Rapamycin analogs and uses thereof

Patent metadata

Field	Value
Publication number	US-11819476-B2
Application number	US-202017111674-A
Country	US
Kind code	B2
Filing date	Dec 4, 2020
Priority date	Dec 5, 2019
Publication date	Nov 21, 2023
Grant date	Nov 21, 2023

Abstract

The present invention provides compounds of formula I, compositions thereof, and methods of using the same as mTORC1 inhibitors.

First claim

We claim:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
L 1 is a covalent bond, or a C 1-30 bivalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-10 methylene units of the chain are independently and optionally replaced with -Cy 1 -, —O—, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —Si(R) 2 —, or —NR—;
each -Cy 1 - is independently an optionally substituted bivalent ring selected from phenylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen or optionally substituted C 1-6 aliphatic;
L 2 is

R 1 is hydrogen, halogen, —OR, —CN, —NO 2 , —NR 2 , or an optionally substituted group selected from a C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein -L 1 -R 1 taken together do not form —OMe;
R 2 is methyl,

or

R 3 is —OH or —OMe;
R 3′ is hydrogen;
R 4 is hydrogen or C 1-6 aliphatic;
R 5 and R 5′ are taken together to form ═O;
R 6 is —OMe; and
X 1 and X 2 are each —CH 2 —.

2. The compound of claim 1 , wherein said compound is selected from any one of the following formulae:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein L 1 is a C 1-30 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-10 methylene units of the chain are independently and optionally replaced with -Cy 1 -, —O—, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —Si(R) 2 —, or —NR—.

4. The compound of claim 1 , wherein L 1 is selected from —O—, —NH—, —O—CH 2 —, —O—(CH 2 ) 2 —, —O—(CH 2 ) 3 —, —O—(CH 2 ) 4 —, —O—(CH 2 ) 5 —, —O—(CH 2 ) 2 —O—, —O—(CH 2 ) 2 —O—(CH 2 ) 2 —, —NH—CH 2 —, —NH—C(O)—, —NH—C(O)O—, —NH—SO 2 —, —NH—SO 2 —(CH 2 ) 2 —, —NH—SO 2 —(CH 2 ) 2 —O—(CH 2 ) 2 —, —O—(CH 2 ) 2 —SO 2 —(CH 2 ) 2 —, —O—(CH 2 ) 2 —SO 2 —(CH 2 ) 2 —SO 2 —, —O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —, and

5. The compound of claim 1 , wherein L 1 is a covalent bond.

6. The compound of claim 1 , wherein each R is independently hydrogen or C 1-6 aliphatic.

7. The compound of claim 1 , wherein R 1 is selected from hydrogen, halogen, —OR, —CN, —NO 2 , or an optionally substituted group selected from a C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

8. The compound of claim 1 , wherein R 1 is selected from hydrogen, halogen, —OR, and —NR 2 .

9. The compound of claim 1 , wherein R 1 is an optionally substituted group selected from: a C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfurs, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

10. The compound of claim 1 , wherein R 1 is selected from —OMe, —(CH 2 ) 2 —OH, —(CH 2 ) 2 —OMe, —SO 2 —NH 2 , —C(O)NH 2 , —C(O)NMe 2 , —OC(O)NHMe, —CO 2 H,

11. The compound of claim 1 , wherein said compound is selected any one of the following:

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutically acceptable composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• O'Neill David John
• Saiah Eddine
• Kang Seong Woo Anthony

Classifications

• A61K31/436 Primary

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D498/18 Primary

  Bridged systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title