Tricyclic DLK inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-10131675-B2
Application number	US-201715699095-A
Country	US
Kind code	B2
Filing date	Sep 8, 2017
Priority date	Mar 9, 2015
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

The invention relates to compounds of formula (I) and salts thereof:

wherein ring A and R 1 -R 2 have any of the values defined in the specification. The compounds and salts are useful for treating DLK mediated disorders. The invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as well as methods of using said compounds, salts, or compositions as DLK inhibitors and for treating neurodegeneration diseases and disorders.

First claim

We claim:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:
A is a 6-10 membered heterocyclyl comprising one or more oxygen atoms, which heterocyclyl is optionally substituted with one or more groups independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl, wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl is optionally substituted with one or more groups independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 carbocyclyl;
X is N or CH;
R 1 is selected from the group consisting of hydrogen, —O—R d , —N(R d ) 2 , a 3-12 membered carbocyclyl,

which 3-12 membered carbocyclyl is optionally substituted with one or more groups independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, halo, —NO 2 , —N(R b ) 2 , —CN, —C(O)—N(R b ) 2 , —O—R b , —O—C(O)—R b , —C(O) R b , —C(O)—OR b , and —N(R b )—C(O)—R b , wherein any C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO 2 , —N(R b ) 2 , —CN, —C(O)—N(R b ) 2 , —O—R b , —O—C(O)—R b , —C(O)—R b , —C(O)—OR b , and —N(R b )—C(O)—R b ;
each R b is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO 2 , —N(R c ) 2 , —CN, —C(O)—N(R c ) 2 , —O—R c , —O—C(O)—R c , —C(O)—R c , —C(O)—ORc, and —N(R c )—C(O)—R c ; or two R b are taken together with the nitrogen to which they are attached to form a 3-8 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;
each R c is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, amino, hydroxy, C 1-6 alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; or two R c are taken together with the nitrogen to which they are attached to form a 3-8 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;
each R d is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, C 3-6 carbocyclyl, —NO 2 , —N(R c ) 2 , —CN, —C(O)—N(R c ) 2 , —O—R c , —O—C(O)—R c , —C(O) R c , —C(O)—ORc, and —N(R c )—C(O)—R c ;
R 2 is a 3-12 membered heterocyclyl, which 3-12 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, oxo, halo, —NO 2 , —N(R e ) 2 , —CN, —C(O)—N(R e ) 2 , —O—R e , —O—C(O)—R e , —C(O)—R e , —C(O)—OR e , and —N(R e )—C(O)—R e , wherein any C 1-6 alkyl, C 2-6 alkenyl, C 3-6 carbocyclyl, and C 2-6 alkynyl, is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO 2 , —N(R e ) 2 , —CN, —C(O)—N(R e ) 2 , —O—R e , —O—C(O)—R e , —C(O)—R e , —C(O)—ORe, and —N(R e )—C(O)—R e ;
each R e is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO 2 , —N(R f ) 2 , —CN, —C(O)—N(R f ) 2 , —O—R f , —O—C(O)—R f , —C(O)—R f , —C(O)—OR f , —N(R f )—C(O)—R f , and C 3-6 carbocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; or two R e are taken together with the nitrogen to which they are attached to form a 3-8 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; and
each R f is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, amino, hydroxy, C 1-6 alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; or two R f are taken together with the nitrogen to which they are attached to form a 3-8 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo.

2. The compound of claim 1 , which is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

Assignees

• Genentech Inc

Inventors

• Estrada Anthony
• Patel Snahel
• Kellar Terry
• Huestis Malcolm
• Shore Daniel
• Siu Michael

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title