Difluoromethyl-aminopyridines and difluoromethyl-aminopyrimidines

Patent metadata

Field	Value
Publication number	US-10640516-B2
Application number	US-201515525779-A
Country	US
Kind code	B2
Filing date	Nov 10, 2015
Priority date	Nov 11, 2014
Publication date	May 5, 2020
Grant date	May 5, 2020

Abstract

The invention relates to novel phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR) and PI3k-related kinase (PIKKs) inhibitor compounds of formula (I),

wherein X 1 , X 2 and X 3 are N or CH, with the proviso that at least two of X 1 , X 2 and X 3 are N; Y is N or CH, These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

First claim

The invention claimed is:

1. A compound of formula (I),

wherein
X 1 , X 2 and X 3 are N;
Y is N or CH;
R 1 and R 2 are independently of each other
(i) a morpholinyl of formula (II)

wherein the arrow denotes the bond in formula (I); and
wherein R 3 and R 4 are independently of each other H, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, CN, or C(O)O—C 1 -C 2 alkyl; or
R 3 and R 4 form together a bivalent residue selected from C 1 -C 3 alkylene optionally substituted with 1 to 4 F, —CH 2 —O—CH 2 —, —CH 2 —NH—CH 2 —, or any of the structures

wherein the arrows denote the bonds in formula (II);

(ii) phenyl optionally substituted with 1 to 3 R 7 , wherein R 7 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 ) 2 ;
(iii) a 5- to 6-membered heteroaryl ring W containing one to four heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 8 , wherein R 8 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 ) 2 ;
(iv) a saturated 4- to 6-membered heterocyclic ring Z containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 9 ; wherein R 9 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, ═O, —NH 2 , NHCH 3 or N(CH 3 ) 2 ; or two R 9 substituents form together a bivalent residue —R 10 R 11 selected from C 1 -C 3 alkylene optionally substituted with 1 to 4 F, —CH 2 —O—CH 2 — or —O—CH 2 CH 2 —O—;
(v) OR 12 , wherein R 12 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 2 alkyleneC 3 -C 6 cycloalkyl; Cycle-P or C 1 -C 2 alkyleneCycle-P, wherein Cycle-P represents a saturated 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 13 , wherein R 13 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 ); Cycle-Q or C 1 -C 2 alkyleneCycle-Q, wherein Cycle-Q represents 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 14 , wherein R 14 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 ); or
(vi) NR 15 R 16 ; wherein R 15 and R 16 are independently of each other H, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl; Cycle-P or C 1 -C 2 alkyleneCycle-P, wherein Cycle-P represents a saturated 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 13 , wherein R 13 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 ); Cycle-Q or C 1 -C 2 alkyleneCycle-Q, wherein Cycle-Q represents 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 14 , wherein R 14 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 );

with the proviso that at least one of R 1 and R 2 is a morpholinyl of formula II;
or a tautomer, solvate, or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1 , wherein said R 1 and said R 2 are independently of each other (i) a morpholinyl of formula (II); (ii) said 5- to 6-membered heteroaryl ring W; (iii) said saturated 4- to 6-membered heterocyclic ring Z; (iv) said OR 12 ; or (v) said NR 15 R 16 .

3. The compound of formula (I) according to claim 1 , wherein said R 1 and said R 2 are independently of each other selected from

4. The compound of formula (I) according to claim 1 , wherein R 1 and R 2 are independently of each other selected from

5. The compound of formula (I) according to claim 1 , wherein R 1 and R 2 are independently of each other selected from

6. The compound of formula (I) according to claim 1 , wherein said compound is selected from
4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;
4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;
5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;
5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;
5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;
5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;
5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;
(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;
(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;
5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;
5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;
4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;
4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;
(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;
(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;
4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;
4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;
5-(4-(8-Oxa

Assignees

• Piqur Therapeutics Ag
• Univ Basel

Inventors

• Cmiljanovic Vladimir
• Hebeisen Paul
• Beaufils Florent
• Bohnacker Thomas
• Rageot Denise
• Sele Alexander
• Wymann Matthias
• Langlois Jean-Baptiste

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D498/08 Primary

  Bridged systems · CPC title

• C07D491/20 Primary

  Spiro-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title