IP Library › Granted Patent US 8,802,692

Granted Patent B2

US 8,802,692 · App. 13/124,586 · Granted Aug 12, 2014

Synergistic effects between sphingosine-1-phosphate receptor antagonists and antimicrotubule agents

Inventors: Geetha Shankar (Palo Alto, CA); Frauke Bentzien (San Francisco, CA); Peter Lamb (Oakland, CA); David Matthews (San Francisco, CA)

Assignee: Exelixis, Inc.

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Quick Facts

Patent No.: US 8,802,692
App. No.: 13/124,586
Granted: Aug 12, 2014
Kind: B2

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Abstract

This invention is based on the discovery that the administration of a sphingosine-1-phosphate receptor antagonist (S1P) and at least one chemotherapeutic agent selected from the the group of antimicrotubule agents provides an unexpectedly superior treatment for cancer. Antimicrobial agents such as the taxane compounds are known in the art, for example, paclitaxel (available as TAXOL® from Bristol-Myers Squibb, Princeton, N.J.), docetaxel (available as TAXOTERE® from Sanofi-aventis, Bridgewater, N.J.) and the like and other compounds that act as antimicrotubule agents, such as Vincristine (ONCOVIN®, VINCASAR PFS®, VCR), Vinblastin (VELBAN®, VELSAR®) and Vinorelbine, and similar compounds. The present invention also provides methods of modulating the growth of selected cell populations, such as cancer cells, by administering a therapeutically effective amount of at least one sphingosine-1-phosphate 1 (S1P1R) receptor antagonists, and at least one antimicrotubule agent.

Claims (1712)

1. A pharmaceutical composition comprising a synergistic combination of at least one S1P1R receptor antagonist and at least one antimicrotubule agent, wherein the S1P1R receptor antagonist is selected from the group of compounds consisting of

1) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-5-phenyl-N-(4-phenoxyphenyl)pentanamide;

2) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

3) (2S,4R)-5-(2-(1H-1,2,3-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide;

4) (2S,4R)-5-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide;

5) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

6) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

7) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

8) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

9) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

10) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

11) (2S,4R)-1-(2-(5-amino-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

12) 1-((2S,4R)-4-benzyl-2-(5-(4-fluorophenoxy)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone;

13) 3-(benzyloxy)-2-((S)-3-hydroxy-3-phenylpropanamido)-N-(4-phenoxyphenyl)propanamide;

14) 3-(benzyloxy)-2-(2-(furan-2-yl)-2-oxoacetamido)-N-(4-phenoxyphenyl)propanamide;

15) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamide;

16) 3-(benzyloxy)-2-(2-hydroxy-2-(2-hydroxyphenyl)acetamido)-N-(4-phenoxyphenyl)propanamide;

17) 4-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-ylcarbamoyl)phenyl acetate;

18) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-5-methylnicotinamide;

19) 3-(benzyloxy)-2-(2-(methylsulfonyl)acetamido)-N-(4-phenoxyphenyl)propanamide;

20) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-1H-indole-5-carboxamide;

21) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-2-bromo-5-fluorobenzamide;

22) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-3,3,3-trifluoropropanamide;

23) (2R)-N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)tetrahydrofuran-2-carboxamide;

24) 3-(benzyloxy)-2-((R)-2-(2-chlorophenyl)-2-hydroxyacetamido)-N-(4-phenoxyphenyl)propanamide;

25) (2S)-1-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-ylamino)-1-oxopropan-2-yl acetate;

26) 3-(benzyloxy)-2-(2-(2-hydroxyphenoxy)acetamido)-N-(4-phenoxyphenyl)propanamide;

27) 3-(benzyloxy)-2-((R)-2-hydroxy-3-phenylpropanamido)-N-(4-phenoxyphenyl)propanamide;

28) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-2-(methylthio)nicotinamide;

29) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-1-(4-chlorobenzyl)-5-oxopyrrolidine-3-carboxamide;

30) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-((1-methyl-1H-indol-2-yl)methylamino)acetyl)pyrrolidine-2-carboxamide;

31) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-phenylacetyl)pyrrolidine-2-carboxamide;

32) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxamide;

33) (2S,4R)-4-benzyl-1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)butanoyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

34) 34,(2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3,3,3-trifluoropropanoyl)pyrrolidine-2-carboxamide;

35) (2S,4R)-4-benzyl-1-(2-(4-(dimethylamino)phenyl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

36) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(tetrahydrofuran-3-carbonyl)pyrrolidine-2-carboxamide;

37) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(2-methyl-1H-indol-3-yl )acetyl)pyrrolidine-2-carboxamide;

38) (2S,4R)-4-benzyl-1-(2-butoxyacetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

39) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-((S)-5-oxotetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxamide;

40) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-((R)-2-hydroxy-2-phenylacetyl)pyrrolidine-2-carboxamide;

41) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)acetamido)propanamide;

42) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(3-methoxyphenyl)piperazin-1-yl)acetamido)propanamide;

43) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(pyrrolidin-1-yl)piperidin-1-yl)acetamido)propanamide;

44) (S)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-phenyloxazol-4-yl)acetamido)propanamide;

45) (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(octahydroquinolin-1(2H)-yl)acetamido)propanamide;

46) (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(3-methylpiperidin-1-yl)acetamido)propanamide;

47) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)-2-methylphenyl)propanamide;

48) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2-methylbenzyl)pyrrolidine-2-carboxamide;

49) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(3-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

50) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

51) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(3-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

52) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

53) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

54) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide;

55) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2-methylbenzyl)pyrrolidine-2-carboxamide;

56) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

57) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

58) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

59) (R)-N-(2-(benzyloxy)-1-(5-(4-fluorophenoxy)-1H-benzo[d]imidazol-2-yl)ethyl)-2-(1H-imidazol-4-yl)acetamide;

60) (R)-N-(2-(benzyloxy)-1-(5-(4-fluorophenoxy)-1H-benzo[d]imidazol-2-yl)ethyl)acetamide;

61) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

62) (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(4-methoxyphenyl)pyrrolidine-2-carboxamide;

63) (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-methylpyrrolidin-1-yl)acetamido)propanamide;

64) (2S,4S)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(thien-2-ylmethyl)pyrrolidine-2-carboxamide;

65) (2S,4S)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

66) (2S,4S)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

67) (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

68) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide;

69) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide;

70) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide;

71) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide;

72) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(thiophen-3-ylmethyl)pyrrolidine-2-carboxamide;

73) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluoro-3-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide;

74) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluoro-2-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide;

75) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

76) (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

77) (2S,4S)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-phenylpyrrolidine-2-carboxamide;

78) (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-phenylpyrrolidine-2-carboxamide;

79) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-chlorophenoxy)phenyl)pyrrolidine-2-carboxamide;

80) (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

81) (S)-3-(benzyloxy)-2-(3-(3-chloro-4-methoxyphenyl)propanamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

82) (2S,4R)-4-benzyl-1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

83) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-thiomorpholinoacetyl)pyrrolidine-2-carboxamide;

84) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(2,3,6-trifluorophenyl)acetyl)pyrrolidine-2-carboxamide;

85) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3-(methylthio)propanoyl)pyrrolidine-2-carboxamide;

86) (2S,4R)-4-benzyl-1-(3-ethoxypropanoyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

87) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(methylsulfonyl)acetyl)pyrrolidine-2-carboxamide;

88) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(2-methoxyethoxy)acetyl)pyrrolidine-2-carboxamide;

89) (2S,4R)-4-benzyl-1-(4-(dimethylamino)-4-oxobutanoyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

90) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3-methoxypropanoyl)pyrrolidine-2-carboxamide;

91) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(4-oxo-4-(thien-2-yl)butanoyl)pyrrolidine-2-carboxamide;

92) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxamide;

93) (2S,4R)-1-((S)-1-acetylpyrrolidine-2-carbonyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

94) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(pyrimidin-2-ylthio)acetyl)pyrrolidine-2-carboxamide;

95) (2S,4R)-4-benzyl-1-(2-(2,6-difluorophenyl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

96) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(pyridin-4-ylthio)acetyl)pyrrolidine-2-carboxamide;

97) (2S,4R)-4-benzyl-1-(2-(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

98) (2S,4R)-1-(2-(1H-indol-3-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

99) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(4-oxo-2-thioxothiazolidin-3-yl)acetyl)pyrrolidine-2-carboxamide;

100) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(4-(2-methoxyethyl)piperazin-1-yl)acetyl)pyrrolidine-2-carboxamide;

101) (S)-3-(benzyloxy)-2-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

102) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(3-(trifluoromethoxy)phenyl)acetamido)propanamide;

103) (S)-tert-butyl 1-(2-((S)-3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-ylamino)-2-oxoethyl)pyrrolidine-2-carboxylate;

104) (S)-N-(3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)-5-phenylpentanamide;

105) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-morpholinopiperidin-1-yl)acetamido)propanamide;

106) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

107) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

108) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide;

109) (2S)-3-(benzyloxy)-2-(2-(3-(diethylamino)pyrrolidin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

110) (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)acetamido)propanamide;

111) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-isopropylpiperazin-1-yl)acetamido)propanamide;

112) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)acetamido)propanamide;

113) (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2(((S)-1-methylpyrrolidin-2-yl)methyl)piperidin-1-yl)acetamido)propanamide,

114) (S)-3-(benzyloxy)-2-(2-(4-ethylpiperazin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

115) (2S,4R)-1-(2-(4-acetylpiperazin-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

116) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-morpholinoacetyl)pyrrolidine-2-carboxamide;

117) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(thien-2-yl)acetyl)pyrrolidine-2-carboxamide;

118) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3-hydroxybutanoyl)pyrrolidine-2-carboxamide;

119) (2S,4R)-4-benzyl-1-(2-(2,6-dichlorophenyl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

120) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide;

121) (2S,4R)-4-benzyl-1-(2-ethoxyacetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

122) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-methoxyacetyl)pyrrolidine-2-carboxamide;

123) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(4-oxopentanoyl)pyrrolidine-2-carboxamide;

124) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(4-oxo-4-phenylbutanoyl)pyrrolidine-2-carboxamide;

125) methyl 4-((2S,4R)-4-benzyl-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-1-yl)-4-oxobutanoate;

126) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(pyridin-2-yl)piperazin-1-yl)acetamido)propanamide;

127) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetamido)propanamide;

128) (S)-2-(2-(azepan-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

129) (2S,4R)-4-benzyl-1-(2-cyanoacetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

130) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-methylpiperidin-1-yl)acetamido))propanamide;

131) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-3-benzyloxy-N-(4-(4-fluorophenoxy)phenyl)propanamide;

132) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-3-(4-fluorobenzyloxy)-N-(4-(4-chlorophenoxy)phenyl)propanamide;

133) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

134) (S)-2-(2-(1H-imidazol-1-yl)acetamido)-3-benzyloxy-N-(4-(4-fluorophenoxy)phenyl)propanamide;

135) (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

136) (S)-3-(benzyloxy)-2-(2-chloroacetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

137) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-5-phenyl-N-(4-(4-fluorophenoxy)phenyl)pentanamide;

138) (S)-2-(2-(2H-1,2,3-triazol-2-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

139) (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)-3-(2-(trifluoromethoxy)benzyloxy)propanamide;

140) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

141) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

142) 2-(2-(1H-imidazol-5-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

143) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

144) (S)-2-(2-(1H-tetrazol-1-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

145) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-3-benzyloxy-N-(4-(4-chlorophenoxy)phenyl)propanamide;

146) (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-phenoxyphenyl)propanamide;

147) (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(3-chloro-4-phenoxyphenyl)propanamide;

148) (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(4-(3-chlorophenoxy)phenyl)propanamide;

149) (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-benzyloxy-N-(4-(4-fluorophenoxy)phenyl)propanamide;

150) (S)-3-(benzyloxy)-2-(2-(3,5-dimethylisoxazol-4-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

151) (S)-2-(2-(1H-benzo [d][1,2,3]triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

152) (S)-3-(benzyloxy)-2-(2-(3,5-dimethyl-1H-pyrazol-4-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

153) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-methyl-1H-1,2,3-triazol-1-yl)acetamido)propanamide;

154) (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(3-chloro-4-(4-chlorophenoxy)phenyl)propanamide;

155) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-morpholinoacetamido)propanamide;

156) (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(4-(5-bromothiazol-2-yloxy)phenyl)propanamide;

157) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-N-(4-(4-chlorophenoxy)phenyl)-4-phenylbutanamide;

158) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-3-(benzyloxy)-N-(4-(p-tolyloxy)phenyl)propanamide;

159) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyrazin-2-yl)acetamido)propanamide;

160) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-methyl-1H-imidazol-1-yl)acetamido)propanamide;

161) (S)-2-(2-(1H-imidazol-4-yl)-2-methylpropanamido)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

162) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-methyl-1H-imidazol-4-yl)acetamido)propanamide;

163) (2S,3S)-1-(2-(1H-imidazol-4-yl)acetyl)-3-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

164) (S)-2-acetamido-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

165) (S)-benzyl 4-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-(4-(4-fluorophenoxy)phenylamino)-5-oxopentylcarbamate;

166) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(3-methyl-1H-pyrazol-5-yl)acetamido)propanamide

167) (2S)-2-(2-(1H-imidazol-4-yl)propanamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

168) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-N-(4-(4-bromophenoxy)phenyl)-3-(4-fluorobenzyloxy)propanamide;

169) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide;

170) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide;

171) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methylbenzyl)pyrrolidine-2-carboxamide;

172) (S)-2-(3-(3,5-dimethylisoxazol-4-yl)ureido)-3-benzyloxy-N-(4-(4-fluorophenoxy)phenyl)propanamide;

173) (2S,4R)-1-(2-(1H-imidazol-5-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

174) (S)-2-(2-(1H-1,2,3-triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

175) 175 (S)-1-(2-(1H-imidazol-4-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)piperazine-2-carboxamide;

176) (2S,4R)-1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

177) (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(5-methyl-1H-pyrazol-3-yl)acetyl)pyrrolidine-2-carboxamide;

178) (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenylthio)phenyl)propanamide;

179) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

180) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2,4-dichlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

181) (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(2-chlorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

182) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(thien-3-ylmethylamino)pyrrolidine-2-carboxamide;

183) 3-(benzyloxy)-2-(2-(2-fluorophenyl)acetamido)-N-(4-phenoxyphenyl)propanamide;

184) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-1H-indole-4-carboxamide;

185) 2-(2-(3-methylisoxazol-5-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

186) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-4-cyclopropyl-4-oxobutanamide;

187) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-1H-indole-6-carboxamide;

188) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-2,3-dihydro-1H-indene-2-carboxamide;

189) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-3-methyl-2-nitrobenzamide;

190) 3-(benzyloxy)-2-(2-(2,5-dichlorophenyl)acetamido)-N-(4-phenoxyphenyl)propanamide;

191) 3-(benzyloxy)-2-(2-(3-chloro-2-fluorophenyl)acetamido)-N-(4-phenoxyphenyl)propanamide;

192) 3-(benzyloxy)-2-(2-(5-chloro-2-fluorophenyl)acetamido)-N-(4-phenoxyphenyl)propanamide;

193) 2-(2-(1-acetylpyrrolidin-2-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

194) (S)-2-{2-((benzoyl)(methyl)amino)acetamido}-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

195) (S)-2-(2-(1-methyl-1H-imidazol-4-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

196) (S)-2-(2-(2-fluorophenyl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

197) (S)-2-(2-(1H-indol-4-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

198) (S)-2-(2-(thien-2-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

199) (S)-2-(2-(2,5-dichlorophenyl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide;

200) (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(4-benzylphenyl)propanamide;

201) (S)-3-(benzyloxy)-2-(2-(2,4-dioxoimidazolidin-1-yl)acetamido)-N-(4-phenoxyphenyl)propanamide;

202) (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(4-(4-methoxyphenoxy)phenyl)propanamide;

203) (S)-2-(2-(1H-imidazol-4-yl)-N-methylacetamido)-3-(benzyloxy)-N-(4-phenoxyphenyl)propanamide;

204) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-N-(4-(4-chlorophenoxy)phenyl)-3-phenylpropanamide;

205) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(piperazin-1-yl)acetamido)propanamide;

206) (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(4-(thiazol-2-yloxy)phenyl)propanamide;

207) (S)-2-(3-(1H-imidazol-5-yl)propanamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

208) (S)-2-(2-(1H-imidazol-5-yl)acetamido)-3-(benzyloxy)-N-(4-(cyclohexyloxy)phenyl)propanamide;

209) (S)-3-(benzyloxy)-N-(4-(4-chlorophenoxy)phenyl)-2-(3-(dimethylamino)propanamido)propanamide;

210) (S)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-morpholinoacetamido)propanamide;

211) (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(4-(benzyloxy)phenyl)propanamide;

212) (S)-3-(benzyloxy)-2-(2-(5-fluoro-1H-indol-3-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

213) (S)-2-(2-(1H-imidazol-4-yl)-2-methylpropanamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

214) (S)-3-(benzyloxy)-2-(2-(2,5-dihydro-1H-pyrrol-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

215) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyrrolidin-1-yl)acetamido)propanamide;

216) (S)-2-(2-(2-(1H-imidazol-4-yl)ethylamino)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

217) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-methoxyphenyl)piperazin-1-yl)acetamido)propanamide;

218) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(4-fluorophenyl)piperazin-1-yl)acetamido)propanamide;

219) (2S)-2-(2-(2,3-dioxa-8-azaspiro[4.5]decan-8-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

220) (S)-3-(benzyloxy)-2-(2-(4-benzylpiperidin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

221) (S)-3-(benzyloxy)-2-(2-(3,4-dihydroisoquinolin-2(1H)-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

222) (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(octahydroisoquinolin-2(1H)-yl)acetamido)propanamide;

223) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(furan-2-carbonyl)piperazin-1-yl)acetamido)propanamide;

224) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(4-methoxyphenyl)piperazin-1-yl)acetamido)propanamide;

225) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-phenylpiperazin-1-yl)acetamido)propanamide;

226) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(3,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

227) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

228) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

229) (S)-2-(2-(4-(4-acetylphenyl)piperazin-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

230) (S)-2-(2-(4-acetylpiperazin-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

231) 1-(2-((S)-3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-ylamino)-2-oxoethyl)-N,N-diethylpiperidine-3-carboxamide;

232) (S,E)-N-(3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)hex-3-enamide;

233) (S)-N-(3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)-3-methylbutanamide;

234) (S)-3-(benzyloxy)-2-(2-((2R,6S)-2,6-dimethylmorpholino)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

235) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(thiazolidin-3-yl)acetamido)propanamide;

236) (S)-2-(2-(4-acetylpiperazin-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

237) (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)acetamido)propanamide;

238) (S)-methyl 1-(2-(3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-ylamino)-2-oxoethyl)piperidine-4-carboxylate;

239) (S)-3-(benzyloxy)-2-(2-(4-(2-chloro-6-fluorobenzyl)piperazin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

240) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(isoindolin-2-yl)acetamido)propanamide;

241) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-methoxyethyl)piperazin-1-yl)acetamido)propanamide;

242) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-ethoxyethyl)piperazin-1-yl)acetamido)propanamide;

243) (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(3-phenoxyphenyl)propanamide;

244) (S)-3-(benzyloxy)-2-(2-(3-bromophenyl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

245) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(3-nitropropanamido)propanamide;

246) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyridin-2-yl)acetamido)propanamide;

247) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyridin-3-yl)acetamido)propanamide;

248) (S)-N-((S)-3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)-3,7-dimethyloct-6-enamide;

249) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-phenylacetamido)propanamide;

250) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyrimidin-5-yl)acetamido)propanamide;

251) (2S,4S)-1-(2-(1H-imidazol-5-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-phenylpyrrolidine-2-carboxamide;

252) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(benzyloxy)-N-(4-(4-fluorohenoxy)phenyl)pyrrolidine-2-carboxamide;

253) benzyl (3R,5S)-1-(2-(1H-imidazol-5-yl)acetyl)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate;

254) (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-acetamido-N-(4-(4-fluorophenoxy)phenyl)pentanamide;

255) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-methyl-2-(1H-1,2,4-triazol-1-yl)propanamido)propanamide;

256) (S)-3-(benzyloxy)-2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

257) (S)-benzyl 4-(2-(1H-imidazol-4-yl)acetyl)-3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate;

258) (S)-2-(2-(3,5-dimethyl-1H-pyrazol-4-yl)acetamido)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

259) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-phenoxypyrrolidine-2-carboxamide;

260) (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(isoindolin-2-pyrrolidine-2-carboxamide;

261) (S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)piperazine-2-carboxamide;

262) (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-((benzylamino)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

263) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

264) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

265) (2S)-3-(benzyloxy)-2-(2-(2,6-dimethylmorpholino)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide;

266) (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-thiomorpholinoacetamido)propanamide;

267) (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

268) (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide;

269) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)acetamide;

270) 4-(methyloxy)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

271) 4-benzyloxy-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)phenylacetamide;

272) 2-bromo-5-(methyloxy)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

273) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)butanamide;

274) 2-chloro-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

275) 3-chloro-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

276) 4-chloro-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

277) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)cyclopropylamide;

278) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-cyclopentylpropanamide;

279) 3,4-dimethyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

280) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2,5-dimethoxyphenylacetamide;

281) 4-(ethyloxy)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

282) N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)-2-ethylhexanamide;

283) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)furan-2-carboxamide;

284) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-methoxyacetamide;

285) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-methoxyphenylacetamide;

286) 2-methyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)pentanamide;

287) 4-methyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)pentanamide;

288) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)naphthalene-2-carboxamide;

289) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)phenoxyacetamide;

290) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(phenyloxy)pyridine-3-carboxamide;

291) 3,4,5-tris(methyloxy)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

292) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)thiophene-2-carboxamide;

293) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)thien-2-ylacetamide;

294) 4-(dimethylamino)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

295) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)hexanamide;

296) 2-chloro-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)pyridine-3-carboxamide;

297) 3-chloro-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-1-benzothiophene-2-carboxamide;

298) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)pent-4-enamide;

299) 3-chloro-2-fluoro-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

300) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-4-phenylbutanamide;

301) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-bromophenylacetamide;

302) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidine-4-carboxamide;

303) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-methoxyethoxyacetamide;

304) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-(4-methoxyphenyl)propanamide;

305) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-acetylamino-4-methylthiazol-5-ylsulfonamide;

306) 4-(methylthio)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

307) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(methylthio)acetamide;

308) 5-fluoro-2-(methyloxy)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

309) 2-methyl-4-(methyloxy)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

310) 5-oxo-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)hexanamide;

311) 4-bromo-2-methyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

312) 4-oxo-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-4-(2-thienyl)butanamide;

313) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(phenylthio)acetamide;

314) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(1H-pyrrol-1-yl)benzamide;

315) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-[2-(methoxy)ethoxy]ethoxyacetamide;

316) 3,5-bis(methyloxy)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

317) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-cyclohexylpropanamide;

318) 5-oxo-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-5-phenylpentanamide;

319) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-4-acetylphenoxyacetamide;

320) 4-[3,4-bis(methyloxy)phenyl]-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)butanamide;

321) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-5-[3-(trifluoromethyl)phenyl]furan-2-carboxamide;

322) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-(1,3-dioxoisoindolin-2-yl)propanamide;

323) 5-oxo-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-5-(2-thienyl)pentanamide;

324) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-oxo-2-phenylacetamide;

325) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-4-(2-thienyl)butanamide;

326) 5-nitro-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)furan-2-carboxamide;

327) (E)-N-(3-(benzyloxy)-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)hex-3-enamide

328) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-1,3-benzodioxol-5-ylacetamide;

329) 1-(2-chloro-6-fluorophenyl)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)cyclopentanecarboxamide;

330) 4-fluoro-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(trifluoromethyl)benzamide;

331) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(pyrimidin-2-ylthio)acetamide;

332) 2,5-bis(methyloxy)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

333) 4-(methylsulfonyl)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

334) 2-chloro-4-(methylsulfonyl)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

335) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)2-(4-oxo-2-thioxothiazolidin-3-yl)acetamide;

336) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)tetrahydrofuran-3-carboxamide;

337) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-methoxypropanamide;

338) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-ethoxyacetamide;

339) N,N-dimethyl-N′-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)butanediamide;

340) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-N-benzoyl-N-methylaminoacetamide;

341) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-1H-indole-3-carboxamide;

342) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-1H-benzimidazole-5-carboxamide;

343) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(4-ethoxyphenyl)acetamide;

344) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)pent-4-ynamide;

345) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-4-(propyloxy)benzamide;

346) 2-methyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)hexanamide;

347) 4-oxo-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)pentanamide;

348) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-(3,4-dimethoxyphenyl)propanamide;

349) 4-oxo-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-4-phenylbutanamide;

350) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)quinoline-3-carboxamide;

351) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)pyrazine-2-carboxamide;

352) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamide;

353) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-methoxy-2-phenylacetamide;

354) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2R-phenylpropanamide;

355) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-1H-pyrazole-4-carboxamide;

356) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)cinnoline-4-carboxamide;

357) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)quinoline-8-carboxamide;

358) 6-hydroxy-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)pyridine-2-carboxamide;

359) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-phenylpropanamide;

360) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-1-(4-methoxyphenyl)cyclopropanecarboxamide;

361) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(2,3,6-trifluorophenyl)acetamide;

362) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2,4-bis(trifluoromethyl)benzamide;

363) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(2,4-difluorophenyl)acetamide;

364) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4(phenyloxy)phenyl]amino}ethyl)-2-(1-methyl-1H-indol-3-yl)acetamide;

365) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)quinoline-4-carboxamide;

366) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-1-benzofuran-2-carboxamide;

367) 7-(methyloxy)-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-1-benzofuran-2-carboxamide;

368) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(4-fluorophenoxy)acetamide;

369) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-(pyridin-3-yl)propanamide;

370) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(3,4-dichlorophenoxy)acetamide;

371) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(naphthalen-1-yloxy)acetamide;

372) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-p-tolylacetamide;

373) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(2,5-dimethylphenyl)acetamide;

374) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(benzylthio)acetamide;

375) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(naphthalen-1-yl)acetamide;

376) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-ethoxypropanamide;

377) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(3-chlorophenyl)acetamide;

378) 5-butyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)pyridine-2-carboxamide;

379) 4-chloro-3-methyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

380) 4-cyano-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

381) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2S-methoxy-2-phenylacetamide;

382) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-(2,5-dimethoxyphenyl)propanamide;

383) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-(1H-indol-3-yl)propanamide;

384) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(3-bromophenyl)acetamide;

385) 3-methyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)pentanamide;

386) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-1H-indole-2-carboxamide;

387) 4-chloro-2-fluoro-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

388) 2-oxo-2-[(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)amino]ethyl acetate;

389) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)thiophene-3-carboxamide;

390) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(4-bromophenyl)acetamide;

391) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(2-chlorophenyl)acetamide;

392) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(3,4,5-trimethoxyphenyl)acetamide;

393) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-2-(p-tolyloxy)acetamide;

394) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-(2-methoxyphenyl)propanamide;

395) 3-hydroxy-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)quinoxaline-2-carboxamide;

396) 4-acetyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

397) methyl 4-{[(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)amino]carbonyl}benzoate;

398) 3-fluoro-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-5-(trifluoromethyl)benzamide;

399) 4-[(difluoromethyl)oxy]-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

400) 3-fluoro-4-methyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)benzamide;

401) 3-methyl-N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)furan-2-carboxamide.

402) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)cyclobutanecarboxamide; and

403) N-(2-oxo-1-{[(phenylmethyl)oxy]methyl}-2-{[4-(phenyloxy)phenyl]amino}ethyl)-3-(thiophen-2-yl)propanamide.

2. The pharmaceutical composition of claim 1 , wherein the antimicrotubule agent is selected from the group consisting of a taxane or a vinca alkaloid.

3. The pharmaceutical composition of claim 2 , wherein the taxane is paclitaxel or docetaxel.

4. The pharmaceutical composition of claim 1 , wherein the S1P1R receptor antagonist is selected from the group consisting of

(2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide,

(2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide,

(2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, and

(2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide.

5. The pharmaceutical composition of claim 2 , wherein the S1P1R receptor antagonist is selected from the group consisting of

(2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide,

(2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide,

(2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, and

(2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide.

6. The pharmaceutical composition of claim 3 , wherein the S1P1R receptor antagonist is selected from the group consisting of

(2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide,

(2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide,

(2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, and

(2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide.

7. The pharmaceutical composition of claim 6 , wherein the S1P1R receptor antagonist is (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, and the taxane is paclitaxel or docetaxel.

8. The pharmaceutical composition of claim 6 , wherein the S1P1R receptor antagonist is (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide and the taxane is paclitaxel or docetaxel.

9. The pharmaceutical composition of claim 6 , wherein the S1P1R receptor antagonist is (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide and the taxane is paclitaxel or docetaxel.

10. The pharmaceutical composition of claim 6 , wherein the S1P1R receptor antagonist is 2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide and the taxane is paclitaxel or docetaxel.

11. The pharmaceutical composition of claim 2 , wherein the vinca alkaloid is vincristine, vinblastine, or vinorelbine.

12. The pharmaceutical composition of claim 11 , wherein the S1P1R receptor antagonist is selected from the group consisting of

(2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide,

(2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide,

(2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, and

(2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide.

13. The pharmaceutical composition of claim 12 , wherein the S1P1R receptor antagonist is (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide and the vinca alkaloid is selected from the group consisting of vincristine, vinblastine or vinorelbine.

14. The pharmaceutical composition of claim 12 , wherein the S1P1R receptor antagonist is (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide and the vinca alkaloid is selected from the group consisting of vincristine, vinblastine or vinorelbine.

15. The pharmaceutical composition of claim 12 , wherein the S1P1R receptor antagonist is (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide and the vinca alkaloid is selected from the group consisting of vincristine, vinblastine or vinorelbine.

16. The pharmaceutical composition of claim 12 , wherein the S1P1R receptor antagonist is (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide and the vinca alkaloid is selected from the group consisting of vincristine, vinblastine or vinorelbine.

17. A method of inhibiting or relieving cancer in a subject, comprising administering a therapeutically effective amount of at least one S1P1R receptor antagonist and at least one antimicrotubule agent, wherein the cancer is breast or lung cancer and the S1P1R receptor antagonist is selected from the group of compounds consisting of