(2-ureidoacetamido)alkyl derivatives as formyl peptide receptor 2 modulators

Patent metadata

Field	Value
Publication number	US-9670150-B2
Application number	US-201313863934-A
Country	US
Kind code	B2
Filing date	Apr 16, 2013
Priority date	Apr 16, 2012
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The present invention relates to (2-ureidoacetamido)alkyl derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of the N-formyl peptide receptor 2.

First claim

What is claimed is:

1. A compound having Formula Ia, an individual geometrical isomer, individual enantiomer, individual diastereoisomer, individual tautomer or individual zwitterion thereof:

wherein:
n is 0 or 1;
R 1 is hydrogen, substituted or unsubstituted C 1-8 alkyl, halogen, —NR 8 R 9 , —NR 21 C(O)R 20 , —OR 10 , —OC(O)R 21 , —SR 11 , —C(O)R 12 , —CN or —NO 2 ;
R 2 is hydrogen, substituted or unsubstituted C 1-8 alkyl, halogen, —NR 8 R 9 , —NR 21 C(O)R 20 , —OR 10 , —OC(O)R 21 , —SR 11 , —C(O)R 12 , —CN or —NO 2 ;
R 3 is substituted or unsubstituted C 1-8 alkyl, halogen, —NR 8 R 9 , —NR 21 C(O)R 20 , —OR 10 , —OC(O)R 21 , —SR 11 , —C(O)R 12 , —CN, —NO 2 , —CF 3 , —S(O)R 15 or —S(O) 2 R 16 ;
R 4 is hydrogen, substituted or unsubstituted C 1-8 alkyl, halogen, —NR 8 R 9 , —NR 21 C(O)R 20 , —OR 10 , —OC(O)R 21 , —SR 11 , —C(O)R 12 , —CN or —NO 2 ;
R 5 is hydrogen, substituted or unsubstituted C 1-8 alkyl, halogen, —NR 8 R 9 , —NR 21 C(O)R 20 , —OR 10 , —OC(O)R 21 , —SR 11 , —C(O)R 12 , —CN or —NO 2 ;
R 6 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 3-8 cycloalkenyl or —CH 2 R 19 ;
R 7 is —N(H)C(O)N(H)S(O) 2 R 19 , —S(O)R 15 , —C(O)N(H)(CN), —C(O)N(H)S(O) 2 R 19 , —S(O) 2 R 16 , —P(O)R 17 R 18 or substituted or unsubstituted heterocycle, wherein said heterocycle is selected from the group consisting of imidazole, triazole, tetrazole, oxadiazole, isothiazole, pyrane, 4H-pyran-4-one, pyrrole, pyrrolidine-one, pyrrolidine-dione, pyrazole, isoxazole and imidazolidine-dione; and wherein said heterocycle substituent is selected from the group consisting halogen, —SC 1-6 alkyl, —S(O) 2 C 1-6 alkyl, —S(O)C 1-6 alkyl, sulfonamide, amide, nitro, cyano, —OC 1-6 alkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, ketone, amine, C 3-8 cycloalkyl, aldehyde, ester, carboxylic acid, phosphonic acid, sulfonic acid and hydroxyl;
R 8 is hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C 6-10 aryl;
R 9 is hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C 6-10 aryl;
R 10 is hydrogen or substituted or unsubstituted C 1-8 alkyl;
R 11 is hydrogen, —CF 3 , or substituted or unsubstituted C 1-8 alkyl;
R 12 is hydrogen, substituted or unsubstituted C 1-8 alkyl, hydroxyl, —OR 24 or —NR 8 R 9 ;
R 13 is —OR 22 ;
R 14 is —OR 23 ;
R 15 is substituted or unsubstituted C 1-8 alkyl;
R 16 is substituted or unsubstituted C 1-8 alkyl, —NR 8 R 9 , —NHS(O) 2 R 19 or hydroxyl;
R 17 is OR 10 or NR 8 R 9 ;
R 18 is OR 10 or NR 8 R 9 ;
R 19 is substituted or unsubstituted heterocycle, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted C 3-8 cycloalkenyl;
R 20 is hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C 6-10 aryl;
R 21 is hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C 6-10 aryl;
R 22 is hydrogen, substituted or unsubstituted C 1-8 alkyl, or together with R 23 forms a cycle;
R 23 is hydrogen, substituted or unsubstituted C 1-8 alkyl, or together with R 22 forms a cycle; and
R 24 is hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C 6-10 aryl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein:
each of R 1 , R 2 , R 4 and R 5 is hydrogen; and
R 6 is substituted or unsubstituted C 1-8 alkyl, or —CH 2 R 19 , wherein R 19 is substituted or unsubstituted C 6-10 aryl.

3. The compound of claim 1 , wherein R 7 is selected from —S(O) 2 R 16 , —P(O)R 17 R 18 and substituted or unsubstituted heterocycle; wherein:
R 16 is substituted or unsubstituted C 1-8 alkyl or hydroxyl;
R 17 is OR 10 , wherein R 10 is hydrogen or substituted or unsubstituted C 1-8 alkyl;
R 18 is OR 10 , wherein R 10 is hydrogen or substituted or unsubstituted C 1-8 alkyl; and said heterocycle is tetrazole or isoxazole, wherein when said heterocycle is substituted, said substituent is hydroxyl.

4. The compound of claim 1 , wherein R 3 is halogen.

5. The compound of claim 1 , wherein:
each of R 1 , R 2 , R 4 and R 5 is hydrogen;
R 3 is —CF 3 , halogen, —SR 11 or —S(O) 2 R 16 ;
R 6 is substituted or unsubstituted C 1-8 alkyl, or —CH 2 R 19 , wherein R 19 is substituted or unsubstituted C 6-10 aryl; and
R 7 is selected from —S(O) 2 R 16 , —P(O)R 17 R 18 and substituted or unsubstituted heterocycle, wherein said heterocycle is tetrazole or isoxazole, and when said heterocycle is substituted, said substituent is hydroxyl;
R 11 is unsubstituted C 1-8 alkyl;
R 16 is unsubstituted C 1-8 alkyl or hydroxyl;
R 17 is OR 10 , wherein R 10 is hydrogen or substituted or unsubstituted C 1-8 alkyl; and
R 18 is OR 10 , wherein R 10 is hydrogen or substituted or unsubstituted C 1-8 alkyl.

6. The compound according to claim 1 selected from the group consisting of:
Diethyl({[(2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-4-methylpentanoyl]amino}methyl)phosphonate;
(2S)-2-({[(4-Bromophenyl)amino]carbonyl}amino)-4-methyl-N-(1H-tetrazol-5-ylmethyl)pentanamide;
(2S)-2-({[(4-Bromophenyl)amino]carbonyl}amino)-4-methyl-N-[2-(1H-tetrazol-5-yl)ethyl]pentanamide;
(2S)-2-({[(4-Bromophenyl)amino]carbonyl}amino)-N-[(3-hydroxyisoxazol-5-yl)methyl]-4-methylpentanamide;
Diethyl({[(2S,3S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-methylpentanoyl]amino}methyl)phosphonate;
Diethyl({[(2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)pentanoyl]amino}methyl)phosphonate;
Diethyl({[(2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoyl]amino}methyl)phosphonate;
Diethyl(2-{[(2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-4-methylpentanoyl]amino}ethyl)phosphonate;
Ethyl hydrogen ({[(2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-4-methyl pentanoyl]amino}methyl)phosphonate;
Ethyl hydrogen ({[(2S,3S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-methyl pentanoyl]amino}methyl)phosphonate;
Ethyl hydrogen ({[(2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)pentanoyl]amino}methyl)phosphonate;
({[(2S)-4-Methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}methyl)phosphonic acid;
Ethyl hydrogen ({[(2S)-4-methyl-2-({[4-(methylsulfonyl)phenyl]carbamoyl}amino) pentanoyl]amino}methyl)phosphonate;
Diethyl({[(2S)-4-methyl-2-({[4-(methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}methyl)phosphonate;
Diethyl({[(2S)-4-methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}methyl)phosphonate;
{[(2S)-4-Methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}methanesulfonic acid;
(2S)-4-Methyl-N-(1H-tetrazol-5-ylmethyl)-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanamide;
Ethyl hydrogen ({[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino) pentanoyl]amino}methyl)phosphonate;
Diethyl({[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}methyl)phosphonate;
Diisopropyl({[(2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-4-methylpentanoyl]amino}methyl)phosphonate;
Propan-

Assignees

• Allergan Inc

Inventors

• Beard Richard L
• Duong Tien
• Donello John E
• Viswanath Veena
• Garst Michael E

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title