IP Library › Granted Patent US 7,816,353
Granted Patent B2
US 7,816,353 · App. 10/576,653 · Granted Oct 19, 2010

P70S6 kinase modulators and method of use

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Quick Facts
Patent No.
US 7,816,353
App. No.
10/576,653
Granted
Oct 19, 2010
Kind
B2
Abstract

Compounds of formula III: wherein R 5a , R 3 , X, Y, Q, R 1a and R 1b are as defined in the specification, pharmaceutically acceptable salts thereof, and methods of use thereof.

Claims (326)

1. A compound according to Formula III,

or a pharmaceutically acceptable salt thereof, wherein:

R 1a is selected from halogen, lower perfluoroalkyl, —NO 2 , and optionally substituted C 1-4 alkyl;

and R 1b is selected from halogen, —N(R 5 )R 5 , —SR 5 , perfluoroalkyl, and optionally substituted lower alkyl;

R 3 is independently selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —OR 5 , —N(R 5 )OR 5 , —ON(R 5 )R 5 , —N(R 5 )N(R 5 )R 5 , —N(R 5 )R 5 , —S(O) 0-2 R 5 , —SO 2 N(R 5 )R 5 , —CO 2 R 5 , —C(O)N(R 5 )R 5 , —N(R 5 )SO 2 R 5 , —N(R 5 )C(O)R 5 , —N(R 5 )CO 2 R 5 , —C(O)R 5 , —C(═NR 7 )N(R 5 )R 5 , —C(═NR 7 )R 5 , —C(═NR 7 )OR 5 , —N(R 5 )C(═NR 7 )N(R 5 )R 5 , optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, and optionally substituted arylalkyl;

R 5a is H;

each R 5 is independently selected from —H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or

two of R 5 , together with the atom or respective atoms to which they are attached, can combine to form an optionally substituted three- to seven-membered heterocyclic;

each R 6 is independently selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 5 , —N(R 5 )R 5 , —S(O) 0-2 R 5 , —SO 2 N(R 5 )R 5 , —CO 2 R 5 , —C(O)N(R 5 )R 5 , —N(R 5 )SO 2 R 5 , —N(R 5 )C(O)R 5 , —N(R 5 )CO 2 R 5 , —C(O)R 5 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, and optionally substituted arylalkyl; or

two of R 6 , together with the atom or atoms to which they are attached, can combine to form one of an optionally substituted three to seven-membered alicylic, and an optionally substituted three to seven-membered heteroalicylic;

each R 7 is independently selected from —H, —CN, —NO 2 , —N(R 5 )R 5 , —OR 5 , —S(O) 0-2 R 5 , —SO 2 N(R 5 )R 5 , —CO 2 R 5 , optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted lower alkynyl; or

R 5 and R 7 , together with the atom or atoms to which they are attached, can combine to form a five- to seven-membered optionally substituted heterocyclyl;

each of X and Y is independently selected from —C(═O)—, —C(R 6 )R 6 —, —O—, —N(R 5 )—, —C(═NR 7 )—, and —S(O) 0-2 —; provided when X is —O— or —N(R 5 )—, then Y cannot contain phenyl, napthyl, cyclohexyl, dihydronapthyl tetrahydronapthyl, or a five- to six-membered heteroaryl, each optionally substituted; and

Q is either ═N— or ═C(H)—.

2. The compound according to claim 1 , wherein R 1a is selected from —NO 2 , halogen, perfluoroalkyl, haloalkyl, and optionally substituted C 1-2 alkyl.

3. The compound according to claim 2 , wherein R 3 is selected from optionally substituted —O—C 1-4 alkyl, —O—C 1-4 perfluoroalkyl, optionally substituted —N(H)C 1-4 alkyl, optionally substituted —N(C 1-4 alkyl)C 1-4 alkyl, optionally substituted —S(O) 0-2 —C 1-4 alkyl, and optionally substituted —S(O) 0-2 —C 1-4 perfluoroalkyl.

4. The compound according to claim 3 , wherein Y is either —N(H)— or —C(R 6 )R 6 —.

5. The compound according to claim 4 , wherein X is selected from —O—, —N(R 5 )— and —S—.

6. The compound according to claim 5 , wherein Y is —C(R 6 )R 6 —; wherein each R 6 is independently selected from —H, halogen, trihalomethyl, —NH 2 , optionally substituted —O—C 1-4 alkyl, optionally substituted —N(H)C 1-4 alkyl, optionally substituted —S—C 1-4 alkyl, optionally substituted lower alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl.

7. The compound according to claim 6 , wherein Y is —C(H)R 6 —; wherein R 6 is independently selected from —H, halogen, trihalomethyl, —NH 2 , optionally substituted —O—C 1-4 alkyl, optionally substituted —N(H)C 1-4 alkyl, optionally substituted —S—C 1-4 alkyl, optionally substituted lower alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl.

8. The compound according to claim 7 , wherein Q is ═C(H)—.

9. The compound according to claim 1 , wherein R 1a is selected from halo, lower perfluoroalkyl, —NO 2 , and optionally substituted C 1-4 alkyl.

10. A compound selected from Table 3:

TABLE 3

Entry

Name

Structure

5

N 2 -[2-amino-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]glycinamide

7

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- [3-(methyloxy)phenyl]acetamide

9

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- (4-chlorophenyl)acetamide

11

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- (3-chlorophenyl)acetamide

14

2-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]oxy}-N- [3-(trifluoromethyl)phenyl]acetamide

16

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- methyl-N-[3- (trifluoromethyl)phenyl]acetamide

20

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]glycinamide

30

2-amino-4-({2-[2,5- bis(methyloxy)phenyl]-2- oxoethyl}thio)-6- (methylthio)pyrimidine-5-carbonitrile

31

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- [4-fluoro-3- (trifluoromethyl)phenyl]acetamide

34

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- [4-chloro-3- (trifluoromethyl)phenyl]acetamide

35

2-amino-4-(methylthio)-6-({2-oxo-1- [3-(trifluoromethyl)phenyl]pyrrolidin- 3-yl}thio)pyrimidine-5-carbonitrile

36

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- [6-(trifluoromethyl)pyridin-2- yl]acetamide

37

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- [4-(trifluoromethyl)pyridin-2- yl]acetamide

41

2-{[2-(acetylamino)-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- [3-(trifluoromethyl)phenyl]acetamide

42

(2S)-2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]oxy}-N- [3- (trifluoromethyl)phenyl]propanamide

46

2-{[2-amino-5-formyl-6- (methylthio)pyrimidin-4-yl]oxy}-N- [3-(trifluoromethyl)phenyl]acetamide

54

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- [2-(methyloxy)-5- (trifluoromethyl)phenyl]acetamide

55

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- [2-chloro-5- (trifluoromethyl)phenyl]acetamide

58

N 2 -[2-amino-5-[(E)- hydrazonomethyl]-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]glycinamide

59

N 2 -[2-amino-5-[(E)- (hydroxyimino)methyl]-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]glycinamide

60

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L- alaninamide

61

2-{[2-amino-5-cyano-6- (methylamino)pyrimidin-4-yl]thio}- N-[3- (trifluoromethyl)phenyl]acetamide

62

2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]thio}-N- [2-amino-5- (trifluoromethyl)phenyl]acetamide

63

2-amino-4-(methylthio)-6-({[6- (trifluoromethyl)-1H-benzimidazol-2- yl]methyl}thio)pyrimidine-5- carbonitrile

64

2-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]hydrazine- carboxamide

65

N 2 -[5-cyano-2-(methylamino)-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]glycinamide

66

2-{[2-amino-5-cyano-6- (dimethylamino)pyrimidin-4-yl]thio}- N-[3- (trifluoromethyl)phenyl]acetamide

67

(S)-1-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]prolinamide

68

(2R)-2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]oxy}-N- [3- (trifluoromethyl)phenyl]propanamide

69

1-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]oxy}-N- [3- (trifluoromethyl)phenyl]cyclopropane carboxamide

70

(2S)-2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]oxy}-3- methyl-N-[3- (trifluoromethyl)phenyl]butanamide

72

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-2- methyl-N-[3- (trifluoromethyl)phenyl]glycinamide

73

1-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]amino}- N-[3- (trifluoromethyl)phenyl]cyclopropane carboxamide

74

N 2 -[2-amino-5-cyano-6- (methylsulfinyl)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L- alaninamide

75

N 2 -[2-amino-5-cyano-6- (methylsulfonyl)pyrimidin-4-yl]-N- [3-(trifluoromethyl)phenyl]-L- alaninamide

76

N 2 -(5-cyano-2-morpholin-4- ylpyrimidin-4-yl)-N-[3- (trifluoromethyl)phenyl]glycinamide

78

N 2 -[2-amino-5-cyano-6- (methyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L- alaninamide

79

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[2- (methyloxy)-5- (trifluoromethyl)phenyl]-L- alaninamide

80

N 2 -[2-amino-5-cyano-6- (methlylthio)pyrimidin-4-yl]-N-[2- chloro-5-(trifluoromethyl)phenyl]-L- alaninamide

83

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-D- alaninamide

84

2-[(2-amino-5-cyano-6-morpholin-4- ylpyrimidin-4-yl)thio]-N-[3- (trifluoromethyl)phenyl]acetamide

85

(R)-1-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]prolinamide

86

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L- ornithinamide

87

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-2-[2- (dimethylamino)ethyl]-N-[3- (trifluoromethyl)phenyl]glycinamide

88

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-alaninamide

89

N 2 -(2,6-diamino-5-cyanopyrimidin- 4-yl)-N-[3-(trifluoromethyl)phenyl]- L-alaninamide

90

N 2 -(2-amino-5-cyanopyrimidin-4- yl)-N-[3-(trifluoromethyl)phenyl]-L- alaninamide

91

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-2- methyl-N-[3- (trifluoromethyl)phenyl]-L- alaninamide

93

2-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-1,2- dimethyl-N-[3- (trifluoromethyl)phenyl]hydrazine- carboxamide

94

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- amino-5-(trifluoromethyl)phenyl]-L- alaninamide

95

ethyl [1-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-2-({[3- (trifluoromethyl)phenyl]amino} carbonyl)hydrazino]acetate

96

2-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-2- methyl-N-[3- (trifluoromethyl)phenyl]hydrazine- carboxamide

100

N 2 -[5-cyano-2-(methylthio)pyrimidin-4- yl]-N-[3- (trifluoromethyl)phenyl]glycinamide

101

N 2 -(2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-2- (tetrahydro-2H-pyran-4-ylmethyl)-N-[3- (trifluoromethyl)phenyl]glycinamide

102

N 2 -(2-amino-5-cyano-6-{[2- (dimethylamino)ethyl]oxy}pyrimidin-4-yl)- N-[3-(trifluoromethyl)phenyl]-L- alaninamide

103

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-6-{[(1,1- dimethylethyl)oxy]carbonyl}-N-[3- (trifluoromethyl)phenyl]-L-lysinamide

104

2-amino-4-(methylthio)-6-(methyl{(1S)-1- [6-(trifluoromethyl)-1H-benzimidazol-2- yl]ethyl}amino)pyrimidine-5-carbonitrile

105

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-2-[2- (tetrahydro-2H-pyran-4-yl)ethyl]-N-[3- (trifluoromethyl)phenyl]glycinamide

106

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3-{[2- (diethylamino)ethyl]amino}-5- (trifluoromethyl)phenyl]-L-alaninamide

107

2-amino-4-(methylthio)-6-({(1S)-1-[6- (trifluoromethyl)-1H-benzimidazol-2- yl]ethyl}amino)pyrimidine-5-carbonitrile

108

2-{2-amino-5-cyano-6-[1-(3- trifluoromethyl-phenylcarbamoyl)-1S- ethylamino]-pyrimidin-4-ylamino}-N-(3- trifluoromethyl-phenyl)-2S-propionamide

109

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-2-methyl-N- (3-methylphenyl)glycinamide

110

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-2-methyl-N- [3-(1-methylethyl)phenyl]glycinamide

111

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-5- [imino(nitroamino)methyl]-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

112

methyl 3-({N-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-L- alanyl}amino)-5-(trifluoromethyl)benzoate

113

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-(3- nitrophenyl)-L-alaninamide

114

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-]3- (trifluoromethyl)phenyl]-L-lysinamide

115

N 2 -[2-amino-5-cyano-6- (propyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-alaninamide

117

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl-L-argininamide

118

N 2 -[2-amino-5-cyano-6- (methylsulfinyl)pyrimidin-4-yl]-N-2-methyl- N-[3-(trifluoromethyl)phenyl]-L- alaninamide

119

N 2 -[2-amino-5-cyano-6- (methyloxy)pyrimidin-4-yl]-N-2-methyl-N- [3-(trifluoromethyl)phenyl]-L-alaninamide

120

N 2 -[2-amino-5-cyano-6- (propyloxy)pyrimidin-4-yl]-N-2-methyl-N- [3-(trifluoromethyl)phenyl]-L-alaninamide

121

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-2-methyl-N-[3- (trifluoromethyl)phenyl]-L-alaninamide

122

N 2 -[2-amino-5-cyano-6-[(1- methylethyl)oxy]pyrimidin-4-yl}-N-[3- (trifluoromethyl)phenyl]-L-alaninamide

123

N-5-acetyl-N-2-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

124

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-(3- aminophenyl)-L-alaninamide

125

3-({N-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-L- alanyl}amino)-N-[2-(dimethylamino)ethyl]- 5-(trifluoromethyl)benzamide

126

2-(methyloxy)ethyl ((4S)-4-{[2-amino-5- cyano-6-(methylthio)pyrimidin-4- yl]amino)-5-oxo-5-{[3- (trifluoromethyl)phenyl]amino}pentyl) carbamate

127

2-[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]hydrazinecarboxamide

128

1,1-dimethylethyl ((4S)-4-{[2-amino-5- cyano-6-(ethyloxy)pyrimidin-4-yl]amino}- 5-oxo-5-{[3- (trifluoromethyl)phenyl]amino}pentyl) carbamate

130

3-({N-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-methyl-L- alanyl}amino)-N-[2- (dimethylamino)ethyl]-5- (trifluoromethyl)benzamide

131

3-({N-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-methyl-L- alanyl}amino)-N-[3-(4-methylpiperazin-1- yl)propyl]-5-(trifluoromethyl)benzamide

132

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N~2~-methyl- N-{3-](trifluoromethyl)oxy]phenyl}-L- alaninamide

133

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-(3- bromophenyl)-N~2~-methyl-L- alaninamide

134

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-{2-{[2- (dimethylamino)ethyl]oxy}-5- [(trifluoromethyl)oxy]phenyl}-N~2~- methyl-L-alaninamide

135

3-({N-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-methyl-L- alanyl}amino)-N-(2-morpholin-4-ylethyl)- 5-(trifluoromethyl)benzamide

136

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N~2~-methyl-N- [3-(trifluoromethyl)phenyl]-L-lysinamide

137

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3-{[2- (dimethylamino)ethyl]oxy}-5- (trifluoromethyl)phenyl]-L-alaninamide

138

(2S)-2-{[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]amino}-3-oxo- 3-{[3-(trifluoromethyl)phenyl]amino}propyl acetate

139

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N~1~-[3- (trifluoromethyl)phenyl]-L-glutamamide

140

2-[2-amino-5-cyano-6- (methyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]hydrazine- carboxamide

141

3-({N-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-L- alanyl}amino)-N-hydroxy-5- (trifluoromethyl)benzamide

142

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-3- (dimethylamino)-N-[3- (trifluoromethyl)phenyl]-L-alaninamide

143

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-5-morpholin-4- yl-N-[3-(trifluoromethyl)phenyl]-L- norvalinamide

144

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N~5~-[2- (methyloxy)ethyl]-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

145

3-({N-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-L- alanyl}amino)-5-(trifluoromethyl)benzoic acid

146

methyl N~2~-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-alpha- glutaminate

147

N 5 -(aminocarbonyl)-N~2~-[2-amino-5- cyano-6-(methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

148

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

149

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-alpha-glutamine

150

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-serinamide

151

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-O- (phenylmethyl)-N-[3- (trifluoromethyl)phenyl-L-serinamide

152

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-argininamide

153

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N~2~-methyl- N~6~-{[(phenylmethyl)oxy]carbonyl}-N-[3- (trifluoromethyl)phenyl]-L-lysinamide

154

N-α-[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-tyrosinamide

155

N 5 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

156

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N~6~,N~6~- dimethyl-N-[3-(trifluoromethyl)phenyl]-L- lysinamide

157

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3-[(4- methylpiperazin-1-yl)carbonyl]-5- (trifluoromethyl)phenyl]-L-alaninamide

158

3-({N-[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-L-alanyl}amino)- N-(3-pyrrolidin-1-ylpropyl)-5- (trifluoromethyl)benzamide

159

3-({N-[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-L-alanyl}amino)- N-(2-morpholin-4-ylethyl)-5- (trifluoromethyl)benzamide

160

3-({N-[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-L-alanyl}amino)- N-[2-(dimethylamino)ethyl]-5- (trifluoromethyl)benzamide

161

3-({N-[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-L-alanyl}amino)- N-[3-(4-methylpiperazin-1-yl)propyl]-5- (trifluoromethyl)benzamide

162

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N~2~-methyl- N 6 -{[(phenylmethyl)oxy]carbonyl}-N-[3- (trifluoromethyl)phenyl]-L-lysinamide

163

1,1-dimethylethyl ((4S)-4-{[2-amino-5- cyano-6-(ethyloxy)pyrimidin-4-yl]amino}- 5-oxo-5-{[3- (trifluoromethyl)phenyl]amino}pentyl) carbamate

164

(2S)-2-{[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]amino}-3-oxo-3- {[3-(trifluoromethyl)phenyl]amino}propyl acetate

165

phenylmethyl N~2~-[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-alpha- glutaminate

166

N 2 ,N 5 -diacetyl-N~2~-[2- (acetylamino)-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

167

2-(methyloxy)ethyl ((4S)-4-{[2-amino-5- cyano-6-(methylthio)pyrimidin-4- yl]amino}-5-oxo-5-{(3- (trifluoromethyl)phenyl]amino}pentyl) carbamate

168

N~2~-[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-5-morpholin-4-yl- N-[3-(trifluoromethyl)phenyl]-L- norvalinamide

169

N-((4S)-4-{[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]amino}-5-oxo-5- {[3-(trifluoromethyl)phenyl]amino}pentyl)- N,N-dimethylmethanaminium

170

Methyl N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-alpha- glutaminate

171

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N~6~,N~6~- dimethyl-N-[3-(trifluoromethyl)phenyl]-L- lysinamide

172

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N~2~-methyl-N- {3-[(trifluoromethyl)oxy]phenyl}-L- alaninamide

173

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-alpha-glutamine

174

N~2~-[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-(3- bromophenyl)-N~2~-methyl-L- alaninamide

175

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N 1 -[3- (trifluoromethyl)phenyl]-L-glutamamide

176

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-3- (dimethylamino)-N-[3- (trifluoromethyl)phenyl]-L-alaninamide

177

Structure possibly contains amino acid derivative which is not supported in current version!

178

N 2 -[2-amino-5-cyano-6- (methyloxy)pyrimidin-4-yl]-3- (dimethylamino)-N-[3- (trifluoromethyl)phenyl]-L-alaninamide

179

N 2 -[2-amino-5-cyano-6- (methyloxy)pyrimidin-4-yl]-N-(3-{(2- (dimethylamino)ethyl]oxy}-5- (trifluoromethyl)phenyl]-L-alaninamide

180

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3-{[2- (dimethylamino)ethyl]oxy}-5- (trifluoromethyl)phenyl]-L-alaninamide

181

N 2 -[2-amino-5-cyano-6- (methyloxy)pyrimidin-4-yl]-N-(3- bromophenyl)-N 2 -methyl-L- alaninamide

182

phenylmethyl N~2~-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-alpha- glutaminate

183

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-O- (phenylmethyl)-N-[3- (trifluoromethyl)phenyl]-L-serinamide

184

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N~5~,N~5~- bis[2-(methyloxy)ethyl]-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

185

1,1-dimethylethyl ((4S)-4-{[2-amino-5- cyano-6-(methyloxy)pyrimidin-4- yl]amino}-5-oxo-5-{[3- (trifluoromethyl)phenyl]amino}pentyl) carbamate

186

N 5 -acetyl-N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-(3- (trifluoromethyl)phenyl]-L-ornithinamide

187

N 5 -acetyl-N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

188

N 2 -[2-amino-5-cyano-6- (methyloxy)pyrimidin-4-yl]-N 2 -methyl- N-{3-[(trifluoromethyl)oxy]phenyl}-L- alaninamide

189

methyl 3-({N-[2-amino-5-cyano-6- (methyloxy)pyrimidin-4-yl]-L- alanyl}amino)-5-(trifluoromethyl)benzoate

190

3-({N-[2-amino-5-cyano-6- (methyloxy)pyrimidin-4-yl]-L- alanyl}amino)-N-[2-(dimethylamino)ethyl]- 5-(trifluoromethyl)benzamide

191

N 2 -{2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-3-morpholin-4- yl-N-[3-(trifluoromethyl)phenyl]-L- alaninamide

192

N 2 -[2-amino-5-cyano-6- (methyloxy)pyrimidin-4-yl]-3-morpholin-4- yl-N-[3-(trifluoromethyl)phenyl]-L- alaninamide

193

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-3-morpholin-4-yl- N-[3-(trifluoromethyl)phenyl]-L- alaninamide

194

N 5 -(aminocarbonyl)-N 2 -[2-amino-5- cyano-6-(ethyloxy)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

195

N~2~-[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N-[3- (trifluoromethyl)phenyl]-D-lysinamide

196

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-N-[3- (trifiuoromethyl)phenyl]-D-lysinamide

197

N 2 -[2-amino-5-cyano-6- (ethyloxy)pyrimidin-4-yl]-O-methyl-N-[3- (trifluoromethyl)phenyl]-L-serinamide

198

N 2 -[2-amino-5-cyano-6- (methylthio)pyrimidin-4-yl]-N~5~- (methylsulfonyl)-N-[3- (trifluoromethyl)phenyl]-L-ornithinamide

11. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2006
From: CHENG, WEI; CO, ERICK WANG; KLEIN, RHETT RONALD; KIM, MOON HWAN; LE, DONNA T; TSUHAKO, AMY LEW; NUSS, JOHN M; XU, WEI
To: EXELIXIS, INC.
Reel/Frame 017854/0195 →