Inhibitors of SYK

Patent metadata

Field	Value
Publication number	US-10112928-B2
Application number	US-201314435823-A
Country	US
Kind code	B2
Filing date	Oct 15, 2013
Priority date	Oct 19, 2012
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

The present invention relates to the use of novel compounds of formula I: wherein all variable substituents are defined as described herein, which are SYK inhibitors and are useful for the treatment of auto-immune and inflammatory diseases.

First claim

We claim:

1. A compound of Formula I

wherein:
R 1 is —OR 1′ or (CH 2 ) n R 1′ ;
R 1′ is phenyl, pyridyl, cycloalkyl, amino cycloalkyl C 1-6 alkyl or C 1-6 alkyl, optionally substituted with one or more R 1″ ;
each R 1″ is independently cyano, amino, amino C 1-6 alkyl, halo, C 1-6 alkyl, cycloalkyl, or amino cycloalkyl C 1-6 alkyl;

R 2 is C 1-6 alkyl, cycloalkyl, cyano C 1-6 alkyl, hydroxy C 1-6 alkyl, halo C 1-6 alkyl, dialkyl amino, or C 1-6 alkoxy;
R 3 is absent;
R 4 is H or C 1-6 alkyl;
X 1 is CH or N;
X 2 is CH, CR 2 or N;
X 3 is CH or N;
Y 1 is N; and
Y 2 is N;
Y 3 is CH; and
n is 0 or 1;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein,

wherein:
R 1 is —OR 1′ (CH 2 ) n R 1′ ;
R 1′ is phenyl, pyridyl, cycloalkyl, or C 1-6 alkyl, optionally substituted with one or more R 1″ ;
each R 1″ is independently cyano, amino, amino C 1-6 alkyl, halo, C 1-6 alkyl, cycloalkyl, or amino cycloalkyl C 1-6 alkyl;

R 2 is C 1-6 alkyl, cycloalkyl, cyano CI-alkyl, hydroxy C 1-6 alkyl, halo C 1-6 alkyl, dialkyl amino, or C 1-6 alkoxy;
R 3 is absent;
R 4 is H or C 1-6 alkyl;
X 1 is CH or N;
X 2 is CH, CR 2 or N;
X 3 is CH or N;
Y 1 is N;
Y 2 is N; and
Y 3 is CH;
or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein R 1′ is C 1-6 alkyl, optionally substituted with one or more R 1′ .

4. The compound according to claim 1 , wherein X 1 is N.

5. The compound according to claim 1 , wherein X 2 is CR 2 and X 3 is CH.

6. The compound according to claim 1 , wherein R 4 is H.

7. The compound according to claim 1 , wherein R 2 is C 1-6 alkyl.

8. The compound according to claim 1 , wherein R 3 is C 1-6 alkoxy or C 1-6 alkyl.

9. The compound according to claim 1 , wherein R 1 is —OR 1′ , optionally substituted with one or more R 1″ .

10. A compound, selected from the group consisting of:
4-(6-methylpyridin-2-ylamino)-6-phenoxypyridazine-3-carboxamide;
6-(3-cyanophenoxy)-4-(6-methylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-(3-(2-aminopropan-2-yl)phenoxy)-4-(6-methylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-(3-fluorophenoxy)-4-(6-methylpyridin-2-ylamino)pyridazine-3-carboxamide;
4-(6-methylpyridin-2-ylamino)-6-(pyridin-3-yloxy)pyridazine-3-carboxamide;
6-(2-cyanophenoxy)-4-(6-methylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-ethylphenoxy)-4-(6-methylpyridin-2-ylamino)pyridazine-3-carboxamide;
4-(6-methylpyridin-2-ylamino)-6-(o-tolyloxy)pyridazine-3-carboxamide;
6-(4-chloro-2-cyanophenoxy)-4-(6-methylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-cyclopropylphenoxy)-4-(6-methylpyridin-2-ylamino)pyridazine-3-carboxamide;
4-(6-Cyclopropyl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridazine-3-carboxylic acid amide;
6-(1-amino-4-methylpentan-2-ylamino)-4-(6-tert-butylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethoxy)-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-chloro-4-(3,5-dimethylphenylamino)pyridazine-3-carboxamide;
6-(1-Aminomethyl-3-methyl-butylamino)-4-(6-isopropyl-5-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide;
6-(2-aminoethylamino)-4-(6-tert-butylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-((R)-1-Aminomethyl-3-methyl-butylamino)-4-(6-tert-butyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide;
(6-(2-aminoethylamino)-4-(6-isopropyl-5-methylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-((1-aminocyclopropyl)methylamino)-4-(6-tert-butylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethylamino)-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethylamino)-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethylamino)-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethylamino)-4-(6-(trifluoromethyl)pyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethylamino)-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethylamino)-4-(6-(dimethylamino)-5-methylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethylamino)-4-(6-(2-methoxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethylamino)-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethylamino)-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide;
6-(2-aminoethylamino)-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxamide; and
6-(2-Aminoethylamino)-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide,
or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

Assignees

• Hoffmann La Roche

Inventors

• Bhagirath Niala
• Kennedy-Smith Joshua
• Le Nam T
• Lucas Matthew C
• Padilla Fernando
• Soth Michael

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title