# US 9,751,843 B2 · Substituted uracils and use thereof

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- Number: US 9,751,843 B2
- Document ID: US9751843B2
- Status: Granted
- Kind: B2
- Application number: 15/034,499
- Filed: 2014-11-05
- Published: 2016-10-13
- Granted: 2017-09-05
- Earliest claimed: 2013-11-08
- Assignees: Bayer Pharma Aktiengesellschaft
- Applicants: Bayer Pharma Aktiengesellschaft
- Inventors: Chantal Fürstner; Jens Ackerstaff; Alexander Straub; Heinrich Meier; Hanna Tinel; Katja Zimmermann; Adrian Tersteegen; Dmitry Zubov; Raimund Kast; Jens Schamberger; Martina Schäfer
- Web page: https://patentgrep.com/patent/US9751843B2

## CPC

- C07D 239/557: with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/10: linked by a carbon chain containing aromatic rings
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Substituted uracil derivatives of the compound of Formula (I), processes for their preparation, their use alone or in combinations for treatment and/or prophylaxis of diseases, and their use for preparing medicaments for treatment and/or prophylaxis of diseases.

## Claims

### Claim 1

A compound of the formula (I)
in which
R1 represents hydrogen or (C1-C4)-alkyl,
R2 represents a group of the formula
where
* represents the point of attachment to the uracil nitrogen atom,
A represents —CH2—, —CH2—CH2—, —O—CH2-## or oxygen, in which ## represents the point of attachment to the phenyl ring,
m represents a number 0, 1 or 2,
R8 represents hydrogen, halogen, difluoromethyl, trifluoromethyl, (C1-C4)-alkyl, difluoromethoxy, trifluoromethoxy or (C1-C4)-alkoxy,
R9A represents hydrogen or deuterium,
R9B represents hydrogen, deuterium or (C1-C4)-alkyl,
R10 represents hydrogen, halogen, (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, nitro or (C1-C4)-alkylthio,
R11 represents hydrogen, halogen, (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, nitro or (C1-C4)-alkylthio,
R12 represents hydrogen or halogen,
R13 represents hydrogen or halogen,
R3 represents hydrogen,
R4 represents hydrogen, halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy,
R5 represents (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl or —N(R14R15),
where (C1-C4)-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxy, 4- to 7-membered heterocyclyl, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl and di-(C1-C4)-alkylaminocarbonyl,
in which 4- to 7-membered heterocyclyl may be substituted by 1 or 2 halogen or oxo substituents,
where (C1-C4)-alkoxy may be substituted by a substituent independently of one another selected from the group consisting of hydroxy, (C1-C4)-alkoxycarbonyl, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl and di-(C1-C4)-alkylaminocarbonyl,
where
R14 represents (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl or (C1-C4)-alkylaminocarbonyl,
in which (C1-C4)-alkyl may be substituted by hydroxy or (C1-C4)-alkoxy,
and
in which (C1-C4)-alkylaminocarbonyl may be substituted by hydroxy or (C1-C4)-alkoxy,
R15 represents hydrogen or (C1-C4)-alkyl,
or
R5 represents 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl,
where 4- to 7-membered heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, (C1-C4)-alkyl, hydroxy, oxo, amino and (C1-C4)-alkoxycarbonyl,
in which (C1-C4)-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxy and —N(R16R17),
in which R6 represents hydrogen, (C1-C4)-alkyl or (C1-C4)-alkylcarbonyl,
in which R17 represents hydrogen or (C1-C4)-alkyl,
where 5- to 6-membered heteroaryl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, (C1-C4)-alkyl, hydroxy, amino and (C1-C4)-alkoxycarbonyl,
in which (C1-C4)-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxy and —N(R16R17),
in which R16 represents hydrogen, (C1-C4)-alkyl or (C1-C4)-alkylcarbonyl,
in which R17 represents hydrogen or (C1-C4)-alkyl,
R6 represents hydrogen, halogen, cyano, (C1-C4)-alkyl or (C1-C4)-alkoxy,
R7 represents hydrogen, halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy, a salt or a solvate thereof, or a solvate of the salt.

### Claim 2 (depends on 1)

The compound of claim 1 in which
R1 represents hydrogen, methyl or ethyl,
R2 represents a group of the formula
where
* represents the point of attachment to the uracil nitrogen atom,
A represents —CH2—, —CH2—CH2— or oxygen,
R8a represents hydrogen, fluorine, chlorine, trifluoromethyl or methyl,
R8b represents hydrogen, fluorine, chlorine, trifluoromethyl or methyl,
R9A represents hydrogen,
R9B represents hydrogen, methyl or ethyl,
R10 represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,
R11 represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,
R12 represents hydrogen,
R13 represents hydrogen,
R3 represents hydrogen,
R4 represents hydrogen, fluorine, chlorine or methoxy,
R5 represents (C1-C4)-alkoxy, 5- or 6-membered heterocyclyl or 5-membered heteroaryl,
where 5- to 6-membered heterocyclyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, methyl, ethyl, hydroxy, oxo and (C1-C4)-alkoxycarbonyl,
in which methyl and ethyl may be substituted by —N(R16R17),
in which R16 represents (C1-C4)-alkylcarbonyl,
in which R17 represents hydrogen,
where 5-membered heteroaryl may be substituted by fluorine, chlorine, trifluoromethyl, methyl, hydroxy, amino or (C1-C4)-alkoxycarbonyl,
in which methyl may be substituted by hydroxy,
R6 represents hydrogen, fluorine, chlorine or methyl,
R7 represents hydrogen, fluorine, chlorine or methyl, a salt or a solvate thereof, or a solvate of the salt.

### Claim 3 (depends on 1)

The compound of claim 1 in which
R1 represents hydrogen, methyl or ethyl,
R2 represents a group of the formula
where
* represents the point of attachment to the uracil nitrogen atom,
A represents —CH2— or —CH2—CH2—,
R8a represents hydrogen, chlorine, trifluoromethyl or methyl,
R8b represents hydrogen,
R9A represents hydrogen,
R9B represents hydrogen, methyl or ethyl,
R10 represents hydrogen, chlorine, trifluoromethyl or methyl,
R11 represents fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,
R12 represents hydrogen,
R13 represents hydrogen,
R3 represents hydrogen,
R4 represents hydrogen, fluorine, chlorine or methoxy,
R5 represents 5- or 6-membered heterocyclyl or 5-membered heteroaryl,
where 5- to 6-membered heterocyclyl may be substituted by 1 or 2 methyl, ethyl or oxo substituents,
where 5-membered heteroaryl may be substituted by methyl or amino, in which methyl may be substituted by hydroxy,
R6 represents hydrogen, fluorine, chlorine or methyl,
R7 represents hydrogen, fluorine or methyl, a salt or a solvate thereof, or a solvate of the salt.

### Claim 4 (depends on 1)

The compound of claim 1 in which
R1 represents hydrogen, methyl or ethyl,
R2 represents a group of the formula
where
* represents the point of attachment to the uracil nitrogen atom,
A represents —CH2— or —CH2—CH2—,
R8a represents chlorine or trifluoromethyl,
R8b represents hydrogen,
R9A represents hydrogen,
R9B represents hydrogen,
R10 represents chlorine, trifluoromethyl or methyl,
R11 represents fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,
R12 represents hydrogen,
R13 represents hydrogen,
R3 represents hydrogen,
R4 represents hydrogen, fluorine or chlorine,
R5 represents a group of the formula
in which
### represents the point of attachment to the phenyl ring,
R6 represents hydrogen, fluorine, chlorine or methyl,
R7 represents hydrogen, fluorine or methyl, a salt or a solvate thereof, or a solvate of the salt.

### Claim 5 (depends on 1)

The compound of claim 1 in which
R1 represents hydrogen, methyl or ethyl,
R2 represents a group of the formula
where
* represents the point of attachment to the uracil nitrogen atom,
A represents —CH2— or —CH2—CH2—,
R8a represents chlorine or trifluoromethyl,
R8b represents hydrogen,
R3 represents hydrogen,
R4 represents hydrogen,
R5 represents a group of the formula
R6 represents hydrogen,
R7 represents hydrogen, a salt or a solvate thereof, or a solvate of the salt.

### Claim 6 (depends on 1)

A method of making compounds of the formula (I) according to claim 1, in which
[A] a compound of the formula (II)
in which
R1a represents (C1-C4)-alkyl,
T1 represents (C1-C4)-alkyl,
T2 represents (C1-C4)-alkyl,
is reacted in an inert solvent, optionally in the presence of a suitable base, with a compound of the formula (III)
in which R3, R4, R5, R6 and R7 are as defined in claim 1,
to give a compound of the formula (IV)
in which R1A, R3, R4, R5, R6 and R7 each have the meanings given above,
this is then reacted in an inert solvent, in the presence of a suitable base, with a compound of the formula (V)
X1—R2 (V)
in which R2 is as defined in claim 1
and
X1 represents hydroxy or a suitable leaving group, selected from chlorine, bromine or iodine,
to give a compound of the formula (I-1)
in which R1A, R2, R3, R4, R5, R6 and R7 each have the meanings given above,
or
[B] a compound of the formula (VI)
in which R1A and T1 each have the meanings mentioned above and
T3 represents (C1-C4)-alkyl,
is converted in an inert solvent or else without solvent with a compound of the formula (III) to a compound of the formula (VII)
in which R1A, R3, R4, R5, R6, R7 and T3 each have the meanings given above, this is subsequently reacted in an inert solvent with chlorosulfonyl isocyanate to give a compound of the formula (IV) and this is subsequently converted analogously to process [A] to a compound of the formula (I-1),
or
[C] a compound of the formula (VIII)
in which R2 is as defined above
is reacted in an inert solvent with a compound of the formula (IX)
in which R1A and T1 each have the meanings given above and
T5 represents (C1-C4)-alkyl,
and cyclized in the presence of a suitable base to give a compound of the formula (X)
in which R1A and R2 each have the meanings mentioned above, and this is then reacted in an inert solvent in the presence of a suitable catalyst and a suitable base with a compound of the formula (XI)
in which R3, R4, R5, R6 and R7 have the meaning given above and
T6 represents hydrogen, (C1-C4)-alkyl or the two radicals T6 together form a —C(CH3)2—C(CH3)2— bridge,
to give a compound of the formula (I-1),
or
[D] a compound of the formula (I-1) is hydrolyzed in an inert solvent in the presence of a suitable acid or base to give a compound of the formula (I-2)
in which R2, R3, R4, R5, R6 and R7 each have the meanings mentioned above
and
R1B represents hydrogen,
any protecting groups are detached and/or the compounds of the formulae (I-1) and (I-2) are, where appropriate, converted with the appropriate (i) solvents and/or (ii) bases or acids to the solvates, salts and/or solvates of the salts thereof.

### Claim 7 (depends on 1)

A medicament comprising the compound of claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

### Claim 8 (depends on 1)

A medicament comprising the compound of claim 1 in combination with one or more further active ingredients selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, diuretics, kinase inhibitors, matrix metalloprotease inhibitors, stimulators and activators of soluble guanylate cyclase and phosphodiesterase inhibitors.

### Claim 9 (depends on 1)

A method for treatment of heart failure, cardiac fibrosis or dermatological fibroses in a human or an animal in need thereof comprising administering to the human or the animal an effective amount of the compound of claim 1, a salt, or a solvate thereof, or a solvate of the salt.

### Claim 10 (depends on 7)

A method for treatment of heart failure, cardiac fibrosis or dermatological fibroses in a human or an animal in need thereof comprising administering to the human or the animal an effective amount of the medicament of claim 7.