Difluoromethyl-aminopyridines and difluoromethyl-aminopyrimidines

Patent metadata

Field	Value
Publication number	US-2022153752-A1
Application number	US-202117499048-A
Country	US
Kind code	A1
Filing date	Oct 12, 2021
Priority date	Nov 11, 2014
Publication date	May 19, 2022
Grant date	—

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 X1, X2 and X3 are N or CH, with the proviso that at least two of X1, X2 and X3 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

1 . A compound of formula (I),

wherein
X 1 , X 2 and X 3 are, independently of each other, 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;
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 —R 5 R 6 — 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;
and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts thereof.

2 . The compound of formula (I) according to claim 1 , wherein X 1 , X 2 and X 3 are N; and tautomers, solvates and pharmaceutically acceptable salts thereof.

3 . 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 .

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

5 . (canceled)

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

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

8 . 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-tr

Assignees

• Torqur Ag
• Univ Basel

Inventors

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

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D491/048

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

• C07D417/14

  containing three or more hetero rings · 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

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title