Substituted heterocycles as hset inhibitors

Patent metadata

Field	Value
Publication number	US-2025084074-A1
Application number	US-202318727543-A
Country	US
Kind code	A1
Filing date	Jan 9, 2023
Priority date	Jan 10, 2022
Publication date	Mar 13, 2025
Grant date	—

Abstract

The invention relates to substituted heterocycles of the general formula I,and the use of the compounds of the present invention for the treatment and/or prevention of hyperproliferative diseases and disorders in mammals, especially humans, and pharmaceutical compositions containing such compound.

First claim

1 . Compound of the formula I,

wherein
W denotes

R 1 denotes Hal, CN, A, COOR 7 , CON(R 7 ) 2 , COA′ or Het 1 ,
R 2 denotes H, Hal, A′,
R 3 denotes

R 4 , R 8 denote independently of one another H, unbranched or branched alkyl with 1-3 C-atoms,
R 5 denotes H or one or more substituents selected from the group of Hal, A, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 and CH 2 CN,
R 6 denotes benzoyl, 2-isoquinolinyl or 4-quinazolinyl, which is unsubstituted or one-, two-, or threefold substituted with Hal, A, OH,
N(R 7 ) 2 , COOR 7 , CN, NO 2 and/or or Het 2 ,
A denotes unbranched or branched alkyl or cycloalkyl with 1-10 C-atoms, wherein two adjacent CH— and/or CH 2 -groups may form a double bond and wherein one or two non-adjacent CH— and/or CH 2 -groups may be replaced by N-, O- and/or S-atoms and wherein 1-7 H-atoms may be replaced by F or CI,
A′ denotes unbranched or branched alkyl with 1-4 C-atoms, wherein 1-7 H-atoms may be replaced by F or Cl,
Het 1 denotes oxadiazolyl, which is unsubstituted or substituted with unbranched or branched alkyl with 1-4 C-atoms,
Het 2 denotes oxadiazolyl, tetrazolyl, pyrazolyl or oxazolyl, which unsubstituted or substituted with unbranched or branched alkyl with 1-4 C-atoms,
R 7 denotes H or A,
Hal denotes F, Cl, Br or I
and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

2 . Compound according to claim 1 , wherein
W denotes

and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A′, Het 1 and Het 2 have the meanings as above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

3 . Compound according to claim 1 , wherein
W denotes

and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A′, Het 1 and Het 2 have the meanings as above and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

4 . Compound according to claim 1 , wherein
W denotes

and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A′, Het 1 and Het 2 have the meanings as above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

5 . Compound according to claim 1 , wherein
R 2 denotes H or A′ and W, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A′, Het 1 and Het 2 have the meanings as above and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

6 . Compound according to claim 1 , wherein
R 2 denotes H or methyl and W, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A′, Het 1 and Het 2 have the meanings as in above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

7 . Compound according to claim 1 , wherein
R 3 denotes

and W, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A′, Het 1 and Het 2 have the meanings as in above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

8 . Compound according to claim 1 , wherein
R 3 denotes

and W, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A′, Het 1 and Het 2 have the meanings as above and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

9 . Compound according to claim 1 , wherein
R 6 denotes benzoyl or 2-isoquinolinyl and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , A, A′, Het 1 and Het 2 have the meanings as above and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

10 . Compound according to claim 1 , wherein
Het 2 denotes oxadiazolyl or tetrazolyl and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A′, and Het 1 have the meanings as above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

11 . Compound according to claim 1 , wherein
Het 2 denotes methyl-oxadiazolyl or methyl-tetrazolyl and W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, A′, and Het 1 have the meanings as above, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereo-isomers thereof, including mixtures thereof in all ratios.

12 . Compound selected from the group consisting of:

1
Ethyl-4-methyl-2-(3-(3-

methylbenzamido)propanamido)thiazole-5-

carboxylate

2
Ethyl-4-methyl-2-(3-(3-(pyrrolidin-1-

yl)benzamido)propanamido)thiazole-5-carboxylate

3
Ethyl-2-(3-(3-(1H-pyrazol-1-yl)benzamido)propanamido)-4-

methylthiazole-5-carboxylate

4
Ethyl-4-methyl-2-(3-(3-(5-methyl-1,2,4-oxadiazol-3-

yl)benzamido)propanamido)thiazole-5-carboxylate

5
Ethyl-4-methyl-2-(3-(5,6,7,8-tetrahydronaphthalene-2-

carboxamido)propanamido)thiazole-5-carboxylate

6
Ethyl-4-methyl-2-(3-(3-(oxazol-5-

yl)benzamido)propanamido)thiazole-5-carboxylate

7
Ethyl-4-methyl-2-(3-(3-

morpholinobenzamido)propanamido)thiazole-

5-carboxylate

8
Ethyl-(S)-2-(2-hydroxy-3-(3-

methylbenzamido)propanamido)-4-

methylthiazole-5-carboxylate

9
Ethyl-2-[3-[(3-

methoxycarbonylbenz

Assignees

• Merck Patent Gmbh
• The Institute Of Cancer Res
• Cancer Res Horizons

Inventors

• Buchstaller Hans-Peter
• Kuhn Daniel
• Collins Ian
• Matthews Thomas
• Lanz Jan
• Caldwell John
• Colombano Giampiero

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D277/56 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• A61K31/5377

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