Treatment of skin lesions

Patent metadata

Field	Value
Publication number	US-10993947-B2
Application number	US-201716301728-A
Country	US
Kind code	B2
Filing date	May 17, 2017
Priority date	May 18, 2016
Publication date	May 4, 2021
Grant date	May 4, 2021

Abstract

The present invention is relates to 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; W is H or F; with the proviso that when W is F, then X 1 , X 2 and X 3 are N; 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); or
(ii) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R 7 ; wherein R 7 is independently at each occurrence C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl; or two R 7 substituents form together a bivalent residue —R 8 R 9 — 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—;

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, for use in the prevention or treatment of a skin lesion in a subject.

First claim

The invention claimed is:

1. A method of preventing or treating a skin lesion in a subject in need thereof comprising administering an effective amount of a compound of formula (I) to said subject,

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;
W is H;
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); or
(ii) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R 7 ; wherein R 7 is independently at each occurrence C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl; or two R 7 substituents form together a bivalent residue —R 8 R 9 — 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—;

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 method according to claim 1 , wherein said R 1 and said R 2 are independently of each other selected from

3. The method according to claim 1 , wherein R and R 2 are independently of each other selected from

4. The method 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-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine;
4′-(difluoromethyl)-2,6-dimorpholino-[4,5′-bipyrimidin]-2′-amine;
4-(difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine;
4′-(difluoromethyl)-4,6-dimorpholino-[2,5′-bipyrimidin]-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-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;
5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;
2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4′-(difluoromethyl)-6-morpholino-[4,5′-bipyrimidin]-2′-amine;
5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine;
4′-(difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5′-bipyrimidin]-2′-amine;
(S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine;
(S)-4′-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5′-bipyrimidin]-2′-amine;
5-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;
5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;
(S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine;
(S)-4′-(difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5′-bipyrimidin]-2′-amine;
4-(difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;
5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;
5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;
4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;
5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;
5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;
5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;
4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine;
4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;
4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;
4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;
4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;
4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;
4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;
4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;
4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;
5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;
5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluo

Assignees

• Piqur Therapeutics Ag
• Univ Pennsylvania
• Torqur

Inventors

• Fabbro Doriano
• Hebeisen Paul
• Hillmann-Wuellner Petra
• Stuetz Anton
• Seykora John T
• Beaufils Florent

Classifications

• A61K31/00

  Medicinal preparations containing organic active ingredients · CPC title

• A61K31/5377 Primary

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

• A61K31/5386 Primary

  spiro-condensed or forming part of bridged ring systems · CPC title

• A61P17/02

  for treating wounds, ulcers, burns, scars, keloids, or the like · CPC title

• A61P35/00

  Antineoplastic agents · CPC title