IP Library › Granted Patent US 10,646,577
Granted Patent B2
US 10,646,577 · App. 16/126,210 · Granted May 12, 2020

mTORC1 inhibitors

Inventors: Kevan Shokat (San Francisco, CA); Masanori Okaniwa (Kanagawa, JP)
Assignee: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
A61K47/55A61K31/436A61K31/519
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Quick Facts
Patent No.
US 10,646,577
App. No.
16/126,210
Granted
May 12, 2020
Kind
B2
Abstract

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

Claims (44)

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein

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 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 20 membered heteroalkylene;

L 5 is a R 35 -substituted or unsubstituted 2 to 20 membered heteroalkylene;

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;

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;

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;

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 28 , R 31 , R 34 , and R 37 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 , or a pharmaceutically acceptable salt thereof, wherein

L 2 is a 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 10 membered heteroalkylene; and

L 5 is a R 35 -substituted or unsubstituted 2 to 10 membered heteroalkylene.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

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

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

L 4 is a 1C-substituted or unsubstituted 2 to 15 membered heteroalkylene; and

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

6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

7. A method of treating a disease in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said disease is a cancer.

8. The method of claim 7 , wherein said administering is through a drug-eluting stent.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 16, 2019
From: SHOKAT, KEVAN M.; OKANIWA, MASANORI
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 049765/0919 →
Continuity (4)
Continuation 15455727 · Mar 10, 2017
Continuation PCTUS2015049693 · Sep 11, 2015
Provisional Application 62049186 · Sep 11, 2014
Related Publication 20190091340A1 · Mar 28, 2019
Cited By (3)
US 12,325,678 US 12,558,356 US 12,594,275