3-AMINO-1,5,6,7-TETRAHYDRO-4H-INDOL-4-ONES
20180155285 · 2018-06-07
Assignee
Inventors
- Keith Graham (Berlin, DE)
- Ulrich Klar (Berlin, DE)
- Hans Briem (Berlin, DE)
- Gerhard Siemeister (Berlin, DE)
- Ursula MÕNNING (Woltersdorf, DE)
- Jozsef Balint (Berlin, DE)
Cpc classification
C07D403/04
CHEMISTRY; METALLURGY
C07C327/46
CHEMISTRY; METALLURGY
A61K31/403
HUMAN NECESSITIES
C07D401/04
CHEMISTRY; METALLURGY
C07D209/40
CHEMISTRY; METALLURGY
C07D491/056
CHEMISTRY; METALLURGY
International classification
C07D209/40
CHEMISTRY; METALLURGY
A61K31/403
HUMAN NECESSITIES
C07D403/04
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
Abstract
Compounds of formula (I) as described hereinprocesses for their production and their use as anti-cancer agents.
##STR00001##
Claims
1. A compound of formula (I), ##STR00408## wherein: R.sup.1 is hydrogen or C.sub.1-C.sub.6-alkyl; R.sup.2 is hydroxy, C.sub.2-C.sub.4-alkenyl, R.sup.7R.sup.8N, R.sup.10OC(O), R.sup.7R.sup.8NC(O), R.sup.6C(O)NR.sup.9, or R.sup.11(C.sub.1-C.sub.4-alkyl)-; wherein said C.sub.2-C.sub.4-alkenyl is optionally substituted with halogen, R.sup.10OC(O), R.sup.7R.sup.8N or phenyl, wherein said phenyl group is optionally substituted, one or more times, independently from each other, with R.sup.4, R.sup.3 is hydrogen or C.sub.1-C.sub.6-alkyl; A is a group selected from: ##STR00409## wherein * indicates the point of attachment of said group with the rest of the molecule and said group is optionally substituted, one or more times, independently from each other, with R.sup.4; R.sup.4 is halogen, hydroxy, nitro, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-haloalkoxy, C.sub.1-C.sub.4-hydroxyalkyl, C.sub.1-C.sub.4-alkyl-C(O), R.sup.10OC(O), R.sup.7R.sup.8NC(O), C.sub.1-C.sub.4-alkyl-C(O)NH, R.sup.7R.sup.8N, or R.sup.7R.sup.8NSO.sub.2; E is a group ##STR00410## wherein * indicates the point of attachment of said group with the rest of the molecule; R.sup.5 is, independently from each other, halogen, hydroxy, nitro, cyano, R.sup.9R.sup.10N, (R.sup.13C(O))(R.sup.14C(O))N, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.6-haloalkoxy, R.sup.6C(O)NR.sup.9 or R.sup.7R.sup.8NC(O)NR.sup.9, wherein said C.sub.1-C.sub.4-alkoxy is optionally substituted, one or more times, independently from each other, with a substituent selected from hydroxy, C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, and 4- to 6-membered heterocycloalkyl; Q is O or NOH; R.sup.6 is, independently from each other, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl, wherein said C.sub.1-C.sub.6-alkyl is optionally substituted, one or more times, independently from each other, with halogen, hydroxy, nitro, cyano, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.6-cycloalkyl, R.sup.7R.sup.8N or phenyl optionally substituted, one or more times, independently from each other, with R.sup.4, wherein said C.sub.3-C.sub.6-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl groups are optionally substituted, one or more times, independently from each other, with halogen, hydroxy, nitro, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, R.sup.10OC(O) or C.sub.1-C.sub.4-haloalkoxy; R.sup.7, R.sup.8 represent are, independently from each other, hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, R.sup.10OC(O) or phenyl, wherein said C.sub.1-C.sub.6-alkyl is optionally substituted, one or more times, independently from each other, with halogen, hydroxy, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.6-cycloalkyl optionally substituted one time with hydroxy, 4- to 6-membered heterocycloalkyl, heteroaryl, or R.sup.9R.sup.10N, wherein said phenyl group is optionally substituted, one or more times, independently from each other, with R.sup.4; or, R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form a 4- to 7-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O, NR.sup.9 and S, and which may be optionally substituted, one or more times, independently from each other, with R.sup.12; whereby when two R.sup.12 substituents are attached to the same ring carbon atom, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form a cyclobutane, azetidine, or oxetane group; said azetidine being optionally substituted one time with C.sub.1-C.sub.3-alkyl, or, R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form a group selected from : ##STR00411## wherein * indicates the point of attachment of said group with the rest of the molecule, R.sup.9 is hydrogen, or C.sub.1-C.sub.6-alkyl; R.sup.10 is hydrogen, C.sub.1-C.sub.6-alkyl or C.sub.3-C.sub.6-cycloalkyl; R.sup.11 is hydroxy, nitro, cyano, C.sub.3-C.sub.6-cycloalkyl, 4- to 6-membered heterocycloalkyl, C.sub.1-C.sub.4-alkyl-C(O), R.sup.10OC(O), R.sup.7R.sup.8NC(O), C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, R.sup.7R.sup.8N, N.sub.3, R.sup.6C(O)NR.sup.9, R.sup.6OC(O)NR.sup.9, R.sup.7R.sup.8NC(O)NR.sup.9, R.sup.6SO.sub.2NR.sup.9, R.sup.6S, R.sup.6SO, R.sup.6SO.sub.2, R.sup.7R.sup.8NSO.sub.2; wherein said C.sub.3-C.sub.6-cycloalkyl or 4- to 6-membered heterocycloalkyl groups are optionally substituted, one or more times, independently from each other, with halogen, hydroxy, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl or C.sub.1-C.sub.4-haloalkoxy, wherein said C.sub.1-C.sub.4-alkoxy is optionally substituted with phenyl, wherein said phenyl group is optionally substituted, one or more times, independently from each other, with R.sup.4, R.sup.12 is halogen, hydroxy, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-haloalkoxy, or R.sup.9R.sup.10N; R.sup.13, R.sup.14 are, independently from each other, C.sub.1-C.sub.4-alkyl, or C.sub.3-C.sub.6-cycloalkyl, wherein said C.sub.3-C.sub.6-cycloalkyl is optionally substituted, one or more times, independently from each other, with halogen; m is 0, 1 or 2; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
2. The compound of formula (I) according to claim 1: wherein: R.sup.1 is hydrogen or C.sub.1-C.sub.4-alkyl; R.sup.2 is hydroxy, C.sub.2-C.sub.4-alkenyl, R.sup.7R.sup.8N, R.sup.10OC(O), R.sup.7R.sup.8NC(O), R.sup.6C(O)NR.sup.9, or R.sup.11(C.sub.1-C.sub.4-alkyl)-; wherein said C.sub.2-C.sub.4-alkenyl is optionally substituted with halogen, R.sup.10OC(O), R.sup.7R.sup.8N or phenyl, wherein said phenyl group is optionally substituted, one or more times, independently from each other, with R.sup.4, R.sup.3 is hydrogen or C.sub.1-C.sub.4-alkyl; A is a group selected from: ##STR00412## wherein * indicates the point of attachment of said group with the rest of the molecule and said group is optionally substituted, one or more times, independently from each other, with R.sup.4; R.sup.4 is halogen, hydroxy, nitro, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, or C.sub.1-C.sub.4-haloalkoxy; E is a group ##STR00413## wherein * indicates the point of attachment of said group with the rest of the molecule; R.sup.5 is, independently from each other, halogen, hydroxy, cyano, R.sup.9R.sup.10N, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-haloalkoxy, R.sup.6C(O)NR.sup.9 or R.sup.7R.sup.8NC(O)NR.sup.9, wherein said C.sub.1-C.sub.4-alkoxy is optionally substituted, one or more times, independently from each other, with a substituent selected from hydroxy, C.sub.1-C.sub.4-alkoxy, and C.sub.3-C.sub.6-cycloalkyl; Q is O or NOH; R.sup.6 is, independently from each other, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl, wherein said C.sub.1-C.sub.6-alkyl is optionally substituted, one or more times, independently from each other, with halogen, hydroxy, cyano, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.6-cycloalkyl, R.sup.7R.sup.8N or phenyl optionally substituted, one or more times, independently from each other, with R.sup.4, wherein said C.sub.3-C.sub.6-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl groups are optionally substituted, one or more times, independently from each other, with halogen, hydroxy, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, R.sup.10OC(O) or C.sub.1-C.sub.4-haloalkoxy; R.sup.7, R.sup.8 represent are, independently from each other, hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, R.sup.10OC(O) or phenyl, wherein said C.sub.1-C.sub.6-alkyl is optionally substituted, one or more times, independently from each other, with halogen, hydroxy, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.6-cycloalkyl optionally substituted one time with hydroxy, 4- to 6-membered heterocycloalkyl, heteroaryl, or R.sup.9R.sup.10N, wherein said phenyl group is optionally substituted, one or more times, independently from each other, with R.sup.4; R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form a 4- to 7-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O, NR.sup.9 and S, and which may be optionally substituted, one or more times, independently from each other, with R.sup.12; R.sup.9 is hydrogen or C.sub.1-C.sub.4-alkyl; R.sup.10 is hydrogen, C.sub.1-C.sub.4-alkyl, or C.sub.3-C.sub.4-cycloalkyl; R.sup.11 is hydroxy, cyano, C.sub.3-C.sub.6-cycloalkyl, 4- to 6-membered heterocycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, R.sup.7R.sup.8N, N.sub.3, R.sup.6 C(O)NR.sup.9, R.sup.6OC(O)NR.sup.9, R.sup.7R.sup.8NC(O)NR.sup.9, R.sup.6SO.sub.2NR.sup.9, R.sup.6S, or R.sup.6SO, R.sup.6SO.sub.2; wherein said C.sub.3-C.sub.6-cycloalkyl or 4- to 6-membered heterocycloalkyl groups are optionally substituted, one or more times, independently from each other, with halogen, hydroxy, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl or C.sub.1-C.sub.4-haloalkoxy, wherein said C.sub.1-C.sub.4-alkoxy is optionally substituted with phenyl, wherein said phenyl group is optionally substituted, one or more times, independently from each other, with R.sup.4, R.sup.12 is halogen, hydroxy, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-haloalkoxy, or R.sup.9R.sup.10N; m is 0, 1 or 2; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
3. The compound of formula (I) according to claim 1, wherein: R.sup.1 is hydrogen or C.sub.1-C.sub.2-alkyl; R.sup.2 is hydroxy, C.sub.2-C.sub.4-alkenyl, R.sup.7R.sup.8N, R.sup.10OC(O), R.sup.7R.sup.8NC(O), R.sup.6C(O)NR.sup.9, or R.sup.11(C.sub.1-C.sub.4-alkyl)-; wherein said C.sub.2-C.sub.4-alkenyl is optionally substituted with R.sup.10OC(O), R.sup.7R.sup.8N or phenyl, wherein said phenyl group is optionally substituted, one or more times, independently from each other, with R.sup.4, R.sup.3 is hydrogen or C.sub.1-C.sub.4-alkyl; A is a group selected from: ##STR00414## wherein * indicates the point of attachment of said group with the rest of the molecule and said group is optionally substituted, one or more times, independently from each other, with R.sup.4; R.sup.4 is halogen; E is a group ##STR00415## wherein * indicates the point of attachment of said group with the rest of the molecule; R.sup.5 is, independently from each other, halogen, R.sup.9R.sup.10N, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, R.sup.6C(O)NR.sup.9 or R.sup.7R.sup.8NC(O)NR.sup.9, wherein said C.sub.1-C.sub.4-alkoxy is optionally substituted, one or more times, independently from each other, with a substituent selected from hydroxy, C.sub.1-C.sub.4-alkoxy, and C.sub.3-C.sub.4-cycloalkyl; Q is O; R.sup.6 is, independently from each other, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl, wherein said C.sub.1-C.sub.6-alkyl is optionally substituted, one or more times, independently from each other, with halogen, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, R.sup.7R.sup.8N or phenyl optionally substituted, one or more times, independently from each other, with R.sup.4, wherein said C.sub.3-C.sub.6-cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl groups are optionally substituted, one or more times, independently from each other, with halogen, hydroxy, C.sub.1-C.sub.4-alkyl, tert-butyl-OC(O), or C.sub.1-C.sub.4-alkoxy; R.sup.7, R.sup.8 are, independently from each other, hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.4-cycloalkyl, tert-butyl-OC(O) or phenyl, wherein said C.sub.1-C.sub.6-alkyl is optionally substituted, one or more times, independently from each other, with halogen, hydroxy, C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl optionally substituted one time with hydroxy, 4- to 6-membered heterocycloalkyl, heteroaryl, or R.sup.9.sub.R.sup.10N, wherein said phenyl group is optionally substituted, one or more times, independently from each other, with R.sup.4; R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR.sup.9, and which may be optionally substituted, one or more times, independently from each other, with R.sup.12; R.sup.9 is hydrogen or C.sub.1-C.sub.2-alkyl; R.sup.10 is hydrogen or C.sub.1-C.sub.4-alkyl; R.sup.11 is hydroxy, 6-membered heterocycloalkyl, C.sub.1-C.sub.2-alkoxy, R.sup.7R.sup.8N, N.sub.3, R.sup.6C(O)NR.sup.9, R.sup.6OC(O)NR.sup.9, R.sup.7R.sup.8NC(O)NR.sup.9, R.sup.6SO.sub.2NR.sup.9, R.sup.6S, R.sup.6SO, R.sup.6SO.sub.2; wherein said 6-membered heterocycloalkyl group is optionally substituted, one or more times, independently from each other, with halogen, hydroxy, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyl or C.sub.1-C.sub.4-haloalkoxy, wherein said C.sub.1-C.sub.4-alkoxy is optionally substituted with phenyl, wherein said phenyl group is optionally substituted, one or more times, independently from each other, with R.sup.4, R.sup.12 is halogen, hydroxy, C.sub.1-C.sub.2-alkyl, R.sup.9R.sup.10N; m is 0, or 1; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
4. The compound of formula (I) according to claim 1, wherein R.sup.1 is hydrogen or methyl; R.sup.2 is hydroxy, C.sub.2-C.sub.4-alkenyl, R.sup.7R.sup.8N, R.sup.10OC(O), R.sup.7R.sup.8NC(O), R.sup.6C(O)NR.sup.9, or R.sup.11(C.sub.1-C.sub.4-alkyl)-; wherein said C.sub.2-C.sub.4-alkenyl is optionally substituted with HOC(O), (CH.sub.3).sub.2N or phenyl, wherein said phenyl group is optionally substituted one, two or three times with F, R.sup.3 is hydrogen, methyl or ethyl; A is a group selected from: ##STR00416## wherein * indicates the point of attachment of said group with the rest of the molecule and said group is optionally substituted, one or two times, independently from each other, with R.sup.4; R.sup.4 is fluoro or chloro; E is a group ##STR00417## wherein * indicates the point of attachment of said group with the rest of the molecule; R.sup.5 is, independently from each other, fluoro, R.sup.9R.sup.10N, C.sub.1-C.sub.2-alkoxy, difluoroethoxy, R.sup.6C(O)NR.sup.9 or R.sup.7R.sup.8NC(O)NR.sup.9, wherein said C.sub.1-C.sub.2-alkoxy is optionally substituted, one or two times, independently from each other, with a substituent selected from hydroxy, methoxy, and cyclopropyl; Q is O; R.sup.6 is, independently from each other, C.sub.1-C.sub.5-alkyl, C.sub.3-C.sub.4-cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, wherein said C.sub.1-C.sub.5-alkyl is optionally substituted, one, two or three times, independently from each other, with fluoro, hydroxy, methoxy, cyclopropyl, or R.sup.7R.sup.8N and optionally substituted one time with phenyl optionally substituted, one, two or three times, independently from each other, with R.sup.4, wherein said C.sub.3-C.sub.4-cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or heteroaryl groups are optionally substituted, one, two or three times, independently from each other, with fluoro, chloro, hydroxy, methyl, tert-butyl-OC(O), methoxy; R.sup.7, R.sup.8 are, independently from each other, hydrogen, C.sub.1-C.sub.5-alkyl, cyclopropyl, cyclobutyl, tert-butyl-OC(O) or phenyl, wherein said C.sub.1-C.sub.5-alkyl is optionally substituted, one or more times, independently from each other, with fluoro, hydroxy, methoxy, C.sub.3-C.sub.4-cycloalkyl optionally substituted one time with hydroxy, 5-membered heterocycloalkyl, 5-membered heteroaryl, or R.sup.9.sub.R.sup.10N, wherein said phenyl group is optionally substituted, one, or two times, independently from each other, with fluoro or chloro; R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O and NR.sup.9, and which may be optionally substituted, one or two times, independently from each other, with R.sup.12; R.sup.9 is hydrogen or methyl; R.sup.10 is hydrogen, methyl or tert-butyl; R.sup.11 is hydroxy, morpholino, methoxy, R.sup.7R.sub.8N, N.sub.3, R.sup.6 C(O)NR.sup.9, R.sup.6OC(O)NR.sup.9, R.sup.7R.sup.8NC(O)NR.sup.9, R.sup.6SO.sub.2NR.sup.9, R.sup.6S, R.sup.6SO, or R.sup.6SO.sub.2; wherein said methoxy group is optionally substituted with phenyl; R.sup.12 is fluoro, hydroxy, methyl, or R.sup.9R.sup.10N; m is 0, or 1; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
5. The compound according to claim 1, which is selected from the group consisting of: (6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, tert-butyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate, (6RS)-6-[(benzyloxy)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, tert-butyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]carbamate, (6RS)-6-amino-3-anilino-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one hydrochloride, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]cyclopropanecarboxamide, (6RS)-4-oxo-N-phenyl-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, methyl (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6RS)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2-hydroxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, methyl (6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, methyl (6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-N-(2-methoxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-ethyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-6-(morpholin-4-ylcarbonyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-3-(phenylamino)-2-(pyridin-4-yl)-6-(pyrrolidin-1-ylcarbonyl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-(azetidin-1-ylcarbonyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-N-(cyclopropylmethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(cyclopropylmethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide (6RS)-N-ethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-tert-butyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-(phenylamino)-6-(piperidin-1-ylcarbonyl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-4-oxo-3-(phenylamino)-N-(propan-2-yl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, methyl (6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-6-(azidomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-[(dimethylamino)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-hydroxymethyl)-1-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-[tert-butyl(dimethyl)silyl]oxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-1-ethyl-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-1-[2-(dimethylamino)ethyl]-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-hydroxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-ethenyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-ethyl-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea, 1-cyclopropyl-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea, 1-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-3-propan-2-ylurea, 1-(furan-2-ylmethyl)-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea, 1-(3-chloro-4-fluorophenyl)-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea, methyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylacetamide, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonamide, (6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, methyl (6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (4E)-5-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoic acid, (4Z)-5-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoic acid, (6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6RS)-6-[(E)-2-(4-fluorophenyl)ethenyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-[(Z)-2-(4-fluorophenyl)ethenyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-(morpholin-4-ylmethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-[methyl(propan-2-yl)amino]methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-[(1E)-3-(dimethylamino)prop-1-en-1-yl]-3 -(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-[(1Z)-3-(dimethylamino)prop-1-en-1-yl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-3-(2RS)-(tetrahydrofuran-2-ylmethyl)urea, (6RS)-N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6R)-N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6R)-N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6S)-N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6S)-N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-[(ethylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, 4-fluoro-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylbenzenesulfonamide, 2-methoxyethyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate, 2-fluoroethyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate, (6RS)-6-[(1,3-benzothiazol-2-ylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcyclopropanecarboxamide, 2-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide, 2-methoxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylacetamide, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcyclobutanecarboxamide, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropane-2-sulfonamide, (6RS)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6R)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6S)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-(3-methoxypyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-(3-fluoropyridin-4-yl)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2-hydroxyethyl)-2-(3-methoxypyridin-4-yl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-[(ethylsulfonyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, 3-methoxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide, (6RS)-2-[2-(acetylamino)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-[2-(acetylamino)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, methyl (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, methyl (6R)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, methyl (6S)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-2-(2-aminopyridin-4-yl)-6-(hydroxymethyl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one, 4-fluoro-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylbenzamide, tert-butyl [(2S)-1-oxo-1-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino)propan-2-yl]carbamate, tert-butyl (2S)-2-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamoyl)pyrrolidine-1-carboxylate, (2S)-2-hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-1,3-thiazole-2-carboxamide, 1-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-1H-pyrrole-2-carboxamide, N-4-[(6RS)-6-(hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyltetrahydro-2H-pyran-4-carboxamide, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylfuran-2-carboxamide, (6RS)-N-(2-hydroxy-2-methylpropyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[(2S)-2-hydroxypropyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(1-hydroxy-2-methylpropan-2-yl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indole-6-carboxamide, (6RS)-N-(2,2-dimethylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-methyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[2-(dimethylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[2-(dimethylamino)ethyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-methyl-N-[2-(methylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2,2-difluoroethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2,2-difluoroethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-tert-butyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[(1-hydroxycyclopropyl)methyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2-hydroxy-2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[(2R)-2-hydroxypropyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6R)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6S)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6RS)-6-[(4-methylpiperazin-1-yl)carbonyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl-3-(phenylamino)-2-(p yridin-4-yl)-1,5,6,7 -tetrahydro-4H-indol-4-one, (6RS)-6-[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-[(3-hydroxyazetidin-1-yl)carbonyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-N,N-diethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]acetamide, 2-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]propanamide, 3-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide, 3-hydroxy-3-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide, 2-cyclopropyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]acetamide, (3S)-3-hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide, 3-hydroxy-2,2-dimethyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]propanamide, (6RS)-N-[(2S)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6R)-N-[(2S)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6S)-N-[(2S)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[(2R)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6R)-N-[(2R)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (3R)-3-hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide, (6S)-N-[(2R)-1-hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[2-(methylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-L-prolinamide, tert-butyl methyl(3-oxo-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1 1H-indol-6-yl]aminopropyl)carbamate, methyl (6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-6-[(1,3-benzothiazol-2-ylsulfonyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-2-[2-([(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, methyl (6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, methyl (6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, 3,3-dimethyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide, (6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, N.sup.3-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]-beta-alaninamide trifluoroacetate, (6RS)-N-[(1-hydroxycyclobutyl)methyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (4E)-5-[(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoic acid, methyl (6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, N-4-[(6RS)-6-(azidomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, (6RS)-N-(2-methoxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2,2-dimethylpropyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, N-4-[(6RS)-6-(aminomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, Methyl (6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6RS)-2-[3(Cyclopropylmethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, Methyl (6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-3-Anilino-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6RS)-2-[3-(2-Methoxyethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2-Hydroxyethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, Methyl (6RS)-3-anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-2-[3-(2-Hydroxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6RS)-2-[3-(2,2-Difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (6RS)-N-Ethyl-N-(2-hydroxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2-Hydroxyethyl)-4-oxo-3-(phenylamino)-N-(propan-2-yl)-2-(pyridin-4-yl)-4,5,6,7 -tetrahydro-1H-indol-6-carboxamide, (6RS)-N-R.sup.1-Hydroxycyclobutyl)methyl) -N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[(2R)-1-Hydroxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[(2S)-1-Hydroxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, N-(4-{(6RS)-3-Anilino-6-methyl-6-[(4-methylpiperazin-1-yl)carbonyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide, (6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, N-{4-[(6RS)-3-Anilino-6-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]carbonyl }-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, N-(4-{(6RS)-3-Anilino-6-[(3-fluoroazetidin-1-yl)carbonyl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide, N-(4-{(6RS)-3-Anilino-6-[(3,3-difluoroazetidin-1-yl)carbonyl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide, (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-methoxyethyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,N-diethyl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, N-4-[(6RS)-6-Methyl-6-azaspiro[3 .3]hept-6-ylcarbonyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-2-methoxypropyl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-1-methoxypropan-2-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-methoxy-2-methylpropyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2,2-dimethylpropyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, N-4-[(6RS)-6-[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, N-4-[(6RS)-6-Methyl-6-[(1R,4R)-5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl]carbonyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, (6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,6-dimethyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, N-4-[(6RS)-6-Methyl-6-[(1R,4R)-2-oxa-5-azabicyclo [2.2.1]hept-5-ylcarbonyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, N-4-[(6RS)-6-[(Ethylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide, N-4-[(6RS)-6-[(tert-Butylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(S)-propan-2-ylsulfinyl]methyl-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N,N-Dimethyl-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, N-{4-[(6RS)-3-Anilino-6-{[(methylsulfonyl)amino]methyl }-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, N-{4-[(6RS)-6-(Acetamidomethyl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, N-{[(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl}-4-methoxybiphenyl-4-carboxamide, 5-[(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pentanoic acid, (6RS)-3-Anilino-N,N-diisopropyl-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-Anilino-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-Anilino-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-Anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-Anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, Methyl (6RS)-3-anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl }amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl }amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl }amino)pyridin-4-yl]N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-4-fluoro-3-methoxybenzamide, N-(4-{(6RS)-3-Anilino-6-[isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-2-fluoro-2-methylpropanamide, 1-(4-{(6RS)-3-Anilino-6-[isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-3-cyclopropylurea, 1-(4-{(6RS)-3-Anilino-6-[isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-3-cyclopropylurea, N-{[(6RS)-3-Anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl}-L-alaninamide, (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl }amino)pyridin-4-yl]N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-Anilino-N,N-diethyl-2-[2-({[(1S ,2S)-2-fluorocyclopropyl]carbonyl }amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]N,6-dimethyl-4-oxo-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-Anilino-2-[2-({[(1S ,2S)-2-fluorocyclopropyl]carbonyl }amino)pyridin-4-yl]N-isobutyl-N,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-Anilino-N-(cyclopropylmethyl)-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-3-Anilino-2-[2-({[(1S ,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (1S ,2S)-N-{4-[(6RS )-3-Anilino-6-methyl-4-oxo-6-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide, (1S ,2S)-N-{4-[(6RS)-3-Anilino-6-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide, (1S ,2S)-N-{4-[(6RS)-3-Anilino-6-methyl-4-oxo-6-(piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide, N-{4-[(6RS)-3-Anilino-6-({[2-(dimethylamino)ethyl]sulfanyl}methyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-4-fluoro-N-methylbenzamide, (6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one, N-4-[(6RS)-6-[(2-Methoxyethyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, N-4-[(6RS)-6-[(1,3-Oxazol-2-ylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(1,3-thiazol-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide, N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(pyridin-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide, N-4-[(6RS)-6-[(4-Fluorobenzyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, (1S,2S)-2-Fluoro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)cyclopropanecarboxamide, N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)-1,3-thiazole-5-carboxamide, 4-Fluoro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide, 4-Chloro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide, 3,4-Dichloro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide N-4-[(6RS)-6-[(Ethylsulfonyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide, 2-Fluoro-2-methyl-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)propanamide, 4-Fluoro-3-methoxy-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide, N-4-[(6RS)-6-[tert-Butylsulfonyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, (6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,N,6-trimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N,N-Diethyl-2-2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(Cyclopropylmethyl)-2-2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, 2-Fluoro-2-methyl-N-4-[(6RS)-6-methyl-4-oxo-3-(phenylamino)-6-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylpropanamide, N-{4-[(6RS)-3-Anilino-6-{[(4-fluorophenyl)sulfanyl]methyl }-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)morpholine-4-carboxamide, N-{4-[(6RS)-3-Anilino-6-{[(3,4-dichlorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamid, N-{4-[(6RS)-3-Anilino-6-{[(4-chlorophenyl)sulfanyl]methyl }-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, N-4-[(6RS)-6-[(4-Fluoro-3-methoxyphenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, N-4-[(6RS)-6-[(3,4-Difluorophenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, N-4-[(6RS)-6-[(4-Methoxyphenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide, Methyl (6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-[(isopropylsulfanyl)methyl]-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one, N-(4-{(6RS)-3-Anilino-4-oxo-6-[(1,3-thiazol-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide, N-{4-[(6RS)-3-Anilino-6-{[(4-fluoro-3-hydroxyphenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, N-{4-[(6RS)-3-Anilino-6-{[(2-methoxyethyl)sulfonyl]methyl }-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, N-{4-[(6RS)-3-Anilino-{[(4-fluorobenzyl)sulfonyl]methyl }-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, (6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, tert-butyl (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-N,N-dimethyl-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[(2S)-2-hydroxypropyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[(2R)-2-hydroxypropyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-[2-(pyrrolidin-1-yl)ethyl]-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-methyl-N-[2-(morpholin-4-yl)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-cyclobutyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-[(2S)-1-methoxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-N-(1-methoxy-2-methylpropan-2-yl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, methyl (6R)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, methyl (6S)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6S)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6R)-2-(3 -fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6S)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7 -tetrahydro-1H-indol-6-carboxamide, (6R)-2-(3-fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide, (6RS)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6R)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6S)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, N-{4-[(6RS)-6-(2-hydroxypropan-2-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, N-{4-[(6RS)-6-(2-hydroxypropan-2-yl)-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7 -tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide, (6RS)-2-(3-fluoropyridin-4-yl)-6-(2-hydroxypropan-2-yl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-3-(phenylamino)-6-(prop-2-en-1-yl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-3-(phenylamino)-6-(prop-2-en-1-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-3-(phenylamino)-6-(prop-2-en-1-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-3-[(3-fluorophenyl)amino]-6-(hydroxymethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-({[2-(dimethylamino)ethyl](methyl)amino}methyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-6-{[4-(dimethylamino)piperidin-1-yl]methyl }-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7 -tetrahydro-4H-indol-4-one, (6RS)-6-[(4-methylpiperazin-1-yl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, 4-fluoro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamide, N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl }-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-1,3-thiazole-5-carboxamide, (1S ,2S)-2-fluoro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl }-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl }cyclopropanecarboxamide, 4-chloro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl }-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamide, 3,4-dichloro-N-{4-[(6RS)-4-oxo-3-(phenylamino)-6-{[(RS)-propan-2-ylsulfinyl]methyl}-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}benzamide, (6RS)-6-(aminomethyl)-3-[(3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-indol-4-one, (6RS)-N-({3-[(3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl}methyl)acetamide, methyl (6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, methyl (6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate, (6RS)-2-(2-aminopyridin-4-yl)-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid, (6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7 -tetrahydro-1H-indol-6-carboxylic, (6S)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7 -tetrahydro-1H-indol-6-carboxylic acid hydrochloride, (6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic, (6R)-2-(2-aminopyridin-4-yl)-3-[(3-fluorophenyl)amino]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid hydrochloride, and (6RS)-3-[(3-fluorophenyl)amino]-6-(hydroxymethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
6. A method of preparing a compound of general formula (I) according to claim 1, said method comprising the step of allowing an intermediate compound of general formula (17): ##STR00418## wherein R.sup.1, R.sup.2, A and E are as defined for the compound of formula (I) in claim 1, with a base and/or oxidizing reagent, preferably an oxidizing agent, such as, for example hydrogen peroxide, thereby giving a compound of general formula (I) : ##STR00419## wherein R.sup.1, R.sup.2, A and B are as defined for the compound of formula (I) in claim 1.
7. A method of preparing a compound of general formula (I) according to claim 1, said method comprising the step of allowing an intermediate compound of general formula (20) : ##STR00420## wherein R.sup.1, R.sup.2, and E are as defined for the compound of formula (I) in claim 1, with an amine of formula A-NH.sub.2 wherein A is as defined for the compound of formula (I) in claim 1, thereby giving a compound of general formula (I): ##STR00421## wherein R.sup.1, R.sup.2, A and E are as defined for the compound of formula (I) in claim 1.
8. A method of treatment or prophylaxis of a disease, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I) according to claim 1, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
9. A method of treatment or prophylaxis of a disease, wherein the disease is a hyperproliferative disease and/or disorder responsive to induction of cell death, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I) according to claim 1, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
10. The method of claim 9, wherein the hyperproliferative disease and/or disorder responsive to induction of cell death is a haematological tumour, solid tumour and/or metastases thereof.
11. The method of claim 10, wherein the tumor is selected from cervical -, breast -, non-small cell lung -, prostate -, colon- and melanoma tumor and/or metastases thereof.
12. A pharmaceutical composition comprising at least one compound according to claim 1, together with at least one pharmaceutically acceptable auxiliary.
13. (canceled)
14. A combination comprising one or more first active ingredients selected from a compound according to claim 1, and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and target-specific anti-cancer agents.
15. A compound selected from: ##STR00422## wherein R.sup.1, R.sup.2, A, and E have the meaning according to claim 1; and ##STR00423## wherein R.sup.1, R.sup.2, E have the meaning according to claim 1.
16. A method of preparing a compound of formula (I) according to claim 1, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer thereof, said method comprising using a compound according to claim 15.
17. A method of treatment or prophylaxis of a disease, wherein the disease is a hyperproliferative disease and/or disorder responsive to induction of cell death, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 12.
18. The method of claim 17, wherein the hyperproliferative disease and/or disorder responsive to induction of cell death is a haematological tumour, solid tumour and/or metastases thereof.
19. The method of claim 18, wherein the tumor is selected from cervical -, breast -, non-small cell lung -, prostate -, colon- and melanoma tumor and/or metastases thereof.
Description
EXAMPLES
Example 1
(6RS)-6-(Hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
1-3: (4RS)-4({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide
[1119] ##STR00051##
[1120] To a solution of (5RS)-5({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-hydroxycyclohex-2-en-1-one (20.0 g, 52.6 mmol; can be prepared according to EP 2617720) and phenylisothiocyanate (6.29 mL, 52.6 mmol) in MeCN (90 mL) was added DBU (13.3 mL, 89.3 mmol) at 3 C. and the mixture was stirred at RT for 16 h. The mixture was concentrated and purified by Biotage (SNAP silica 340 g, EtOAc:Hexane) to give the title compound (20.1 g, 74%).
1-2: (4RS)-4({[tert-Butyl(diphenyl)silyl]oxy}methyl)-6-oxo-N-phenyl-2-[(pyridin-4-ylmethypamino]cyclohex-1-ene-1-carbothioamide
[1121] ##STR00052##
[1122] A solution of (4RS)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide (3-3; 20.1 g, 39.0 mmol) and 4-(methylamino)pyridine (7.92 mL, 77.9 mmol) in DMA (110 mL) was heated at 100 C. for 2 h. The mixture was concentrated and purified by Biotage (SNAP silica 340 g, EtOAc:Hexane) to give the title compound (11.0 g, 67%).
1-1: 3-Anilino-6({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1123] ##STR00053##
[1124] A mixture of (4RS)-4({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide (3-2; 11.0 g, 18.2 mmol), SIBX (45%, 11.3 g, 18.2 mmol) in EtOH (540 mL) was stirred at Rt for 16 h. Et.sub.3N (6 mL) were added, the mixture was concentrated and purified by Biotage (SNAP silica 375 g, EtOH:DCM) to give the title compound (7.70 g, 74%).
(6RS)-6-(Hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1125] ##STR00054##
[1126] A mixture of 3-anilino-6({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (3-1; 10.0 g, 17.5 mmol) and TBAF (22.7 mL, 1M in THF) in THF (250 mL) was stirred at RT for 16 h. EtOAc (1 L) was added, the mixture washed with sodium hydroxide (2.5% in water), brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by Biotage (SNAP silica 340 g, MeOH:DCM) to give the title compound (4.31 g, 74%).
[1127] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.20-2.37 (3H), 2.55 (1H), 2.96 (1H), 3.44 (2H), 4.76 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 8.41 (2H), 11.91 (1H)
Example 2
tert-Butyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate
2-2: tert-Butyl {[(1 RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-en-1-yl]methyl}carbamate
[1128] ##STR00055##
[1129] To a solution of tert-butyl {[(1RS)-3-hydroxy-5-oxocyclohex-3-en-1-yl]methyl}carbamate (1.00 g, 4.14 mmol; commercially available from FCH Group Company) and phenylisothiocyanate (496 L, 4.14 mmol) in MeCN (50 mL) was added DBU (619 L, 4.14 mmol) and the mixture was stirred at RT for 16 h. Ethyl acetate was added, the mixture extracted with hydrochloric acid (1 M), washed with water and brine and dried over sodium sulfate. After filtration the mixture was concentrated and purified by Biotage (SNAP silica 100 g, EtOAc:Hexane) to give the title compound (353 mg, 23%).
2-1: tert-Butyl ({(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-en-1-yl}methyl)carbamate
[1130] ##STR00056##
[1131] A solution of tert-butyl [(6R.sup.5)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate (2-2; 353 mg, 938 mol) and 4-(methylamino)pyridine (228 L, 2.25 mmol) in EtOH (20 mL) and EtOAc (20 mL) was heated at 90 C. for 6 h. The mixture was concentrated and purified by Biotage (SNAP silica 100 g, EtOAc:Hexane) to give the title compound (84 mg, 19%).
tert-Butyl [(6RS-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate
[1132] ##STR00057##
[1133] A mixture of tert-butyl ({(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-en-1-yl}methyl)carbamate (2-1; 80 mg, 171 mol), hydrogen peroxide (34% in water, 31 L, 343 mol) in DMSO (1 mL) was heated at 90 C. for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (20 mg, 27%).
[1134] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.40 (9H), 2.20-2.33 (2H), 2.59-2.65 (2H), 2.92 (1H), 3.04 (2H), 6.57 (2H), 6.83 (1H), 7.04 (3H), 7.42 (1H), 7.46 (2H), 8.41 (2H), 11.91 (1H)
Example 3
(6RS)-6-[(Benzyloxy)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one 3-2: (4RS)-4-[(Benzyloxy)methyl]-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide
[1135] ##STR00058##
[1136] To a solution of (5RS)-5-[(benzyloxy)methyl]-3-hydroxycyclohex-2-en-1-one (350 mg, 1.51 mmol; can be prepared according to Archie der Pharmazie, 1979 , 312 (3), p. 240-247) and phenylisothiocyanate (200 L, 1.67 mmol) in MeCN (1 mL) was added DBU (300 L, 2.01 mmol) and the mixture was stirred at RT for 18 h. Hydrochloric acid (1 M) was added, the mixture extracted with diethyl ether, washed with water and brine and dried over sodium sulfate. After filtration the mixture was concentrated and purified by column chromatography on silica (DCM) to give the title compound (420 mg, 76%).
3-1: (4RS)-4-[(Benzyloxy)methyl]-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide
[1137] ##STR00059##
[1138] A solution of (4RS)-4-[(benzyloxy)methyl]-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide (3-2; 400 mg, 1.09 mmol) and 4-(methylamino)pyridine (130 mg, 1.20 mmol) in EtOH (2 mL) was heated at 100 C. for 3 h. The mixture was concentrated and purified by column chromatography on silica (EtOAc) to give the title compound (340 mg, 68%).
(6RS)-6-[(Benzyloxy)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1139] ##STR00060##
[1140] A mixture of (4RS)-4-[(benzyloxy)methyl]-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide (3-1; 300 mg, 656 mol), hydrogen peroxide (35% in water, 120 L, 1.37 mmol) in EtOH (1 mL) was heated at 80 C. for 10 minutes. The mixture was concentrated and purified by column chromatography on silica (EtOAc:diethyl ether) to give the title compound (66 mg, 21%).
[1141] .sup.1H NMR (400 MHz, CDCI.sub.3) ppm 2.25 (2H), 2.50 (1H), 2.68 (1H), 2.98 (1H), 3.41 (2H), 4.45 (2H), 6.51 (2H), 6.56 (1H), 6.97 (2H), 7.20-7.42 (8H), 8.34 (2H), 11.83 (1H)
Example 4
tert-Butyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]carbamate
4-4: tert-Butyl (3,5-dihydroxyphenyl) carbamate
[1142] ##STR00061##
[1143] To a stirred solution of 5-aminoresorcinol (75 g, 600 mmol; CAS-No 20734-67-2) in THF (1.5 L) was added TEA (102 mL, 720 mmol) at room temperature and then (Boc).sub.2O (130.8 g, 600 mmol) was added slowly drop wise. The reaction mixture was stirred for 16 h at room temperature. After completion of reaction (TLC), the reaction mixture was concentrated under vacuum and then water was added to residue, extracted with ethyl acetate. The combined organic layer was dried over to Na.sub.2SO.sub.4 and concentrated to afford the desired product after silica chromatography (68 g, 51%).
4-3: tert-Butyl [(1RS)-3-hydroxy-5-oxocyclohex-3-en-1-yl]carbamate
[1144] ##STR00062##
[1145] To a compound 3 (50 g) in 0.1M NaOH solution (500 mL) was added 10% Pd/C (15 g) at room temperature using a Parr apparatus. The reaction mass was hydrogenated with H2 (250 psi) at 60 eC for 16 h. After completion of reaction (TLC), the reaction mixture was filtered through celite bed and filtrate was extracted with ethyl acetate. The combined organic layer was dried over to Na.sub.2SO.sub.4 and concentrated to afford crude product. The solid residue was recrystallized in diethyl ether to obtained the desired product (7.0 g, 14%).
4-2: tert-Butyl [(1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-en-1-yl]carbamate
[1146] ##STR00063##
[1147] To a solution of tert-butyl [(1RS)-3-hydroxy-5-oxocyclohex-3-en-1-yl]carbamate (4-3; 5.0 g, 22.0 mmol) and phenylisothiocyanate (2.63 mL, 22.0 mmol) in MeCN (50 mL) was added DBU (7.50 mL, 50.3 mmol) at 3 C. and the mixture was stirred a t RT for 64 h. The mixture was concentrated and purified by Biotage (SNAP silica 340 g, EtOAc:Hexane) to give the title compound (4.02 g, 50%).
4-1: tert-Butyl {(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-en-1-yl}carbamate
[1148] ##STR00064##
[1149] A solution of tert-butyl [(1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-en-1-yl]carbamate (4-2; 1.33 g, 3.67 mmol) and 4-(methylamino)pyridine (731 L, 7.34 mmol) in DMA (10 mL) was heated at 130 C. for 2 h. The mixture wa s concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the title compound (945 mg, 57%).
tert-Butyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]carbamate
[1150] ##STR00065##
[1151] A mixture of tert-butyl {(1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-en-1-yl}carbamate (4-1; 940 mg, 2.08 mmol), hydrogen peroxide (34% in water, 374 L, 4.15 mmol) in MeOH (50 mL) was heated at 80 C. for 6 h. T he mixture was concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the title compound (600 mg, 69%).
[1152] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.41 (9H), 2.39-2.49 (2H), 2.81 (1H), 3.15 (1H), 4.02 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.28 (1H), 7.44 (1H), 7.46 (2H), 8.42 (2H), 11.97 (1H)
Example 5
(6RS)-6-Amino-3-anilino-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one hydrochloride
[1153] ##STR00066##
[1154] A mixture of tert-butyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]carbamate (4; 400 mg, 956 mol) and HCl in dioxane (10 mL, 1M) was stirred at RT for 1 h. The mixture was concentrated to give the title compound (412 mg, crude).
[1155] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.73 (2H), 3.14 (1H), 3.48 (1H), 3.94 (1H), 6.72 (2H), 6.76 (1H), 7.13 (2H), 7.89 (2H), 8.04 (1H), 8.48 (3H), 8.63 (2H), 13.16 (1H)
Example 6
N-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]cyclopropanecarboxamide
[1156] ##STR00067##
[1157] A mixture of 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 83 mg, 212 mol) and cyclopropanecarbonyl chloride (39 L, 424 mol) in pyridine (2 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative HPLC (basic Method) to give the title compound (26 mg, 32%).
[1158] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.61-0.73 (4H), 1.57 (1H), 2.42-2.56 (2H), 2.87 (1H), 3.17 (1H), 4.33 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.45 (1H), 7.47 (2H), 8.42 (2H), 8.45 (1H), 11.97 (1H)
Example 7
(6RS)-4-Oxo-N-phenyl-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide 7-2: (1RS)-3-hydroxy-5-oxo-N-phenyl-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxamide
[1159] ##STR00068##
[1160] To a solution of methyl (1RS)-3-hydroxy-5-oxocyclohex-3-ene-1-carboxylate (630 mg, 3.70 mmol; commercially available from FCH Group Company) and phenylisothiocyanate (443 L, 3.72 mmol) in MeCN (5.7 mL) was added DBU (867 L, 5.81 mmol) at 3 C. and the mixture was stirred at RT for 24 h. The mixture was concentrated and purified by Biotage (SNAP silica 100 g, EtOAc:Hexane) to give the title compound (93 mg, 7%).
[1161] 7-1: (1RS)-5-Oxo-N-phenyl-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxamide
##STR00069##
[1162] A solution of (1RS)-3-hydroxy-5-oxo-N-phenyl-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxamide (7-2; 90 mg, 246 mol) and 4-(methylamino)pyridine (50 L, 491 mol) in DMA (800 L) was heated at 120 C. for 1.5 h. The mixture was concentrated and purified by Biotage (SNAP silica 25 g, MeOH:DCM) to give the title compound (67 mg, 60%). (6RS)-4-Oxo-N-phenyl-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
##STR00070##
[1163] A mixture of (1RS)-5-oxo-N-phenyl-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxamide (7-1; 65 mg, 142 mol), hydrogen peroxide (34% in water, 26 L, 285 mol) in MeOH (5 mL) was heated at 80 C. for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (14 mg, 23%).
[1164] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.52-2.57 (2H), 2.65 (1H), 3.14 (2H), 6.59 (2H), 6.64 (1H), 7.01-7.09 (3H), 7.32 (2H), 7.46 (1H), 7.48 (2H), 7.62 (2H), 8.43 (2H), 10.07 (1H), 12.00 (1H)
Example 8
Methyl (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
8-2: Methyl (1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate
[1165] ##STR00071##
[1166] To a solution of methyl (1RS)-3-hydroxy-5-oxocyclohex-3-ene-1-carboxylate (630 mg, 3.70 mmol; commercially available from FCH Group Company) and phenylisothiocyanate (443 L, 3.72 mmol) in MeCN (5.7 mL) was added DBU (867 L, 5.81 mmol) at 3 C. and the mixture was stirred at RT for 24 h. The mixture was concentrated and purified by Biotage (SNAP silica 100 g, EtOAc:Hexane) to give the title compound (216 mg, 19%).
8-1: Methyl (1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate
[1167] ##STR00072##
[1168] A solution of methyl (1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate (8-2; 3.00 g, 9.83 mmol) and 4-(methylamino)pyridine (2.0 mL, 19.6 mmol) in dioxane (15 mL) was heated at 1200 for 1.5 h. The mixture was concentrated and purified by Biotage (SNAP silica 340 g, MeOH:DCM) to give the title compound (2.71 g, 70%).
Methyl (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1169] ##STR00073##
[1170] A mixture of methyl (1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate (8-1; 2.70 mg, 6.83 mmol), hydrogen peroxide (34% in water, 1.23 mL, 13.7 mmol) in MeOH (50 mL) was heated at 80C for 16 h. The mixture was concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the title compound (1.42 g, 58%).
[1171] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.56-2.62 (2H), 3.09-3.21 (2H), 3.37 (1H), 3.64 (3H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44-7.49 (3H), 8.42 (2H), 12.00 (1H)
Example 9
(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1172] ##STR00074##
[1173] A mixture of methyl (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (8; 2.70 g, 7.47 mmol), potassium hydroxide (29.9 mL, 4M in water), THF (29.7 mL) and MeOH (29.7 mL) was stirred at RT for 10 minutes. Hydrochloric acid (39.8 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (2.52 g, 97%).
[1174] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.60 (2H), 3.17 (2H), 3.27 (1H), 6.63 (2H), 6.69 (1H), 7.08 (2H), 7.63 (2H), 7.77 (1H), 8.50 (2H), 12.39 (1H), 12.65 (1H)
Example 10
(6RS)-N-Methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1175] ##STR00075##
[1176] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol), DMF (2 mL), DIPEA (75 L, 432 mol), N-methanamine (216 L, 2M in THF) and T3P (130 L, 50% in DMF) was stirred at RT for 3 days. The mixture was concentrated, EtOAc was added, washed with sodium hydrogencarbonate, filtered and dried to give the title compound (40 mg, 73%).
[1177] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.38 (1H), 2.55 (1H), 2.61 (3H), 2.95-3.11 (3H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (2H), 7.48 (1H), 7.95 (1H), 8.41 (2H), 11.97 (1H)
Example 11
(6RS)-4-Oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1178] ##STR00076##
[1179] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 47 mg, 134 mol), DMF (2 mL), DIPEA (70 L, 401 mol), propan-1-amine (33 L, 402 mol) and T3P (121 L, 50% in DMF) was stirred at RT for 2 h. The mixture was concentrated, DCM was added, washed with sodium hydrogencarbonate, filtered and dried to give the title compound (34 mg, 61%).
[1180] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.86 (3H), 1.42 (2H), 2.38 (1H), 2.55 (1H), 2.95-3.11 (5H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (2H), 7.47 (1H), 7.98 (1H), 8.42 (2H), 11.97 (1H)
Example 12
(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1181] ##STR00077##
[1182] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol), DMF (2 mL), DIPEA (75 L, 432 mol), ammonia (863 L, 0.5 M in water) and T3P (130 L, 50% in DMF) was stirred at RT for 3 days. The mixture was concentrated, EtOAc was added, washed with sodium hydrogencarbonate, filtered and dried to give the title compound (40 mg, 76%).
[1183] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.41 (1H), 2.54 (1H), 2.98-3.11 (3H), 6.58 (2H), 6.63 (1H), 7.01 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 7.49 (1H), 8.41 (2H), 12.00 (1H)
Example 13
(6RS)-N-(2-Hydroxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1184] ##STR00078##
[1185] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol), DMF (2 mL), DIPEA (75 L, 432 mol), N-methanamine (216 L, 2M in THF) and T3P (65 L, 50% in DMF) was stirred at RT for 2 h. The mixture was concentrated, washed with sodium hydrogencarbonate, filtered and dried to give the title compound (34 mg, 54%).
[1186] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.38 (1H), 2.54 (1H), 2.97-3.19 (5H), 3.41 (2H), 4.75 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 8.07 (1H), 8.41 (2H), 12.07 (1H)
Example 14
Methyl (6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate 14-1: methyl (1RS)-3-{[(3-fluoropyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate
[1187] ##STR00079##
[1188] A solution of methyl (1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate (8-2; 900 mg, 2.95 mmol) and 1-(3-fluoropyridin-4-yl)methanamine (630 L, 5.89 mmol) in DMA (9 mL) was heated at 120 C. for 1.5 h. The mixture was concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the title compound (524 mg, 41%).
Methyl (6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1189] ##STR00080##
[1190] A mixture of methyl (1RS)-3-{[(3-fluoropyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (14-1; 500 mg, 1.21 mmol), hydrogen peroxide (34% in water, 218 L, 2.42 mmol) in MeOH (25 mL) was heated at 80 C. for 2 h. The mixture was concentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the title compound (230 mg, 50%).
[1191] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.61 (2H), 3.15 (2H), 3.39 (1H), 3.65 (3H), 6.55 (2H), 6.60 (1H), 6.99 (2H), 7.40 (1H), 7.55 (1H), 8.25 (1H), 8.51 (1H), 11.73 (1H)
Example 15
Methyl (6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
15-1: methyl (1RS)-3-{[(3-methoxypyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate
[1192] ##STR00081##
[1193] A solution of methyl (1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate (8-2; 900 mg, 2.95 mmol) and 1-(3-methoxypyridin-4-yl)methanamine (814 mg, 5.89 mmol) in DMA (9 mL) was heated at 120 C. for 1. 5 h. The mixture was concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the title compound (754 mg, 57%).
[1194] Methyl (6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
##STR00082##
[1195] A mixture of methyl (1RS)-3-{[(3-methoxypyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (15-1; 720 mg, 1.69 mmol), hydrogen peroxide (34% in water, 305 L, 3.38 mmol) in MeOH (33 mL) was heated at 80 C. for 2 h. The mixture was concentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the title compound (234 mg, 35%).
[1196] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.59 (2H), 3.11 (1H), 3.20 (1H), 3.36 (1H), 3.65 (3H), 3.89 (3H), 6.52 (2H), 6.58 (1H), 6.98 (2H), 7.31 (1H), 7.41 (1H), 8.01 (1H), 8.35 (1H), 11.40 (1H)
Example 16
(6RS)-N-(2-Methoxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1197] ##STR00083##
[1198] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), 2-methoxyethanamine (53 L, 605 mol) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (45 mg, 53%).
[1199] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.37 (1H), 2.54 (1H), 2.97-3.16 (3H), 3.24 (2H), 3.26 (3H), 3.36 (2H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 8.11 (1H), 8.42 (2H), 11.96 (1H)
Example 17
(6RS)-N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1200] ##STR00084##
[1201] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), 2-(methylamino)ethanol (49 L, 605 mol) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (53 mg, 61%).
[1202] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.30-2.38 (1H), 2.46-2.57 (1H), 2.86+3.10 (3H), 2.92-3.07 (2H), 3.28-3.55 (4H), 3.64+3.72 (1H), 4.69+4.86 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.42-7.48 (3H), 8.41 (2H), 11.96 (1H)
Example 18
(6RS)-N-Ethyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1203] ##STR00085##
[1204] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), N-methylethanamine (52 L, 605 mol) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (56 mg, 67%).
[1205] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.02+1.13 (3H), 2.25-2.36 (1H), 2.46-2.59 (1H), 2.83+3.04 (3H), 2.94 (1H), 3.04 (1H), 3.22-3.47 (2H), 3.61 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.42 (2H), 11.95 (1H)
Example 19
(6RS)-6-(Morpholin-4-ylcarbonyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1206] ##STR00086##
[1207] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), morpholine (53 L, 605 mol) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (65 mg, 73%).
[1208] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.33 (1H), 2.54 (1H), 2.96 (1H), 3.05 (1H), 3.48 (2H), 3.58 (6H), 3.66 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.42 (2H), 11.97 (1H)
Example 20
(6RS)-3-(Phenylamino)-2-(pyridin-4-yl)-6-(pyrrolidin-1-ylcarbonyl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1209] ##STR00087##
[1210] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), pyrrolidine (50 L, 605 mol) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (60 mg, 71%).
[1211] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.79 (2H), 1.89 (2H), 2.36 (1H), 2.52 (1H), 2.96 (1H), 3.05 (1H), 3.21-3.32 (2H), 3.44 (1H), 3.52 (2H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.47 (2H), 8.42 (2H), 11.96 (1H)
Example 21
(6RS)-6-(Azetidin-1-ylcarbonyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1212] ##STR00088##
[1213] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), azetidine (41 L, 605 mol) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (44 mg, 54%).
[1214] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.20 (2H), 2.32 (1H), 2.47 (1H), 2.89-3.01 (2H), 3.20 (1H), 3.87 (2H), 4.21 (2H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.42 (1H), 7.47 (2H), 8.42 (2H), 11.97 (1H)
Example 22
(6RS)-N-(Cyclopropylmethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1215] ##STR00089##
[1216] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), 1-cyclopropylmethanamine (52 L, 605 mol) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (57 mg, 67%).
[1217] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.16 (2H), 0.41 (2H), 0.96 (1H), 2.38 (1H), 2.56 (1H), 2.95-3.14 (5H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 8.08 (1H), 8.41 (2H), 11.96 (1H)
Example 23
(6RS)-N-(Cyclopropylmethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1218] ##STR00090##
[1219] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), 1-cyclopropyl-N-methylmethanamine (58 L, 605 mol) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (58 mg, 66%).
[1220] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.21+0.26 (2H), 0.44+0.50 (2H), 0.96 (1H), 2.26-2.37 (1H), 2.45-2.58 (1H), 2.91+3.11 (3H), 2.92-3.08 (2H), 3.21 (1H), 3.31 (1H), 3.65 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.94 (1H)
Example 24
(6RS)-N-Methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-y0-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1221] ##STR00091##
[1222] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), N-methylpropan-1-amine (62 L, 605 mol) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (63 mg, 74%).
[1223] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.81+0.86 (3H), 1.47+1.55 (2H), 2.24-2.36 (1H), 2.47-2.59 (2H), 2.83+3.04 (3H), 2.89-3.08 (2H), 3.19-3.36 (1H), 3.64 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.42 (2H), 11.95 (1H)
Example 25
(6RS)-N,N-Dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1224] ##STR00092##
[1225] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), N-methylmethanamine (302 L, 2M in THF) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (53 mg, 67%).
[1226] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.33 (1H), 2.46 (1H), 2.85 (3H), 2.95 (1H), 3.03 (1H), 3.07 (3H), 3.66 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.96 (1H)
Example 26
(6RS)-N-Ethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1227] ##STR00093##
[1228] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 70 mg, 202 mol), DMF (2 mL), DIPEA (105 L, 605 mol), ethanamine (302 L, 2M in THF) and T3P (181 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (25 mg, 32%).
[1229] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.03 (3H), 2.38 (1H), 2.55 (1H), 2.95-3.15 (5H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.47 (2H), 7.99 (1H), 8.41 (2H), 11.96 (1H)
Example 27
(6RS)-N-tert-Butyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1230] ##STR00094##
[1231] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol), DMF (2 mL), DIPEA (75 L, 432 mol), 2-methylpropan-2-amine (45 L, 432 mol) and T3P (65 L, 50% in DMF) was stirred at RT for 3 days. The mixture was concentrated, sodium hydrogencarbonate was added, the precipitate filtered and purified by preparative HPLC (basic method) to give the title compound (5 mg, 8%).
[1232] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.27 (9H), 2.33 (1H), 2.50 (1H), 2.89-3.10 (3H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 7.59 (1H), 8.41 (2H), 11.95 (1H)
Example 28
(6RS)-3-(Phenylamino)-6-(piperidin-1-ylcarbonyl)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1233] ##STR00095##
[1234] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol), DMF (2 mL), DIPEA (75 L, 432 mol), piperidine (43 L, 432 mmol) and T3P (130 L, 50% in DMF) was stirred at RT for 3 days. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (16 mg, 25%).
[1235] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.44 (2H), 1.52 (2H), 1.60 (2H), 2.29 (1H), 2.54 (1H), 2.94 (1H), 3.04 (1H), 3.46 (2H), 3.49 (2H), 3.66 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.95 (1H)
Example 29
(6RS)-4-Oxo-3-(phenylamino)-N-(propan-2O2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1236] ##STR00096##
[1237] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol), DMF (2 mL), DIPEA (75 L, 432 mol), propan-2-amine (37 L, 432 mol) and T3P (65 L, 50% in DMF) was stirred at RT for 3 days. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (18 mg, 32%).
[1238] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.06 (6H), 2.36 (1H), 2.54 (1H), 2.92-3.07 (3H), 3.84 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.85 (1H), 8.42 (2H), 11.95 (1H)
Example 30
(6RS)-6-(Hydroxymethyl)-6-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
30-3: (4RS)-4({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethypamino]cyclohex-1-ene-1-carbothioamide
[1239] ##STR00097##
[1240] To a solution of (5RS)-5({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-hydroxy-5-methylcyclohex-2-en-1-one (5.00 g, 12.7 mmol; can be prepared according to Synthesis, 2014, 46 (3), 381-386) and phenylisothiocyanate (1.52 mL, 12.7 mmol) in MeCN (25 mL) was added DBU (1.89 mL, 12.7 mmol) at 3 C. and the mixture was stirred at RT for 2.5 days. The mixture was poured into water, extracted with EtOAc, washed with brine and dried over sodium sulfate. After filtration the mixture was concentrated and purified by Biotage (SNAP silica 100 g, EtOAc:Hexane) to give the title compound (5.18 g, 77%).
30-2: (4RS)-4({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide
[1241] ##STR00098##
[1242] A solution of (4RS)-4({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide (30-3; 3.33 g, 6.29 mmol) and 4-(methylamino)pyridine (894 L, 8.80 mmol) in DMA (16.7 mL) was heated at 80 C. for 2 h. The mixture was concentrated and purified by Biotage (SNAP silica 100 g, EtOAc:Hexane) to give the title compound (1.78 g, 43%).
30-1: (6RS)-3-Anilino-6({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methyl-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1243] ##STR00099##
[1244] A mixture of (4RS)-4({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide (30-2; 1.41 g, 2.28 mmol), SIBX (45%, 1.70 g, 2.73 mmol) in MeOH (32 mL) and DCM (85 mL) was stirred at RT for 1 h. The mixture was poured into saturated sodium hydrogencarbonate, extracted with DCM and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 100 g, EtOAc:DCM) to give the title compound (662 mg, 50%).
(6RS)-6-(Hydroxymethyl)-6-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1245] ##STR00100##
[1246] A mixture of (6RS)-3-anilino-6({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methyl-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (30-1; 3.1 g, 5.29 mmol) and TBAF (7.94 mL, 1M in THF) in THF (75 mL) was stirred at 60 C. for 16 h. EtOAc (1 L) was added, the mixture washed with sodium hydroxide (2.5% in water), brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the title compound (800 mg, 41%).
[1247] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.98 (3H), 2.08 (1H), 2.38 (1H), 2.59 (1H), 2.97 (1H), 3.27 (2H), 4.89 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 8.41 (2H), 11.87 (1H)
Example 31
methyl (6RS)-2-(2-Aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate 31-1: methyl (1RS)-3-{[(2-aminopyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate
[1248] ##STR00101##
[1249] A solution of methyl (1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethypamino]cyclohex-3-ene-1-carboxylate (8-2; 6.00 g, 19.6 mmol) and 4-(aminomethyl)pyridin-2-amine (4.84 g, 39.3 mmol) in DMA (30 mL) was heated at 130 C. for 1.5 h. The mixture was concentrated and purified by Biotage (SNAP silica 340 g, MeOH:DCM) to give the title compound (4,12 g, 51%).
Methyl (6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1250] ##STR00102##
[1251] A mixture of methyl (1RS)-3-{[(2-aminopyridin-4-yl)methyl]amino}-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (31-1; 4.11 g, 10.0 mmol), hydrogen peroxide (34% in water, 1.81 mL, 20.0 mmol) in MeOH (103 mL) was heated at 90 C. for 2 h. The mixture was concentrated and purified by Biotage (SNAP silica 110 g, MeOH:DCM) to give the title compound (2.40 g, 64%).
[1252] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.52-2.62 (2H), 3.07 (1H), 3.14 (1H), 3.33 (1H), 3.34 (3H), 5.76 (2H), 6.55 (2H), 6.57 (1H), 6.60 (1H), 6.68 (1H), 7.02 (2H), 7.24 (1H), 7.77 (1H), 11.79 (1H)
Example 32
(6RS)-6-(Azidomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one 32-1: [(6RS)-3-Anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate
[1253] ##STR00103##
[1254] A mixture of (6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (1; 2.00 g, 6.00 mmol), methanesulfonyl chloride (557 L, 7.20 mmol) in pyridine (32 mL) was stirred at RT for 4 h. MeOH was added, the mixture concentrated and purified by Biotage (SNAP silica 110 g, MeOH:DCM) to give the title compound (2.16 g, 88%).
(6RS)-6-(Azidomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1255] ##STR00104##
[1256] A mixture of [(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (32-1; 1.00 g, 2.43 mmol), sodium azide (1.58 g, 24.3 mmol) in DMA (40 mL) was stirred at 80 C. for 2 days. After filtration, the mixture was concentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the title compound (865 mg, 99%).
[1257] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.26-2.40 (2H), 2.45-2.55 (1H), 2.71 (1H), 3.02 (1H), 3.51 (2H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 8.42 (2H), 11.96 (1H)
Example 33
(6RS)-6-[(Dimethylamino)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1258] ##STR00105##
[1259] A mixture of [(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (32-1; 50 mg, 122 mol), N-methylmethanamine (243 L, 2M in THF) in DMA (1 mL) was stirred at 60C for 1 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (11 mg, 25%).
[1260] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.15 (6H), 2.17-2.24 (2H), 2.27-2.47 (3H), 2.58 (1H), 3.01 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.91 (1H)
Example 34
(6RS)-6-(Hydroxymethyl)-1-methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1261] ##STR00106##
[1262] A mixture of (6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (1; 50 mg, 150 mol), DIAD (47 L, 240 mol), triphenylphosphine (63 mg, 240 mol), MeOH (30 L, 750 mol) in THF (3 mL) was stirred at RT for 2.5 days. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (18 mg, 32%).
[1263] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.23-2.37 (3H), 2.64 (1H), 3.02 (1H), 3.47 (2H), 3.57 (3H), 4.79 (1H), 6.47 (2H), 6.52 (1H), 6.94 (2H), 7.22 (1H), 7.35 (2H), 8.50 (2H)
Example 35
(6RS)-6-[tert-Butyl(dimethyl)silyl]oxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
35-4: (5RS)-5-hydroxycyclohex-2-en-1-one
[1264] ##STR00107##
[1265] A solution of benzene-1,3,5-triol (100 g, 792.96 mmol) and NaOH (31.72 g, 792.96 mmol) in H2O (1.5 L) was added Rh-Al (10%, 2 g). The mixture was stirred for 14 hours at 30 C. under H 2 (60 psi). TLC (DCM: MeOH =15:1) indicated the starting material was consumed completely. The solid was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography eluted with DCM: MeOH =10:1 to give crude 5-hydroxycyclohexane-1,3-dione (120 g) as a yellow solid.
[1266] 1H NMR (400 MHz, CDCl3): ppm 4.18-4.15. (m, 1H), 3.35 (s, 3 H), 2.58-2.52 (m, 2H), 2.35-2.29 (m, 2H).
35-3: (5RS)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxycyclohex-2-en-1-one
[1267] ##STR00108##
[1268] To a solution of crude 5-hydroxycyclohexane-1,3-dione (35-4; 130 g) in DMF (800 mL) was added NaH (80.8 g, 2.02 mol) in one portion at 5 C. unde r N2. The mixture was stirred at 5 C. for 10 min. Then TBSCI (229.39 g, 1.52 mol) in DMF (200 mL) was added at -5 C. The mixture was stirred for another 14 hr at 15 C. TLC indicated the reaction completed. The mixture was cooled to 1 C. and quenched by water at 0 C. The aqueous pha se was extracted with EA (1 L). The aqueous phase was adjusted to pH 56 with aq. HCl (1M). The solid was filtered to give 5-[tert-butyl(dimethyl) silyl]oxycyclohexane-1,3-dione (40 g) as a white solid.
[1269] 1H NMR (400 MHz, CDCI3): ppm 4.52-4.50. (m, 1H), 3.49-3.32 (m, 2H), 2.81-2.66 (m, 4 H), 0.83 (s, 6 H), 0.07 (s, 6 H).
35-2: (4RS)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide
[1270] ##STR00109##
[1271] To a solution of (5RS)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxycyclohex-2-en-1-one (35-3; 1.00 g, 4.13 mmol) and phenylisothiocyanate (494 L, 4.13 mmol) in MeCN (10 mL) was added DBU (1.40 mL, 9.38 mmol) at 3 C. and the mixture was stirred a t RT for 1 h. The mixture was poured into ice cold water, acidified with hydrochloric acid, extracted with EtOAc, washed with brine and dried over sodium sulfate. After filtration the mixture was concentrated and purified by Biotage (SNAP silica 100 g, EtOAc:Hexane) to give the title compound (386 mg, 25%).
35-1: (4RS)-4-{[tert-Butyl(dimethyl)silyl]oxy}-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide
[1272] ##STR00110##
[1273] A solution of (4RS)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide (35-2; 235 mg, 622 mol) and 4-(methylamino)pyridine (124 L, 1.24 mmol) in EtOH (5 mL) and EtOAc (5 mL) was heated at 90 C. for 6 h. The mixture was concentrated and purified by Biotage (SNAP silica 25 g, EtOAc:Hexane) to give the title compound (113 mg, 39%).
(6RS)-6-[tert-Butyl(dimethypsily]oxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1274] ##STR00111##
[1275] A mixture of (4RS)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide (35-1; 106 mg, 226 mol), hydrogen peroxide (34% in water, 41 L, 453 mol) in EtOH (5 mL) was heated at 90 C. for 2 h. The mixture was concentrated and purified by Biotage (SNAP silica 25 g, MeOH:DCM) to give the title compound (70 mg, 71%).
[1276] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.08 (3H), 0.09 (3H), 0.84 (9H), 2.42 (1H), 2.55 (1H), 2.86 (1H), 3.17 (1H), 4.48 (1H), 6.57 (2H), 6.62 (1H), 7.03 (2H), 7.44 (1H), 7.47 (2H), 8.42 (2H), 11.94 (1H)
Example 36
(6RS)-6-(Aminomethyl)-3-(phenylamino)-2-(pyridin-4-y0-1,5,6,7-tetrahydro-4H-indol-4-one
[1277] ##STR00112##
[1278] A mixture of (6RS)-6-(azidomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (32; 801 mg, 2.24 mmol), triphenylphosphine (1.31 g, 4.98 mmol) ammonia (4.78 mL, 25% in water) in THF (35 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by Biotage (SNAP silica 28 g, MeOH:DCM) to give the title compound (722 mg, 96%).
[1279] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.13-2.27 (2H), 2.37 (1H), 2.59-2.69 (3H), 2.97 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 8.40 (2H), 11.90 (1H)
Example 37
(6RS)-1-Ethyl-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1280] ##STR00113##
[1281] A mixture of (6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (1; 50 mg, 150 mol), DIAD (47 L, 240 mol), triphenylphosphine (63 mg, 240 mol), EtOH (1 mL) in THF (3 mL) was stirred at 80 C. for 2.5 days. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (6 mg, 10%).
[1282] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.15 (3H), 2.21-2.37 (3H), 2.68 (1H), 3.04 (1H), 3.48 (2H), 4.00 (2H), 4.79 (1H), 6.45 (2H), 6.51 (1H), 6.93 (2H), 7.16 (1H), 7.32 (2H), 8.52 (2H)
Example 39
(6RS)-6-Hydroxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1283] ##STR00114##
[1284] A mixture of (6RS)-6-[tert-butyl(dimethyl)silyl]oxy-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (35; 64 mg, 148 mol) and TBAF (295 L, 1M in THF) in THF (10 mL) was stirred at RT for 4 h. The mixture was poured into saturated sodium hydrogencarbonate, extracted with EtOAc, washed with brine and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 10 g, MeOH:DCM) to give the title compound (48 mg, max 100%).
[1285] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.39 (1H), 2.55 (1H), 2.83 (1H), 3.13 (1H), 4.29 (1H), 5.20 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.92 (1H)
Example 40
(6RS)-6-Ethenyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
40-1: (6RS)-3-Anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carbaldehyde
[1286] ##STR00115##
[1287] A solution of ethanedioyl dichloride (196 L, 2.25 mmol) in DCM (6 mL) was cooled to 78 C. DMSO (319 L, 4.50 mmol) was added slowly followed by a solution of (6RS)-6-(hydroxymethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (1; 300 mg, 900 mol) in DCM (6 mL) and DMSO (1.2 mL). The mixture was stirred at 78 C. for 1 h, Et.sub.3N (1.0 mL) was added and the mixture warmed to RT. Water was added, the mixture extracted with DCM/MeOH and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 25 g, MeOH:DCM) to give the title compound (158 mg, 53%).
(6RS)-6-Ethenyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1288] ##STR00116##
[1289] To a solution of methyl(triphenyl)phosphonium bromide (270 mg, 754 mol) in THF (5 mL) was added KO.sup.tBu (85 mg, 754 mol) at 0 C. and the mixture stirred at 0 C. to RT for 0.5 h. A solution of (6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carbaldehyde (40-1; 50 mg, 151 mol) in THF (2 mL) was added at 0 C. and the mixture stirred for 2 h. Water and EtOAc were added, the mixture washed with saturated ammonium chloride solution and dried over sodium sulfate. After filtration and concentration the residue was purified by preparative TLC (MeOH:DCM) to give the title compound (29 mg, 55%).
[1290] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.38 (2H), 2.79 (1H), 2.92-3.05 (2H), 5.07 (1H), 5.14 (1H), 5.95 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.47 (2H), 8.42 (2H), 11.96 (1H)
Example 41
1-Ethyl-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea
[1291] ##STR00117##
[1292] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), isocyanatoethane (14 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (23 mg, 59%).
[1293] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.00 (3H), 2.16-2.35 (3H), 2.60 (1H), 2.93 (1H), 2.99-3.08 (3H), 3.13 (1H), 5.81 (1H), 6.04 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.92 (1H)
Example 42
1-Cyclopropyl-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea
[1294] ##STR00118##
[1295] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), isocyanatocyclopropane (15 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (22 mg, 55%).
[1296] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.35 (2H), 0.58 (2H), 2.17-2.35 (3H), 2.41(1H), 2.60 (1H), 2.93 (1H), 3.04-3.19 (2H), 6.11 (1H), 6.17 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.93 (1H)
Example 43
1-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-3-propan-2-ylurea
[1297] ##STR00119##
[1298] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), 2-isocyanatopropane (18 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (17 mg, 42%).
[1299] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.03 (3H), 1.04 (3H), 2.16-2.35 (3H), 2.59 (1H), 2.92 (1H), 3.02-3.18 (2H), 3.67 (1H), 5.68 (1H), 5.93 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.93 (1H)
Example 44
1-(Furan-2-ylmethyl)-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea
[1300] ##STR00120##
[1301] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), 2-(isocyanatomethyl)furan (19 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (20 mg, 46%).
[1302] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.17-2.35 (3H), 2.60 (1H), 2.93 (1H), 3.05-3.20 (2H), 4.21 (2H), 6.18 (1H), 6.20 (1H), 6.30 (1H), 6.38 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 7.57 (1H), 8.41 (2H), 11.94 (1H)
Example 45
1-(3-Chloro-4-fluoropheny0-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylurea
[1303] ##STR00121##
[1304] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), 2-chloro-1-fluoro-4-isocyanatobenzene (22 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (23 mg, 48%).
[1305] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.22-2.41 (3H), 2.66 (1H), 2.97 (1H), 3.13-3.32(2H), 6.55 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.24 (1H), 7.27 (1H), 7.44 (1H), 7.46 (2H), 7.79 (1H), 8.41 (2H), 8.81 (1H), 11.93 (1H)
Example 46
Methyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate
[1306] ##STR00122##
[1307] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), methyl carbonochloridate (14 L, 181 mol) in pyridine (1 mL) was stirred at RT for 2 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (20 mg, 54%).
[1308] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.18-2.38 (3H), 2.62 (1H), 2.94 (1H), 3.10 (2H), 3.55 (3H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.34 (1H), 7.43 (1H), 7.46 (2H), 8.40 (2H), 11.94 (1H)
Example 47
N-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylacetamide
[1309] ##STR00123##
[1310] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), acetyl chloride (13 L, 181 mol) in pyridine (1 mL) was stirred at RT for 2 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (8 mg, 23%).
[1311] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.85 (3H), 2.22 (1H), 2.28-2.37 (2H), 2.61 (1H), 2.93 (1H), 3.11 (1H), 3.19 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.47 (2H), 8.00 (1H), 8.40 (2H), 11.98 (1H)
Example 48
N-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylmethanesulfonamide
[1312] ##STR00124##
[1313] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), methanesulfonyl chloride (14 L, 181 mol) in pyridine (1 mL) was stirred at RT for 2 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (13 mg, 3%).
[1314] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.26 (1H), 2.32-2.41 (2H), 2.67 (1H), 2.93 (3H), 2.99-3.08 (3H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.22 (1H), 7.44 (1H), 7.47 (2H), 8.41 (2H), 11.97 (1H)
Example 49
(6RS)-2-(3-Methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1315] ##STR00125##
[1316] A mixture of methyl (6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (15; 291 mg, 743 mol), potassium hydroxide (2.97 mL, 4M in water), THF (6 mL) and MeOH (6 mL) was stirred at RT for 15 minutes. Hydrochloric acid (4 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (215 mg, 77%).
[1317] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.55 (1H), 3.06-3.22 (4H), 3.89 (3H), 6.52 (2H), 6.58 (1H), 6.98 (2H), 7.30 (1H), 7.42 (1H), 8.01 (1H), 8.34 (1H), 11.38 (1H), 12.61 (1H)
Example 50
Methyl (6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1318] ##STR00126##
[1319] A mixture of methyl (6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (31; 177 mg, 470 mol), acetyl chloride (67 L, 940 mol) in pyridine (5 mL) and THF (0.5 mL) was stirred at RT for 1 h. MeOH was added, the mixture concentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the title compound (161 mg, 82%).
[1320] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.58 (2H), 3.11 (1H), 3.18 (1H), 3.34 (1H), 3.64 (3H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.37 (1H), 8.09 (1H), 8.23 (1H), 10.36 (1H), 12.01 (1H)
Example 51
(4E/Z)-5-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoic acid
[1321] ##STR00127##
[1322] To a solution of (3-carboxypropyl)(triphenyl)phosphonium bromide (324 mg, 754 mol) in THF (5 mL) was added KO.sup.tBu (169 mg, 1.51 mmol) at 0 C. and the mixture stirred at 0 C. to RT for 0.5 h. A solution of (6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carbaldehyde (40-1; 50 mg, 151 mol) in THF (2 mL) was added at 0 C. and the mixture stirred for 2 h. Water and EtOAc were added, the mixture washed with brine and dried over sodium sulfate. After filtration and concentration the residue was purified by preparative TLC (MeOH:DCM) to give the title compound (27 mg, 42%).
[1323] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.15-2.37 (6H), 2.71 (1H), 2.93 (1H), 3.26 (1H), 5.40 (2H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.49 (2H), 8.40 (2H), 12.17 (1H)
Example 52
(6RS)-2-(3-Fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1324] ##STR00128##
[1325] A mixture of methyl (6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (14; 222 mg, 585 mol), potassium hydroxide (2.34 mL, 4M in water), THF (5 mL) and MeOH (5 mL) was stirred at RT for 15 minutes. Hydrochloric acid (3.1 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (185 mg, 85%).
[1326] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.42-2.62 (3H), 3.10 (2H), 6.55 (2H), 6.60 (1H), 6.99 (2H), 7.39 (1H), 7.56 (1H), 8.24 (1H), 8.50 (1H), 11.67 (1H)
Example 53
(6RS)-6-[(E/Z)-2-(4-Fluorophenyl)ethenyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1327] ##STR00129##
[1328] To a solution of (4-fluorobenzyl)(triphenyl)phosphonium bromide (340 mg, 754 mol) in THF (5 mL) was added KO.sup.tBu (85 mg, 754 mol) at 0 C. and the mixture stirred at 0 C. to RT for 0.5 h. A solution of (6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carbaldehyde (40-1; 50 mg, 151 mol) in THF (2 mL) was added at 0 C. and the mixture stirred for 2 h. Water and EtOAc were added, the mixture washed with brine and dried over sodium sulfate. After filtration and concentration the residue was purified by preparative TLC (MeOH:DCM) to give the title compound (34 mg, 50%).
[1329] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.30-2.53 (2H), 2.83-2.93 (1H), 2.96-3.48 (2H), 5.73+6.37 (1H), 6.47-6.65 (4H), 7.04 (2H), 7.14-7.22 (2H), 7.35 (1H), 7.43-7.50 (4H), 8.39-8.44 (2H), 11.99 (1H)
Example 54
(6RS)-6-(Morpholin-4-ylmethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1330] ##STR00130##
[1331] A mixture of [(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (32-1; 50 mg, 122 mol), morpholine (53 L, 608 mol) in DMA (1.5 mL) was stirred at 100 C. for 2 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (15 mg, 30%).
[1332] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.20 (1H), 2.26-2.45 (7H), 2.47-2.56 (1H), 2.60 (1H), 3.05 (1H), 3.59 (4H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.91 (1H)
Example 55
(6RS)-6-[Methyl(propan-2-yl)amino]methyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1333] ##STR00131##
[1334] A mixture of [(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (32-1; 50 mg, 122 mol), N-methylpropan-2-amine (101 L, 972 mol) in DMA (1.5 mL) was stirred at 100 C. for 4 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (15 mg, 29%).
[1335] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.93 (6H), 2.15 (3H), 2.17 (1H), 2.27-2.41 (4H), 2.59 (1H), 2.75 (1H), 3.02 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.40 (2H), 11.89 (1H)
Example 56
(6RS)-6-[(1E/Z)-3-(Dimethylamino)prop-1-en-1-yl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1336] ##STR00132##
[1337] To a solution of [2-(dimethylamino)ethyl](triphenyl)phosphonium bromide (688 mg, 1.66 mmol) in THF (11 mL) was added KO.sup.tBu (186 mg, 1.66 mmol) at 0 C. and the mixture stirred at 0 C. to RT for 0.5 h. A solution of (6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carbaldehyde (40-1; 110 mg, 332 mol) in THF (5 mL) was added at 0 C. and the mixture stirred for 2 h. Water was added, the mixture extracted with EtOAc, washed with brine and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 28 g, MeOH:DCM) to give the title compound (49 mg, 38%).
[1338] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.13 (6H), 2.22 (1H), 2.37 (1H), 2.75 (1H), 2.85-2.95 (3H), 3.28 (1H), 5.47 (1H), 5.57 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.47 (2H), 8.41 (2H), 11.94 (1H)
Example 57
1-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-3-(2RS)-(tetrahydrofuran-2-ylmethyl)urea
[1339] ##STR00133##
[1340] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), (2R.sup.5)-2-(isocyanatomethyl)tetrahydrofuran (21 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (28 mg, 61%).
[1341] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.48 (1H), 1.74-1.90 (3H), 2.16-2.33 (3H), 2.59 (1H), 2.92 (1H), 2.96-3.19 (4H), 3.61 (1H), 3.72-3.83 (2H), 5.91 (1H), 6.15 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.93 (1H)
Example 58
N-Methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide Isomer 1
[1342] ##STR00134##
[1343] (6RS)-N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetra hydro-1H-indol-6-carboxamide (24; 20.5 mg, 51 mol) were separated by preparative HPLC (chiral method) to give the title compound (8 mg, 39%).
[1344] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.81+0.86 (3H), 1.47+1.55 (2H), 2.24-2.36 (1H), 2.47-2.59 (2H), 2.83+3.04 (3H), 2.89-3.08 (2H), 3.19-3.36 (1H), 3.64 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.42 (2H), 11.95 (1H)
Example 59
N,N-Dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide Isomer 1
[1345] ##STR00135##
[1346] (6RS)-N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide (25; 110 mg, 294 mol) were separated by preparative HPLC (chiral method) to give the title compound (41 mg, 37%).
[1347] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.33 (1H), 2.46 (1H), 2.85 (3H), 2.95 (1H), 3.03 (1H), 3.07 (3H), 3.66 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.96 (1H)
Example 60
N,N-Dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide Isomer 2
[1348] ##STR00136##
[1349] (6RS)-N,N-dimethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide (25; 110 mg, 294 mol) were separated by preparative HPLC (chiral method) to give the title compound (42 mg, 38%).
[1350] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.33 (1H), 2.46 (1H), 2.85 (3H), 2.95 (1H), 3.03 (1H), 3.07 (3H), 3.66 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.96 (1H)
Example 61
N-Methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide Isomer 2
[1351] ##STR00137##
[1352] (6RS)-N-methyl-4-oxo-3-(phenylamino)-N-propyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide (24; 20.5 mg, 51 mol) were separated by preparative HPLC (chiral method) to give the title compound (9 mg, 44%).
[1353] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.81+0.86 (3H), 1.47+1.55 (2H), 2.24-2.36 (1H), 2.47-2.59 (2H), 2.83+3.04 (3H), 2.89-3.08 (2H), 3.19-3.36 (1H), 3.64 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.42 (2H), 11.95 (1H)
Example 62
(6RS)-3-(Phenylamino)-6-[(propan-2-ylsulfany0methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1354] ##STR00138##
[1355] A mixture of [(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (32-1; 150 mg, 365 mol), sodium propane-2-thiolate (179 mg, 1.82 mmol) in DMA (5 mL) was stirred at 100 C. for 5 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (63 mg, 44%).
[1356] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.22 (6H), 2.30 (1H), 2.37 (1H), 2.46 (1H), 2.62-2.72 (3H), 2.95 (1H), 3.13 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.47 (2H), 8.41 (2H), 11.94 (1H)
Example 63
(6RS)-6-[(Ethylsulfany0methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1357] ##STR00139##
[1358] A mixture of [(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (32-1; 150 mg, 365 mol), sodium ethanethiolate (153 mg, 1.82 mmol) in DMA (5 mL) was stirred at 100 C. for 5 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (45 mg, 32%).
[1359] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.19 (3H), 2.29 (1H), 2.39 (1H), 2.45 (1H), 2.54 (2H), 2.60-2.72 (3H), 3.13 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.94 (1H)
Example 64
4-Fluoro-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylbenzenesulfonamide
[1360] ##STR00140##
[1361] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), 4-fluorobenzenesulfonyl chloride (35 mg, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (26 mg, 56%).
[1362] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.20 (1H), 2.28-2.35 (2H), 2.64 (1H), 2.86 (2H), 2.99 (1H), 6.56 (2H), 6.63 (1H), 7.04 (2H), 7.42-7.49 (5H), 7.85-7.90 (3H), 8.41 (2H), 11.94 (1H)
Example 65
2-Methoxyethyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate
[1363] ##STR00141##
[1364] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), 2-methoxyethyl carbonochloridate (21 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (24 mg, 57%).
[1365] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.22 (1H), 2.27-2.37 (2H), 2.62 (1H), 2.94 (1H), 3.10 (2H), 3.26 (3H), 3.50 (2H), 4.08 (2H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.41-7.49 (4H), 8.41 (2H), 11.93 (1H)
Example 66
2-Fluoroethyl [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamate
[1366] ##STR00142##
[1367] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), 2-fluoroethyl carbonochloridate (17 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (23 mg, 57%).
[1368] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.23 (1H), 2.28-2.39 (2H), 2.63 (1H), 2.95 (1H), 3.12 (2H), 4.16 (1H), 4.26 (1H), 4.54 (1H), 4.66 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 7.53 (1H), 8.41 (2H), 11.94 (1H)
Example 67
(6RS)-6-[(1,3-Benzothiazol-2-ylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1369] ##STR00143##
[1370] A mixture of [(6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (32-1; 150 mg, 365 mol), sodium 1,3-benzothiazole-2-thiolate (345 mg, 1.82 mmol) in DMA (5 mL) was stirred at 100 C. for 5 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (70 mg, 40%).
[1371] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.43 (1H), 2.53-2.55 (1H), 2.71 (1H), 2.83 (1H), 3.16 (1H), 3.59 (2H), 6.58 (2H), 6.62 (1H), 7.03 (2H), 7.37 (1H), 7.42-7.47 (4H), 7.83 (1H), 8.02 (1H), 8.40 (2H), 11.94 (1H)
Example 68
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1372] ##STR00144##
[1373] A mixture of methyl (6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (50; 158 mg, 378 mol), potassium hydroxide (1.51 mL, 4M in water), THF (1.5 mL) and MeOH (1.5 mL) was stirred at RT for 15 minutes. Hydrochloric acid (2.0 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (106 mg, 66%).
[1374] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.51-2.61 (2H), 3.07-3.23 (3H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.37 (1H), 8.08 (1H), 8.22 (1H), 10.36 (1H), 11.98 (1H), 12.62 (1H)
Example 69
N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcyclopropanecarboxamide
[1375] ##STR00145##
[1376] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), cyclopropanecarbonyl chloride (16 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (27 mg, 71%).
[1377] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.62-0.73 (4H), 1.58 (1H), 2.24 (1H), 2.30-2.40 (2H), 2.61 (1H), 2.94 (1H), 3.14 (1H), 3.23 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 8.22 (1H), 8.41 (2H), 11.93 (1H)
Example 70
2-Methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide
[1378] ##STR00146##
[1379] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), 2-methylpropanoyl chloride (19 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (27mg, 70%).
[1380] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.03 (6H), 2.23 (1H), 2.28-2.43 (3H), 2.60 (1H), 2.92 (1H), 3.09-3.22 (2H), 6.57 (2H), 6.63 (1H), 7.04(2H), 7.43 (1H), 7.46 (2H), 7.89 (1H), 8.41 (2H), 11.92 (1H)
Example 71
2-Methoxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylacetamide
[1381] ##STR00147##
[1382] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), methoxyacetyl chloride (17 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (30 mg, 77%).
[1383] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.22 (1H), 2.31 (1H), 2.41 (1H), 2.61 (1H), 2.92 (1H), 3.15-3.28 (2H), 3.34 (3H), 3.84 (2H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.02 (1H), 8.41 (2H), 11.92 (1H)
Example 72
N-[(6RS)-4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcyclobutanecarboxamide
[1384] ##STR00148##
[1385] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), cyclobutanecarbonyl chloride (21 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (26 mg, 67%).
[1386] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.77 (1H), 1.89 (1H), 1.99-2.07 (2H), 2.08-2.20 (2H), 2.24 (1H), 2.28-2.39 (2H), 2.59 (1H), 2.91 (1H), 3.03 (1H), 3.11 (1H), 3.19 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 7.81 (1H), 8.41 (2H), 11.92 (1H)
Example 73
N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropane-2-sulfonamide
[1387] ##STR00149##
[1388] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 50 mg, 150 mol), propane-2-sulfonyl chloride (68 L, 602 mol) in pyridine (1.7 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (8 mg, 11%).
[1389] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.24 (6H), 2.22-2.44 (3H), 2.66 (1H), 2.99-3.10 (3H), 3.20 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.21 (1H), 7.44 (1H), 7.47 (2H), 8.41 (2H), 11.96 (1H)
Example 74
N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide Isomer 1
[1390] ##STR00150##
[1391] (6RS)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide (17; 120 mg, 297 mol) were separated by preparative HPLC (chiral method) to give the title compound (36 mg, 30%).
[1392] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.30-2.38 (1H), 2.46-2.57 (1H), 2.86+3.10 (3H), 2.92-3.07 (2H), 3.28-3.55 (4H), 3.64+3.72 (1H), 4.69+4.86 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.42-7.48 (3H), 8.41 (2H), 11.96 (1H)
Example 75
N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide Isomer 2
[1393] ##STR00151##
[1394] (6RS)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide (17; 120 mg, 297 mol) were separated by preparative HPLC (chiral method) to give the title compound (30 mg, 24%).
[1395] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.30-2.38 (1H), 2.46-2.57 (1H), 2.86+3.10 (3H), 2.92-3.07 (2H), 3.28-3.55 (4H), 3.64+3.72 (1H), 4.69+4.86 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.42-7.48 (3H), 8.41 (2H), 11.96 (1H)
Example 76
(6RS)-2-(3-Fluoropyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1396] ##STR00152##
[1397] A mixture comprising (6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (52; 70 mg, 192 mol), DMF (2 mL), DIPEA (100 L, 575 mol), N-methylmethanamine (287 L, 2M in THF) and T3P (173 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (53 mg, 70%).
[1398] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.35 (1H), 2.52 (1H), 2.85 (3H), 2.94-3.03 (2H), 3.07 (3H), 3.67 (1H), 6.59 (2H), 6.60 (1H), 6.99 (2H), 7.40 (1H), 7.54 (1H), 8.24 (1H), 8.50 (1H), 11.68 (1H)
Example 77
(6RS)-2-(3-Methoxypyridin-4-yl)-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1399] ##STR00153##
[1400] A mixture comprising (6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (49; 70 mg, 185 mol), DMF (2 mL), DIPEA (97 L, 556 mol), N-methylmethanamine (287 L, 2M in THF) and T3P (167 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (47 mg, 63%).
[1401] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.32 (1H), 2.52 (1H), 2.85 (3H), 2.96-3.01 (2H), 3.07 (3H), 3.65 (1H), 3.89 (3H), 6.54 (2H), 6.58 (1H), 6.98 (2H), 7.30 (1H), 7.41 (1H), 8.01 (1H), 8.34 (1H), 11.34 (1H)
Example 78
(6RS)-2-(3-Fluoropyridin-4-yl)-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1402] ##STR00154##
[1403] A mixture comprising (6RS)-2-(3-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (52; 70 mg, 192 mol), DMF (2 mL), DIPEA (100 L, 575mol) , 2-(methylamino)ethanol (46 L, 575mol) and T3P (173 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (41 mg, 48%).
[1404] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.35 (1H), 2.54 (1H), 2.86+3.11 (3H), 2.95-3.03 (2H), 3.29-3.55 (4H), 3.64+3.72 (1H), 4.68+4.86 (1H), 6.57 (2H), 6.60 (1H), 6.99 (2H), 7.40 (1H), 7.54 (1H), 8.25 (1H), 8.50 (1H), 11.68 (1H)
Example 79
(6RS)-N-(2-Hydroxyethyl)-2-(3-methoxypyridin-4-yl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1405] ##STR00155##
[1406] A mixture comprising (6RS)-2-(3-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (49; 70 mg, 185 mol), DMF (2 mL), DIPEA (97 L, 556 mol), 2-(methylamino)ethanol (45 L, 556 mol) and T3P (167 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (54 mg, 67%).
[1407] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.29-2.36 (1H), 2.54 (1H), 2.86+3.11 (3H), 2.95-3.03 (2H), 3.36-3.55 (4H), 3.62+3.71 (1H), 3.88+3.89 (3H), 4.68+4.85 (1H), 6.54 (2H), 6.58 (1H), 6.98 (2H), 7.30 (1H), 7.40+7.41 (1H), 8.01 (1H), 8.34 (1H), 11.34 (1H)
Example 80
(6RS)-3-(Phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1408] ##STR00156##
[1409] A mixture comprising (6RS)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (62; 130 mg, 332 mol), mCPBA (70 mg, 75%) and DMA (10 mL) was stirred at RT. After 4 h a second portion mCPBA (35 mg, 75%) was added and after 4 h a third portion mCPBA (35 mg, 75%). The mixture was stirred at RT for 16 h, Et.sub.3N (200 L) was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (93 mg, 63%).
[1410] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.27 (6H), 2.42 (1H), 2.53-2.59 (2H), 2.79-2.95 (2H), 3.24-3.32 (3H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.48 (2H), 8.42 (2H), 12.01 (1H)
Example 81
(6RS)-6-[(Ethylsulfonyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1411] ##STR00157##
[1412] A mixture comprising (6RS)-6-[(ethylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (63; 128 mg, 339 mol), mCPBA (72 mg, 75%) and DMA (10 mL) was stirred at RT. After 4 h a second portion mCPBA (36 mg, 75%) was added and after 4 h a third portion mCPBA (36 mg, 75%). The mixture was stirred at RT for 16 h, Et.sub.3N (200 L) was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (82 mg, 56%).
[1413] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.24 (3H), 2.40 (1H), 2.53 (1H), 2.79-2.91 (2H), 3.16 (2H), 3.24-3.35 (3H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 8.41 (2H), 12.01 (1H)
Example 82
3-Methoxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide
[1414] ##STR00158##
[1415] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), 3-methoxypropanoyl chloride (22 mg, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. MeOH was added, the mixture concentrated and purified by crystallization from MeOH to give the title compound (13 mg, 34%).
[1416] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.27-2.42 (5H), 2.68 (1H), 3.00 (1H), 3.13-3.25 (2H), 3.22 (3H), 3.54 (2H), 6.70 (2H), 6.76 (1H), 7.12 (2H), 7.79 (2H), 8.03-8.10 (2H), 8.59 (2H), 12.63 (1H)
Example 83
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1417] ##STR00159##
[1418] A mixture comprising (6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (68; 50 mg, 123 mol), DMF (2 mL), DIPEA (65 L, 371 mol), N-methylmethanamine (185 L, 2M in THF) and T3P (111 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (28 mg, 52%).
[1419] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.31 (1H), 2.49 (1H), 2.85 (3H), 2.94-3.01 (2H), 3.06 (3H), 3.64 (1H), 6.57 (2H), 6.61 (1H), 7.02 (2H), 7.15 (1H), 7.36 (1H), 8.08 (1H), 8.23 (1H), 10.35 (1H), 11.95 (1H)
Example 84
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1420] ##STR00160##
[1421] A mixture comprising (6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (68; 50 mg, 123 mol), DMF (2 mL), DIPEA (65 L, 371 mol), 2-(methylamino)ethanol (30 L, 371 mol) and T3P (111 L, 50% in DMF) was stirred at RT for 16 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (33 mg, 55%).
[1422] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.28-2.36 (1H), 2.53-2.59 (1H), 2.85+3.10 (3H), 2.93-3.03 (2H), 3.29-3.54 (4H), 3.62+3.69 (1H), 4.69+4.85 (1H), 6.57 (2H), 6.61 (1H), 7.02 (2H), 7.15 (1H), 7.35+7.36 (1H), 8.08 (1H), 8.23 (1H), 10.35 (1H), 11.96 (1H)
Example 85
Methyl 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate Isomer 1
[1423] ##STR00161##
Methyl (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (8; 213 mg, 589 mol) were separated by preparative HPLC (chiral method) to give the title compound (80 mg, 38%).
[1424] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.56-2.62 (2H), 3.09-3.21 (2H), 3.37 (1H), 3.64 (3H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44-7.49 (3H), 8.42 (2H), 12.00 (1H)
Example 86
Methyl 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate Isomer 2
[1425] ##STR00162##
Methyl (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (8; 213 mg, 589 mol) were separated by preparative HPLC (chiral method) to give the title compound (85 mg, 38%).
[1426] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.56-2.62 (2H), 3.09-3.21 (2H), 3.37 (1H), 3.64 (3H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44-7.49 (3H), 8.42 (2H), 12.00 (1H)
Example 87
(6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one
87-2: (4RS)-2-{[(2-Aminopyridin-4-yl)methyl]amino}-4({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide
[1427] ##STR00163##
[1428] A solution of (4RS)-4({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-hydroxy-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide (1-3; 33.9 g, 65.7 mmol) and 4-(aminomethyl)pyridin-2-amine (16.2 g, 131 mmol) in DMA (250 mL) was heated at 120 C. for 2 h. The mixture was concentrated and purified by Biotage (SNAP silica 750 g, EtOH:DCM) to give the title compound (24.8 g, 60%).
87-1: (6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1429] ##STR00164##
[1430] A mixture of (4RS)-2-{[(2-Aminopyridin-4-yl)methyl]amino}-4({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide (87-2; 16.3 g, 26.3 mmol), hydrogen peroxide (30% in water, 10.7 mL, 105 mmol) in MeOH (500 mL) was heated at 50 C. for 16 h. The mixture was concentrated and purified by Biotage (SNAP silica 375 g, MeOH:DCM) to give the title compound (8.95 g, 58%).
(6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one
[1431] ##STR00165##
[1432] A mixture of (6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,5,6,7-tetrahydro-4H-indol-4-one (87-1; 3.0 g, 5.11 mmol) and TBAF (6.1 mL, 1M in THF) in THF (80 mL) was stirred at 50 C. for 2 h. EtOAc (1 L) was added, the mixture washed with sodium hydroxide (2.5% in water), brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by Biotage (SNAP silica 110 g, MeOH:DCM) to give the title compound (1.17 g, 62%).
[1433] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.16-2.34 (3H), 2.62 (1H), 2.93 (1H), 3.43 (2H), 4.74 (1H), 5.73 (2H), 6.53-6.62 (4H), 6.69 (1H), 7.02 (2H), 7.23 (1H), 7.75 (1H), 11.69 (1H)
Example 88
4-Fluoro-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylbenzamide
[1434] ##STR00166##
[1435] A solution of 4-fluorobenzoic acid (34 mg, 241 mol) and HATU (92 mg, 241 mol) in DMA (1 mL) was added to a mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 40 mg, 120 mol) and DIPEA (42 L, 241 mol) in DMA (1 mL) and the reaction was stirred at 50C for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (33 mg, 58%).
[1436] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.28-2.41 (2H), 2.53-2.58 (1H), 2.69 (1H), 2.99 (1H), 3.31-3.46 (2H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.32 (2H), 7.44 (1H), 7.46 (2H), 7.96 (2H), 8.40 (2H), 8.66 (1H), 11.92 (1H)
Example 89
tert-Butyl [(2S)-1-oxo-1-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino)propan-2-yl]carbamate
[1437] ##STR00167##
[1438] A solution of N-(tert-butoxycarbonyl)-L-alanine (129 mg, 680 mol) and HATU (258 mg, 680 mol) in DMA (3 mL) was added to a mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 113 mg, 340 mol) and DIPEA (118 L, 680 mol) in DMA (3 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by Biotage (SNAP silica 28 g, MeOH:DCM) to give the title compound (56 mg, 33%).
[1439] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.20 (3H), 1.36 (9H), 2.19-2.40 (3H), 2.61 (1H), 2.90 (1H), 3.09-3.29 (2H), 3.94 (1H), 6.57 (2H), 6.63 (1H), 6.92 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 7.93 (1H), 8.41 (2H), 11.93 (1H)
Example 90
tert-Butyl (2S)-2-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamoyl)pyrrolidine-1-carboxylate
[1440] ##STR00168##
[1441] A solution of 1-(tert-butoxycarbonyl)-L-proline (97 mg, 451 mol) and HATU (172 mg, 451 mol) in DMA (2 mL) was added to a mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 75 mg, 226 mol) and DIPEA (79 L, 451 mol) in DMA (2 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by Biotage (SNAP silica 28 g, MeOH:DCM) to give the title compound (85 mg, 71%).
[1442] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.31+1.38 (9H), 1.73-1.88 (3H), 2.12 (1H), 2.24 (1H), 2.25-2.42 (2H), 2.63 (1H), 2.92 (1H), 3.13 (1H), 3.20-3.31 (2H), 3.40 (1H), 4.06 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.42 (1H), 7.47 (2H), 7.96+8.05 (1H), 8.41 (2H), 11.91 (1H)
Example 91
(2S)-2-Hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylpropanamide
[1443] ##STR00169##
[1444] A solution of (2S)-2-hydroxypropanoic acid (22 mg, 241 mol) and HATU (92 mg, 241 mol) in DMA (1 mL) was added to a mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 40 mg, 120 mol) and DIPEA (42 L, 241 mol) in DMA (1 mL) and the reaction was stirred at 50 C. for 16 h. The mixture was concentrated and purified preparative HPLC (basic method) to give the title compound (29 mg, 56%).
[1445] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.24 (3H), 2.22 (1H), 2.30 (1H), 2.40 (1H), 2.61 (1H), 2.91 (1H), 3.13-3.27 (2H), 4.00 (1H), 5.51 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 7.91 (1H), 8.40 (2H), 11.93 (1H)
Example 92
N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-1,3-thiazole-2-carboxamide
[1446] ##STR00170##
[1447] A solution of 1,3-thiazole-2-carboxylic acid (31 mg, 241 mol) and HATU (92 mg, 241 mol) in DMA (1 mL) was added to a mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 40 mg, 120 mol) and DIPEA (42 L, 241 mol) in DMA (1 mL) and the reaction was stirred at 50 C. for 16 h. The mixture was concentrated and purified preparative HPLC (basic method) to give the title compound (22 mg, 39%).
[1448] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.26-2.38 (2H), 2.55 (1H), 2.68 (1H), 2.97 (1H), 3.31-3.47 (2H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.42-7.47 (3H), 8.04 (1H), 8.07 (1H), 8.40 (2H), 9.09 (1H), 11.91 (1H)
Example 93
1-Methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-1H-pyrrole-2-carboxamide
[1449] ##STR00171##
[1450] A solution of 1-methyl-1H-pyrrole-2-carboxylic acid (30 mg, 241 mol) and HATU (92 mg, 241 mol) in DMA (1 mL) was added to a mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 40 mg, 120 mol) and DIPEA (42 L, 241 mol) in DMA (1 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified preparative HPLC (basic method) to give the title compound (6 mg, 11%).
[1451] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.24-2.39 (2H), 2.42-2.54 (1H), 2.66 (1H), 2.98 (1H), 3.22-3.36 (2H), 3.84 (3H), 6.02 (1H), 6.57 (2H), 6.63 (1H), 6.81 (1H), 6.90 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.12 (1H), 8.40 (2H), 11.92 (1H)
Example 94
N-4-[(6RS)-6-(Hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
94-1: N-{4-[(6RS)-3-Anilino-6({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide
[1452] ##STR00172##
[1453] A mixture of (6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,5,6,7-tetrahydro-4H-indol-4-one (87-1; 2.34 g, 3.99 mmol), acetyl chloride (425 L, 5.98 mmol) in THF (100 mL) and pyridine (2.78 mL) was stirred at RT for 1 h. MeOH was added, the mixture concentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the title compound (2.46 g, 98%).
N-4-[(6RS)-6-(Hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1454] ##STR00173##
[1455] A mixture of N-{4-[(6RS)-3-anilino-6({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide (94-1; 2.45 g, 3.90 mmol) and TBAF (4.68 mL, 1M in THF) in THF (65 mL) was stirred at RT for 16 h. EtOAc was added, the mixture washed with sodium hydroxide (2.5% in water), brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by crystallization from MeOH/DCM and Biotage (SNAP silica 25 g, MeOH:DCM) of the mother liquor to give the title compound (1.17 g, 77%).
[1456] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.19-2.35 (3H), 2.65 (1H), 2.96 (1H), 3.39-3.48 (2H), 4.75 (1H), 6.56 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.36 (1H), 8.08 (1H), 8.22 (1H), 10.34 (1H), 11.91 (1H)
Example 95
N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyltetrahydro-2H-pyran-4-carboxamide
[1457] ##STR00174##
[1458] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), tetrahydro-2H-pyran-4-carbonyl chloride (27 mg, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (19 mg, 45%).
[1459] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.57-1.65 (4H), 2.20-2.43 (4H), 2.60 (1H), 2.92 (1H), 3.16 (2H), 3.26-3.35 (2H), 3.87 (2H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.47 (2H), 7.95 (1H), 8.40 (2H), 11.98 (1H)
Example 96
N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylfuran-2-carboxamide
[1460] ##STR00175##
[1461] A mixture of (6RS)-6-(aminomethyl)-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (36; 30 mg, 90 mol), 2-furoyl chloride (18 L, 181 mol) in pyridine (1 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (16 mg, 40%).
[1462] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.28 (1H), 2.36 (1H), 2.45-2.54 (1H), 2.66 (1H), 2.97 (1H), 3.26-3.42 (2H), 6.57 (2H), 6.63 (1H), 6.64 (1H), 7.04 (2H), 7.13 (1H), 7.44 (1H), 7.45 (2H), 7.86 (1H), 8.40 (2H), 8.55 (1H), 11.91 (1H)
Example 97
(6RS)-N-(2-Hydroxy-2-methylpropyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1463] ##STR00176##
[1464] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (1.5 mL), DIPEA (89 L, 518 mol), 2-methyl-1-(methylamino)propan-2-ol (61 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (49 mg, 66%).
[1465] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.04+1.11 (6H), 2.28+2.38 (1H), 2.47-2.57 (1H), 2.88-3.08 (2H), 2.94+3.18 (3H), 3.23-3.39 (2H), 3.68+3.83 (1H), 4.51+4.60 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.92+11.95 (1H)
Example 98
(6RS)-N-[(2S)-2-Hydroxypropyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1466] ##STR00177##
[1467] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (0.95 mL), DIPEA (89 L, 518 mol), (2S)-1-aminopropan-2-ol (41 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (42 mg, 57%).
[1468] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.02 (3H), 2.39 (1H), 2.55 (1H), 2.95-3.18 (5H), 3.65 (1H), 4.69 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 7.99 (1H), 8.42 (2H), 11.96 (1H)
Example 99
(6RS)-N-(1-Hydroxy-2-methylpropan-2-yl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1469] ##STR00178##
[1470] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 2-amino-2-methylpropan-1-ol (49 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (26 mg, 36%).
[1471] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.19 (6H), 2.36 (1H), 2.47-2.55 (1H), 2.91-3.15 (3H), 3.41 (2H), 4.81 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.42-7.49 (4H), 8.41 (2H), 11.95 (1H)
Example 100
(6RS)-N-(2,2-Dimethylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1472] ##STR00179##
[1473] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 2,2-dimethylpropan-1-amine (61 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (48 mg, 60%).
[1474] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.84 (9H), 2.37 (1H), 2.57 (1H), 2.89-3.09 (4H), 3.17 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 7.90 (1H), 8.41 (2H), 11.97 (1H)
Example 101
(6RS)-N-(2-Methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1475] ##STR00180##
[1476] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 2-methylpropan-1-amine (51 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (48 mg, 69%).
[1477] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.85 (6H), 1.69 (1H), 2.38 (1H), 2.56 (1H), 2.86-3.05 (4H), 3.10 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 7.99 (1H), 8.41 (2H), 11.98 (1H)
Example 102
(6RS)-N-Methyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1478] ##STR00181##
[1479] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), N,2-dimethylpropan-1-amine (62 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (32 mg, 44%).
[1480] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.80-0.89 (6H), 1.90 (1H), 2.25+2.35 (1H), 2.46-2.58 (1H), 2.83+3.05 (3H), 2.92-3.25 (4H), 3.66 (1H), 6.58-6.66 (3H), 7.05 (2H), 7.43-7.47 (3H), 8.41 (2H), 11.95 (1H)
Example 103
(6RS)-N-[2-(Dimethylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1481] ##STR00182##
[1482] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), N,N-dimethylethane-1,2-diamine (57 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (27 mg, 36%).
[1483] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.15 (6H), 2.29 (2H), 2.37 (1H), 2.54 (1H), 2.94-3.21 (5H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 7.95 (1H), 8.41 (2H), 11.95 (1H)
Example 104
(6RS)-N-[2-(Dimethylamino)ethyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1484] ##STR00183##
[1485] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), N,N,N-trimethylethane-1,2-diamine (67 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (33 mg, 42%).
[1486] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.15+2.17 (6H), 2.28-2.42 (3H), 2.46-2.55 (1H), 2.86+3.07 (3H), 2.92-3.05 (2H), 3.36-3.51 (2H), 3.63 (1H), 6.59 (2H), 6.64 (1H), 7.04 (2H), 7.43-7.47 (3H), 8.41 (2H), 11.95 (1H)
Example 105
(6RS)-N-Methyl-N-[2-(methylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1487] ##STR00184##
[1488] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), N,N-dimethylethane-1,2-diamine (56 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (15 mg, 19%).
[1489] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.27+2.28 (3H), 2.29-2.37 (1H), 2.48-2.55 (1H), 2.60 (2H), 2.85+3.07 (3H), 2.92-3.03 (2H), 3.32-3.45 (2H), 3.64 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.96 (1H)
Example 106
(6RS)-N-(2,2-Difluoroethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1490] ##STR00185##
[1491] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 2,2-difluoroethanamine (37 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (36 mg, 46%).
[1492] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.41 (1H), 2.56 (1H), 3.03 (2H), 3.17 (1H), 3.52 (2H), 6.03 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 8.42 (2H), 8.44 (1H), 11.97 (1H)
Example 107
(6RS)-N-Methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1493] ##STR00186##
[1494] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 2,2,2-trifluoro-N-methylethanamine (59 mg, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (21 mg, 26%).
[1495] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.26+2.36 (1H), 2.47-2.56 (1H), 2.88-3.07 (2H), 2.98+3.20 (3H), 3.76 (1H), 4.21+4.49 (2H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.42 (2H), 11.97 (1H)
Example 108
(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1496] ##STR00187##
[1497] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 3,3,3-trifluoropropan-1-amine (51 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (38 mg, 47%).
[1498] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.35-2.58 (5H), 2.96-3.12 (3H), 3.31 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.26 (1H), 8.41 (2H), 11.97 (1H)
Example 109
(6RS)-N-(2,2-Difluoroethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1499] ##STR00188##
[1500] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 2,2-difluoro-N-methylethanamine (61 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (31 mg, 42%).
[1501] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.29+2.36 (1H), 2.44-2.57 (1H), 2.89-3.07 (2H), 2.93+3.16 (3H), 3.64-3.81+3.96 (3H), 6.12 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.46 (2H), 8.42 (2H), 11.97 (1H)
Example 110
(6RS)-N-tert-Butyl-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1502] ##STR00189##
[1503] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), N,2-dimethylpropan-2-amine (62 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 day. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (16 mg, 20%).
[1504] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.35 (9H), 2.32 (1H), 2.48 (1H), 2.89-3.05 (2H), 2.95 (3H), 3.64 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.45 (2H), 8.41 (2H), 11.92 (1H)
Example 111
(6RS)-N-[(1-Hydroxycyclopropyl)methyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1505] ##STR00190##
[1506] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 1-(aminomethyl)cyclopropanol (38 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 day. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (25 mg, 31%).
[1507] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.48 (2H), 0.52 (2H), 2.38 (1H), 2.54 (1H), 2.94-3.09 (2H), 3.14 (1H), 3.24 (2H), 5.34 (1H), 6.57 (2H), 6.62 (1H), 7.03 (2H), 7.44 (1H), 7.45 (2H), 8.03 (1H), 8.41 (2H), 11.95 (1H)
Example 112
(6RS)-N-(2-Hydroxy-2-methylpropyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1508] ##STR00191##
[1509] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 2,2-dimethylpropan-1-amine (61 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (41 mg, 72%).
[1510] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.05 (3H), 1.06 (3H), 2.38 (1H), 2.56 (1H), 2.96-3.11 (4H), 3.20 (1H), 4.47 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 7.90 (1H), 8.41 (2H), 11.96 (1H)
Example 113
(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1511] ##STR00192##
[1512] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 2,2-dimethylpropan-1-amine (61 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (30 mg, 36%).
[1513] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.41 (1H), 2.56 (1H), 3.04 (2H), 3.20 (1H), 3.94 (2H), 6.57 (2H), 6.62 (1H), 7.03 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 8.70 (1H), 11.97 (1H)
Example 114
(6RS)-N-Methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1514] ##STR00193##
[1515] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 3,3,3-trifluoro-N-methylpropan-1-amine hydrochloride (85 mg, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (48 mg, 79%).
[1516] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.31 (1H), 2.41-2.56 (3H), 2.85+3.08 (3H), 2.91-3.04 (2H), 3.46-3.68 (3H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.96 (1H)
Example 115
(6RS)-N-[(2R)-2-Hydroxypropyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1517] ##STR00194##
[1518] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 2(2R)-1-aminopropan-2-ol (41 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (42 mg, 57%).
[1519] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.02 (3H), 2.39 (1H), 2.55 (1H), 2.95-3.08 (4H), 3.14 (1H), 3.65 (1H), 4.71 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 7.99 (1H), 8.42 (2H), 11.96 (1H)
Example 116
4-Oxo-3-(phenylamino)-2-(pyridin-4-y0-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid Isomer 1
[1520] ##STR00195##
[1521] 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol) were separated by preparative HPLC (chiral method) to give the title compound (15 mg, 29%).
[1522] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.60 (2H), 3.17 (2H), 3.27 (1H), 6.63 (2H), 6.69 (1H), 7.08 (2H), 7.63 (2H), 7.77 (1H), 8.50 (2H), 12.39 (1H), 12.65 (1H)
Example 117
4-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid Isomer 2
[1523] ##STR00196##
[1524] 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol) were separated by preparative HPLC (chiral method) to give the title compound (15 mg, 29%).
[1525] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.60 (2H), 3.17 (2H), 3.27 (1H), 6.63 (2H), 6.69 (1H), 7.08 (2H), 7.63 (2H), 7.77 (1H), 8.50 (2H), 12.39 (1H), 12.65 (1H)
Example 118
(6RS)-6-[(4-Methylpiperazin-1-yl)carbonyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1526] ##STR00197##
[1527] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol), DMF (1.5 mL), DIPEA (75 L, 432 mol), 1-methylpiperazine (48 L, 432 mol) and T3P (130 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (40 mg, 65%).
[1528] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.19 (3H), 2.22-2.36 (5H), 2.53 (1H), 2.93-3.07 (2H), 3.41-3.58 (4H), 3.67 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.95 (1H)
Example 119
(6RS)-6-[(3S)-3-Hydroxypyrrolidin-1-yl]carbonyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1529] ##STR00198##
[1530] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (90 L, 518 mol), (3S)-pyrrolidin-3-ol (42 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (44 mg, 61%).
[1531] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.71-1.99 (2H), 2.32-2.39 (1H), 2.44-2.55 (2H), 2.92-3.09 (2H), 3.24-3.69 (4H), 4.26+4.32 (1H), 4.94+5.03 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.97 (1H)
Example 120
(6RS)-6-[(3R)-3-Hydroxypyrrolidin-1-yl]carbonyl-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1532] ##STR00199##
[1533] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), (3R)-pyrrolidin-3-ol (42 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (38 mg, 48%).
[1534] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.72-1.99 (2H), 2.32-2.39 (1H), 2.42-2.55 (2H), 2.92-3.09 (2H), 3.26-3.68 (4H), 4.26+4.32 (1H), 4.95+5.03 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.97 (1H)
Example 121
(6RS)-64(3-Hydroxyazetidin-1-yl)carbonyl1-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1535] ##STR00200##
[1536] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol), DMF (1.5 mL), DIPEA (150 L, 863 mol), azetidin-3-ol hydrochloride (47 mg, 432mol) and T3P (130 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (54 mg, 58%).
[1537] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.31 (1H), 2.45 (1H), 2.89-3.02 (2H), 3.23 (1H), 3.60 (1H), 3.93 (1H), 4.06 (1H), 4.39 (1H), 4.46 (1H), 5.75 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.42 (2H), 11.97 (1H)
Example 122
(6RS)-N,N-Diethyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1538] ##STR00201##
[1539] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 50 mg, 144 mol), DMF (1.5 mL), DIPEA (75 L, 432 mol), N-ethylethanamine (46 L, 432 mol) and T3P (130 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (37 mg, 61%).
[1540] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.03 (3H), 1.13 (3H), 2.27 (1H), 2.56 (1H), 2.92 (1H), 3.05 (1H), 3.24 (1H), 3.30-3.42 (3H), 3.55 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.95 (1H)
Example 123
[1541] N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]acetamide
##STR00202##
[1542] A mixture of 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 40 mg, 102 mol), acetyl chloride (15 L, 204 mol) in pyridine (2 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (11 mg, 27%).
[1543] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.82 (3H), 2.43 (1H), 2.53 (1H), 2.84 (1H), 3.16 (1H), 4.30 (1H), 6.58-6.60 (2H), 6.64 (1H), 7.05 (2H), 7.47 (1H), 7.48 (2H), 8.25 (1H), 8.43 (2H), 12.00 (1H)
Example 124
2-Methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]propanamide
[1544] ##STR00203##
[1545] A mixture of 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 40 mg, 102 mol), 2-methylpropanoyl chloride (21 L, 204 mol) in pyridine (2 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (9 mg, 23%).
[1546] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.99 (3H), 1.00 (3H), 2.37 (1H), 2.44-2.53 (2H), 2.84 (1H), 3.15 (1H), 4.29 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.46 (1H), 7.47 (2H), 8.11 (1H), 8.42 (2H), 11.96 (1H)
Example 125
3-Methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide
[1547] ##STR00204##
[1548] A mixture of 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 40 mg, 102 mol), 3-methylbutanoyl chloride (25 L, 204 mol) in pyridine (2 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (15 mg, 35%).
[1549] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.87 (6H), 1.91-2.00 (3H), 2.46 (1H), 2.53 (1H), 2.86 (1H), 3.16 (1H), 4.32 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 8.18 (1H), 8.42 (2H), 11.97 (1H)
Example 126
3-Hydroxy-3-methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide
[1550] ##STR00205##
[1551] A mixture comprising 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 40 mg, 102 mol), DMF (1.5 mL), DIPEA (107 L, 613 mol), 3-hydroxy-3-methylbutanoic acid (33 L, 307mol) and T3P (184 L, 50% in DMF) was stirred at RT for 2 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (9 mg, 20%).
[1552] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.14 (6H), 2.21 (2H), 2.45 (1H), 2.53 (1H), 2.88 (1H), 3.17 (1H), 4.36 (1H), 4.73 (1H), 6.60 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.46 (2H), 8.21 (1H), 8.42 (2H), 11.97 (1H)
Example 127
2-Cyclopropyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]acetamide
[1553] ##STR00206##
[1554] A mixture comprising 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 40 mg, 102 mol), DMF (1.5 mL), DIPEA (107 L, 613 mol), cyclopropylacetic acid (29 L, 307mol) and T3P (184 L, 50% in DMF) was stirred at RT for 2 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (17 mg, 39%).
[1555] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.11 (2H), 0.42 (2H), 0.95 (1H), 1.99 (2H), 2.44 (2H), 2.86 (1H), 3.16 (1H), 4.32 (1H), 6.60 (2H), 6.64 (1H), 7.05 (2H), 7.44 (1H), 7.47 (2H), 8.10 (1H), 8.42 (2H), 11.96 (1H)
Example 128
(3S)-3-Hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide
[1556] ##STR00207##
[1557] A mixture comprising 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 40 mg, 102 mol), DMF (1.5 mL), DIPEA (107 L, 613 mol), (3S)-3-hydroxybutanoic acid (32 mg, 307mol) and T3P (184 L, 50% in DMF) was stirred at RT for 2 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (18 mg, 39%).
[1558] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.25 (1H), 1.06 (3H), 2.11 (1H), 2.22 (1H), 2.44 (1H), 2.85 (1H), 3.15 (1H), 3.60 (1H), 3.98 (1H), 4.32 (1H), 6.59 (2H), 6.63 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.19 (1H), 8.42 (2H), 11.96 (1H)
Example 129
3-Hydroxy-2,2-dimethyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]propanamide
[1559] ##STR00208##
[1560] A mixture comprising 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 40 mg, 102 mol), DMF (1.5 mL), DIPEA (107 L, 613 mol), 3-hydroxy-2,2-dimethylpropanoic acid (36 mg, 307mol) and T3P (184 L, 50% in DMF) was stirred at RT for 2 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (11 mg, 24%).
[1561] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.04 (6H), 2.41 (1H), 2.54 (1H), 2.90 (1H), 3.09 (1H), 3.37 (2H), 4.34 (1H), 4.90 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.44 (1H), 7.47 (2H), 7.65 (1H), 8.42 (2H), 11.95 (1H)
Example 130
N-[(2S)-1-Hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide Isomer 1
[1562] ##STR00209##
[1563] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (90 L, 518 mol), (2S)-2-aminopropan-1-ol (40 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (28 mg, 36%).
[1564] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.04 (3H), 2.38 (1H), 2.53 (1H), 2.93-3.12 (3H), 3.23 (1H), 3.32-3.37 (1H), 3.78 (1H), 4.71 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.80 (1H), 8.41 (2H), 11.96 (1H)
Example 131
N-[(2S)-1-Hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide Isomer 2
[1565] ##STR00210##
[1566] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (90 L, 518 mol), (2S)-2-aminopropan-1-ol (40 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (29 mg, 39%).
[1567] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.03 (3H), 2.37 (1H), 2.54 (1H), 2.94-3.12 (3H), 3.25 (1H), 3.37 (1H), 3.77 (1H), 4.71 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.79 (1H), 8.41 (2H), 11.95 (1H)
Example 132
N-[(2R)-1-Hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyriclin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide Isomer 1
[1568] ##STR00211##
[1569] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (90 L, 518 mol), (2R)-2-aminopropan-1-ol (40 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (26 mg, 35%).
[1570] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.04 (3H), 2.38 (1H), 2.53 (1H), 2.93-3.12 (3H), 3.23 (1H), 3.34 (1H), 3.78 (1H), 4.71 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.80 (1H), 8.41 (2H), 11.95 (1H)
Example 133
(3R)-3-Hydroxy-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-y0-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide
[1571] ##STR00212##
[1572] A mixture comprising 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 40 mg, 102 mol), DMF (1.5 mL), DIPEA (107 L, 613 mol), (3R)-3-hydroxybutanoic acid (32 mg, 307mol) and T3P (184 L, 50% in DMF) was stirred at RT for 2 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (14 mg, 30%).
[1573] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.06 (3H), 2.11 (1H), 2.22 (1H), 2.40-2.55 (2H), 2.85 (1H), 3.15 (1H), 3.97 (1H), 4.32 (1H), 4.64 (1H), 6.59 (2H), 6.63 (1H), 7.05 (2H), 7.44 (1H), 7.46 (2H), 8.19 (1H), 8.42 (2H), 11.96 (1H)
Example 134
N-[(2R)-1-Hydroxypropan-2-yl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide Isomer 2
[1574] ##STR00213##
[1575] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (90 L, 518 mol), (2R)-2-aminopropan-1-ol (40 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (27 mg, 37%).
[1576] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.03 (3H), 2.37 (1H), 2.53 (1H), 2.93-3.12 (3H), 3.24 (1H), 3.36 (1H), 3.77 (1H), 4.71 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.79 (1H), 8.41 (2H), 11.96 (1H)
Example 135
(6RS)-N-[2-(Methylamino)ethyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1577] ##STR00214##
[1578] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), N-methylethane-1,2-diamine (45 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 day. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (19 mg, 25%).
[1579] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.35 (3H), 2.42 (1H), 2.55 (1H), 2.65 (2H), 2.99-3.13 (3H), 3.21 (2H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.47 (2H), 8.13 (1H), 8.32 (1H), 8.42 (2H), 12.02 (1H)
Example 136
N-[(6RS)-Oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl-L-prolinamide
[1580] ##STR00215##
[1581] A mixture comprising tert-butyl (2S)-2-([(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylcarbamoyl)pyrrolidine-1-carboxylate (90; 82 mg, 155 mol), TFA (179 L, 2.32 mmol) and DCM (5 mL) was stirred at RT for 16 h. The mixture was poured into ammonia (25% in water), extracted with DM/MeOH, the organic layer was washed with water and dried over sodium sulfate. After filtration and concentration, the residue was purified by preparative HPLC (basic method) to give the title compound (49 mg, 70%).
[1582] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.61 (2H), 1.86 (1H), 1.96 (1H), 2.17-2.31 (2H), 2.38 (1H), 2.60 (1H), 2.78-2.93 (3H), 3.11-3.27 (2H), 3.53 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.46 (2H), 8.11 (1H), 8.41 (2H), 11.92 (1H)
Example 137
tert-Butyl methyl(3-oxo-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]aminopropyl)carbamate
[1583] ##STR00216##
[1584] A mixture comprising 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 40 mg, 102 mol), DMF (1.5 mL), DIPEA (107 L, 613 mol), N-(tert-butoxycarbonyl)-N-methyl-beta-alanine (62 mg, 307 mol) and T3P (184 L, 50% in DMF) was stirred at RT for 2 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (21 mg, 39%).
[1585] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.39 (9H), 2.29 (2H), 2.43 (1H), 2.53 (1H), 2.76 (3H), 2.85 (1H), 3.16 (1H), 3.36 (2H), 4.31 (1H), 6.60 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 8.33 (1H), 8.42 (2H), 11.96 (1H)
Example 138
Methyl (6RS)-2-[2-[rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1586] ##STR00217##
[1587] A solution of rel-(1R,2R)-2-fluorocyclopropanecarboxylic acid (318 mg, 3.06 mmol) and HATU (1.16 g, 3.06 mmol) in DMF (1 mL) was added to a mixture of methyl (6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (31; 500 mg, 1.33 mmol) and DIPEA (532 L, 3.06 mmol) in DMF (1 mL) and the reaction was stirred at 50 C. for 16 h. MeOH was added, the mixture concentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the title compound (812 mg, max. 100%).
[1588] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.26 (2H), 1.64 (1H), 2.20 (1H), 2.52 (1H), 2.58 (1H), 3.08-3.21 (2H), 3.64 (3H), 4.94 (1H), 6.55 (2H), 6.60 (1H), 7.02 (2H), 7.16 (1H), 7.39 (1H), 8.09 (1H), 8.26 (1H), 10.74 (1H), 12.04 (1H)
Example 139
(6RS)-6-[(1,3-Benzothiazol-2-ylsulfonyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one
[1589] ##STR00218##
[1590] A mixture comprising (6RS)-6-[(1,3-benzothiazol-2-ylsulfanyl)methyl]-3-(phenylamino)-2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-indol-4-one (67; 115 mg, 238 mol), mCPBA (50 mg, 75%) and DMA (7 mL) was stirred at RT. After 4 h a second portion mCPBA (25 mg, 75%) was added and after 4 h a third portion mCPBA (25 mg, 75%). The mixture was stirred at RT for 4 h, Et.sub.3N (400 L) was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (5 mg, 4%).
[1591] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.42-2.56 (2H), 2.85-2.98 (2H), 3.29 (1H), 3.96 (1H), 4.05 (1H), 6.57 (2H), 6.62 (1H), 7.04 (2H), 7.42 (1H), 7.46 (2H), 7.69-7.76 (2H), 8.27 (1H), 8.37 (1H), 8.41 (2H), 12.01 (1H)
Example 140
(6RS)-2-[2-([rel-(1R,2R)-2-Fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1592] ##STR00219##
[1593] A mixture of methyl methyl (6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (138; 614 mg, 1.33 mmol), potassium hydroxide (5.3 mL, 4M in water), THF (5.4 mL) and MeOH (5.4 mL) was stirred at RT for 10 minutes. Hydrochloric acid (6 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (452 mg, 76%).
[1594] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.18 (1H), 1.64 (1H), 2.20 (1H), 2.48-2.59 (2H), 3.06-3.25 (3H), 4.94 (1H), 6.56 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.39 (1H), 8.09 (1H), 8.26 (1H), 10.73 (1H), 12.02 (1H), 12.60 (1H)
Example 141
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
141-4: methyl (1RS)-3-hydroxy-1-methyl-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate
[1595] ##STR00220##
[1596] To a solution of methyl (1RS)-3-hydroxy-1-methyl-5-oxocyclohex-3-ene-1-carboxylate (6.98 g, 37.9 mmol; can be prepared according to Australian Journal of Chemistry, 1989 , 42(8), 1217-1225) and phenylisothiocyanate (5.44 mL, 45.5 mmol) in MeCN (75 mL) at 3 C. was added DBU (6.79 mL, 45.5 mmol) and the mixture was stirred at 3 C. for 16 h. The mixture was poured into water (1L), hydrochloric acid (10 mL, 4M) was added, the mixture was extracted with ethyl acetate, the organic layer was washed with water and brine and dried over sodium sulfate. After filtration the mixture was concentrated and dried to give the title compound (8.55 g, 71%).
141-3: Methyl (1RS)-3-{[(2-aminopyridin-4-yl)methyl]amino}-1-methyl-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate
[1597] ##STR00221##
[1598] A solution of methyl (1RS)-3-hydroxy-1-methyl-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (141-3; 8.55 g, 26.8 mmol) and 4-(methylamino)pyridine (5.94 g, 48.2 mmol) in DMA (75 mL) was heated at 100 C. for 1 h. The mixture was poured into water (1L), extracted with DCM, the organic layer was washed with water and brine and dried over sodium sulfate. After filtration the mixture was concentrated and purified by Biotage (SNAP silica 340 g, MeOH:DCM) to give the title compound (8.67 g, 76%).
141-2: Methyl (6RS)-2-(2-aminopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1599] ##STR00222##
[1600] A mixture of methyl (1RS)-3-{[(2-aminopyridin-4-yl)methyl]amino}-1-methyl-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (141-3; 6.07 g, 14.3 mmol), hydrogen peroxide (30% in water, 5.84 mL, 57.2 mmol) in MeOH (272 mL) was heated at 50 C. for 3 h. The mixture was concentrated and purified by Biotage (SNAP silica 110 g, MeOH:DCM) to give the title compound (3.19 g, 57%).
[1601] 141-1: Methyl (6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
##STR00223##
[1602] To a solution of methyl (6RS)-2-(2-aminopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (141-2; 1.60 g, 4.1 mmol) in THF (54 mL) and pyridine (2.86 mL) was added the solution of acetyl chloride (437 L, 6.15 mmol) in THF (10 mL) over 20 minutes and the mixture was stirred at RT for 1 h. MeOH was added, the mixture concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the title compound (1.48 g, 84%).
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1603] ##STR00224##
[1604] A mixture of methyl (6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (141-1; 1.48 g, 3.42 mmol), lithium hydroxide (20.5 mL, 1M in water), THF (61 mL) and MeOH (19 mL) was stirred at RT for 3 h. Citric acid (1.38 g) in water (20 mL) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (1.19 g, 77%).
[1605] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.32 (3H), 2.07 (3H), 2.41 (1H), 2.64 (1H), 2.85 (1H), 3.31 (1H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.37 (1H), 8.08 (1H), 8.21 (1H), 10.35 (1H), 11.95 (1H), 12.59 (1H)
Example 142
Methyl (6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1606] ##STR00225##
[1607] A solution of 4-fluorobenzoic acid (428 mg, 3.06 mmol) and HATU (1.16 g, 3.06 mmol) in DMF (2 mL) was added to a mixture of methyl (6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (31; 500 mg, 1.33 mmol) and DIPEA (532 L, 3.06 mmol) in DMF (2 mL) and the reaction was stirred at 50 C. for 16 h. MeOH and EtOAc were added, the mixture washed with saturated sodium hydrogencarbonate solution, concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the title compound (603 mg, 91%).
[1608] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.55-2.63 (2H), 3.10-3.23 (2H), 3.37 (1H), 3.65 (3H), 6.58 (2H), 6.61 (1H), 7.03 (2H), 7.24 (1H), 7.36 (2H), 7.43 (1H), 8.11 (2H), 8.18 (1H), 8.34 (1H), 10.76 (1H), 12.08 (1H)
Example 143
Methyl (6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbony0amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1609] ##STR00226##
[1610] A solution of 1,3-thiazole-5-carboxylic acid (395 mg, 3.06 mmol) and HATU (1.16 g, 3.06 mmol) in DMF (2 mL) was added to a mixture of methyl (6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (31; 500 mg, 1.33 mmol) and DIPEA (532 L, 3.06 mmol) in DMF (2 mL) and the reaction was stirred at 50 C. for 16 h. MeOH and EtOAc were added, the mixture washed with saturated sodium hydrogencarbonate solution, concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the title compound (645 mg, 90%).
[1611] .sup.1H NMR (400 MHz, DMSO-d6) ppm 2.54-2.65 (2H), 3.09-3.22 (2H), 3.37 (1H), 3.64 (3H), 6.58 (2H), 6.61 (1H), 7.02 (2H), 7.25 (1H), 7.44 (1H), 8.20 (1H), 8.30 (1H), 8.88 (1H), 9.33 (1H), 11.12 (1H), 12.07 (1H)
Example 144
3,3-Dimethyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]butanamide
[1612] ##STR00227##
[1613] A mixture of 4-[(6RS)-6-ammonio-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridinium chloride (5; 40 mg, 102 mol), 3,3-dimethylbutanoyl chloride (28 L, 204 mol) in pyridine (2 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the title compound (14 mg, 33%).
[1614] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.94 (9H), 1.96 (2H), 2.43 (1H), 2.52 (1H), 2.87 (1H), 3.15 (1H), 4.32 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 8.12 (1H), 8.42 (2H), 11.96 (1H)
Example 145
(6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1615] ##STR00228##
[1616] A mixture of methyl (6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (142; 527 mg, 1.06 mmol), potassium hydroxide (4.2 mL, 4M in water), THF (4.2 mL) and MeOH (4.2 mL) was stirred at RT for 10 minutes. Hydrochloric acid (5.6 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (450 mg, 88%).
[1617] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.53-2.63 (2H), 3.08-3.27 (3H), 6.59 (2H), 6.61 (1H), 7.02 (2H), 7.24 (1H), 7.36 (2H), 7.43 (1H), 8.11 (2H), 8.18 (1H), 8.34 (1H), 10.75 (1H), 12.05 (1H), 12.62 (1H)
Example 146
(6RS)-Oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1618] ##STR00229##
[1619] A mixture of methyl (6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (143; 625 mg, 1.28 mmol), potassium hydroxide (5.1 mL, 4M in water), THF (5.1 mL) and MeOH (5.1 mL) was stirred at RT for 10 minutes. Hydrochloric acid (6.8 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (480 mg, 79%).
[1620] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.52-2.62 (2H), 3.07-3.26 (3H), 6.58 (2H), 6.61 (1H), 7.02 (2H), 7.25 (1H), 7.44 (1H), 8.20 (1H), 8.29 (1H), 8.88 (1H), 9.33 (1H), 11.11 (1H), 12.05 (1H), 12.62 (1H)
Example 147
[1621] N.sup.3-Methyl-N-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]-beta-alaninamide trifluoroacetate
##STR00230##
[1622] A solution of tert-butyl methyl(3-oxo-3-[(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7- tetrahydro-1H-indol-6-yl]aminopropyl)carbamate (137; 20 mg, 40 mol) in TFA (2.5 mL) was stirred at RT for 1 h, concentrated and dried to give the title compound (23 mg, 100%).
[1623] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.47-2.58 (5H), 2.64 (1H), 2.93 (1H), 3.10 (2H), 3.24 (1H), 4.41 (1H), 6.72 (2H), 6.77 (1H), 7.13 (2H), 7.73 (2H), 8.06 (1H), 8.31 (2H), 8.57 (1H), 8.61 (2H), 12.50 (1H)
Example 148
(6RS)-N-[(1-Hydroxycyclobutyl)methyl]-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1624] ##STR00231##
[1625] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (90 L, 518 mol), 1-(aminomethyl)cyclobutanol (52 mg, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (40 mg, 54%).
[1626] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.42 (1H), 1.61 (1H), 1.84-1.97 (4H), 2.37 (1H), 2.56 (1H), 2.94-3.10 (2H), 3.16-3.27 (3H), 5.17 (1H), 6.58 (2H), 6.63 (1H), 7.04 (2H), 7.45 (1H), 7.46 (2H), 7.97 (1H), 8.41 (2H), 11.96 (1H)
Example 149
(4E)-5-[(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoic acid
149-1: N-{4-[(6RS)-3-Anilino-6-formyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl)}acetamide
[1627] ##STR00232##
[1628] A solution of ethanedioyl dichloride (196 L, 2.25 mmol) in DCM (6 mL) was cooled to 78 C. DMSO (318 L, 4.50 mmol) was added slowly followed by a solution of N-4-[(6RS)-6-(hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide (94; 350 mg, 896 mol) in DCM (6 mL). The mixture was stirred at 78 C. for 1 h, Et .sub.3N (1.0 mL) was added and the mixture warmed to RT. Water was added, the mixture extracted with DCM/MeOH and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 25 g, MeOH:DCM) to give the title compound (69 mg, 20%).
(4E)-5-[(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoic acid
[1629] ##STR00233##
[1630] To a solution of (3-carboxypropyl)(triphenyl)phosphonium bromide (790 mg, 1.84 mmol) in THF (12 mL) was added KO.sup.tBu (413 mg, 3.68 mmol) at 0 C. and the mixture stirred at 0 C. to RT for 0.5 h. A solution of N-{4-[(6RS)-3-Anilino-6-formyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide (149-1; 143 mg, 368 mol) in THF (5 mL) was added at 0 C. and the mixture stirred for 2 h. Water and EtOAc were added, the mixture washed with brine and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 25 g, MeOH:DCM) followed ba preparative TLC (MeOH:DCM) to give the title compound (38 mg, 20%).
[1631] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.59 (1H), 2.06 (3H), 2.10-2.39 (6H), 2.69 (1H), 2.92 (1H), 5.34-5.44 (2H), 6.57 (2H), 6.60 (1H), 7.01 (2H), 7.17 (1H), 7.35 (1H), 8.08 (1H), 8.22 (1H), 10.33 (1H), 12.02 (1H)
Example 150
Methyl (6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
150-1: Methyl (1RS)-3-({[3-(2,2-difluoroethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate
[1632] ##STR00234##
[1633] A solution of methyl (1RS)-5-oxo-4-(phenylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate (8-2; 863 mg, 2.83 mmol) and 1-[3-(2,2-difluoroethoxy)pyridin-4-yl]methanamine (638 mg, 3.39 mmol; commercially available e.g. from UkrOrgSynthesis Ltd.) in DMA (12 mL) was heated at 130 C. for 1 h. The mixture was concentrated and purified by Biotage (SNAP silica 50 g, EtOAc:Hexane) to give the title compound (660 mg, 49%).
Methyl (6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1634] ##STR00235##
[1635] A mixture of methyl (1RS)-3-({[3-(2,2-difluoroethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (150-1; 510 mg, 1.07 mmol), hydrogen peroxide (34% in water, 193 L, 2.15 mmol) in MeOH (7.9 mL) was heated at 80 C. for 1 h. The mixture was concentrated and purified by Biotage (SNAP silica 25 g, EtOAc:Hexane) to give the title compound (140 mg, 30%).
[1636] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.57-2.66 (2H), 3.10 (1H), 3.18 (1H), 3.37 (1H), 3.65 (3H), 4.33 (2H), 6.33 (1H), 6.51 (2H), 6.57 (1H), 6.96 (2H), 7.29 (1H), 7.44 (1H), 8.13 (1H), 8.38 (1H), 11.40 (1H)
Example 151
N-4-[(6RS)-6-(Azidomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
151-1: [(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate
[1637] ##STR00236##
[1638] A solution of N-4-[(6RS)-6-(hydroxymethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide (94; 1.18 g, 3.01 mmol), DMAP (37 mg, 0.3 mmol) and methanesulfonyl chloride (280 L, 3.61 mmol) in pyridine (16 mL) was stirred at RT for 5 h. MeOH was added, the mixture concentrated and purified by crystallization from MeOH to give the title compound (1.26 g, 90%).
N-4-[(6RS)-6-(Azidomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1639] ##STR00237##
[1640] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 200 mg, 427 mol), sodium azide (278 mg, 4.27 mmol) in DMA (8 mL) was stirred at 60 C. for 16 h. The mixture was filtered, concentrated and purified by Biotage (SNAP silica 10 g, MeOH:DCM) to give the title compound (164 mg, 88%).
[1641] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.28 (1H), 2.35 (1H), 2.47 (1H), 2.69 (1H), 3.02 (1H), 3.50 (2H), 6.56 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.36 (1H), 8.08 (1H), 8.23 (1H), 10.35 (1H), 11.97 (1H)
Example 152
(6RS)-N-(2-Methoxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1642] ##STR00238##
[1643] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (89 L, 518 mol), 2-methoxy-N-methylethanamine (56 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (45 mg, 59%).
[1644] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.27-2.35 (1H), 2.47-2.57 (1H), 2.86+3.09 (3H), 2.91-3.06 (2H), 3.25+3.27 (3H), 3.39-3.51 (3H), 3.56-3.70 (2H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.42-7.48 (3H), 8.41 (2H), 11.95 (1H)
Example 153
(6RS)-2-[2-([rel-(1R,2R)-2-Fluorocyclopropyl]carbonylamino)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1645] ##STR00239##
[1646] A mixture comprising (6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (140; 60 mg, 134 mol), DMF (2 mL), DIPEA (70 L, 401 mol), 2-(methylamino)ethanol (32 L, 401 mol) and T3P (120 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (38 mg, 56%).
[1647] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.18 (1H), 1.64 (1H), 2.20 (1H), 2.32 (1H), 2.46-2.57 (1H), 2.85+3.10 (3H), 2.92-3.03 (2H), 3.28-3.55 (4H), 3.61+3.70 (1H), 4.55-4.95 (1H), 4.85+5.02 (1H), 6.58 (2H), 6.61 (1H), 7.02 (2H), 7.16 (1H), 7.36+7.37 (1H), 8.08 (1H), 8.26 (1H), 10.73 (1H), 11.98 (1H)
Example 154
(6RS)-2-[2-([rel-(1R,2R)-2-Fluorocyclopropyl]carbonylamino)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1648] ##STR00240##
[1649] A mixture comprising (6RS)-2-[2-([rel-(1R,2R)-2-fluorocyclopropyl]carbonylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (140; 60 mg, 134 mol), DMF (2 mL), DIPEA (70 L, 401 mol), N-methylmethanamine (201 L, 2M in THF) and T3P (124 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (37 mg, 58%).
[1650] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.18 (1H), 1.64 (1H), 2.20 (1H), 2.31 (1H), 2.49 (1H), 2.85 (3H), 2.92-3.03 (2H), 3.06 (3H), 3.64 (1H), 4.93 (1H), 6.58 (2H), 6.61 (1H), 7.02 (2H), 7.15 (1H), 7.37 (1H), 8.08 (1H), 8.26 (1H), 10.73 (1H), 11.98 (1H)
Example 155
(6RS)-N-(2,2-Dimethylpropyl)-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1651] ##STR00241##
[1652] A mixture comprising 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (180 L, 1.04 mmol), N,2,2-trimethylpropan-1-amine hydrochloride (71 mg, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (59 mg, 79%).
[1653] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.88+0.92 (9H), 2.24+2.36 (1H), 2.42-2.61 (1H), 2.91+3.14 (3H), 2.95-3.07 (2H), 3.13-3.30 (2H), 3.68 (1H), 6.59 (2H), 6.63 (1H), 7.5 (2H), 7.44 (1H), 7.46 (2H), 8.41 (2H), 11.95 (1H)
Example 156
N-4-[(6RS)-6-(Aminomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1654] ##STR00242##
[1655] A mixture of N-4-[(6RS)-6-(azidomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide (151; 155 mg, 373 mol), triphenylphosphine (218 mg, 832 mol) ammonia (798 L, 25% in water) in THF (5.5 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by Biotage (SNAP silica 28 g, MeOH:DCM) to give the title compound (129 mg, 86%).
[1656] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.16-2.26 (2H), 2.36 (1H), 2.58-2.67 (3H), 2.97 (1H), 6.56 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.35 (1H), 8.07 (1H), 8.22 (1H), 10.34 (1H), 11.91 (1H)
Example 157
Methyl (6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
157-1: Methyl 3-({[3-(cyclopropylmethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate
[1657] ##STR00243##
[1658] A solution of methyl (1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (8-2; 50 mg, 164 mol) and 1-[3-(cyclopropylmethoxy)pyridin-4-yl]methanamine (157-2; 25 mg, 196 mol; commercially available e.g. from UkrOrgSynthesis Ltd.) in DMA (0.7 mL) was heated at 1300 for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (75 mg, 98%).
Methyl (6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1659] ##STR00244##
[1660] A mixture of methyl 3-({[3-(cyclopropylmethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (157-1; 450 mg, 967 mol), hydrogen peroxide (34% in water, 174 L, 1.93 mmol) in MeOH (7.1 mL) was heated at 90 C. for 5.5 h. Saturated sodium thiosulphate solution was added, the mixture concentrated and purified by Biotage (SNAP silica 25 g, MeOH:DCM) to give the title compound (110 mg, 26%).
[1661] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.34 (2H), 0.56 (2H), 1.29 (1H), 2.54-2.65 (2H), 3.07-3.21 (2H), 3.36 (1H), 3.65 (3H), 3.94 (2H), 6.52 (2H), 6.57 (1H), 6.97 (2H), 7.27 (1H), 7.36 (1H), 8.04 (1H), 8.33 (1H), 11.37 (1H)
Example 158
(6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1662] ##STR00245##
[1663] A mixture of methyl (6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (157; 104 mg, 241 mol), potassium hydroxide (964 L, 4M in water), THF (1 mL) and MeOH (1 mL) was stirred at RT for 10 minutes. Hydrochloric acid (1.26 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (45 mg, 45%).
[1664] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.34 (2H), 0.56 (2H), 1.29 (1H), 2.49-2.63 (2H), 3.06-3.18 (2H), 3.24 (1H), 3.93 (2H), 6.52 (2H), 6.57 (1H), 6.97 (2H), 7.28 (1H), 7.39 (1H), 8.05 (1H), 8.32 (1H), 11.35 (1H), 12.58 (1H)
Example 159
(6RS)-2-[3-(Cyclopropylmethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1665] ##STR00246##
[1666] A mixture comprising (6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (158; 30 mg, 72 mol), DMF (0.8 mL), DIPEA (38 L, 216 mol), 2-(methylamino)ethanol (17 L, 216 mol) and T3P (65 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (32 mg, 94%).
[1667] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.35 (2H), 0.56 (2H), 1.29 (1H), 2.30-2.37 (1H), 2.48-2.58 (1H), 2.86+3.11 (3H), 2.92-3.04 (2H), 3.31-3.56 (4H), 3.65+3.73 (1H), 3.88-3.97 (2H), 4.68+4.85 (1H), 6.54 (2H), 6.57 (1H), 6.98 (2H), 7.27 (1H), 7.36+7.37 (1H), 8.04 (1H), 8.31 (1H), 11.31 (1H)
Example 160
Methyl (6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
160-1: Methyl (1RS)-3-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate
[1668] ##STR00247##
[1669] A solution of methyl (1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (8-2; 700 mg, 2.29 mmol) and 1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (160-2; 584 mg, 3.21 mmol; commercially available e.g. from UkrOrgSynthesis Ltd.) in DMA (10 mL) was heated at 130 C. for 1 h. The mixture was concentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the title compound (515 mg, 48%).
Methyl (6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1670] ##STR00248##
[1671] A mixture of methyl (1RS)-3-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (160-1; 460 mg, 980 mol), hydrogen peroxide (34% in water, 177 L, 1.96 mmol) in MeOH (7.2 mL) was heated at 90 C. for 5.5 h. Saturated lo sodium thiosulphate solution was added, the mixture concentrated and purified by Biotage (SNAP silica 25 g, MeOH:DCM) to give the title compound (165 mg, 39%).
[1672] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.54-2.66 (2H), 3.07-3.20 (2H), 3.36 (1H), 3.38 (3H), 3.65 (3H), 3.75 (2H), 4.28 (2H), 6.53 (2H), 6.58 (1H), 6.98 (2H), 7.30 (1H), 7.39 (1H), 8.05 (1H), 8.39 (1H), 11.28 (1H)
Example 161
(6RS)-3-Anilino-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1673] ##STR00249##
[1674] A mixture of methyl (6RS)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (160; 121 mg, 278 mol), potassium hydroxide (1.11 mL, 4M in water), THF (1.1 mL) and MeOH (1.1 mL) was stirred at RT for 10 minutes. Hydrochloric acid (1.5 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (100 mg, 85%).
[1675] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.51-2.63 (2H), 3.06-3.17 (2H), 3.24 (1H), 3.39 (3H), 3.75 (2H), 4.29 (2H), 6.53 (2H), 6.58 (1H), 6.98 (2H), 7.30 (1H), 7.40 (1H), 8.04 (1H), 8.39 (1H), 11.25 (1H), 12.60 (1H)
Example 162
(6RS)-2-[3-(2-Methoxyethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1676] ##STR00250##
[1677] A mixture comprising (6RS)-3-anilino-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (161; 30 mg, 71 mol), DMF (1.1 mL), DIPEA (37 L, 213 mol), N-methylmethanamine (107 L, 2M in THF) and T3P (64 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (30 mg, 94%).
[1678] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.33 (1H), 2.51 (1H), 2.85 (3H), 2.91-3.05 (2H), 3.07 (3H), 3.38 (3H), 3.68 (1H), 3.75 (2H), 4.29 (2H), 6.56 (2H), 6.59 (1H), 6.99 (2H), 7.30 (1H), 7.39 (1H), 8.04 (1H), 8.39 (1H), 11.20 (1H)
Example 163
(6RS)-N-(2-Hydroxyethyl)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-N-methyl-4-oxo-3-(phenylamine)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1679] ##STR00251##
[1680] A mixture comprising (6RS)-3-anilino-2-[3-(2-methoxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (161; 30 mg, 71 mol), DMF (0.8 mL), DIPEA (37 L, 213 mol), 2-(methylamino)ethanol (16 mg, 214 mol) and T3P (64 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (30 mg, 88%).
[1681] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.30-2.38 (1H), 2.48-2.59 (1H), 2.86+3.11 (3H), 2.91-3.06 (2H), 3.31-3.56 (4H), 3.38 (3H), 3.61-3.77 (3H), 4.28 (2H), 4.68+4.86 (1H), 6.55 (2H), 6.59 (1H), 6.99 (2H), 7.29-7.33 (1H), 7.39 (1H), 8.04 (1H), 8.39 (1H), 11.21 (1H)
Example 164
Methyl (6RS)-3-anilino-2-[3-(2-hydroxyethoxy)pyridi n -4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
164-1: Methyl (1RS)-3-({[3-(2-hydroxyethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate
[1682] ##STR00252##
[1683] A solution of methyl (1RS)-3-hydroxy-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (8-2; 1.51 g, 4.95 mmol) and 2-{[4-(aminomethyl)pyridin-3-yl]oxy}ethanol (164-2; 1.00 g, 5.95 mmol; commercially available e.g. from UkrOrgSynthesis Ltd.) in DMA (2 mL) was heated at 130C for 5 h. The mixture was concentrated and purified by Biotage (SNAP silica 340 g, MeOH:DCM) to give the title compound (352 mg, 16%).
Methyl (6RS)-3-anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1684] ##STR00253##
[1685] A mixture of methyl (1RS)-3-({[3-(2-hydroxyethoxy)pyridin-4-yl]methyl}amino)-5-oxo-4-(phenylcarbamothioyl)cyclohex-3-ene-1-carboxylate (164-1; 387 mg, 850 mol), hydrogen peroxide (34% in water, 153 L, 1.70 mmol) in MeOH (5 mL) was heated at 90 C. for 24 h. The mixture was concentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the title compound (133 mg, 37%).
[1686] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.53-2.65 (2H), 3.04-3.19 (2H), 3.37 (1H), 3.65 (3H), 3.84 (2H), 4.25 (2H), 5.61 (1H), 6.55 (2H), 6.58 (1H), 6.99 (2H), 7.31 (1H), 7.44 (1H), 8.02 (1H), 8.42 (1H), 11.59 (1H)
Example 165
(6RS)-2-[3-(2-Hydroxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1687] ##STR00254##
[1688] A mixture of methyl methyl (6RS)-3-anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (164; 255 mg, 605 mol), potassium hydroxide (2.42 mL, 4M in water), THF (2.4 mL) and MeOH (2.4 mL) was stirred at RT for 10 minutes. Hydrochloric acid (3.2 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (149 mg, 58%).
[1689] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.48-2.63 (2H), 3.03-3.16 (2H), 3.23 (1H), 3.85 (2H), 4.25 (2H), 5.61 (1H), 6.56 (2H), 6.59 (1H), 6.99 (2H), 7.31 (1H), 7.44 (1H), 8.02 (1H), 8.42 (1H), 11.57 (1H), 12.62 (1H)
Example 166
(6RS)-2-[3-(2,2-Difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,74etrahydro-1H-indol-6-carboxylic acid
[1690] ##STR00255##
[1691] A mixture of methyl (6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (150; 510 mg, 1.07 mmol), hydrogen peroxide (34% in water, 193 L, 2.15 mmol) in MeOH (7.9 mL) was heated at 90C for 1 h. The mixture was concentrated and purified by Biotage (SNAP silica 25 g, MeOH:DCM) to give the title compound (290 mg, 61%).
[1692] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.53-2.66 (2H), 3.06-3.21 (2H), 3.37 (1H), 3.65 (3H), 4.33 (2H), 6.33 (1H), 6.51 (2H), 6.57 (1H), 6.96 (2H), 7.29 (1H), 7.44 (1H), 8.13 (1H), 8.38 (1H), 11.40 (1H)
Example 167
(6RS)-N-Ethyl-N-(2-hydroxyethyl)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1693] ##STR00256##
[1694] A mixture comprising (6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (90 L, 518 mol), 2-(ethylamino)ethanol (51 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (51 mg, 67%).
[1695] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.03+1.12 (3H), 1.47+1.75 (1H), 2.27+2.32 (1H), 2.48-2.60 (1H), 2.89-3.53 (7H), 3.57+3.68 (1H), 4.70+4.85 (1H), 6.59 (2H), 6.64 (1H), 7.05 (2H), 7.43 (1H), 7.46 (2H), 8.41 (2H), 11.96 (1H)
Example 168
(6RS)-N-(2-Hydroxyethyl)-4-oxo-3-(phenylamino)-N-(propan-2-yl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1696] ##STR00257##
[1697] A mixture comprising (6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (90 L, 518 mol), 2-(isopropylamino)ethanol (83 L, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (13 mg, 16%).
[1698] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.91-1.17 (6H), 1.41-1.56 (2H), 2.26+2.30 (1H), 2.46-2.59 (2H), 2.89-3.70 (5H), 4.21+4.46 (1H), 6.56-6.66 (3H), 7.05 (2H), 7.43-7.49 (3H), 8.42 (2H), 11.96+11.99 (1H)
Example 169
(6RS)-N-[(1-Hydroxycyclobutyl)methyl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1699] ##STR00258##
[1700] A mixture comprising (6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (90 L, 518 mol), 1-[(methylamino)methyl]cyclobutanol (60 mg, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (52 mg, 61%).
[1701] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.42-2.06 (6H), 2.27-2.37 (1H), 2.45-2.59 (1H), 2.90-3.08 (2H), 2.93+3.16 (3H), 3.45-3.54 (2H), 3.65-3.81 (1H), 5.18+5.32 (1H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.43+7.44 (1H), 7.46 (2H), 8.41 (2H), 11.95 (1H)
Example 170
(6RS)-N-[(2R)-1-Hydroxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1702] ##STR00259##
[1703] A mixture comprising (6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol), DMF (2 mL), DIPEA (90 L, 518 mol), (2R)-2-(methylamino)propan-1-ol (65 mg, 518 mol) and T3P (156 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (22 mg, 27%).
[1704] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.97+1.08 (3H), 2.23-2.62 (4H), 2.68+2.90 (3H), 2.92-3.09 (2H), 3.37-3.47 (1H), 3.57-3.74 (1H), 4.07+4.54 (1H), 6.56-6.66 (3H), 7.05 (2H), 7.41-7.50 (3H), 8.39-8.43 (2H), 11.96+12.03 (1H)
Example 171
(6RS)-N-[(2S)-1-Hydroxypropan-2-yl]-N-methyl-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1705] ##STR00260##
[1706] A mixture comprising (6RS)-3-anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 115 mol), DMF (2 mL), DIPEA (60 L, 345 mol), (2S)-2-(methylamino)propan-1-ol (65 mg, 345 mol) and T3P (104 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (22 mg, 41%).
[1707] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.97+1.08 (3H), 2.23-2.59 (4H), 2.68+2.90 (3H), 2.92-3.11 (2H), 3.36-3.45 (1H), 3.58-3.75 (1H), 4.08+4.54 (1H), 6.55-6.66 (3H), 7.05 (2H), 7.41-7.49 (3H), 8.39-8.43 (2H), 11.95+12.00 (1H)
Example 172
N-(4-{(6RS)-3-Anilino-6-methyl-6-[(4-methylpiperazin-1-yl)carbonyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide
[1708] ##STR00261##
[1709] A mixture comprising (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 50 mg, 119 mol), EtOAc (4 mL), DIPEA (62 L, 358 mol), 1-methylpiperazine (80 L, 717 mol) and T3P (142 L, 50% in DMF) was stirred at 40 C. for 16 h. Water was added, the mixture extract ed with EtOAc and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 11 g, MeOH:DCM) and digestion with ether to give the title compound (26 mg, 41%).
[1710] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.40 (3H), 2.07 (3H), 2.16 (3H), 2.25 (4H), 2.44 (1H), 2.73 (1H), 2.93 (1H), 3.43 (1H), 3.51 (4H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.35 (1H), 8.07 (1H), 8.21 (1H), 10.35 (1H), 11.87 (1H)
Example 173
(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1711] ##STR00262##
[1712] A mixture comprising (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 50 mg, 119 mol), EtOAc (4 mL), DIPEA (62 L, 358 mol), N-methylmethanamine (358 L, 2M in THF) and T3P (142 L, 50% in DMF) was stirred at 40 C. for 16 h. Water was added, the mixt ure extracted with EtOAc and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 11 g, MeOH:DCM) and preparative TLC (MeOH:DCM) to give the title compound (24 mg, 43%).
[1713] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.40 (3H), 2.07 (3H), 2.45 (1H), 2.78 (1H), 2.91 (1H), 2.94 (6H), 3.51 (1H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.13 (1H), 7.36 (1H), 8.07 (1H), 8.21 (1H), 10.35 (1H), 11.87 (1H)
Example 174
N-{4-[(6RS)-3-Anilino-6-{[(2R,63)-2,6-dimethylmorpholin-4-yl]carbonyl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide
[1714] ##STR00263##
[1715] A mixture comprising (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 50 mg, 119 mol), EtOAc (4 mL), DIPEA (62 L, 358 mol), (2R,6S)-2,6-dimethylmorpholine (44 L, 358 mol) and T3P (142 L, 50% in DMF) was stirred at 40 C. for 16 h. Water was added, the mixture extracted with EtOAc and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 11 g, MeOH:DCM) and preparative TLC (MeOH:DCM) to give the title compound (18 mg, 28%).
[1716] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.09 (6H), 1.41 (3H), 2.07 (3H), 2.46 (1H), 2.73 (1H), 2.95 (1H), 3.28-3.47 (5H), 4.12 (2H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.15 (1H), 7.34 (1H), 8.08 (1H), 8.20 (1H), 10.35 (1H), 11.87 (1H)
Example 175
N-(4-{(6RS)-3-Anilino-6-[(3-fluoroazetidin-1-yl)carbonyl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide
[1717] ##STR00264##
[1718] A mixture comprising (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indole-6-carboxylic acid (141; 50 mg, 119 mol), EtOAc (4 mL), DIPEA (62 L, 358 mol), 3-fluoroazetidine (40 mg, 358 mol) and T3P (142 L, 50% in DMF) was stirred at 40 C. for 16 h. Water was added, the mixture extract ed with EtOAc and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 11 g, MeOH:DCM) and digestion with ether to give the title compound (25 mg, 42%).
[1719] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.30 (3H), 2.07 (3H), 2.47 (1H), 2.64 (1H), 2.81 (1H), 3.39 (1H), 3.84 (1H), 4.13 (1H), 4.44 (1H), 4.71 (1H), 5.36 (1H), 6.54 (2H), 6.59 (1H), 7.01 (2H), 7.15 (1H), 7.39 (1H), 8.09 (1H), 8.21 (1H), 10.36 (1H), 11.92 (1H)
Example 176
N-(4-{(6RS)-3-Anilino-6-[(3,3-difluoroazetidin-1-yl)carbonyl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide
[1720] ##STR00265##
[1721] A mixture comprising (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 50 mg, 119 mol), EtOAc (4 mL), DIPEA (62 L, 358 mol), 3,3-difluoroazetidine (46 mg, 358 mol) and T3P (142 L, 50% in DMF) was stirred at 40 C. for 16 h. Water was added, the mixture extracted with EtOAc and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 11 g, MeOH:DCM) to give the title compound (22 mg, 36%).
[1722] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.33 (3H), 2.07 (3H), 2.54 (1H), 2.64 (1H), 2.85 (1H), 3.39 (1H), 4.32 (2H), 4.76 (2H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.15 (1H), 7.39 (1H), 8.09 (1H), 8.21 (1H), 10.37 (1H), 11.92 (1H)
Example 177
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-methoxyethyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1723] ##STR00266##
[1724] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 50 mg, 119 mol) and HATU (68 mg, 179 mol) in DMA (1 mL) was added to a mixture of 2-methoxy-N-methylethanamine (16 L, 143 mol) and DIPEA (25 L, 143 mol) in DMA (1 mL) and the reaction was stirred at RT for 3 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (26 mg, 41%).
[1725] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.40 (3H), 2.07 (3H), 2.42 (1H), 2.75 (1H), 2.92 (1H), 3.08 (2H), 3.12 (3H), 3.22-3.41 (4H), 3.44-3.55 (2H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.13 (1H), 7.34 (1H), 8.07 (1H), 8.21 (1H), 10.34 (1H), 11.86 (1H)
Example 178
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,N-diethyl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1726] ##STR00267##
[1727] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 50 mg, 119 mol) and HATU (91 mg, 239 mol) in DMA (1 mL) was added to a mixture of N-ethylethanaminium chloride (39 mg, 358 mol) and DIPEA (125 L, 717 mol) in DMA (1 mL) and the reaction was stirred at RT for 3 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (23 mg, 39%).
[1728] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.01 (6H), 1.39 (3H), 2.07 (3H), 2.45 (1H), 2.72 (1H), 2.91 (1H), 3.30 (4H), 3.42 (1H), 6.53 (2H), 6.58 (1H), 6.99 (2H), 7.14 (1H), 7.33 (1H), 8.07 (1H), 8.20 (1H), 10.34 (1H), 11.87 (1H)
Example 179
N-4-[(6RS)-6-Methyl-6-(2-oxa-6-azaspiro[3.3]hept-6-ylcarbonyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1729] ##STR00268##
[1730] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 50 mg, 119 mol) and HATU (91 mg, 239 mol) in DMA (0.9 mL) was added to a mixture of 2-oxa-6-azaspiro[3.3]heptane (52 mg, 358 mol) and DIPEA (167 L, 956 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 3 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (14 mg, 23%).
[1731] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.27 (3H), 2.07 (3H), 2.45 (1H), 2.62 (1H), 2.78 (1H), 3.37 (1H), 3.97 (2H), 4.56 (2H), 4.64 (4H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.37 (1H), 8.08 (1H), 8.21 (1H), 10.35 (1H), 11.90 (1H)
Example 180
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-2-methoxypropyl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
180-2: tert-Butyl [(2S)-2-methoxypropyl]methylcarbamate
[1732] ##STR00269##
[1733] From 1.83 g sodium hydride (60%) the mineral oil was removed and THF (60 mL) was added followed by iodomethane (2.84 mL, 45.7 mmol) and tert-butyl [(2R)-2-hydroxypropyl]carbamate (CAS-No: 119768-44-4; 2.00 g, 11.4 mmol) solved in THF (10 mL). The mixture was stirred at RT for 4 h, methanol was added and the solvents were removed. Dichloromethane was added, the suspension was filtered through silica gel and concentrated to give 960 mg (34%) of the title compound.
180-1: (2S)-2-Methoxy-N-methylpropan-1-aminium chloride
[1734] ##STR00270##
[1735] A mixture comprising tert-butyl [(2S)-2-methoxypropyl]methylcarbamate (180-2; 960 mg, 4.72 mmol) and hydrochloric acid (14 mL, 4M in dioxane) was heated at 50 C. for 16 hours. The solvents were removed, the residue digested with diethyl ether and the precipitate was dried to give 425 mg (61%) of the title compound.
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-2-methoxypropyl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1736] ##STR00271##
[1737] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1 H-indol-6-carboxylic acid (141; 50 mg, 119 mol) and HATU (91 mg, 239 mol) in DMA (0.9 mL) was added to a mixture of (2S)-2-methoxy-N-methylpropan-1-aminium chloride (180-1; 50 mg, 358 mol) and DIPEA (125 L, 717 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 3 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (20 mg, 31%).
[1738] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.80+0.83 (3H), 1.41 (3H), 2.07 (3H), 2.38 (1H), 2.76 (1H), 2.94 (1H), 3.03+3.08 (3H), 3.10-3.32 (5H), 3.37+3.46 (1H), 3.54+3.58 (1H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.12 (1H), 7.31+7.32 (1H), 8.06 (1H), 8.19 (1H), 10.34 (1H), 11.85+11.86 (1H)
Example 181
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-1-methoxypropan-2-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
181-2: tert-Butyl [(2S)-1-methoxypropan-2-yl]methylcarbamate
[1739] ##STR00272##
[1740] From 1.83 g sodium hydride (60%) the mineral oil was removed, THF (60 mL) was added followed by iodomethane (2.84 mL, 45.7 mmol) and tert-butyl [(2S)-1-methoxypropan-2-yl]methylcarbamate (CAS-No: 167938-56-9; 2.00 g, 11.4 mmol) solved in THF (10 mL). The mixture was stirred at RT for 4 h, methanol was added and the solvents were removed. Dichloromethane was added, the suspension was filtered through silica gel and concentrated to give 1.00 g (38%) of the title compound.
181-1: (2S)-1-Methoxy-N-methylpropan-2-aminium chloride
[1741] ##STR00273##
[1742] A mixture comprising tert-butyl [(2S)-1-methoxypropan-2-yl]methylcarbamate (180-2; 1.00 g, 4.92 mmol) and hydrochloric acid (12.3 mL, 4M in dioxane) was heated at 50 C. for 16 hours. The solvents were removed, the residue digested with diethyl ether and the precipitate was dried to give 446 mg (62%) of the title compound.
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-[(2S)-1-methoxypropan-2-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1743] ##STR00274##
[1744] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 50 mg, 119 mol) and HATU (91 mg, 239 mol) in DMA (0.9 mL) was added to a mixture of (2S)-1-methoxy-N-methylpropan-2-aminium chloride (181-1; 50 mg, 358 mol) and DIPEA (125 L, 717 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 3 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (22 mg, 34%).
[1745] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.01 (3H), 1.41 (3H), 2.07 (3H), 2.39+2.47 (1H), 2.63-3.55 (11H), 4.39+4.45 (1H), 6.53 (2H), 6.58 (1H), 6.99 (2H), 7.13 (1H), 7.33 (1H), 8.07 (1H), 8.20 (1H), 10.34 (1H), 11.85 (1H)
Example 182
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2-methoxy-2-methylpropyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1746] ##STR00275##
[1747] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 50 mg, 119 mol) and HATU (91 mg, 239 mol) in DMA (1 mL) was added to a mixture of 2-methoxy-N,2-dimethylpropan-1-aminium chloride (30 mg, 195 mol) and DIPEA (83 L, 479 mol) in DMA (1 mL) and the reaction was stirred at RT for 6 h and at 50 C. for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (10 mg, 16%).
[1748] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.69 (3H), 0.85 (3H), 1.43 (3H), 2.07 (3H), 2.38 (1H), 2.77 (1H), 2.95 (1H), 3.03 (4H), 3.22 (3H), 3.54-3.62 (2H), 6.53 (2H), 6.60 (1H), 6.99 (2H), 7.09 (1H), 7.29 (1H), 8.05 (1H), 8.18 (1H), 10.34 (1H), 11.84 (1H)
Example 183
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,6-dimethyl-4-oxo-3-(phenylamino)-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1749] ##STR00276##
[1750] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1 H-indol-6-carboxylic acid (141; 50 mg, 119 mol) and HATU (91 mg, 239 mol) in DMA (1 mL) was added to a mixture of N-methylpropan-1-amine (18 L, 179 mol) and DIPEA (62 L, 358 mol) in DMA (1 mL) and the reaction was stirred at RT for 3 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (19 mg, 32%).
[1751] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.69 (3H), 1.37 (2H), 1.40 (3H), 2.07 (3H), 2.42 (1H), 2.76 (1H), 2.91 (1H), 2.99 (3H), 3.11 (1H), 3.29 (1H), 3.51 (1H), 6.53 (2H), 6.59 (1H), 6.99 (2H), 7.13 (1H), 7.32 (1H), 8.07 (1H), 8.20 (1H), 10.35 (1H), 11.85 (1H)
Example 184
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N-(2,2-dimethylpropyl)-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1752] ##STR00277##
[1753] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 45 mg, 108 mol) and HATU (82 mg, 215 mol) in DMA (1 mL) was added to a mixture of N,2,2-trimethylpropan-1-aminium chloride (44 mg, 323 mol) and DIPEA (112 L, 645 mol) in DMA (1 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (23 mg, 40%).
[1754] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.63 (9H), 1.42 (3H), 2.07 (3H), 2.39 (1H), 2.79 (2H), 2.92 (1H), 3.22 (3H), 3.39 (1H), 3.60 (1H), 6.54 (2H), 6.59 (1H), 6.99 (2H), 7.06 (1H), 7.28 (1H), 8.05 (1H), 8.18 (1H), 10.33 (1H), 11.83 (1H)
Example 185
N-4-[(6RS)-6-[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1755] ##STR00278##
[1756] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 45 mg, 108 mol) and HATU (82 mg, 215 mol) in DMA (1 mL) was added to a mixture of (3R)-N,N-dimethylpyrrolidin-3-amine (41 L, 323 mol) and DIPEA (56 L, 323 mol) in DMA (1 mL) and the reaction was stirred at RT for 3 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (15 mg, 26%).
[1757] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.34 (3H), 1.85-3.55 (10H) 2.07 (3H), 2.15 (6H), 3.85 (1H), 6.52 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.36 (1H), 8.08 (1H), 8.21 (1H), 10.34+10.35 (1H), 11.87 (1H)
Example 186
N-4-[(6RS)-6-Methyl-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1758] ##STR00279##
[1759] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 45 mg, 108 mol) and HATU (82 mg, 215 mol) in DMA (1 mL) was added to a mixture of (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (60 mg, 323 mol) and DIPEA (169 L, 968 mol) in DMA (1 mL) and the reaction was stirred at RT for 3 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (11 mg, 19%).
[1760] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.34 (3H), 1.41-1.86 (2H), 2.07 (3H), 2.23+2.25 (3H), 2.35-2.61 (2H), 2.69-3.86 (7H), 4.36-4.83 (1H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.34 (1H), 8.08 (1H), 8.21 (1H), 10.34+10.35 (1H), 11.88+11.90 (1H)
Example 187
(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-N,6-dimethyl-N-(2-methylpropy0-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1761] ##STR00280##
[1762] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 45 mg, 108 mol) and HATU (82 mg, 215 mol) in DMA (1 mL) was added to a mixture of N,2-dimethylpropan-1-amine (39 L, 323 mol) and DIPEA (56 L, 323 mol) in DMA (1 mL) and the reaction was stirred at RT for 3 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (16 mg, 29%).
[1763] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.55 (3H), 0.67 (3H), 1.41 (3H), 1.72 (1H), 2.07 (3H), 2.38 (1H), 2.77 (1H), 2.81 (1H), 2.92 (1H), 3.10 (3H), 3.25 (1H), 3.56 (1H), 6.53 (2H), 6.59 (1H), 6.99 (2H), 7.11 (1H), 7.29 (1H), 8.06 (1H), 8.19 (1H), 10.34 (1H), 11.84 (1H)
Example 188
N-4-[(6RS)-6-Methyl-6-[(1 R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylcarbonyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1764] ##STR00281##
[1765] A solution of (6RS)-2-[2-(acetylamino)pyridin-4-yl]-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (141; 45 mg, 108 mol) and HATU (82 mg, 215 mol) in DMA (1 mL) was added to a mixture of (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (44 mg, 323 mol) and DIPEA (112 L, 645 mol) in DMA (1 mL) and the reaction was stirred at RT for 3 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (24 mg, 42%).
[1766] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.37 (3H), 1.53-1.87 (2H), 2.07 (3H), 2.38-2.59 (2H), 2.74 (1H), 2.89-3.85 (5H), 4.49-5.12 (2H), 6.50-6.61 (3H), 7.00 (2H), 7.15 (1H), 7.36 (1H), 8.08 (1H), 8.21+8.22 (1H), 10.35+10.36 (1H), 11.89+11.91 (1H)
Example 189
N-4-[(6RS)-6-[(Ethylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1767] ##STR00282##
[1768] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol) and sodium ethanethiolate (81 mg, 960 mol) in DMA (2.3 mL) was stirred at 100 C. for 5 h. Water was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (44 mg, 60%).
[1769] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.19 (3H), 2.07 (3H), 2.26 (1H), 2.35-2.47 (2H), 2.54 (2H), 2.59-2.70 (3H), 3.11 (1H), 6.56 (2H), 6.60 (1H), 7.01 (2H), 7.14 (1H), 7.34 (1H), 8.06 (1H), 8.24 (1H), 10.32 (1H), 11.95 (1H)
Example 190
[1770] N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide
##STR00283##
[1771] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol) and sodium propane-2-thiolate (94 mg, 960 mol) in DMA (2.3 mL) was stirred at 100 C. for 5 h. Water was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (43 mg, 57%).
[1772] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.22 (6H), 2.07 (3H), 2.25-2.39 (2H), 2.44 (1H), 2.60-2.72 (3H), 2.95 (1H), 3.13 (1H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.35 (1H), 8.08 (1H), 8.23 (1H), 10.34 (1H), 11.95 (1H)
Example 191
N-4-[(6RS)-6-[(tert-Butylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1773] ##STR00284##
[1774] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol) and sodium 2-methylpropane-2-thiolate (108 mg, 960 mol) in DMA (3 mL) was stirred at 1001 for 5 h. Water was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (45 mg, 58%).
[1775] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.29 (9H), 2.07 (3H), 2.25-2.36 (2H), 2.40-2.48 (1H), 2.61-2.71 (3H), 3.11 (1H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.35 (1H), 8.07 (1H), 8.23 (1H), 10.33 (1H), 11.94 (1H)
Example 192
(6RS)-2-(2-Aminopyriclin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfany0methyl]-1,5,6,7-tetrahydro-4H-indol-4-one
192-1: [(6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate
[1776] ##STR00285##
[1777] A solution of (6RS)-2-(2-aminopyridin-4-yl)-6-(hydroxymethyl)-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one (87; 1.17 g, 3.34 mmol), DMAP (41 mg, 334 mol) and methanesulfonyl chloride (311 L, 4.01 mmol) in pyridine (18 mL) was stirred at RT for 4 h. MeOH was added, the mixture concentrated and purified by Biotage (SNAP silica 110 g, MeOH:DCM) to give the title compound (1.27 g, 89%).
(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one
[1778] ##STR00286##
[1779] A mixture of [(6R.sup.5)-2-(2-aminopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (192-1; 512 mg, 1.20 mmol) and sodium propane-2-thiolate (707 mg, 7.20 mmol) in DMA (17 mL) was stirred at 100 C. for 5 h. Water was added, the mixture concentrated and purified by Biotage (SNAP silica 55 g, MeOH:DCM) to give the title compound (411 mg, 84%).
[1780] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.22 (6H), 2.26 (1H), 2.35 (1H), 2.42 (1H), 2.59-2.71 (3H), 2.94 (1H), 3.09 (1H), 5.74 (2H), 6.55 (2H), 6.58 (1H), 6.60 (1H), 6.69 (1H), 7.02 (2H), 7.22 (1H), 7.76 (1H), 11.71 (1H)
Example 193
(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(S)-propan-2-ylsulfinyl]methyl-1,5,6,7-tetrahydro-4H-indol-4-one
[1781] ##STR00287##
[1782] A mixture comprising (6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (192; 714 mg, 1.76 mmol), mCPBA (741 mg, 75%) and DMA (50 mL) was stirred at RT for 16 h. TEA (1 mL) was added, the mixture concentrated and purified by Biotage (SNAP silica 55 g, MeOH:DCM) to give the title compound (246 mg, 32%).
[1783] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.18 (6H), 2.39 (1H), 2.46 (1H), 2.63-2.90 (5H), 3.15 (1H), 5.84 (2H), 6.54-6.63 (4H), 6.71 (1H), 7.03 (2H), 7.26 (1H), 7.76 (1H), 11.78+11.81 (1H)
Example 194
(6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonAmethyl]-1,5,6,7-tetrahydro-4H-indol-4-one
[1784] ##STR00288##
[1785] A mixture comprising (6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (192; 714 mg, 1.76 mmol), mCPBA (741 mg, 75%) and DMA (50 mL) was stirred at RT for 16 h. TEA (1mL) was added, the mixture concentrated and purified by Biotage (SNAP silica 55 g, MeOH:DCM) to give the title compound (173 mg, 21%).
[1786] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.26 (6H), 2.39 (1H), 2.48 (1H), 2.76-2.88 (2H), 3.20-3.33 (4H), 5.81 (2H), 6.54-6.63 (4H), 6.71 (1H), 7.03 (2H), 7.25 (1H), 7.76 (1H), 11.81 (1H)
Example 195
(6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-N,N-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1787] ##STR00289##
[1788] A mixture comprising (6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (145; 60 mg, 123 mol), DMF (2 mL), DIPEA (65 L, 372 mol), N-methylmethanamine (186 L, 2M in THF) and T3P (112 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (36 mg, 54%).
[1789] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.33 (1H), 2.53 (1H), 2.86 (3H), 2.94-3.03 (2H), 3.07 (3H), 3.65 (1H), 6.59-6.64 (3H), 7.03 (2H), 7.24 (1H), 7.36 (2H), 7.41 (1H), 8.10 (2H), 8.18 (1H), 8.34 (1H), 10.74 (1H), 12.02 (1H)
Example 196
(6RS)-2-2-[(4-Fluorobenzoyl)amino]pyridin-4-yl-N-(2-hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1790] ##STR00290##
[1791] A mixture comprising (6RS)-2-2-[(4-fluorobenzoyl)amino]pyridin-4-yl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (145; 60 mg, 123 mol), DMF (2 mL), DIPEA (65 L, 372 mol), 2-(methylamino)ethanol (30 L, 372 mol) and T3P (112 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (49 mg, 69%).
[1792] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.30-2.38 (1H), 2.46-2.58 (1H), 2.86+3.11 (3H), 2.93-3.07 (2H), 3.29-3.56 (4H), 3.60-3.76 (1H), 4.69+4.86 (1H), 6.59-6.64 (3H), 7.03 (2H), 7.24 (1H), 7.35 (2H), 7.41+7.42 (1H), 8.10 (2H), 8.18 (1H), 8.34 (1H), 10.74 (1H), 12.02 (1H)
Example 197
(6RS)-N,N-Dimethyl-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1793] ##STR00291##
[1794] A mixture comprising (6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (146; 60 mg, 127 mol), DMF (2 mL), DIPEA (66 L, 380 mol), N-methylmethanamine (190 L, 2M in THF) and T3P (114 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (43 mg, 64%).
[1795] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.33 (1H), 2.53 (1H), 2.86 (3H), 2.93-3.03 (2H), 3.07 (3H), 3.66 (1H), 6.56-6.64 (3H), 7.03 (2H), 7.25 (1H), 7.42 (1H), 8.20 (1H), 8.29 (1H), 8.88 (1H), 9.33 (1H), 11.11 (1H), 12.02 (1H)
Example 198
(6RS)-N-(2-Hydroxyethyl)-N-methyl-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1796] ##STR00292##
[1797] A mixture comprising (6RS)-4-oxo-3-(phenylamino)-2-2-[(1,3-thiazol-5-ylcarbonyl)amino]pyridin-4-yl-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (146; 60 mg, 127 mol), DMF (2 mL), DIPEA (66 L, 380 mol), 2-(methylamino)ethanol (31 L, 380 mol) and T3P (114 L, 50% in DMF) was stirred at RT for 1 h. The mixture was filtered and purified by preparative HPLC (basic method) to give the title compound (49 mg, 69%).
[1798] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.34 (1H), 2.47-2.56 (1H), 2.86+3.11 (3H), 2.89-3.05 (3H), 3.19-3.76 (4H), 3.89 (1H), 6.57-6.64 (3H), 7.03 (2H), 7.25 (1H), 7.41+7.42 (1H), 8.19 (1H), 8.29 (1H), 8.88 (1H), 9.33 (1H), 11.12 (1H), 12.05 (1H)
Example 199
N-{4-[(6RS)-3-Anilino-6-{[(methylsulfonyl)amino]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide
[1799] ##STR00293##
[1800] A mixture of N-4-[(6RS)-6-(aminomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide (156; 40 mg, 103 mol), methanesulfonyl chloride (16 L, 205 mol) in pyridine (1.2 mL) was stirred at RT for 16 h. MeOH was added, the mixture concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (36 mg, 70%).
[1801] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.25 (1H), 2.31-2.40 (2H), 2.65 (1H), 2.92 (3H), 2.99-3.07 (3H), 6.56 (2H), 6.60 (1H), 7.01 (2H), 7.16 (1H), 7.21 (1H), 7.36 (1H), 8.08 (1H), 8.23 (1H), 10.35 (1H), 11.97 (1H)
Example 200
N-{4-[(6RS)-6-(Acetamidomethyl)-3-anilino-4-oxo-4,5,6,74etrahydro-1H-in do1-2-yl]pyridin-2-yl}acetamide
[1802] ##STR00294##
[1803] A mixture of N-4-[(6RS)-6-(aminomethyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide (156; 40 mg, 103 mol), acetyl chloride (15 L, 205 mol) in pyridine (1.2 mL) was stirred at RT for 16 h. MeOH was added, the mixture concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (28 mg, 59%).
[1804] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.85 (3H), 2.07 (3H), 2.22 (1H), 2.27-2.36 (2H), 2.59 (1H), 2.93 (1H), 3.10 (1H), 3.18 (1H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.35 (1H), 8.00 (1H), 8.08 (1H), 8.22 (1H), 10.34 (1H), 11.95 (1H)
Example 202
5-[(6RS)-2-[2-(Acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pentanoic acid
[1805] ##STR00295##
[1806] A mixture comprising (4E)-5-[(6RS)-2-[2-(acetylamino)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-yl]pent-4-enoic acid (149; 27 mg, 59 mol), Pd/C (6.3 mg, 10%), THF (1 mL) and EtOH (1.3 mL) was stirred under an atmosphere of hydrogen at RT for 16 h. After filtration the mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (9 mg, 32%).
[1807] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.29-1.45 (4H), 1.50 (2H), 2.06 (3H), 2.18 (4H), 2.31 (1H), 2.54 (1H), 2.97 (1H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.35 (1H), 8.07 (1H), 8.22 (1H), 10.34 (1H), 11.93 (1H)
Example 203
(6RS)-3-Anilino-N,N-dlisopropyl-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1808] ##STR00296##
[1809] A solution of (6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (9; 60 mg, 173 mol) and HATU (66 mg, 173 mol) in DMA (1 mL) was added to a mixture of N-isopropylpropan-2-amine (73 L, 518 mol) and DIPEA (30 L, 173 mol) in DMA (1 mL) and the reaction was stirred at 50eC for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (16 mg, 22%).
[1810] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.17 (6H), 1.30 (6H), 2.24 (1H), 2.57 (1H), 2.90 (1H), 3.03 (1H), 3.42-3.61 (2H), 4.14 (1H), 6.59 (2H), 6.64 (1H), 7.08 (2H), 7.43 (1H), 7.46 (2H), 8.42 (2H), 11.93 (1H)
Example 204
(6RS)-3-Anilino-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1811] ##STR00297##
[1812] A mixture comprising of (6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (166; 30 mg, 70 mol), DMF (1.1 mL), DIPEA (55 L, 316 mol), N-methylmethanamine (158 L, 2M in THF) and T3P (95 L, 50% in DMF) was stirred at RT for 2 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (5 mg, 16%).
[1813] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.32 (1H), 2.47-2.52 (1H), 2.84 (3H), 2.93 (1H), 2.99 (1H), 3.06 (3H), 3.66 (1H), 4.30 (2H), 6.30 (1H), 6.52 (2H), 6.55 (1H), 6.94 (2H), 7.28 (1H), 7.42 (1H), 8.11 (1H), 8.35 (1H), 11.34 (1H)
Example 205
(6RS)-3-Anilino-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1814] ##STR00298##
[1815] A mixture comprising of (6RS)-2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (166; 30 mg, 70 mol), DMF (0.8 mL), DIPEA (37 L, 211 mol), 2-(methylamino)ethanol (17 L, 211 mol) and T3P (63 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (10 mg, 29%).
[1816] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.32 (1H), 2.45-2.57 (1H), 2.84+3.10 (3H), 2.92 (1H), 3.00 (1H), 3.30-3.54 (4H), 3.64+3.72 (1H), 4.29 (2H), 4.67+4.83 (1H), 6.30 (1H), 6.51 (2H), 6.55 (1H), 6.95 (2H), 7.28 (1H), 7.42+7.43 (1H), 8.11 (1H), 8.35 (1H), 11.33+11.35 (1H)
Example 206
(6RS)-3-Anilino-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-. 1H-indol-6-carboxamide
[1817] ##STR00299##
[1818] A mixture comprising of (6RS)-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (165; 50 mg, 123 mol), DMF (1.8 mL), DIPEA (64 L, 368 mol), N-methylmethanamine (184 L, 2M in THF) and T3P (114 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (8 mg, 14%).
[1819] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.34 (1H), 2.52 (1H), 2.87 (3H), 2.94 (1H), 3.00 (1H), 3.08 (3H), 3.68 (1H), 3.86 (2H), 4.26 (2H), 5.59 (1H), 6.59 (2H), 6.61 (1H), 7.01 (2H), 7.32 (1H), 7.43 (1H), 8.02 (1H), 8.42 (1H), 11.55 (1H)
Example 207
(6RS)-3-Anilino-2-[3-(2-hydroxyeth oxy)pyridin-4-yl]-N-(2-hydroxyethyl)-N-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1820] ##STR00300##
[1821] A mixture comprising of (6RS)-2-[3-(2-hydroxyethoxy)pyridin-4-yl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (165; 50 mg, 123 mol), DMF (1.8 mL), DIPEA (64 L, 368 mol), 2-(methylamino)ethanol (30 L, 368 mol) and T3P (111 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (12 mg, 19%).
[1822] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.32-2.38 (1H), 2.49-2.59 (1H), 2.87+3.12 (3H), 2.93 (1H), 3.01 (1H), 3.29-3.55 (4H), 3.66+3.73 (1H), 3.85 (2H), 4.21-4.30 (2H), 4.67+4.83 (1H), 5.57 (1H), 6.56-6.63 (3H), 7.01 (2H), 7.33 (1H), 7.42+7.44 (1H), 8.02+8.03 (1H), 8.42 (1H), 11.55 (1H)
Example 208
(6RS)-3-Anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indol-6-carboxamide
[1823] ##STR00301##
[1824] A mixture comprising of (6RS)-3-anilino-2-[3-(cyclopropylmethoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (158; 30 mg, 72 mol), DMF (1.1 mL), DIPEA (38 L, 216 mol), N-methylmethanamine (108 L, 2M in THF) and T3P (65 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (15 mg, 47%).
[1825] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.35 (2H), 0.56 (2H), 1.29 (1H), 2.32 (1H), 2.51 (1H), 2.86 (3H), 2.92-3.04 (2H), 3.07 (3H), 3.67 (1H), 3.93 (2H), 6.54 (2H), 6.57 (1H), 6.97 (2H), 7.27 (1H), 7.36 (1H), 8.04 (1H), 8.31 (1H), 11.30 (1H)
Example 209
Methyl (6RS)-3-anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1826] ##STR00302##
[1827] A solution of methyl (6RS)-2-(2-aminopyridin-4-yl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (31; 150 mg, 398 mol) and HATU (348 mg, 917 mol) in DMF (1 mL) was added to a mixture of (1RS)-2,2-difluorocyclopropanecarboxylic acid (112 mg, 917 mol) and DIPEA (160 L, 917 mol) in DMF (1 mL) and the reaction was stirred at 50 C. for 16 h. The mixture was concentrated and purified by Biotage (SNAP silica 10 g, MeOH:DCM) to give the title compound (154 mg, 72%).
[1828] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.01 (2H), 2.53 (1H), 2.58 (1H), 2.98 (1H), 3.10 (1H), 3.18 (1H), 3.35 (1H), 3.64 (3H), 6.55 (2H), 6.61 (1H), 7.01 (2H), 7.19 (1H), 7.41 (1H), 8.12 (1H), 8.22 (1H), 10.90 (1H), 12.05 (1H)
Example 210
(6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1829] ##STR00303##
[1830] A mixture of methyl (6RS)-3-anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (209; 150 mg, 312 mol), potassium hydroxide (1.25 mL, 4M in water), THF (1.2 mL) and MeOH (1.2 mL) was stirred at RT for 10 minutes. Hydrochloric acid (1.67 mL, 3M) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (111 mg, 77%).
[1831] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.91-2.06 (2H), 2.51-2.61 (2H), 2.98 (1H), 3.06-3.17 (2H), 3.22 (1H), 6.55 (2H), 6.61 (1H), 7.01 (2H), 7.18 (1H), 7.41 (1H), 8.11 (1H), 8.22 (1H), 10.89 (1H), 12.02 (1H), 12.59 (1H)
Example 211
(6RS)-3-Anilino-2-[2-({[(1RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,N-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-le-6-carboxamide
[1832] ##STR00304##
[1833] A mixture comprising of (6RS)-3-Anilino-2-[2-({[(1 RS)-2,2-difluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (210; 55 mg, 118 mol), DMF (1.5 mL), DIPEA (62 L, 354 mol), N-methylmethanamine (177 L, 2M in THF) and T3P (106 L, 50% in DMF) was stirred at RT for 1 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (24 mg, 39%).
[1834] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.01 (2H), 2.33 (1H), 2.48-2.56 (1H), 2.86 (3H), 2.94-3.04 (2H), 3.07 (3H), 3.33 (1H), 3.65 (1H), 6.59 (2H), 6.63 (1H), 7.03 (2H), 7.19 (1H), 7.37 (1H), 8.12 (1H), 8.23 (1H), 10.87 (1H), 11.97 (1H)
Example 212
N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfany0methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2yl)-4-fluoro-3-methoxybenzamide
[1835] ##STR00305##
[1836] A solution of 4-fluoro-3-methoxybenzoic acid (42 mg, 246 mol) and HATU (94 mg, 246 mol) in DMA (1.2 mL) was added to a mixture of (6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (192; 50 mg, 123 mol) and DIPEA (43 L, 246 mol) in DMA (1.2 mL) and the reaction was stirred at 50 C. for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) and crystallization from MeOH to give the title compound (18 mg, 25%).
[1837] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.21 (6H), 2.29 (1H), 2.37 (1H), 2.44 (1H), 2.61-2.71 (3H), 2.94 (1H), 3.13 (1H), 3.93 (3H), 6.57 (2H), 6.60 (1H), 7.01 (2H), 7.23 (1H), 7.35 (1H), 7.39 (1H), 7.63 (1H), 7.84 (1H), 8.17 (1H), 8.34 (1H), 10.77 (1H), 12.00 (1H)
Example 213
N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-2-fluoro-2-methylpropanamide
[1838] ##STR00306##
[1839] A solution of 2-fluoro-2-methylpropanoic acid (26 mg, 246 mol) and HATU (94 mg, 246 mol) in DMA (1.2 mL) was added to a mixture of (6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (192; 50 mg, 123 mol) and DIPEA (43 L, 246 mol) in DMA (1.2 mL) and the reaction was stirred at 50 C. for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) and crystallization from MeOH to give the title compound (17 mg, 27%).
[1840] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.21 (6H), 1.54 (3H), 1.58 (3H), 2.28 (1H), 2.36 (1H), 2.44 (1H), 2.59-2.70 (3H), 2.93 (1H), 3.12 (1H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.22 (1H), 7.40 (1H), 8.11-8.14 (2H), 9.70 (1H), 11.98 (1H)
Example 214
1-(4-{(6RS)-3-Anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-3-cyclopropylurea
[1841] ##STR00307##
[1842] A mixture of (6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (192; 60 mg, 148 mol), isocyanatocyclopropane (25 L, 295 mol) in pyridine (1.6 mL) was stirred at RT for 2.5 days. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) and crystallization from MeOH to give the title compound (10 mg, 13%).
[1843] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.41 (2H), 0.64 (2H), 1.20 (6H), 2.27 (1H), 2.34 (1H), 2.43 (1H), 2.56 (1H), 2.60-2.69 (3H), 2.93 (1H), 3.10 (1H), 6.54 (2H), 6.59 (1H), 6.98-7.03 (3H), 7.31 (1H), 7.53 (1H), 7.95 (1H), 8.03 (1H), 8.98 (1H), 11.87 (1H)
Example 215
1-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-3-cyclopropylurea
[1844] ##STR00308##
[1845] A mixture of (6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (194; 30 mg, 68 mol), isocyanatocyclopropane (11 L, 137 mol) in pyridine (0.8 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by crystallization from MeOH to give the title compound (21 mg, 55%).
[1846] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.41 (2H), 0.64 (2H), 1.25 (6H), 2.39 (1H), 2.50 (1H), 2.56 (1H), 2.76-2.86 (2H), 3.22-3.31 (4H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.02 (1H), 7.32 (1H), 7.54 (1H), 7.96 (1H), 8.03 (1H), 8.99 (1H), 11.96 (1H)
Example 216
N-{[(6RS)-3-Anilino-4-oxo-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl}-L-alaninamide
[1847] ##STR00309##
[1848] A mixture comprising tert-butyl [(2S)-1-oxo-1-( [(6RS)-4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino)propan-2-yl]carbamate (89; 54 mg, 107 mol), TFA (124 L, 1.61 mmol) and DCM (3.5 mL) was stirred at RT for 16 h. Ammonia (0.5 mL, 25% in water) and DMSO (3 mL) were added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (36 mg, 79%).
[1849] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.17 (3H), 2.24 (1H), 2.31 (1H), 2.38 (1H), 2.62 (1H), 2.72 (1H), 2.92 (1H), 3.13-3.27 (2H), 3.32 (1H), 6.57 (2H), 6.63 (1H), 7.04 (2H), 7.43 (1H), 7.47 (2H), 8.02 (1H), 8.41 (2H), 11.93 (1H)
Example 217
(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
217-2: Methyl (6RS)-3-anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1850] ##STR00310##
[1851] A solution of (1S,2S)-2-fluorocyclopropanecarboxylic acid (373 mg, 3.59 mmol) and HATU (1.36 g, 3.59 mmol) in DMF (13 mL) was added to a mixture of methyl (6RS)-2-(2-aminopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (141-2; 700 mg, 1.79 mmol) and DIPEA (625 L, 3.59 mmol) in DMF (13 mL) and the reaction was stirred at RT for 2.5 days. The mixture was concentrated and EtOAc was added. The mixture was washed with water, brine and dried over sodium sulfate. After filtration and removal of the solvent, the title compound (578 mg, 64%) was used without further purification.
217-1: (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1852] ##STR00311##
[1853] A mixture of methyl (6RS)-3-anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (217-2; 574 mg, 1.21 mmol), lithium hydroxide (7.2 mL, 1M in water), THF (21 mL) and MeOH (6.7 mL) was stirred at RT for 16 h. and at 50 C. for 3 h. Citric acid (486 mg) in water (10 mL) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (425 mg, 72%).
(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,N,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1854] ##STR00312##
[1855] A solution of (6RS)-3-Anilino-2-[2-({[(1S,23)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (217-1; 47 mg, 102 mol) and HATU (77 mg, 203 mol) in DMA (0.9 mL) was added to a mixture of N-methylmethanamine (152 L, 2M in THF) and DIPEA (53 L, 305 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (25 mg, 48%).
[1856] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.18 (1H), 1.40 (3H), 1.64 (1H), 2.20 (1H), 2.44 (1H), 2.77 (1H), 2.91 (1H), 2.94 (6H), 3.51 (1H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 7.01 (2H), 7.14 (1H), 7.37 (1H), 8.07 (1H), 8.24 (1H), 10.72 (1H), 11.89 (1H)
Example 218
(6RS)-3-Anilino-N,N-diethyl-2-[2-({[(1 S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1857] ##STR00313##
[1858] A solution of (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (217-1; 47 mg, 102 mol) and HATU (77 mg, 203 mol) in DMA (0.9 mL) was added to a mixture of N-ethylethanaminium chloride (33 mg, 305 mol) and DIPEA (106 L, 610 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (22 mg, 40%).
[1859] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.01 (6H), 1.18 (1H), 1.39 (3H), 1.64 (1H), 2.20 (1H), 2.44 (1H), 2.72 (1H), 2.91 (1H), 3.30 (4H), 3.42 (1H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 6.99 (2H), 7.15 (1H), 7.35 (1H), 8.07 (1H), 8.23 (1H), 10.72 (1H), 11.90 (1H)
Example 219
(6RS)-3-Anilino-2-[2-({[(1 S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1860] ##STR00314##
[1861] A solution of (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (217-1; 47 mg, 102 mol) and HATU (77 mg, 203 mol) in DMA (0.9 mL) was added to a mixture of N-methylpropan-1-amine (31 L, 305 mol) and DIPEA (53 L, 305 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (16 mg, 29%).
[1862] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.69 (3H), 1.18 (1H), 1.37 (2H), 1.40 (3H), 1.64 (1H), 2.20 (1H), 2.42 (1H), 2.75 (1H), 2.91 (1H), 2.95-3.17 (4H), 3.29 (1H), 3.51 (1H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.13 (1H), 7.34 (1H), 8.07 (1H), 8.23 (1H), 10.72 (1H), 11.88 (1H)
Example 220
(6RS)-3-Anilino-2-[2-({[(1 S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N-isobutyl-N,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1863] ##STR00315##
[1864] A solution of (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (217-1; 47 mg, 102 mol) and HATU (77 mg, 203 mol) in DMA (0.9 mL) was added to a mixture of N,2-dimethylpropan-1-amine (37 L, 305 mol) and DIPEA (53 L, 305 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (16 mg, 27%).
[1865] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.55 (3H), 0.67 (3H), 1.18 (1H), 1.41 (3H), 1.58-1.77 (2H), 2.20 (1H), 2.38 (1H), 2.76 (1H), 2.82 (1H), 2.93 (1H), 3.10 (3H), 3.26 (1H), 3.57 (1H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 6.99 (2H), 7.11 (1H), 7.31 (1H), 8.06 (1H), 8.22 (1H), 10.71 (1H), 11.86 (1H)
Example 221
(6RS)-3-Anilino-N-(cyclopropylmethyl)-2-[2-({[(1 S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1866] ##STR00316##
[1867] A solution of (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (217-1; 47 mg, 102 mol) and HATU (77 mg, 203 mol) in DMA (0.9 mL) was added to a mixture of cyclopropyl-N-methylmethanaminium chloride (37 mg, 305 mol) and DIPEA (106 L, 610 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (12 mg, 21%).
[1868] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.05 (1H), 0.13 (1H), 0.30 (1H), 0.36 (1H), 0.81 (1H), 1.18 (1H), 1.41 (3H), 1.64 (1H), 2.20 (1H), 2.42 (1H), 2.77 (1H), 2.92 (1H), 3.01-3.12 (4H), 3.25 (1H), 3.53 (1H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 6.99 (2H), 7.13 (1H), 7.35 (1H), 8.07 (1H), 8.23 (1H), 10.72 (1H), 11.89 (1H)
Example 222
(6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-N,6-dimethyl-4-oxo-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1869] ##STR00317##
[1870] A solution of (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (217-1; 47 mg, 102 mol) and HATU (77 mg, 203 mol) in DMA (0.9 mL) was added to a mixture of 3,3,3-trifluoro-N-methylpropan-1-aminium chloride (50 mg, 305 mol) and DIPEA (106 L, 610 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (30 mg, 49%).
[1871] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.18 (1H), 1.39 (3H), 1.64 (1H), 2.20 (1H), 2.27-2.39 (2H), 2.43 (1H), 2.75 (1H), 2.94 (1H), 3.13 (3H), 3.32 (1H), 3.44-3.55 (2H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 6.99 (2H), 7.15 (1H), 7.34 (1H), 8.07 (1H), 8.24 (1H), 10.72 (1H), 11.89 (1H)
Example 223
(1S,2S)-N-{4-[(6RS)-3-Anilino-6-methyl-4-oxo-6-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1 H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide
[1872] ##STR00318##
[1873] A solution of (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (217-1; 47 mg, 102 mol) and HATU (77 mg, 203 mol) in DMA (0.9 mL) was added to a mixture of pyrrolidine (25 L, 305 mol) and DIPEA (53 L, 305 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (26 mg, 46%).
[1874] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.18 (1H), 1.33 (3H), 1.64 (1H), 1.78 (4H), 2.20 (1H), 2.47 (1H), 2.80 (1H), 2.86 (1H), 3.10-3.81 (5H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.15 (1H), 7.38 (1H), 8.08 (1H), 8.24 (1H), 10.72 (1H), 11.90 (1H)
Example 224
(1S,2S)-N-{4-[(6RS)-3-Anilino-6-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide
[1875] ##STR00319##
[1876] A solution of (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (217-1; 47 mg, 102 mol) and HATU (77 mg, 203 mol) in DMA (0.9 mL) was added to a mixture of (3R)-N,N-dimethylpyrrolidin-3-amine (39 L, 305 mol) and DIPEA (53 L, 305 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (18 mg, 30%).
[1877] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.18 (1H), 1.34 (3H), 1.46-1.80 (2H), 1.83-2.25 (2H), 2.15 (6H), 2.41 (1H), 2.77 (1H), 2.92 (1H), 2.98-3.99 (6H), 4.93 (1H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.38 (1H), 8.08 (1H), 8.24 (1H), 10.73 (1H), 11.89 (1H)
Example 225
(1S,2S)-N-{4-[(6RS)-3-Anilino-6-methyl-4-oxo-6-(piperidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1 H-indol-2-yl]pyridin-2-yl}-2-fluorocyclopropanecarboxamide
[1878] ##STR00320##
[1879] A solution of (6RS)-3-Anilino-2-[2-({[(1S,2S)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (217-1; 47 mg, 102 mol) and HATU (77 mg, 203 mol) in DMA (0.9 mL) was added to a mixture of piperidine (30 L, 305 mol) and DIPEA (53 L, 305 mol) in DMA (0.9 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (31 mg, 55%).
[1880] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.18 (1H), 1.40 (3H), 1.44 (4H), 1.53-1.70 (3H), 2.20 (1H), 2.44 (1H), 2.73 (1H), 2.93 (1H), 3.39-3.53 (5H), 4.93 (1H), 6.53 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.36 (1H), 8.07 (1H), 8.24 (1H), 10.72 (1H), 11.90 (1H)
Example 226
N-{4-[(6RS)-3-Anilino-6-({[2-(dimethylamino)ethyl]sulfanyl}methyl)-4-oxo-4,5,6,7-tetrahydro-1 H-indol-2-yl]pyridin-2-yl}acetamide
[1881] ##STR00321##
[1882] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol) and sodium 2-(dimethylamino)ethanethiolate (122 mg, 960 mol) in DMA (3 mL) was stirred at 1001 for 5 h. Water was added, the mixture concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (7 mg, 9%).
[1883] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.14 (6H), 2.27 (1H), 2.35-2.49 (4H), 2.59-2.71 (5H), 3.13 (1H), 6.56 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.35 (1H), 8.08 (1H), 8.23 (1H), 10.34 (1H), 11.95 (1H)
Example 227
N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)-4-fluoro-N-methylbenzamide
[1884] ##STR00322##
[1885] A mixture of (6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (194; 30 mg, 68 mol) and (4-fluorophenyl)methylcarbamic chloride (26 mg, 137 mol) in pyridine (0.8 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (9 mg, 21%).
[1886] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.26 (6H), 2.41 (1H), 2.53 (1H), 2.75-2.89 (2H), 3.23-3.32 (4H), 3.26 (3H), 6.57 (2H), 6.62 (1H), 7.03 (2H), 7.10 (1H), 7.29 (2H), 7.36 (1H), 7.41 (2H), 7.92 (1H), 7.95 (1H), 8.04 (1H), 12.03 (1H)
Example 228
(6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one
228-2: (4RS)-2-{[(2-Aminopyridin-4-yl)methyl]amino}-4({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenylcyclohex-1-ene-1-carbothioamide
[1887] ##STR00323##
[1888] A solution of (4RS)-4({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethyl)amino]cyclohex-1-ene-1-carbothioamide (30-3; 9.9 g, 18.7 mmol) and 4-(aminomethyl)pyridin-2-amine (4.14 g, 33.6 mmol) in DMA (52 mL) was heated at 90-100 C. for 10 h. The mixture was poured into water, extracted with EtOAc, washed with brine and dried over sodium sulfate. After filtration the mixture was concentrated and purified by Biotage (SNAP silica 340 g, EtOAc:Hexane) to give the title compound (6.07 g, 51%).
228-1: (6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one
[1889] ##STR00324##
[1890] A mixture of (4RS)-4({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-6-oxo-N-phenyl-2-[(pyridin-4-ylmethypamino]cyclohex-1-ene-1-carbothioamide (228-2; 27.9 g, 43.9 mmol), hydrogen peroxide (30% in water, 17.9 mL, 176 mmol) in MeOH (836 mL) was heated at 50 C. for 16 h. The mixture was concentrated and purified by Biotage (SNAP silica 340 g, EtOAc:Hexane) to give the title compound (18.6 g, 71%).
(6RS)-2-(2-Aminopyridin-4-yl)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one
[1891] ##STR00325##
[1892] A mixture of (6RS)-2-(2-aminopyridin-4-yl)-3-anilino-6({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one (228-1; 1.5 g, 2.5 mmol) and TBAF (6.2 mL, 1M in THF) in THF (35 mL) was stirred at 50 C. for 16 h. EtOAc (100 mL) was added, the mixture washed with sodium hydroxide (2.5% in water), brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by Biotage (SNAP silica 340 g, MeOH:DCM) to give the title compound (540 mg, 57%).
[1893] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.98 (3H), 2.06 (1H), 2.37 (1H), 2.56 (1H), 2.93 (1H), 3.24 (1H), 3.29 (1H), 4.85 (1H), 5.73 (2H), 6.56 (2H), 6.60 (1H), 6.61 (1H), 6.71 (1H), 7.03 (2H), 7.22 (1H), 7.77 (1H), 11.65 (1H)
Example 229
N-4-[(6RS)-6-[(2-Methoxyethyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1894] ##STR00326##
[1895] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol) and sodium 2-methoxyethanethiolate (110 mg, 960 mol) in DMA (3 mL) was stirred at 100 C. for 5 h. Water was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (54 mg, 72%).
[1896] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.08 (3H), 2.28 (1H), 2.40 (1H), 2.45 (1H), 2.62-2.73 (5H), 3.14 (1H), 3.26 (3H), 3.50 (2H), 6.57 (2H), 6.61 (1H), 7.02 (2H), 7.16 (1H), 7.34 (1H), 8.09 (1H), 8.23 (1H), 10.32 (1H), 11.94 (1H)
Example 230
N-4-[(6RS)-6-[(1,3Oxazol-2-ylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1897] ##STR00327##
[1898] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol) and sodium 1,3-oxazole-2-thiolate (118 mg, 960 mol) in DMA (3 mL) was stirred at 100 C. for 5 h. Water was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (54 mg, 68%).
[1899] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.08 (3H), 2.37 (1H), 2.45 (1H), 2.59 (1H), 2.74 (1H), 3.13 (1H), 3.29-3.41 (2H), 6.56 (2H), 6.61 (1H), 7.02 (2H), 7.16 (1H), 7.27 (1H), 7.33 (1H), 8.09 (1H), 8.17 (1H), 8.23 (1H), 10.32 (1H), 11.96 (1H)
Example 231
N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(1,3-thiazol-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide
[1900] ##STR00328##
[1901] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol) and sodium 1,3-thiazole-2-thiolate (134 mg, 960 mol) in DMA (3 mL) was stirred at 100 C. for 5 h. Water was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (53 mg, 64%).
[1902] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.08 (3H), 2.39 (1H), 2.47 (1H), 2.60 (1H), 2.77 (1H), 3.15 (1H), 3.42 (2H), 6.57 (2H), 6.61 (1H), 7.02 (2H), 7.16 (1H), 7.33 (1H), 7.68 (1H), 7.75 (1H), 8.09 (1H), 8.23 (1H), 10.32 (1H), 11.95 (1H)
Example 232
N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(pyridin-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide
[1903] ##STR00329##
[1904] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol) and sodium pyridine-2-thiolate (128 mg, 960 mol) in DMA (3 mL) was stirred at 1000 for 5 h. Water was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (54 mg, 66%).
[1905] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.36 (1H), 2.47 (1H), 2.50 (1H), 2.73 (1H), 3.12 (1H), 3.28-3.40 (2H), 6.56 (2H), 6.60 (1H), 7.01 (2H), 7.09-7.18 (2H), 7.32 (1H), 7.36 (1H), 7.65 (1H), 8.06 (1H), 8.23 (1H), 8.44 (1H), 10.29 (1H), 11.92 (1H)
Example 233
N-4-[(6RS)-6-[(4-Fluorobenzyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1906] ##STR00330##
[1907] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol) and sodium (4-fluorophenyl)methanethiolate (158 mg, 960 mol) in DMA (3 mL) was stirred at 100 C. for 5 h. Water was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (64 mg, 74%).
[1908] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.08 (3H), 2.23 (1H), 2.36-2.44 (2H), 2.56 (1H), 2.63 (1H), 3.09 (1H), 3.35 (1H), 3.78 (2H), 6.57 (2H), 6.61 (1H), 7.02 (2H), 7.12-7.17 (3H), 7.33 (1H), 7.38 (2H), 8.06 (1H), 8.25 (1H), 10.29 (1H), 11.93 (1H)
Example 234
(15,25)-2-Fluoro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)cyclopropanecarboxamide
[1909] ##STR00331##
[1910] A solution of (1S,2S)-2-fluorocyclopropanecarboxylic acid (26 mg, 246 mol) and HATU (94 mg, 246 mol) in DMA (1.2 mL) was added to a mixture of (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (192; 50 mg, 123 mol) and DIPEA (43 L, 246 mol) in DMA (1.2 mL) and the reaction was stirred at 50 C. for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (24 mg, 38%).
[1911] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.16 (1H), 1.20 (6H), 1.62 (1H), 2.18 (1H), 2.27 (1H), 2.34 (1H), 2.43 (1H), 2.58-2.70 (3H), 2.93 (1H), 3.12 (1H), 4.90 (1H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.35 (1H), 8.07 (1H), 8.24 (1H), 10.70 (1H), 11.97 (1H)
Example 235
N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)-1,3-thiazole-5-carboxamide
[1912] ##STR00332##
[1913] A solution of 1,3-thiazole-5-carboxylic acid (32 mg, 246 mol) and HATU (94 mg, 246 mol) in DMA (1.2 mL) was added to a mixture of (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (192; 50 mg, 123 mol) and DIPEA (43 L, 246 mol) in DMA (1.2 mL) and the reaction was stirred at 50 C. for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (30 mg, 45%).
[1914] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.21 (6H), 2.29 (1H), 2.36 (1H), 2.44 (1H), 2.60-2.71 (3H), 2.93 (1H), 3.13 (1H), 6.57 (2H), 6.60 (1H), 7.01 (2H), 7.24 (1H), 7.40 (1H), 8.18 (1H), 8.28 (1H), 8.86 (1H), 9.31 (1H), 11.08 (1H), 12.00 (1H)
Example 236
4-Fluoro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide
[1915] ##STR00333##
[1916] A solution of 4-fluorobenzoic acid (34 mg, 246 mol) and HATU (94 mg, 246 mol) in DMA (1.2 mL) was added to a mixture of (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (192; 50 mg, 123 mol) and DIPEA (43 L, 246 mol) in DMA (1.2 mL) and the reaction was stirred at 50 C. for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (24 mg, 34%).
[1917] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.21 (6H), 2.29 (1H), 2.37 (1H), 2.45 (1H), 2.60-2.71 (3H), 2.94 (1H), 3.13 (1H), 6.57 (2H), 6.59 (1H), 7.01 (2H), 7.23 (1H), 7.34 (2H), 7.39 (1H), 8.08(2H), 8.16 (1H), 8.32 (1H), 10.72 (1H), 11.99 (1H)
Example 237
4-Chloro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide
[1918] ##STR00334##
[1919] A solution of 4-chlorobenzoic acid (39 mg, 246 mol) and HATU (94 mg, 246 mol) in DMA (1.2 mL) was added to a mixture of (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (192; 50 mg, 123 mol) and DIPEA (43 L, 246 mol) in DMA (1.2 mL) and the reaction was stirred at 50 C. for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (26 mg, 37%).
[1920] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.21 (6H), 2.29 (1H), 2.36 (1H), 2.44 (1H), 2.60-2.71 (3H), 2.94 (1H), 3.13 (1H), 6.57 (2H), 6.59 (1H), 7.01 (2H), 7.23 (1H), 7.40 (1H), 7.58 (2H), 8.02 (2H), 8.16 (1H), 8.32 (1H), 10.78 (1H), 12.00 (1H)
Example 238
3,4-Dichloro-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide
[1921] ##STR00335##
[1922] A solution of 3,4-dichlorobenzoic acid (39 mg, 246 mol) and HATU (94 mg, 246 mol) in DMA (1.2 mL) was added to a mixture of (6RS)-2-(2-Aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (192; 50 mg, 123 mol) and DIPEA (43 L, 246 mol) in DMA (1.2 mL) and the reaction was stirred at 50 C. for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (26 mg, 37%).
[1923] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.21 (6H), 2.29 (1H), 2.37 (1H), 2.44 (1H), 2.59-2.71 (3H), 2.94 (1H), 3.13 (1H), 6.57 (2H), 6.60 (1H), 7.01 (2H), 7.24 (1H), 7.40 (1H), 7.79 (1H), 7.96 (1H), 8.18 (1H), 8.25 (1H), 8.31 (1H), 10.91 (1H), 12.00 (1H)
Example 239
N-4-[(6RS)-6-[(Ethylsulfonyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1924] ##STR00336##
[1925] A mixture comprising N-4-[(6RS)-6-[(ethylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide (189; 37 mg, 85 mol), mCPBA (36 mg, 75%) and DMA (2.5 mL) was stirred at RT. After 16 h a second portion mCPBA (9 mg, 75%) was added. The mixture was stirred at RT for 4 h, DMSO (750 L) was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (23 mg, 58%).
[1926] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.25 (3H), 2.08 (3H), 2.41 (1H), 2.48-2.57 (2H), 2.81-2.89 (2H), 3.16 (2H), 3.25-3.31 (2H), 6.58 (2H), 6.62 (1H), 7.03 (2H), 7.18 (1H), 7.35 (1H), 8.09 (1H), 8.24 (1H), 10.32 (1H), 12.01 (1H)
Example 240
N-(4-(6RS)-Oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)acetamide
[1927] ##STR00337##
[1928] A mixture comprising N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-ypacetamide (190; 36 mg, 80 mol), mCPBA (34 mg, 75%) and DMA (2.5 mL) was stirred at RT. After 16 h a second portion mCPBA (8 mg, 75%) was added. The mixture was stirred at RT for 4 h, DMSO (750 L) was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (23 mg, 57%).
[1929] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.25 (6H), 2.05 (3H), 2.39 (1H), 2.51 (1H), 2.77-2.86 (2H), 3.23-3.31 (4H), 6.55 (2H), 6.59 (1H), 7.00 (2H), 7.15 (1H), 7.34 (1H), 8.07 (1H), 8.22 (1H), 10.33 (1H), 12.01 (1H)
Example 241
2-Fluoro-2-methyl-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)propanamide
[1930] ##STR00338##
[1931] A mixture comprising N-(4-{(6RS)-3-anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1 H-indol-2-yl}pyridin-2-yl)-2-fluoro-2-methylpropanamide (213; 28 mg, 57 mol), mCPBA (30 mg, 75%) and DMA (2 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (18 mg, 58%).
[1932] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.28 (6H), 1.57 (3H), 1.61 (3H), 2.44 (1H), 2.49-2.57 (2H), 2.81-2.90 (2H), 3.26-3.38 (3H), 6.59 (2H), 6.63 (1H), 7.04 (2H), 7.27 (1H), 7.41 (1H), 8.15 (1H), 8.17 (1H), 9.68 (1H), 12.07 (1H)
Example 242
4-Fluoro-3-methoxy-N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-yl)benzamide
[1933] ##STR00339##
[1934] A mixture comprising N-(4-{(6RS)-3-anilino-6-[(isopropylsulfanyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1 H-indol-2-yl}pyridin-2-yl)-4-fluoro-3-methoxybenzamide (212; 32 mg, 57 mol), mCPBA (30 mg, 75%) and DMA (2 mL) was stirred at RT for 16 h. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (16 mg, 44%).
[1935] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.28 (6H), 2.44 (1H), 2.48-2.58 (2H), 2.81-2.92 (2H), 3.27-3.35 (3H), 3.96 (3H), 6.61 (2H), 6.63 (1H), 7.04 (2H), 7.27 (1H), 7.37 (1H), 7.41 (1H), 7.66 (1H), 7.86 (1H), 8.20 (1H), 8.37 (1H), 10.76 (1H), 12.09 (1H)
Example 243
N-4-[(6RS)-6-[(tert-Butylsulfonyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1936] ##STR00340##
[1937] A mixture comprising N-4-[(6RS)-6-[(tert-butylsulfanyl)methyl]-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide (191; 39 mg, 84 mol), mCPBA (36 mg, 75%) and DMA (2.5 mL) was stirred at RT. After 16 h a second portion mCPBA (9 mg, 75%) was added. The mixture was stirred at RT for 4 h, DMSO (750 L) was added, the mixture concentrated and purified by preparative HPLC (basic method) to give the title compound (25 mg, 57%).
[1938] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.35 (9H), 2.08 (3H), 2.44 (1H), 2.56 (1H), 2.78-2.91 (2H), 3.24-3.39 (3H), 6.57 (2H), 6.61 (1H), 7.03 (2H), 7.18 (1H), 7.35 (1H), 8.09 (1H), 8.24 (1H), 10.32 (1H), 12.02 (1H)
Example 244
(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,N,6-trimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
244-2: Methyl (6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1939] ##STR00341##
[1940] A solution of 2-fluoro-2-methylpropanoic acid (340 L, 3.59 mmol) and HATU (1.36 g, 3.59 mmol) in DMA (13 mL) was added to a mixture of methyl (6RS)-2-(2-aminopyridin-4-yl)-3-anilino-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (141-2; 700 mg, 1.79 mmol) and DIPEA (625 L, 3.59 mmol) in DMA (13 mL) and the reaction was stirred at RT for 16 h. The mixture was concentrated, EtOAc was added, the mixture washed with water, brine and dried over sodium sulfate. After filtration and removal of the solvent, the mixture was purified Biotage (SNAP NH 28 g, EtOAc:Hexane) to give the title compound (603 mg, 67%).
244-1: (6RS)-3-Anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid
[1941] ##STR00342##
[1942] A mixture of methyl (6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylate (244-2; 1.600 mg, 1.25 mmol), lithium hydroxide (7.5 mL, 1M in water), THF (22 mL) and MeOH (7 mL) was stirred at RT for 16 h. Citric acid (506 mg) in water (10 mL) was added and the mixture concentrated. The precipitate was washed with water and dried to give the title compound (304 mg, 50%).
(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,N,6-trimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1943] ##STR00343##
[1944] A solution of (6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (244-1; 43 mg, 92 mol) and HATU (70 mg, 185 mol) in DMA (1 mL) was added to a mixture of N-methylmethanamine (139 L, 2M in THF) and DIPEA (48 L, 277 mol) in DMA (1 mL) and the reaction was stirred at RT for 1 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (19 mg, 40%).
[1945] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.39 (3H), 1.54 (3H), 1.59 (3H), 2.44 (1H), 2.77 (1H), 2.90 (1H), 2.93 (6H), 3.49 (1H), 6.52 (2H), 6.59 (1H), 6.99 (2H), 7.20 (1H), 7.40 (1H), 8.11 (1H), 8.12 (1H), 9.70 (1H), 11.90 (1H)
Example 245
(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-phenylamino)-N-propyl-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1946] ##STR00344##
[1947] A solution of (6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (244-1; 43 mg, 92 mol) and HATU (70 mg, 185 mol) in DMA (1 mL) was added to a mixture of N-methylpropan-1-amine (28 L, 277 mol) and DIPEA (48 L, 277 mol) in DMA (1 mL) and the reaction was stirred at RT for 1 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (19 mg, 37%).
[1948] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.70 (3H), 1.39 (2H), 1.43 (3H), 1.57 (3H), 1.61 (3H), 2.45 (1H), 2.78 (1H), 2.94 (2H), 3.01 (3H), 3.13 (1H), 3.52 (1H), 6.55 (2H), 6.61 (1H), 7.01 (2H), 7.22 (1H), 7.38 (1H), 8.11-8.16 (2H), 9.68 (1H), 11.89 (1H)
Example 246
(6RS)-N,N-Diethyl-2-2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl-6-methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1949] ##STR00345##
[1950] A solution of (6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (244-1; 43 mg, 92 mol) and HATU (70 mg, 185 mol) in DMA (1 mL) was added to a mixture of N-ethylethanaminium chloride (30 mg, 277 mol) and DIPEA (97 L, 554 mol) in DMA (1 mL) and the reaction was stirred at RT for 1 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (21 mg, 41%).
[1951] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.03 (6H), 1.41 (3H), 1.57 (3H), 1.61 (3H), 2.47 (1H), 2.75 (1H), 2.93 (1H), 3.18-3.43 (4H), 3.44 (1H), 6.55 (2H), 6.61 (1H), 7.01 (2H), 7.23 (1H), 7.38 (1H), 8.11-8.16 (2H), 9.67 (1H), 11.91 (1H)
Example 247
(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-N-(2-methylpropyl)-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1952] ##STR00346##
[1953] A solution of (6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (244-1; 43 mg, 92 mol) and HATU (70 mg, 185 mol) in DMA (1 mL) was added to a mixture of N,2-dimethylpropan-1-amine (33 L, 277 mol) and DIPEA (48 L, 277 mol) in DMA (1 mL) and the reaction was stirred at RT for 1 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (18 mg, 35%).
[1954] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.57 (3H), 0.68 (3H), 1.43 (3H), 1.57 (3H), 1.61 (3H), 1.74 (1H), 2.41 (1H), 2.79 (1H), 2.84 (1H), 2.95 (1H), 3.11 (3H), 3.26 (1H), 3.57 (1H), 6.55 (2H), 6.62 (1H), 7.01 (2H), 7.20 (1H), 7.35 (1H), 8.10-8.15 (2H), 9.67 (1H), 11.88 (1H)
Example 248
(6RS)-2-2-[(2-Fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1955] ##STR00347##
[1956] A solution of (6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (244-1; 43 mg, 92 mol) and HATU (70 mg, 185 mol) in DMA (1 mL) was added to a mixture of 3,3,3-trifluoro-N-methylpropan-1-aminium chloride (45 mg, 277 mol) and DIPEA (97 L, 554 mol) in DMA (1 mL) and the reaction was stirred at RT for 1 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (24 mg, 43%).
[1957] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.41 (3H), 1.57 (3H), 1.61 (3H), 2.35 (2H), 2.47 (1H), 2.77 (1H), 2.96 (1H), 3.15 (3H), 3.36 (1H), 3.52 (2H), 6.55 (2H), 6.61 (1H), 7.01 (2H), 7.23 (1H), 7.37 (1H), 8.11-8.17 (2H), 9.68 (1H), 11.91 (1H)
Example 249
(6RS)-N-(Cyclopropylmethyl)-2-2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl-N,6-dimethyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxamide
[1958] ##STR00348##
[1959] A solution of (6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (244-1; 43 mg, 92 mol) and HATU (70 mg, 185 mol) in DMA (1 mL) was added to a mixture of cyclopropyl-N-methylmethanaminium chloride (34 mg, 277 mol) and DIPEA (97 L, 554 mol) in DMA (1 mL) and the reaction was stirred at RT for 1 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (10 mg, 19%).
[1960] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.06 (1H), 0.14 (1H), 0.31 (1H), 0.37 (1H), 0.83 (1H), 1.43 (3H), 1.57 (3H), 1.61 (3H), 2.45 (1H), 2.80 (1H), 2.95 (1H), 3.07 (1H), 3.09 (3H), 3.27 (1H), 3.54 (1H), 6.55 (2H), 6.61 (1H), 7.01 (2H), 7.22 (1H), 7.39 (1H), 8.10-8.15 (2H), 9.68 (1H), 11.90 (1H)
Example 250
2-Fluoro-2-methyl-N-4-[(6RS)-6-methyl-4-oxo-3-(phenylamino)-6-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylpropanamide
[1961] ##STR00349##
[1962] A solution of (6RS)-3-anilino-2-{2-[(2-fluoro-2-methylpropanoyl)amino]pyridin-4-yl}-6-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-carboxylic acid (244-1; 43 mg, 92 mol) and HATU (70 mg, 185 mol) in DMA (1 mL) was added to a mixture of pyrrolidine (23 L, 277 mol) and DIPEA (48 L, 277 mol) in DMA (1 mL) and the reaction was stirred at RT for 1 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (20 mg, 41%).
[1963] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.36 (3H), 1.58 (3H), 1.61 (3H), 1.79 (4H), 2.49 (1H), 2.83 (1H), 2.88 (1H), 3.14-3.79 (5H), 6.55 (2H), 6.61 (1H), 7.02 (2H), 7.24 (1H), 7.42 (1H), 8.10-8.17 (2H), 9.68 (1H), 11.92 (1H)
Example 251
N-{4-[(6RS)-3-Anilino-6-{[(4-fluorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide
[1964] ##STR00350##
[1965] A mixture of [(6RS)-2-(2-acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol) and sodium 4-fluorobenzenethiolate (156 mg, 960 mol) in DMA (3 mL) was stirred at 100 C. for 5 h. Water was added, the mixture concentrated and purified by preparative HPLC (basic method) and preparative TLC (MeOH:DCM) to give the title compound (40 mg, 47%).
[1966] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.30-2.39 (2H), 2.46 (1H), 2.71 (1H), 3.06-3.18 (3H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.14 (1H), 7.18 (2H), 7.33 (1H), 7.46 (2H), 8.08 (1H), 8.22 (1H), 10.35 (1H), 11.95 (1H)
Example 252
N-(4-{(6RS)-3-Anilino-6-[(isopropylsulfonyl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)morpholine-4-carboxamide
[1967] ##STR00351##
[1968] A mixture of (6RS)-2-(2-aminopyridin-4-yl)-3-(phenylamino)-6-[(propan-2-ylsulfonyl)methyl]-1,5,6,7-tetrahydro-4H-indol-4-one (194; 30 mg, 68 mol) and morpholine-4-carbonyl chloride (24 L, 205 mol) in pyridine (0.8mL) was stirred at RT for 2 days. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (12 mg, 31%).
[1969] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.26 (6H), 2.41 (1H), 2.76-2.89 (2H), 3.14 (1H), 3.23-3.33 (3H), 3.45 (4H), 3.54-3.62 (5H), 6.57 (2H), 6.61 (1H), 7.02 (2H), 7.11 (1H), 7.35 (1H), 7.91 (1H), 8.02 (1H), 9.11 (1H), 11.99 (1H)
Example 253
N-{4-[(6RS)-3-Anilino-6-{[(3,4-dichlorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide
[1970] ##STR00352##
[1971] A mixture of [(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol), sodium 3,4-dichlorobenzenethiolate (193 mg, 960 mol) in DMA (3 mL) was stirred at 100 C. for 5 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (59 mg, 66%).
[1972] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.37 (1H), 2.41-2.49 (2H), 2.72 (1H), 3.13 (1H), 3.18 (1H), 3.26 (1H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.34 (1H), 7.38 (1H), 7.56 (1H), 7.65 (1H), 8.08 (1H), 8.22 (1H), 10.35 (1H), 11.95 (1H)
Example 254
N-{4-[(6RS)-3-Anilino-6-{[(4-chlorophenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamicle
[1973] ##STR00353##
[1974] A mixture of [(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol), sodium 4-chlorobenzenethiolate (160 mg, 960 mol) in DMA (3 mL) was stirred at 100 C. for 5 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (50 mg, 60%).
[1975] .sup.1H NMR (400 MHz, DMSO-d6) ppm 2.07 (3H), 2.32-2.48 (3H), 2.72 (1H), 3.09-3.17 (2H), 3.20 (1H), 6.54 (2H), 6.59 (1H), 7.01 (2H), 7.15 (1H), 7.32-7.43 (5H), 8.08 (1H), 8.22 (1H), 10.34 (1H), 11.95 (1H)
Example 255
N-4-[(6RS)-6-[(4-Fluoro-3-methoxyphenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1976] ##STR00354##
[1977] A mixture of [(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol), sodium 4-fluoro-3-methoxybenzenethiolate (173 mg, 960 mol) in DMA (3 mL) was stirred at 100 C. for 5 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (34 mg, 38%).
[1978] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.29-2.48 (3H), 2.70 (1H), 3.05 (1H), 3.09-3.16 (2H), 3.81 (3H), 6.54 (2H), 6.59 (1H), 7.00 (2H), 7.10-7.16 (2H), 7.20 (1H), 7.33 (1H), 7.35 (1H), 8.08 (1H), 8.22 (1H), 10.35 (1H), 11.94 (1H)
Example 256
N-4-[(6RS)-6-[(3,4-Difluorophenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1979] ##STR00355##
[1980] A mixture of [(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol), sodium 3,4-difluorobenzenethiolate (161 mg, 960 mol) in DMA (3 mL) was stirred at 1001 for 5 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (41 mg, 46%).
[1981] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.31-2.47 (3H), 2.71 (1H), 3.10-3.17 (2H), 3.21 (1H), 6.55 (2H), 6.60 (1H), 7.01 (2H), 7.15 (1H), 7.23 (1H), 7.34 (1H), 7.40 (1H), 7.55 (1H), 8.08 (1H), 8.22 (1H), 10.35 (1H), 11.94 (1H)
Example 257
N-4-[(6RS)-6-[(4-Metehoxyphenyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide
[1982] ##STR00356##
[1983] A mixture of [(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol), sodium 4-methoxybenzenethiolate (156 mg, 960 mol) in DMA (3 mL) was stirred at 100 C. for 5 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (54 mg, 60%).
[1984] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.26-2.37 (2H), 2.38-2.47 (1H), 2.70 (1H), 2.98 (1H), 3.06 (1H), 3.13 (1H), 3.73 (3H), 6.54 (2H), 6.59 (1H), 6.92 (2H), 7.00 (2H), 7.14 (1H), 7.33 (1H), 7.38 (2H), 8.08 (1H), 8.22 (1H), 10.35 (1H), 11.94 (1H)
Example 258
Methyl (6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
258-2: Methyl (1RS)-3-hydroxy-5-oxo-4-(pyridin-2-ylcarbamothioyl)cyclohex-3-ene-1-carboxylate
[1985] ##STR00357##
[1986] To a solution of methyl (1RS)-3-hydroxy-5-oxocyclohex-3-ene-1-carboxylate (4.96 g, 29.2 mmol; commercially available from FCH Group Company) and 2-isothiocyanatopyridine (3.97 g, 29.2 mmol) in MeCN (100 mL) was added TEA (1.64 mL, 11.7 mmol) and the mixture was stirred at reflux for 16 h. Ethyl acetate was added, the mixture washed with water and brine and dried over sodium sulfate. After filtration and concentration the residue was purified by Biotage (SNAP silica 100 g, EtOAc:Hexane) to give the title compound (1.35 g, 14%).
258-1: Methyl (1RS)-5-oxo-4-(pyridin-2-ylcarbamothioyl)-3-[(pyridin-4-ylmethyl)amino]cyclohex-3-ene-1-carboxylate
[1987] ##STR00358##
[1988] A solution of methyl (1RS)-3-hydroxy-5-oxo-4-(pyridin-2-ylcarbamothioyl)cyclohex-3-ene-1-carboxylate (258-2; 1.35 g, 4.41 mmol) and 1-(pyridin-4-yl)methanamine (895 L, 8.81 mmol) in DMA (5 mL) was heated at 120 C. for 1.5 h. The mixtu re was concentrated and purified by Biotage (SNAP silica 100 g, MeOH:DCM) to give the title compound (280 mg, 14%).
Methyl (6RS)-4-oxo-2-(pyridin-4-yl)-3-(pyridin-2-ylamino)-4,5,6,7-tetrahydro-1H-indol-6-carboxylate
[1989] ##STR00359##
[1990] A mixture of methyl (1RS)-3-hydroxy-5-oxo-4-(pyridin-2-ylcarbamothioyl)cyclohex-3-ene-1-carboxylate (258-1; 275 mg, 693 mol), hydrogen peroxide (34% in water, 121 L, 1.39 mmol) in MeOH (25 mL) was heated at 90 C. for 24 h. The mixtu re was concentrated and purified by Biotage (SNAP silica 50 g, MeOH:DCM) to give the title compound (35 mg, 14%).
[1991] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.57 (2H), 3.12 (1H), 3.18 (1H), 3.37 (1H), 3.64 (3H), 6.37 (1H), 6.58 (1H), 7.38 (1H), 7.52 (2H), 7.94 (1H), 8.02 (1H), 8.45 (2H), 12.01 (1H)
Example 259
(6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-[(isopropylsulfanyl)methyl]-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one
259-1: [(6RS)-3-Anilino-6-methyl-2-{2-[(methylsulfonyl)amino]pyridin-4-yl}-4-oxo-4,5,6,7-tetrahydro-1 H-indol-6-yl]methyl methanesulfonate
[1992] ##STR00360##
[1993] A solution of (6RS)-2-(2-aminopyridin-4-yl)-6-(hydroxymethyl)-6-methyl-3-(phenylamino)-1,5,6,7-tetrahydro-4H-indol-4-one (228; 6.70 g, 18.5 mmol), DMAP (452 mg, 3.70 mmol) and methanesulfonyl chloride (2.15 mL, 27.7 mmol) in pyridine (100 mL) was stirred at RT for 4 h. MeOH was added, the mixture concentrated and purified by Biotage (SNAP silica 340 g, MeOH:DCM) and by crystallization from MeOH to give the title compound (873 mg, 9%).
(6RS)-2-(2-Aminopyridin-4-yl)-3-anilino-6-[(isopropylsulfanyl)methyl]-6-methyl-1,5,6,7-tetrahydro-4H-indol-4-one
[1994] ##STR00361##
[1995] A mixture of [(6RS)-3-anilino-6-methyl-2-{2-[(methylsulfonyl)amino]pyridin-4-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (259-1; 100 mg, 227 mol), sodium propane-2-thiolate (134 mg, 1.36 mmol) in DMA (3.2 mL) was stirred at 100 C. for 5 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (8 mg, 8%).
[1996] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.07 (3H), 1.17 (6H), 2.24 (1H), 2.39 (1H), 2.66 (2H), 2.74 (1H), 2.83 (1H), 2.95 (1H), 5.73 (2H), 6.52-6.61 (4H), 6.70 (1H), 7.01 (2H), 7.23 (1H), 7.76 (1H), 11.70 (1H)
Example 260
N-(4-{(6RS)-3-Anilino-4-oxo-6-[(1,3-thiazol-2-ylsulfonyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}pyridin-2-yl)acetamide
[1997] ##STR00362##
[1998] A mixture comprising N-(4-(6RS)-4-oxo-3-(phenylamino)-6-[(1,3-thiazol-2-ylsulfanyl)methyl]-4,5,6,7-tetrahydro-1H-indol-2-ylpyridin-2-ypacetamide (231; 45 mg, 92 mol), mCPBA (48 mg, 75%) and DMA (2.5 mL) was stirred at RT for 16 h, DMSO was added, the mixture filtered and purified by preparative HPLC (basic method) to give the title compound (6 mg, 14%).
[1999] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.23 (3H), 2.44 (2H), 2.77 (1H), 2.87 (1H), 3.25 (1H), 3.81 (1H), 3.89 (1H), 6.57 (2H), 6.61 (1H), 7.03 (2H), 7.20 (1H), 7.36 (1H), 8.19-8.25 (2H), 8.35 (1H), 8.48 (1H), 10.41 (1H), 12.08 (1H)
Example 261
N-{4-[(6RS)-3-Anilino-6-{[(4-fluoro-3-hydroxyphenyl)sulfanyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1 H-indol-2-yl]pyridin-2-yl}acetamide
[2000] ##STR00363##
[2001] A mixture of [(6RS)-2-(2-Acetamidopyridin-4-yl)-3-anilino-4-oxo-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl methanesulfonate (151-1; 75 mg, 160 mol), sodium 4-fluoro-3-methoxybenzenethiolate (173 mg, 960 mol) in DMA (3 mL) was stirred at 1001 for 5 h. The mixture was concentrated and purified by preparative TLC (MeOH:DCM) to give the title compound (34 mg, 38%).
[2002] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.27-2.37 (2H), 2.44 (1H), 2.69 (1H), 3.00 (1H), 3.07 (1H), 3.12 (1H), 6.54 (2H), 6.59 (1H), 6.91 (1H), 7.00 (2H), 7.07 (1H), 7.15 (1H), 7.26 (1H), 7.33 (1H), 8.08 (1H), 8.22 (1H), 10.04 (1H), 10.34 (1H), 11.94 (1H)
Example 262
N-{4-[(6RS)-3-Anilino-6-{[(2-methoxyethyl)sulfonyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide
[2003] ##STR00364##
[2004] A mixture comprising N-4-[(6RS)-6-[(2-methoxyethyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide (229; 46 mg, 99 mol), mCPBA (52 mg, 75%) and DMA (2.5 mL) was stirred at RT for 16 h, DMSO was added, the mixture filtered and purified by preparative HPLC (basic method) to give the title compound (7 mg, 13%).
[2005] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.39 (1H), 2.47 (1H), 2.79-2.90 (1H), 3.20-3.35 (4H), 3.28 (3H), 3.44 (2H), 3.71 (2H), 6.56 (2H), 6.60 (1H), 7.02 (2H), 7.17 (1H), 7.36 (1H), 8.08 (1H), 8.24 (1H), 10.35 (1H), 12.02 (1H)
Example 263
N-{4-[(6RS)-3-Anilino-6-{[(4-fluorobenzy0sulfonyl]methyl}-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-yl}acetamide
[2006] ##STR00365##
[2007] A mixture comprising N-4-[(6RS)-6-[(4-fluorobenzyl)sulfanyl]methyl-4-oxo-3-(phenylamino)-4,5,6,7-tetrahydro-1H-indol-2-yl]pyridin-2-ylacetamide (233; 55 mg, 107 mol), mCPBA (56 mg, 75%) and DMA (2.5 mL) was stirred at RT 16 h, DMSO was added, the mixture filtered and purified by preparative HPLC (basic method) to give the title compound (8 mg, 14%).
[2008] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (3H), 2.38 (1H), 2.47 (1H), 2.79-2.91 (2H), 3.21-3.31 (3H), 4.57 (2H), 6.56 (2H), 6.60 (1H), 7.02 (2H), 7.17 (1H), 7.26 (2H), 7.36 (1H), 7.46 (2H), 8.09 (1H), 8.24 (1H), 10.35 (1H), 12.03 (1H)
[2009] The compounds of examples 264 to 311 have been prepared according to the general procedures outlined in schemes 1 to 19 and in analogy to the experiments described for examples 1 to 263:
TABLE-US-00008 Structure IUPAC-Name Mass found (M + 1) Example .sup.1H-NMR 264
[2010] Biological Investigations
[2011] The following assays can be used to illustrate the commercial utility of the compounds according to the present invention.
[2012] Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein [2013] the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested and [2014] the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
[2015] Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values calculated utilizing data sets obtained from testing of one or more synthetic batch.
[2016] Biological Assay 1.0:
[2017] Bub1 kinase assay
[2018] Bub1-inhibitory activities of compounds described in the present invention were quantified using a time-resolved fluorescence energy transfer (TR-FRET) kinase assay which measures phosphorylation of the synthetic peptide Biotin-Ahx-VLLPKKSFAEPG (SEQ ID No.1) (C-terminus in amide form), purchased from e.g. Biosyntan (Berlin, Germany) by the (recombinant) catalytic domain of human Bub1 (amino acids 704-1085), expressed in Hi5 insect cells with an N-terminal His6-tag and purified by affinity-(Ni-NTA) and size exclusion chromatography.
[2019] In a typical assay 11 different concentrations of each compound (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 M, 0.51 M, 1.7 M, 5.9 M and 20 M) were tested in duplicate within the same microtiter plate. To this end, 100-fold concentrated compound solutions (in DMSO) were previously prepared by serial dilution (1:3.4) of 2 mM stocks in a clear low volume 384-well source microtiter plate (Greiner Bio-One, Frickenhausen, Germany), from which 50 nl of compounds were transferred into a black low volume test microtiter plate from the same supplier. Subsequently, 2 L of Bub1 (the final concentration of Bub1 was adjusted depending on the activity of the enzyme lot in order to be within the linear dynamic range of the assay: typically 200 ng/mL were used) in aqueous assay buffer [50 mM Tris/HCl pH 7.5, 10 mM magnesium chloride (MgCl2), 200 mM potassium chloride (KCI), 1.0 mM dithiothreitol (DTT), 0.1 mM sodium ortho-vanadate, 1% (v/v) glycerol, 0.01% (w/v) bovine serum albumine (BSA), 0.005% (v/v) Trition X-100 (Sigma), 1 Complete EDTA-free protease inhibitor mixture (Roche)] were added to the compounds in the test plate and the mixture was incubated for 15 min at 22 C. to allow pre-equilibration of the putative enzyme-inhibitor complexes before the start of the kinase reaction, which was initiated by the addition of 3 L 1.67-fold concentrated solution (in assay buffer) of adenosine-tri-phosphate (ATP, 10 M final concentration) and peptide substrate (1 M final concentration). The resulting mixture (5 L final volume) was incubated at 22 C. during 60 min. and the reaction was stopped by the addition of 5 L of an aqueous EDTA-solution (50 mM EDTA, in 100 mM HEPES pH 7.5 and 0.2% (w/v) bovine serum albumin) which also contained the TR-FRET detection reagents (0.2 M streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM anti-phosho-Serine antibody [Merck Millipore, cat. # 35-002] and 0.4 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product no. AD0077, alternatively a Terbium-cryptate-labeled anti-mouse IgG antibody from Cisbio Bioassays can be used]). The stopped reaction mixture was further incubated 1 h at 22 C. in order to allow the formation of complexes between peptides and detection reagents. Subsequently, the amount of product was evaluated by measurement of the resonance energy transfer from the Eu-chelate-antibody complex recognizing the Phosphoserine residue to the streptavidin-XL 665 bound to the biotin moiety of the peptide. To this end, the fluorescence emissions at 620 nm and 665 nm after excitation at 330-350 nm were measured in a TR-FRET plate reader, e.g. a Rubystar or Pherastar (both from BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer) and the ratio of the emissions (665 nm/622 nm) was taken as indicator for the amount of phosphorylated substrate. The data were normalised using two sets of control wells for high(=enzyme reaction without inhibitor=0% =Minimum inhibition) and low(=all assay components without enzyme=100%=Maximum inhibition) Bub1 activity. IC.sub.50 values were calculated by fitting the normalized inhibition data to a 4-parameter logistic equation (Minimum, Maximum, IC.sub.50, Hill; Y =Max+(Min-Max)/(1+(X/IC.sub.50)Hill)).
TABLE-US-00009 TABLE 1 Inhibition of Bub1 kinase Example IC.sub.50 Nr. [nM] 1 13 2 62 3 125 4 33 5 29 6 37 7 70 8 10 9 117 10 10 11 32 12 10 13 20 14 10 15 14 16 45 17 9 18 8 19 16 20 21 21 25 22 30 23 14 24 10 25 7 26 13 27 47 28 24 29 27 30 8 31 40 32 9 33 16 34 291 35 19 36 8 37 85 39 14 40 5 41 52 42 38 43 65 44 37 45 6010 46 12 47 13 48 7 49 179 50 9 51 8 52 64 53 103 54 15 55 23 56 55 57 69 58 4 59 4 60 14 61 17 62 5 63 4 64 21 65 44 66 19 67 116 68 88 69 34 70 34 71 37 72 46 73 19 74 7 75 22 76 7 77 20 78 8 79 37 80 10 81 6 82 68 83 16 84 29 85 3 86 28 87 83 88 153 89 66 90 232 91 16 92 37 93 94 94 15 95 83 96 57 97 13 98 27 99 22 100 65 101 53 102 5 103 15 104 19 105 14 106 16 107 12 108 35 109 11 110 27 111 21 112 32 113 25 114 14 115 21 116 62 117 56 118 49 119 29 120 31 121 19 122 7 123 19 124 38 125 46 126 47 127 47 128 38 129 30 130 14 131 81 132 91 133 29 134 18 135 19 136 11 137 173 138 12 139 18 140 65 141 91 142 6 143 7 144 169 145 40 146 59 147 61 148 27 149 17 150 10 151 7 152 13 153 12 154 11 155 14 156 9 157 7 158 106 159 18 160 5 161 56 162 8 163 13 164 11 165 161 166 573 167 10 168 17 169 26 170 13 171 22 172 400 173 15 174 1690 175 103 176 131 177 153 178 60 179 932 180 588 181 52 182 2360 183 89 184 1820 185 925 186 1150 187 156 188 480 189 8 190 8 191 19 192 49 193 411 194 63 195 5 196 8 197 7 198 15 199 13 200 38 202 25 203 7 204 29 205 38 206 22 207 19 208 11 209 16 210 81 211 11 212 37 213 206 214 88 215 19 216 11 217 11 218 17 219 15 220 32 221 40 222 119 223 19 224 142 225 37 226 18 227 73 228 32 229 8 230 10 231 8 232 12 233 70 234 18 235 13 236 30 237 119 238 247 239 8 240 13 241 56 242 11 243 27 244 60 245 194 246 127 247 639 248 1610 249 1090 250 241 251 42 252 19 253 236 254 56 255 28 256 31 257 31 258 28 259 136 260 97 261 19 262 9 263 25 264 462 265 29 266 40 267 15 268 18 269 27 270 20 271 10 274 27 275 58 276 10 277 19 278 30 279 55 280 5 281 23 282 5 283 4 284 9 285 7 286 10 287 7 288 3 290 10 291 10 294 296 11 297 60 298 52 299 60 300 92 301 94 302 99 303 261 304 nd 305 nd 306 nd 307 nd 308 639 309 nd 310 nd 311 nd nd: not determined