NOVEL COMPOUNDS

Abstract

The invention relates to compounds of formula (I): and related aspects.

##STR00001##

Claims

1-72. (canceled)

73. A compound of formula (I): ##STR00207## wherein: R.sub.1a is H or methyl; R.sub.1b is H or F; A is group (Aa), (Ab), (Ac) or (Ad): wherein group (Aa) is: ##STR00208## wherein: R.sub.2 is H, C.sub.1-4alkyl, C.sub.1-4alkylene(aryl), C.sub.1-4alkylene(OH), C.sub.1-4alkylene(C.sub.3-6cycloalkyl), C.sub.1-4alkylene(4-7 membered heterocycloalkyl), C.sub.1-4alkoxy, OC.sub.1-4alkylene(aryl), C.sub.1-4alkyleneOC.sub.1-4alkyl, C.sub.1-4alkyleneOC.sub.3-6cycloalkyl, C.sub.1-4alkyleneO(4-7 membered heterocycloalkyl), C.sub.1-4alkyleneO(aryl), C.sub.3-6alkynyl or C.sub.1-4alkenylO(C.sub.3-6alkynyl); wherein said aryl, heterocycloalkyl and cycloalkyl are optionally substituted by 1, 2 or 3 substituents each independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, halo, CN, OH, NR.sub.2aR.sub.2b, SO.sub.2R.sub.2c and NHSO.sub.2R.sub.2c; R.sub.2a is selected from H and C.sub.1-4alkyl; R.sub.2b is selected from H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R.sub.2c is selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; each R.sub.3 is independently halo, methyl, ethyl or n-propyl; m is 0, 1, 2, 3 or 4; wherein group (Ab) is: ##STR00209## wherein: R.sub.4 is H, C.sub.1-4alkyl or C.sub.1-4alkylene(aryl); wherein said aryl is optionally substituted by 1, 2 or 3 substituents each independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, halo, CN, OH, NR.sub.4aR.sub.4b, SO.sub.2R.sub.4c and NHSO.sub.2R.sub.4c; R.sub.4a is selected from H and C.sub.1-4alkyl; R.sub.4b is selected from H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R.sub.4c is selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R.sub.5 is H or C.sub.1-4alkyl; each R.sub.6 is independently C.sub.1-4alkyl or halo; n is 0, 1, 2 or 3; wherein group (Ac) is: ##STR00210## wherein: R.sub.7 is C.sub.1-4alkyl, C.sub.1-4alkylene(OH) or C.sub.1-4alkyleneOC.sub.1-4alkyl; o is 1 or 2; wherein group (Ad) is: ##STR00211## wherein: X is a bond, O or CH.sub.2; each R.sub.8 is independently halo, C.sub.1-4alkyl, C.sub.1-4alkoxy, OC.sub.1-4haloalkyl, OC.sub.1-4alkylene(C.sub.3-6cycloalkyl), OC.sub.1-4alkylene(4-7 membered heterocycloalkyl) or OH; wherein said heterocycloalkyl and cycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, halo, CN, OH, NR.sub.8aR.sub.8b, SO.sub.2R.sub.8c and NHSO.sub.2R.sub.8c; R.sub.8a is selected from H and C.sub.1-4alkyl; R.sub.8b is selected from H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R.sub.8c is selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; each R.sub.9 is independently halo or C.sub.1-4alkyl; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; wherein B is group (Ba), (Bb) or (Bc): wherein group (Ba) is: ##STR00212## wherein: Y is C(R.sub.11)(R.sub.12), N(R.sub.13), O or S; each R.sub.10 is independently halo or C.sub.1-4alkyl; r is 0, 1, 2 or 3; R.sub.11 is H or C.sub.1-4alkyl; R.sub.12 is H or C.sub.1-4alkyl; or R.sub.11 and R.sub.12 together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl; R.sub.13 is H, C.sub.1-4alkyl or C.sub.3-6cycloalkyl; wherein said cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, halo, CN, OH, NR.sub.13aR.sub.13b, SO.sub.2R.sub.13c and NHSO.sub.2R.sub.13c; R.sub.13a is selected from H and C.sub.1-4alkyl; R.sub.13b is selected from H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R.sub.13c is selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; wherein group (Bb) is: ##STR00213## wherein: each R.sub.14 is independently halo or C.sub.1-4alkyl; s is 0, 1, 2 or 3; wherein group (Bc) is: ##STR00214## wherein: R.sub.15 is C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.3-6cycloalkyl, C.sub.1-4haloalkyl, halo or CN; wherein said cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, halo, CN, OH, NR.sub.15aR.sub.15b, SO.sub.2R.sub.15c and NHSO.sub.2R.sub.15c; R.sub.15a is selected from H and C.sub.1-4alkyl; R.sub.15b is selected from H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R.sub.15c is selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R.sub.16 is H, halo or C.sub.1-4alkyl; and D, E and F are each independently C(R.sub.16); or one of D, E and F is N, and the two remaining D, E and F groups are independently C(R.sub.16); or a pharmaceutically acceptable salt and/or solvate thereof.

74. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, which is a compound of formula (I): ##STR00215## wherein: R.sub.1a is H or methyl; R.sub.1b is H or F; A is group (Aa), (Ab), (Ac) or (Ad): wherein group (Aa) is: ##STR00216## wherein: R.sub.2 is H, C.sub.1-4alkyl, C.sub.1-4alkylene(aryl), C.sub.1-4alkylene(OH), C.sub.1-4alkylene(C.sub.3-6cycloalkyl), C.sub.1-4alkylene(4-7 membered heterocycloalkyl), C.sub.1-4alkoxy, OC.sub.1-4alkylene(aryl), C.sub.1-4alkyleneOC.sub.1-4alkyl, C.sub.1-4alkyleneOC.sub.3-6cycloalkyl, C.sub.1-4alkyleneO(4-7 membered heterocycloalkyl), C.sub.1-4alkyleneO(aryl), C.sub.3-6alkynyl or C.sub.1-4alkenylO(C.sub.3-6alkynyl); wherein said aryl, heterocycloalkyl and cycloalkyl may be optionally substituted by up to 3 substituents each independently selected from C.sub.1-4alkyl, C.sub.3-6cycloaklyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, halo and CN; each R.sub.3 is independently halo, methyl, ethyl or n-propyl; m is 0, 1, 2, 3 or 4; wherein group (Ab) is: ##STR00217## wherein: R.sub.4 is H, C.sub.1-4alkyl or C.sub.1-4alkylene(aryl); wherein said aryl may be optionally substituted by up to 3 substituents each independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, halo and CN; R.sub.5 is H or C.sub.1-4alkyl; each R.sub.6 is independently C.sub.1-4alkyl or halo; n is 0, 1, 2 or 3; wherein group (Ac) is: ##STR00218## wherein: R.sub.7 is C.sub.1-4alkyl, C.sub.1-4alkylene(OH) or C.sub.1-4alkyleneOC.sub.1-4alkyl; o is 1 or 2; wherein group (Ad) is: ##STR00219## wherein: X is a bond, O or CH.sub.2; each R.sub.8 is independently halo, C.sub.1-4alkyl, C.sub.1-4alkoxy or OH; each R.sub.9 is independently halo or C.sub.1-4alkyl; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; wherein B is group (Ba), (Bb) or (Bc): wherein group (Ba) is: ##STR00220## wherein: Y is C(R.sub.11)(R.sub.12), N(R.sub.13), O or S; each R.sub.10 is independently halo or C.sub.1-4alkyl; r is 0, 1, 2 or 3; R.sub.11 is H or C.sub.1-4alkyl; R.sub.12 is H or C.sub.1-4alkyl; or R.sub.11 and R.sub.12 together with the carbon atom to which they are attached form a C.sub.3-6cycloalkyl; R.sub.13 is H, C.sub.1-4alkyl or C.sub.3-6cycloalkyl; wherein group (Bb) is: ##STR00221## wherein: each R.sub.14 is independently halo or C.sub.1-4alkyl; s is 0, 1, 2 or 3; wherein group (Bc) is: ##STR00222## wherein: R.sub.15 is C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4haloalkyl or CN; R.sub.16 is H, halo or C.sub.1-4alkyl; and D, E and F are each independently C(R.sub.16); or one of D, E and F is N, and the two remaining D, E and F groups are independently C(R.sub.16); or a pharmaceutically acceptable salt and/or solvate thereof.

75. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein A is group (Aa): ##STR00223##

76. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein R.sub.2 is C.sub.1-4alkyl, C.sub.1-4alkylene(aryl), C.sub.1-4alkylene(OH), C.sub.1-4alkyleneOC.sub.1-4alkyl, C.sub.1-4alkyleneOC.sub.3-6cycloalkyl, C.sub.1-4alkyleneO(aryl), C.sub.1-4alkylene(4-7 membered heterocycloalkyl), C.sub.1-4alkyleneO(4-7 membered heterocycloalkyl) or C.sub.1-4alkyleneO(C.sub.3-6alkynyl); wherein said aryl, heterocycloalkyl and cycloalkyl may be optionally substituted by up to 3 substituents each independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, halo and CN.

77. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein R.sub.2 is methyl, CH.sub.2OH or CH.sub.2OMe.

78. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein each R.sub.3 is independently fluoro or methyl.

79. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein m is 1 or 2.

80. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein m is 1 and R.sub.3 is in the 3-position.

81. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein m is 1 and R.sub.3 is in the 6-position.

82. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein m is 2, one R.sub.3 is in the 3-position, and the other R.sub.3 is in the 6-position.

83. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein group B is group (Bc): ##STR00224##

84. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 83, wherein R.sub.15 is methyl, ethyl, cyclopropyl, CF.sub.3, CN, OMe, chloro or fluoro.

85. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 84, wherein R.sub.15 is OMe, chloro or fluoro.

86. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 84, wherein R.sub.15 is methyl, CN, chloro or fluoro.

87. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein D, E and F are C(R.sub.16).

88. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, wherein each R.sub.16 is independently H, fluoro, chloro or methyl.

89. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, which is a compound of formula (Ia): ##STR00225## wherein: A is group (Aa), group (Ab), group (Ad) or group (Ad); R.sub.15d is methyl, ethyl, cyclopropyl, CN, CF.sub.3, OMe, chloro or fluoro; wherein group (Aa) is: ##STR00226## wherein: R.sub.2d is H, methyl or CH.sub.2OMe; each R.sub.3a is independently H, fluoro or methyl; and wherein group (Ab) is: ##STR00227## wherein: R.sub.4d is methyl; wherein group (Ad) is: ##STR00228## wherein: R.sub.8d is H, methyl, OCH.sub.2-cyclopropyl, OCH.sub.2-oxetanyl, OCH.sub.2CH.sub.2F, OMe or OEt; each R.sub.9a is independently H or fluoro; wherein group (Ad) is: ##STR00229## wherein: R.sub.8d is methyl; and each R.sub.9a is independently H or fluoro; or a pharmaceutically acceptable salt and/or solvate thereof.

90. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, which is selected from the group consisting of: (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide; (E)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxospiro[cyclopropane-1,3-indolin]-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl) acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide; (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide; (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yI)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl) acrylamide; (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl) acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl) acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide, (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl) acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; Racemic-(E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3,5-difluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1 S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; and (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; or a pharmaceutically acceptable salt and/or solvate of any one thereof.

91. A method of preventing or treating a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject, which comprises administering to a subject an effective amount of a compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73.

92. A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 73, and a pharmaceutically acceptable carrier or excipient.

Description

EXAMPLES

[0468] The invention is illustrated by the compounds described below. The following examples describe the laboratory synthesis of specific compounds of the invention and are not meant to limit the scope of the invention in any way with respect to compounds or processes. It is understood that, although specific reagents, solvents, temperatures and time periods are used, there are many possible equivalent alternatives that can be used to produce similar results. The invention is meant to include such equivalents.

[0469] General Experimental Details

[0470] Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Unless otherwise stated, all compounds with chiral centres are racemic. Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Compounds synthesised may have various purities, ranging from for example 85% to 99%. Calculations of number of moles and yield are in some cases adjusted for this.

[0471] Purity of final compounds was confirmed by HPLC/MS analysis and determined to be at least 90%, and in the significant majority of cases 95%. Analytical LCMS was conducted using the instrumentation shown in Table 1. .sup.1H NMR were recorded at 300K in a Bruker 300 MHz instruments (ADVANCE Ill and ADVANCE Ill HD). Flash prep HPLC was conducted using the following columns: XBridge Prep C18 OBD Column, 5 um, 19150 mm; Welch Xtimate C18, 21.2250 mm, 5 um; SunFire Prep C18 OBD 19150 mm5 um. SFC purification was conducted using the following columns; (a) CHIRALPAK AS-H, 3*25 cm, 5 um (b) SFC-YMC Cellulose-SB, 4.6100 mm, 3 um.

TABLE-US-00001 TABLE 1 Analytical LC-MS conditions Instrument Flow ID Column Mobile Phase Rate LCMS01 Halo-C18, A: H.sub.2O/0.05% TFA; B: ACN 1.5 30*3.0 mm, mL/min 2.0 m LCMS02 Cortecs C18+, A: H.sub.2O/0.05% TFA; B: ACN/ 1.5 50*3.0 mm, 0.05% TFA mL/min 2.7 m LCMS03 Halo-C18, A: H.sub.2O/0.1% TFA; B: ACN/ 1.5 30*3.0 mm, 0.05% FA mL/min 2.0 m LCMS04 Kinetex XB- A: H.sub.2O/0.01% TFA; B: ACN/ 1.5 C18, 0.01% FA mL/min 50*3.0 mm, 2.6 m LCMS05 Poroshell HPH- A: H.sub.2O/5 mM NH.sub.4HCO.sub.3; B: 1.0 C18, MeOH mL/min 50*3.0 mm, 2.7 m LCMS06 Xbridge C18, A: H.sub.2O/5 mM NH.sub.4HCO.sub.3 + 0.05% 1.2 50*3.0 mm, NH.sub.3H.sub.2O; B: 5% H.sub.2O in ACN mL/min 3.5 m LCMS07 Poroshell HPH- A: H.sub.2O/0.05% NH.sub.3H.sub.2O; B: ACN 1.2 C18, mL/min 50*3.0 mm, 2.7 m LCMS08 Halo C18, A: H.sub.2O/0.05% TFA; B: ACN 1.5 50*3.0 mm, mL/min 2.7 m LCMS09 Poroshell HPH- A: H.sub.2O/0.05% NH.sub.3H.sub.2O; B: ACN 1.2 C18, mL/min 50*3.0 mm, 2.7 m

Abbreviations

[0472] CH.sub.3CN Acetonitrile [0473] Cs.sub.2CO.sub.3 Cesium Carbonate [0474] DCM Dichloromethane [0475] DIPEA Diisopropylethylamine [0476] DMF Dimethylformamide [0477] Et Ethyl [0478] Et.sub.3N Triethylamine [0479] EtOAc Ethyl acetate [0480] EtOH Ethyl alcohol [0481] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate [0482] heps hepatocytes [0483] HCl Hydrochloric acid [0484] K.sub.2CO.sub.3 Potassium Carbonate [0485] K.sub.3PO.sub.4 Potassium Phosphate [0486] LiHMDS Lithium bis(trimethylsilyl)amide [0487] Me Methyl [0488] MeOH Methanol [0489] NaHCO.sub.3 Sodium bicarbonate [0490] NaOAc Sodium acetate [0491] NaOH Sodium hydroxide [0492] NBS N-Bromosuccinimide [0493] NCS N-Chlorosuccinimide [0494] NH.sub.4Cl Ammonium chloride [0495] PE Petroleum ether [0496] Pd(OAc).sub.2 Palladium(II) Acetate [0497] Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [0498] Pd(dppf)Cl.sub.2 Bis(diphenylphosphino)ferrocene]dichloropalladium(II) [0499] RT room temperature [0500] o/n overnight (16 h) [0501] TFA Trifluoroacetic acid [0502] THF Tetrahydrofuran [0503] THP Tetrahydropyranyl [0504] T.sub.3P Propanephosphonic anhydride [0505] uL microlitre [0506] uM micromolar

Preparation of Comparative Example 1

Comparative Example 1: (E)-N-(2-methyl-3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide

[0507] ##STR00064##

[0508] Comparative Example 1 was prepared according to methods described in Chen et al. (Assay and Drug Development Technologies, 2018, 16, 445-455). Comparative Example 1 may also be prepared using analogous synthetic methods to those described herein for Examples 1 to 64.

Preparation of Examples 1 to 74

Intermediate 1: N-(3-fluoro-2-methylphenyl)acrylamide

[0509] ##STR00065##

[0510] To a stirred solution of 3-fluoro-2-methyl aniline (1.0 g, 8.0 mmol, 1.0 eq.) and DIPEA (3.1 g, 23.9 mmol, 3.0 eq.) in DCM (40 mL) was added acryloyl chloride (0.71 mL, 8.8 mmol, 1.1 eq.) dropwise at 0 C. under nitrogen. The resulting mixture was stirred at 25 C. under an inert atmosphere of nitrogen for 3 h. The resulting mixture was washed with 230 mL of water and the organic layer was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:5). This resulted in 1.04 g (73%) of N-(3-fluoro-2-methylphenyl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=180

Intermediate 2: N-(3-chloro-2-methylphenyl)acrylamide

[0511] ##STR00066##

[0512] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-chloro-2-methyl-aniline (300 mg, 2.12 mmol, 1.0 eq.), DCM (15 mL), Et.sub.3N (1 mL, 7.19 mmol, 3.0 eq.). This was followed by the addition of acryloyl chloride (260 mg, 2.9 mmol, 1.2 eq.) dropwise with stirring at 25 C. The resulting solution was stirred for 5 h at 25 C. The resulting mixture was washed with 210 ml of water and the organic layer was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/PE (1:5). This resulted in 300 mg (74%) of N-(3-chloro-2-methylphenyl)acrylamide as a light yellow solid. LC-MS (ES, m/z): [M+H].sup.+=196

Example 1: (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide

[0513] ##STR00067##

[0514] To a microwave vial with N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 100 mg, 0.56 mmol, 1.0 eq.), 5-bromo-3H-1,2,3-benzotriazole (110 mg, 0.56 mmol, 1.0 equiv), Pd(OAc).sub.2 (19 mg, 0.084 mmol, 0.15 equiv), tris(2-methylphenyl)phosphane (34 mg, 0.112 mmol, 0.20 equiv) and tetrabutylammonium chloride (155 mg, 0.558 mmol, 1.0 equiv) was added DMF (1.5 mL). The resulting solution was stirred for 12 h at 115 C. The resulting mixture was diluted with 20 mL EtOAc washed with 210 mL of 1 M aq. K.sub.2CO.sub.3 and the organic layer was concentrated and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column. The resulting crude product was purified by Flash-Prep-HPLC.

[0515] This resulted in 9 mg (5%) of (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl) acrylamide as a pale grey solid. LC-MS (ES, m/z): [M+H].sup.+=297;

[0516] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): 9.65 (s, 1H), 8.15 (s, 1H), 7.96-7.92 (m, 1H), 7.79 (d, J=16.0 Hz, 1H), 7.71-7.66 (m, 1H), 7.49 (s, 1H) 7.27-7.20 (m, 1H), 7.10-6.96 (m, 2H), 2.18 (s, 3H).

Intermediate 3: (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid

[0517] ##STR00068##

[0518] Step 1: Into a 250-mL 3-necked round-bottom flask, was placed 6-bromo-3-methyl-1H-indazole (2.50 g, 11.84 mmol, 1.00 equiv), methyl acrylate (1.53 g, 17.76 mmol, 1.50 equiv), Et.sub.3N (3.60 g, 35.53 mmol, 3.00 equiv), Pd(dppf)Cl.sub.2 (0.87 g, 1.18 mmol, 0.10 equiv), DMF (100.00 mL). The resulting solution was stirred for 10 hr at 120 C. The mixture was concentrated and the residue was applied onto a silica gel column with THF/PE (1/1). This resulted in 0.9 g (35% yield) of methyl (2E)-3-(3-methyl-1H-indazol-6-yl)prop-2-enoate as a light yellow solid.

##STR00069##

[0519] Step 2: Into a 40-mL vial, was placed methyl (2E)-3-(3-methyl-1H-indazol-6-yl)prop-2-enoate (890.00 mg, 4.12 mmol, 1.00 equiv), NaOH (329.24 mg, 8.23 mmol, 2.00 equiv) in H.sub.2O (10.00 mL) and MeOH (10.00 mL). The resulting solution was stirred for 2 hr at 20 C. The pH value of the solution was adjusted to 3 with HCl (1 mol/L). The solids were collected by filtration. This resulted in 500 mg (60% yield) of (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid as a off-white solid.

Example 2: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide

[0520] ##STR00070##

[0521] To a microwave vial with N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 180 mg, 1.0 mmol, 1.0 equiv), 5-bromo-3H-1,3-benzothiazol-2-one (231 mg, 1.0 mmol, 1.0 equiv), Pd(OAc).sub.2 (34 mg, 0.151 mmol, 0.15 equiv), tris(2-methylphenyl)phosphane (62 mg, 0.201 mmol, 0.20 equiv) and tetrabutylammonium chloride (279 mg, 1.0 mmol, 1.0 equiv) was added DMF (2.8 mL). The resulting solution was stirred for 12 h at 115 C. The resulting mixture was diluted with 30 mL EtOAc washed with 215 mL of 1 M aq. K.sub.2CO.sub.3 and the organic layer was concentrated and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column. The resulting crude product was purified by Flash-Prep-HPLC.

[0522] This resulted in 6 mg (2%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=329

[0523] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): 12.12 (s, 1H), 9.66 (s, 1H), 7.66-7.56 (m, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.39-7.30 (m, 2H), 7.29-7.21 (m, 1H) 7.06-6.92 (m, 2H), 2.17 (s, 3H).

Example 3: (E)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl) acrylamide

[0524] ##STR00071##

[0525] To a microwave vial with N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 185 mg, 1.03 mmol, 1.0 equiv), 6-bromo-3,3-dimethyl-1H-indol-2-one (240 mg, 1.03 mmol, 1.0 equiv), Pd(OAc).sub.2 (35 mg, 0.155 mmol, 0.15 equiv), tris(2-methylphenyl)phosphane (63 mg, 0.206 mmol, 0.20 equiv) and tetrabutylammonium chloride (286 mg, 1.03 mmol, 1.0 equiv) was added DMF (2.9 mL). The resulting solution was stirred for 12 h at 115 C. The resulting mixture was diluted with 30 mL EtOAc washed with 215 mL of 1 M aq. K.sub.2CO.sub.3 and the organic layer was concentrated and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column. The resulting crude product was purified by Flash-Prep-HPLC. This resulted in 76 mg (22%) of (E)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=339

[0526] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): 10.54 (s, 1H), 9.63 (s, 1H), 7.75 (d, J=15.7 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H) 7.28-7.17 (m, 2H), 7.09 (d, J=1.5 Hz, 1H), 7.05-6.97 (m, 1H), 6.93 (d, J=15.7 Hz, 1H), 2.16 (s, 3H), 1.27 (s, 6H).

Example 4: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxospiro[cyclopropane-1,3-indolin]-6-yl)acrylamide

[0527] ##STR00072##

[0528] To a microwave vial with N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 130 mg, 0.725 mmol, 1.0 equiv), 6-bromo-1H-spiro[cyclopropane-1,3-indol]-2-one (172 mg, 0.725 mmol, 1.0 equiv), Pd(OAc).sub.2 (24 mg, 0.109 mmol, 0.15 equiv) tris(2-methylphenyl)phosphane (44 mg, 0.145 mmol, 0.20 equiv) and tetrabutylammonium chloride (278 mg, 0.725 mmol, 1.0 equiv) was added DMF (2 mL). The resulting solution was stirred for 12 h at 115 C. The resulting mixture was diluted with 30 mL EtOAc washed with 215 mL of 1 M aq. K.sub.2CO.sub.3 and the organic layer was concentrated and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column. The resulting crude product was purified by Flash-Prep-HPLC. This resulted in 10 mg (4%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxospiro[cyclopropane-1,3-indolin]-6-yl)acrylamide as a white solid.

[0529] LC-MS (ES, m/z): [M+H].sup.+=337

[0530] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): 10.77 (s, 1H), 9.62 (s, 1H), 7.57 (d, J=15.7 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.29-7.18 (m, 2H), 7.16 (s, 1H), 7.06 (d, J=7.7 Hz, 1H), 7.01 (t, J=9.0 Hz, 1H), 6.95 (d, J=15.7 Hz, 1H), 2.17 (d, J=2.0 Hz, 3H), 1.66-1.60 (m, 2H), 1.55-1.50 (m, 2H).

Example 5: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide

[0531] ##STR00073##

[0532] Prepared according to the methodology described above using Intermediate 1 and 6-bromo-7-fluoro-1,3-dihydro-2H-Indol-2-one. LC-MS (ES, m/z): 327 [MH].sup.+

[0533] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 10.59 (s, 1H), 9.72 (s, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.45-7.19 (m, 3H), 7.04-6.98 (m, 3H), 3.56 (s, 2H), 2.16 (s, 3H).

Example 6: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0534] ##STR00074##

[0535] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, (50 mg, 0.28 mmol, 1.0 equiv), DMF (4 mL), 5-bromo-2-benzoxazolinone, (66 mg, 0.31 mmol, 1.10 equiv), Et.sub.3N (0.12 mL, 0.84 mmol, 3.0 equiv), and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (11 mg, 0.014 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 120 C. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 5 mL of DCM and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 21 mg (24%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC MS (ES, m/z): [M+H].sup.+=313

[0536] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 11.89 (brs, 1H), 9.59 (s, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.44-7.31 (m, 3H), 7.26-7.19 (m, 1H), 7.07-6.95 (m, 2H), 2.16 (s, 3H).

Example 7: (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

[0537] ##STR00075##

[0538] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 90 mg, 0.50 mmol, 1.0 equiv), DMF (5 mL), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (137 mg, 0.60 mmol, 1.20 equiv), Et.sub.3N (0.21 mL, 1.51 mmol, 3.0 equiv), and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (20 mg, 0.025 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 120 C. and cooled to 25 C. The mixture was purified by Prep-HPLC. This resulted in 7 mg (4%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as an off-white solid. LC MS (ES, m/z): [M+H].sup.+=326

[0539] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 11.03 (s, 1H), 9.51 (s, 1H), 7.60 (d, J=15.6 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.33 (dd, J=8.1, 1.5 Hz, 1H), 7.29-7.16 (m, 3H), 7.0-6.98 (m, 1H), 6.88 (d, J=15.6 Hz, 1H), 2.16 (s, 3H).

Example 8: (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide

[0540] ##STR00076##

[0541] Step 1: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-1H-indole-2,3-dione (3.5 g, 15.48 mmol, 1.0 eq), THF (70 mL). The 3M Methylmagnesium bromide (5.2 mL, 15.48 mmol, 1.0 eq) was added dropwise at 78 C. over 0.5 h. The resulting solution was allowed to react, with stirring, for an additional 5 h at 78 C. and then warmed to 25 C. The reaction was then quenched by the addition of 10 mL of 0.2 M HCl. The resulting solution was extracted with 250 mL of EtOAc, and the organic was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (35/65). This resulted in 3 g (80%) of 6-bromo-3-hydroxy-3-methyl-1H-indol-2-one as an off-white solid. LC-MS (ES, m/z): [MH].sup.+=240

##STR00077##

[0542] Step 2: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-3-hydroxy-3-methyl-1H-indol-2-one (2.0 g, 8.26 mmol, 1.0 eq) and THF (30 mL). This was followed by the addition of diethylaminosulfur trifluoride (DAST) (2.0 g, 12.39 mmol, 1.50 eq) at 78 C. The resulting solution was stirred for 1 h from 78 C. and warmed to 25 C. The reaction was then quenched by the addition of 10 mL of Sat. NaHCO.sub.3. The resulting solution was extracted with 250 mL of EtOAc, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (25/75). This resulted in 1.65 g (82%) of 6-bromo-3-fluoro-3-methyl-1H-indol-2-one as a white solid. LC-MS (ES, m/z): [MH].sup.+=242

##STR00078##

[0543] Step 3: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-3-fluoro-3-methyl-1H-indol-2-one (200 mg, 0.82 mmol, 1.0 eq), N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 147 mg, 0.82 mmol, 1.0 eq), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (13 mg, 0.02 mmol, 0.02 eq), DMF (4 mL), Et.sub.3N (0.23 mL, 1.64 mmol, 2.0 eq). The resulting solution was stirred for 2 h at 110 C. The solids were filtered out. The filtrate was concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 13 mg (4.5%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(3-fluoro-3-methyl-2-oxoindolin-6-yl)acrylamide and 12 mg (4%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide.

[0544] (E)-N-(3-fluoro-2-methylphenyl)-3-(3-fluoro-3-methyl-2-oxoindolin-6-yl)acrylamide LC-MS (ES, m/z): [M+H].sup.+=343

[0545] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 10.87 (s, 1H), 9.68 (s, 1H), 7.60-7.46 (m, 3H), 7.34-7.19 (m, 2H), 7.12 (s, 1H), 7.04-6.97 (m, 2H), 2.16 (s, 3H), 1.70 (d, J=22.5 Hz, 3H).

[0546] E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide LC-MS (ES, m/z): [M+H].sup.+=325

[0547] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 10.53 (s, 1H), 9.62 (s, 1H), 7.58-7.46 (m, 2H), 7.34-7.21 (m, 3H), 7.06-6.90 (m, 3H), 3.48-3.45 (m, 1H), 2.16 (s, 3H), 1.34 (d, J=7.8 Hz, 3H).

Example 9: (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) acrylamide

[0548] ##STR00079##

[0549] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-chloro-2-methylphenyl)prop-2-enamide (Intermediate 2, 55 mg, 0.28 mmol, 1.0 equiv), DMF (4 mL), 2-benzoxazolinone, 5-bromo-(66 mg, 0.31 mmol, 1.10 equiv), Et.sub.3N (0.12 mL, 0.84 mmol, 3.0 equiv) and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (11 mg, 0.014 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 120 C. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 5 mL of DCM and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 21 mg (24%) of (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC MS (ES, m/z): [M+H].sup.+=329

[0550] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 11.83 (s, 1H), 9.68 (s, 1H), 7.61 (d, J=15.6 Hz, 1H), 7.53-7.51 (m, 1H), 7.43-7.30 (m, 5H), 6.91 (d, J=15.6 Hz, 1H), 2.28 (s, 3H).

Example 10: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide

[0551] ##STR00080##

[0552] Into a 40-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-3-fluoro-2-methylphenyl)prop-2-enamide (Intermediate 1, (500 mg, 2.79 mmol, 1.0 eq), 6-bromo-1,3-dihydroindol-2-one (592 mg, 2.79 mmol, 1.0 eq), DMF (20 mL), Et.sub.3N (1.2 mL, 8.37 mmol, 3.0 eq) and Pd(dppf)Cl.sub.2 (41 mg, 0.05 mmol, 0.02 eq). The reaction mixture was stirred for 2 h at 110 C. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 102 mg (11%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a white solid. LC-MS (ES, m/z): [MH].sup.+=309

[0553] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 10.57 (s, 1H), 9.62 (s, 1H), 7.55 (d, J=15.9 Hz, 1H), 7.48-7.45 (m, 1H), 7.29-7.18 (m, 3H), 7.05-6.89 (m, 3H), 3.52 (s, 2H), 2.26 (s, 3H).

Example 11: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0554] ##STR00081##

[0555] Step 1: Into a 500-mL sealed tube, was placed 5-bromobenzo[d]oxazol-2(3H)-one 1.0 g, 46.96 mmol, 1.0 equiv), methyl acrylate (12.1 g, 140.8 mmol, 3.0 equiv), Et.sub.3N (19.6 mL, 140.8 mmol, 3.0 equiv), Pd(dppf)Cl.sub.2 (350 mg, 4.7 mmol, 0.01 equiv) in DMF (200 mL). The resulting solution was stirred for 2 h at 120 C. The resulting solution was concentrated. The residue was applied onto a silica gel column eluting with THF/hexane (20/80). This resulted in 11 g (82%) of methyl (E)-3-(3-(3-methoxy-3-oxopropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate as a yellow solid.

##STR00082##

[0556] Step 2: Into a 500 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed THF (300 mL), methyl (E)-3-(3-(3-methoxy-3-oxopropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (11.0 g, 36.1 mmol, 1.0 equiv), t-BuOK (13.2 g, 108.2 mmol, 3.0 equiv). The resulting solution was stirred for 2 h at 60 C. The reaction was then quenched by the addition of 600 mL of Satd. NH.sub.4Cl. The resulting solution was extracted with 2300 mL of EtOAc. The organic layer was washed with 2400 ml of Water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting solution was concentrated. The residue was applied onto a silica gel column with EtOAc/hexane (40/60). This resulted in 5.5 g (69%) of methyl (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate as a light-red solid.

##STR00083##

[0557] Step 3: Into a 100 mL 3-necked round-bottom flask purged, was placed THF (20 mL), methyl (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (2.5 g, 11.4 mmol, 1.0 equiv), 2 M NaOH (17.1 mL, 34.2 mmol, 3.0 equiv). The resulting solution was stirred for 2 h at 25 C. The reaction mixture was concentrated under low temperature (<30 C.). The residue was dissolved into water (30 mL), and the pH was adjusted to 2-3 with 2 M HCl. The solid was collected. This resulted in 2.5 g (65%) of (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid as an off-white solid.

##STR00084##

[0558] Step 4: In each vial was added (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid (30 mg, 0.146 mmol, 1.0 equiv) in DMF (2 mL). Then T.sub.3P (70 mg, 0.22 mmol, 1.50 equiv) and DIPEA (28 mg, 0.22 mmol, 1.50 equiv), 1-indanamine (0.161 mmol, 1.1 equiv) were added. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched by water and extracted with EtOAc, the organic layer was concentrated under vacuum to afford crude product. The crude product was then purified by Prep-HPLC directly. The collected fraction was lyophilized to get the final compounds. LC-MS (ES, m/z): 321 [M+H].sup.+

[0559] .sup.1H NMR: (300 MHz, DMSO-d.sub.6, ppm): 11.77 (s, 1H), 8.44 (d, J=8.4 Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.34-7.18 (m, 7H), 6.65 (d, J=15.9 Hz, 1H), 5.42-5.33 (m, 1H), 2.96-2.81 (m, 2H), 2.48-2.42 (m, 1H), 1.85-1.81 (m, 1H).

[0560] General Procedure A:

##STR00085##

[0561] To each vial was added methyl (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (Example 11, Step 2, 30 mg, 0.14 mmol, 1.0 equiv) in THF (2 mL). The amine (0.18 mmol, 1.30 equiv) was added and the reaction mixture was cooled to 0 C. Then 1M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv) was added. The reaction mixture was stirred for 1 h at 25 C. The reaction mixture was quenched by water and extracted with EtOAc, the organic was concentrated under vacuum to afford crude product which was then purified by Prep-HPLC. The collected fraction was lyophilized to get the final compounds.

Example 12: (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide

[0562] ##STR00086##

[0563] Synthesised using general procedure A using 2-methyl aniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate to give (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide as a solid. LC-MS (ES, m/z): 295 [M+H].sup.+

[0564] .sup.1H NMR: (300 MHz, DMSO-d6, ppm): 9.40 (brs, 1H), 7.63-7.57 (m, 2H), 7.38-7.32 (m, 3H), 7.25-6.91 (m, 4H), 2.26 (s, 3H).

Example 13: (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) acrylamide

[0565] ##STR00087##

[0566] Synthesised using general procedure A using 2-isopropyl aniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate to give (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m/z): 323[M+H].sup.+

[0567] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 11.83 (brs, 1H), 9.48 (brs, 1H), 7.59 (d, J=15.6 Hz, 1H), 7.40-7.34 (m, 5H), 7.24-7.18 (m, 2H), 6.93 (d, J=15.3 Hz, 1H), 3.23-0.319 (m, 1H), 1.17 (d, J=6.6 Hz, 6H)

Example 14: (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) acrylamide

[0568] ##STR00088##

[0569] Synthesised using general procedure A using 2-isopropyl-6-methyl aniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate to give (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m/z): 337[M+H].sup.+

[0570] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 11.82 (brs, 1H), 9.43 (brs, 1H), 7.57 (d, J=15.6 Hz, 1H), 7.40-7.33 (m, 3H), 7.27-7.09 (m, 3H), 6.85 (d, J=15.6 Hz, 1H), 3.15-.3.06 (m, 1H), 2.18 (s, 3H), 1.173 (d, J=6.9 Hz, 6H)

Example 15: (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) acrylamide

[0571] ##STR00089##

[0572] Synthesised using general procedure A using 5-chloro-2-isopropyl aniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate to give (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m/z): 357[M+H].sup.+

[0573] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 11.79 (brs, 1H), 9.56 (brs, 1H), 7.64-7.58 (m, 2H), 7.37-7.23 (m, 5H), 6.95 (d, J=15.6 Hz, 1H), 3.25-.3.20 (m, 1H), 1.16 (d, J=6.9 Hz, 6H).

Example 16: (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) acrylamide

[0574] ##STR00090##

[0575] Synthesised using general procedure A using 4,5-difluoro-2-methyl aniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate to give (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m/z): 331[M+H].sup.+, 373 [M+CH.sub.3CN].sup.+.

Example 17: (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl) acrylamide

[0576] ##STR00091##

[0577] Synthesised using general procedure A using 5-fluoro-2-methyl aniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate to give (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m/z): 311[M+H].sup.+

Example 18: (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl) acrylamide

[0578] ##STR00092##

[0579] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-fluoro-2-methylphenyl)acrylamide (60.0 mg, 0.34 mmol, 1.0 eq), 6-bromo-4-fluoroindolin-2-one (78 mg, 0.34 mmol, 1.0 eq), Et.sub.3N (0.14 mL, 1.0 mmol, 3.0 eq), DMF (4.0 mL), Pd(dppf)Cl.sub.2 (25.2 mg, 0.034 mmol, 0.10 eq). The resulting solution was stirred for 2 h at 120 C. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 11.8 mg (11%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl)acrylamide as an off-white solid.

[0580] LC-MS (ES, m/z): [M+H].sup.+=329

[0581] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 10.80 (brs, 1H), 9.66 (s, 1H), 7.55 (d, J=15.9 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.24-7.22 (m, 1H), 7.10-6.93 (m, 4H), 3.60 (s, 2H), 2.15 (s, 3H)

Example 19: (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide

[0582] ##STR00093##

[0583] Step 1: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-1,3-dihydroindol-2-one (20.0 g, 94.32 mmol, 1.0 equiv), DMF (350 mL), methyl acrylate (6.50 g, 75.50 mmol, 0.80 equiv), Et.sub.3N (26.3 mL, 188.64 mmol, 2.0 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (0.77 g, 0.94 mmol, 0.01 equiv). The resulting solution was stirred for 2 hr at 120 C. The reaction mixture was cooled to RT. The mixture was applied onto a silica gel column with THF/PE (2/1). This resulted in 7.4 g (36%) of methyl (2E)-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate as a light yellow solid.

##STR00094##

[0584] Step 2: Into a 250-mL round-bottom flask, was placed methyl (2E)-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate (3.0 g, 13.81 mmol, 1.0 equiv), MeOH/H.sub.2O (80/40 mL), NaOH (1.7 g, 41.43 mmol, 3.0 equiv). The resulting solution was stirred for 12 h at 25 C. The resulting mixture was concentrated. The resulting solution was diluted with 40 mL of water. The resulting solution was extracted with 250 mL of DCM. The pH value of the aqueous phase was adjusted to 5 with 2M HCl. The solids were collected by filtration. This resulted in 1.8 g (64%) of (2E)-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoic acid as a light yellow solid.

##STR00095##

[0585] Step 3: Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen was added (E)-3-(2-oxoindolin-6-yl)acrylic acid (60.0 mg, 0.30 mmol, 1.0 equiv) in DMF (4.0 mL). Then HATU (167.6 mg, 0.44 mmol, 1.50 equiv) and DIPEA (56.8 mg, 0.44 mmol, 1.50 equiv), 2,6-dimethylbenzenamine (39.5 mg, 0.33 mmol, 1.10 equiv) were added. The reaction mixture was stirred for 2 h at room temperature. The crude mixture was then purified by Prep-HPLC. This resulted in 12 mg (13%) of (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=307

[0586] .sup.1HNMR (300 MHz, DMSO-d.sub.6, ppm) 10.53 (brs, 1H), 9.47 (brs, 1H), 7.51 (d, J=15.9 Hz, 1H), 7.29-7.18 (m, 2H), 7.10-7.05 (m, 4H), 6.83 (d, J=15.9 Hz, 1H), 3.52 (s, 2H), 2.18 (s, 6H).

Example 20: (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide

[0587] ##STR00096##

[0588] Into a 8-mL round-bottom flask, was placed 6-bromoindolin-2-one (100 mg, 0.47 mmol, 1.0 equiv), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (Prepared according to the procedure described for Intermediate 1 from 2,6-dimethyl-3-fluoroaniline and acryloyl chloride; 90.7 mg, 0.47 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2 (34.4 mg, 0.047 mmol, 0.10 equiv), Et.sub.3N (0.2 mL, 1.41 mmol, 3.0 equiv), DMF (4.0 mL). The resulting solution was stirred for 2 hr at 120 C. in an oil bath. The mixture was applied onto a silica gel column with PE/THF (1/1). This resulted in 11 mg (7%) of (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a solid.

[0589] LC-MS (ES, m/z): [M+H].sup.+=325

[0590] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 10.55 (s, 1H), 9.63 (s, 1H), 7.55 (d, J=15.6 Hz, 1H), 7.29-7.03 (m, 5H), 6.84 (d, J=15.9 Hz, 1H), 3.53 (s, 2H), 2.14 (s, 3H), 2.07 (s, 3H).

Example 21: (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide

[0591] ##STR00097##

[0592] Into a 8-mL vial, was placed (E)-3-(2-oxoindolin-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.0 equiv), 2-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride (45.20 mg, 0.25 mmol, 1.0 equiv), HATU (141.38 mg, 0.37 mmol, 1.50 equiv) and DIPEA (95.41 mg, 0.74 mmol, 3.0 equiv) in DMF (2.0 mL). The resulting solution was stirred for 2 h at 20 C. The mixture was purified by Flash-Prep-HPLC. This resulted in 27 mg (33%) of ((E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=333

[0593] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm) 10.51 (brs, 1H), 8.45-8.20 (m, 1H), 7.50-7.45 (m, 1H), 7.26-7.13 (m, 6H), 7.05-6.96 (m, 1H), 6.68-6.63 (m, 1H), 5.45-5.0 (m, 1H), 3.51 (s, 2H), 3.10-3.0 (m, 1H), 2.70-2.20 (m, 2H), 1.20-0.90 (m, 3H).

Example 22: (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide

[0594] ##STR00098##

[0595] Step 1: Into a 100-mL sealed tube, was placed 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.09 mmol, 1.0 eq), EtOH (8.0 mL, 1.0 eq), ethylamine (22.73 mL, 45.45 mmol, 5.0 eq, 2 M in ethanol). The resulting solution was stirred for 4 h at 50 C. The resulting mixture was concentrated. The residue was diluted with 15 mL of H.sub.2O and stirred 15 min. The solids were collected by filtration. This resulted in 2.2 g (98%) of 4-bromo-N-ethyl-2-nitroaniline as a red solid. LC-MS (ES, m/z): [M+H].sup.+=245

##STR00099##

[0596] Step 2: Into a 50-mL round-bottom flask, was placed 4-bromo-N-ethyl-2-nitroaniline (2.0 g, 8.16 mmol, 1.0 eq), acetone (16.0 mL), H.sub.2O (2.0 mL), NH.sub.4Cl (4.37 g, 81.61 mmol, 10.0 eq), Zn (2.67 g, 40.80 mmol, 5.0 eq). The resulting solution was stirred for 3 h at room temperature. The solids were filtered out. The filtrate was concentrated. The residue was diluted with 20 mL of H.sub.2O and stirred 15 min. The solids were collected by filtration. This resulted in 1.1 g (63%) of 4-bromo-N.sup.1-ethylbenzene-1,2-diamine as a light yellow solid. LC-MS (ES, m/z): [M+H].sup.+=215

##STR00100##

[0597] Step 3: Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-N.sup.1-ethylbenzene-1,2-diamine (400.0 mg, 1.86 mmol, 1.0 eq), DCM (8.0 mL), Triphosgene (441.5 mg, 1.48 mmol, 0.80 eq). This was followed by the addition of Et.sub.3N (0.8 mL, 5.58 mmol, 3.0 eq) at 0 C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of 5 mL of water. The organic phase was separated and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with (THF/PE=18/82). This resulted in 210 mg (47%) of 5-bromo-1-ethyl-3H-1,3-benzodiazol-2-one as a light brown solid.

[0598] LC-MS (ES, m/z): [M+H].sup.+=240

##STR00101##

[0599] Step 4: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-fluoro-2-methylphenyl)acrylamide (120.0 mg, 0.67 mmol, 1.0 eq), 5-bromo-1-ethyl-3H-1,3-benzodiazol-2-one (161.5 mg, 0.67 mmol, 1.0 eq), Et.sub.3N (0.28 mL, 2.01 mmol, 3.0 eq), DMF (5.0 mL), Pd(dppf)Cl.sub.2 (9.8 mg, 0.01 mmol, 0.02 eq). The resulting solution was stirred for 2 h at 120 C. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 25 mg (11%) of (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=340

[0600] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 11.05 (brs, 1H), 9.52 (s, 1H), 7.62-7.48 (m, 2H), 7.33-7.19 (m, 4H), 7.11-6.85 (m, 2H), 3.88-3.81 (m, 2H), 2.27 (s, 3H), 1.31-1.19 (m, 3H).

Example 23: (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide

[0601] ##STR00102##

[0602] Step 1: Into a 40-mL sealed tube, was placed 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.09 mmol, 1.0 eq), aminocyclopropane (2.60 g, 45.45 mmol, 5.0 eq), EtOH (20.0 mL). The resulting solution was stirred for 4 h at 50 C. The resulting mixture was concentrated. The residue compound was diluted with 15 mL of H.sub.2O and stirred 15 min. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 2.4 g (96%) of 4-bromo-N-cyclopropyl-2-nitroaniline as a red solid. LC-MS (ES, m/z): [M+H].sup.+=257

##STR00103##

[0603] Step 2: Into a 40-mL sealed tube, was placed 4-bromo-N-cyclopropyl-2-nitroaniline (2.0 g, 7.8 mmol, 1.0 eq), acetone (16.0 mL), H.sub.2O (2.0 mL), Zn (2.54 g, 38.89 mmol, 5.0 eq), NH.sub.4Cl (4.16 g, 77.8 mmol, 10.0 eq). The resulting solution was stirred for 3 h at 25 C. The solids were filtered out. The filtrate was concentrated. The residue was diluted with 20 mL of H.sub.2O and stirred 15 min. The solids were collected by filtration. This resulted in 1 g (56%) of 4-bromo-N.sup.1-cyclopropylbenzene-1,2-diamine as a light brown solid.

[0604] LC-MS (ES, m/z): [M+H].sup.+=227

##STR00104##

[0605] Step 3: Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-N.sup.1-cyclopropylbenzene-1,2-diamine (300.0 mg, 1.32 mmol, 1.0 eq), Triphosgene (313.60 mg, 1.06 mmol, 0.80 eq), DCM (6.0 mL). This was followed by the addition of Et.sub.3N (0.6 mL, 3.96 mmol, 3.0 eq) at 0 C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of 5 mL of water. The organic phase was separated and dried over anhydrous sodium sulfate and concentrated. This resulted in 180 mg (53%) of 5-bromo-1-cyclopropyl-3H-1,3-benzodiazol-2-one as a light brown solid. LC-MS (ES, m/z): [M+H].sup.+=253

##STR00105##

[0606] Step 4: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-fluoro-2-methylphenyl)acrylamide (120.0 mg, 0.67 mmol, 1.0 eq), 5-bromo-1-cyclopropyl-3H-1,3-benzodiazol-2-one (169.5 mg, 0.67 mmol, 1.0 eq), Et.sub.3N (0.2 mL, 1.34 mmol, 2.0 eq), DMF (5.0 mL), Pd(dppf)Cl.sub.2 (9.80 mg, 0.013 mmol, 0.02 equiv). The resulting solution was stirred for 2 h at 120 C. The solids were filtered out. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 21 mg (9%) of (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as an off-white solid.

[0607] LC-MS (ES, m/z): [M+H].sup.+=352

[0608] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm): 10.96 (brs, 1H), 9.54 (brs, 1H), 7.61-7.47 (m, 2H), 7.33-7.18 (m, 4H), 7.02-6.85 (m, 2H), 2.95-2.87 (m, 1H), 2.28 (s, 3H), 1.04-0.88 (m, 4H).

Example 24: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

[0609] ##STR00106##

[0610] Step 1: Into a 500-mL 3-necked round-bottom flask, acryloyl chloride (6.80 g, 75.08 mmol, 1.0 equiv), was added to indanamine (10.0 g, 75.08 mmol, 1.0 equiv) and Et.sub.3N (20.9 mL, 150.16 mmol, 2.0 equiv) in DCM (200.0 mL) at 0 C. The resulting solution was stirred for 15 h at 25 C.

[0611] The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 2100 mL of dichloromethane and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (10/1, resulting in 7.3 g (52%) of N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=188

##STR00107##

[0612] Into a 8-mL vial, was placed N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.0 equiv), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (121.27 mg, 0.53 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2 (39.08 mg, 0.05 mmol, 0.10 equiv) and Et.sub.3N (0.22 mL, 1.60 mmol, 3.0 equiv) in DMF (4.0 mL, 25.844 mmol). The resulting solution was stirred for 15 h at 120 C. in an oil bath. The reaction mixture was cooled. The crude mixture was purified by Flash-Prep-HPLC.

[0613] This resulted in 7.8 mg (4%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=334

[0614] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm): 10.98 (brs, 1H), 8.37 (d, J=8.4 Hz, 1H), 7.50 (d, J=15.9 Hz, 1H), 7.34-7.03 (m, 7H), 6.56 (d, J=15.6 Hz, 1H), 5.42-5.39 (m, 1H), 3.29 (s, 3H), 3.02-2.77 (m, 2H), 2.47-2.37 (m, 1H), 1.93-1.72 (m, 1H).

Example 25: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0615] ##STR00108##

[0616] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (135.27 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (87.23 mg, 0.11 mmol, 0.20 equiv), DMF (4.0 mL), Et.sub.3N (0.22 mL, 1.60 mmol, 3.0 equiv). The resulting solution was stirred overnight at 120 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 64 mg (38%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a off-white solid. LC-MS (ES, m/z): [M+H].sup.+=318

[0617] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.77 (brs, 1H), 8.46 (d, J=8.4 Hz, 1H), 7.73-7.60 (m, 3H), 7.31-7.17 (m, 5H), 6.74 (d, J=15.9 Hz, 1H), 5.46-5.38 (m, 1H), 3.02-2.93 (m, 1H), 2.89-2.79 (m, 1H), 2.51 (s, 3H), 2.48-2.41 (m, 1H), 1.90-1.77 (m, 1H).

Example 26: (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide

[0618] ##STR00109##

[0619] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-1H-indazole-3-carbonitrile (142.30 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (43.61 mg, 0.05 mmol, 0.10 equiv), DMF (4 mL), Et.sub.3N (0.22 mL, 1.60 mmol, 3.0 equiv). The resulting solution was stirred overnight at 120 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 24 mg (14%) of (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=329

[0620] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm): 14.33 (brs, 1H), 8.55 (d, J=8.1 Hz, 1H), 7.93-7.91 (m, 2H), 7.70 (d, J=15.9 Hz, 1H), 7.62-7.59 (m, 1H), 7.30-7.17 (m, 4H), 6.84 (d, J=15.6 Hz, 1H), 5.47-5.39 (m, 1H), 3.03-2.94 (m, 1H), 2.90-2.80 (m, 1H), 2.47-2.42 (m, 1H), 1.91-1.76 (m, 1H).

Example 27: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl) acrylamide

[0621] ##STR00110##

[0622] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 5-bromo-6-fluoro-3H-1,2,3-benzotriazole (138.44 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (43.61 mg, 0.05 mmol, 0.10 equiv), DMF (4.0 mL), Et.sub.3N (0.22 mL, 1.60 mmol, 3.0 equiv). The resulting solution was stirred overnight at 140 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 6.3 mg (4%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl) acrylamide as a off-white solid. LC-MS (ES, m/z): [M+H].sup.+=323

[0623] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 8.63 (d, J=8.1 Hz, 1H), 8.27 (d, J=6.6 Hz, 1H), 7.82 (d, J=10.8 Hz, 1H), 7.68 (d, J=16.2 Hz, 1H), 7.29-7.18 (m, 4H), 6.88 (d, J=15.9 Hz, 1H), 5.47-5.40 (m, 1H), 3.01-2.94 (m, 1H), 2.90-2.79 (m, 1H), 2.49-2.44 (m, 1H), 1.92-1.79 (m, 1H).

Example 28: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl) acrylamide

[0624] ##STR00111##

[0625] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-3-(trifluoromethyl)-1H-indazole (169.9 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (43.61 mg, 0.05 mmol, 0.10 equiv), DMF (4.0 mL), Et.sub.3N (0.22 mL, 1.60 mmol, 3.0 equiv). The resulting solution was stirred overnight at 120 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 80 mg (40%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl) acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=372

[0626] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 14.16 (brs, 1H), 8.55 (d, J=8.1 Hz, 1H), 7.89-7.83 (m, 2H), 7.70 (d, J=15.9 Hz, 1H), 7.58-7.54 (m, 1H), 7.30-7.17 (m, 4H), 6.83 (d, J=15.6 Hz, 1H), 5.47-5.39 (m, 1H), 3.03-2.94 (m, 1H), 2.90-2.80 (m, 1H), 2.47-2.42 (m, 1H), 1.91-1.78 (m, 1H).

Example 29: (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

[0627] ##STR00112##

[0628] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,6-dimethylphenyl)prop-2-enamide ((Prepared as for Intermediate 1 from acroyl chloride and 2,6-dimethylaniline) 50.0 mg, 0.29 mmol, 1.0 equiv), DMF (4.0 mL), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (71.3 mg, 0.31 mmol, 1.10 equiv), Et.sub.3N (0.12 mL, 0.86 mmol, 3.0 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (11.65 mg, 0.014 mmol, 0.05 equiv). The resulting solution was stirred for 5 h at 120 C. The reaction mixture was cooled to RT. The crude mixture was applied onto a silica gel column with EtOAc/PE (1/1). This resulted in 20 mg (22%) of (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as an off-white solid.

[0629] LC-MS (ES, m/z): [M+H].sup.+=322

[0630] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 11.02 (s, 1H), 9.38 (s, 1H), 7.56 (d, J=15.6 Hz, 1H), 7.33-7.31 (m, 1H), 7.24 (s, 1H), 7.16-7.09 (m, 4H), 6.78 (d, J=15.6 Hz, 1H), 3.32 (s, 1H), 2.17 (s, 6H).

Example 30: (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

[0631] ##STR00113##

[0632] Step 1: Into a 40-mL vial, was placed 1-bromo-4-fluoro-3-methyl-2-nitrobenzene (500.0 mg, 2.14 mmol, 1.0 equiv), trimethyl-1,3,5,2,4,6-trioxatriborinane (268.20 mg, 2.13 mmol, 1.0 equiv), K.sub.2CO.sub.3 (590.6 mg, 4.27 mmol, 2.0 equiv) and Pd(dppf)Cl.sub.2 (156.3 mg, 0.21 mmol, 0.10 equiv) in dioxane (10.0 mL) and H.sub.2O (2.0 mL). The resulting solution was stirred for 1 h at 110 C. in an oil bath. The crude mixture was applied onto a silica gel column with EtOAc/PE (1/10). This resulted in 250 mg (69%) of 1-fluoro-2,4-dimethyl-3-nitrobenzene as a solid.

##STR00114##

[0633] Step 2: Into a 40-mL vial, was placed 1-bromo-4-fluoro-3-methyl-2-nitrobenzene (0.50 g, 2.14 mmol, 1.0 equiv) in AcOH (10.0 mL) was added Fe (596.6 mg, 10.68 mmol, 5.0 equiv), The resulting solution was stirred for 1 h at RT. The solids were filtered out. The resulting solution was diluted with 20 mL water and extracted with 40 mL of EtOAc. The organic layer was dried and concentrated. This resulted in 250 mg (84%) of 3-fluoro-2,6-dimethylaniline as a solid.

[0634] LC-MS (ES, m/z): [M+H].sup.+=140

##STR00115##

[0635] Step 3: Into a 8-mL vial, was placed 6-bromo-3-fluoro-2-methylaniline (100.0 mg, 0.49 mmol, 1.0 equiv) and Et.sub.3N (0.2 mL, 1.47 mmol, 3.0 equiv) in DCM (4 mL) was added acryloyl chloride (53.2 mg, 0.59 mmol, 1.20 equiv), The resulting solution was stirred for 1 h at 0 C. The resulting mixture was concentrated under vacuum. The residue was purified with flash chromatography (PE/EA=10/1). This resulted in 120 mg (126.72%) of N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=194

##STR00116##

[0636] Step 4: Into a 8-mL round-bottom flask, was placed 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (100 mg, 0.44 mmol, 1.0 equiv), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (85.1 mg, 0.44 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2 (32.2 mg, 0.044 mmol, 0.10 equiv), Et.sub.3N (0.18 mL, 1.32 mmol, 3.0 equiv), DMF (4.0 mL). The resulting solution was stirred for 2 h at 120 C. in an oil bath. The mixture was applied onto a silica gel column with PE/THF (1/1). This resulted in 45 mg (30%) of (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as a solid. LC-MS (ES, m/z): [M+H].sup.+=340

[0637] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 11.04 (s, 1H), 9.53 (s, 1H), 7.58 (d, J=15.3 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.24 (s, 1H), 7.17-7.01 (m, 3H), 6.79 (d, J=15.6 Hz, 1H), 3.31 (s, 3H), 2.15 (s, 3H), 2.07 (s, 3H).

Example 31: (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0638] ##STR00117##

[0639] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,6-dimethylaniline (160.0 mg, 1.32 mmol, 1.0 equiv), DCM (10.0 mL), Et.sub.3N (0.55 mL, 3.96 mmol, 3.0 equiv). This was followed by the addition of acryloyl chloride (143.40 mg, 1.58 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 3 h at 25 C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 210 mL of dichloromethane and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (1/3). This resulted in 150 mg (65%) of N-(2,6-dimethylphenyl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=176

##STR00118##

[0640] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,6-dimethylphenyl)prop-2-enamide (50.0 mg, 0.29 mmol, 1.0 equiv), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (66.3 mg, 0.31 mmol, 1.10 equiv), Et.sub.3N (0.12 mL, 0.86 mmol, 3.0 equiv) and Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (11.7 mg, 0.014 mmol, 0.05 equiv). The resulting solution was stirred for 5 h at 120 C. The reaction mixture was cooled to 25 C. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 30 mg (34%) of (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=306

[0641] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.81 (s, 1H), 9.49 (s, 1H), 7.77-7.67 (m, 3H), 7.40 (d, J=8.4 Hz, 1H), 7.11 (s, 3H), 6.97 (d, J=15.6 Hz, 1H), 2.51 (s, 3H), 2.19 (s, 6H).

Example 32: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide

[0642] ##STR00119##

[0643] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(Example 24, Step 1, 2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-3-ethyl-1H-indazole (144.3 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (43.6 mg, 0.05 mmol, 0.10 equiv), DMF (4.0 mL) and Et.sub.3N (0.22 mL, 1.60 mmol, 3.0 equiv). The resulting solution was stirred overnight at 120 C. The reaction mixture was cooled to room temperature. The crude product was purified by Prep-HPLC. This resulted in 86 mg (49%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide as a off-white solid. LC MS (ES, m/z): [M+H].sup.+=332

[0644] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.77 (brs, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.63-7.61 (m, 2H), 7.31-7.17 (m, 5H), 6.75 (d, J=15.9 Hz, 1H), 5.45-5.39 (m, 1H), 3.03-2.79 (m, 4H), 2.47-2.41 (m, 1H), 1.90-1.78 (m, 1H), 1.34-1.29 (m, 3H).

Example 33: (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide

[0645] ##STR00120##

[0646] Into a 8-mL vial, was placed N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-3-cyclopropyl-1H-indazole (126.6 mg, 0.53 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2 (39.1 mg, 0.05 mmol, 0.10 equiv), Et.sub.3N (0.22 mL, 1.60 mmol, 3.0 equiv), DMF (4 mL). The resulting solution was stirred for 2 h at 120 C. in an oil bath. The reaction mixture was cooled. The mixture was applied onto a silica gel column with PE/THF (1/1). This resulted in 15 mg (8%) of (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide as a solid. LC MS (ES, m/z): [M+H].sup.+=344

[0647] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.70 (s, 1H), 8.48 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.63 (m, 2H), 7.37-7.16 (m, 5H), 6.74 (d, J=15.6 Hz, 1H), 5.49-5.37 (m, 1H), 3.10-2.75 (m, 2H), 2.48-2.39 (m, 1H), 2.33-2.20 (m, 1H), 1.91-1.77 (m, 1H), 1.06-0.89 (m, 4H).

Example 34: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide

[0648] ##STR00121##

[0649] Into a 8-mL vial, was placed 6-bromo-4-fluoro-3-methyl-1H-indazole (Example 24, Step 1, 100.0 mg, 0.44 mmol, 1.0 equiv), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (81.8 mg, 0.44 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2 (31.9 mg, 0.04 mmol, 0.10 equiv), Et.sub.3N (0.18 mL, 1.31 mmol, 3.0 equiv), DMF (4.0 mL). The resulting solution was stirred for 2 h at 120 C. in an oil bath. The reaction mixture was cooled. The residue was applied onto a silica gel column with PE/THF (1/1). This resulted in 17 mg (12%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide as a solid. LC MS (ES, m/z): [M+H].sup.+=336

[0650] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm) 13.09 (s, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.61 (d, J=15.6 Hz, 1H), 7.48 (s, 1H), 7.35-7.15 (m, 4H), 7.01 (d, J=12.0 Hz, 1H), 6.73 (d, J=15.6 Hz, 1H), 5.49-5.36 (m, 1H), 3.06-2.76 (m, 2H), 2.56 (s, 3H), 2.47-2.38 (m, 1H), 1.92-1.76 (m, 1H).

Example 35: (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide

[0651] ##STR00122##

[0652] Step 1: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3,5-difluoroaniline (1.0 g, 7.8 mmol, 1.0 equiv), CH.sub.3CN (30 mL), NCS (1.1 g, 8.16 mmol, 1.05 equiv). The resulting solution was stirred for 5 h at 80 C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:4-1:1). This resulted in 500 mg (39%) of 4-chloro-3,5-difluoroaniline as a grey solid.

##STR00123##

[0653] Step 2: Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-3,5-difluoroaniline (500.0 mg, 2.40 mmol, 1.0 equiv), CH.sub.3CN (20.0 mL), NBS (1.3 g, 7.21 mmol, 3.0 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:5-1:3). This resulted in 700 mg (91%) of 2,6-dibromo-4-chloro-3,5-difluoroaniline as a yellow solid.

##STR00124##

[0654] Step 3: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,6-dibromo-4-chloro-3,5-difluoroaniline (3.0 g, 9.36 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (0.76 g, 0.94 mmol, 0.10 equiv), dioxane (60.0 mL), Cs.sub.2CO.sub.3 (12.20 g, 37.46 mmol, 4.0 equiv), trimethyl-1,3,5,2,4,6-trioxatriborinane (8.23 g, 32.77 mmol, 3.50 equiv, 50%).

[0655] The resulting solution was stirred overnight at 100 C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude mixture was purified by Prep-HPLC. This resulted in 600 mg (33%) of 4-chloro-3,5-difluoro-2,6-dimethylaniline as an off-white solid.

##STR00125##

[0656] Step 4: Into a 100-mL pressure tank reactor, was placed 4-chloro-3,5-difluoro-2,6-dimethylaniline (280.0 mg, 1.46 mmol, 1.0 equiv), EtOH (20.0 mL), HCl (1.0 mL), Pd/C (77.76 mg). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The resulting solution was stirred overnight at 70 C. under an atmosphere of hydrogen (30 atm). The reaction mixture was cooled to room temperature. The solids were filtered out and the resulting mixture was concentrated. This resulted in 220 mg (crude) of 3,5-difluoro-2,6-dimethylaniline hydrochloride as an off-white solid.

##STR00126##

[0657] Step 5: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3,5-difluoro-2,6-dimethylaniline hydrochloride (220.0 mg, 1.14 mmol, 1.0 equiv), DCM (20.0 mL), Et.sub.3N (0.48 mL, 3.41 mmol, 3.0 equiv). This was followed by the addition of acryloyl chloride (123.4 mg, 1.36 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:5-1:3). This resulted in 160 mg (67%) of N-(3,5-difluoro-2,6-dimethylphenyl)prop-2-enamide as a off-white solid.

##STR00127##

[0658] Step 6: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3,5-difluoro-2,6-dimethylphenyl)prop-2-enamide (160.0 mg, 0.76 mmol, 1.0 equiv), 6-bromo-1,3-dihydroindol-2-one (192.8 mg, 0.91 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (61.7 mg, 0.076 mmol, 0.10 equiv), DMF (5.0 mL), Et.sub.3N (0.32 mL, 2.27 mmol, 3.0 equiv). The resulting solution was stirred for 2 h at 100 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 14.8 mg (6%) of (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a solid.

[0659] LC MS (ES, m/z): [M+H].sup.+=343

[0660] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 10.56 (s, 1H), 9.77 (s, 1H), 7.56 (d, J=15.6 Hz, 1H), 7.29-7.06 (m, 4H), 6.85 (d, J=15.9 Hz, 1H), 3.53 (s, 2H), 2.05 (s, 6H).

Example 36: (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide

[0661] ##STR00128##

[0662] Step 1: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed benzenamine, 3,4-difluoro-(1.0 g, 7.75 mmol, 1.0 equiv), CH.sub.3CN (30.0 mL), NBS (2.9 g, 16.27 mmol, 2.10 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:5-1:3). This resulted in 1.4 g (63%) of 2,6-dibromo-3,4-difluoroaniline as a dark brown solid.

##STR00129##

[0663] Step 2: Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,6-dibromo-3,4-difluoroaniline (1.20 g, 4.18 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (340.7 mg, 0.42 mmol, 0.10 equiv), Cs.sub.2CO.sub.3 (4.8 g, 14.64 mmol, 3.50 equiv), dioxane (50.0 mL), trimethyl-1,3,5,2,4,6-trioxatriborinane (3.2 g, 12.55 mmol, 3.0 equiv, 50%).

[0664] The resulting solution was stirred overnight at 100 C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude mixture was purified by Prep-HPLC. This resulted in 350 mg (53%) of 3,4-difluoro-2,6-dimethylaniline as a off-white solid.

##STR00130##

[0665] Step 3: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3,4-difluoro-2,6-dimethylaniline (210.0 mg, 1.34 mmol, 1.0 equiv), DCM (20 mL), Et.sub.3N (0.28 mL, 2.0 mmol, 1.50 equiv). This was followed by the addition of acryloyl chloride (145.13 mg, 1.60 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 2 hr at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:5-1:3). This resulted in 180 mg (64%) of N-(3,4-difluoro-2,6-dimethylphenyl)prop-2-enamide as a off-white solid.

##STR00131##

[0666] Step 4: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3,4-difluoro-2,6-dimethylphenyl)prop-2-enamide (100.0 mg, 0.47 mmol, 1.0 equiv), 6-bromo-1,3-dihydroindol-2-one (120.47 mg, 0.57 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (38.57 mg, 0.05 mmol, 0.10 equiv), DMF (4.0 mL), Et.sub.3N (0.2 mL, 1.42 mmol, 3.0 equiv). The resulting solution was stirred overnight at 120 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 11.3 mg (7%) of (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid.

[0667] LCMS (ES, m/z): [M+H].sup.+=343

[0668] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 10.55 (s, 1H), 9.63 (s, 1H), 7.53 (d, J=15.9 Hz, 1H), 7.29-7.18 (m, 3H), 7.06 (s, 1H), 6.82 (d, J=15.9 Hz, 1H), 3.53 (s, 2H), 2.05 (s, 3H), 2.10 (s, 3H).

Example 37: (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0669] ##STR00132##

[0670] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 110.0 mg, 0.61 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (155.47 mg, 0.74 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (100.01 mg, 0.12 mmol, 0.20 equiv), DMF (4.0 mL), Et.sub.3N (0.26 mL, 1.84 mmol, 3.0 equiv). The resulting solution was stirred overnight at 120 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 26 mg (14%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid.

[0671] LC MS (ES, m/z): [M+H].sup.+=310

[0672] .sup.1H NMR 300 MHz, DMSO-d.sub.6, ppm): 12.83 (brs, 1H), 9.62 (brs, 1H), 7.78-7.69 (m, 3H), 7.49 (d, J=7.8 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.27-7.20 (m, 1H), 7.09-6.98 (m, 2H), 2.51 (s, 3H), 2.17 (s, 3H).

Example 38: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide

[0673] ##STR00133##

[0674] Into a 8-mL vial, was placed 6-bromo-3-methyl-1H-indazole (40.0 mg, 0.19 mmol, 1.0 equiv), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Prepared according to Example 24, Step 1 using 2-methylindanamine, 38.14 mg, 0.19 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2 (13.87 mg, 0.02 mmol, 0.10 equiv) and Et.sub.3N (0.8 mL, 0.57 mmol, 3.0 equiv) in DMF (2.0 mL). The resulting solution was stirred for 2 hr at 120 C. in an oil bath. The reaction solution was cooled to RT. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 29 mg (44%) of (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide as a off-white solid.

[0675] LC MS (ES, m/z): [M+H].sup.+=332

[0676] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm) 12.78 (brs, 1H), 8.45-8.21 (m, 1H), 7.82-7.57 (m, 3H), 7.42-7.11 (m, 5H), 6.88-6.74 (m, 1H), 5.40-5.0 (m, 1H), 3.12-2.95 (m, 1H), 2.75-2.58 (m, 2H), 2.49 (s, 3H), 2.38-2.24 (m, 1H), 1.24-0.88 (m, 3H).

Example 39: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide

[0677] ##STR00134##

[0678] Step 1: Into a 50-m 3-necked round-bottom as purge an maintained with an inert atmosphere of nitrogen, was placed 1-methylindazol-7-amine (400.0 mg, 2.71 mmol, 1.0 eq), DCM (10.0 mL), Et.sub.3N (0.6 mL, 4.07 mmol, 1.50 eq). This was followed by the addition of acryloyl chloride (246 mg, 2.71 mmol, 1.0 eq) at 30 C. The resulting solution was stirred for 10 min at 30 C. The reaction was then quenched by the addition of 8 mL of water. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (15:85). This resulted in 120 mg (21%) of N-(1-methylindazol-7-yl)prop-2-enamide as an off-white solid. LC MS (ES, m/z): [M+H].sup.+=202

##STR00135##

[0679] Step 2: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(1-methylindazol-7-yl)prop-2-enamide (100.0 mg, 0.49 mmol, 1.0 eq), 6-bromo-3-methyl-1H-indazole (104.8 mg, 0.49 mmol, 1.0 eq), DMF (4.0 mL), Et.sub.3N (0.14 mL, 0.99 mmol, 2.0 eq), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (41 mg, 0.05 mmol, 0.10 eq). The resulting solution was stirred for 2 h at 120 C. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 33 mg (20%) of (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide as an off-white solid.

[0680] LC MS (ES, m/z): [M+H].sup.+=332

[0681] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.83 (brs, 1H), 10.14 (brs, 1H), 8.07 (s, 1H), 7.81-7.67 (m, 4H), 7.44-7.41 (m, 1H), 7.25-7.11 (m, 2H), 7.01 (d, J=15.9 Hz, 1H), 4.12 (s, 3H), 2.50 (s, 3H).

Example 40: (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0682] ##STR00136##

[0683] Step 1: Into a 40-mL sealed tube, was placed 5-fluoro-2,3-dihydroinden-1-one (800.0 mg, 5.33 mmol, 1.0 eq), NaOAc (874.14 mg, 10.66 mmol, 2.0 eq), MeOH (15.0 mL), Hydroxylamine hydrochloride (1.10 g, 15.98 mmol, 3.0 eq). The resulting solution was stirred for 16 h at 60 C. The resulting mixture was concentrated. The crude product was diluted with of EtOAc (30.0 mL) and H.sub.2O (15.0 mL). The organic phase was washed with 20 ml of H.sub.2O. The organic layer was concentrated. This resulted in 810 mg (92%) of N-[5-fluoro-2,3-dihydroinden-1-ylidene]hydroxylamine as an off-white solid. LC MS (ES, m/z): [M+H].sup.+=166

##STR00137##

[0684] Step 2: Into a 50-mL round-bottom flask, was placed N-[5-fluoro-2,3-dihydroinden-1-ylidene]hydroxylamine (810.0 mg, 4.90 mmol, 1.0 eq), MeOH (20.0 mL). This was followed by the addition of Pd/C (104.38 mg) under H.sub.2. The resulting solution was stirred for 16 h at room temperature. The solid was filtered out and washed with 10 mL MeOH. The combined solution was concentrated. This resulted in 530 mg (71%) of 5-fluoro-2,3-dihydro-1H-inden-1-amine as an off-white solid. LC MS (ES, m/z): [M+H].sup.+=152

##STR00138##

[0685] Step 3: Into a 25-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-fluoro-2,3-dihydro-1H-inden-1-amine (210.0 mg, 1.38 mmol, 1.0 eq), DCM (5.0 mL), Et.sub.3N (0.4 mL, 2.77 mmol, 2.0 eq). This was followed by the addition of acryloyl chloride (188.58 mg, 2.08 mmol, 1.50 eq) at 30 C. The resulting solution was stirred for 10 min at 30 C. The reaction was then quenched by the addition of 5 mL of water. The organic layer was separated and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (80:20). This resulted in 200 mg (70%) of N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)prop-2-enamide as an off-white solid. LC MS (ES, m/z): [M+H].sup.+=206

##STR00139##

[0686] Step 4: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)acrylamide (100.0 mg, 0.48 mmol, 1.0 eq), 6-bromo-3-methyl-1H-indazole (102.8 mg, 0.48 mmol, 1.0 eq), Et.sub.3N (0.14 mL, 0.97 mmol, 2.0 eq), DMF (5.0 mL), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (39.69 mg, 0.05 mmol, 0.10 eq). The resulting solution was stirred for 2 h at 120 C. The reaction solution was cooled to RT. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 34 mg (20%) of (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a white solid. LC MS (ES, m/z): [M+H].sup.+=336

[0687] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.78 (s, 1H), 8.48 (d, J=8.1 Hz, 1H), 7.74-7.61 (m, 3H), 7.32-7.24 (m, 2H), 7.13-7.09 (m, 2H), 6.73 (d, J=15.9 Hz, 1H), 5.40-5.37 (m, 1H), 3.16-2.73 (m, 2H), 2.52 (s, 3H), 2.50-1.83 (m, 2H).

Example 41: (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0688] ##STR00140##

[0689] Step 1: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-fluoro-3-methylaniline (600.0 mg, 4.79 mmol, 1.0 equiv), DCM (20.0 mL), Et.sub.3N (2.0 mL, 14.38 mmol, 3.0 equiv). This was followed by the addition of acryloyl chloride (520.73 mg, 5.75 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:5-1:3). This resulted in 400 mg (56%) of N-(4-fluoro-3-methylphenyl)prop-2-enamide as a light yellow solid.

##STR00141##

[0690] Step 2: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(4-fluoro-3-methylphenyl)prop-2-enamide (110.0 mg, 0.61 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (155.47 mg, 0.74 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (100.01 mg, 0.12 mmol, 0.20 equiv), DMF (4.0 mL), Et.sub.3N (0.26 mL, 1.84 mmol, 3.0 equiv). The resulting solution was stirred overnight at 120 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 20.4 mg (11%) of (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a off-white solid.

[0691] LC MS (ES, m/z): [M+H].sup.+=310

[0692] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.82 (brs, 1H), 10.16 (brs, 1H), 7.77-7.67 (m, 3H), 7.62-7.59 (m, 1H), 7.56-7.51 (m, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.14-7.08 (m, 1H), 6.88 (d, J=15.6 Hz, 1H), 2.51 (s, 3H), 2.24 (s, 3H).

Example 42: (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0693] ##STR00142##

[0694] Step 1: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-fluoro-4-methylaniline (550.0 mg, 4.40 mmol, 1.0 equiv), DCM (20.0 mL), Et.sub.3N (1.2 mL, 8.79 mmol, 2.0 equiv). This was followed by the addition of acryloyl chloride (477.34 mg, 5.27 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:5-1:3). This resulted in 450 mg (57%) of N-(3-fluoro-4-methylphenyl)prop-2-enamide as a off-white solid.

##STR00143##

[0695] Step 2: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-fluoro-4-methylphenyl)prop-2-enamide (110.0 mg, 0.61 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (155.5 mg, 0.74 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (100.0 mg, 0.12 mmol, 0.20 equiv), DMF (4.0 mL), Et.sub.3N (0.26 mL, 1.84 mmol, 3.0 equiv). The resulting solution was stirred overnight at 120 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 35.8 mg (19%) of (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a off-white solid.

[0696] LC MS (ES, m/z): [M+H].sup.+=310

[0697] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.83 (brs, 1H), 10.30 (brs, 1H), 7.77-7.67 (m, 4H), 7.39-7.35 (m, 1H), 7.30-7.20 (m, 2H), 6.87 (d, J=15.6 Hz, 1H), 2.51 (s, 3H), 2.20 (s, 3H).

Example 43: Racemic-(E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide

[0698] ##STR00144##

[0699] Step 1: Into a 25-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Racemic-trans-(1R,2R)-2-methylcyclohexan-1-amine hydrochloride (300.0 mg, 2.0 mmol, 1.0 eq), DCM (6.0 mL), Et.sub.3N (0.84 mL, 6.01 mmol, 3.0 eq). This was followed by the addition of acryloyl chloride (181.43 mg, 2.0 mmol, 1.0 eq) at 0 C. The resulting solution was stirred for 40 min at room temperature. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was diluted with 10 mL of DCM. The resulting mixture was washed with 10 ml of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (22:78). This resulted in 200 mg (60%) of N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide as an off-white solid.

[0700] LC-MS (ES, m/z): [M+H].sup.+=168

##STR00145##

[0701] Step 2: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed DMF (4.0 mL), N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide (100.0 mg, 0.60 mmol, 1.0 eq), 6-bromo-3-methyl-1H-indazole (126. mg, 0.60 mmol, 1.0 eq), Et.sub.3N (0.25 mL, 1.79 mmol, 3.0 eq), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (48.71 mg, 0.06 mmol, 0.10 eq). The resulting solution was stirred for 2 h at 120 C. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 41 mg (23%) of Racemic (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide as an off-white solid. LC MS (ES, m/z): [M+H].sup.+=298

[0702] .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4, ppm): 7.75-7.60 (m, 3H), 7.43-7.40 (m, 1H), 6.70 (d, J=15.6 Hz, 1H), 3.54-3.50 (m, 1H), 2.57 (s, 3H), 1.96-1.71 (m, 4H), 1.48-1.37 (m, 5H), 1.30 (d, J=9.3 Hz, 3H).

Example 44: (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide

[0703] ##STR00146##

[0704] Into a 8-mL vial, was placed 6-bromo-1H-indazole-3-carbonitrile (40.0 mg, 0.18 mmol, 1.0 equiv), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Prepared according to Example 24, Step 1 using 2-methylindanamine, 36.26 mg, 0.18 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2 (13.18 mg, 0.018 mmol, 0.10 equiv) and Et.sub.3N (0.075 mL, 0.54 mmol, 3.0 equiv) in DMF (2.0 mL) The resulting solution was stirred for 2 h at 120 C. in an oil bath. The mixture was cooled to RT. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 16 mg (26%) of (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide as a off-white solid. LC MS (ES, m/z): [M+H].sup.+=343

[0705] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm) 8.59-8.30 (m, 1H), 8.05-7.87 (m, 2H), 7.77-7.55 (m, 2H), 7.34-7.08 (m, 4H), 6.97-6.79 (m, 1H), 5.50-4.98 (m, 1H), 3.06-2.95 (m, 1H), 2.84-2.62 (m, 1H), 2.39-2.19 (m, 1H), 1.25-0.88 (m, 3H).

Example 45: (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

[0706] ##STR00147##

[0707] Into a 8-mL vial, was placed 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (50.0 mg, 0.22 mmol, 1.0 equiv), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Prepared according to Example 24, Step 1 using 2-methylindanamine 44.3 mg, 0.22 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2 (16.1 mg, 0.022 mmol, 0.10 equiv) and Et.sub.3N (0.092 mL, 0.66 mmol, 3.0 equiv) in DMF (2.0 mL). The resulting solution was stirred for 2 h at 120 C. in an oil bath. The reaction solution was cooled to RT. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 29 mg (38%) of (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as a off-white solid. LC MS (ES, m/z): [M+H].sup.+=348

[0708] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm) 10.99 (s, 1H), 8.32-8.12 (m, 1H), 7.54-7.46 (m, 1H), 7.28-7.10 (m, 7H), 6.69-6.57 (m, 1H), 5.40-5.02 (m, 1H), 3.30 (s, 3H), 3.07-3.0 (m, 1H), 2.69-2.50 (m, 1H), 2.27-2.20 (m, 1H), 1.21-0.90 (m, 3H).

Example 46: (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0709] ##STR00148##

[0710] Into a 8-mL vial, was placed 2-benzoxazolinone, 5-bromo-(50.0 mg, 0.23 mmol, 1.0 equiv), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Prepared according to Example 24, Step 1 using 2-methylindanamine 47.0 mg, 0.23 mmol, 1.0 equiv), Pd(dppf)Cl.sub.2 (17.1 mg, 0.023 mmol, 0.10 equiv) and Et.sub.3N (0.098 mL, 0.70 mmol, 3.0 equiv) in DMF (2.0 mL). The resulting solution was stirred for 2 hr at 120 C. in an oil bath. The reaction solution was cooled to RT. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 29 mg (37%) of (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a off-white solid. LCMS (ES, m/z): [M+H].sup.+=335

[0711] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm) 11.76 (brs, 1H), 8.40-8.19 (m, 1H), 7.56-7.48 (m, 1H), 7.33-7.12 (m, 6H), 6.74-6.63 (m, 1H), 5.39-4.99 (m, 1H), 3.10-2.94 (m, 1H), 2.69-2.20 (m, 2H), 1.21-0.91 (m, 3H).

Example 47: (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide

[0712] ##STR00149##

[0713] Step 1: Into a 40-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed DMF (20.0 mL), 6-bromo-1,3-dihydroindol-2-one (1.0 g, 4.72 mmol, 1.0 eq), methyl 2-fluoroacrylate (0.59 g, 5.66 mmol, 1.20 eq), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (77.0 mg, 0.094 mmol, 0.02 eq), Et.sub.3N (1.3 mL, 9.43 mmol, 2.0 eq). The resulting solution was stirred for 2 h at 110 C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with (25/75). This resulted in 420 mg (37%) of methyl 2-fluoro-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate as a yellow solid. LC-MS-PH-NRG0255-1 (ES, m/z): [MH].sup.+=234

##STR00150##

[0714] Step 2: Into a 8-mL sealed tube, was placed methyl 2-fluoro-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate (150.0 mg, 0.64 mmol, 1.0 eq), 3-fluoro-2-methyl-aniline (239.42 mg, 1.91 mmol, 3.0 eq), THF (3.0 mL). This was followed by the addition of LiHMDS (1.92 mL, 1.92 mmol, 3.0 eq) at 0 C. The resulting solution was stirred for 30 min at room temperature. The reaction was then quenched by the addition of 15 mL of H.sub.2O. The resulting solution was extracted with 210 mL of EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 28 mg (13%) of (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a white solid. LC MS (ES, m/z): [M+H].sup.+=329

[0715] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 10.50 (s, 1H), 10.16 (s, 1H), 7.31-6.93 (m, 7H), 3.53 (s, 2H), 2.12 (s, 3H).

Example 48: (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0716] ##STR00151##

[0717] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed (E)-methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (Prepared according to Example 11, Step 2, 30.0 mg, 0.14 mmol, 1.0 equiv) in THF (2.0 mL). Then 3-chloro-N,2-dimethylbenzenamine (27.60 mg, 0.18 mmol, 1.30 equiv) was added. The reaction mixture was cooled to 0 C. Then 1M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv) was added. The reaction mixture was stirred 1 h at RT. The reaction mixture was quenched by 1 mL water and extracted with 25 mL EtOAc, the organic was concentrated under vacuum to afford crude product. The crude product was then purified by Prep-HPLC. This resulted in 9.6 mg (21%) of (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=343

Example 49: (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0718] ##STR00152##

[0719] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed (E)-methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (Prepared according to Example 11, Step 2, 30.0 mg, 0.14 mmol, 1.0 equiv) in THF (2.0 mL). Then 2-methylcyclopentanamine (17.6 mg, 0.18 mmol, 1.30 equiv) was added. The reaction mixture was cooled to 0 C. Then 1M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv) was added. The reaction mixture was stirred 1 h at RT. The reaction mixture was quenched by 1 mL water and extracted with 25 mL EtOAc, the organic was concentrated under vacuum to afford crude product. The crude product was then purified by Prep-HPLC. This resulted in 19 mg (48%) of (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid.

[0720] LC-MS (ES, m/z): [M+H].sup.+=287

Example 50: (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0721] ##STR00153##

[0722] Step 1: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed THF (50.0 mL), 2-fluoro-6-nitrobenzoic acid (2.0 g, 10.80 mmol, 1.0 eq). This was followed by the addition of borane (32.41 mL, 32.41 mmol, 3.0 eq, 1 M/THF) at 0 C. The resulting solution was stirred for 10 h at 50 C. The reaction was then quenched by the addition of 20 mL of 3 M HCl. The resulting solution was diluted with 50 mL of EtOAc. The organic layer was washed with 230 ml of brine. The solution was dried over sodium sulfate and evaporated under reduced pressure. This resulted in 1.3 g (70%) of (2-fluoro-6-nitrophenyl)methanol as a light brown solid.

##STR00154##

[0723] Step 2: Into a 40-mL sealed tube, was placed (2-fluoro-6-nitrophenyl)methanol (1.30 g, 7.59 mmol, 1.0 eq), DMF (20.0 mL), methyl iodide (5.39 g, 37.98 mmol, 5.0 eq). This was followed by the addition of Cs.sub.2CO.sub.3 (3.71 g, 11.39 mmol, 1.50 eq) at 0 C. The resulting solution was stirred for 5 h at 50 C. The solids were filtered out. The filtrate solution was diluted with 100 mL of EtOAc. The resulting mixture was washed with 350 ml of H.sub.2O and 50 mL of brine. The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by Flash-Prep-HPLC. This resulted in 0.91 g (64%) of 1-fluoro-2-(methoxymethyl)-3-nitrobenzene as yellow oil.

##STR00155##

[0724] Step 3: Into a 40-mL sealed tube, was placed 1-fluoro-2-(methoxymethyl)-3-nitrobenzene (0.70 g, 3.78 mmol, 1.0 eq), MeOH (20.0 mL), H.sub.2O (3.0 mL), NH.sub.4Cl (1.21 g, 22.68 mmol, 6.0 eq). This was followed by the addition of Zn (1.24 g, 18.90 mmol, 5.0 eq) at 10 C. The resulting solution was stirred for 1 h at 25 C. The solids were filtered out. The resulting solution was diluted with 20 mL of DCM. The mixture was dried over anhydrous sodium sulfate and concentrated (low temp). This resulted in 0.21 g (35%) of 3-fluoro-2-(methoxymethyl)aniline as light brown oil (the amine was unstable and was used in next step directly and quickly). LC-MS (ES, m/z): [M+H].sup.+=156

##STR00156##

[0725] Step 4: Into a 8-mL sealed tube, was placed 3-fluoro-2-(methoxymethyl)aniline (200.0 mg, 1.28 mmol, 1.0 eq), DCM (4.0 mL), Et.sub.3N (0.36 mL, 2.57 mmol, 2.0 eq). This was followed by the addition of acryloyl chloride (116.6 mg, 1.28 mmol, 1.0 eq) at 0 C. The resulting solution was stirred for 0.5 h at 0 C. The reaction was then quenched by the addition of 2 mL of water. The resulting mixture was washed with 2 ml of brine. The organic layer was dried over sodium sulfate and concentrated. This resulted in 160 mg (59%) of N-[3-fluoro-2-(methoxymethyl)phenyl]prop-2-enamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=210

##STR00157##

[0726] Step 5: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed N-[3-fluoro-2-(methoxymethyl)phenyl]prop-2-enamide (100.0 mg, 0.47 mmol, 1.0 eq), DMF (4.0 mL), 6-bromo-3-methyl-1H-indazole (100.88 mg, 0.47 mmol, 1.0 eq), Et.sub.3N (0.2 mL, 1.43 mmol, 3.0 eq), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (38.94 mg, 0.048 mmol, 0.10 eq). The resulting solution was stirred for 2 h at 120 C. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 71 mg (43%) of (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=340

[0727] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.84 (s, 1H), 9.55 (s, 1H), 7.78-7.69 (m, 4H), 7.44-7.38 (m, 2H), 7.11-7.02 (m, 2H), 4.56 (s, 2H), 3.32 (s, 3H), 2.51 (s, 3H).

Example 51: (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide

[0728] ##STR00158##

[0729] Step 1: Into a 40-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-1H-indazole-3-carbonitrile (220.0 mg, 0.99 mmol, 1.0 equiv), dihydropyran (416.7 mg, 4.95 mmol, 5.0 equiv), DCM (10.0 mL), TsOH (34.1 mg, 0.20 mmol, 0.20 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:20-1:8). This resulted in 300 mg (99%) of 6-bromo-1-(oxan-2-yl) indazole-3-carbonitrile as a off-white solid.

##STR00159##

[0730] Step 2: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-fluoro-2-methylphenyl)acrylamide (150.0 mg, 0.84 mmol, 1.0 equiv), 6-bromo-1-(oxan-2-yl) indazole-3-carbonitrile (307.5 mg, 1.0 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (68.2 mg, 0.08 mmol, 0.10 equiv), DMF (4.0 mL), Et.sub.3N (0.35 mL, 2.51 mmol, 3.0 equiv). The resulting solution was stirred for 3 h at 120 C. The reaction mixture was cooled to room temperature. The mixture was applied onto a silica gel column with THF:PE (1:4-1:1). This resulted in 150 mg (44%) of (2E)-3-[3-cyano-1-(oxan-2-yl) indazol-6-yl]-N-(3-fluoro-2-methylphenyl)acrylamideas a light brown solid.

##STR00160##

[0731] Step 3: Into a 40-mL sealed tube, was placed (2E)-3-[3-cyano-1-(oxan-2-yl) indazol-6-yl]-N-(3-fluoro-2-methylphenyl)acrylamide (150.0 mg, 0.37 mmol, 1.0 equiv), 4M HCl/dioxane (10 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC. This resulted in 12.5 mg (11%) of (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as a off-white solid.

[0732] LC-MS (ES, m/z): [M+H].sup.+=321

[0733] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 14.55 (brs, 1H), 9.68 (s, 1H), 8.0-7.95 (m, 2H), 7.80 (d, J=15.9 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.49 (d, J=9.6 Hz, 1H), 7.28-7.20 (m, 1H), 7.15 (d, J=15.9 Hz, 1H), 7.05-6.99 (m, 1H), 2.17 (s, 3H).

Example 52: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide

[0734] ##STR00161##

[0735] Step 1: Into a 25-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine (110.0 mg, 0.67 mmol, 1.0 equiv), DCM (10.0 mL), Et.sub.3N (0.19 mL, 1.35 mmol, 2.0 equiv). This was followed by the addition of acryloyl chloride (67.10 mg, 0.74 mmol, 1.10 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 215 mL of dichloromethane dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (1/5). This resulted in 110 mg (75%) of N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide as a light yellow solid.

[0736] LC-MS (ES, m/z): [M+H].sup.+=218

##STR00162##

[0737] Step 2: Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide (120.0 mg, 0.55 mmol, 1.0 equiv), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (116.6 mg, 0.55 mmol, 1.0 equiv), Et.sub.3N (0.23 mL, 1.66 mmol, 3.0 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (22.50 mg, 0.028 mmol, 0.05 equiv). The resulting solution was stirred for 5 h at 120 C. The reaction mixture was cooled to room temperature. The residue was applied onto a silica gel column with EtOAc (1/3). This resulted in 55 mg (29%) of (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide as a off-white solid. LC-MS (ES, m/z): [M+H].sup.+=348

[0738] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.80 (brs, 1H), 8.52-8.33 (m, 1H), 7.74-7.62 (m, 3H), 7.33-7.28 (m, 1H), 7.18-7.13 (m, 2H), 6.92-6.73 (m, 3H), 5.24-4.81 (m, 1H), 4.24-4.10 (m, 1H), 3.98-3.88 (m, 1H), 2.50-2.49 (m, 3H), 2.28-2.04 (m, 1H), 0.98-0.90 (m, 3H).

Example 53: (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0739] ##STR00163##

[0740] Step 1: Into a 25-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (160.0 mg, 0.99 mmol, 1.0 equiv), DCM (10.0 mL), Et.sub.3N (0.28 mL, 1.98 mmol, 2.0 equiv). This was followed by the addition of acryloyl chloride (98.79 mg, 1.09 mmol, 1.10 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 210 mL of DCM and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (1/5). This resulted in 140 mg (66%) of N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)prop-2-enamide as a light yellow solid.

[0741] LC-MS (ES, m/z): [M+H].sup.+=216

##STR00164##

[0742] Step 2: Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)prop-2-enamide (140.0 mg, 0.65 mmol, 1.0 equiv), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (137.3 mg, 0.65 mmol, 1.0 equiv), Et.sub.3N (0.27 mL, 1.95 mmol, 3.0 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (26.5 mg, 0.033 mmol, 0.05 equiv). The resulting solution was stirred for 5 h at 120 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 30 mg (13%) of (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a off-white solid. LC-MS (ES, m/z): [M+H].sup.+=346

[0743] .sup.1H NMR (300 MHz, DMSO-d6, ppm): 12.77 (brs, 1H), 8.39-8.15 (m, 1H), 7.74-7.59 (m, 3H), 7.34-7.11 (m, 5H), 6.84-6.76 (m, 1H), 5.23-4.76 (m, 1H), 2.84-2.77 (m, 2H), 2.51-2.48 (m, 3H), 2.08-1.98 (m, 1H), 1.97-1.52 (m, 2H), 1.10-0.90 (m, 3H).

Example 54: (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0744] ##STR00165##

[0745] Step 1: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (300.0 mg, 1.50 mmol, 1.0 equiv), DCM (20.0 mL), Et.sub.3N (0.31 mL, 2.25 mmol, 1.50 equiv). This was followed by the addition of acryloyl chloride (163.2 mg, 1.80 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:5-1:3). This resulted in 200 mg (61%) of N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide as a off-white solid.

##STR00166##

[0746] Step 2: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (140.0 mg, 0.64 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (163.2 mg, 0.77 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (52.5 mg, 0.064 mmol, 0.10 equiv), DMF (4 mL), Et.sub.3N (0.27 mL, 1.93 mmol, 3.0 equiv). The resulting solution was stirred for 1 h at 120 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 28.6 mg (13%) of (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=348

[0747] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.78 (brs, 1H), 8.58 (d, J=8.7 Hz, 1H), 7.74-7.62 (m, 3H), 7.33-7.18 (m, 5H), 6.75 (d, J=15.6 Hz, 1H), 5.34-5.30 (m, 1H), 4.07-4.01 (m, 1H), 3.38 (s, 3H), 3.35-3.27 (m, 1H), 2.84-2.76 (m, 1H), 2.49 (s, 3H).

Example 55: (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0748] ##STR00167##

[0749] Step 1: Into a 8-mL sealed tube, was placed (1R)-2,3-dihydro-1H-inden-1-amine (100.0 mg, 0.75 mmol, 1.0 equiv), DCM (5.0 mL), Et.sub.3N (0.21 mL, 1.50 mmol, 2.0 equiv). This was followed by the addition of acryloyl chloride (81.54 mg, 0.90 mmol, 1.20 equiv) at 30 C. The resulting solution was stirred for 10 min at 30 C. The reaction was then quenched by the addition of 5 mL of water. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (15:75). This resulted in 93 mg (66%) of N-[(1R)-2,3-dihydro-1H-inden-1-yl]prop-2-enamide as a white solid. LC-MS-PH-NRG0457-1 (ES, m/z): [M+H].sup.+=188

##STR00168##

[0750] Step 2: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-[(1R)-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (60.0 mg, 0.32 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (67.63 mg, 0.32 mmol, 1.0 equiv), DMF (2.0 mL), Et.sub.3N (0.09 mL, 0.64 mmol, 2.0 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (5.2 mg, 0.06 mmol, 0.02 equiv). The resulting solution was stirred for 2 h at 120 C. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 41 mg (40%) of (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=318

[0751] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.78 (s, 1H), 8.47 (d, J=8.4 Hz, 1H), 7.73-7.62 (m, 3H), 7.32-7.17 (m, 5H), 6.74 (d, J=15.9 Hz, 1H), 5.47-5.39 (m, 1H), 3.03-2.79 (m, 2H), 2.51-2.41 (m, 4H), 1.90-1.81 (m, 1H).

Example 56: (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0752] ##STR00169##

[0753] Prepared according to Example 11, Step 4 using (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid and chroman-4-amine to give (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=337

Example 57: (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide

[0754] ##STR00170##

[0755] Prepared according to Example 11, Step 4 using (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid and 1,2,3,4-tetrahydronaphthalen-1-amine to give (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide as a white solid.

[0756] LC-MS (ES, m/z): [M+H].sup.+=335

Example 58: (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide

[0757] ##STR00171##

[0758] Into a 8-mL vial, was placed (E)-3-(2-oxoindolin-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.00 equiv), 2-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (40.3 mg, 0.25 mmol, 1.00 equiv), HATU (141.4 mg, 0.37 mmol, 1.50 equiv) and DIPEA (95.4 mg, 0.74 mmol, 3.00 equiv) in DMF (2.00 mL). The resulting solution was stirred for 2 h at 20 C. The mixture was purified by Flash-Prep-HPLC. This resulted in 19 mg (22%) of (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as a off-white solid. LC-MS (ES, m/z): [M+H].sup.+=347

[0759] .sup.1H NMR (300 MHz, DMSO-d6, ppm) 10.51 (brs, 1H), 8.40-8.20 (m, 1H), 7.50-7.45 (m, 1H), 7.27-7.14 (m, 6H), 7.05-6.96 (m, 1H), 6.68-6.63 (m, 1H), 5.45-5.00 (m, 1H), 3.51 (s, 2H), 3.10-3.00 (m, 1H), 2.70-2.20 (m, 4H), 1.20-0.91 (m, 3H).

Example 59: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide

[0760] ##STR00172##

[0761] Into a 8-mL vial, was placed (E)-3-(2-oxoindolin-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.00 equiv), 2,3-dihydro-1H-inden-1-amine (33.3 mg, 0.25 mmol, 1.00 equiv), HATU (141.4 mg, 0.37 mmol, 1.50 equiv) and DIPEA (95.4 mg, 0.74 mmol, 3.00 equiv) in DMF (2.00 mL). The resulting solution was stirred for 2 h at 20 C. The mixture was purified by Flash-Prep-HPLC. This resulted in 15 mg (19%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as a off-white solid. LC-MS (ES, m/z): [M+H].sup.+=319

[0762] .sup.1H NMR (300 MHz, DMSO-d6, ppm) 10.50 (brs, 1H), 8.46 (d, J=8.1 Hz, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.29-7.12 (m, 6H), 6.98 (s, 1H), 6.62 (d, J=15.9 Hz, 1H), 5.45-5.37 (m, 1H), 3.51 (s, 2H), 3.02-2.79 (m, 2H), 2.50-2.40 (m, 1H), 1.89-1.82 (m, 1H).

Example 60: (E)-N-(3,5-difluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide

[0763] ##STR00173##

[0764] Step 1: Into a 100-mL pressure tank reactor, was placed 4-chloro-3,5-difluoro-2-methylaniline (160.00 mg, 0.90 mmol, 1.00 equiv), EtOH (30.00 mL), 4M HCl/EtOH (1.00 mL), Pd/C (47.94 mg). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The resulting solution was stirred overnight at 70 C. under an atmosphere of hydrogen (30 atm). The reaction mixture was cooled to room temperature. The solids were filtered out. The resulting mixture was concentrated. This resulted in 120 mg (crude) of 3,5-3,5-difluoro-2-methylaniline hydrochloride.

##STR00174##

[0765] Step 2: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3,5-difluoro-2-methylaniline hydrochloride (120.00 mg, 0.67 mmol, 1.00 equiv), DCM (20 mL), Et.sub.3N (0.28 mL, 2.01 mmol, 3.00 equiv). This was followed by the addition of acryloyl chloride (90.7 mg, 1.00 mmol, 1.50 equiv) dropwise with stirring at 0 C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:5-1:3). This resulted in 120 mg (91%) of N-(3,5-difluoro-2-methylphenyl)prop-2-enamide as a off-white solid.

##STR00175##

[0766] Step 3: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(3,5-difluoro-2-methylphenyl)prop-2-enamide (120.00 mg, 0.61 mmol, 1.00 equiv), 6-bromo-1,3-dihydroindol-2-one (154.9 mg, 0.73 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (49.6 mg, 0.06 mmol, 0.10 equiv), DMF (4.00 mL), Et.sub.3N (0.25 mL, 1.83 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 100 C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 11.3 mg (6%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as a off-white solid.

[0767] LC-MS (ES, m/z): [M+H].sup.+=329

[0768] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 10.57 (s, 1H), 9.88 (s, 1H), 7.95-7.90 (m, 1H), 7.54 (d, J=15.6 Hz, 1H), 7.31-7.17 (m, 3H), 7.04 (s, 1H), 6.96 (d, J=15.3 Hz, 1H), 3.52 (s, 2H), 2.22 (s, 3H).

Example 61: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide

[0769] ##STR00176##

[0770] Into a 8-mL round-bottom flask, was placed 5-bromo-4-fluoro-3H-1,2,3-benzotriazole (50.0 mg, 0.23 mmol, 1.00 equiv), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (43.3 mg, 0.23 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2 (16.9 mg, 0.023 mmol, 0.10 equiv), Et.sub.3N (0.096 mL, 0.70 mmol, 3.00 equiv), DMF (3.00 mL). The resulting solution was stirred for 2 h at 120 C. in an oil bath. The reaction mixture was cooled. The residue was applied onto a silica gel column with PE/THF (1/1). This resulted in 19 mg (25%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide as a solid. LC-MS (ES, m/z): [M+H].sup.+=323

[0771] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 8.63 (d, J=8.1 Hz, 1H), 7.93-7.63 (m, 3H), 7.32-7.15 (m, 4H), 6.85 (d, J=15.9 Hz, 1H), 5.47-5.35 (m, 1H), 3.06-2.81 (m, 2H), 2.47-2.39 (m, 1H), 1.90-1.78 (m, 1H).

Example 62: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide

[0772] ##STR00177##

[0773] Into a 8-mL round-bottom flask, was placed 6-bromo-4-fluoro-1H-1,2,3-benzotriazole (40.00 mg, 0.18 mmol, 1.00 equiv), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (34.7 mg, 0.18 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2 (13.6 mg, 0.019 mmol, 0.10 equiv) and Et.sub.3N (0.077 mL, 0.55 mmol, 3.00 equiv) in DMF (2.00 mL). The resulting solution was stirred for 1 h at 120 C. in an oil bath. The reaction mixture was cooled. The mixture was applied onto a silica gel column with PE/THF (1/1). This resulted in 17.8 mg (30%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide as a white solid. LC MS (ES, m/z): [M+H].sup.+=323

[0774] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 8.51 (d, J=8.1 Hz, 1H), 7.90 (s, 1H), 7.68 (d, J=15.6 Hz, 1H), 7.41 (d, J=12.0 Hz, 1H), 7.28-7.15 (m, 4H), 6.77 (d, J=15.6 Hz, 1H), 5.47-5.34 (m, 1H), 3.03-2.81 (m, 2H), 2.44-2.35 (m, 1H), 1.93-1.78 (m, 1H).

Example 63: (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0775] ##STR00178##

[0776] Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed (E)-methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (30.0 mg, 0.14 mmol, 1.00 equiv) in THF (2.00 mL). Then 5-chloro-2-methylbenzenamine (25.4 mg, 0.18 mmol, 1.30 equiv) was added. The reaction mixture was cooled to 0 C. Then 1M LiHMDS (0.68 mL, 0.68 mmol, 5.00 equiv) was added. The reaction mixture was stirred 1 h at RT. The reaction mixture was quenched by 1 mL water and extracted with 25 mL ETOAc, the organic was concentrated under vacuum to afford crude product. The crude product was then purified by Prep-HPLC. This resulted in 5 mg (11%) of (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H].sup.+=329

[0777] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm) 9.42 (s, 1H), 7.85 (s, 1H), 7.60 (d, J=15.9 Hz, 1H), 7.36-7.11 (m, 5H), 6.97 (d, J=15.6 Hz, 1H), 2.26 (s, 3H).

Example 64: (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide

[0778] ##STR00179##

[0779] Into a 8-mL vial, was placed (E)-3-(2-oxoindolin-6-yl)acrylic acid (50.00 mg, 0.25 mmol, 1.00 equiv), 2-methylcyclohexanamine (28.25 mg, 0.25 mmol, 1.00 equiv), HATU (141.38 mg, 0.37 mmol, 1.50 equiv) and DIPEA (95.41 mg, 0.74 mmol, 3.00 equiv) in DMF (2.00 mL). The resulting solution was stirred for 2 h at 20 C. The mixture was purified by Flash-Prep-HPLC. This resulted in 8.3 mg (11%) of (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide as a off-white solid. LC-MS (ES, m/z): [M+H].sup.+=299

Example 65: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide

[0780] ##STR00180##

[0781] Step 1: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,3-dihydro-1-benzopyran-4-one (15.00 g, 101.24 mmol, 1.00 equiv) and THF (200 mL). This was followed by the addition of LiHMDS (1 M in THF, 1.20 equiv) dropwise with stirring at 78 C. The resulting solution was stirred for 40 min at 78 C. To this was added a solution of Mel (17.24 g, 121.49 mmol, 1.20 equiv) in THF (10 mL) dropwise with stirring at 78 C. The resulting solution was allowed to react, with stirring, for an additional 40 min at 78 C. Then stirred for an additional 1 h at 25 C. The reaction was then quenched by the addition of 150 mL of NH.sub.4Cl. The resulting solution was extracted with 2150 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 5 g (30% yield) of 3-methyl-2,3-dihydro-1-benzopyran-4-one as a light yellow oil.

##STR00181##

[0782] Step 2: Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 3-methyl-2,3-dihydro-1-benzopyran-4-one (1.10 g, 6.78 mmol, 1.00 equiv), MeOH (20.00 mL), NH.sub.2OH.Math.HCl (1.41 g, 20.35 mmol, 3.00 equiv), Et.sub.3N (2.06 g, 20.35 mmol, 3.00 equiv). The resulting solution was stirred for 15 h at 70 C. The resulting mixture was concentrated. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 210 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The resulting mixture was concentrated. This resulted in 1 g (83% yield) of N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ylidene]hydroxylamine as a white solid.

##STR00182##

[0783] Step 3: Into a 100-mL 1-necked round-bottom flask purged and maintained with an inert atmosphere of H.sub.2, was placed N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ylidene]hydroxylamine (0.70 g, 3.95 mmol, 1.00 equiv), MeOH (20.00 mL), Pd/C (0.06 g). The resulting solution was stirred for 12 h at 40 C. The solids were filtered out. The resulting mixture was concentrated. This resulted in 530 mg (82% yield) of 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine as light yellow oil.

##STR00183##

[0784] Step 4: Into a 40-mL vial, was placed 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine (300.00 mg, 1.838 mmol, 1.00 equiv), DCM (10.00 mL), Et.sub.3N (371.98 mg, 3.676 mmol, 2.00 equiv). This was followed by the addition of a solution of acryloyl chloride (182.99 mg, 2.022 mmol, 1.10 equiv) in DCM (2 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 5 h at 0 C. The reaction was then quenched by the addition of 8 mL of water. The resulting solution was extracted with 215 mL of dichloromethane and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2). This resulted in 280 mg (70% yield) of N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide as an off-white solid.

##STR00184##

[0785] Step 5: Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide (150.00 mg, 0.690 mmol, 1.00 equiv), DMF (6.00 mL), 6-bromo-3-methyl-1H-indazole (145.72 mg, 0.690 mmol, 1.00 equiv), Et.sub.3N (174.65 mg, 1.725 mmol, 2.50 equiv), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (33.74 mg, 0.041 mmol, 0.06 equiv). The resulting solution was stirred overnight at 120 C. The reaction mixture was cooled to room temperature. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 110 mg racemic mixture of cis/trans isomers as a light yellow solid. The mixture was purified by Chiral-Prep-HPLC to give the 4 separated stereoisomers, including (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide (Example 65c). The cis-trans isomers were assigned using NOESY NMR. The stereochemistry of each enantiomeric pair has been assigned arbitrarily.

Example 65a: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methylchroman-4-yl)acrylamide

[0786] LC-MS (ES, m/z): [M+H].sup.+=348

[0787] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm): 12.77 (s, 1H), 8.33 (d, J=6.6 Hz, 1H), 7.73-7.61 (m, 3H), 7.30-7.16 (m, 3H), 6.91-6.77 (m, 3H), 5.23-5.20 (m, 1H), 4.13 (d, J=8.1 Hz, 1H),

Example 65b: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methylchroman-4-yl)acrylamide

[0788] LC-MS1 (ES, m/z): [M+H].sup.+=348

[0789] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm): 12.77 (s, 1H), 8.33 (d, J=6.9 Hz, 1H), 7.73-7.61 (m, 3H), 7.30-7.16 (m, 3H), 6.91-6.77 (m, 3H), 5.23-5.20 (m, 1H), 4.13 (d, J=8.1 Hz, 1H), 3.94-3.89 (m, 1H), 2.55-2.50 (m, 3H), 2.29-2.33 (m, 1H), 0.91 (d, J=4.5 Hz, 3H).

Example 65c: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide

[0790] LC-MS (ES, m/z): [M+H].sup.+=348

[0791] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm): 12.77 (s, 1H), 8.49 (d, J=6.3 Hz, 1H), 7.73-7.62 (m, 3H), 7.32-7.30 (m, 1H), 7.18-7.13 (m, 2H), 6.91-6.87 (m, 1H), 6.81-6.74 (m, 2H), 4.86-4.82 (m, 1H), 4.23-4.21 (m, 1H), 3.97-3.95 (m, 1H), 2.55-2.50 (m, 3H), 2.08-2.05 (m, 1H), 0.97 (d, J=5.1 Hz, 3H).

Example 65d: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methylchroman-4-yl)acrylamide

[0792] LC-MS (ES, m/z): [M+H].sup.+=348

[0793] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm): 12.77 (s, 1H), 8.49 (d, J=6.3 Hz, 1H), 7.73-7.62 (m, 3H), 7.32-7.30 (m, 1H), 7.18-7.13 (m, 2H), 6.91-6.87 (m, 1H), 6.81-6.74 (m, 2H), 4.86-4.82 (m, 1H), 4.23-4.21 (m, 1H), 3.97-3.95 (m, 1H), 2.55-2.50 (m, 3H), 2.08-2.05 (m, 1H), 0.97 (d, J=5.1 Hz, 3H).

Example 66: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide

[0794] ##STR00185##

[0795] Step 1: Into a 100-mL 3-necked round-bottom flask, was placed oxetan-3-ylmethanol (2.00 g, 22.70 mmol, 1.00 equiv), triflic anhydride (9.61 g, 34.050 mmol, 1.50 equiv), Et.sub.3N (4.59 g, 45.40 mmol, 2.00 equiv), DCM (50.00 mL). The resulting solution was stirred for 10 hr at 20 C. The resulting mixture was washed with 250 ml of NaCO.sub.3 aq. and 150 mL of NaCl aq. The organic layer was dried over anhydrous sodium sulfate and concentrated and used for next step without purification.

##STR00186##

[0796] Step 2: Into a 100-mL 3-necked round-bottom flask, was placed tert-butyl N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (1.00 g, 4.01 mmol, 1.00 equiv), oxetan-3-ylmethyl trifluoromethanesulfonate (0.88 g, 4.01 mmol, 1.00 equiv), NaH (0.14 g, 6.01 mmol, 1.50 equiv) in THF (20.00 mL). The resulting solution was stirred for 10 hr at 20 C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 220 mL of ethyl acetate and the organic layers combined. The organic layer was concentrated and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 150 mg of tert-butyl N-[(1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a solid.

##STR00187##

[0797] Step 3: Into a 8-mL vial, was placed tert-butyl N-[(1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate (140.00 mg, 0.438 mmol, 1.00 equiv) in 2M HCl(g) in MeOH (2.00 mL) and MeOH (2.00 mL). The resulting solution was stirred for 2 hr at 10 C. The resulting mixture was concentrated. This resulted in 35 mg of (1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-amine as a solid.

##STR00188##

[0798] Step 4: Into a 8-mL vial, was placed (1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-amine (25.00 mg, 0.114 mmol, 1.00 equiv), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (Intermediate 3, 22.83 mg, 0.114 mmol, 1.00 equiv), HATU (65.02 mg, 0.171 mmol, 1.50 equiv) and Et.sub.3N (34.61 mg, 0.342 mmol, 3.00 equiv) in DMF (3.00 mL). The resulting solution was stirred for 2 hr at 20 C. The crude mixture was purified by Prep-HPLC. This resulted in 15 mg of (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=404

[0799] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm) 12.78 (s, 1H), 8.58 (d, J=8.4 Hz, 1H), 7.74-7.63 (m, 3H), 7.33-7.22 (m, 5H), 6.75 (d, J=15.9 Hz, 1H), 5.34-5.29 (m, 1H), 4.65-4.60 (m, 2H), 4.32-4.28 (m, 2H), 4.17-4.14 (m, 1H), 3.89-3.86 (m, 1H), 3.84-3.74 (m, 1H), 3.36-3.34 (m, 1H), 3.32-3.31 (m, 1H), 2.86-2.78 (m, 1H), 2.50 (s, 3H).

Example 67: (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0800] ##STR00189##

[0801] Step 1: Into a 8-mL vial, was placed tert-butyl N-(2-hydroxy-octahydro-1H-inden-1-yl)carbamate (200.00 mg, 0.783 mmol, 1.00 equiv), allyl bromide (94.75 mg, 0.783 mmol, 1.00 equiv) and NaH (5.00 mg, 0.783 mmol, 60%) in THF (3.00 mL). The resulting solution was stirred for 10 hr at 20 C. The reaction was then quenched by the addition of 0.5 mL of water. The mixture was concentrated and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 150 mg (66% yield) of tert-butyl N-[(1S,2S)-2-(prop-2-en-1-yloxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a light yellow solid.

##STR00190##

[0802] Step 2: Into a 40-mL vial, was placed tert-butyl N-[2-(prop-2-en-1-yloxy)-octahydro-1H-inden-1-yl]carbamate (140.00 mg, 0.474 mmol, 1.00 equiv), 1M ZnEt.sub.2 (4.74 mL, 4.739 mmol, 10.00 equiv), CH.sub.2I.sub.2(1015.41 mg, 3.791 mmol, 8.00 equiv) and TFA (432.28 mg, 3.791 mmol, 8.00 equiv) in DCM (5.00 mL). The resulting solution was stirred for 10 hr at 20 C. The mixture was concentrated and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (10/1). This resulted in 70 mg (48% yield) of tert-butyl N-[(1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a solid.

##STR00191##

[0803] Step 3: Into a 8-mL vial, was placed tert-butyl N-[2-(cyclopropylmethoxy)-octahydro-1H-inden-1-yl]carbamate (50.00 mg, 1.00 equiv). in 2M HCl(g) in MeOH (3.00 mL) and MeOH (3.00 mL). The resulting solution was stirred for 2 hr at 20 C. The resulting mixture was concentrated. This resulted in 30 mg of (1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-amine as an off-white solid.

##STR00192##

[0804] Step 4: Into a 8-mL vial, was placed (1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-amine (20.00 mg, 0.098 mmol, 1.00 equiv), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (19.70 mg, 0.098 mmol, 1.00 equiv), HATU (56.11 mg, 0.148 mmol, 1.50 equiv) and Et.sub.3N (29.87 mg, 0.295 mmol, 3.00 equiv) in DMF (2.00 mL). The resulting solution was stirred for 2 hr at 20 C. The mixture was purified by Flash-Prep-HPLC. This resulted in 20 mg (52% yield) of (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=388

[0805] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm) 8.57 (d, J=8.7 Hz, 1H), 7.74-7.62 (m, 3H), 7.31 (d, J=7.8 Hz, 1H), 7.25-7.19 (m, 4H), 6.74 (d, J=15.6 Hz, 1H), 5.31-5.27 (m, 1H), 4.19-4.12 (m, 1H), 3.48-3.44 (m, 1H), 3.38-3.32 (m, 2H), 2.84-2.73 (m, 1H), 1.04-1.00 (m, 1H), 0.53-0.42 (m, 2H), 0.24-0.12 (m, 2H)

Example 68: (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0806] ##STR00193##

[0807] Step 1: Into a 100-mL 3-necked round-bottom flask, was placed 2-fluoroethanol (3.20 g, 49.95 mmol, 1.00 equiv), triflic anhydride (14.09 g, 49.95 mmol, 1.00 equiv) and Et.sub.3N (10.11 g, 99.91 mmol, 2.00 equiv) in DCM (60.00 mL). The resulting solution was stirred for 10 hr at 78 C. in a liquid nitrogen bath. The resulting mixture was washed with 250 ml of NaCO.sub.3 aq. and 150 mL of NaCl aq. The organic layer was dried over anhydrous sodium sulfate and concentrated, the resulted in 9.7 g was used for the next step without purification.

##STR00194##

[0808] Step 2: Into a 20-mL vial, was placed tert-butyl N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (400.00 mg, 1.60 mmol, 1.00 equiv), 2-fluoroethyl trifluoromethanesulfonate (629.32 mg, 3.21 mmol, 2.00 equiv), NaH (77.01 mg, 3.21 mmol, 2.00 equiv) in THF (10.00 mL). The resulting solution was stirred for 10 hr at 20 C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 220 mL of ethyl acetate and the organic layers combined. The organic layer was concentrated and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 300 mg (63% yield) of tert-butyl N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a light yellow solid.

##STR00195##

[0809] Step 3: Into a 20-mL vial, was placed tert-butyl N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate (300.00 mg) in 2M HCl(g) in MeOH (5.00 mL) and MeOH (5.00 mL) was stirred for 10 hr at 20 C. The resulting mixture was concentrated. This resulted in 120 mg of (1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-amine as a light yellow solid.

##STR00196##

[0810] Step 4: Into a 8-mL vial, was placed (1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-amine (40.00 mg, 0.205 mmol, 1.00 equiv), ((E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (Intermediate 3, 41.03 mg, 0.205 mmol, 1.00 equiv), HATU (116.85 mg, 0.307 mmol, 1.50 equiv), DIPEA (79.44 mg, 0.615 mmol, 3.00 equiv), DMF (2.00 mL). The resulting solution was stirred for 10 hr at 20 C.

[0811] The mixture was purified by Flash-Prep-HPLC. This resulted in 21 mg of (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=380

[0812] .sup.1H-NMR1(300 MHz, DMSO-d.sub.6, ppm) 612.78 (s, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.74-7.62 (m, 3H), 7.33-7.22 (m, 5H), 6.75 (d, J=15.6 Hz, 1H), 5.34-5.29 (m, 1H), 4.65-4.62 (m, 1H), 4.49-4.46 (m, 1H), 4.20-4.16 (m, 1H), 3.97-3.71 (m, 2H), 3.37-3.35 (m, 1H), 2.88-2.80 (m, 1H), 2.50 (s, 3H)

Example 69: (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0813] ##STR00197##

[0814] Step 1: Into a 20-mL vial, was placed tert-butyl N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (400.00 mg, 1.604 mmol, 1.00 equiv), ethyl iodide (500.47 mg, 3.209 mmol, 2.00 equiv) and NaH (128.36 mg, 3.209 mmol, 2.00 equiv, 60%) in THF (10.00 mL). The resulting solution was stirred for 10 hr at 20 C. The mixture was quenched with 5 ml H.sub.2O and extracted with 30 mL of ethyl acetate. The organic layers combined and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 200 mg (45% yield) of tert-butyl N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]carbamate as a light yellow solid.

##STR00198##

[0815] Step 2: Into a 20-mL vial, was placed tert-butyl N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]carbamate (170.00 mg) in 2M HCl(g) in MeOH (5.00 mL) and MeOH (5.00 mL) was stirred for 10 hr at 20 C. The resulting mixture was concentrated. This resulted in 80 mg of (1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-amine as a light yellow solid.

##STR00199##

[0816] Step 3: Into a 8-mL vial, was placed (1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-amine (40.00 mg, 0.226 mmol, 1.00 equiv), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (Intermediate 3, 45.19 mg, 0.226 mmol, 1.00 equiv), HATU (128.71 mg, 0.339 mmol, 1.50 equiv) and DIPEA (87.50 mg, 0.677 mmol, 3.00 equiv) in DMF (2.00 mL). The resulting solution was stirred for 2 hr at 20 C. The mixture was purified by Prep-HPLC. This resulted in 25 mg of (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a off-white solid.

[0817] LC-MS (ES, m/z): [M+H].sup.+=362

[0818] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm) 8.57 (d, J=8.4 Hz, 1H), 7.74-7.63 (m, 3H), 7.33-7.17 (m, 5H), 6.75 (d, J=15.6 Hz, 1H), 5.32-5.28 (m, 1H), 4.14-4.10 (m, 1H), 3.69-3.55 (m, 2H), 3.34-3.26 (m, 1H). 2.83-2.73 (m, 1H), 2.78-2.76 (m, 3H). 1.16-1.12 (m, 3H)

Example 70: (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

[0819] ##STR00200##

[0820] Into a 8-mL vial, was placed N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equiv), 6-bromo-3-cyclopropyl-1H-indazole (65.48 mg, 0.276 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2 (20.21 mg, 0.028 mmol, 0.10 equiv), Et.sub.3N (83.83 mg, 0.828 mmol, 3.00 equiv) in DMF (2.00 mL). The resulting solution was stirred for 3 hr at 120 C. The mixture was purified by Prep-HPLC. This resulted in 31 mg of (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=374

[0821] .sup.1H-NMR-(300 MHz, DMSO-d.sub.6, ppm) 8.61-8.58 (d, J=8.7 Hz, 1H), 7.87-7.78 (d, J=8.7 Hz, 1H), 7.68-7.62 (m, 2H), 7.32-7.20 (m, 5H), 6.77-6.72 (d, J=15.9 Hz, 1H), 5.34-5.32 (m, 1H), 4.08-4.07 (m, 1H), 3.38 (s, 3H). 3.35-3.27 (m, 1H), 2.84-2.77 (m, 1H). 2.29-2.24 (m, 1H), 1.01-0.94 (m, 4H).

Example 71: (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

[0822] ##STR00201##

[0823] Into a 8-mL vial, was placed N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equiv), 6-bromo-3-methoxy-1H-indazole (62.70 mg, 0.276 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2 (20.21 mg, 0.028 mmol, 0.10 equiv), Et.sub.3N (83.83 mg, 0.828 mmol, 3.00 equiv) in DMF (2.00 mL). The resulting solution was stirred for 3 hr at 120 C. The mixture was purified by Prep-HPLC. This resulted in 33 mg of (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. The compounds was converted to the HCl. LC-MS (ES, m/z): [M+H].sup.+=364

[0824] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm) 12.09 (s, 1H), 8.59 (d, J=8.4 Hz, 1H), 7.67-7.54 (m, 3H), 7.26-7.17 (m, 5H), 6.74 (d, J=15.9 Hz, 1H), 5.34-5.30 (m, 1H), 4.07-4.01 (m, 4H), 3.38 (s, 3H), 3.37-3.29 (m, 1H), 2.84-2.78 (m, 1H)

Example 72: (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

[0825] ##STR00202##

[0826] Into a 8-mL vial, was placed N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (60.00 mg, 0.276 mmol, 1.00 equiv), 6-bromo-3-chloro-1H-indazole (63.92 mg, 0.276 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2 (20.21 mg, 0.028 mmol, 0.10 equiv), Et.sub.3N (83.83 mg, 0.828 mmol, 3.00 equiv) in DMF (4.00 mL). The resulting solution was stirred for 3 hr at 120 C. The mixture was purified by Prep-HPLC. This resulted in 32 mg of (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=368

[0827] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm) 613.45 (s, 1H), 8.62 (d, J=8.7 Hz, 1H), 7.75-7.67 (m, 3H), 7.46 (d, J=9.6 Hz, 1H), 7.28-7.17 (m, 4H), 6.80 (d, J=15.9 Hz, 1H), 5.35-5.30 (m, 1H), 4.08-4.01 (m, 1H), 3.38 (s, 3H), 3.35-3.27 (m, 1H), 2.84-2.77 (m, 1H)

Example 73: (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

[0828] ##STR00203##

[0829] Step 1: Into a 40-mL vial, was placed 6-bromo-1H-indazole (500.00 mg, 2.54 mmol, 1.00 equiv), Selectfluor (1797.95 mg, 5.075 mmol, 2.00 equiv) in CH.sub.3CN (10.00 mL) and AcOH (1.00 mL). The resulting solution was stirred for 15 hr at 95 C. The mixture was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 110 mg (20% yield) of 6-bromo-3-fluoro-1H-indazole as a light yellow solid.

##STR00204##

[0830] Step 2: Into a 8-mL vial, was placed N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equiv), 6-bromo-3-fluoro-1H-indazole (59.38 mg, 0.276 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2 (20.21 mg, 0.028 mmol, 0.10 equiv), Et.sub.3N (83.83 mg, 0.828 mmol, 3.00 equiv) in DMF (2.00 mL). The resulting solution was stirred for 14 hr at 120 C. The mixture was purified by Prep-HPLC. This resulted in 34 mg of (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as a off-white solid. LC-MS1 (ES, m/z): [M+H].sup.+=352

[0831] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm) 612.72 (s, 1H), 8.62 (d, J=8.7 Hz, 1H), 7.75-7.66 (m, 3H), 7.41 (d, J=8.7 Hz, 1H), 7.27-7.18 (m, 4H), 6.79 (d, J=15.9 Hz, 1H), 5.35-5.30 (m, 1H), 4.08-4.01 (m, 1H), 3.39 (s, 3H), 3.35-3.27 (m, 1H), 2.84-2.78 (m, 1H)

Example 74: (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

[0832] ##STR00205##

[0833] Step 1: Into a 8-mL vial, was placed N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 70.0 mg, 0.322 mmol, 1.00 equiv), 6-bromo-1-(oxan-2-yl) indazole-3-carbonitrile (98.64 mg, 0.322 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2 (23.57 mg, 0.032 mmol, 0.10 equiv), Et.sub.3N (97.81 mg, 0.967 mmol, 3.00 equiv) in DMF (4.00 mL). The resulting solution was stirred for 3 hr at 120 C. The mixture was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/1). This resulted in 60 mg (42% yield) of (E)-3-(3-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as a light yellow solid.

##STR00206##

[0834] Step 2: Into a 8-mL vial, was placed (E)-3-(3-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide (60.00 mg, 0.136 mmol, 1.00 equiv) in 2M HCl(g) in MeOH (2.00 mL) and MeOH (2.00 mL). The resulting solution was stirred for 2 hr at 10 C. The resulting mixture was concentrated. The residue was purified by Prep-HPLC. This resulted in 31 mg of (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H].sup.+=359

[0835] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, ppm) 14.52 (s, 1H), 8.64 (d, J=8.4 Hz, 1H), 7.94-7.91 (m, 2H), 7.73 (d, J=15.9 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.26-7.18 (m, 4H), 6.83 (d, J=15.6 Hz, 1H), 5.34-5.30 (m, 1H), 4.07-4.01 (m, 1H), 3.38 (s, 3H), 3.35-3.27 (m, 1H), 2.84-2.73 (m, 1H).

BIOLOGICAL EXAMPLES

Biological Example 1mPTP Activity Assay in Isolated Rat Liver Mitochondria, Human Platelet Mitochondria and Isolated Rat Brain Mitochondria

[0836] Rat Liver Mitochondria Assay

[0837] Pharmacological inhibition or modulation of the mPTP can be measured in well characterised Ca.sup.2+ retention assays performed in isolated mitochondria. In vitro, isolated mitochondria rapidly sequester exogenous Ca.sup.2+ until the intramitochondrial Ca.sup.2+ concentration reaches the threshold for mPTP activation. Once the pore is activated, mitochondrial integrity is compromised and the stored Ca.sup.2+ is released. The distribution of Ca.sup.2+ between extra- and intra-mitochondrial compartments can be measured in real time with the use of membrane-impermeant Ca.sup.2+ sensitive fluorescent dyes. Depending on the configuration of the assay, inhibition or modulation of the mPTP either delays the opening of the pore or increases the concentration of Ca.sup.2+ required to induce mPTP opening.

[0838] MPTP activity was measured in mitochondria freshly isolated from female Sprague Dawley (250 to 300 gram) rat livers using the following method. Cervical dislocation was performed on the rat. The liver was then perfused in-situ with 40 ml cold Dulbecco's Phosphate Buffered Saline (DPBS) prior to dissection and transferred into 30 ml Isolation Buffer (250 mM Sucrose, 10 mM KCl, 1 mM EGTA, 1 mM EDTA, 25 mM HEPES, adjusted to pH 7.5 with 1M NaOH). Each lobe of the liver was then removed from the buffer, minced using tweezers and a scalpel into 5 mm pieces then transferred into a 50 ml Potterton dounce homogenization tube on ice containing 30 ml ice-cold centrifugation buffer (300 mM Trehalose, 25 mM HEPES, 1 mM EGTA, 1 mM EDTA, 10 mM KCl, adjusted to pH 7.5 with 1M NaOH and supplemented with 0.1% bovine serum albumin (BSA) and complete protease inhibitor cocktail (one tablet of inhibitor per 50 mls of buffer). Homogenisation was carried out using a teflon pestle at 1800 rpm. The slurry was centrifuged at 800 g for 10 min at 4 C., then the supernatant centrifuged at 10,000 g for 10 min. The pellet was washed once with FLIPR assay buffer (75 mM Mannitol, 25 mM Sucrose, 5 mM Potassium Phosphate Monobasic, 20 mM Tris base, 100 mM KCl, 0.1% BSA adjusted to pH 7.4 with 5M HCl) centrifuged again, then resuspended in FLIPR assay buffer to a concentration of 8.8 mg/ml protein.

[0839] Tested compounds (10 mM stock in DMSO) were serially diluted in DMSO in half log steps to generate 10 test concentrations (final concentrations in assay 30 M to 1 nM). An intermediate dilution of 5 l DMSO samples into 247 l FLIPR assay buffer was carried out prior to transfer of 5 l into duplicate wells of a 384 well polypropylene assay plate. Control wells were 0.5% (v/v) DMSO and 5 M cyclosporin A.

[0840] A stock mitochondria/Fluo5N assay solution was prepared in 5.6 ml FLIPR assay buffer (at RT) supplemented with succinate disodium salt (10 mM), rotenone (1 M), Fluo5N pentapotassium salt (2 M) and 1 ml mitochondria suspension, then transferred (15 l) into the assay plate containing test compounds and incubated for 10 min at RT. Assay plates were then transferred to a FLIPR Tetra plate reader (Molecular Devices). Dye fluorescence was then measured every 3 sec for a total of 10 min. After 12 sec, a 2.5 l bolus of CaCl.sub.2 (75 M) was added from a source plate containing 675 M CaCl.sub.2 in FLIPR assay buffer. IC50 values for tested compounds were calculated using the fluorescence value collected at the 10 min timepoint with % inhibition calculated using the DMSO control and cyclosporin A values as 100 and 0% respectively.

[0841] Human Platelet Mitochondria Assay

[0842] The mPTP cell based assay was performed using a mitochondria membrane potential flow cytometry assay in stimulated human platelets. Simulation of platelets results in the rapid influx of Ca.sup.2+ across the platelet membrane. The Ca.sup.2+ is then sequestered by mitochondria until the threshold for mPTP opening is reached, at which point the pore opens and the mitochondrial membrane potential is dissipated. Changes in mitochondria membrane potential due to mPTP opening can be quantified in live platelets using standard mitochondrial membrane potential dyes e.g. 3,3-dihexyloxacarbocyanine Iodide; DiOC6(3), enabling pharmacological characterisation of mPTP inhibitors.

[0843] Fresh human blood (20 ml) was collected from consented donors into 3.2% sodium citrate. Platelets were isolated by centrifugation at 200 g for 20 min at room temperature, then the platelet rich plasma layer transferred to a fresh tube. Prostaglandin 12 is added to the platelets at a final concentration of 20 ng/ml. After centrifugation at 640 g for 10 min, the platelet rich pellet was resuspended in 4 ml HEPES assay buffer (137 mM NaCl, 2.7 mM KCl, 11.9 mM NaHCO.sub.3, 0.42 mM NaH.sub.2PO.sub.4, 1 mM MgCl.sub.2, 5.5 mM glucose, 0.1% bovine serum albumin, 10 mM HEPES adjusted to pH 7.4) and stored on ice.

[0844] Test compounds were prepared from 10 mM stocks in DMSO and serially diluted in assay buffer containing 0.4% DMSO and 25 l transferred into a 96 well plate. Platelets were loaded with the mitochondrial membrane potential dye DiOC6(3) (3,3-dihexyloxacarbocyanine Iodide; Invitrogen) at 200 nM for 30 min, then 50 l plated into each well of the 96 well plate containing diluted test compound and incubated for 15 min. Control wells included DMSO (0.1% final concentration) only or 5 M cyclosporin A. Platelets were then stimulation with the addition of assay buffer (25 l) containing CaCl.sub.2, alpha thrombin and Convulxin to achieve a final concentrations of 2 mM, 0.017 U/ml and 0.167 g/ml respectively and incubated for 14 min. The reaction was stopped by the addition of 25 l 15 mM EDTA in assay buffer. The mitochondrial membrane potential across the population of platelets in each well was then quantified by flow cytometry using a Guava easyCyte 5 Benchtop Flow Cytometer with 3000 events per well. The percentage of platelets with a depolarised mitochondrial membrane potential was calculated for each well. A plC50 for each compound was then calculated using a standard four parameter curve fit model (GraphPad Prism).

[0845] Rat Brain Mitochondria Assay

[0846] MPTP activity was measured in brain mitochondria freshly isolated from female Sprague Dawley (250 to 300 gram) rats. Anaesthetised rats were perfused in-situ with 40 ml cold Dulbecco's Phosphate Buffered Saline (DPBS), then brains dissected and transferred into 30 ml Isolation Buffer (225 mM mannitol, 75 mM sucrose, 1 mM EGTA, adjusted to pH 7.4 with 1M NaOH). The brain was minced using tweezers and a scalpel into 5 mm pieces then transferred into a 50 ml Potterton Dounce homogenization tube on ice containing 10 ml ice-cold isolation buffer (as above with addition of Complete Protease inhibitor; 1 tablet per 50 ml buffer). Homogenisation was carried out using a teflon pestle at 1800 rpm. The slurry was centrifuged at 2000 g for 10 min at 4 C., then the supernatant centrifuged at 12,000 g for 9 min. The pellet was resuspended with a dounce homogeniser in isolation buffer as above but with the addition of 0.02% digitonin, centrifuged at 12,000 g for 11 min and finally resuspended in 5 ml modified isolation buffer (as above but with EGTA reduced to 0.1 mM).

[0847] Test compounds were prepared in 384 well polypropylene assay plates as described above for the liver mitochondria assay. A stock mitochondria/Fluo5N assay solution was prepared in 5.6 ml assay buffer (120 mM mannitol, 40 mM MOPS, 5 mM KH.sub.2PO.sub.4, 60 mM KCl, 10 mM pyruvate, 2 mM malate, 2 mM MgCl.sub.2, 20 M ADP, 1.26 M oligomycin A, adjusted to pH 7.4) supplemented with Fluo5N pentapotassium salt (2 M) and 1 ml mitochondria suspension, then transferred (15 l) into the assay plate containing test compounds and incubated for 10 min at RT. Assay plates were then transferred to a FLIPR Tetra plate reader (Molecular Devices). Dye fluorescence was then measured every 3 sec for a total of 10 min. After 12 sec, a 2.5 l bolus of Ca2+ (75 M) was added from a source plate containing 675 M CaCl.sub.2 in FLIPR assay buffer. IC50 values for test compounds were calculated using the fluorescence value collected at the 10 min timepoint with % inhibition calculated using the DMSO control and cyclosporin A values at 100% and 0% respectively.

[0848] General cytotoxicity was assessed using standard cell viability methods (Cell Titre Glo; Promega) in HEK293 and SHSY5Y cells, following incubation of test compound for between 24 and 96 hours.

[0849] Results: mPTP pIC.sub.50 values for certain Example compounds of the invention in a range of mPTP assays are provided in Table 3 below. Table 3 also provides the pIC.sub.50 values for Comparative Example 1. The results indicate that the tested compounds of the invention display inhibition of mPTP, with many Example compounds displaying pIC.sub.50 values of 6.0 or greater. Examples 37 and 51 showed the highest activity in the rat liver mitochondria assay and Example 51 also showed the highest activity in the rat brain mitochondria assay. Table 3 also presents mPTP human platelet pIC.sub.50 values for certain Example compounds and Comparative Example 1. Table 3 also presents mPTP rat brain mitochondria pIC.sub.50 values for certain Example compounds and Comparative Example 1. These results indicate that the tested Example compounds are active against isolated rat liver mitochondria, isolated rat brain mitochondria and human platelet mitochondria.

Biological Example 2Cytochrome P450 Assays

[0850] Studies to assess tested compound mediated inhibition of cytochrome P450 enzyme isoform CYP2D6 were performed using human liver microsomes (BD Gentest) using either a single concentration (1 M) of test compound or concentration response (0.1, 0.3, 1, 3, 10 and 30 M) to derive an IC50. Tested compound solutions were prepared from 10 mM stocks in DMSO and diluted to 200 M in DMSO. Reactions were prepared in a 96 deep well plate by combining 1 l test compound with 179 l reaction mixture (100 mM phosphate buffered saline (PBS), 0.2 mg/mL microsomes and 2 M Dextromethorphan prepared from stocks as detailed below).

TABLE-US-00002 TABLE 2 Summary of incubation mixtures Buffer Stock Concentration Volume Final Concentration Microsomes 20 mg/mL 2 L 0.2 mg/mL Phosphate buffer 100 mM 176 L 100 mM Substrate 1 L

[0851] The positive control inhibitor, quinidine, was used at a final concentration of 0.5 M when used at a single concentration. The final concentrations of quinidine used to derive an IC50 were 0, 0.1, 0.3, 1, 3, 10 and 30 M. Plates were warmed at 37 C. for 15 min before starting reactions with 20 l 10 mM NADPH solution in PBS and incubated for 20 min at 37 C. The assay is performed in duplicate. Reactions were quenched with 200 l cold acetonitrile containing internal standards (200 nM labetalol, 200 nM alprazolam and 100 nM tolbutamide). The plate was centrifuged at 4000 rpm for 30 minutes, placed on ice for 20 minutes and then centrifuged at 4000 rpm for 30 minutes again to precipitate protein. 100 L of the supernatant was transferred to a new plate and diluted with 100 L pure water before being analysed using UPLC/MS/MS. The products of the transformation for dextromethorphan to dextrophan was monitored by UPLC-MS/MS. The inhibition of CYP2D6 in human liver microsomes was measured as the percentage decrease in the activity of dextrophan formation compared to non-inhibited controls (=100% activity). The IC.sub.50 value was calculated (test compound concentration which produces 50% inhibition) by using Excel XLfit.

[0852] Results: CYP2D6% inhibition values for certain compounds of the invention are presented in Table 3. Table 3 also presents the CYP2D6% inhibition value for Comparative Example 1. The results indicate that the tested compounds displayed a significantly reduced inhibition of CYP2D6 than Comparative Example 1. Negative values indicate that there was no effective inhibition of CYP2D6 at 1 uM concentration of the tested compound. Table 3 also presents CYP2D6 IC.sub.50 values for certain Example compounds and for Comparative Example 1. The results show that Comparative Example 1 is a highly potent inhibitor of CYP2D6, and significantly more potent than the tested Example compounds. This is consistent with the potent CYP2D6% inhibition value displayed for Comparative Example 1. Therefore, the tested compounds of the invention are expected to display improved in vivo properties, such as the reduction of deleterious drug-drug interactions and reduced inhibition in the production of neurotransmitters in the central nervous system, in particular dopamine.

TABLE-US-00003 TABLE 3 Summary of results from Biological Examples 1 and 2 mPTP mPTP mPTP Rat Human Rat CYP2D6% CYP2D6 liver Platelets brain inh @ IC50 Example No. pIC50* pIC50 pIC50 1 uM** uM** Comparative 8.0 6.9 7.6 86.5 0.074 Example 1 1 7.3 2.11 2 6.0 3 6.4 1.87 4 6.5 2.89 5 6.7 2.57 6 6.8 7.0 5.08 19.02 7 6.8 7.2 6.9 2.27 >30 8 5.9 3.13 9 7.4 2.59 10 6.7 7.0 6.5 3.66 >30 11 6.1 0.63 12 6.5 3.05 13 6.0 3.84 14 6.5 0.52 15 6.9 0.28 16 6.8 1.72 17 6.4 1.91 18 6.0 1.20 19 6.2 3.04 20 6.8 1.76 21 6.1 0.91 22 6.6 2.05 23 6.6 0.7 24 6.1 0.77 25 6.9 2.05 13.80 26 7.2 3.49 8.80 27 6.6 14.28 28 6.7 8.27 29 6.9 3.03 30 7.4 7.6 3.33 31 7.7 19.89 32 6.6 4.01 33 6.3 0.55 34 6.7 4.37 35 7.2 2.83 36 7.2 2.57 37 8.1 5.04 38 7.2 7.30 39 7.5 3.83 40 6.6 6.65 41 7.1 1.20 42 6.1 1.97 43 6.3 44 7.1 8.94 45 6.3 46 6.3 47 5.9 1.91 48 5.9 6.34 49 5.8 4.52 50 7.3 1.30 51 7.9 8.3 52 6.9 53 6.7 54 7.6 7.7 55 7.1 56 5.8 57 5.8 58 5.5 59 5.5 60 5.7 61 5.6 62 5.6 63 4.9 64 4.9 65c 7.7 66 7.2 7.3 67 7.2 7.3 68 7.8 7.7 69 7.7 7.6 70 7.5 71 7.0 72 8.2 9.98 73 8.1 7.7 34.57 74 8.0 8.0 *average value from multiple experiments (n 2) **average value from two experiments.

Biological Example 3PBS and FaSSIF Solubility

[0853] Test compounds were prepared as 10 mM stocks in DMSO and 15 l samples transferred in duplicate into 1.5 mL glass flat bottom vials (BioTech Solutions). Fasted state simulated intestinal fluid (FaSSIF) or PBS (pH 7.4) was added to each vial to final volume of 500 l. One PTFE encapsulated stir stick (V&P Scientific) was placed in each vial before sealing with PTFE/SIL plugs (BioTech Solutions). Vials were shaken at 1100 rpm for 2 hr at 25 C. Samples were then filtered through MultiScreen Solvinert filter plates (Millipore) via vacuum filtration. Aliquots of filtrate (5 l) plus 5 l DMSO were diluted in 490 l 50% acetonitrile in water containing internal standard. The filtrate was analysed and quantified against a standard of known concentration using LC-MS/MS. Solubility values of the test compound and control compound were calculated as follows:

[Sample]=(Area ratios.sub.sample*INJ VOL STD*DF.sub.Sample*[STD])/(Area ratio STD*INJ VOL.sub.Sample).

[0854] Results: The solubility values for certain compounds of the invention are provided in Table 4 below. Table 4 also presents results for Comparative Example 1. The results indicate that certain compounds of the invention display higher solubility in PBS and/or FaSSIF than Comparative Example 1. Certain compounds of the invention display solubility in either PBS or FaSSIF, whilst certain compounds display higher solubility values in both PBS and FaSSIF. Therefore, certain compounds of the invention may be expected to display improved bioavailability and/or improved systemic exposure than Comparative Example 1, particularly when said compounds are dosed orally.

Biological Example 4Liver Microsome and Hepatocyte Intrinsic Clearance Assays

[0855] Hepatocyte Clearance Assay

[0856] In vitro clearance studies were performed in primary rat and human hepatocytes (BioIVT). Vials of cryopreserved rat or human hepatocytes were thawed in a 37 C. water bath for 2 min. Cells were transferred into thawing medium (Williams' Medium E containing 30% Percoll, 1GlutaMAX-1, 15 mM HEPES, 5% fetal bovine serum (FBS), 4 g/ml insulin, 1 M dexamethasone), centrifuged at 100 g for 10 min then resuspended in culture medium (Leibovitz's L-15 Medium) at a concentration of 0.510.sup.6 viable cells/mL (number of viable cells assessed using AO/PI staining). Hepatocytes (198 L) were transferred into wells of a 96-well non-coated plate and placed in a 37 C. incubator for 10 min. Test compound solutions were prepared from 10 mM stocks in DMSO, diluted to 100 M in 50% (v/v in water) acetonitrile. Test compound samples (2 l) were added to each well of hepatocytes and incubated at 37 C. Samples (25 l) were collected at t=0, 15, 30, 60, 60 and 120 min, mixed with 6 volumes (150 l) of acetonitrile containing internal standard (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide), vortexed for 5 min and centrifuged for 45 min at 3220 g. An aliquot of supernatant (100 L) was diluted with 100 L ultra-pure water, and the mixture was used for LC/MS/MS analysis. All incubations were performed in duplicate. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. The in vitro half-life (in vitro t) was determined from the slope value: in vitro t=0.693/k. Conversion of the in vitro t (in min) into the in vitro intrinsic clearance (in vitro CL.sub.int, in L/min/110.sup.6 cells) was done using the following equation (mean of duplicate determinations):

in vitro CL.sub.int=kV/N [0857] V=incubation volume (0.2 mL) [0858] N=number of hepatocytes per well (0.110.sup.6 cells).

[0859] Microsomal Clearance Assay

[0860] The microsomal stability of test compounds was evaluated using rat liver microsomes (BioIVT) with and without the cofactors nicotinamide adenine dinucleotide phosphate (NADPH) and uridine-diphosphate-glucuronic acid (UDPGA). Reactions were performed in a final volume of 250 l pre-warmed (37 C.) 100 mM phosphate buffer containing 5 mM MgCl.sub.2, 0.025 mg/ml alamethicin, and 0.5 mg/ml rat liver microsomes. NADPH and UDPGA were included at 1 mM and 2 mM respectively, where appropriate. Reactions were started with the addition of 1 M (final concentration) test compound. Verapamil was used as the positive control. Solutions were incubated in a water bath at 37 C. and aliquots collected at 0.5, 5, 15, 30 and 60 min. Reactions were stopped by the addition of 5 volumes of cold acetonitrile with internal standards (200 nM caffeine and 100 nM tolbutamide). Samples were centrifuged at 3220 g for 40 min. An aliquot of supernatant was diluted 1:1 In ultra-pure H20, then used for LC-MS/MS analysis. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. The in vitro half-life (in vitro t1/2) was determined from the slope value: in vitro t1/2=0.693/k. Conversion of the in vitro t1/2 (min) into the in vitro intrinsic clearance (in vitro CL.sub.int, in L/min/mg protein) was done using the following equation (mean of duplicate determinations):

in vitro Clint=(0.693/t1/2)*(Vol of incubation (l)/amount of protein (mg)).

[0861] Results: Intrinsic clearance values for certain compounds of the invention are presented in Table 4. Table 4 also presents intrinsic clearance values for Comparative Example 1. These results indicate that certain compounds of the invention may be expected to have improved oral bioavailability and/or improved systemic exposure when compared to Comparative Example 1 i.e. they exhibited lower intrinsic clearance (CL.sub.int) values in at least human or rat species. Certain compounds exhibited lower intrinsic clearance (CL.sub.int) values than Comparative Example 1 in both human and rat species.

TABLE-US-00004 TABLE 4 Summary of results from Biological Examples 3 and 4 Rat Human Solubil- Solubil- heps Rat liver heps ity ity Cl.sub.int microsomes Cl.sub.int PBS uM FaSSIF uL/min/ Cl.sub.int uL/min/ Example (pH 7.4) uM 10.sup.6 cells* uL/min/mg* 10.sup.6 cells* Comparative 0.9 4 89 43 13 Example 1 1 22.2 106 3 1.75 4 0.31 5 6.78 66 27 17 6 3.71 18 53.3 17 <3 7 1.4 22.5 27 6.5 7.63 8 33.64 219.97 46 13 9 0.6 10 4.7 74 21.1 13 3.3 13 5.3 14 16 15 0.03 17 0.15 18 1.11 23 19 134.23 9.1 20.04 4.02 20 11.9 6.08 21 25.99 38.04 22 0.4 26.12 9.85 16.2 23 6.13 35.74 9.8 17.4 25 3.69 36.3 52.88 21.8 26 87.55 28 73.64 29 33.48 69.83 16.1 30 5.73 135.43 12.08 18.1 36 65.93 9.41 7.26 37 2.95 47 0.5 36.8 50 23.7 47.81 15.59 51 48.08 11.02 65c 9.2 37.9 9.4 66 36.1 25.4 67 73.3 42.1 68 61.7 34.9 12 69 180.7 73 17.9 70 18.4 70.1 24.6 71 19.94 72 8.9 72 24.4 77 11.3 73 37.5 73.5 7.7 74 1.2 *average value from two experiments.

[0862] Conclusion: The results of Biological Examples 1 and 2 demonstrate that the tested compounds of the invention are inhibitors of mPTP in a range of mPTP assays. The tested compounds of the invention also showed a reduced inhibition of CYP2D6 compared to Comparative Example 1. The results of Biological Examples 3 and 4 demonstrate that certain compounds of the invention show improved solubility and/or lower intrinsic clearance compared to Comparative Example 1 and as such are expected to display improved oral bioavailability and/or improved systemic exposure compared to Comparative Example 1.

[0863] Therefore, the compounds of the invention are believed to be useful pharmaceuticals, particularly for the treatment or prophylaxis of diseases and disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect.

[0864] Throughout the specification and the claims which follow, unless the context requires otherwise, the word comprise, and variations such as comprises and comprising, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

[0865] The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the claims which follow.

[0866] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

REFERENCES

[0867] Yu et al., TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS, Cell, Volume 183, Issue 3, 2020, pages 636-649.e18. Jang et al., Proximal tubule cyclophilin D mediates kidney fibrogenesis in obstructive nephropathy, 2021, American Journal of Physiology: Renal physiology, doi: 10.1152/ajprenal.00171.2021. Epub ahead of print. PMID: 34396791. [0868] Plyte et al., Cinnamic Anilides as New Mitochondrial Permeability Transition Pore Inhibitors Endowed with Ischemia-Reperfusion Injury Protective Effect in Vivo, J. Med Chem. 2014, 57, 5333-47 [0869] Chen et al., Probing Mitochondrial Permeability Transition Pore Activity in Nucleated Cells and Platelets by High-Throughput Screening Assays Suggests Involvement of Protein Phosphatase 2B in Mitochondrial Dynamics, Assay and Drug Development Technologies, 2018, 16, 445-45.