Amide derivatives of n-urea substituted amino acids as formyl peptidereceptor like-1 (fprl-1) receptor modulators

A compound represented by Formula II, its enantiomers, diastereoisomers, tautomers, hydrates, solvates or a pharmaceutically acceptable salt thereof,

• Formula II
• wherein:
• a is 1 and b is 0;
• a is 0 and b is 1;
• a is 1 and b is 1;
• R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, —NR11R12 or —OR13;
• R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl;
• R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, —COOR15, —OR13, —NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl;
• R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, —COOR15, —OR13, —NR11R12, N02, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl;
• R5 is halogen, —CF3 or —S(O)nR14;
• n is 0, 1 or 2;
• R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, —COOR15, —OR13, —NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl;
• R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, —COOR15, —OR13, —NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl;
• R8 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl;
• R9 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl;
• R10 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl;
• R9a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl;
• R10a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl;
• R11 is hydrogen or optionally substituted C1-8 alkyl;
• R12 is hydrogen or optionally substituted C1-8 alkyl;
• R13 is hydrogen or optionally substituted C1-8 alkyl;
• R14 is hydrogen, CF3 or optionally substituted C1-8 alkyl;
• R15 is hydrogen or optionally substituted C1-8 alkyl;
• with the provisos:
• a). when a=1 and b=0 then:
• R9 is not optionally substituted benzyl;
• and
• R11 is not:
• and
• the compound of Formula II is not of structures:
• and
• b). when a=0 and b=1 then:
• R1 is OR13;
• and
• the compound of Formula II is not of structure:
• and
• c). when a=1 and b=1 then:
• R11 is not:

A method of treating dry eye in a subject in need of such treatment, the method comprising administering to the subject a compound of Formula II:

• wherein:
• a is 1 and b is 0;
• R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, —NR11R12 or —OR13;
• R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl;
• R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, —COOR15, —OR13, —NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl;
• R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, —COOR15, —OR13, —NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl;
• R5 is halogen;
• R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, —COOR15, —OR13, —NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl;
• R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, —COOR15, —OR13, —NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl;
• R8 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl;
• R9 is hydrogen;
• R10 is hydrogen;
• R11 is hydrogen or optionally substituted C1-8 alkyl;
• R12 is hydrogen;
• R13 is hydrogen or optionally substituted C1-8 alkyl;
• and
• R15 is hydrogen or optionally substituted C1-8 alkyl;
• or a tautomer, hydrate or solvate thereof;
• or a pharmaceutically acceptable salt of the foregoing;
• provided that the compound is not:

A method of treating dry eye in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound selected from:

• {[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}acetic acid;
• tert-butyl{[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}acetate;
• [(4-amino-2-{[(4-bromophenyl)carbamoyl]amino}-4-oxobutanoyl)amino]acetic acid;
• tert-butyl [(4-amino-2-{[(4-bromophenyl)carbamoyl]amino}-4-oxobutanoyl)amino]acetate;
• 2-{[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoic acid;
• tert-butyl 2-{[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoate;
• {[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-imidazol-4-yl)propanoyl]amino}acetic acid;
• tert-butyl{[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-imidazol-4-yl)propanoyl]amino}acetate;
• {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfonyl)butanoyl]amino}acetic acid;
• tert-butyl{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfonyl)butanoyl]amino}acetate;
• {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfanyl)butanoyl]amino}acetic acid;
• tert-butyl{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfanyl)butanoyl]amino}acetate;
• 2-methyl-2-{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoic acid;
• tert-butyl 2-methyl-2-{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoate;
• {[(2S)-4-methyl-2-({[4-(methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid;
• tert-butyl{[(2S)-4-methyl-2-({[4-(methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;
• {[(2S)-4-methyl-2-({[4-(methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid;
• tert-butyl{[(2S)-4-methyl-2-({[4-(methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;
• 2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoic acid;
• tert-butyl 2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoate;
• ({(2S)-4-methyl-2-[({4-[(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetic acid;
• tert-butyl({(2S)-4-methyl-2-[({4-[(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetate;
• {[(2S)-4-methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid;
• tert-butyl{[(2S)-4-methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;
• {[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid;
• tert-butyl{[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetate;
• {[(2R,3R)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic acid tert-butyl{[(2R,3R)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetate;
• {[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid;
• tert-butyl{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;
• {[(2R)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[2-(dimethylamino)-2-oxoethyl]-4-methylpentanamide;
• [(2-{[(4-bromophenyl)carbamoyl]amino}-2-methylpropanoyl)amino]acetic acid;
• tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}-2-methylpropanoyl)amino]acetate;
• [(2-{[(4-bromophenyl)carbamoyl]amino}-2-ethylbutanoyl)amino]acetic acid;
• tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}-2-ethylbutanoyl)amino]acetate;
• [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetic acid;
• tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetate;
• (2S)—N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;
• (2S)-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}(phenyl)ethanoic acid;
• tert-butyl (2S)-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}(phenyl)ethanoate;
• (2S)—N-[(2S)-1-amino-1-oxopentan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;
• (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentanoic acid;
• tert-butyl (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentanoate;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[(2R)-1-hydroxypropan-2-yl]-4-methylpentanamide;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2,3-dihydroxypropyl)-4-methylpentanamide;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(1,3-dihydroxypropan-2-yl)-4-methylpentanamide;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxy-2-methylpropyl)-4-methylpentanamide;
• (2S)—N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;
• (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3-methylbutanoic acid;
• tert-butyl (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3-methylbutanoate;
• (2S)—N-[(2S)-1-amino-1-oxopropan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;
• (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoic acid;
• tert-butyl (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoate;
• (2S)—N-[(2S)-1-amino-1-oxopropan-2-yl]-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanamide;
• (2S)-2-{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoic acid;
• tert-butyl (2S)-2-{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoate;
• (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-4-methylpentanamide;
• (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamide;
• (2S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanamide;
• {[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid;
• tert-butyl{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetate;
• (2S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}pentanamide;
• (2S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}pentanamide;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamide;
• (2S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;
• {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-4-methylpentanamide;
• tert-butyl{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetate;
• {[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid;
• tert-butyl{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetate;
• (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-oxopropyl)pentanamide;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-oxopropyl)pentanamide;
• propan-2-yl {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate;
• ethyl {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate;
• methyl {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate;
• (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)pentanamide;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)pentanamide;
• (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-phenylpropanamide;
• {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid;
• tert-butyl{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate;
• (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-oxopropyl)-3-phenylpropanamide;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-oxopropyl)-3-phenylpropanamide;
• (2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-methylpentanamide;
• (2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-methylpentanamide;
• (2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methyl-N-(2-oxopropyl)pentanamide;
• (2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methyl-N-(2-oxopropyl)pentanamide;
• (2S,3S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanamide;
• (2S,3S)—N-(2-amino-2-oxoe;thyl)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanamide {[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic acid;
• tert-butyl{[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetate;
• {[(2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic acid;
• tert-butyl{[(2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetate;
• (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-phenylpropanamide;
• 3-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}propanoic acid;
• tert-butyl 3-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}propanoate;
• {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}acetic acid;
• and
• tert-butyl{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}acetate;
• and enantiomers, diastereoisomers, tautomers, hydrates or solvates thereof;
• and pharmaceutically acceptable salts of the foregoing.