# US 11,026,936 B2 · Piperidinyl-propanone derivatives

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- Number: US 11,026,936 B2
- Document ID: US11026936B2
- Status: Granted
- Kind: B2
- Application number: 16/089,463
- Filed: 2017-03-27
- Published: 2020-08-13
- Granted: 2021-06-08
- Earliest claimed: 2016-03-29
- Assignees: Merck Patent GmbH
- Applicants: Merck Patent GmbH
- Inventors: Hans-Peter Buchstaller
- Web page: https://patentgrep.com/patent/US11026936B2

## CPC

- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/08: linked by a carbon chain containing alicyclic rings
- C07D 401/14: containing three or more hetero rings
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/08: linked by a carbon chain containing alicyclic rings
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds of the formula I in which X, Q, R1 and R2 have the meanings indicated in Claim 1, are inhibitors of pyruvate dehydrogenase kinase (PDHK), and can be employed, inter alia, for the treatment of diseases such as cancer.

## Claims

### Claim 1

A compound of the formula I
in which
X denotes NH or O,
Q denotes C(CH3)2 or 1,1-cyclopropylene,
R1 denotes H, A, Cyc, Ar or Het,
R2 denotes H or CH3,
R3 denotes H or A′,
Ar denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, NO2, CN, A, OR3, S(O)mR3, N(R3)2, COA, COOR3, CON(R3)2, SO2N(R3)2, NR3COR3, NR3SO2A and/or NR3CON(R3)2,
Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono- or disubstituted by Hal, NO2, CN, A, OR3, S(O)mR3, N(R3)2, COA, COOR3, CON(R3)2, SO2N(R3)2, NR3COR3, NR3SO2A and/or NR3CON(R3)2,
A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH2-groups may be replaced by N-, O- and/or S-atoms and/or wherein 1-7 H-atoms may be replaced by R4,
R4 denotes F, Cl or OH,
A′ denotes unbranched or branched alkyl with 1-6 C-atoms, wherein 1-5 H-atoms may be replaced by F,
Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, which is unsubstituted or monosubstituted by OH,
Hal denotes F, Cl, Br or I,
m denotes 0, 1 or 2,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 2 (depends on 1)

A compound according to claim 1 in which
R1 denotes A, Cyc, Ar or Het,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 3 (depends on 1)

A compound according to claim 1, in which
R3 denotes H or CH3,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 4 (depends on 1)

A compound according to claim 1, in which
Ar denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, A and/or OR3,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 5 (depends on 1)

A compound according to claim 1, in which
Het denotes pyrimidyl, pyridyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, triazolyl, oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono- or disubstituted by Hal, A, CN and/or OR3,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 6 (depends on 1)

A compound according to claim 1, in which
Het denotes pyrimidyl, pyridyl, pyridazinyl or pyrazinyl, each of which is unsubstituted or mono- or disubstituted by A and/or OR3,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 7 (depends on 1)

A compound according to claim 1, in which
A denotes unbranched or branched alkyl with 1-6 C-atoms, wherein 1-5 H-atoms may be replaced by F,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 8 (depends on 1)

A compound according to claim 1, in which
Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 9 (depends on 1)

A compound according to claim 1 in which
X denotes NH or O,
Q denotes C(CH3)2 or 1,1-cyclopropylene,
R1 denotes A, Cyc, Ar or Het,
R2 denotes H or CH3,
R3 denotes H or CH3,
Ar denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, A and/or OR3,
Het denotes pyrimidyl, pyridyl, pyridazinyl or pyrazinyl, each of which is unsubstituted or mono- or disubstituted by A and/or OR3,
A denotes unbranched or branched alkyl with 1-6 C-atoms, wherein 1-5 H-atoms may be replaced by F,
Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms,
Hal denotes F, Cl, Br or I,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 10 (depends on 1)

A compound according to claim 1, that is:
No.
Name
“A1”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-phenyl-1H-
[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A2”
(R)-3,3,3-Trifluoro-1-{4-{1-[5-(4-fluorophenyl)-4H-[1,2,4]triazol-3-
yl]-cyclopropyl}-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one
“A3”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-methyl-1-(5-phenyl-4H-
[1,2,4]triazol-3-yl)-ethyl]-piperidin-1-yl}-propan-1-one
“A4”
(R)-1-{4-[1-(5-Cyclohexyl-4H-[1,2,4]triazol-3-yl)-1-methyl-ethyl]-
piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one
“A5”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-phenyl-
[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A6”
(R)-3,3,3-Trifluoro-1-{4-{1-[5-(4-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-
cyclopropyl}-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one
“A7”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-methyl-
[1,3,4]oxadizaol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A8”
(R)-1-{4-[1-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-
3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one
“A9”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-methyl-1-(5-phenyl-
[1,3,4]oxadiazol-2-yl)-ethyl]-piperidin-1-yl}-propan-1-one
“A10”
(R)-1-{4-[1-(5-Cyclohexyl-[1,3,4]oxadiazol-2-yl)-1-methyl-ethyl]-
piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one
“A11”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-phenyl-1H-
[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A12”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-phenyl-
[1,3,4]oxadizaol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A13”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3R,4R)-3-methyl-4-[1-(5-phenyl-4H-
[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A14”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3S,4S)-3-methyl-4-[1-
(5-phenyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A15”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(S)-3-methyl-4-[1-(5-phenyl-
[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A16”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(R)-3-methyl-4-[1-(5-phenyl-
[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A17”
(R)-3,3,3-Trifluoro-1-(4-{1-[5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-
cyclopropyl}-3-methyl-piperidin-1-yl)-2-hydroxy-2-methyl-propan-1-one
“A18”
(R)-3,3,3-Trifluoro-1-((3R,4R)-4-{1-[5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-
cyclopropyl}-3-methyl-piperidin-1-yl)-2-hydroxy-2-methyl-propan-1-one
“A19”
(R)-3,3,3-Trifluoro-1-((3S,4S)-4-{1-[5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-
cyclopropyl}-3-methyl-piperidin-1-yl)-2-hydroxy-2-methyl-propan-1-one
“A20”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-p-tolyl-4H-[1,2,4]
triazol-3-yl}-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A21”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3R,4R)-3-methyl-4-[1-(5-p-tolyl-4H-
[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A22”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3S,4S)-3-methyl-4-[1-(5-p-tolyl-4H-
[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl)-propan-1-one
“A23”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-p-tolyl-[1,3,4]oxadiazol-
2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A24”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3R,4R)-3-methyl-4-[1-(5-p-tolyl-
[1,3,4]oxadiazo1-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A25”
(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3S,4S)-3-methyl-4-[1-(5-p-tolyl-
[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one
“A26”
(R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-
cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A27”
(R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(4-methoxy-phenyl)-4H-
[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A28”
(R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(4-methoxy-phenyl)-4H-
[1,2,4]trizaol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A29”
(R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(4-methoxy-phenyl)-
[1,3,4]oxadizaol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A30”
(R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-
cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A31”
(R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-
cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A32”
(R)-1-(4-{1-[5-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-
3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one
“A33”
(R)-1-((3R,4R)-4-{1-[5-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-
3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one
“A34”
(R)-1-((3S,4S)-4-{1-[5-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-
3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one
“A35”
(R)-1-(4-{1-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-
3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one
“A36”
(R)-1-((3R,4R)-4-{1-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-
3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one
“A37”
(R)-1-((3S,4S)-4-{1-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-
3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one
“A38”
(R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(6-methoxy-pyridin-3-yl)-4H-
[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A39”
(R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(6-methoxy-pyridin-3-yl)-4H-
[1,2,4]triazol-3-yl]cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A40”
(R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(6-methoxy-pyridin-3-yl)-4H-
[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A41”
(R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(6-methoxy-pyridin-3-yl)-
[1,3,4]oxadizaol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A42”
(R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(6-methoxy-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-
cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
“A43”
(R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(6-methoxy-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-
cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 11 (depends on 1)

A process for the preparation of a compound of the formula I according to claim 1 and pharmaceutically acceptable salts, tautomers and stereoisomers thereof,
wherein X denotes NH,
wherein
a compound of the formula II
in which
Q denotes C(CH3)2 or 1,1-cyclopropylene,
R2 denotes H or CH3,
is reacted with a compound of the formula III
R1—C(═NH)OCH3 III
in which
R1 denotes H, A, Cyc, Ar or Het,
and/or
a base or acid of the formula I is converted into one of its salts.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising at least one compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios, and optionally a pharmaceutically acceptable carrier, excipient or vehicle.

### Claim 13 (depends on 1)

A method for treating cancer or diabetes comprising administering a compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

### Claim 14 (depends on 12)

A method for treating cancer comprising administering a pharmaceutical composition according to claim 12.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising at least one compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios, and at least one further active ingredient.

### Claim 16 (depends on 1)

A set (kit) consisting of separate packs of
(a) an effective amount of a compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, tautomer and or stereoisomer thereof, including mixtures thereof in all ratios, and
(b) an effective amount of a further active ingredient.

### Claim 17 (depends on 1)

A method of inhibiting PDHK comprising administering a compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.