# US 11,111,238 B2 · Coumarin derivatives, processes for their preparation and uses thereof for the treatment of cancer

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- Number: US 11,111,238 B2
- Document ID: US11111238B2
- Status: Granted
- Kind: B2
- Application number: 16/648,348
- Filed: 2018-09-20
- Published: 2020-09-17
- Granted: 2021-09-07
- Earliest claimed: 2017-09-20
- Assignees: Lead Discovery Center GmbH; Max Planck Gesellschaft zur Förderung der Wissenschften e.V.; SOTIO a.s.
- Applicants: Lead Discovery Center GmbH; Max Planck Gesellschaft zur Förderung der Wissenschaften e. V.; SOTIO a.s.
- Inventors: Raffaella Di Lucrezia; Tim Bergbrede; Peter Nussbaumer; Uwe Koch; Bert Klebl; Axel Choidas; Anke Unger; Nils-Göran Larsson; Maria Falkenberg-Gustafsson; Claes M. Gustafsson
- Web page: https://patentgrep.com/patent/US11111238B2

## CPC

- C07D 413/14: containing three or more hetero rings
- C07D 311/18: substituted otherwise than in position 3 or 7
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D 491/052: the oxygen-containing ring being six-membered
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)

## Abstract

The invention provides novel coumarin derivatives as specific mitochondrial RNA polymerase inhibitors for the treatment of cancer.

## Claims

### Claim 1

A compound of the general formula (I)
wherein
R is —C1-C4-alkyl;
R1 is —H, or -methyl;
M is CH or N;
W is
wherein
R2 is C1-C4-alkyl, -halogen, —CN;
X is -halogen, or —CN;
n=0, 1, or 2;
Y is —NR3R4 wherein
R3 is —H, or —C1-C4-alkyl, and
R4 is —C1-C4-alkyl or —C3-C6-cycloalkyl; or
an unsubstituted or substituted pyridine residue; or
an unsubstituted or substituted phenyl residue; or
Y is —NR3R4 with N, R3 and R4 forming an unsubstituted or substituted 5- or 6-membered saturated heterocycle; or
Y is —OR11, with R11 is —H or —C1-C4-alkyl;
or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein
R is —C1-C4-alkyl;
R1 is —H, or -methyl;
M is —CH;
W is
wherein
R2 is methyl, -halogen, —CN;
X is -halogen, or —CN;
n=0, 1, or 2;
Y is —NR3R4 wherein
R3 is —H, or —C1-C4-alkyl, and
R4 is —C1-C4-alkyl or —C3-C6-cycloalkyl; or
an unsubstituted or substituted pyridine residue; or
an unsubstituted or substituted phenyl residue;
Y is —NR3R4 with N, R3 and R4 forming an unsubstituted or substituted 5- or 6-membered saturated heterocycle; or
Y is —OR11, with R11 is —H or —C1-C4-alkyl;
or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Y is —NR3R4, wherein
R3 is —H, or —C1-C4-alkyl, and
R4 is a pyridine residue; or a phenyl residue substituted with —(CH2)pOH with p=1 or 2; or
—C1-C4-alkyl or —C3-C6-cycloalkyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein N, R3 and R4 together form an unsubstituted or substituted piperidine, piperazine or pyrrolidine residue, each optionally and independently substituted with one or more of the following residues:
—C1-C4-alkyl;
—(CH2)m—COOR5 with R5 is —H, —C1-C8-alkyl, —C2-C4-alkyl-N-morpholine or the group
—(CH2)mCONR6R7 with R6 and R7 is independently —H, or —C1-C4-alkyl;
—CO—(C2-C4-alkenyl); —CO—CH2—Cl; —CO—CH2—CH3;
NH—CO—(C2-C4-alkenyl); —NH—CO—CH2—Cl; —NH—CO—CH2—CH3;
—F;
—CN;
—SO3H;
—SO2NR8R9 with R8 and R9 independently are —H, or —C1-C4-alkyl;
—SONHR10 with R10 is —C1-C4-alkyl; or
and
m=0, 1, or 2.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein N, R3 and R4 together form an unsubstituted or substituted piperidine or pyrrolidine residue, each optionally and independently substituted with one or more of the following residues:
—C1-C4-alkyl;
—(CH2)m—COOR5 with R5 is —H, —C1-C8-alkyl, —C2-C4-alkyl-N-morpholine or the group
—(CH2)mCONR6R7 with R6 and R7 is independently —H, or —C1-C4-alkyl;
—F;
—CN;
—SO3H;
—SO2NR8R9 with R5 and R9 independently are —H, or —C1-C4-alkyl;
—SONHR10 with R10 is —C1-C4-alkyl; or
and
m=0, 1, or 2.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein
R is -methyl;
R1 is —H;
m=0, or 1;
W is
wherein
R2 is methyl, or —Cl;
X is —F with n=1;
Y is —NR3R4
wherein
R3 is —H, and
R4 is a pyridine residue,
a phenyl residue substituted at the para position;
or with
N, R3 and R4 forming together a piperidine residue, or a pyrrolidine residue, each optionally and independently substituted with one of the following residues: —COOH, —COOCH3, —COOC2H5, —CH2COOH, —CH2COOCH3, —CH2COOCH2CH3, —CONH2, —CONHCH3, —CON(CH3)2, —CH2CONHCH3, —SO2NH2, —SO2NHCH3, or —CN.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein
R is (R)-methyl;
R1 is —H;
W is
with
R2 is methyl, or Cl;
X is —F with n=1;
Y is —NR3R4
with
N, R3 and R4 forming a piperidine residue, or a pyrrolidine residue, each optionally and independently substituted with one of the following residues: —COOH, —CH2COOH, —CONHCH3, —CH2CONHCH3, —SO2NH2, —SO2NHCH3, or —CN.

### Claim 8 (depends on 4)

The compound according to claim 4, wherein the piperidine residue or the pyrrolidine residue is substituted at the 3-position.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein X is at the para-position of the phenyl ring.

### Claim 10 (depends on 1)

The compound of claim 1, wherein
R is -methyl or -ethyl;
R1 is —H;
M is CH or N;
W is
wherein
R2 is -methyl, -ethyl, —Cl, or —Br;
X is —Cl, or —F;
n=0, 1 or 2;
Y is —NR3R4 wherein
R3 is —H or -methyl, and
R4 is -methyl, -ethyl, -isopropyl, or -cyclopropyl; or
an unsubstituted or substituted pyridine residue; or
an unsubstituted or a phenyl residue substituted at the para position; or
Y is —NR3R4 with N, R3 and R4 forming an unsubstituted or substituted 5- or 6-membered saturated heterocycle; or
Y is —OR11, wherein R11 is -methyl, -ethyl, or -isopropyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein
R is -methyl;
R1 is —H;
M is —CH:
W is
wherein
R2 is -methyl, —Cl, or —Br;
X is —F;
n=1 or 2;
Y is —NR3R4, wherein
R3 is —H or -methyl, and
R4 is -methyl, -ethyl, -isopropyl, or -cyclopropyl; or
an unsubstituted or substituted pyridine residue; or
an unsubstituted or a substituted phenyl residue, substituted at the para position;
Y is —NR3R4 with N, R3 and R4 forming an unsubstituted or substituted 5- or 6-membered saturated heterocycle; or
Y is —OR11, wherein R11 is -methyl, -ethyl, or -isopropyl.

### Claim 12 (depends on 4)

The compound of claim 4, wherein
R5 is —H, -methyl, -ethyl, -isopropyl, -tert-butyl, -n-heptyl, 2-morpholinoethyl or -isopropoxycarbonyloxymethyl;
R10 is -methyl; and
m is 0 or 1.

### Claim 13 (depends on 1)

The compound of formula (I) according to claim 1, selected from
7-[1-methyl-2-oxo-2-(1-piperidyl)ethoxy]-4-(o-tolyl)chromen-2-one, 4-(2-chlorophenyl)-7-[1-methyl-2-oxo-2-(1-piperidyl)ethoxy]chromen-2-one,
(3S)-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxy-N-(2-pyridyl)propanamide,
7-(1-methyl-2-oxo-2-pyrrolidin-1-yl-ethoxy)-4-(o-tolyl)chromen-2-one,
methyl -1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
methyl -1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-sulfonic acid,
1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-sulfonic acid,
1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-sulfonamide,
4-(2-chlorophenyl)-7-(1-methyl-2-oxo-2-pyrrolidin-1-yl-ethoxy)chromen-2-one,
(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-N-methyl-piperidine-3-carboxamide,
ethyl (3S)-1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
ethyl (3S)-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
N-methyl-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-sulfonamide,
N-[4-(2-hydroxyethyl)phenyl]-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxy-propanamide,
1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-N-methyl-piperidine-3-sulfonamide,
N-methyl-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxamide,
(3S)-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]pyrrolidine-3-carboxylic acid,
(3S)-1-[(2R)-2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-sulfonamide,
N-cyclopropyl-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxy-propanamide,
2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-N-cyclopropyl-propanamide,
(3S)-1-[(2R)-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
(3S)-1-[(2R)-2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carbonitrile,
(3S)-1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]pyrrolidine-3-carboxylic acid,
7-[(1R)-1-methyl-2-oxo-2-(1-piperidyl)ethoxy]-4-(o-tolyl)chromen-2-one,
2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-N-(2-pyridyl)propanamide,
(3S)-1-[(2R)-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carbonitrile,
(3S)-1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
4-(2-chlorophenyl)-7-[(1R)-1-methyl-2-oxo-2-(1-piperidyl)ethoxy]chromen-2-one,
2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-N-[4-(2-hydroxyethyl)phenyl]propanamide,
(2R)—N-isopropyl-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxy-propanamide,
1-[2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-methyl-piperidine-3-carboxylic acid,
N,N-dimethyl-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxy-propanamide,
4-(2-chlorophenyl)-7-[1-methyl-2-oxo-2-[3-(2H-tetrazol-5-yl)-1-piperidyl]ethoxy]chromen-2-one,
ethyl 2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoate,
1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carbonitrile,
7-[1-methyl-2-oxo-2-[3-(2H-tetrazol-5-yl)-1-piperidyl]ethoxy]-4-(o-tolyl)chromen-2-one,
3-methyl-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
(2R)—N,N-dimethyl-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxy-propanamide,
(2R)-2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-N,N-dimethyl-propanamide,
(3R)-1-[2-[4-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
(3S)-1-[2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carbonitrile,
2-[4-(2-chloro-3-fluoro-phenyl)-2-oxo-chromen-7-yl]oxy-N-isopropyl-propanamide,
(3S)-1-[2-[4-(2-chloro-3-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-N-methyl-propanamide,
1-[2-[4-(2-chloro-3-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-sulfonamide,
(3R)-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-methyl-piperidine-3-carboxylic acid,
isopropyl (2R)-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoate,
(2R)-2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-N-isopropyl-propanamide,
ethyl 2-[4-(2-chloro-3-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoate,
ethyl 2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoate,
2-[1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-4-piperidyl]acetic acid,
2-[1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]-4-piperidyl]acetic acid,
2-[4-(2-chloro-3-fluoro-phenyl)-2-oxo-chromen-7-yl]oxy-N-cyclopropyl-propanamide,
N-isopropyl-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxy-propanamide,
1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]pyrrolidine-3-sulfonamide, isopropyl (2R)-2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoate,
2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxy-N-isopropyl-propanamide,
2-[1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetic acid,
(3R)-1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-N,N-dimethyl-piperidine-3-carboxamide,
2-[4-(2-chloro-3-fluoro-phenyl)-2-oxo-chromen-7-yl]oxy-N-ethyl-propanamide,
1-[2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-sulfonamide,
2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-N-isopropyl-propanamide,
7-[2-(4,4-difluoro-1-piperidyl)-1-methyl-2-oxo-ethoxy]-4-(o-tolyl)chromen-2-one,
2-[1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetic acid,
7-[1-methyl-2-[3-(methyl sulfonimidoyl)-1-piperidyl]-2-oxo-ethoxy]-4-(o-tolyl)chromen-2-one,
4-(2-chlorophenyl)-7-[2-(4,4-difluoro-1-piperidyl)-1-methyl-2-oxo-ethoxy]chromen-2-one,
ethyl 1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-methyl-piperidine-3-carboxylate,
(3S)-1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-N,N-dimethyl-piperidine-3-carboxamide,
1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]pyrrolidine-3-sulfonamide,
(3R)—N,N-dimethyl-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxamide,
4-(2-chlorophenyl)-7-[1-methyl-2-[3-(methylsulfonimidoyl)-1-piperidyl]-2-oxo-ethoxy]chromen-2-one,
methyl 2-[1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-4-piperidyl]acetate,
ethyl 2-[4-(2-bromophenyl)-2-oxo-chromen-7-yl]oxypropanoate,
ethyl 2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoate,
methyl 2-[1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]-4-piperidyl]acetate,
(3S)—N,N-dimethyl-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxamide,
N-ethyl-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxy-propanamide,
ethyl 2-[1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate,
ethyl 2-[1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate,
ethyl 3-methyl-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
2-[4-(2-bromophenyl)-2-oxo-chromen-7-yl]oxy-N,N-dimethyl-propanamide,
2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxy-N-cyclopropyl-propanamide,
2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxy-N-ethyl-propanamide, isopropyl 2-[4-(2-bromophenyl)-2-oxo-chromen-7-yl]oxypropanoate,
2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-N,N-dimethyl-propanamide,
2-[4-(2-chloro-3-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoic acid,
ethyl 1-[2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-methyl-piperidine-3-carboxylate,
2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoic acid,
2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoic acid,
2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-N-ethyl-propanamide,
2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoic acid,
methyl 2-[(3S)-1-[(2R)-2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate,
methyl 2-[(3R)-1-[(2R)-2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate,
2-[(3S)-1-[(2R)-2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetic acid,
2-[(3R)-1-[(2R)-2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetic acid,
methyl 2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate,
methyl 2-[(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate,
2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetic acid,
2-[(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetic acid,
(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
ethyl (3S)-1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxybutanoyl]piperidine-3-carboxylate,
(3S)-1-[2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxybutanoyl]piperidine-3-carboxylic acid,
ethyl (3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-2-methyl-propanoic acid,
ethyl 2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-2-methyl-propanoate,
2-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-N-isopropyl-2-methyl-propanamide,
N-isopropyl-2-methyl-2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxy-propanamide,
(3S)-1-[2-[4-[4-(2-chlorophenyl)-2-oxo-chromen-7-yl]oxy-2-methyl-propanoyl]piperidine-3-carboxylic acid,
isopropyl (3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
tert-butyl (3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
2-morpholinoethyl (3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
heptyl (3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
isopropoxycarbonyloxymethyl (3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
(3S)—N-methyl-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl piperidine-3-carboxamide,
isopropyl 2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate,
tert-butyl 2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate,
2-morpholinoethyl 2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate,
heptyl 2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate,
isopropoxycarbonyloxymethyl 2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetate, and
2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]-N-methyl-acetamide,
methyl 1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-4-carboxylate,
(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxy-N-[4-(hydroxymethyl) phenyl]propanamide,
1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-4-carboxylic acid,
(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxamide,
2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetamide,
(3S)-1-[(2R)-2-[4-(2-ethylphenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
methyl (2S)-4-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperazine-2-carboxylate,
methyl (2R)-4-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperazine-2-carboxylate,
methyl 1-methyl-4-[rac-(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperazine-2-carboxylate,
(2S)-4-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperazine-2-carboxylic acid,
3-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]benzoic acid,
(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxy-N-[4-(2-methoxyethyl) phenyl]propanamide,
4-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]benzoic acid,
methyl 2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]pyrrolidin-3-yl]acetate,
methyl 5-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-3-carboxylate,
methyl 2-[(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]pyrrolidin-3-yl]acetate,
2-[(3R)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]pyrrolidin-3-yl]acetic acid,
methyl 2-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-4-carboxylate,
2-[(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]pyrrolidin-3-yl]acetic acid,
5-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-3-carboxylic acid,
methyl 6-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-2-carboxylate,
(2R)-4-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperazine-2-carboxylic acid,
6-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-2-carboxylic acid,
2-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-4-carboxylic acid,
methyl 5-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-2-carboxylate,
5-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-2-carboxylic acid,
5-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-2-carboxylic acid,
6-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-3-carboxylic acid,
methyl 4-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-2-carboxylate,
methyl (3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]pyrrolidine-3-carboxylate,
(3S)-1-[(2R)-2-[4-(4-fluoro-2-methyl-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]pyrrolidine-3-carboxylic acid,
4-[[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]amino]pyridine-2-carboxylic acid,
1-methyl-4-[rac-(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperazine-2-carboxylic acid,
(3S)-1-[(2R)-2-[4-(2-cyanophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
(3S)-1-[(2R)-2-[4-(2,6-dichlorophenyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
4-(2-chloro-4-fluoro-phenyl)-7-[(1R)-1-methyl-2-oxo-2-(4-prop-2-enoylpiperazin-1-yl)ethoxy]chromen-2-one,
N-[(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]prop-2-enamide,
7-[(1R)-2-[4-(2-chloroacetyl)piperazin-1-yl]-1-methyl-2-oxo-ethoxy]-4-(2-chloro-4-fluoro-phenyl)chromen-2-one,
2-chloro-N-[(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]acetamide,
4-(2-chloro-4-fluoro-phenyl)-7-[(1R)-1-methyl-2-oxo-2-(4-propanoylpiperazin-1-yl) ethoxy]chromen-2-one,
N-[(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-chromen-7-yl]oxypropanoyl]-3-piperidyl]propanamide,
rac-(3S)-1-[2-[4-(2-chlorophenyl)-2-oxo-pyrano[2,3-b]pyridin-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
tert-butyl rac-(3S)-1-[2-[4-(2-chlorophenyl)-2-oxo-pyrano[2,3-b]pyridin-7-yl]oxypropanoyl]piperidine-3-carboxylate,
(3S)-1-[(2R)-2-[4-(2-chlorophenyl)-2-oxo-pyrano[2,3-b]pyridin-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
(3S)-1-[(2R)-2-[4-(2-chloro-4-fluoro-phenyl)-2-oxo-pyrano[2,3-b]pyridin-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
(3S)-1-[(2R)-2-[4-(3-methyl-2-thienyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
ethyl 2-[4-(2-fluorophenyl)-2-oxo-chromen-7-yl]oxypropanoate, and
ethyl 2-[4-(2,6-difluorophenyl)-2-oxo-chromen-7-yl]oxypropanoate,
or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and pharmaceutically or veterinary acceptable carriers and/or excipients.

### Claim 15 (depends on 1)

A process for manufacturing a compound according to claim 1 comprising the steps of:
(a) reacting a compound of formula (A)
wherein W is as defined in claim 1,
with resorcin or 2,6-dihydroxypyridine to obtain a compound of formula (B)
wherein W and M are as defined in claim 1, or
(a1) reacting a compound of formula (K)
wherein W and M are as defined in claim 1,
with boron tribromide to obtain a compound of formula (B)
wherein W and M are as defined in claim 1, and
(b) alkylating a compound of formula (B) as defined above with an alkylating agent,
to obtain a compound of formula (C)
wherein W, M and Z are as defined above.

### Claim 16 (depends on 1)

A process for manufacturing a compound according to claim 1, wherein Y is —NR3R4 as defined in claim 1, comprising the steps of:
(a) hydrolyzing a compound of formula (D)
wherein W, M, R, R1, and R11 are as defined in claim 1
to obtain a compound of formula (E)
wherein W, M, R, and R1 are as defined in claim 1, and
(b) amidating the compound of formula (E) to obtain a compound of formula (F)
wherein W, M, R, R1, R3, and R4, are as defined in claim 1.

### Claim 17 (depends on 1)

A method of treating cancer comprising administering a therapeutically effective amount of a compound of claim 1.

### Claim 18 (depends on 1)

A method of treating cancer comprising administering a therapeutically effective amount of a compound of claim 1 in simultaneous, alternating or subsequent combination with an additional cancer therapy.

### Claim 19 (depends on 17)

The method of claim 17, wherein the cancer is selected from the group consisting of melanoma, metastatic melanoma, pancreatic cancer, hepatocellular carcinoma, lymphoma, acute myeloid leukemia, breast cancer, glioblastoma, cervical cancer, renal cancer, colorectal cancer or ovarian cancer.

### Claim 20 (depends on 19)

The method of claim 19, wherein the additional cancer therapy is selected from the group consisting of chemotherapy, immunotherapy, hormone therapy, stem cell transplantation therapy, radiation therapy and surgery.