubstituted heteroalkyl, R 37 -substituted or unsubstituted cycloalkyl, R 37 -substituted or unsubstituted heterocycloalkyl, R 37 -substituted or unsubstituted aryl, or R 37 -substituted or unsubstituted heteroaryl; and

R 22 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and R 58 , are independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

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

3. The compound of claim 1 , having the formula:

4. The compound of claim 1 , having the formula:

5. The compound of claim 3 , wherein R 3 is R 20 -substituted or unsubstituted aryl or R 20 -substituted or unsubstituted heteroaryl.

6. The compound of claim 3 , wherein R 3 is R 20 -substituted or unsubstituted fused ring heteroaryl.

7. The compound of claim 3 , wherein R 3 is R 20 -substituted benzoxazolyl, R 20 -substituted pyrimidinyl, R 20 -substituted thiophenyl, R 20 -substituted furanyl, R 20 -substituted indolyl, R 20 -substituted benzoxadiazolyl, R 20 -substituted benzodioxolyl, R 20 -substituted benzodioxanyl, R 20 -substituted thianaphthanyl, R 20 -substituted pyrrolopyridinyl, R 20 -substituted indazolyl, R 20 -substituted quinolinyl, R 20 -substituted quinoxalinyl, R 20 -substituted pyridopyrazinyl, R 20 -substituted quinazolinonyl, R 20 -substituted benzoisoxazolyl, R 20 -substituted imidazopyridinyl, R 20 -substituted benzofuranyl, R 20 -substituted benzothiophenyl, R 20 -substituted phenyl, R 20 -substituted naphthyl, R 20 -substituted biphenyl, R 20 -substituted pyrrolyl, R 20 -substituted pyrazolyl, R 20 -substituted imidazolyl, R 20 -substituted pyrazinyl, R 20 -substituted oxazolyl, R 20 -substituted isoxazolyl, R 20 -substituted thiazolyl, R 20 -substituted furylthienyl, R 20 -substituted pyridyl, R 20 -substituted pyrimidyl, R 20 -substituted benzothiazolyl, R 20 -substituted purinyl, R 20 -substituted benzimidazolyl, R 20 -substituted isoquinolyl, R 20 -substituted thiadiazolyl, R 20 -substituted oxadiazolyl, R 20 -substituted pyrrolyl, R 20 -substituted diazolyl, R 20 -substituted triazolyl, R 20 -substituted tetrazolyl, R 20 -substituted benzothiadiazolyl, R 20 -substituted isothiazolyl, R 20 -substituted pyrazolopyrimidinyl, R 20 -substituted pyrrolopyrimidinyl, R 20 -substituted benzotriazolyl, or R 20 -substituted quinolyl.

8. The compound of claim 1 , wherein

L 2 is R 26 -substituted or unsubstituted 2 to 8 membered heteroalkylene;

L 3 is a R 29 -substituted or unsubstituted 5 to 10 membered heteroarylene;

L 4 is a R 32 -substituted or unsubstituted 2 to 15 membered heteroalkylene; and

L 5 is a R 35 -substituted or unsubstituted 2 to 15 membered heteroalkylene.

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

10. 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.

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

12. The compound of claim 1 , wherein

L 2 is 2 to 8 membered heteroalkylene comprising at least one NH or O;

L 3 is 5 to 10 membered heteroarylene;

L 4 is —[(CH 2 ) b11 O] b12 —;

L 5 is CH 2 CH 2 C═(O)NH(CH 2 ) 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.

13. The compound of claim 1 , wherein

L 2 is —CH 2 CH 2 OCH 2 —;

L 3 is triazolylene;

L 4 is —(CH 2 CH 2 O) b —;

L 5 is —CH 2 CH 2 C═(O)NH(CH 2 ) 4 ; and

b is an integer from 4 to 8.

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

15. 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.

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

17. The compound of claim 1 , having the formula:

18. The compound of claim 1 , wherein

each alkyl is a C 1 -C 20 alkyl;

each heteroalkyl is a 2 to 20 membered heteroalkyl;

each cycloalkyl is a C 3 -C 8 cycloalkyl;

each heterocycloalkyl is a 3 to 8 membered heterocycloalkyl;

each aryl is a C 6 -C 10 aryl;

each heteroaryl is a 5 to 10 membered heteroaryl;

each alkylene is a C 1 -C 20 alkylene;

each heteroalkylene is a 2 to 20 membered heteroalkylene;

each cycloalkylene is a C 3 -C 8 cycloalkylene;

each heterocycloalkylene is a 3 to 8 membered heterocycloalkylene;

each arylene is a C 6 -C 10 arylene; and

each heteroarylene is a 5 to 10 membered heteroarylene.

19. The compound of claim 1 , wherein each alkyl is a C 1 -C 8 alkyl;

each heteroalkyl is a 2 to 8 membered heteroalkyl;

each cycloalkyl is a C 3 -C 7 cycloalkyl;

each heterocycloalkyl is a 3 to 7 membered heterocycloalkyl;

each aryl is a C 6 -C 10 aryl;

each heteroaryl is a 5 to 9 membered heteroaryl;

each alkylene is a C 1 -C 8 alkylene;

each heteroalkylene is a 2 to 8 membered heteroalkylene;

each cycloalkylene is a C 3 -C 7 cycloalkylene;

each heterocycloalkylene is a 3 to 7 membered heterocycloalkylene;

each arylene is a C 6 -C 10 arylene; and

each heteroarylene is a 5 to 9 membered heteroarylene.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 19, 2018

From: SHOKAT, KEVAN M.; OKANIWA, MASANORI

To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Reel/Frame 046398/0103 →

Continuity (3)

Continuation PCTUS2015049693 · Sep 11, 2015

Provisional Application 62049186 · Sep 11, 2014

Related Publication 20170246305A1 · Aug 31, 2017

Cited By (5)

US 12,187,746 US 12,539,305 US 12,544,448 US 12,558,356 US 12,594,275