INDOLE CARBOXAMIDES EN TANT QU'INHIBITEURS D'IKK2

INDOLE CARBOXAMIDES AS IKK2 INHIBITORS

Abrégé français

L'invention concerne de nouveaux dérivés d'indole carboxamide. Plus particulièrement, l'invention concerne des composés de formule (I) dans laquelle R1, R2, R3, U et V sont définis ci-après et leurs sels pharmaceutiquement acceptables. Les composés de l'invention sont des inhibiteurs d'IKK2 et peuvent être utiles dans le traitement de troubles associés à une activité IKK2 appropriée (également connue comme IKK.beta.), telle que la polyarthrite rhumatoïde, l'asthme et la MPOC (maladie pulmonaire obstructive chronique). En conséquence, l'invention concerne également des compositions pharmaceutiques renfermant un composant de l'invention. L'invention concerne également des méthodes d'inhibition de l'activité IKK2 et de traitement de troubles associés utilisant un composé de l'invention ou une composition pharmaceutique renfermant un composé de l'invention.

Abrégé anglais

The invention is directed to novel indole carboxamide derivatives.
Specifically, the invention is directed to compounds according to formula I:
Formula (I) where R1 , R2, R3, U and V are defined below and to
pharmaceutically acceptable salts thereof. The compounds of the invention are
inhibitors of IKK2 and can be useful in the treatment of disorders associated
with inappropriate IKK2 (also known as IKK.beta.) activity, such as rheumatoid
arthritis, asthma, and COPD (chronic obstructive pulmonary disease).
Accordingly, the invention is further directed to pharmaceutical compositions
comprising a compound of the invention. The invention is still further
directed to methods of inhibiting IKK2 activity and treatment of disorders
associated therewith using a compound of the invention or a pharmaceutical
composition comprising a compound of the invention.

Revendications

What is claimed is:
1. A compound according to formula (I):
<IMG>
wherein
<IMG>
R1 is the group -XYZ or
X is phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, or 2,3-dihydro-1H-
indenyl,
where said phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, and 2,3-dihydro-
1H-indenyl are optionally substituted with one or two substituents each
independently
selected from the following:
1) halo,
2) nitro,
3) cyano,
4) -NR7R8,
5) C1-C6-alkyl,
6) CHO,
7) CONH2, and
8) -OR4,
where said C1-C6-alkyl is optionally substituted with one -NR4R5 group;
Y is a bond or C1-C6 alkylene,
where C1-C6 alkylene is optionally substituted with one or two substituents
each
independently selected from the following:
1) C1-C3-alkyl optionally substituted by one OR4 group,
2) C3-C7-cycloalkyl,
3) methoxy,
342

4) hydroxy, and
5) heteroaryl;
Z is -NR4R5 or heterocycloalkyl,
where said heterocycloalkyl is optionally substituted with one or two
substituents
each independently selected from the following:
1) C1-C6-alkyl optionally substituted by one OR4 or one heterocycloalkyl
group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) -CONH2
5) hydroxy,
6) heteroaryl;
7) CF3,
8) phenyl,
9) heterocycloalkyl, and
10) N(CH3)2;
R2 is selected from
1) H,
2) fluoro, and
3) chloro;
R3 is selected from
1) H,
2) fluoro, and
3) chloro;
R4 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxy or one
methoxy
group;
343

R5 is selected from
1) H,
2) C5-C6-heterocycloalkyl,
3) -CO2Et,
4) C1-C6-alkoxy,
5) C3-C7-cycloalkyl,
6) C1-C6-alkyl,
7) -SO2R10, and
8) -C(O)R10,
where said C3-C7-cycloalkyl and C1-C6-alkyl are optionally substituted with
one
to three substituents selected from R6;
each R6 is independently selected from
1) -NR7R8,
2) -SO2R7,
3) -CONH2,
4) -CF3,
5) -CN,
6) -CO2R7,
7) -OCH2CH2OR7,
8) -SR5,
9) C3-C4 alkenyl,
10) OH,
11) C1-C6-alkoxy,
12) heteroaryl,
13) C3-C7-cycloalkyl,
14) phenyl,
15) heterocycloalkyl, and
16) halo,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to two substituents selected from R9;
R7 is selected from
1) H,
344

2) C1-C3-alkyl, and
3) phenyl;
R8 is selected from
1) H,
2) C1-C3-alkyl, and
3) -C(O)R4;
each R9 is independently selected from
1) hydroxy,
2) -OMe,
3) nitro,
4) C1-C6-alkyl,
5) NH2,
6) halo,
7) CF3,
8) C1-C6-alkoxy, and
9) CN;
R10 is selected from
1) C1-C6-alkyl,
2) phenyl,
3) C3-C7-cycloalkyl,
4) heteroaryl,
5) C1-C6-heteroaryl, and
6) heterocycloalkyl,
where said C1-C6-alkyl is substituted one to two substituents each
independently
selected from C3-C7-cycloalkyl and -S-R7; where said heterocycloalkyl is
optionally
substituted with one -C(O)R7 group; and where said phenyl, heteroaryl and C1-
C6-
heteroaryl are optionally substituted with one to two substituents selected
from R11;
each R11 is independently selected from
1) H,
345

2) C1-C6-alkyl, and
3) halo;
U is a bond, C1-C6 alkylene or C2-C6 alkenylene;
V is phenyl, 5 or 6 membered heteroaryl, 5-7 membered heterocycloalkyl, C5-C7
cycloalkyl, or C5-C7 cycloalkenyl, each of which is substituted by -N(R7)S(O)m
R12, -
S(O)m N(R7)R12, -S(O)m R12, or -C(O)R12;
m is 1 or 2; and
R12 is C1-C6-alkyl, C3-C7 cycloalkyl, C1-C6-alkyl-C3-C7cycloalkyl, or C1-C6-
alkyl-
phenyl; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
2. A compound according to claim 1 wherein:
R1 is the group -XYZ;
X is phenyl or heteroaryl,
where said phenyl and heteroaryl are optionally substituted with one or two
substituents each independently selected from the following:
1) halo,
2) nitro,
3) cyano,
4) -NR7R8,
5) C1-C6-alkyl,
6) CHO,
7) CONH2, and
8) -OR4,
where said C1-C6-alkyl is optionally substituted with one -NR4R5 group;
Y is a bond or C1-C6 alkylene,
where C1-C6 alkylene is optionally substituted with one or two substituents
each
independently selected from the following:
1) C1-C3-alkyl optionally substituted by one OR4 group,
346

2) C3-C7-cycloalkyl,
3) methoxy,
4) hydroxy, and
5) heteroaryl;
Z is -NR4R5 or heterocycloalkyl,
where said heterocycloalkyl is optionally substituted with one or two
substituents
each independently selected from the following:
1) C1-C6-alkyl optionally substituted by one OR4 group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) hydroxy, and
5) heteroaryl;
R2 is selected from
1) H,
2) fluoro, and
3) chloro;
R3 is selected from
1) H,
2) fluoro, and
3) chloro;
R4 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxy or one
methoxy
group;
R5 is selected from
1) H,
2) C1-C6-alkoxy,
3) C3-C7-cycloalkyl,
347

4) C1-C6-alkyl,
5) -SO2R10, and
6) -C(O)R10,
where said C3-C7-cycloalkyl and C1-C6-alkyl are optionally substituted with
one
to three substituents selected from R6;
each R6 is independently selected from
1) -NR7R8,
2) -SO2R7,
3) OH,
4) methoxy,
5) heteroaryl,
6) C3-C7-cycloalkyl,
7) phenyl,
8) heterocycloalkyl, and
9) halo,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to two substituents selected from R9;
R7 is selected from
1) H and
2) C1-C3-alkyl;
R8 is selected from
1) H and
2) C1-C3-alkyl;
each R9 is independently selected from
1) hydroxy,
2) nitro,
3) C1-C6-alkyl,
4) NH27
5) halo,
6) CF3,
348

7) C1-C6-alkoxy, and
8) CN;
R10 is selected from
1) C1-C6-alkyl,
2) phenyl,
3) C3-C7-cycloalkyl, and
4) heteroaryl,
where said C1-C6-alkyl is substituted one to two substituents each
independently
selected from C3-C7-cycloalkyl and -S-R7; where said heterocycloalkyl is
optionally
substituted with one -C(O)R7 group; and where said phenyl and heteroaryl are
optionally
substituted with one to two substituents selected from R11;
each R11 is independently selected from
1) H,
2) C1-C6-alkyl, and
3) halo;
U is a bond, C1-C6 alkylene or C2-C6 alkenylene;
V is phenyl, 5 or 6 membered heteroaryl, 5-7 membered heterocycloalkyl, C5-C7
cycloalkyl, or C5-C7 cycloalkenyl, each of which is substituted by -N(R7)S(O)m
R12, -
S(O)m N(R7)R12, -S(O)m R12, or -C(O)R12;
m is 1 or 2; and
R12 is C1-C6-alkyl, C3-C7 cycloalkyl, C1-C6-alkyl-C3-C7cycloalkyl, or C1-C6-
alkyl-
phenyl; or a pharmaceutically acceptable salt, solvate or polymorph thereof.
3. A compound according to claim 1 wherein:
<IMG>
R1 is the group -XYZ or
349

X is phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, or 2,3-dihydro-1H-
indenyl;
Y is a bond or C1-C6 alkylene;
Z is -NR4R5 or heterocycloalkyl,
where said heterocycloalkyl is optionally substituted with one or two
substituents
each independently selected from the following:
1) C1-C6-alkyl optionally substituted by one OR4 or one heterocycloalkyl
group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) -CONH2
5) hydroxy,
6) heteroaryl;
7) CF3,
8) phenyl,
9) heterocyoloalkyl, and
10) N(CH3)2;
R2 is H;
R3 is H;
R4 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxy or one
methoxy
group;
R5 is selected from
1) H,
2) C5-C6-heterocycloalkyl,
3) -CO2Et,
4) C1-C6-alkoxy,
5) C3-C7-cycloalkyl,
6) C1-C6-alkyl,
350

7) -SO2R10, and
8) -C(O)R10,
where said C3-C7-cycloalkyl and C1-C6-alkyl are optionally substituted with
one
to three substituents selected from R6;
each R6 is independently selected from
1) -NR7R8,
2) -SO2R7,
3) -CONH2,
4) -CF3,
5) -CN,
6) -CO2R7,
7) -OCH2CH2OR7,
8) -SR5,
9) C3-C4 alkenyl;
10) OH,
11) C1-C6-alkoxy,
12) heteroaryl,
13) C3-C7-cycloalkyl,
14) phenyl,
15) heterocycloalkyl, and
16) halo,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to two substituents selected from R9;
R7 is selected from
1) H,
2) C1-C3-alkyl, and
3) phenyl;
R8 is selected from
1) H,
2) C1-C3-alkyl, and
3) -C(O)R4;
351

each R9 is independently selected from
1) hydroxy,
2) -OMe
3) nitro,
4) C1-C6-alkyl,
5) NH2,
6) halo,
7) CF3,
8) C1-C6-alkoxy, and
9) CN;
R10 is selected from
1) C1-C6-alkyl,
2) C3-C7-cycloalkyl,
3) heteroaryl,
4) C1-C6-heteroaryl, and
5) heterocycloalkyl,
where said C1-C6-alkyl is substituted with one to two substituents each
independently selected from C3-C7-cycloalkyl and -S-R7; where said
heterocycloalkyl is
optionally substituted with one -C(O)R7 group; and where said phenyl,
heteroaryl and C1-
C6-heteroaryl are optionally substituted with one to two substituents selected
from R11;
each R11 is independently selected from
1) H,
2) C1-C6-alkyl, and
3) halo;
U is a bond;
V is a 5-7 membered heterocycloalkyl substituted by -S(O)m R12;
m is i or 2; and
R12 is C1-C6-alkyl; or a pharmaceutically acceptable salt, solvate or
polymorph thereof.
352

4. A compound according to claim 1 wherein:
R1 is the group -XYZ;
X is phenyl or heteroaryl;
Y is a bond or C1-C6 alkylene;
Z is -NR4R5 or heterocycloalkyl,
where said heterocycloalkyl is optionally substituted with one or two
substituents
each independently selected from the following:
1) C1-C6-alkyl optionally substituted by one OR4 group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) hydroxy, and
5) heteroaryl;
R2 is H;
R3 is H;
R4 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxy or one
methoxy
group;
R5 is selected from
1) H,
2) C1-C6-alkoxy,
3) C3-C7-cycloalkyl,
4) C1-C6-alkyl,
5) -SO2R10, and
6) -C(O)R10,
where said C3-C7-cycloalkyl and C1-C6-alkyl are optionally substituted with
one
to three substituents selected from R6;
each R6 is independently selected from
353

1) -NR7R8,
2) SO2R7,
3) OH,
4) methoxy,
5) heteroaryl,
6) C3-C7-cycloalkyl,
7) phenyl,
8) heterocycloalkyl, and
9) halo,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to two substituents selected from R9;
R7 is selected from
1) H and
2) C1-C3-alkyl;
R8 is selected from
1) H and
2) C1-C3-alkyl;
each R9 is independently selected from
1) hydroxy,
2) nitro,
3) C1-C6-alkyl,
4) NH2,
5) halo,
6) CF3,
7) C1-C6-alkoxy, and
8) CN;
R10 is selected from
1) C1-C6-alkyl,
2) phenyl,
3) C3-C7-cycloalkyl, and
354

4) heteroaryl,
where said C1-C6-alkyl is substituted with one or two substituents each
independently selected from C3-C7-cycloalkyl and -S-R7; where said
heterocycloalkyl is
optionally substituted with one -C(O)R7 group; and where said phenyl and
heteroaryl are
optionally substituted with one to two substituents selected from R11;
each R11 is independently selected from
1) H,
2) C1-C6-alkyl, and
3) halo;
U is a bond;
V is a 5-7 membered heterocycloalkyl substituted by -S(O)m R12;
m is 1 or 2; and
R12 is C1-C6-alkyl; or a pharmaceutically acceptable salt, solvate or
polymorph thereof.
5. A compound according to claim 1 wherein:
R1 is the group -XYZ;
X is 2- or 3- thiophenyl;
Y is a bond or C1-C4 alkylene;
Z is -NR4R5 or heterocycloalkyl,
1) C1-C6-alkyl optionally substituted by one OR4 or one heterocycloalkyl
group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) -CONH2,
5) hydroxy,
6) heteroaryl;
7) CF3,
8) phenyl,
9) heterocycloalkyl, and
10) N(CH3)2;
R2 is H;
355

R3 is H;
R4 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxy or one
methoxy
group;
R5 is selected from
1) C3-C7-cycloalkyl,
2) C1-C6-alkyl,
where said C3-C7-cycloalkyl and C1-C6-alkyl are optionally substituted with
one
to three substituents selected from R6;
each R6 is independently selected from
1) -NR7R8,
2) -CONH2,
3) -CN,
4) -OCH2CH2OR7,
5) C3-C4 alkenyl,
6) OH,
7) C1-C6-alkoxy,
8) heteroaryl,
9) C3-C7-cycloalkyl,
10) phenyl,
11) heterocycloalkyl, and
12) halo,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to two substituents selected from R9;
R7 is selected from
1) H,
2) C1-C3-alkyl, and
3) phenyl;
356

R8 is selected from
1) H,
2) C1-C3-alkyl, and
3) -C(O)R4;
each R9 is independently selected from
1) C1-C6-alkyl;
U is a bond;
V is 4-piperidinyl substituted by -S(O)2R12; and
R12 is ethyl or isopropyl; or a pharmaceutically acceptable salt, solvate, or
polymorph
thereof.
<IMG>
6. A compound according to claim 1 wherein the group U-V is and R12 is
ethyl or isopropyl; or a pharmaceutically acceptable salt, solvate or
polymorph thereof.
7. A compound according to claim 1 that is a compound of formula (II):
<IMG>
where R13 is -NR14R15 or heterocycloalkyl
where said heterocycloalkyl is optionally substituted with one or two
substituents
selected from the following:
1) C1-C6-alkyl optionally substituted by one OR14 group,
2) hydroxy,
3) methoxy, and
4) heteroaryl;
357

R14 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxyl or one
methoxy
group;
R15 is selected from
1) H,
2) methoxy,
3) C3-C7 cycloalkyl, and
4) C1-C6-alkyl,
where said C3-C7cycloalkyl and C1-C6-alkyl are optionally substituted with one
to
three substituents selected from R16;
each R16 is independently selected from
1) -NR17R18,
2) -SO2R17,
4) OH,
5) methoxy
6) heteroaryl,
7) C3-C7cycloalkyl,
8) phenyl, and
9) heterocycloalkyl,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to three substituents selected from R19;
R17 is selected from
1) H and
2) C1-C3-alkyl;
R18 is selected from
1) H and
2) C1-C3-alkyl;
358

R19 is selected from
1) hydroxy,
2) nitro,
3) C1-C6-alkyl,
4) NH2,
5) halo,
6) CF3, and
7) C1-C6-alkoxy; and
n is 1 to 3; or a pharmaceutically acceptable salt, solvate or polymorph
thereof.
8. A compound according to claim 1 which is:
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperazinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({methyl[2-
(methylsulfonyl)ethyl]amino}
methyl)phenyl]-1H-indole-7-carboxamide;
5-(3-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}phenyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(4-{2-[(2-hydroxyethyl)oxy]ethyl}-1-
piperazinyl)methyl]phenyl}-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[3-(hydroxymethyl)-1-
piperidinyl]methyl}phenyl)-
1H-indole-7-carboxamide;
5-[3-({bis[2-(methyloxy)ethyl]amino}methyl)pheny{]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-{3-[(2,6-dimethyl-4-morpholinyl)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(1,3-thiazol-2-yl)-1-
pyrrolidinyl] methyl}phenyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(2-thienyl)-1-
pyrrolidinyl]methyl} phenyl)-1H-
indole-7-carboxamide;
359

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-2-phenylethyl)(methyl)
amino]methyl}phenyl)-1H-indole-7-carboxamide;
5-(3-{[ethyl(methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-
carboxamide;
5-{3-[(cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-[3-({[(3,4-dihydroxyphenyl)methyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
thienylmethyl)amino]methyl}phenyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-(hydroxymethyl)-3-
methylbutyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-1-methylethyl)
amino]methyl}phenyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(trans-4-hydroxycyclohexyl)
amino]methyl}phenyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[({[1-(1-piperidinyl)cyclohexyl]
methyl}amino)methyl]phenyl}-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-hydroxypropyl]amino}
methyl)phenyl]-1H-
indole-7-carboxamide;
5-{3-[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-
7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(propylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1-methylethyl)amino]
methyl}phenyl)-1H-indole-7-
carboxamide;
5-(3-{[(1-ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-piperidinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
360

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
5-[4-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
5-{3-[(cyclopropylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-{3-[(cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-[4-(1-
piperidinylmethyl)phenyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(2-methylpropyl)amino]-2,3-dihydro-
1H-inden-5-yl}-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{8-[(2-methylpropyl)amino]-5,6,7,8-
tetrahydro-2-
naphthalenyl}-1H-indole-7-carboxamide;
5-(5-{[(2-cyanoethyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-{[(2,2,2-
trifluoroethyl)amino]methyl}phenyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1,2,3,4-tetrahydro-7-isoquinolinyl)-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2,2,2-
trifluoroethyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
5-(3-{[(2-amino-2-oxoethyl)(methyl)amino}methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2,2,2-trifluoroethyl)amino]methyl}-
1,3-thiazol-4-
yl)-1H-indole-7-carboxamide;
5-(3-cyano-5-{[(2,2,2-trifluoroethyl)amino}methyl}phenyl)-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-
piperidinyl)amino]methyl}-3-
thienyl)-1H-indole-7-carboxamide;
5-(5-{[(2-cyanoethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
5-(5-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
361

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-
(phenylsulfonyl)ethyl]amino}methyl)-3-
thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(1-piperidinylmethyl)-1-
pyrrolidinyl]methyl}-3-
thienyl)-1H-indole-7-carboxamide;
5-(5-{[(2R)-2-(aminocarbonyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-(5-{[(2S)-2-(dimethylamino)-1-pyrrolidinyl]methyl}-3-thienyl}-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-(1-{2-[4-(dimethylamino)-1-piperidinyl]ethyl}-1H-pyrazol-4-yl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
5-[3,4-bis(methyloxy)-5-(4-morpholinylmethyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4,5-
bis(methyloxy)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4,5-
bis(methyloxy)phenyl]-1H-indole-7-carboxamide;
5-[3-{[(2,2-dimethylpropyl)amino]methyl}-4,5-bis(methyloxy)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(2-
hydroxyethyl)(methyl)amino]methyl}-4,5-
bis(methyloxy)phenyl]-1H-indole-7-carboxamide;
5-[3,4-bis(methyloxy)-5-(1-pyrrolidinylmethyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-{4-[(dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(1-methylethyl)amino]methyl}-2,3-
dihydro-1-
benzofuran-6-yl)-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)-2,3-dihydro-1-
benzofuran-6-
yl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[1-methyl-2-
(methyloxy)ethyl]amino}methyl)-2-
thienyl]-1H-indole-7-carboxamide;
362

5-(5-{[(2-cyanoethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2,2,2-trifluoroethyl)amino]methyl}-
3-pyridinyl)-1H-
indole-7-carboxamide;
5-{3-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-
carboxamide;
5-(5-{[[2-(diethylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-(5-{[butyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(propyl)amino]methyl}-3-
thienyl)-1H-indole-
7-carboxamide;
5-(5-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-(5-{[[3-(dimethylamino)propyl](methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-(5-{[cyclopentyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-[[methyl(pentyl)amino]methyl}-3
thienyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-methylpropyl)amino]methyl}-
3-thienyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(phenylmethyl)amino]methyl}-3-
thienyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-
hydroxyethyl)(methyl)amino]methyl}-3-thienyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(2-
pyridinyl)ethyl]amino}methyl}-3-
thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-
furanylmethyl)(methyl)amino]methyl}-3-thienyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(4-
pyridinylmethyl)amino]methyl}-3-thienyl)-
1H-indole-7-carboxamide; ;
363

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methyl{[1-(1-methylethyl)-3-
pyrrolidinyl]methyl}amino)methyl]-3-thienyl}-1H-indole-7-carboxamide; ;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-
thienylmethyl)amino]methyl}-3-thienyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-({methyl[1-(2-
thienyl)ethyl]amino}methyl)-3-thienyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(3-
thienylmethyl)amino]methyl}-3-thienyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(tetrahydro-2H-pyran-4-
ylmethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; trifluoroacetate
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(3-
pyridinylmethyl)amino]methyl}-3-thienyl)-
1H-indole-7-carboxamide; trifluoroacetate
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(4-
pyrimidinylmethyl)amino]methyl}-3-
thienyl)-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-
(methyloxy)ethyl]amino}methyl)-3-
thienyl]-1H-indole-7-carboxamide;
5-{3-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-[[methyl(1-methylethyl)amino]methyl}-
3-thienyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(3-pyridinyl)-1-
pyrrolidinyl]methyl}-3-thienyl)-1H-
indole-7-carboxamide;
5-(5-{[2-(1,1-dimethylethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-{5-[(2-ethyl-1-pyrrolidinyl)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1-
pyrrolidinyl]methyl}-3-
thienyl)-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(1-methylethyl)-1-
pyrrolidinyl]methyl}-3-thienyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2S)-2-[(methyloxy)methyl]-1-
pyrrolidinyl}methyl)-
3-thienyl]-1H-indole-7-carboxamide;
364

5-(5-{[cyclohexyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1-
pyrrolidinyl]methyl}-3-
thienyl)-1H-indole-7-carboxamide;
5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(propyl)amino]methyl}-3-
thienyl)-1H-indole-
7-carboxamide;
3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-(5-
{[methyl(propyl)amino]methyl}-3-thienyl)-
1H-indole-7-carboxamide;
5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-
piperidinyl}-
1H-indole-7-carboxamide;
3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-[5-({methyl[2-
(methyloxy)ethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-2-thienyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-
thienyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(propylamino)methyl]-3-thienyl}-1H-
indole-7-
carboxamide;
5-{5-[(diethylamino)methyl}-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-(5-{[(2R,5R)-2,5-dimethyl-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-{5-[(cyclopropylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
5-{5-[(cyclobutylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
5-{5-[(dimethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-(5-{[(cyclopentylmethyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
365

5-[5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-
4-piperidinyl]-
1H-indole-7-carboxamide;
5-{5-[(cyclopentylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
5-(5-{[(cyclopropylmethyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-[5-({[(1S)-1,2-dimethylpropyl]amino}methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-
4-piperidinyl]-
1H-indole-7-carboxamide;
5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(phenylmethyl)amino]methyl}-3-
thienyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)-3-
thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(tetrahydro-2H-pyran-4-
ylmethyl)amino]methyl}-3-
thienyl)-1H-indole-7-carboxamide;
5-{5-[(butylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2R)-tetrahydro-2-
furanylmethyl]amino}methyl)-3-
thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2S)-2-[(methyloxy)methyl]-1-
pyrrolidinyl}methyl)-
3-thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2R)-2-[(methyloxy)methyl]-1-
pyrrolidinyl} methyl)-
3-thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(propylamino)ethyl]phenyl}-1H-
indole-7-
carboxamide;
5-{4-[2-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-
yl]carbonyl}amino)methyl]phenyl}-3-
[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(4-
pyridinylcarbonyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
366

5-(4-{[(cyclopentylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-
furanylcarbonyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
5-{4-[2-(acetylamino)ethyl]phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{2-
[(methylsulfonyl)amino]ethyl}phenyl)-1H-indole-
7-carboxamide;
5-(4-{2-[(cyclobutylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-(4-{2-[(cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{2-
[(methylsulfonyl)amino]ethyl}phenyl)-1H-indole-
7-carboxamide;
5-(3-{2-[(cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperazinyl)-3-pyridinyl]-1H-
indole-7-carboxamide
trifluoroacetate;
5-[6-(4-ethyl-1-piperazinyl)-3-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-piperidinylmethyl) phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(1-methylethyl)amino]methyl}phenyl)-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(propylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
5-(4-{[(1-ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
5-{4-[(cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
367

5-{4-[(cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-{4-[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-
7-
carboxamide;
5-{4-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-{4-[(diethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-pyrrolidinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1S)-2-hydroxy-1-
methylethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1R)-2-hydroxy-1-
methylethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(2R)-2-
hydroxypropyl]amino}methyl)phenyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[2-hydroxy-1-
(hydroxymethyl)ethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1-methylbutyl)amino]methyl}phenyl)-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1R)-1-
methylpropyl]amino}methyl)phenyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
methylpropyl)amino]methyl}phenyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl)-5-[3-({[(1S)-1-
methylpropyl]amino}methyl)phenyl]-1H-
indole-7-carboxamide;
5-{4-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(propanoylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
5-(4-{[(cyclopropylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
368

5-(4-{[(cyclobutylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-
thienylacetyl)amino]methyl}phenyl)-1H-indole-
7-carboxamide;
5-[4-({[(1S)-1,2-dimethylpropyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
5-{4-[(butanoylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-
methylpropanoyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(3-
methylbutanoyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-
{[(methylsulfonyl)amino]methyl}phenyl)-1H-indole-7-
carboxamide;
5-[3-({[(1R)-1,2-dimethylpropyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
5-(4-{[(ethylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
5-(4-{[(butylsulfonyl)amino]methyl)phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1-
methylethyl)sulfonyl]amino}methyl)phenyl]-1H-
indole-7-carboxamide;
5-(6-amino-2-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1H-pyrazol-1-yl)phenyl]-1H-indole-7-
carboxamide;
5-[4-(dimethylamino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-
carboxamide;
5-(3-aminophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl-2-
thienyl}-1H-
indole-7-carboxamide;
5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-2-
thienyl)-1H-indole-
7-carboxamide;
5-{5-[(cyclopropylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
369

5-(5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-(5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-3-
pyridinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(methyloxy)propyl]amino}methyl)-
3-pyridinyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinylmethyl)-3-pyridinyl]-1H-
indole-7-
carboxamide;
5-{5-[(ethylamino)methyl]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-{5-[(dimethylamino)methyl]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-3-
pyridinyl}-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-
pyridinyl)-1H-
indole-7-carboxamide;
5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-
thienyl)-1H-indole-
7-carboxamide;
5-[5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-
4-piperidinyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(pentylamino)methyl]-2-thienyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2S)-2-methylbutyl]amino}methyl)-2-
thienyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylbutyl)amino]methyl}-2-
thienyl)-1H-indole-
7-carboxamide;
5-{5-[(butylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
370

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-2-
thienyl]-1H-
indole-7-carboxamide;
5-{5-[(cyclopentylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(3-methylbutyl)amino]methyl}-2-
thienyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-
pyridinyl)-1H-
indole-7-carboxamide;
5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-
carboxamide;
5-[5-({[3-(ethyloxy)propyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(methyloxy)propyl]amino}methyl)-
2-thienyl]-1H-
indole-7-carboxamide;
5-(5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[({3-[(1-
methylethyl)oxy]propyl}amino)methyl]-2-
thienyl}-1H-indole-7-carboxamide;
5-[5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(propyloxy)propyl]amino}methyl)-
2-thienyl]-1H-
indole-7-carboxamide;
5-(5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(1S)-1,2,2-
trimethylpropyl]amino}methyl)-2-
thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(hexylamino)methyl]-2-thienyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylsulfonyl)amino]phenyl}-1H-
indole-7-
carboxamide;
5-[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-pyrrolidinyl)-4-pyridinyl]-1H-
indole-7-
carboxamide;
371

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinyl)-4-pyridinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-[(2-methylpropyl)amino]-4-pyridinyl}-
1H-indole-7-
carboxamide;
5-{2-[(2,2-dimethylpropyl)amino]-4-pyridinyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(propylamino)-4-pyridinyl]-1H-indole-
7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1 -pyrrolidinylmethyl)-2-thienyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-methylpropyl)amino]methyl}-2-
thienyl)-1H-
indole-7-carboxamide;
5-{4-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(1S)-1-(1-pyrrolidinyl)ethyl]-3-
thienyl}-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(1R)-1-(1-pyrrolidinyl)ethyl]-3-
thienyl}-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-
2-thienyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({(2S)-2-[(methyloxy)methyl]-1-
pyrrolidinyl}methyl)-
2-thienyl]-1H-indole-7-carboxamide;
5-(4-{[(2R,5R)-2,5-dimethyl-1-pyrrolidinyl]methyl}-2-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-methyl-1-
pyrrolidinyl]methyl}-3-thienyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2R)-2-methyl-1-
pyrrolidinyl]methyl}-3-thienyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[1-(1-pyrrolidinyl)propyl]-3-thienyl}-
1H-indole-7-
carboxamide;
5-{5-[(dimethylamino)methyl]-3-thienyl}-3-{1-[(1-methylethyl)sulfonyl]-4-
piperidinyl}-1H-
indole-7-carboxamide;
5-[5-(aminomethyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-
carboxamide;
372

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{2-[(2-methylpropyl)amino]ethyl}-3-
thienyl)-1H-
indole-7-carboxamide;
5-{5-[2-(dimethylamino)ethyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-pyrrolidinyl)-3-pyridinyl]-1H-
indole-7-
carboxamide;
5-{6-[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-[6-(dimethylamino)-3-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(propylamino)-3-pyridinyl]-1H-indole-
7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{6-[(1-methylethyl)amino]-3-pyridinyl}-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(4-morpholinyl)-3-pyridinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-
thienyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1 -pyrrolidinylmethyl)-3-thienyl]-1H-
indole-7-
carboxamide;
5-{5-[(ethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(1R)-2-hydroxy-1-
methylethyl]amino}methyl)-3-
thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-piperidinylmethyl)-3-thienyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinylmethyl)-3-thienyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-furanyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[1-(1-pyrrolidinyl)ethyl]-3-thienyl}-
1H-indole-7-
carboxamide;
373

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-2-thienyl]-1H-
indole-7-
carboxamide;
5-{5-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(propylamino)methyl]-2-thienyl}-1H-
indole-7-
carboxamide;
5-{5-[(diethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-2-
thienyl)-1H-
indole-7-carboxamide;
5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-
furanyl)-1H-
indole-7-carboxamide;
5-(5-{[(cyclopentylmethyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-3-furanyl]-1H-
indole-7-
carboxamide;
5-{5-[(diethylamino)methyl]-3-furanyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-1,3-thiazol-2-
yl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[2-methyl-1-(1-pyrrolidinyl)propyl]-3-
thienyl}-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1 -pyrrolidinylmethyl)-1,3-thiazol-2-
yl]-1H-indole-7-
carboxamide;
5-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-
4-yl}-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-
yl}-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-
pyrazol-4-yl)-
1H-indole-7-carboxamide;
374

5-{1-[2-(butylamino)ethyl]-1H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-
carboxamide;
5-{1-[2-(cyclobutylamino)ethyl]-1H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-[1-(2-{[2-(diethylamino)ethyl]amino}ethyl)-1H-pyrazol-4-yl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(1-methylethyl)amino]ethyl}-1H-
pyrazol-4-yl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-methylpropyl)amino]ethyl}-1H-
pyrazol-4-yl)-
1H-indole-7-carboxamide;
5-(1-{2-[(cyclopentylmethyl)amino]ethyl}-1H-pyrazol-4-yl)-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(methyloxy)-3-(1-
pyrrolidinylmethyl)phenyl]-1H-
indole-7-carboxamide;
5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(methyloxy)-3-(4-
morpholinylmethyl)phenyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4-
(methyloxy)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-[(methylamino)methyl]-4-
(methyloxy)phenyl]-1H-
indole-7-carboxamide;
5-[3-{[(2,2-dimethylpropyl)amino]methyl}-4-(methyloxy)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-
hydroxyethyl)(methyl)amino]ethyl}-1H-
pyrazol-4-yl)-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-fluoro-3-[(methylamino)methyl]phenyl}-
1H-indole-7-
carboxamide;
5-{3,5-bis[(methylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-fluoro-3-({[2-hydroxy-1-
(hydroxymethyl)ethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
375

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-fluoro-3-({[(1S)-2-hydroxy-1-
methylethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
5-{3-[(cyclopropylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-{3-[(cyclobutylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-pyrrolidinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
5-{3,5-bis[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-{3,5-bis[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperidinyl)phenyl]-1H-indole-7-
carboxamide;
5-{3-[1-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-{3-[1-(dimethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-
1H-indole-7-
carboxamide;
5-{3-[(ethylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(propylamino)methyl]phenyl}-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(1-
methylethyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-
methylpropyl)amino]methyl}phenyl)-
1H-indole-7-carboxamide;
5-{3-[(cyclobutylamino)methyl}-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-{3-[(dimethylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1-
pyrrolidinylmethyl)phenyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(4-morpholinylmethyl)phenyl]-
1H-indole-7-
carboxamide;
376

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1-piperidinylmethyl)phenyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[1-(methylamino)ethyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(1-
methylethyl)amino]ethyl}phenyl)-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-
methylpropyl)amino]ethyl}phenyl)-1H-indole-
7-carboxamide;
5-{3-[1-(cyclobutylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[1-(1-pyrrolidinyl)ethyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(3-thiomorpholinyl)phenyl]-1H-indole-
7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-piperazinyl)-2-thienyl]-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-piperazinyl)phenyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(4-morpholinyl)-3-pyridazinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-pyrrolidinyl)-3-pyridazinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-[(methylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
thienylmethyl)amino]methyl}phenyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-methyl-2-
furanyl)methyl]amino}methyl)phenyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2R)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
5-(3-{[(2,2-dimethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-
1H-indole-7-
carboxamide;
377

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-
methylbutyl]amino}methyl)phenyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1R)-1,2,2-
trimethylpropyl]amino}methyl)phenyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2R)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
5-[3-({[(1S)-1,2-dimethylpropyl]amino}methyl)-5-fluorophenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-[3-({[(1R)-1,2-dimethylpropyl}amino}methyl)-5-fluorophenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(1-
methylpropyl)amino]methyl}phenyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1S)-1,2,2-
trimethylpropyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-2-
methylbutyl]amino}methyl)phenyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-
methylbutyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1R)-1,2,2-
trimethylpropyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
5-(3-{[(2,2-dimethylpropyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1H-indole-7-carboxamide;
5-(3-{[(cyclopropylmethyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
5-(3-{[(cyclopentylmethyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(tetrahydro-2H-pyran-4-
ylmethyl)amino]methyl}phenyl)-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-
thienylmethyl)amino]methyl}phenyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[2-
(methyloxy)ethyl]amino}methyl)phenyl]-
1H-indole-7-carboxamide;
378

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[3-
(methyloxy)propyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-
furanylmethyl)amino]methyl}phenyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(3-
methylbutyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(5-methyl-2-
furanyl)methyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
methylpropyl)amino]methyl}phenyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-pyrrolidinyl)phenyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(propylamino)methyl]phenyl}-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-{[(2-
methylpropyl)amino]methyl}phenyl)-
1H-indole-7-carboxamide;
5-(5-{[(2,2-dimethylpropyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1H-indole-7-carboxamide;
5-[5-({[(1S)-1,2-dimethylpropyl]amino}methyl)-2-fluorophenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-[5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-fluorophenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-(5-{[(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-(1-
pyrrolidinylmethyl)phenyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[2-
(methyloxy)ethyl]amino}methyl)phenyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[3-
(methyloxy)propyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-methyl-2-pyrrolidinyl)phenyl]-1H-
indole-7-
carboxamide;
379

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{2-[(2-
methylpropyl)amino]ethyl}phenyl)-1H-indole-
7-carboxamide;
5-{3-[2-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[2-(propylamino)ethyl]phenyl}-1H-
indole-7-
carboxamide;
5-{3-[2-(dimethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-{3-[2-(dipropylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-[3-({[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinylmethyl)-1,3-thiazol-4-
yl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-
thiazol-4-yl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-pyrrolidinylmethyl)-1,3-thiazol-4-
yl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-piperidinylmethyl)-1,3-thiazol-4-
yl]-1H-indole-7-
carboxamide;
5-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-
7-carboxamide;
5-(2-{[ethyl(methyl)amino]methyl}-1,3-thiazol-4-yl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-(3-cyano-5-{[(2-methylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
5-{3-cyano-5-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylsulfonyl)amino]phenyl}-1H-
indole-7-
carboxamide;
5-[4-(acetylamino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-
carboxamide;
5-[3-(acetylamino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
380

5-{3-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-
{[(methylsulfonyl)amino]methyl}phenyl)-1H-indole-7-
carboxamide;
5-{3-[(butanoylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4-
fluorophenyl)carbonyl]amino}methyl)phenyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
methylpropanoyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
furanylcarbonyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
5-(3-{[(cyclopentylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
5-(3-{[(2-ethylbutanoyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-indole-
7-carboxamide;
5-(3-{[(1-benzothien-2-ylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
5-[3-({[(1-acetyl-4-piperidinyl) carbonyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1-methyl-1H-pyrrol-2-
yl)carbonyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(3-methyl-2-
butenoyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(heptanoylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(octanoylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
methylpentanoyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(3-
methylbutanoyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
381

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
thienylacetyl)amino]methyl}phenyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(hexanoylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
methylbutanoyl)amino]methyl}phenyl)-1H-
indole-7-carboxamide;
5-(3-{[(cyclobutylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-(3-{[(cyclopropylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(propanoylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
5-(3-{[(cyclopentylacetyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[3-
(methylthio)propanoyl]amino}methyl)phenyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1-
methylethyl)sulfonyl]amino}methyl)phenyl]-1H-
indole-7-carboxamide;
5-(3-{[(cyclopropylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1H-indole-7-carboxamide;
5-[3-({[(4-bromophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
5-[3-({[(4-chlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(3-
fluorophenyl)sulfonyl]amino}methyl)phenyl]-
1H-indole-7-carboxamide;
5-[3-({[(2-chlorophenyl)sulfonyl}amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
5-[3-({[(2,5-dichloro-3-thienyl)sulfonyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-[3-({[(2-chloro-6-methylphenyl)sulfonyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
382

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-fluoro-2-
methylphenyl)sulfonyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
5-[3-({[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-
{[(propylsulfonyl)amino]methyl}phenyl)-1H-indole-7-
carboxamide;
5-(3-{[(butylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-
{[(phenylsulfonyl)amino]methyl}phenyl)-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4-
fluorophenyl)sulfonyl]amino}methyl)phenyl]-
1H-indole-7-carboxamide;
5-[3-({[(4-bromo-2-ethylphenyl)sulfonyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-(3-{[(1-benzothien-3-ylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
5-{3-[({[4-(1,1-dimethylethyl)phenyl]sulfonyl}amino)methyl]phenyl}-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-[3-({[(3,4-difluorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1H-indole-7-carboxamide;
5-(3-{[(ethylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
5-(3-{[(2,1,3-benzoxadiazol-4-ylsulfonyl)amino]methyl}phenyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(tetrahydro-3-
furanylcarbonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide;
5-{4-[(cyclopentylsulfonyl)amino]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-methyl-2-oxo-1-piperazinyl)phenyl]-
1H-indole-7-
carboxamide;
5-[6-(4-acetyl-1-piperazinyl)-3-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)amino]methyl}phenyl)-1H-
indole-7-
carboxamide;
383

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)amino]methyl}phenyl)-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[4-(1-pyrrolidinyl)-1-
piperidinyl]methyl}-3-thienyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-(trifluoromethyl)-1-
pyrrolidinyl]methyl}-3-
thienyl)-1H-indole-7-carboxamide;
5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide;
5-(5-{[(3S)-3-hydroxy-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-
piperidinyl}-1H-indole-7-carboxamide;
5-(5-{[cyclopentyl(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-
piperidinyl}-1H-indole-7-carboxamide;
5-(5-{[(2-hydroxyethyl)(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-
piperidinyl}-1H-indole-7-carboxamide;
5-(5-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-
4-piperidinyl}-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-propen-1-yl)amino]methyl}-
3-thienyl)-1H-
indole-7-carboxamide;
5-(5-{[[(3,5-dimethyl-1H-pyrazol-4-yl)methyl](methyl)amino]methyl}-3-thienyl)-
3-[1-
(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide;
5-(5-{[(cyanomethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-
3-thienyl)-
1H-indole-7-carboxamide;
5-(5-{[[2-(ethyloxy)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-(5-{[cyclobutyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({2-[(methyloxy)methyl]-1-
pyrrolidinyl}methyl)-3-
thienyl]-1H-indole-7-carboxamide;
5-(5-{[(1,1-dimethylethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[3-(trifluoromethyl)-1-
piperidinyl]methyl}-3-thienyl)-
1H-indole-7-carboxamide;
384

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide;
5-(5-{[(cyclopropylmethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
5-(5-{[[2-(acetylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1R,2R)-2-
hydroxycyclopentyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide;
5-(5-{[(1,1-dimethylpropyl)(methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(2S)-2-
hydroxypropyl](methyl)amino]methyl}-3-
thienyl)-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[(2R)-tetrahydro-2-
furanylmethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[{2-[(2-
hydroxyethyl)oxy]ethyl}(methyl)amino]methyl}-3-thienyl)-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-{methyl[2-
(methyloxy)ethyl]amino}ethyl)-3-
thienyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{1-[methyl(propyl)amino]ethyl}-3-
thienyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; or
5-(5-{[(1,1-dioxidotetrahydro-3-thienyl)(methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; or a pharmaceutically
acceptable
salt, solvate, or polymorph thereof.
9. A compound according to claim 1 which is
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperazinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({methyl[2-
(methylsulfonyl)ethyl]amino}
methyl)phenyl]-1H-indole-7-carboxamide;
385

5-(3-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}phenyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(4-{2-[(2-hydroxyethyl)oxy]ethyl}-1-
piperazinyl)methyl]phenyl}-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[3-(hydroxymethyl)-1-
piperidinyl]methyl} phenyl)-
1H-indole-7-carboxamide;
5-[3-({bis[2-(methyloxy)ethyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
5-{3-[(2,6-dimethyl-4-morpholinyl)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(1,3-thiazol-2-yl)-1-
pyrrolidinyl] methyl}phenyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(2-thienyl)-1-
pyrrolidinyl]methyl} phenyl)-1H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-2-phenylethyl)(methyl)
amino]methyl}phenyl)-1H-indole-7-carboxamide;
5-(3-{[ethyl(methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-
carboxamide;
5-{3-[(cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-[3-({[(3,4-dihydroxyphenyl)methyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]
methyl}phenyl)-1H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-(hydroxymethyl)-3-
methylbutyl]amino}methyl)phenyl]-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-l-methylethyl)
amino]methyl}phenyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(trans-4-hydroxycyclohexyl)
amino]methyl}phenyl)-
1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[({[1-(1-piperidinyl)cyclohexyl]
methyl}amino)methyl]phenyl}-1H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-hydroxypropyl]amino}
methyl)phenyl]-1H-
indole-7-carboxamide;
386

5-{3-[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-
7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(propylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1-methylethyl)amino]
methyl}phenyl)-1H-indole-7-
carboxamide;
5-(3-{[(1-ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-piperidinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylamino)methyl]phenyl}-1H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
5-[4-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1H-
indole-7-
carboxamide;
5-{3-[(cyclopropylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
5-{3-[(cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-
indole-7-
carboxamide;
3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-[4-(1-
piperidinylmethyl)phenyl]-
1H-indole-7-carboxamide; or
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(2-methylpropyl)amino]-2,3-dihydro-
1H-inden-5-yl}-
1H-indole-7-carboxamide; or a pharamceuically acceptable salt, solvate, or
polymorph
thereof.
10. A pharmaceutical composition comprising a compound according to claims 1or
2
and one or more pharmaceutically-acceptable excipients.
11. A method of treating a disorder mediated by inappropriate IKK2 activity
comprising administering a safe and effective amount of a compound according
to claims
1or 2 to a patient in need thereof.
387

12. A method according to claim 11 wherein the disorder mediated by
inappropriate
IKK2 activity is selected from the group consisting of: rheumatoid arthritis,
inflammatory
bowel disease, asthma, COPD (chronic obstructive pulmonary disease)
osteoarthritis,
osteoporosis, psoriasis, atopic dermatitis, ultraviolet radiation (UV)-induced
skin damage,
systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis,
alkylosing spondylitis,
tissue rejection, organ rejection, Alzheimer's disease, stroke,
atherosclerosis, restonosis,
diabetes, glomerulonephritis, Hodgkins disease, cachexia, inflammation
associated with
infection and certain viral infections, including acquired immune deficiency
syndrome
(AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia.
13. A method according to claim 11 wherein the disorder mediated by
inappropriate
IKK2 activity is an inflammatory or tissue repair disorder.
14. A method according to claim 11 wherein the disorder mediated by
inappropriate
IKK2 activity is rheumatoid arthritis, asthma or COPD.
15. A method according to claim 11 wherein the disorder mediated by
inappropriate
IKK2 activity is rheumatoid arthritis.
16. A method according to claim 11 wherein the disorder mediated by
inappropriate
IKK2 activity is asthma.
17. A method according to claim 11 wherein the disorder mediated by
inappropriate
IKK2 activity is COPD.
18. A method according to claim 11 wherein the disorder mediated by
inappropriate
IKK2 activity is selected from the group consisting of: Alzheimer's disease,
stroke
atherosclerosis, restenosis, diabetes, glomerulonephritis, osteoarthritis,
osteoporosis, and
Ataxia Telangiestasia.
19. A method according to claim 11 wherein the disorder mediated by
inappropriate
IKK2 activity is an autoimmune disease.
388

20. A method according to claim 19 wherein the autoimmune disease is systemic
lupus eythematosus, multiple sclerosis, psoriatic arthritis, or alkylosing
spondylitis.
21. A method according to claim 11 wherein the disorder mediated by
inappropriate
IKK2 activity is cancer or cachexia.
22. A method according to claim 21 wherein the cancer is Hodgkin's disease.
389

Description

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
CHEMICAL COMPOUNDS
FIELD OF THE INVENTION
The invention is directed to certain indole carboxamide compounds, which are
inhibitors
of kinase activity. More specifically, the compounds are IKK2 inhibitors.
These
compounds are useful in the treatment of disorders associated with
inappropriate IKK2
(also known as IKKR) activity, in particular in the treatment and prevention
of disorders
mediated by IKK2 mechanisms including inflammatory and tissue repair
disorders. Such
disorders include rheumatoid arthritis, asthma, and COPD (chronic obstructive
pulmonary
disease).
BACKGROUND OF THE INVENTION
An important large family of enzymes is the protein kinase enzyme family.
Currently,
there are about 500 different known protein kinases. However, because three to
four
percent of the human genome is a code for the formation of protein kinases,
there may be
many thousands of distinct and separate kinases in the human body. Protein
kinases
serve to catalyze the phosphorylation of an amino acid side chain in various
proteins by
the transfer of the y-phosphate of the ATP-Mg2+ complex to said amino acid
side chain.
These enzymes control the majority of the signaling processes inside cells,
thereby
governing cell function, growth, differentiation and destruction (apoptosis)
through
reversible phosphorylation of the hydroxyl groups of serine, threonine and
tyrosine
residues in proteins. Studies have shown that protein kinases are key
regulators of many
cell functions, including signal transduction, transcriptional regulation,
cell motility, and
cell division. Several oncogenes have also been shown to encode protein
kinases,
suggesting that kinases play a role in oncogenesis. These processes are highly
regulated, often by complex intermeshed pathways where each kinase will itself
be
regulated by one or more kinases. Consequently, aberrant or inappropriate
protein kinase
activity can contribute to the rise of disease states associated with such
aberrant kinase
activity. Due to their physiological relevance, variety and ubiquitousness,
protein kinases
have become one of the most important and widely studied family of enzymes in
biochemical and medical research.
The protein kinase family of enzymes is typically classified into two main
subfamilies:
Protein Tyrosine Kinases and Protein Serine/Threonine Kinases, based on the
amino
acid residue they phosphorylate. The serine/threonine kinases (PSTK), includes
cyclic
1

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
AMP- and cyclic GMP-dependent protein kinases, calcium and phospholipid
dependent
protein kinase, calcium- and calmodulin-dependent protein kinases, casein
kinases, cell
division cycle protein kinases and others. These kinases are usually
cytoplasmic or
associated with the particulate fractions of cells, possibly by anchoring
proteins. Aberrant
protein serine/threonine kinase activity has been implicated or is suspected
in a number
of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone
loss, many
cancers and other proliferative diseases. Accordingly, serine/threonine
kinases and the
signal transduction pathways which they are part of are important targets for
drug design.
The tyrosine kinases phosphorylate tyrosine residues. Tyrosine kinases play an
equally
important role in cell regulation. These kinases include several receptors for
molecules
such as growth factors and hormones, including epidermal growth factor
receptor, insulin
receptor, platelet derived growth factor receptor and others. Studies have
indicated that
many tyrosine kinases are transmembrane proteins with their receptor domains
located
on the outside of the cell and their kinase domains on the inside. Much work
is also
under progress to identify modulators of tyrosine kinases as well.
Nuclear factor KB (NF-KB) belongs to a family of closely related dimeric
transcription
factor complexes composed of various combinations of the ReI/NF-xB family of
polypeptides. The family consists of five individual gene products in mammals,
RelA
(p65), NF-xB1 (p50/ p105), NF-xB2 (p49/ p100), c-Rel, and RelB, all of which
can form
hetero- or homodimers. These proteins share a highly homologous 300 amino acid
"Rel
homology domain" which contains the DNA binding and dimerization domains. At
the
extreme C-terminus of the Rel homology domain is a nuclear translocation
sequence
important in the transport of NF-xB from the cytoplasm to the nucleus. In
addition, p65
and cRel possess potent transactivation domains at their C-terminal ends.
The activity of NF-xB is regulated by its interaction with a member of the
inhibitor IxB
family of proteins. This interaction effectively blocks the nuclear
localization sequence on
the NF-KB proteins, thus preventing migration of the dimer to the nucleus. A
wide variety
of stimuli activate NF-xB through what are likely to be multiple signal
transduction
pathways. Included are bacterial products (LPS), some viruses (HIV-1, HTLV-1),
inflammatory cytokines (TNFa, IL-1), environmental and oxidative stress and
DNA
damaging agents. Apparently common to all stimuli however, is the
phosphorylation and
subsequent degradation of IKB. IKB is phosphorylated on two N-terminal serines
by the
recently identified IxB kinases (IKK-a and IKK-(3). IKK-(3 is also known as
IKK2. Site-
2

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
directed mutagenesis studies indicate that these phosphorylations are critical
for the
subsequent activation of NF-xB in that once phosphorylated the protein is
flagged for
degradation via the ubiquitin-proteasome pathway. Free from IxB, the active NF-
xB
complexes are able to translocate to the nucleus where they bind in a
selective manner to
preferred gene-specific enhancer sequences. Included in the genes regulated by
NF-KB
are a number of cytokines and chemokines, cell adhesion molecules, acute phase
proteins, immunoregualtory proteins, eicosanoid metabolizing enzymes and anti-
apoptotic
genes.
It is well-known that NF-xB plays a key role in the regulated expression of a
large number
of pro-inflammatory mediators including cytokines such as TNF, IL-1(3, IL-6
and IL-8, cell
adhesion molecules, such as ICAM and VCAM, and inducible nitric oxide synthase
(iNOS). Such mediators are known to play a role in the recruitment of
leukocytes at sites
of inflammation and in the case of iNOS, may lead to organ destruction in some
inflammatory and autoimmune diseases.
The importance of NF-KB in inflammatory disorders is further strengthened by
studies of
airway inflammation including asthma, in which NF-xB has been shown to be
activated.
This activation may underlie the increased cytokine production and leukocyte
infiltration
characteristic of these disorders. In addition, inhaled steroids are known to
reduce airway
hyperresponsiveness and suppress the inflammatory response in asthmatic
airways. In
light of the recent findings with regard to glucocorticoid inhibition of NF-
xB, one may
speculate that these effects are mediated through an inhibition of NF-KB.
Further evidence for a role of NF-xB in inflammatory disorders comes from
studies of
rheumatoid synovium. Although NF-KB is normally present as an inactive
cytoplasmic
complex, recent immunohistochemical studies have indicated that NF-KB is
present in the
nuclei, and hence active, in the cells comprising rheumatoid synovium.
Furthermore, NF-
KB has been shown to be activated in human synovial cells in response to
stimulation
with TNF-a or IL-1(3. Such a distribution may be the underlying mechanism for
the
increased cytokine and eicosanoid production characteristic of this tissue.
See Roshak,
A. K., et al., J. Biol. Chem., 271, 31496-31501 (1996). Expression of IKK-P
has been
shown in synoviocytes of rheumatoid arthritis patients and gene transfer
studies have
demonstrated the central role of IKK-(3 in stimulated inflammatory mediator
production in
these cells. See Aupperele et aL J. Immunology 1999. 163:427-433 and Aupperle
et al.
3

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
J. Immunology 2001;166:2705-11. More recently, the intra-articular
administration of a
wild type IKK-(3 adenoviral construct was shown to cause paw swelling while
intra-
articular administration of dominant-negative IKK(3 inhibited adjuvant-induced
arthritis in
rat. See Tak et al. Arthritis and Rheumatism 2001, 44:1897-1907.
The NF-KB/Rel and IxB proteins are also likely to play a key role in
neoplastic
transformation and metastasis. Family members are associated with cell
transformation in
vitro and in vivo as a result of over expression, gene amplification, gene
rearrangements
or translocations. In addition, rearrangement and/or amplification of the
genes encoding
these proteins are seen in 20-25% of certain human lymphoid tumors. Further,
NF-xB is
activated by oncogenic ras, the most common defect in human tumors and
blockade of
NF-KB activation inhibits ras mediated cell transformation. In addition, a
role for NF-KB in
the regulation of apoptosis has been reported strengthening the role of this
transcription
factor in the regulation of tumor cell proliferation. TNF, ionizing radiation
and DNA
damaging agents have all been shown to activate NF-xB which in turn leads to
the
upregulated expression of several anti-apoptotic proteins. Conversely,
inhibition of NF-
KB has been shown to enhance apoptotic-killing by these agents in several
tumor cell
types. As this likely represents a major mechanism of tumor cell resistance to
chemotherapy, inhibitors of NF-KB activation may be useful chemotherapeutic
agents as
either single agents or adjunct therapy. Recent reports have implicated NF-KB
as an
inhibitor of skeletal cell differentiation as well as a regulator of cytokine-
induced muscle
wasting (Guttridge et al. Science; 2000; 289: 2363-2365.) further supporting
the potential
of NF-KB inhibitors as novel cancer therapies.
Several NF-KB inhibitors are described in C. Wahl, et al. J. Clin. Invest.
101(5), 1163-
1174 (1998), R. W. Sullivan, et al. J. Med. Chem. 41, 413-419 (1998), J. W.
Pierce, et al.
J. Biol. Chem. 272, 21 096-21 1 03 (1997).
The marine natural product hymenialdisine is known to inhibit NF-xB. Roshak,
A., et al.,
JPET, 283, 955-961 (1997). Breton, J. J and Chabot-Fletcher, M. C., JPET, 282,
459-
466 (1997).
Additionally, patent applications have been filed on aminothiophene inhibitors
of the IKK2,
see Callahan, et al., WO 2002030353; Baxter, et al., WO 2001058890, Faull, et
al., WO
2003010158; Griffiths, et al., W02003010163; Fancelli, et al., WO 200198290;
Granetto,
4

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
et al., WO 2003037886; imidazole inhibitors of IKK2, see Callahan, et al., WO
200230423; anilinophenylpyrimidine inhibitors of IKK2, see Kois, etal., WO
2002046171;
(3-carboline inhibitors of IKK2 , see Ritzeler, et al, WO 2001068648,
Ritzeler, et al, EP
1134221; Nielsch, et al. DE 19807993; Ritzeler, et al., EP 1209158; indole
inhbitors of
IKK2, see Ritzeler, et aL, WO 2001030774; benzimidazole inhibitors of the
IKK2, see
Ritzeler, et al., DE 19928424; Ritzeler et al, WO 2001000610; Ritzeler, et aL,
WO
2004022553; aminopyridine inhibitors of IKK2, see Lowinger, et al, WO
2002024679;
Murata, et al, WO 2002024693; Murata, et al., WO 2002044153; aminopyrimidine
inhibitors of IKK2, see Bolibuck, et al., WO 2004089913; pyrazole inhibitors
of IKK2, see
Bergmanis, et al., WO 2003024935;, Metz, et al., WO 2003024936; Geng et al.,
WO
2003027075; Stealey, et al., WO 2003035625; Xu, et al., WO 200307076; Lennon,
et al.,
WO 2003095430; pyrazinone inhibitors of IKK2, see Boys, et aL, WO 2005035527;
pyrazolaquinazoline inhibitors of IKK2, see Beaulieu, et al., WO 2002028860;
Burke et al,
WO 2002060386; Burke, et aL US 20030022898; thiophene tricyclic inhibitors of
IKK2,
see Belema, et aL, WO 2003084959; pyrazolopurine inhibitors of IKK2, see Qiu,
et al.,
WO 2004075846; oxazolo and thiazolo pyridine inhibitors of IKK2, see Pitts, et
aL, WO
2004106293; quinoline inhibitors of IKK2, Browner, et al., W02002041843,
Browner, et
al., US 20020161004 and pyridylcyanoguanidine inhibitors of IKK2, see
Bjorkling, et al.,
WO 2002094813, Binderup et al, WO 2002094322 and Madsen, et al., WO 200294265;
thienopyridine inhibitors of IKK2, see Cywin, et al., WO 2003103661; Liu, et
al., WO
2005035537; benzothiophene inhibitors of IKK2, see Chen et al., WO 2005012283;
The
natural products staurosporine, quercetin, K252a and K252b have been shown to
be
IKK2 inhibitors, see Peet, G. W. and Li, J. J. Biol. Chem., 274, 32655-32661
(1999) and
Wisniewski, D., et al., Analytical Biochem. 274, 220-228 (1999). Synthetic
inhibitors of
IKK2 have also been described, see Burke, et al. J. Biol. Chem., 278, 1450-
1456 (2003),
Murata, et al., Bioorg. Med. Chem. Lett., 13, 913-198 (2003), Murata, et al.,
Bioorg. Med.
Chem. Lett., 14, 4013-4017 (2004), and Murata, et aL, Bioorg. Med. Chem.
Lett., 14,
4019-4022 (2004) have described IKK2 inhibitors.
Thus, attempts have been made to prepare compounds that inhibit IKK2 activity
and a
number of such compounds have been disclosed in the art. However, in view of
the
number of pathological responses that are mediated by IKK2, there remains a
continuing
need for inhibitors of IKK2 which can be used in the treatment of a variety of
conditions.
5

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
The present inventors have discovered novel indole carboxamide compounds,
which are
inhibitors of kinase activity, in particular inappropriate IKK2 activity. Such
indole
carboxamide derivatives are therefore useful in the treatment of disorders
associated with
inappropriate kinase, in particular inappropriate IKK2 activity in particular
in the treatment
and prevention of disease states mediated by IKK2 mechanisms including
inflammatory
and tissue repair disorders, particularly rheumatoid arthritis, inflammatory
bowel disease,
asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis,
osteoporosis
and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and
ultraviolet
radiation (UV)-induced skin damage; autoimmune diseases including systemic
lupus
eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis,
tissue and
organ rejection, Alzheimer's disease, stroke, atherosclerosis, restonosis,
diabetes,
glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation
associated with infection and certain viral infections, including acquired
immune
deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia
Telangiestasia.
SUMMARY OF THE INVENTION
The invention is directed to novel indole carboxamide derivatives.
Specifically, the
invention is directed to compounds according to formula (I):
R2 U-V
R1 ViNq
R3 0 NH2 (1)
where R1, R2, R3, U and V are defined below and to pharmaceutically acceptable
salts
thereof.
The compounds of the invention are inhibitors of IKK2 and can be useful in the
treatment
of disorders associated with inappropriate IKK2 (also known as IKK(3)
activity, such as
rheumatoid arthritis, asthma, and COPD (chronic obstructive pulmonary
disease).
Accordingly, the invention is further directed to pharmaceutical compositions
comprising a
compound of the invention. The invention is still further directed to methods
of inhibiting
IKK2 activity and treatment of disorders associated therewith using a compound
of the
invention or a pharmaceutical composition comprising a compound of the
invention.
6

CA 02613068 2007-12-20
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DETAILED DESCRIPTION OF THE INVENTION
The invention is directed to compounds according to formula (I):
R2 U-V
R1 /
~ \
R3 \ N
H
O NH2 (~)
R5~ R5
N N
I I
where R1 is the group -XYZ or or
X is phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, or 2,3-dihydro-1 H-
indenyl,
where said phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, and 2,3-dihydro-
1 H-indenyl are optionally substituted with one or two substituents each
independently
selected from the following:
1) halo,
2) nitro,
3) cyano,
4) -NR7R8,
5) C1-C6-alkyl,
6) CHO,
7) CONH2, and
8) -OR4,
where said C1-C6-alkyl is optionally substituted with one -NR4R5 group;
Y is a bond or C1-C6 alkylene,
where C1-C6 alkylene is optionally substituted with one or two substituents
each
independently selected from the following:
1) C1-C3-alkyl optionally substituted by one OR4 group,
2) C3-C7-cycloalkyl,
3) methoxy,
7

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
4) hydroxy, and
5) heteroaryl;
Z is -NR4R5 or heterocycloalkyl,
where said heterocycloalkyl is optionally substituted with one or two
substituents
each independently selected from the following:
1) C1-C6-alkyl optionally substituted by one OR4 or one heterocycloalkyl
group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) -CONH2
5) hydroxy,
6) heteroaryl,
7) CF3,
8) phenyl,
9) heterocycloalkyl, and
10) N(CH3)2;
R2 is selected from
1) H,
2) fluoro, and
3) chloro;
R3 is selected from
1) H,
2) fluoro, and
3) chloro;
R4 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxy or one
methoxy
group;
8

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
R5 is selected from
1) H,
2) C5-C6-heterocycloalkyl,
3) -CO2Et,
4) C1-C6-alkoxy,
5) C3-C7-cycloalkyl,
6) C1-C6-alkyl,
7) -SO2R10, and
8) -C(O)R10,
where said C3-C7-cycloalkyl and C1-C6-alkyl are optionally substituted with
one
to three substituents selected from R6;
each R6 is independently selected from
1) -NR7R8,
2) -S02R7,
3) -CONH2,
4) -CF3,
5) -CN,
6) -C02R7,
7) -OCH2CH2OR7,
8) -SR5,
9) C3-C4 alkenyl,
10) OH,
11) C1-C6-alkoxy,
12) heteroaryl,
13) C3-C7-cycloalkyl,
14) phenyl,
15) heterocycloalkyl, and
16) halo,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to two substituents selected from R9;
R7 is selected from
1) H,
9

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
2) C1-C3-alkyl, and
3) phenyl;
R8 is selected from
1) H,
2) C1-C3-alkyl, and
3) -C(O)R4;
each R9 is independently selected from
1) hydroxy,
2) -OMe,
3) nitro,
4) C1-C6-alkyl,
5) NH2,
6) halo,
7) CF3,
8) C1-C6-alkoxy, and
9) CN;
R10 is selected from
1) H,
2) C1-C6-alkyl,
3) phenyl,
4) C3-C7-cycloalkyl,
5) heteroaryl,
6) C1-C6-heteroaryl, and
7) heterocycloalkyl,
where said C1-C6-alkyl is optionally substituted with one or two substituents
each
independently selected from C3-C7-cycloalkyl and -S-R7; where said
heterocycloalkyl is
optionally substituted with one -C(O)R7 group; and where said phenyl,
heteroaryl and C1-
C6-heteroaryl are optionally substituted with one to two substituents selected
from R11;
each R11 is independently selected from

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
1) H,
2) C1-C6-alkyl, and
3) halo;
U is a bond, C1-C6 alkylene or C2-C6 alkenylene;
V is phenyl, 5 or 6 membered heteroaryl, 5-7 membered heterocycloalkyl, C5-C7
cycloalkyl, or C5-C7 cycloalkenyl, each of which is substituted by -
N(R7)S(O)mR12, -
S(O)mN(R7)R12, -S(O)mR12, or -C(O)R12;
m is 1 or 2; and
R12 is C1-C6-alkyl, C3-C7 cycloalkyl, C1-C6-alkyl-C3-C7cycloalkyl, or C1-C6-
alkyl-
phenyl; or a pharmaceutically acceptable salt thereof.
One embodiment of the present invention is a compound according to formula
(I):
where R1 is the group -XYZ;
X is phenyl or heteroaryl,
where said phenyl and heteroaryl are optionally substituted with one or two
substituents each independently selected from the following:
1) halo,
2) nitro,
3) cyano,
4) -NR7R8,
5) C1-C6-alkyl,
6) CHO,
7) CONH2, and
8) -OR4,
where said C1-C6-alkyl is optionally substituted with one -NR4R5 group;
Y is a bond or C1-C6 alkylene,
where C1-C6 alkylene is optionally substituted with one or two substituents
each
independently selected from the following:
11

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
1) C1-C3-alkyl optionally substituted by one OR4 group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) hydroxy, and
5) heteroaryl;
Z is -NR4R5 or heterocycloalkyl,
where said heterocycloalkyl is optionally substituted with one or two
substituents
each independently selected from the following:
1) C1-Cg-alkyl optionally substituted by one OR4 group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) hydroxy, and
5) heteroaryl;
R2 is selected from
1) H,
2) fluoro, and
3) chloro;
R3 is selected from
1) H,
2) fluoro, and
3) chloro;
R4 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxy or one
methoxy
group;
R5 is selected from
1) H,
2) C1-C6-alkoxy,
12

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
3) C3-C7-cycloalkyl,
4) C1-C6-alkyl,
5) -SO2R10, and
6) -C(O)R10,
where said C3-C7-cycloalkyl and C1-C6-alkyl are optionally substituted with
one
to three substituents selected from R6;
each R6 is independently selected from
1) -NR7R8,
2) -S02R7,
3) OH,
4) methoxy,
5) heteroaryl,
6) C3-C7-cycloalkyl,
7) phenyl,
8) heterocycloalkyl, and
9) halo,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to two substituents selected from R9;
R7 is selected from
1) H and
2) C1-C3-alkyl;
R8 is selected from
1) H and
2) C1-C3-alkyl;
each R9 is independently selected from
1) hydroxy,
2) nitro,
3) C1-C6-alkyl,
4) NH2,
5) halo,
13

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
6) CF33
7) C1-C6-alkoxy, and
8) CN;
R10 is selected from
1) H,
2) C1-C6-alkyl,
3) phenyl,
4) C3-C7-cycloalkyl, and
5) heteroaryl,
where said C1-C6-alkyl is optionally substituted with one or two substituents
each
independently selected from C3-C7-cycloalkyl and -S-R7; where said
heterocycloalkyl is
optionally substituted with one -C(O)R7 group; and where said phenyl and
heteroaryl are
optionally substituted with one to two substituents selected from R11;
each R11 is independently selected from
1) H,
2) C1-C6-alkyl, and
3) halo;
U is a bond, C1-C6 alkylene or C2-C6 alkenylene;
V is phenyl, 5 or 6 membered heteroaryl, 5-7 membered heterocycloalkyl, C5-C7
cycloalkyl, or C5-C7 cycloalkenyl, each of which is substituted by -
N(R7)S(O)mR12, -
S(O)mN(R7)R12, -S(O)mR12, or -C(O)R12;
m is 1 or 2; and
R12 is C1-C6-alkyl, C3-C7 cycloalkyl, C1-C6-alkyl-C3-C7cycloalkyl, or C1-C6-
alkyl-
phenyl; or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is a compound according to formula
(I):
14

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
R5\ R5
N N
I I
where R1 is the group -XYZ or or
X is phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, or 2,3-dihydro-1 H-
indenyl;
Y is a bond or C1-C6 alkylene;
Z is -NR4R5 or heterocycloalkyl,
where said heterocycloalkyl is optionally substituted with one or two
substituents
each independently selected from the following:
1) C1-C6-alkyl optionally substituted by one OR4 or one heterocycloalkyl
group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) -CONH2
5) hydroxy,
6) heteroaryl;
7) CF3,
8) phenyl,
9) heterocycloalkyl, and
10) N(CH3)2;
R2 is H;
R3 is H;
R4 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxy or one
methoxy
group;
R5 is selected from
1) H,
2) C5-C6-heterocycloalkyl,

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
3) -CO2Et,
4) C1-C6-alkoxy,
5) C3-C7-cycloalkyl,
6) C1-C6-alkyl,
7) -SO2R10, and
8) -C(O)R10,
where said C3-C7-cycloalkyl and C1-C6-alkyl are optionally substituted with
one
to three substituents selected from R6;
each R6 is independently selected from
1) -NR7R8,
2) -S02R7,
3) -CONH2,
4) -CF3,
5) -CN,
6) -CO2R7,
7) -OCH2CH2OR7,
8) -SR5,
9) C3-C4 alkenyl,
10) OH,
11) C1-C6-alkoxy,
12) heteroaryl,
13) C3-C7-cycloalkyl,
14) phenyl,
15) heterocycloalkyl, and
16) halo,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to two substituents selected from R9;
R7 is selected from
1) H,
2) C1-C3-alkyl, and
3) phenyl;
16

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
R8 is selected from
1) H,
2) C1-C3-alkyl, and
3) -C(O)R4;
each R9 is independently selected from
1) hydroxy,
2) -OMe
3) nitro,
4) C1-C6-alkyl,
5) NH2,
6) halo,
7) CF3,
8) C1-C6-alkoxy, and
9) CN;
R10 is selected from
1) H,
2) C1-C6-alkyl,
3) phenyl,
4) C3-C7-cycloalkyl,
5) heteroaryl,
6) C1-C6-heteroaryl, and
7) heterocycloalkyl,
where said C1-C6-alkyl is optionally substituted with one or two substituents
each
independently selected from C3-C7-cycloalkyl and -S-R7; where said
heterocycloalkyl is
optionally substituted with one -C(O)R7 group; and where said phenyl,
heteroaryl and C1-
Cg-heteroaryl are optionally substituted with one to two substituents selected
from R11;
each R11 is independently selected from
1) H,
2) C1-C6-alkyl, and
3) halo;
17

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U is a bond;
V is a 5-7 membered heterocycloalkyl substituted by -S(O)mR12;
m is 1 or 2; and
R12 is C1-Cg-alkyl; or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is a compound according to formula
(I):
where R1 is the group -XYZ;
X is phenyl or heteroaryl;
Y is a bond or C1-C6 alkylene;
Z is -NR4R5 or heterocycloalkyl,
where said heterocycloalkyl is optionally substituted with one or two
substituents
each independently selected from the following:
1) C1-Cg-alkyl optionally substituted by one OR4 group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) hydroxy, and
5) heteroaryl;
R2 is H;
R3 is H;
R4 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-Cg-alkyl is optionally substituted with one hydroxy or one
methoxy
group;
R5 is selected from
1) H,
2) C1-Cg-alkoxy,
3) C3-C7-cycloalkyl,
4) C1-Cg-alkyl,
18

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5) -SO2R10, and
6) -C(O)R10,
where said C3-C7-cycloalkyl and C1-C6-alkyl are optionally substituted with
one
to three substituents selected from R6;
each R6 is independently selected from
1) NR7R8,
2) S02R7,
3) OH,
4) methoxy,
5) heteroaryl,
6) C3-C7-cycloalkyl,
7) phenyl,
8) heterocycloalkyl, and
9) halo,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to two substituents selected from R9;
R7 is selected from
1) Hand
2) C1-C3-alkyl;
R8 is selected from
1) H and
2) C1-C3-alkyl;
each R9 is independently selected from
1) hydroxy,
2) nitro,
3) C1-C6-alkyl,
4) NH2,
5) halo,
6) CF3,
7) C1-C6-alkoxy, and
19

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8) CN;
R10 is selected from
1) H,
2) C1-Cg-alkyl,
3) phenyl,
4) C3-C7-cycloalkyl, and
5) heteroaryl,
where said C1-C6-alkyl is optionally substituted with one or two substituents
each
independently selected from C3-C7-cycloalkyl and -S-R7; where said
heterocycloalkyl is
optionally substituted with one -C(O)R7 group; and where said phenyl and
heteroaryl are
optionally substituted with one to two substituents selected from R11;
each R11 is independently selected from
1) H,
2) C1-C6-alkyl, and
3) halo;
U is a bond;
V is a 5-7 membered heterocycloalkyl substituted by -S(O)mR12;
m is 1 or 2; and
R12 is C1-Cg-alkyl; or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is a compound of formula (I)
where:
where R1 is the group -XYZ;
X is 2- or 3- thiophenyl;
Y is a bond or C1-C4 alkylene;
Z is -NR4R5 or heterocycloalkyl,
1) C1-Cg-alkyl optionally substituted by one OR4 or one heterocycloalkyl
group,
2) C3-C7-cycloalkyl,
3) methoxy,
4) -CONH2,
5) hydroxy,

CA 02613068 2007-12-20
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6) heteroaryl;
7) CF3,
8) phenyl,
9) heterocycloalkyl, and
10) N(CH3)2;
R2 is H;
R3 is H;
R4 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxy or one
methoxy
group;
R5 is selected from
1) C3-C7-cycloalkyl,
2) C1-C6-alkyl,
where said C3-C7-cycloalkyl and C1-C6-alkyl are optionally substituted with
one
to three substituents selected from R6;
each R6 is independently selected from
1) -NR7R8,
2) -CONH2,
3) -CN,
4) -OCH2CH2OR7,
5) C3-C4 alkenyl,
6) OH,
7) C1-C6-alkoxy,
8) heteroaryl,
9) C3-C7-cycloalkyl,
10) phenyl,
11) heterocycloalkyl, and
12) halo,
21

CA 02613068 2007-12-20
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where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to two substituents selected from R9;
R7 is selected from
1) H,
2) C1-C3-alkyl, and
3) phenyl;
R8 is selected from
1) H,
2) C1-C3-alkyl, and
3) -C(O)R4;
each R9 is independently selected from
1) C1-C6-alkyl;
U is a bond;
V is 4-piperidinyl substituted by -S(O)2R12; and
R12 is ethyl or isopropyl; or a pharmaceutically acceptable salt thereof.
Another embodiment'of the present invention is a compound according to formula
(I)
0
u
N' S~ R12
where the group U-V is M and R12 is ethyl or isopropyl.
Another embodiment of the present invention is a compound of formula (II)
Q j
0=S
R13
)n N
N
H
H2N O (II)
where R13 is -NR14R15 or heterocycloalkyl
22

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where said heterocycloalkyl is optionally substituted with one or two
substituents
selected from the following:
1) C1-C6-alkyl optionally substituted by one OR14 group,
2) hydroxy,
3) methoxy, and
4) heteroaryl;
R14 is selected from
1) H and
2) C1-C6-alkyl,
where said C1-C6-alkyl is optionally substituted with one hydroxyl or one
methoxy
group;
R15 is selected from
1) H,
2) methoxy,
3) C3-C7 cycloalkyl, and
4) C1-C6-alkyl,
where said C3-C7cycloalkyl and C1-C6-alkyl are optionally substituted with one
to
three substituents selected from R16;
each R16 is independently selected from
1) -NR17R18,
2) -S02R17,
3) OH,
4) methoxy
5) heteroaryl,
6) C3-C7cycloalkyl,
7) phenyl, and
8) heterocycloalkyl,
where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally
substituted with one to three substituents selected from R19;
23

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R17 is selected from
1) H and
2) C1-C3-alkyl;
R18 is selected from
1) H and
2) C1-C3-alkyl;
R19 is selected from
1) hydroxy,
2) nitro,
3) C1-C6-alkyl,
4) NH27
5) halo,
6) CF3, and
7) C1-C6-alkoxy; and
n is 1 to 3; or a pharmaceutically acceptable salt thereof.
Specific examples of compounds of the present invention include the following:
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperazinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({methyl[2-
(methylsulfonyl)ethyl]amino}
methyl)phenyl]-1 H-indole-7-carboxamide;
5-(3-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}phenyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(4-{2-[(2-hydroxyethyl)oxy]ethyl}-1-
piperazinyl)methyl]phenyl}-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[3-(hydroxymethyl)-1-
piperidinyl]methyl} phenyl)-
11--1-indole-7-carboxamide;
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5-[3-({bis[2-(methyloxy)ethyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
5-{3-[(2,6-dimethyl-4-morpholinyl)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 f-f-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(1,3-thiazol-2-yl)-1-
pyrrolidinyl] methyl}phenyl)-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(2-thienyl)-1-
pyrrolidinyl]methyl} phenyl)-1 H-
indole-7-carboxamide;
3-[1 -(ethylsu Ifonyl)-4-pi pe ridinyl]-5-(3-{[(2-hyd roxy-2-p h enyl ethyl)
(methyl)
amino]methyl}phenyl)-1 H-indole-7-carboxamide;
5-(3-{[ethyl(methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide;
5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide;
5-{3-[(cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-[3-({[(3,4-dihydroxyphenyl)methyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]
methyl}phenyl)-1 H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-(hydroxymethyl)-3-
methylbutyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-1-methylethyl)
amino]methyl}phenyl)-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(trans-4-hydroxycyclohexyl)
amino]methyl}phenyl)-
1ll indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[({[1-(1-piperidinyl)cyclohexyl]
methyl}amino)methyl]phenyl}-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-hydroxypropyl]amino}
methyl)phenyl]-1 f-1-
indole-7-carboxamide;
5-{3-[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(propylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1-methylethyl)amino]
methyl}phenyl)-1 H-indole-7=
carboxamide;

CA 02613068 2007-12-20
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5-(3-{[(1-ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-piperidinyimethyl)phenyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
5-[4-(aminomethyl)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
5-{3-[(cyclopropylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{3-[(cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-[4-(1-
piperidinylmethyl)phenyl]-
11--/-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(2-methylpropyl)amino]-2,3-dihydro-1
H-inden-5-yi}-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{8-[(2-methylpropyl)amino], 5,6,7,8-
tetrahydro-2-
naphthalenyl}-1 H-indole-7-carboxamide;
5-(5-{[(2-cyanoethyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-{[(2,2,2-
trifluoroethyl)amino]methyl}phenyl)-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1,2,3,4-tetrahydro-7-isoquinolinyl)-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2,2,2-
trifluoroethyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
5-(3-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2,2,2-trifluoroethyl)amino]methyl}-
1,3-thiazol-4-
yi)-1 H-indole-7-carboxamide;
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5-(3-cyano-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-
piperidinyl)amino]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
5-(5-{[(2-cyanoethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
5-(5-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-
(phenylsulfonyl)ethyl]amino}methyl)-3-
thienyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(1-piperidinylmethyl)-1-
pyrrolidinyl]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
5-(5-{[(2R)-2-(aminocarbonyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(5-{[(2S)-2-(dimethylamino)-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(1-{2-[4-(dimethylamino)-1-piperidinyl]ethyl}-1 H-pyrazol-4-yl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-[3,4-bis(methyloxy)-5-(4-morpholinylmethyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4,5-
bis(methyloxy)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4,5-
bis(methyloxy)phenyl]-1 H-indole-7-carboxamide;
5-[3-{[(2,2-dimethylpropyl)amino]methyl}-4,5-bis(methyloxy)phenyl]-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(2-
hydroxyethyi)(methyl)amino]methyl}-4,5-
bis(methyloxy)phenyl]-1 H-indole-7-carboxamide;
5-[3,4-bis(methyloxy)-5-(1 -pyrrolidinylmethyl)phenyl]-3-[1 -(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
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5-{4-[(dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(1-methylethyl)amino]methyl}-2,3-
dihydro-1-
benzofuran-6-yl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)-2,3-dihydro-1-
benzofuran-6-yl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[1-methyl-2-
(methyloxy)ethyl]amino}methyl)-2-
thienyl]-1 H-indole-7-carboxamide;
5-(5-{[(2-cyanoethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2,2,2-trifluoroethyl)amino]methyl}-
3-pyridinyl)-
1 H-indole-7-carboxamide;
5-{3-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
5-(5-{[[2-(diethylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(5-{[butyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(propyl)amino]methyl}-3-
thienyl)-1 H-
indole-7-carboxamide;
5-(5-{[[2-(di methylamino) ethyl] (methyl)amino] methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(5-{[[3-(dimethylamino)propyl](methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-
4-piperidinyl]-1 H-indole-7-carboxamide;
5-(5-{[cyclopentyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(pentyl)amino]methyl}-3-
thienyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-methylpropyl)amino]methyl}-
3-
thienyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(phenylmethyl)amino]methyl}-3-
thienyl)-
1 H-indole-7-carboxamide;
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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-
hydroxyethyl)(methyl)amino]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(2-
pyridinyl)ethyl]amino}methyl)-3-
thienyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsuifonyl)-4-piperidinyl]-5-(5-{[(2-
furanylmethyl)(methyl)amino]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(4-
pyridinylmethyl)amino]methyl}-3-
thienyl)-1 H-indole-7-carboxamide; ;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methyl{[1-(1-methylethyl)-3-
pyrrolidinyl]methyl}amino)methyl]-3-thienyl}-1 H-indole-7-carboxamide; ;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-
thienylmethyl)amino]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[1-(2-
thienyl)ethyl]amino}methyl)-3-
thienyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(3-
thienylmethyl)amino]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(tetrahydro-2H-pyran-4-
ylmethyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; trifluoroacetate
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(3-
pyridinylmethyl)amino]methyl}-3-
thienyl)-1 H-indole-7-carboxamide; trifluoroacetate
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(4-
pyrimidinylmethyl)amino]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-
(methyloxy)ethyl]amino}methyl)-3-
thienyl]-1 H-indole-7-carboxamide;
5-{3-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylethyl)amino]methyl}-
3-thienyl)-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(3-pyridinyl)-1-
pyrrolidinyl]methyl}-3-thienyl)-
1 H-indole-7-carboxamide;
5-(5-{[2-(1,1-dimethylethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
29

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5-{5-[(2-ethyl-1-pyrrolidinyl)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1-
pyrrolidinyl]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(1-methylethyl)-1-
pyrrolidinyl]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2S)-2-[(methyloxy)methyl]-1-
pyrrolidinyl}methyl)-3-thienyl]-1 H-indole-7-carboxamide;
5-(5-{[cyclohexyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1-
pyrrolidinyl]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(propyl)amino]methyl}-3-
thienyl)-1 H-
i ndole-7-carboxamide;
3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-(5-
{[methyl(propyl)amino]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-
piperidinyl}-1 H-indole-7-carboxamide;
3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-[5-({methyl[2-
(methyloxy)ethyl]amino}methyl)-3-thienyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-2-thienyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-
thienyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(propylamino)methyl]-3-thienyl}-1 H-
indole-7-
carboxamide;
5-{5-[(diethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-(5-{[(2R,5R)-2,5-dimethyl-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;

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5-{5-[(cyclopropylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
5-{5-[(cyclobutylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
5-{5-[(dimethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide;
5-(5-{[(cyclopentylmethyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
5-[5-({[(1 R)-1,2-dimethylpropyl]amino}methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1 H-indole-7-carboxamide;
5-{5-[(cyclopentylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
5-(5-{[(cyclopropylmethyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
5-[5-({[(1 S)-1,2-dimethylpropyl]amino}methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(phenylmethyl)amino]methyl}-3-
thienyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)-3-thienyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(tetrahydro-2H-pyran-4-
ylmethyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide;
5-{5-[(butylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2R)-tetrahydro-2-
furanylmethyl]amino}methyl)-3-thienyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2S)-2-[(methyloxy)methyl]-1-
pyrrolidinyl}methyl)-3-thienyl]-1 H-indole-7-carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2R)-2-[(methyloxy)methyl]-1-
pyrrolidinyl}methyl)-3-thienyi]-1 H-indole-7-carboxamide;
3-[1-(ethylsuIfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-1 H-
indole-7-
carboxamide;
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3-[1-(ethylsulfonyi)-4-piperidinyi]-5-{4-[2-(propylamino)ethyl]phenyi}-1 H-
indole-7-
carboxamide;
5-{4-[2-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1 H-pyrazol-5-
yl]carbonyl}amino)methyl]phenyl}-
3-[1-(ethylsulfonyi)-4-piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(4-
pyridinylcarbonyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
5-(4-{[(cyclopentylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-
furanylcarbonyl)amino]methyl}phenyi)-1 H-
indole-7-carboxamide;
5-{4-[2-(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{2-
[(methylsulfonyl)amino]ethyl}phenyl)-1 H-
indole-7-carboxamide;
5-(4-{2-[(cyclobutylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
5-(4-{2-[(cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{2-
[(methylsulfonyl)amino]ethyl}phenyl)-1 H-
indole-7-carboxamide;
5-(3-{2-[(cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyi)-4-piperidinyi]-5-[6-(1-piperazinyl)-3-pyridinyl]-1 H-
indole-7-
carboxamide trifluoroacetate;
5-[6-(4-ethyl-1-piperazinyl)-3-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-7-
carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(1 -piperidinylmethyl) phenyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(1-methylethyl)amino]methyl}phenyl)-
1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(propylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
5-(4-{[(1-ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-
indole-7-carboxamide;
5-{4-[(cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{4-[(cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{4-[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{4-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{4-[(diethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-pyrrolidinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1 S)-2-hydroxy-1-
methylethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1 R)-2-hydroxy-1-
methylethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(2R)-2-
hydroxypropyl]amino}methyl)phenyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[2-hydroxy-1-
(hydroxymethyl)ethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1-methylbutyi)amino]methyl}phenyl)-
1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1 R)-1-
methylpropyl]amino}methyl)phenyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
methylpropyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
33

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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1 S)-1-
methylpropyl]amino}methyl)phenyl]-
1 H-indole-7-carboxamide;
5-{4-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(propanoylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
5-(4-{[(cyclopropylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
5-(4-{[(cyclobutylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-
thienylacetyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
5-[4-({[(1 S)-1,2-dimethylpropyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-{4-[(butanoylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-
methylpropanoyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(3-
methylbutanoyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-
{[(methylsulfonyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
5-[3-({[(1 R)-1,2-dimethylpropy[]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(4-{[(ethylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
5-(4-{[(butylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1-
methylethyl)sulfonyl]amino}methyl)phenyl]-
1 H-indole-7-carboxamide;
5-(6-amino-2-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1 H-pyrazol-1-yl)phenyl]-1 H-indole-
7-
carboxamide;
5-[4-(dimethylamino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide;
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5-(3-aminophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-2-
thienyl}-1 H-
indole-7-carboxamide;
5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-2-
thienyl)-1 H-
indole-7-carboxamide;
5-{5-[(cyclopropylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
5-(5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
5-(5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-3-
pyridinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(methyloxy)propyl]amino}methyl)-
3-
pyridinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinylmethyl)-3-pyridinyl]-1
H-indole-7-
carboxamide;
5-{5-[(ethylamino)methyl]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{5-[(dimethylamino)methyl]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-3-
pyridinyl}-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-
pyridinyl)-1 H-
indole-7-carboxamide;
5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-
thienyl)-1 H-
indole-7-carboxamide;
5-[5-({[(1 R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1 H-indole-7-carboxamide;

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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(pentylamino)methyl]-2-thienyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2S)-2-methylbutyl]amino}methyl)-2-
thienyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylbutyl)amino]methyl}-2-
thienyl)-1 H-
indole-7-carboxamide;
5-{5-[(butylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-2-
thienyl]-
1 H-indole-7-carboxamide;
5-{5-[(cyclopentylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(3-methylbutyl)amino]methyl}-2-
thienyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-
pyridinyl)-1 H-
indole-7-carboxamide;
5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
5-[5-({[3-(ethyloxy)propyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(methyloxy)propyl]amino}methyl)-
2-thienyl]-
1 H-indole-7-carboxamide;
5-(5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[({3-[(1-
methylethyl)oxy]propyl}amino)methyl]-2-
thienyl}-1 H-indole-7-carboxamide;
5-[5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(propyloxy)propyl]amino}methyl)-
2-thienyl]-
1 H-indole-7-carboxamide;
5-(5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(1 S)-1,2,2-
trimethylpropyl]amino}methyl)-2-
thienyl]-1 H-indole-7-carboxamide;
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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(hexylamino)methyl]-2-thienyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyi)-4-piperidinyi]-5-{4-[(methylsulfonyl)amino]phenyl}-1 H-
indole-7-
carboxamide;
5-[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-pyrrolidinyl)-4-pyridinyl]-1 H-
indole-7-
carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinyl)-4-pyridinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-[(2-methylpropyl)amino]-4-pyridinyl}-
1 H-indole-
7-carboxamide;
5-{2-[(2,2-dimethylpropyl)amino]-4-pyridinyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(propylamino)-4-pyridinyl]-1 H-indole-
7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1 H-
indole-7-
carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(1 -pyrrolidinylmethyl)-2-thienyl]-1
H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-methylpropyl)amino]methyl}-2-
thienyl)-1 H-
indole-7-carboxamide;
5-{4-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide;
3-[=1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(1 S)-1-(1-pyrrolidinyl)ethyl]-3-
thienyl}-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(1 R)-1-(1-pyrrolidinyl)ethyl]-3-
thienyl}-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-
2-thienyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({(2S)-2-[(methyloxy)methyl]-1-
pyrrolidinyl}methyl)-2-thienyl]-1 H-indole-7-carboxamide;
5-(4-{[(2R,5R)-2,5-dimethyl-1-pyrrolidinyl]methyl}-2-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-methyl-1-
pyrrolidinyl]methyl}-3-thienyl)-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2R)-2-methyl-l-
pyrrolidinyl]methyl}-3-thienyl)-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[1-(1-pyrrolidinyl)propyl]-3-thienyl}-
1 H-indole-7-
carboxamide;
5-{5-[(dimethylamino)methyl]-3-thienyl}-3-{1-[(1-methylethyl)sulfonyl]-4-
piperidinyl}-
1 H-indole-7-carboxamide;
5-[5-(aminomethyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{2-[(2-methylpropyl)amino]ethyl}-3-
thienyl)-1 H-
indole-7-carboxamide;
5-{5-[2-(dimethylamino)ethyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-pyrrolidinyl)-3-pyridinyl]-1 H-
indole-7-
carboxamide;
5-{6-[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-[6-(dimethylamino)-3-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(propylamino)-3-pyridinyl]-1 H-indole-
7-
carboxamide;
3-[i -(ethylsulfonyl)-4-piperidinyl]-5-{6-[(1-methylethyl)amino]-3-pyridinyl}-
1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(4-morpholinyl)-3-pyridinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-
thienyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-3-thienyl]-1 H-
indole-7-
carboxamide;
5-{5-[(ethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
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3-[1-(ethylsuifonyl)-4-piperidinyl]-5-[5-({[(1 R)-2-hydroxy-1-
methylethyl]amino}methyl)-
3-thienyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-piperidinylmethyl)-3-thienyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinylmethyl)-3-thienyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-furanyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[1-(1-pyrrolidinyl)ethyl]-3-thienyl}-
1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-2-thienyl]-1 H-
indole-7-
carboxamide;
5-{5-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(propylamino)methyl]-2-thienyl}-1 H-
indole-7-
carboxamide;
5-{5-[(diethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-2-
thienyl)-1 H-
indole-7-carboxamide;
5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-
furanyl)-1 H-
indole-7-carboxamide;
5-(5-{[(cyclopentylmethyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-3-furanyl]-1 H-
indole-7-
carboxamide;
5-{5-[(diethylamino)methyl]-3-furanyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-1,3-thiazol-2-
yl]-1 H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[2-methyl-1-(1-pyrrolidinyl)propyl]-3-
thienyl}-1 H-
indole-7-carboxamide;
39

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3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(1 -pyrrolidinylmethyl)-1,3-thiazol-
2-yl]-1 H-indole-
7-carboxamide;
5-{1-[2-(dimethylamino)ethyl]-1 H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(1-pyrrolidinyl)ethyl]-1 H-pyrazol-
4-yl}-1 H-
indole-7-carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{1 -[2-(4-morpholinyl) ethyl] - 1 H-
pyrazol-4-yl}-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1 H-
pyrazol-4-
yI)-1 H-indole-7-carboxamide;
5-{1-[2-(butylamino)ethyl]-1 H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
5-{1 -[2-(cyclobutylami no) ethyl]- 1 H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
5-[1-(2-{[2-(diethylamino)ethyl]amino}ethyl)-1 H-pyrazol-4-yi]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(1-methylethyl)amino]ethyl}-1 H-
pyrazol-4-yl)-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-methylpropyl)amino]ethyl}-1 H-
pyrazol-4-
yI)-1 H-indole-7-carboxamide;
5-(1-{2-[(cyclopentylmethyl)amino]ethyl}-1 H-pyrazol-4-yi)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(methyloxy)-3-(1-
pyrrolidinylmethyl)phenyl]-1 H-
indole-7-carboxamide;
5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4-
piperidinyl]-
1 H-.indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(methyloxy)-3-(4-
morpholinylmethyl)phenyl]-1 H-
i ndole-7-carboxamide;
3-[1-(ethylsulfonyl}-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4-
(methyloxy)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyi]-5-[3-[(methylamino)methyl]-4-
(methyloxy)phenyl]-1 H-
indole-7-carboxamide;
5-[3-{[(2,2-dimethylpropyl)amino]methyl}-4-(methyloxy)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;

CA 02613068 2007-12-20
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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-
hydroxyethyl)(methyl)amino]ethyl}-1 H-
pyrazol-4-yi)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-fluoro-3-[(methylamino)methyl]phenyl}-
1 H-
indole-7-carboxamide;
5-{3,5-bis[(methylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-fluoro-3-({[2-hydroxy-1-
(hydroxymethyl)ethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-fluoro-3-({[(1 S)-2-hydroxy-1-
methylethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
5-{3-[(cyclopropylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
5-{3-[(cyclobutylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-pyrrolidinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
5-{3,5-bis[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{3,5-bis[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-
7-carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperidinyl)phenyl]-1 H-indole-7-
carboxamide;
5-{3-[1-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{3-[1-(dimethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-
1 H-
indole-7-carboxamide;
5-{3-[(ethylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(propylamino)methyl]phenyl}-
1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(1-
methylethyl)amino]methyl}phenyl)-
1 H-indole-7-carboxamide;
41

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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-
methylpropyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide;
5-{3-[(cyclobutylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
5-{3-[(dimethylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1-
pyrrolidinylmethyl)phenyl]-1 H-indole-
7-carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-f luoro-5-(4-
morpholinylmethyl)phenyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1-piperidinylmethyl)phenyl]-
1 H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[1-(methylamino)ethyl]phenyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(1-
methylethyl)amino]ethyl}phenyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-
methylpropyl)amino]ethyl}phenyl)-1 H-
indole-7-carboxamide;
5-{3-[1-(cyclobutylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[1-(1-pyrrolidinyl)ethyl]phenyl}-1 H-
indole-7-
carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(3-thiomorpholinyl)phenyl]-1 H-
indole-7-
carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-piperazinyl)-2-thienyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-piperazinyl)phenyl]-1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(4-morpholinyl)-3-pyridazinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-pyrrolidinyl)-3-pyridazinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
42

CA 02613068 2007-12-20
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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
thienylmethyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-methyl-2-
furanyl)methyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2R)-tetrahydro-2-
furany[methyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
5-(3-{[(2,2-dimethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-
1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-
methylbutyl]amino}methyl)phenyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1 R)-1,2,2-
trimethylpropyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2R)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
5-[3-({[(1 S)-1,2-dimethylpropyl]amino}methyl)-5-fluorophenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-[3-({[(1 R)-1,2-dimethylpropyl]amino}methyl)-5-fluorophenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(1-
methylpropyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1 S)-1,2,2-
trimethylpropy[]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-2-
methylbutyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-
methylbutyl)amino]methyl}phenyl)-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1 R)-1,2,2-
trimethylpropyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
43

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5-(3-{[(2,2-dimethylpropyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(3-{[(cyclopropylmethyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(3-{[(cyclopentylmethyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(tetrahydro-2H-pyran-4-
ylmethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-
thienylmethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[2-
(methyloxy)ethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[3-
(methyloxy)propyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-
furanylmethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(3-
methylbutyl)amino]methyl}phenyl)-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyi)-4-piperidinyl]-5-[3-fluoro-5-({[(5-methyl-2-
furanyl)methyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
methylpropyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-pyrrolidinyl)phenyl]-1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-
1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(propylamino)methyl]phenyl}-
1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fiuoro-5-{[(2-
methylpropyl)amino]methyl}phenyl}-1 H-indole-7-carboxamide;
5-(5-{[(2,2-dimethylpropyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1 H-indole-7-carboxamide;
5-[5-({[(1 S)-1,2-dimethylpropyl]amino}methyl)-2-fluorophenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-[5-({[(1 R)-1,2-dimethylpropyl]amino}methyl)-2-fluorophenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
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5-(5-{[(cyclopropylmethyl)amino]methyi}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-(1-
pyrrolidinylmethyl)phenyl]-1 H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-
1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[2-
(methyloxy)ethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[3-
(methyloxy)propyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(1 -methyl-2-pyrrolidinyl)phenyl]-1
H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{2-[(2-
methylpropyl)amino]ethyl}phenyl)-1 H-
indole-7-carboxamide;
5-{3-[2-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[2-(propylamino)ethyl]phenyl}-1 H-
indole-7-
carboxamide;
5-{3-[2-(dimethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-{3-[2-(dipropylamino)ethyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
5-[3-({[2-(3,5-dimethyl-1 H-pyrazol-1-yl)ethyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-
4-piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinylmethyl)-1,3-thiazol-4-
yi]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-
thiazol-4-
yI)-1 H-indole-7-carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -pyrrolidinylmethyl)-1,3-thiazol-
4-yl]-1 H-indole-
7-carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -piperidinylmethyl)-1,3-thiazol-4-
yl]-1 H-indole-
7-carboxamide;
5-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;

CA 02613068 2007-12-20
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5-(2-{[ethyl(methyl)amino]methyl}-1,3-thiazol-4-yl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
5-(3-cyano-5-{[(2-methylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-{3-cyano-5-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylsulfonyl)amino]phenyl}-1 H-
indole-7-
carboxamide;
5-[4-(acetylamino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide;
5-[3-(acetylamino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1 H-
indole-7-
carboxamide;
5-{3-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-
{[(methylsulfonyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
5-{3-[(butanoylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4-
fluorophenyl)carbonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
methylpropanoyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
furanylcarbonyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
5-(3-{[(cyclopentylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
5-(3-{[(2-ethylbutanoyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
5-(3-{[(1-benzothien-2-ylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-[3-({[(1-acetyl-4-piperidinyl)carbonyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1-methyl-1 H-pyrrol-2-
yI)carbonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(3-methyl-2-
butenoyl)amino]methyl}phenyl)-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(heptanoylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(octanoylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
methylpentanoyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(3-
methylbutanoyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
thienylacetyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(hexanoylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-
methylbutanoyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
5-(3-{[(cyclobutylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
5-(3-{[(cyclopropylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(propanoylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide;
5-(3-{[(cyclopentylacetyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[3-
(methylthio)propanoyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1-
methylethyl)sulfonyl]amino}methyl)phenyl]-
1 H-indole-7-carboxamide;
5-(3-{[(cyclopropylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl}-1 H-
indole-7-carboxamide;
5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1 H-indole-7-carboxamide;
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5-[3-({[(4-bromophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-[3-({[(4-chlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(3-
fluorophenyl)sulfonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
5-[3-({[(2-chlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-[3-({[(2,5-dichloro-3-thienyl)sulfonyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-[3-({[(2-chloro-6-methylphenyl)sulfonyi]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-fluoro-2-
methylphenyl)sulfonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
5-[3-({[(1,2-dimethyl-1 H-imidazol-4-yl)sulfonyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-
{[(propylsulfonyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
5-(3-{[(butylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-
{[(phenylsulfonyl)amino]methyl}phenyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4-
fluorophenyl)sulfonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide;
5-[3-({[(4-bromo-2-ethylphenyl)sulfonyl]amino}methyl)phenyl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(3-{[(1-benzothien-3-ylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-{3-[({[4-(1,1-dimethylethyl)phenyl]sulfonyl}amino)methyl]phenyl}-3-[1-
(ethylsulfonyl)-
4-piperidinyl]-1 H-indole-7-carboxamide;
5-[3-({[(3,4-difluorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(3-{[(ethylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-
7-carboxamide;
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5-(3-{[(2,1,3-benzoxadiazol-4-ylsulfonyl)amino]methyl}phenyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(tetrahydro-3-
furanylcarbonyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide;
5-{4-[(cyclopentylsulfonyl)amino]phenyl}-3-[1-(ethylsuIfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-methyl-2-oxo-1-piperazinyl)phenyl]-
1 H-
indole-7-carboxamide;
5-[6-(4-acetyl-1-piperazinyl)-3-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)amino]methyl}phenyl)-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)amino]methyl}phenyl)-1 H-
indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[4-(1-pyrrolidinyl)-1-
piperidinyl]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-(trifluoromethyl)-1-
pyrrolidinyl]methyl}-
3-thienyl)-1 H-indole-7-carboxamide;
5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-piperidinyl}-1 H-indole-7-carboxamide;
5-(5-{[(3S)-3-hydroxy-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-
piperidinyl}-1 H-indole-7-carboxamide;
5-(5-{[cyclopentyl(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-
piperidinyl}-1 H-indole-7-carboxamide;
5-(5-{[(2-hydroxyethyl)(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-
4-piperidinyl}-1 H-indole-7-carboxamide;
5-(5-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-piperidinyl}-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-propen-1-yl)amino]methyl}-
3-thienyl)-
1 H-indole-7-carboxamide;
5-(5-{[[(3,5-dimethyl-1 H-pyrazol-4-yl)methyl](methyl)amino]methyl}-3-thienyl)-
3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide;
5-(5-{[(cyanomethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
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3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-
3-
thienyl)-1 H-indole-7-carboxamide;
5-(5-{[[2-(ethyloxy)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(5-{[cyclobutyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({2-[(methyloxy)methyl]-1-
pyrrolidinyl}methyl)-3-
thienyl]-1 H-indole-7-carboxamide;
5-(5-{[(1,1-dimethylethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[3-(trifluoromethyl)-1-
piperidinyl]methyl}-3-
thienyl)-1 H-indole-7-carboxamide;
3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide;
5-(5-{[(cyclopropylmethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
5-(5-{[[2-(acetylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 R,2R)-2-
hydroxycyclopentyl](methyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide;
5-(5-{[(1,1-dimethylpropyl)(methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(2S)-2-
hydroxypropyl](methyl)amino]methyl}-
3-thienyl)-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[(2R)-tetrahydro-2-
furanylmethyl]amino}methyl)-3-thienyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[{2-[(2-
hydroxyethyl)oxy]ethyl}(methyl)amino]methyl}-3-thienyl)-1 H-indole-7-
carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-{methyl[2-
(methyloxy)ethyl]amino}ethyl)-3-
thienyl]-1 H-indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{1-[methyl(propyl)amino]ethyl}-3-
thienyl)-1 H-
indole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; and

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5-(5-{[(1,1-dioxidotetrahydro-3-thienyl)(methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; or a pharmaceutically
acceptable salt thereof.
Terms and Definitions
"Alkyl" refers to a saturated hydrocarbon chain having the specified number of
member
atoms. For example, C1-C6 alkyl refers to an alkyl group having from 1 to 6
member
atoms. Alkyl groups may be optionally substituted with one or more
substituents as
defined herein. Alkyl groups may be straight or branched. Representative
branched alkyl
groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl
(n-propyl
and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl,
isopentyl, and
neopentyl), and hexyl.
"Alkylene" when used alone or in forming other groups (such as the C1-C6
alkylene-
heteroaryl, C1-C6 alkylene-heterocycloalkyl, C1-C6 alkylene-C4-C7cycloalkyl,
and C1-
C6 alkylene-C5-C7cycloalkenyl groups) refers to a saturated divalent
hydrocarbon chain
having the specified number of member atoms. For example, C1-C6 alkylene
refers to an
alkylene group having from 1 to 6 member atoms. Alkylene groups may be
optionally
substituted with one or more substituents as defined herein. Alkylene groups
may be
straight or branched. Representative branched alkylene groups have one, two,
or three
branches. Alkylene includes methylene, ethylene, propylene (n-propylene and
isopropylene), butylene (n-butylene, isobutylene, and t-butylene), pentylene
(n-pentylene,
isopentylene, and neopentylene), and hexylene.
"Alkenyl" refers to an unsaturated hydrocarbon chain having the specified
number of
member atoms and having one or more carbon-carbon double bond within the
chain. For
example, C2-C6 alkenyl refers to an alkenyl group having from 2 to 6 member
atoms. In
certain embodiments alkenyl groups have one carbon-carbon double bond within
the
chain. In other emodiments, alkenyl groups have more than one carbon-carbon
double
bond within the chain. Alkenyl groups may be optionally substituted with one
or more
substituents as defined herein. Alkenyl groups may be straight or branched.
Representative branched alkenyl groups have one, two, or three branches.
Alkenyl
includes ethylenyl, propenyl, butenyl, pentenyl, and hexenyl.
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"Alkenylene" refers to an unsaturated divalent hydrocarbon chain having the
specified
number of member atoms and having one or more carbon-carbon double bond within
the
chain. For example, C2-C6 alkenylene refers to an alkenylene group having from
2 to 6
member atoms. In certain embodiments alkenylene groups have one carbon-carbon
double bond within the chain. In other emodiments, alkenylene groups have more
than
one carbon-carbon double bond within the chain. Alkenylene groups may be
optionally
substituted with one or more substituents as defined herein. Alkenylene groups
may be
straight or branched. Representative branched alkenylene groups have one, two,
or
three branches. Alkenyl includes ethylenylene, propenylene, butenylene,
pentenylene,
and hexenylene.
"Alkynylene" refers to an unsaturated divalent hydrocarbon chain having the
specified
number of member atoms and having one or more carbon-carbon triple bond within
the
chain. For example, C2-C6 alkynylene refers to an alkynylene group having from
2 to 6
member atoms. In certain embodiments alkynylene groups have one carbon-carbon
triple bond within the chain. In other emodiments, alkynylene groups have more
than one
carbon-carbon triple bond within the chain. For the sake of clarity,
unsaturated divalent
hydrocarbon chains having one or more carbon-carbon triple bond within the
chain and
one or more carbon-carbon double bond within the chain are alkynylene groups.
Alkynylene groups may be optionally substituted with one or more substituents
as defined
herein. Alkynylene groups may be straight or branched. Representative branched
alkynylene groups have one, two, or three branches. Alkynyl includes
ethylynylene,
propynylene, butynylene, pentynylene, and hexynylene.
"Aryl" refers to an aromatic hydrocarbon ring. Aryl groups are monocyclic ring
systems
or bicyclic ring systems. Monocyclic aryl ring refers to phenyl. Bicyclic aryl
rings refer to
napthyl and rings wherein phenyl is fused to a cycloalkyl or cycloalkenyl ring
having 5, 6,
or 7 member atoms. Aryl groups may be optionally substituted with one or more
substituents as defined herein.
"Cycloalkyl" refers to a saturated hydrocarbon ring having the specified
number of
member atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-
C6
cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms.
Cycloalkyl
groups may be optionally substituted with one or more substituents as defined
herein.
Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
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"Cycloalkenyl" refers to an unsaturated hydrocarbon ring having the specified
number of
member atoms and having a carbon-carbon double bond within the ring. For
example,
C3-C6 cycloalkenyl refers to a cycloalkenyl group having from 3 to 6 member
atoms. In
certain embodiments cycloalkenyl groups have one carbon-carbon double bond
within the
ring. In other emodiments, cycloalkenyl groups have more than one carbon-
carbon
double bond within the ring. However, cycloalkenyl rings are not aromatic.
Cycloalkenyl
groups are monocyclic ring systems. Cycloalkenyl groups may be optionally
substituted
with one or more substituents as defined herein. Cycloalkenyl includes
cyclopropenyl,
cyclobutenyl, cyclopentenyl, and cyclohexenyl.
"Enantiomerically enriched" refers to products whose enantiomeric excess is
greater
than zero. For example, enantiomerically enriched refers to products whose
enantiomeric
excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.
"Enantiomeric excess" or "ee" is the excess of one enantiomer over the other
expressed as a percentage. As a result, since both enantiomers are present in
equal
amounts in a racemic mixture, the enantiomeric excess is zero (0% ee).
However, if one
enantiomer was enriched such that it constitutes 95% of the product, then the
enantiomeric excess would be 90% ee (the amount of the enriched enantiomer,
95%,
minus the amount of the other enantiomer, 5%).
"Enantiomerically pure" refers to products whose enantiomeric excess is 99% ee
or
greater.
"Half-life" ( or "half-lives") refers to the time required for half of a
quantity of a substance
to be converted to another chemically distinct specie in vitro or in vivo.
"Halo" refers to the halogen radical fluoro, chloro, bromo, or iodo.
"Haloalkyl" refers to an alkyl group wherein at least one hydrogen atom
attached to a
member atom within the alkyl group is replaced with halo. Haloalkyl includes
trifluoromethyl.
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"Heteroaryl" refers to an aromatic ring containing from 1 to 4 heteroatoms as
member
atoms in the ring. Heteroaryl groups containing more thari one heteroatoni may
contain
different heteroatoms: "Heteroaryl groups may be optionally substituted with
one or more
substituents as defined herein. Heteroaryl groups are monocyclic ring systems
or are
fused, spiro, or bridged bicyclic ring systems. Monocyclic heteroaryl rings
have 5 or 6
member atoms. Bicyclic heteroaryl rings have from 7 to 11 member atoms.
Bicyclic
heteroaryl rings include those rings wherein, phenyl and a moriocyclic
heterocycloalkyl
ring are attached forming a fused, spiro, or bridged bicyclic ring system, and
those rings
wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl,
cycloalkenyl,
heterocycloalkyl, or heteroaryl ring are attached forming a fused, spiro, or
bridged bicyclic
ring system. Heteroaryl includes pyrrolyl, pyrazolyl, irriidazolyl, oxazolyl,
isoxazolyl,
thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl,
pyrimidinyl, pyridazinyl,
pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indolizinyl, indazolyl,
purinyl, quinolinyl,
isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl,
benzimidazolyl, benopyranyl,
benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl,
furopyridinyl,
and napthyridinyl.
"Heteroatom" refers to a nitrogen, sulphur, or oxygen atom.
"Heterocycloalkyl" refers to a saturated or unsaturated ring containing from 1
to 4
heteroatoms as member atoms in the ring. However, heterocycloalkyl rings are
not
aromatic. Heterocycloalkyl groups containing more than one heteroatom may
contain
different heteroatoms. Heterocycloalkyl groups may be optionally substituted
with one or
more substituents as defined herein. Heterocycloalkyl groups are monocyclic
ring
systems having from 4 to 7 member atoms. In certain embodiments,
heterocycloalkyl is
saturated. In other embodiments, heterocycloalkyl is unsaturated but not
aromatic.
Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,
pyranyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl,
oxazolidinyl,
thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl,
thiamorpholinyl, 1,3-
dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-
dithianyl, and
azetidinyl.
"Member atoms" refers to the atom or atoms that form a chain or ring. Where
more than
one member atom is present in a chain and within a ring, each member atom is
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covalently bound to an adjacent member atom in the chain or ring. Atoms that
make up a
substituent group on a chain or ring are not member atoms in the chain or
ring.
"Optionally substituted" indicates that a group, such as alkyl, alkenyl,
alkynyl, aryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be
unsubstituted or
substituted with one or more substituents as defined herein. "Substituted" in
reference
to a group indicates that a hydrogen atom attached to a member atom within a
group is
replaced. It should be understood that the term "substituted" includes the
implicit
provision that such substitution be in accordance with the permitted valence
of the
substituted atom and the substituent and that the substitution results in a
stable
compound (i.e. one that does not spontaneously undergo transformation such as
by
rearrangement, cyclization, or elimination). In certain embodiments, a single
atom may
be substituted with more than one substituent as long as such substitution is
in
accordance with the permitted valence of the atom. Suitable substituents are
defined
herein for each substituted or optionally substituted group.
"Pharmaceutically acceptable" refers to those compounds, materials,
compositions,
and dosage forms which are, within the scope of sound medical judgment,
suitable for
use in contact with the tissues of human beings and animals without excessive
toxicity,
irritation, or other problem or complication, commensurate with a reasonable
benefit/risk
ratio.
As used herein the symbols and conventions used in these processes, schemes
and
examples are consistent with those used in the contemporary scientific
literature, for
example, the Journal of the American Chemical Society or the Journal of
Biological
Chemistry. Standard single-letter or three-letter abbreviations are generally
used to
designate amino acid residues, which are assumed to be in the L-configuration
unless
otherwise noted. Unless otherwise noted, all starting materials were obtained
from
commercial suppliers and used without further purification. Specifically, the
following
abbreviations may be used in the examples and throughout the specification:
g (grams); mg (milligrams);
L (liters); mL (milliliters);
pL (microliters); psi (pounds per square inch);
M (molar); mM (millimolar);

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i. v. (intravenous); Hz (Hertz);
MHz (megahertz); mol (moles);
mmol (millimoles); rt (room temperature);
min (minutes); h (hours);
mp (melting point); TLC (thin layer chromatography);
Tr (retention time); RP (reverse phase);
MeOH (methanol); i-PrOH (isopropanol);
TEA (triethylamine); TFA (trifluoroacetic acid);
TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran);
DMSO (dimethylsulfoxide); AcOEt (ethyl acetate);
DME (1,2-dimethoxyethane); DCM (dichloromethane);
DCE (dichloroethane); DMF (N,IV dimethylformamide);
DMPU (N,N=dimethylpropyleneurea); CDI (1,1-carbonyidiimidazole);
IBCF (isobutyl chloroformate); HOAc (acetic acid);
HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole);
mCPBA (meta-chloroperbenzoic acid;
EDC (1-[3-dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride);
BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl);
DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);
Ac (acetyl); atm (atmosphere);
TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl);
TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);
DMAP (4-dimethylaminopyridine); BSA (bovine serum albumin);
ATP (adenosine triphosphate); HRP (horseradish peroxidase);
DMEM (Dulbecco's modified Eagle medium);
HPLC (high pressure liquid chromatography);
BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);
TBAF (tetra-n-butylammonium fluoride);
HBTU (O-Benzotriazole-1-yl-N,N,N',N'-tetramethyluroniumhexafluoro phosphate);
H EPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid);
DPPA (diphenylphosphoryl azide);
fHNO3 (fuming HNO3);
EDTA (ethylenediaminetetraacetic acid);
TMEDA (N,N,N',N'-tetramethyl-l,2-ethanediamine);
NBS (N-bromosuccinimide);
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HATU (O-(7azabenzobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate);
DIPEA (diisopropylethylamine);
Imes (1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride);
dppf (1,1'-bis(diphenylphosphino)ferrocene);
MDAP (Mass Directed AutoPrep);
CH3CN (acetonitrile);
EtOAc (ethyl acetate);
and NIS (N-iodsuccinimide).
All references to ether are to diethyl ether and brine refers to a saturated
aqueous
solution of NaCl.
The compounds according to formulae I-II may contain one or more asymmetric
center
(also referred to as a chiral center) and may, therefore, exist as individual
enantiomers,
diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral
centers,
such as chiral carbon atoms, may also be present in a substituent such as an
alkyl group.
Where the stereochemistry of a chiral center present in formulae I-II, or in
any chemical
structure illustrated herein, is not specified the structure is intended to
encompass any
stereoisomer and all mixtures thereof. Thus, compounds according to formulae I-
II
containing one or more chiral center may be used as racemic mixtures,
enantiomerically
enriched mixtures, or as enantiomerically pure individual stereoisomers.
Individual stereoisomers of a compound according to formulae I-II which
contain one or
more asymmetric center may be resolved by methods known to those skilled in
the art.
For example, such resolution may be carried out (1) by formation of
diastereoisomeric
salts, complexes or other derivatives; (2) by selective reaction with a
stereoisomer-
specific reagent, for example by enzamatic oxidation or reduction; or (3) by
gas-liquid or
liquid chromatography in a chiral environment, for example, on a chiral
support such as
silica with a bound chiral ligand or in the presence of a chiral solvent. The
skilled artisan
will appreciate that where the desired stereoisomer is converted into another
chemical
entity by one of the separation procedures described above, a further step is
required to
liberate the desired form. Alternatively, specific stereoisomers may be
synthesized by
asymmetric synthesis using optically active reagents, substrates, catalysts or
solvents, or
by converting one enantiomer to the other by asymmetric transformation.
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The compounds according to formulae I-II may also contain double bonds or
other
centers of geometric asymmetry. Where the stereochemistry of a center of
geometric
asymmetry present in formulae I-II, or in any chemical structure illustrated
herein, is not
specified, the structure is intended to encompass the trans (E) geometric
isomer, the cis
(Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms
are also
included in formulae I-II whether such tautomers exist in equilibrium or
predominately in
one form.
The skilled artisan will appreciate that pharmaceutically-acceptable salts of
the
compounds according to formulae I-II may be prepared. Indeed, in certain
embodiments
of the invention, pharmaceutically-acceptable salts of the compounds according
to
formulae I-11 may be preferred over the respective free base or free acid
because such
salts impart greater stability or solubility to the molecule thereby
facilitating formulation
into a dosage form. Accordingly, the invention is further directed to
pharmaceutically-
acceptable salts of the compounds according to formulae I-II.
As used herein, the term "pharmaceutically-acceptable salts" refers to salts
that retain the
desired biological activity of the subject compound and exhibit minimal
undesired
toxicological effects. These pharmaceutically-acceptable salts may be prepared
in situ
during the final isolation and purification of the compound, or by separately
reacting the
purified compound in its free acid or free base form with a suitable base or
acid,
respectively.
In certain embodiments, compounds according to formulae I-I1 may contain an
acidic
functional group. Suitable pharmaceutically-acceptable salts include salts of
such acidic
functional groups. Representative salts include pharmaceutically-acceptable
metal salts
such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc
salts;
carbonates and bicarbonates of a pharmaceutically-acceptable metal cation such
as
sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc;
pharmaceutically-
acceptable organic primary, secondary, and tertiary amines including aliphatic
amines,
aromatic amines, aliphatic diamines, and hydroxy alkylamines such as
methylamine,
ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine,
ethanolamine, diethanolamine, and cyclohexylamine.
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In certain embodiments, compounds according to formulae I-II may contain a
basic
functional group and are therefore capable of forming pharmaceutically-
acceptable acid
addition salts by treatment with a suitable acid. Suitable acids include
pharmaceutically-
acceptable inorganic acids and pharmaceutically-acceptable organic acids.
Representative pharmaceutically-acceptable acid addition salts include
hydrochloride,
hydrobromide, nitrate, methyinitrate, sulfate, bisulfate, sulfamate,
phosphate, acetate,
trifluoroacetate, hydroxyacetate, phenylacetate, propionate, butyrate,
isobutyrate,
valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate,
citrate, salicylate,
p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate,
succinate,
benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate,
ascorbate,
paimitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate,
estolate,
methanesulfonate (mesylate), ethanesulfonate (esylate), 2-
hydroxyethanesulfonate,
benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate
(tosylate),
and napthalene-2-sulfonate.
As used herein, the term "compounds of the invention" means both the compounds
according to formulae I-II and the pharmaceutically-acceptable salts thereof.
The compounds of the invention may exist in solid or liquid form. In the solid
state, the
compounds of the invention may exist in crystalline or noncrystalline form, or
as a mixture
thereof. For compounds of the invention that are in crystalline form, the
skilled artisan will
appreciate that pharmaceutically-acceptable solvates may be formed wherein
solvent
molecules are incorporated into the crystalline lattice during
crystallization. Solvates may
involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid,
ethanolamine, and ethyl acetate, or they may involve water as the solvent that
is
incorporated into the crystalline lattice. Solvates wherein water is the
solvent that is
incorporated into the crystalline lattice are typically referred to as
"hydrates." Hydrates
include stoichiometric hydrates as well as compositions containing variable
amounts of
water. The invention includes all such solvates.
The skilled artisan will further appreciate that certain compounds of the
invention that
exist in crystalline form, including the various solvates thereof, may exhibit
polymorphism
(i.e. the capacity to occur in different crystalline structures). These
different crystalline
forms are typically known as "polymorphs." The invention includes all such
polymorphs.
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Polymorphs have the same chemical composition but differ in packing,
geometrical
arrangement, and other descriptive properties of the crystalline solid state.
Polymorphs,
therefore, may have different physical properties such as shape, density,
hardness,
deformability, stability, and dissolution properties. Polymorphs typically
exhibit different
melting points, IR spectra, and X-ray powder diffraction patterns, which may
be used for
identification. The skilled artisan will appreciate that different polymorphs
may be
produced, for example, by changing or adjusting the reaction conditions or
reagents, used
in making the compound. For example, changes in temperature, pressure, or
solvent
may result in polymorphs. In addition, one polymorph may spontaneously convert
to
another polymorph under certain conditions.
Compound Preparation
The compounds of this invention may be made by a variety of methods, including
standard chemistry. Any previously defined variable will continue to have the
previously
defined meaning unless otherwise indicated. Illustrative general synthetic
methods are
set out below and then specific compounds of the invention are prepared in the
Examples
section.
Compounds of formulae I and II can be prepared, for example, according to
Schemes 1,
2, and 3 depicted below:
Scheme 1
R2 R2 R2 R2
b::N Br Br R1 a.b.c d.e.f \ g=h R3 3 NBOC R3 H R3 H
H
O O HO O H2N O
1 ~ 2 3 4
R2 U-V R2 U-V
R1 k R1
R3 H \ R3 H
HZN O HZN O
5 6

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Conditions: a) (BOC)20, THF; b) s-BuLi, CICO2Me, TMEDA, Et20; c) N-
bromosuccinimide, Methylene chloride; d) TFA; e) Mn02, THF; f) LiOH, MeOH,
water; g)
R1 B(OR)2, Imes-HCI, Pd(OAc)2, Dioxane/water; h) HATU, NH3, DMF; i) RCHO (or)
RC(O)R', NaOMe, MeOH; j) Pd(OH)2, H2, HOAc, EtOH; k) R4CI, TEA, Methylene
chloride
(or) (R4)20, DMAP, Methylene chloride
Scheme 1 represents a general scheme for the preparation of compounds
according to
formulae I and II wherein R2 and R3 are H, F, or Cl, U is a bond or C1-C6
alkylene or C2-
C6 alkenylene and V is C5-C7 cycloalkyl or C5-C7 cycloalkenyl or
heterocycloalkyl or
heterocycloalkenyl. Scheme 1 also represents a general scheme for the
preparation of
compounds according to formulae I and 11 wherein U is C1-C6 alkylene or C2-C6
alkenylene and V is aryl, or heteroaryl. In Scheme 1, R1 is defined above
unless defined
otherwise. The indoline 1 depicted as starting material is commercially
available.
Reaction conditions are as described above in the scheme; however, the skilled
artisan
will appreciate that certain modifications in the reaction conditions and/or
reagents used
are possible.
Treatment of indoline 1 with di-tertbutyl dicarbonate in a suitable solvent
such as THF or
methylene chloride produces the desired BOC protected product. Further
transformation
to the desired bromide 2 can be accomplished via lithiation using sec-
butyllithium in the
presence of TMEDA and quenching with methyl chloroformate followed by
bromination
with N-bromosuccinimide. Treatment of bromide 2 with trifluoroacetic acid
followed by
oxidation of the resulting indoline to the indole with manganese dioxide and
subsequent
hydrolysis of the methyl ester to the acid yields the desired carboxylic acid
3. Installation
of the substituent R1 can be accomplished via a transition metal mediated
coupling using
an appropriate catalyst and coupling partner. As an example of such a
transformation, for
the case in Scheme 1 condition "g", a Suzuki cross-coupling reaction can be
completed
using a boronic ester or acid in the presence of Pd(OAc)2, Imes-HCI, and
Cs2CO3 in 1,4-
dioxane and water. Preparation of the primary carboxamide 4 can be completed
via
reaction of the carboxylic acid with ammonia in the presence of HATU.
Conversion of 4
to 5 incorporating the group U-V is performed via reaction with the
appropriate aidehyde
or ketone precursor to U-V. This transformation can be completed under either
basic or
acidic conditions. For the case where the group U-V is fully saturated, a
subsequent
reduction of the intermediate product will produce the desired product 5. As
an example
of such a reduction, for the case in Scheme 1 condition "j", a hydrogenation
reaction in
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the presence of Pd(OH)2 completes the transformation to 5. In the case where U-
V
and/or R1 contains a suitable protecting group, removal of the protecting
group under the
appropriate conditions and further transformation to other products may be
accomplished.
Subsequent transformation of the amine function of the group U-V to either the
sulfonamide or amide of R4 can be performed with the appropriate sulfonyl or
acid
chloride or acid anhydride of R4. It will be appreciated by the skilled
artisan that upon
conversion to either the sulfonamide or amide of R4 the resulting product may
require
further elaboration to R4. This can include but is not limited to suitable
protecting and
functional group manipulations and reactions with amines/alcohols R5.
Scheme 2
Br R1 R1 u-v R1 u-v
~ ~ V I a.b.c d e ~ H N N
H H
HO O H2N O HZN O H2N O
3 9 10 11
Conditions: a) R1 B(OR)2i Imes-HCI, Pd(OAc)2, dioxane/water; b) HATU, NH3,
DMF; c) N-
iodosuccinimide, Methylene chloride; d) VUB(OR)2, Pd(PPh3)4, Cs2CO3, 1,4-
dioxane,
water; e) R2CI, TEA, Methylene chloride (or) (R2)20, DMAP, Methylene chloride
Scheme 2 represents a general scheme for the preparation of compounds
according to
formulae I and II wherein U is a bond and V is aryl or heteroaryl. In Scheme
2, R1 is
defined above unless defined otherwise. The indolecarboxylic acid 3 depicted
as starting
material is obtained as described in Scheme 1. Reaction conditions are as
described
above in the scheme; however, the skilled artisan will appreciate that certain
modifications in the reaction conditions and/or reagents used are possible.
The skilled artisan will appreciate that if a substituent described herein is
not compatible
with the synthetic methods described herein, the substituent may be protected
with a
suitable protecting group that is stable to the reaction conditions. The
protecting group
may be removed at a suitable point in the reaction sequence to provide a
desired
intermediate or target compound. Suitable protecting groups and the methods
for
protecting and de-protecting different substituents using such suitable
protecting groups
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are well known to those skilled in the art; examples of which may be found in
T. Greene
and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley &
Sons, NY
(1999). In some instances, a substituent may be specifically selected to be
reactive
under the reaction conditions used. Under these circumstances, the reaction
conditions
convert the selected substituent into another substituent that is either
useful as an
intermediate compound or is a desired substituent in a target compound.
Methods of Use
The compounds of the invention are inhibitors of IKK2. These compounds can be
useful
in the treatment of disorders wherein the underlying pathology is (at least in
part)
attributable to inappropriate IKK2 (also known as IKK(3) activity such as
rheumatoid
arthritis, inflammatory bowel disease, asthma, and COPD (chronic obstructive
pulmonary
disease). "Inappropriate IKK2 activity" refers to any IKK2 activity that
deviates from the
normal IKK2 activity expected in a particular patient. Inappropriate IKK2
activity may take
the form of, for instance, an abnormal increase in activity, or an aberration
in the timing
and or control of IKK2 activity. Such inappropriate activity may result then,
for example,
from overexpression or mutation of the protein kinase leading to inappropriate
or
uncontrolled activation. Accordingly, in another aspect the invention is
directed to
methods of treating such disorders.
Such disorders include inflammatory and tissue repair disorders, particularly
rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive
pulmonary
disease); osteoarthritis, osteoporosis and fibrotic diseases; dermatosis,
including
psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin
damage;
autoimmune diseases including systemic lupus eythematosus, multiple sclerosis,
psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection,
Alzheimer's disease,
stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer,
including
Hodgkins disease, cachexia, inflammation associated with infection and certain
viral
infections, including acquired immune deficiency syndrome (AIDS), adult
respiratory
distress syndrome, and Ataxia Telangiestasia.
The methods of treatment of the invention comprise administering a safe and
effective
amount of a compound according to formulae I-II or a pharmaceutically-
acceptable salt
thereof to a patient in need thereof. Individual embodiments of the invention
include
methods of treating any one of the above-mentioned disorders by administering
a safe
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and effective amount of a compound according to formulae I-II or a
pharmaceutically-
acceptable salt thereof to a patient in need thereof.
As used herein, "treat" in reference to a disorder means: (1) to ameliorate or
prevent the
disorder or one or more of the biological manifestations of the disorder, (2)
to interfere
with (a) one or more points in the biological cascade that leads to or is
responsible for the
disorder or (b) one or more of the biological manifestations of the disorder,
(3) to alleviate
one or more of the symptoms or effects associated with the disorder, or (4) to
slow the
progression of the disorder or one or more of the biological manifestations of
the disorder.
As indicated above, "treatment" of a disorder includes prevention of the
disorder. The
skilled artisan will appreciate that "prevention" is not an absolute term. In
medicine,
"prevention" is understood to refer to the prophylactic administration of a
drug to
substantially diminish the likelihood or severity of a disorder or biological
manifestation
thereof, or to delay the onset of such disorder or biological manifestation
thereof.
As used herein, "safe and effective amount" in reference to a compound of the
invention
or other pharmaoeutically-active agent means an amount of the compound
sufficient to
treat the patient's condition but low enough to avoid serious side effects (at
a reasonable
benefit/risk ratio) within the scope of sound medical judgment. A safe and
effective
amount of a compound will vary with the particular compound chosen (e.g.
consider the
potency, efficacy, and half-life of the compound); the route of administration
chosen; the
disorder being treated; the severity of the disorder being treated; the age,
size, weight,
and physical condition of the patient being treated; the medical history of
the patient to be
treated; the duration of the treatment; the nature of concurrent therapy; the
desired
therapeutic effect; and like factors, but can nevertheless be routinely
determined by the
skilled artisan.
As used herein, "patient" refers to a human or other animal.
The compounds of the invention may be administered by any suitable route of
administration, including both systemic administration and topical
administration.
Systemic administration includes oral administration, parenteral
administration,
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transdermal administration, rectal administration, and administration by
inhalation.
Parenteral administration refers to routes of administration other than
enteral,
transdermal, or by inhalation, and is typically by injection or infusion.
Parenteral
administration includes intravenous, intramuscular, and subcutaneous injection
or
infusion. Inhalation refers to administration into the patient's lungs whether
inhaled
through the mouth or through the nasal passages. Topical administration
includes
application to the skin as well as intraocular, otic, intravaginal, and
intranasal
administration.
The compounds of the invention may be administered once or according to a
dosing
regimen wherein a number of doses are administered at varying intervals of
time for a
given period of time. For example, doses may be administered one, two, three,
or four
times per day. Doses may be administered until the desired therapeutic effect
is
achieved or indefinitely to maintain the desired therapeutic effect. Suitable
dosing
regimens for a compound of the invention depend on the pharmacokinetic
properties of
that compound, such as absorption, distribution, and half-life, which can be
determined by
the skilled artisan. In addition, suitable dosing regimens, including the
duration such
regimens are administered, for a compound of the invention depend on the
disorder being
treated, the severity of the disorder being treated, the age and physical
condition of the
patient being treated, the medical history of the patient to be treated, the
nature of
concurrent therapy, the desired therapeutic effect, and like factors within
the knowledge
and expertise of the skilled artisan. It will be further understood by such
skilled artisans
that suitable dosing regimens may require adjustment given an individual
patient's
response to the dosing regimen or over time as individual patient needs
change.
Typical daily dosages may vary depending upon the particular route of
administration
chosen. Typical daily dosages for oral administration range from 0.001 mg to
50mg per
kg of total body weight.
Additionally, the compounds of the invention may be administered as prodrugs.
As used
herein, a "prodrug" of a compound of the invention is a functional derivative
of the
compound which, upon administration to a patient, eventually liberates the
compound of
the invention in vivo. Administration of a compound of the invention as a
prodrug may
enable the skilled artisan to do one or more of the following: (a) modify the
onset of the
compound in vivo; (b) modify the duration of action of the compound in vivo;
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the transportation or distribution of the compound in vivo; (d) modify the
solubility of the
compound in vivo; and (e) overcome or overcome a side effect or other
difficulty
encountered with the compound. Typical functional derivatives used to prepare
prodrugs
include modifications of the compound that are chemically or enzymatically
cleaved in
vivo. Such modifications, which include the preparation of phosphates, amides,
esters,
thioesters, carbonates, and carbamates, are well known to those skilled in the
art.
The invention also provides a compound of the invention for use in medical
therapy, and
particularly in the treatment of disorders mediated by IKK2 activity. Thus, in
a further
aspect, the invention is directed to the use of a compound according to
formulae I-II or a
pharmaceutical ly-acceptabi e salt thereof in the preparation of a medicament
for the
treatment of a disorder characterized by inappropriate IKK2 activity.
Particular disorders characterised by inappropriate IKK2 activity include
inflammatory and
tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel
disease,
asthma and CQPD (chronic obstructive pulmonary disease); osteoarth ritis,
osteoporosis
and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and
ultraviolet
radiation (UV)-induced skin damage; autoimmune diseases including systemic
lupus
eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis,
tissue and organ
rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes,
glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation
associated
with infection and certain viral infections, including acquired immune
deficiency syndrome
(AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia as a
result of
inhibition of the protein kinase IKK2.
Compositions
The compounds of the invention will normally, but not necessarily, be
formulated into
pharmaceutical compositions prior to administration to a patient. Accordingly,
in another
aspect the invention is directed to pharmaceutical compositions comprising a
compound
of the invention and one or more pharmaceutically-acceptable excipient.
The pharmaceutical compositions of the invention may be prepared and packaged
in bulk
form wherein a safe and effective amount of a compound of the invention can be
extracted and then given to the patient such as with powders or syrups.
Alternatively, the
pharmaceutical compositions of the invention may be prepared and packaged in
unit
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dosage form wherein each physically discrete unit contains a safe and
effective amount
of a compound of the invention. When prepared in unit dosage form, the
pharmaceutical
compositions of the invention typically may contain, for example, from 0.5mg
to 1 g, or
from 1 mg to 700mg, or from 5mg to 100mg of a compound of the invention.
The pharmaceutical compositions of the invention typically contain one
compound of the
invention. However, in certain embodiments, the pharmaceutical compositions of
the
invention contain more than one compound of the invention. For example, in
certain
embodiments the pharmaceutical compositions of the invention contain two
compounds
of the invention. In addition, the pharmaceutical compositions of the
invention may
optionally further comprise one or more additional pharmaceutically active
compounds.
As used herein, "pharmaceutically-acceptable excipient" means a
pharmaceutically
acceptable material, composition or vehicle involved in giving form or
consistency to the
pharmaceutical composition. Each excipient must be compatible with the other
ingredients of the pharmaceutical composition when commingled such that
interactions
which would substantially reduce the efficacy of the compound of the invention
when
administered to a patient and interactions which would result in
pharmaceutical
compositions that are not pharmaceutically acceptable are avoided. In
addition, each
excipient must of course be of sufficiently high purity to render it
pharmaceutically-
acceptable.
The compound of the invention and the pharmaceutically-acceptable excipient or
excipients will typically be formulated into a dosage form adapted for
administration to the
patient by the desired route of administration. For example, dosage forms
include those
adapted for (1) oral administration such as tablets, capsules, capiets, pills,
troches,
powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and
cachets; (2)
parenteral administration such as sterile solutions, suspensions, and powders
for
reconstitution; (3) transdermal administration such as transdermal patches;
(4) rectal
administration such as suppositories; (5) inhalation such as aerosols,
solutions, and dry
powders; and (6) topical administration such as creams, ointments, lotions,
solutions,
pastes, sprays, foams, and gels.
Suitable pharmaceutically-acceptable excipients will vary depending upon the
particular
dosage form chosen. In addition, suitable pharmaceutically-acceptable
excipients may
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be chosen for a particular function that they may serve in the composition.
For example,
certain pharmaceutically-acceptable excipients may be chosen for their ability
to facilitate
the production of uniform dosage forms. Certain pharmaceutically-acceptable
excipients
may be chosen for their ability to facilitate the production of stable dosage
forms. Certain
pharmaceutically-acceptable excipients may be chosen for their ability to
facilitate the
carrying or transporting the compound or compounds of the invention once
administered
to the patient from one organ, or portion of the body, to another organ, or
portion of the
body. Certain pharmaceutically-acceptable excipients may be chosen for their
ability to
enhance patient compliance.
Suitable pharmaceutically-acceptable excipients include the following types of
excipients:
Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating
agents, coating
agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers,
sweetners,
flavoring agents, flavor masking agents, coloring agents, anticaking agents,
hemectants,
chelating agents, plasticizers, viscosity increasing agents, antioxidants,
preservatives,
stabilizers, surfactants, and buffering agents. The skilled artisan will
appreciate that
certain pharmaceutically-acceptable excipients may serve more than one
function and
may serve alternative functions depending on how much of the excipient is
present in the
formulation and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to
select
suitable pharmaceutically-acceptable excipients in appropriate amounts for use
in the
invention. In addition, there are a number of resources that are available to
the skilled
artisan which describe pharmaceutically-acceptable excipients and may be
useful in
selecting suitable pharmaceutically-acceptable excipients. Examples include
Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of
Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of
Pharmaceutical Excipients (the American Pharmaceutical Association and the
Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques
and
methods known to those skilled in the art. Some of the methods commonly used
in the art
are described in Remington's Pharmaceutical Sciences (Mack Publishing
Company).
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In one aspect, the invention is directed to a solid oral dosage form such as a
tablet or
capsule comprising a safe and effective amount of a compound of the invention
and a
diluent or filler. Suitable diluents and fillers include lactose, sucrose,
dextrose, mannitol,
sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized
starch), cellulose and
its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and
dibasic calcium
phosphate. The oral solid dosage form may further comprise a binder. Suitable
binders
include starch (e.g. corn starch, potato starch, and pre-gelatinized starch),
gelatin, acacia,
sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose
and its
derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may
further
comprise a disintegrant. Suitable disintegrants include crospovidone, sodium
starch
glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
The oral solid
dosage form may further comprise a lubricant. Suitable lubricants include
stearic acid,
magnesuim stearate, calcium stearate, and talc.
Where appropriate, dosage unit formulations for oral administration can be
microencapsulated. The composition can also be prepared to prolong or sustain
the
release as for example by coating or embedding particulate material in
polymers, wax or
the like.
The compounds of the invention may also be coupled with soluble polymers as
targetable
drug carriers. Such polymers can include polyvinylpyrrolidone, pyran
copolymer,
polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or
polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore,
the
compounds of the invention may be coupled to a class of biodegradable polymers
useful
in achieving controlled release of a drug, for example, polylactic acid,
polepsilon
caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans,
polycyanoacrylates and cross-linked or amphipathic block copolymers of
hydrogels.
In another aspect, the invention is directed to a liquid oral dosage form.
Oral liquids such
as solution, syrups and elixirs can be prepared in dosage unit form so that a
given
quantity contains a predetermined amount of a compound of the invention.
Syrups can
be prepared by dissolving the compound of the invention in a suitably flavored
aqueous
solution, while elixirs are prepared through the use of a non-toxic alcoholic
vehicle.
Suspensions can be formulated by dispersing the compound of the invention in a
non-
toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl
alcohols and
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polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as
peppermint oil or
natural sweeteners or saccharin or other artificial sweeteners, and the like
can also be
added.
In another aspect, the invention is directed to a dosage form adapted for
administration to
a patient by inhalation. For example, the compound of the invention may be
inhaled into
the lungs as a dry powder, an aerosol, a suspension, or a solution.
Dry powder compositions for delivery to the lung by inhalation typically
comprise a
compound of the invention as a finely divided powder together with one or more
pharmaceutically-acceptable excipients as finely divided powders.
Pharmaceutically-
acceptable excipients particularly suited for use in dry powders are known to
those skilled
in the art and include lactose, starch, mannitol, and mono-, di-, and
polysaccharides.
The dry powder may be administered to the patient via a reservoir dry powder
inhaler
(RDPI) having a reservoir suitable for storing multiple (un-metered doses) of
medicament
in dry powder form. RDPIs typically include a means for metering each
medicament dose
from the reservoir to a delivery position. For example, the metering means may
comprise
a metering cup, which is movable from a first position where the cup may be
filled with
medicament from the reservoir to a second position where the metered
medicament dose
is made available to the patient for inhalation.
Alternatively, the dry powder may be presented in capsules (e.g. gelatin or
plastic),
cartridges, or blister packs for use in a multi-dose dry powder inhaler
(MDPI). MDPIs are
inhalers wherein the medicament is comprised within a multi-dose pack
containing (or
otherwise carrying) multiple defined doses (or parts thereof) of medicament.
When the
dry powder is presented as a blister pack, it comprises multiple blisters for
containment of
the medicament in dry powder form. The blisters are typically arranged in
regular fashion
for ease of release of the medicament therefrom. For example, the blisters may
be
arranged in a generally circular fashion on a disc-form blister pack, or the
blisters may be
elongate in form, for example comprising a strip or a tape. Each capsule,
cartridge, or
blister may, for example, contain between 20 g-10mg of the compound of the
invention.
Aerosols may be formed by suspending or dissolving a compound of the invention
in a
liquified propellant. Suitable propellants include halocarbons, hydrocarbons,
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liquified gases. Representative propellants include: trichlorofluoromethane
(propellant
11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane
(propellant 114),
tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane
(HFA-32),
pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane,
perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols
comprising
a compound of the invention will typically be administered to a patient via a
metered dose
inhaler (MDI). Such devices are known to those skilled in the art.
The aerosol may contain additional pharmaceutically-acceptable excipients
typically used
with MDis such as surfactants, lubricants, cosolvents and other excipients to
improve the
physical stability of the formulation, to improve valve performance, to
improve solubility,
or to improve taste.
Suspensions and solutions comprising a compound of the invention may also be
administered to a patient via a nebulizer. The solvent or suspension agent
utilized for
nebulization may be any pharmaceutically-acceptable liquid such as water,
aqueous
saline, alcohols or glycols, e.g., ethanol, isopropylalcohol, glycerol,
propylene glycol,
polyethylene glycol, etc. or mixtures thereof. Saline solutions utilize salts
which display
little or no pharmacological activity after administration. Both organic
salts, such as alkali
metal or ammonium halogen salts, e.g., sodium chloride, potassium chloride or
organic
salts, such as potassium, sodium and ammonium salts or organic acids, e.g.,
ascorbic
acid, citric acid, acetic acid, tartaric acid, etc. may be used for this
purpose.
Other pharmaceutically-acceptable excipients may be added to the suspension or
solution. The compound of the invention may be stabilized by the addition of
an inorganic
acid, e.g., hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric
acid; an organic
acid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc.,
a complexing agent
such as EDTA or citric acid and salts thereof; or an antioxidant such as
antioxidant such
as vitamin E or ascorbic acid. These may be used alone or together to
stabilize the
compound of the invention. Preservatives may be added such as benzalkonium
chloride
or benzoic acid and salts thereof. Surfactant may be added particularly to
improve the
physical stability of suspensions. These include lecithin, disodium
dioctylsulphosuccinate, oleic acid and sorbitan esters.
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Pharmaceutical compositions adapted for transdermal administration may be
presented
as discrete patches intended to remain in intimate contact with the epidermis
of the
patient for a prolonged period of time. For example, the active ingredient may
be
delivered from the patch by iontophoresis as generally described in
Pharmaceutical
Research, 3(6), 318 (1986).
Pharmaceutical compositions adapted for topical administration may be
formulated as
ointments, creams, suspensions, lotions, powders, solutions, pastes, gels,
sprays,
aerosols or oils.
For treatments of the eye or other external tissues, for example mouth and
skin, the
compositions may be applied as a topical ointment or cream. When formulated in
an
ointment, the compound of the invention may be employed with either a
paraffinic or a
water-miscible ointment base. Alternatively, the compound of the invention may
be
formulated in a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical compositions adapted for nasal administration wherein the
carrier is a
solid include a coarse powder having a particle size for example in the range
20 to 500
microns which is administered by rapid inhalation through the nasal passage
from a
container of the powder held close up to the nose. Suitable compositions
wherein the
carrier is a liquid, for administration as a nasal spray or as nasal drops,
include aqueous
or oil solutions of the compound of the invention.
Pharmaceutical compositions adapted for parenteral administration include
aqueous and
non-aqueous sterile injection solutions which may contain anti-oxidants,
buffers,
bacteriostats and solutes which render the formulation isotonic with the blood
of the
intended recipient; and aqueous and non-aqueous sterile suspensions which may
include
suspending agents and thickening agents. The compositions may be presented in
unit-
dose or multi-dose containers, for example sealed ampoules and vials, and may
be
stored in a freeze-dried (lyophilized) condition requiring only the addition
of the sterile
liquid carrier, for example water for injections, immediately prior to use.
Extemporaneous
injection solutions and suspensions may be prepared from sterile powders,
granules and
tablets.
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EXAMPLES
The following examples illustrate the invention. These examples are not
intended to limit
the scope of the present invention, but rather to provide guidance to the
skilled artisan to
prepare and use the compounds, compositions, and methods of the present
invention.
While particular embodiments of the present invention are described, the
skilled artisan
will appreciate that various changes and modifications can be made without
departing
from the spirit and scope of the invention.
All references to ether are to diethyl ether; brine refers to a saturated
aqueous solution of
NaCI. Unless otherwise indicated, all temperatures are expressed in C
(degrees
Centigrade). All reactions are conducted under an inert atmosphere at room
temperature
unless otherwise noted.
'H NMR spectra were recorded on a Brucker DPX400, a Brucker DPX250, a Brucker
AC400, or a Varian Inova 400. Chemical shifts are expressed in parts per
million (ppm, S
units). Splitting patterns describe apparent multiplicities and are designated
as s
(singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m
(multiplet), br (broad).
Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA, JOEL SX-
102, or a SCIEX-APliii spectrometer; LC-MS were recorded on Waters ZQ or PE
Sciex
Single Quadrupole LC/MS API-150 spectrometers.
Preparative HPLC refers to methods where the material was purified by high
performance
liquid chromatography on a HPLC ABZ+ 5pm column (10 cm x 21.2 mm i.d.) with
0.1%
formic acid in water and 0.05% formic acid in acetonitrile utilising gradient
elution at a flow
rate of 8 ml/min and UV detection at 254nM.
Unless otherwise stated, silica flash column chromatography and Combiflash
refers to the
purification of material using RedisepTM pre-packed silica flash columns on an
ISCO
sq16x machine with the stated solvent systems.
Reverse phase HPLC method A refers to methods where the materials were
purified by
high performance liquid chromatography on an HPLC S-5 pm column (75x30 mm
i.d.)
utilizing gradient elution with the stated solvent systems and UV detection at
254 nm.
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Reverse phase HPLC method B refers to methods where the materials was purified
by
high performace liquid chromatography on a HPLC Luna C18 (2) 100A column
(50x21.2
mm i.d.) utilizing gradient elution with the stated solvent system and UV
detection at 254
nm.
LC-MS Experimental Conditions for PE Sciex Single Quadrupole LC/MS API-150:
Liquid Chromatograph:
System: Shimadzu LC system with SCL-10A Controller and dual UV
detector
Autosampler: Leap CTC with a Valco six port injector
Column: Aquasil/Aquasil (C18 40x1 mm)
Inj. Volume (pL): 2.0
Solvent A: H20, 0.02% TFA
Solvent B: MeCN, 0.018% TFA
Gradient: linear
Channei A: UV 214 nm
Channel B: ELS
Step Time (min) Dura.(min) Flow (pUmin) SoI.A SoI.B
0 0.00 0.00 300.00 95.00 5.00
1 0.00 0.01 300.00 95.00 5.00
2 0.01 3.20 300.00 10.00 90.00
3 3.21 1.00 300.0010.00 90.00
4 4.21 0.10 300.00 95.00 5.00
5 4.31 0.40 300.00 95.00 5.00
Mass Spectrometer: PE Sciex Single Quadrupole LC/MS API-150
Polarity: Positive
Acquisition mode: Profile
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Intermediates
Intermediate 1: 1,1-dimethylethyl 2,3-dihydro-1 H-indole-l-carboxylate
O~N
O
O
A-
Indoline (10 g, 84 mmol) was dissolved in tetrahydrofuran (100 mL) and di-tert-
butylcarbonate (22 g, 0.1 mol) was added. The mixture was left stirring for 16
hours at
room temperature under an inert nitrogen atmosphere. The tetrahydrofuran was
removed
in vacuo and the crude product purified by vacuum distillation to give the
title compound
(15.1 g) as a clear pale pink oil that crystallised upon standing
(temperature: 160-162 C,
pressure 1 - 0.1 mm Hg).
1H NMR (400 MHz, DMSO-D6) S ppm 1.50 (s, 9 H) 3.04 (t, J=8.7 Hz, 2 H) 3.89 (t,
J=8.8
Hz, 2 H) 6.91 (td, J=7.3, 0.8 Hz, 1 H) 7.13 (t, J=7.5 Hz, 1 H) 7.18 (d, J=7.3
Hz, 1 H) 7.5-
7.8 (bs, 1 H) r.t. 3.44 min.
Intermediate 2: 1-(1,1-dimethylethyl) 7-methyl 2,3-dihydro-1 H-indole-1,7-
dicarboxylate
N
O
O 00
I A,
1,1-dimethylethyl 2,3-dihydro-lH-indole-l-carboxylate (5 g, 22.8 mmol) and
N,N,M,N-
tetramethyl-1,2-ethanediamine (4.6 mL, 30.5 mmol) was dissolved in dry diethyl
ether
(300 mL) and cooled to -78 C in an acetone/dry ice bath. Sec-butyl lithium
(1.4 M
solution in cyclohexanes, 17.6 mL, 24.6 mmol) was added dropwise over 10
minutes and
the reaction left stirring for 90 minutes at this temperature. Methyl
chloroformate (8.8 mL,
10.8 g, 0.1 mol) was added to the mixture and the reaction was allowed to warm
up to
room temperature over 1 hour. Water was added carefully to the mixture and the
organic
layer separated and washed 3 times with more water. The organic layer was
dried over

CA 02613068 2007-12-20
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magnesium sulfate, filtered and concentrated in vacuo to give the title
compound (4.91 g)
as a gummy yellow solid.
1 H NMR (400 MHz, DMSO-D6) S ppm 1.44 (s, 9 H) 3.06 (t, J=8.2 Hz, 2 H) 3.69
(s, 3 H)
4.02 (t, J=8.3 Hz, 2 H) 7.06 (t, J=7.5 Hz, 1 H) 7.35 (d, J=7.5 Hz, 1 H) 7.39
(dd, J=7.4, 1.1
Hz, 1 H) MS m/z 278 (M+1)+ r.t. 3.18 min.
Intermediate 3: 1-(1,1-dimethylethyl) 7-methyl 5-bromo-2,3-dihydro-1 H-indole-
1,7-
dicarboxylate
Br
N
O 00
I A,
1 -(1, 1 -dimethylethyl) 7-methyl 2,3-dihydro-1 H-indole-1,7-dicarboxylate
(3.1 g, 11.2 mmol)
and N-bromosuccinimide (2.0 g, 11.2 mmol) were dissolved in dry
dichloromethane (100
mL) and stirred under a nitrogen atmosphere at room temperature for 16 hours.
The
reaction was partitioned with sodium hydroxide solution (2 M), separated and
washed
with more sodium hydroxide solution. The organic layer was dried over
magnesium
sulfate and concentrated in vacuo to give the title compound as a gummy red
solid (3.55
g).
1 H NMR (400 MHz, DMSO-D6) S ppm 1.41 (s, 9 H) 3.09 (t, J=8.3 Hz, 2 H) 3.70
(s, 3 H)
4.02 (t, J=8.3 Hz, 2 H) 7.46 (s, 1 H) 7.60 (s, 1 H) MS m/z 356/358 (1:1 ratio)
(M+1)+ r.t.
3.52 min.
Intermediate 4: methyl 5-bromo-2,3-dihydro-1 H-i ndole-7-carboxyl ate
Br ~
~ /
N
H
O O
1
1-(1,1-dimethylethyl) 7-methyl 5-bromo-2,3-dihydro-1 H-indole-1,7-
dicarboxylate (9 g, 25
mmol) was dissolved in trifluoroacetic acid (6 mL) and stirred at room
temperature for 16
hours. Dichloromethane and sodium hydroxide solution (2 M) were added and the
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organic layer washed twice with sodium hydroxide solution until the aqueous
layer pH >
7. The organic layer was then concentrated in vacuo to give the title compound
as a
brown solid (6.5 g).
1 H NMR (400 MHz, DMSO-D6) S ppm 2.99 (t, J=8.5 Hz, 2 H) 3.61 (t, J=8.4 Hz, 2
H) 3.78
(s, 3 H) 6.72 (s, 1 H) 7.28 (d, J=1 Hz, 1 H) 7.46 (d, J=2 Hz, 1 H) MS m/z
256/258 (1:1
ratio) (M+1)+ r.t. 3.32 min.
Intermediate 5: methyl 5-bromo-1 H-indole-7-carboxyiate
Br
~ \
N
H
O O
1
Methyl 5-bromo-2,3-dihydro-1 H-indole-7-carboxylate (6.5 g, 25 mmol) was
dissolved in
tetrahydrofuran (100 mL). Activated manganese dioxide (5 m particle size, 22
g, 0.25
mol) was added and the mixture stirred at room temperature for 16 hours. A
further 22 g
of activated manganese dioxide was added and the reaction stirred for 96
hours. The
reaction was then filtered through celite and concentrated in vacuo to give
the title
compound (5.1 g) as a beige solid.
1 H NMR (400 MHz, DMSO-D6) S ppm 3.94 (s, 3 H) 6.58 (d, J=3 Hz, 1 H) 7.48 (d,
J=3 Hz,
1 H) 7.8 (d, J=2 Hz, 1 H) 8.07 (d, J=1.8 Hz, 1 H) 11.39 (bs, 1 H) MS m/z
252/254 (1:1
ratio) (M-1) r.t. 3.41 min.
Intermediate 6: 5-bromo-1 H-indole-7-carboxylic acid
Br
~ \
N
H
HO O
5-bromo-1 H-indole-7-carboxylate (5 g, 19.7 mmol) was dissolved in methanol
(200 mL)
and a solution of lithium hydroxide (0.99 g, 41 mmol) in water (10 mL) was
added. The
mixture was heated at reflux for 50 hours. The methanol was removed in vacuo
and the
residue diluted with aqueous hydrochloric acid (2 M). The resulting
precipitate was
filtered off and dried in a heated vacuum pistol to give the title compound as
a beige solid
(4.7 g).
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1 H NMR (400 MHz, DMSO-D6) 8 ppm 6.54 (dd, J=2.0, 3.2 Hz, 1 H) 7.42 (t, J=2.8
Hz, 1
H) 7.77 (d, J=2 Hz, 1 H) 8.03 (d, J=1.8 Hz, 1 H) 11.27 (s, 1 H) 13.1-13.7 (bs,
1 H) MS m/z
238/240 (1:1 ratio) (M-1) r.t. 3.41 min.
Intermediate 7: 5-bromo-1 H-indole-7-carboxamide
Br ~
~ \
~ N
H
H2N O
To a solution of 5-bromo-ll-l-indole-7-carboxylic acid (10.0 g, 42 mmol) in
CH2CI2 (100
mL) at room temperature, EDC (9.66 g, 50.4 mmol), HOBt (6.81 g, 50.4 mmol) and
NH3
(2.0 M in MeOH, 84 mL, 168 mmol) were added. The reaction mixture was stirred
at room
temperature for 16 hours. The solvent was evaporated and the residue
partitioned
between ethyl acetate (100 mL) and water (100 mL). The water layer was
extracted with
ethyl acetate (100 mLx2) and the combined organic phase was dried over MgSO4
and
concentrated to give the crude product (10 g, 98%). This crude product was
used directly
in the next step without further purification.
LC/MS: m/z 240.0 (M+H), 1.95 min.
Intermediate 8: 1 1-dimethylethyl 447-(aminocarbonyl)-5-bromo-1l-Nindol-3-yl1-
3,6-
dihydro-1(21i)-pyridinecarboxylate
O
O
N
Br
N
H
O NH2
To a solution of 5-bromo-1 H-indole-7-carboxamide (10 g, 41.84 mmol) in
methanol (5mL),
1,1-dimethylethyl 4-oxo-l-piperidinecarboxylate (684 mg, 3.42 mmol) and sodium
methoxide (0.5 M in THF, 13.7 mL, 6.84 mmol) were added. The reaction mixture
was
stirred at reflux temperature for 16 hours. All solvent was evaporated under
reduced
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pressure. The residue was partitioned between ethyl acetate (100 mL) and water
(100
mL). The combined organic phase was dried over MgSO4 and concentrated under
reduced pressure, and purified by flash column chromatography (ethyl
acetate/hexanes,
1/1) to give the desired product (7.4 g, 43 %).
LC/MS: m/z 420.0 (M+H), 2.35 min.
Intermediate 9: 1,1-dimethylethyl 4-f7-(aminocarbonyl)-5-bromo-1 H-indol-3-yll-
1-
piperidine carboxylate
O
O
N
Br
N
H
O NH2
To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1 H-indol-3-
yl]-3,6-
dihydro-1(2H)-pyridinecarboxylate (7.41 g, 17.64 mmol) in ethanol (600 mL),
platinum
oxide (200 mg, 5%) was added. The reaction mixture was hydrogenated under an
atmosphere of H2 for 16 hours. The resulting mixture was filtered through
celite and the
filtrate was concentrated. The resulting residue was purified by flash column
chromatography (Ethyl acetate/hexanes, 1:4 to 2:1 v/v) to give the desired
product (3.6g,
48%).
LC-MS: m/z 422.0 (M+H), 2.25 min.
Intermediate 10: 5-bromo-3-(4-piperidinyl)-1 /+indole-7-carboxamide
H
N
Br
N
H
O N H2
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CA 02613068 2007-12-20
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To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1 H-indol-3-
yl]-1-
piperidinecarboxylate (1.56 g, 3.7 mmol) in methanol (10 mL), HCI in dioxane
(4M, 35.5
mL) was added. The reaction mixture was stirred at room temperature for 2
hours. The
solvent was evaporated under reduced pressure and the resulting residue was
partitioned
between ethyl acetate (50 mL) and 5% of aqueous NaOH (50 mL). The aqueous
layer
was washed with ethyl acetate (2x50 mL) and the combined organic phases were
dried
with MgSO4 and concentrated under reduced pressure to give the desired product
(685
mg, 58%), which was used in the next step without further purification.
LC-MS: m/z 322.0 (M+H), 1.45 min.
Intermediate 11: 5-bromo-3-f1-(ethanesuifonyl)-4-piperidinyll-1 H-indole-7-
carboxamide
OZS~~O
N
Br
N
H
O NH2
Ethanesulfonyl chloride (4.5 mL, 47.4 mmol) was added dropwise to a solution
of 5-
bromo-3-(4-piperidinyl)-1 H-indole-7-carboxamide hydrochloride (8.49 g, 23.7
mmol) and
triethylamine (13.2 mL, 94.7 mmol) in DMF (80 mL) at 02C (bath temperature).
The
reaction mixture was stirred at 0 C for 45 min. and was then poured into a 2:1
mixture of
EtOAc/H20 (300 mL). The resulting precipitate was filtered off, washed with
EtOAc (2 x
50 mL), and set aside. The EtOAc/H20 bilayer was separated, and the aqueous
layer
was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed
with
saturated NaCI (1 x 100 mL), dried (MgSOq.), filtered, and concentrated under
reduced
pressure. The crude product was combined with the precipitate isolated above
and
washed with MeOH (1 x 10 mL) to give 8.19 g of the title compound (83%).
Alternatively, the title compound may be prepared as follows:
To 5-bromo-3-(4-piperidinyl)-1 H-indole-7-carboxamide (900 mg, 2.8 mmol) in
CH2CI2
(100mL) at 0 C, ethanesulfonyl chloride (0.8 mg, 8.4 mmol) and triethylamine
(1.6 mL,

CA 02613068 2007-12-20
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11.2 mmol) were added. The reaction mixture was stirred at 0 C for 30 min.,
after which
time the mixture was partitioned between CH2CI2 and water. The aqueous phase
was
extracted with CH2CI2 (50 mL x 2) and the combined organic phase dried over
MgSO4
and concentrated under reduced pressure. The resulting residue was purified by
solid
phase extraction on a 500 mg aminopropyl column (International Sorbent
Technologies)
eluting with chloroform (30 mL x 2) and ethyl acetate (50 mL) to give 800 mg
of the title
compound (69%).
LC/MS: m/z 414.0 (M+H), 2.2 min.
Intermediate 12: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-f3-
(hydroxymethyl)phenyll-1 H-
i ndole-7-carboxamide
S'
OH O
N
\ \ ~
N
H
O NH2
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-11-f-indole-7-
carboxamide (20.0
mg, 0.048 mmol), K3P04 ( 21.0 mg, 0.096 mmol) and [3-(hydroxymethyl) phenyl]
boronic
acid (30.0 mg, 0.193 mmol) in dioxane/H20 ( 2 mU0.7 mL) was bubbled argon for
5
minutes prior to addition of Pd(PPh3)4 (5.0 mg, 0.0048 mmol). The reaction
mixture was
heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160 C. The
solvent
was evaporated, and the residue was partitioned between ethyl acetate and
water. The
organic layer was washed with brine (10 mL), dried over MgSO4i concentrated,
and
purified by reverse phase HPLC method A(water/ CH3CN, 0.1 % TFA 10-90%) to
give
the title compound (9.7 mg, 46%).
1 H NMR (400 MHz, DMSO-D6) 8 ppm 1.25 (t, J=7.2 Hz, 3H), 1.65 (m, 2H), 2.02
(m, 2H),
2.99 (m, 7H), 3.71 ( m, 2H), 7.16 (s, 1 H), 7.42 (m, 3H), 7.77 (m, 2H), 8.02
(m, 2H), 8.22
(m, 1 H), 10.91 (s, 1 H).
LC/MS: m/z 442.4 (M+H), r.t: 1.73 min.
Intermediate 13: 3-f1-(ethyisulfonvl)-4-piperidinyll-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide
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S'-O
N
0
\ \ ~
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-
(hydroxymethyl)phenyl]-1 f I indole-
7-carboxamide (52.0 mg, 0.120 mmol) in THF (10 mL), Mn02 (360.0 mg, 3.5 mmol)
was
added at ambient temperature. The resulting suspension was stirred overnight,
filtered
through celite, and the solid rinsed with THF (3X1 0 mL). The filtrate was
concentrated to
give the title compound (51.0 mg, 98%) which was used in the next step without
purification.
LC/MS: m/z 440.4 (M+H), r.t: 1.97 min.
Intermediate 14: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f4-
(hydroxymethyl)phenyll-1 F!-
indole-7-carboxamide
O~S'-O
OH N
I / \
N
H
O NH2
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (20.0
mg, 0.048 mmol), K3PO4 ( 21.0 mg, 0.096 mmol) and [4-(hydroxymethyl) phenyl]
boronic
acid (30.0 mg, 0.193 mmol) in dioxane/H20 ( 2 mU0.7 mL) was bubbled argon for
5
minutes prior to addition of Pd(PPh3)4 (5.0 mg, 0.0048 mmol). The reaction
mixture was
heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160 C. The
solvent
was evaporated, and the residue was partitioned between ethyl acetate and
water. The
organic layer was washed with brine (10 mL), dried over MgSO4, filtered,
concentrated,
and purified by reverse phase HPLC method A(water/ CH3CN, 0.1 % TFA 10-90%) to
give the title compound (6.4 mg, 30%).
LC/MS: m/z 442.4 (M+H), r.t: 1.78 min.
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Intermediate 15: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide
~
D,S\O
O N
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-
(hydroxymethyl)phenyl]-1 H-indole-
7-carboxamide (25 mg, 0.058 mmol) in THF (5 mL), Mn02 (160.0 mg, 1.73 mmol)
was
added at ambient temperature. The resulting suspension was stirred overnight,
filtered
through celite, and the solid rinsed with THF (3X10 mL). The filtrate was
concentrated to
give the title compound (15 mg, 58%) which was used in the next step without
purification.
LC/MS: m/z 440.4 (M+H), r.t: 2.02 min.
Intermediate 16: 3-f1-(ethylsuifonyl)-4-piperidinyil-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide
O\Szz:-O
N
O'B I \ ~
N
H
O NH2
To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (1.0
g, 2.42 mmol), Bis(pinacolato)diborane (2.45 g, 9.66 mmol) and potassium
carbonate
(2.10 g, 21.8 mmol) in DME (15.0 mL) was added Pd2CI2(dppf) after degassing
for 5 min.
The mixture was then heated in the microwave at 130 C for 11000 sec. Reaction
mixture was then diluted with EtOAc (300 mL) and H20 (100 mL) and solid was
filtered.
The organic layer was then washed with H20 (3 x 80 mL) and brine. Organic laye
was
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CA 02613068 2007-12-20
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dried over MgSO4 and concentrated. DCM (40 mL) was then added to remove any by-
product to afford 2.4 g of the title compound.
LC/MS: m/z 462.3 (M+H), r.t: 2.03 min.
Intermediate 17: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-(5-formyl-2-thienyl)-1
H-indole-
7-carboxamide
r
O
SO
O N
S
N
H
O NH2
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (200
mg, 0.49 mmol) in dioxane (4.5 mL) and H20 (1.5 mL) was added [5-
(hydroxymethyl)-2-
thienyl]boronic acid (232 mg, 1.47 mmol), potassium carbonate (406 mg, 2.94
mmol) and
tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.049 mmol). Reaction was
run in the
microwave at 150 C for 20 min. Aqueous work-up with EtOAc/H20 gave 447 mg of
3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-thienyl]-1 H-indole-7-
carboxamide.
To a solution of 3-[i -(ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-
thienyl]-1 H-
indole-7-carboxamide (200 mg, 0.46 mmol) in THF (5.0 mL) was added Mn02 (1.21
g,
13.9 mmol). The mixture was stirred at room temperature for 3 h. Filtration of
reaction
mixture thru celite afforded 100 mg of the title compound (48.8%)
LC/MS: m/z 446.2 (M+H), r.t: 2.27 min.
Intermediate 18: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-(4-formyl-2-thienyl)-1
H-indole-
7-carboxamide
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O\SZZ-O
N
s
O~
N
H
O NH2
To a solution of 3-thiophenecarbaldehyde (3.0 g, 26.8 mmol) in DCM (54 mL) was
added
aluminum trichloride (8.37 g, 63 mmol) at 0 C. The reaction was then heated
to reflux
and bromine (1.6 mL, 30.28 mmol) was added dropwise. After addition, the
reaction
mixture was stirred at reflux for 4 h. After cooling to room temperature, cold
H20 (100
mL) was added and extracted with DCM (2 x 100 mL). The combined organic layer
was
washed with NaHCO3 and dried. It was purified by flash chromatography to give
3.62 g
of 5-bromo-3-thiophenecarbaldehyde (71 %).
To a solution of 5-bromo-3-thiophenecarbaidehyde (250 mg, 1.29 mmol) in
dioxane (4.5
mL) and H20 (1.5 mL) was added 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-
tetramethyl-
1,3,2-dioxaborolan-2-yl)-1 H-indole-7-carboxamide (200 mg, 0.43 mmol),
potassium
carbonate (250 mg, 2.58 mmol) and tetrakis(triphenylphosphine)palladium (0)
(56 mg,
0.049 mmol). The reaction was run in the microwave at 1500 C for 20 min. It
was then
treated with EtOAc and H20 to obtain the crude product. This was then treated
with
MeOH (10 mL) and the solid was filtered and collected to give 310 mg of the
desired title
compound.
LC/MS: m/z 446.4 (M+H), r.t: 1.94 min.
Intermediate 19: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-formyl-3-thienyl)-1
H-indole-
7-carboxamide

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O\ r-
S_ O
N
O S
H
N
H
O NH2
To a solution of 4-bromo-2-thiophenecarbaidehyde (1.0 g, 4.48 mmol) in DME (16
mL)
was added Bis(pinacolato)diborane (1.48 g, 5.82 mmol), KOAc (1.14 g, 5.11
mmol) and
Pd2Cl2(dppf) (106 mg, .448 mmol). The reaction was run in the microwave at
1502 C for
20 min. The solvent was concentrated and an aqueous work-up was performed
using
EtOAc and H20. The compound was purified by flash chromatography using hexanes
and EtOAc to give 1.8 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-
thiophenecarbaidehyde.
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (909
mg, 2.2 mmol) in dioxane (7.5 mL) and H20 (2.5 mL) was added 4-(4,4,5,5-
tetramethyl-
1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (1.57 g, 6.6 mmol), potassium
carbonate (1.82 g, 13.2 mmol), and tetrakis(triphenylphospine)palladium (0)
(30 mg,
.22mmol). The reaction was heated in the microwave at 1502 C for 20 min. The
mixture
was then concentrated to dryness. EtOAc (50 mL) was added to the residue and
washed
with brine. The precipitate which formed between the water and organic layer
was filtered
and collected as a brown solid to give 874 mg of the title compound (89%).
LC/MS: m/z 446.4 (M+H), r.t: 1.93 min.
Intermediate 20: 5-Bromoisoindoline
Br NH
In a dried 5OmL two necked round-bottom flask equipped with an addition funnel
and
CaCI2 drying tube was placed 2.Og (1 3.6mmol) of phthalimide. The flask was
then cooled
to 0 C in a salt and ice bath. An ice cold mixture of concentrated sulfuric
acid and fuming
nitric acid (1:1 v/v) 8mL was gradually added with constant stirring. The
mixture was then
stirred for 30min. at 0 C and allowed to slowly warm to room temperature with
stirring
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over a period of 1 h. The reaction mixture was then poured into ice. The
resulting solid
product was filtered and dried to give 1.6g (61.3%) of 5-nitro-1 H-isoindole-
1,3(2H)-dione
as a yellow colour solid.
To a solution of 5-nitro-1 H-isoindole-1,3(2H)-dione (1.0g, 5.2mmol) in dry
THF (15mL)
was added 10% Pd/C (0.2g). The mixture was hydrogenated at 30-40 psi for 17h.
The
catalyst was filtered, and the filtrate was evaporated under vacuo to give
0.5g (59.3%) of
5-amino-1 hl isoindole-1,3(2H)-dione as a yellow colour solid.
To a stirred solution of 5-amino-1 H-isoindole-1,3(2H)-dione (1.0g, 6.2mmol)
dissolved in
sulfuric acid solution (2mL of Con. H2SO4 in 7.5mL of H20) at 0 C, was added
ice cold
sodium nitrite solution ( 0.8g in 2mL of H20) dropwise. After 45min of
stirring at 0 C,
CuBr (3.4g, 23.7mmol) and HBr[48%] (13.6mL, 4vol. w.r.t. CuBr) were added at
the same
temperature. The resulting mixture was stirred at 80 C for 8h then poured into
crushed
ice. Filtered the solid, washed with ice cold water and dried thoroughly to
give 0.6g
(43.0%) of 5-bromo-1 f 1 isoindole-1,3(2H)-dione as a brown colour solid.
In a dried 500mL three necked round bottom flask equipped with a reflux
condenser and
addition funnel was taken BH3-THF (160mL) solution with dry THF (50mL). The
mixture
was cooled to 0 C. To this cold solution 5-bromo-1 H-isoindole-1,3(2H)-dione
(8.0g,
35.4mmol) in dry THF (100mL) was added gradually and allowed to warm to room
temperature. After 10min at room temperature the mixture was refluxed for 16h.
The
reaction mixture was then cooled to 0 C and quenched with methanol. (Caution:
vigorous
foaming will occur). 20-30mL of 2N HCL was added and refluxed the mixture for
1 h.
Cooled the mixture and basified with NaOH solution and extracted with ethyl
acetate.
Combined organic extracts were washed with water, saturated NaCI solution,
dried over
Na2SO4 and concentrated under vacuo. To the crude product in MeOH (150mL),
Et3N
(12mL) and di-tert-butyl dicarbonate (13.8g, 63.23mmol) were added and stirred
at room
temperature for 16h. The reaction mixture was then concentrated under vacuo.
The
crude product was diluted with CH2CI2 (200mL), washed with water, saturated
NaCl
solution, and dried over Na2SO4. Crude product was purified by column
chromatography
using 20%ethyl acetate in hexanes as eluant to afford a colourless solid. To
this dioxane-
HCI was added at room temperature and stirred for 10 min, the solid obtained
was then
filtered and dried to give 3.Og (42.8%) of 5-bromoisoindoline hydrochloride
salt as an ash
colour solid.
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Intermediate 21: 5-bromo-3-(4-piperidinyl)-1 I+indole-7-carboxamide
hydrochloride
H
N
Br + HCI
N
H
O NH2
A 4M solution of HCI in dioxane (194 mL) was added to a solution of 1, 1 -
dimethylethyl 4-
[7-(aminocarbonyl)-5-bromo-1 H-indol-3-yl]-1-piperidinecarboxylate (10 g, 23.7
mmol) in
methanol (50 mL). The reaction mixture was stirred at room temperature for 4
hours, and
the solvent was evaporated under reduced pressure to give the title compound
(9.5 g),
which was used in the next step without further purification.
LC-MS: m/z 322.4 (M+H), 1.40 min.
Intermediate 22: 5-bromo-3-f 140 -methylethyl)sulfonyll-4-piperidinyl}-11,1
indole-7-
carboxamide
OS;O
N
Br
N
H
O NH2
Triethylamine (2.6 mL, 18.7 mmol) was added to a solution of 5-bromo-3-(4-
piperidinyl)-
1 H-indole-7-carboxamide hydrochloride in DMF (15 mL) at 0 C. The mixture was
stirred
at room temperature for 10 min, and 2-propanesulfonyl chloride (1.04 mL, 9.32
mmol)
was added. Stirring continued for another 30 min, and the reaction mixture was
diluted
with 1:1 EtOAc/H20 (200 mL). The layers were separated, and the aqueous layer
was
extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with
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saturated NaCI (1 x 100 mL), dried (MgSO4), and concentrated under reduced
pressure.
The crude product was washed with MeOH (2 x 10 mL) to give the title compound
(1.5 g,
75%).
LC/MS: m/z 427.8 (M+H), 1.98 min.
Intermediate 23: 5-(5-formyl-3-thienyl)-3-f1-f(1-methylethyl)sulfonyll-4-
piperidinyl}-
1 H-indole-7-carboxamide
oz:~
5;O
N
S
OHC
I \ ~
N
H
O NH2
The boronate ester used to make the title compound was prepared in 6 separate
equal
batches according to the following procedure: To a solution of 4-bromo-2-
thiophenecarbaldehyde (1.0 g, 4.48 mmol) in DME (20 mL) was added
bis(pinacolato)diborane (1.48 g, 5.82 mmol), KOAc (1.14 g, 5.11 mmol) and
Pd2CI2(dppf)
(106 mg, 0.448 mmol). The reactions were run in a Smith microwave at 150 C
for 20
min. The 6 reactions were pooled and concentrated under reduced pressure. The
residue was taken up in EtOAc (200 mL) and H20 (50 mL). The layers were
separated,
the organic layer was washed with saturated NaCI (1 x 50 mL), dried (Na2SO4),
and
concentrated under reduced pressure. The crude product was purified by flash
chromatography eluting with hexanes/EtOAc to give 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-2-thiophenecarbaidehyde (5 g, 78%).
A solution of 5-bromo-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H-indole-
7-
carboxamide (428 mg, 1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
2-
thiophenecarbaldehyde (960 mg, 4 mmol), Cs2CO3 (800 mg, 2.46 mmol), and
Pd(PPh3)4
(100 mg, 0.0865 mmol) were heated in a Smith microwave at 160 C for 20 min.
The
reaction mixture was filtered and concentrated under reduced pressure. The
crude
product was washed with MeOH (1 x 5 mL) to give the title compound (395 mg,
86%).
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LC/MS: m/z 460.4 (M+H), 1.98 min.
Examples
Example 1: 3-f7-(ethylsulfonyl)-4-piperidinyll-543-(1-
piperidinylmethyl)phenyll-1 H-
i ndole-7-carboxamide
O_S_O
N
(DN
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (15.0 mg, 0.034 mmol) in DCM (2 mL) was added piperidine (4.0 ul,
0.04
mmol). The reaction solution was stirred at ambient temperature for 1 hr prior
to addition
of NaBH(OAc)3 (23.0 mg, 0.109 mmol). The resulting mixture was stirred
overnight at
ambient temperature after which time the solvent was removed under reduced
pressure.
The resulting residue was dissolved in 1.2 mL DMSO and all undissolved solid
was
filtered off. This DMSO solution of crude product was purified by reverse
phase HPLC
(H20/CH3CN, 0.1 % TFA 10-90%) to give the title compound (8.8 mg, 50.5%).
LC/MS: m/z 509.4 (M+H), r.t: 1.87 min.
Example 2: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(1-
piperazinylmethyl)phenyll-1 FI-
indole-7-carboxamide
O;S;O
N
HON
N
H
O NHZ

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Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (15.0 mg, 0.034 mmol), piperazine (3.5
mg, 0.04
mmol) and NaBH(OAc)3 (23.0 mg, 0.102 mmol) were reacted to give the title
compound
(3.4 mg, 19.7%).
LC/MS: m/z 510.2 (M+H), r.t: 1.43 min.
Example 3: 341-(ethylsuIfonyl)-4-piperidinyll-543-(4-morpholinylmethyl)phenyil-
1 M-
indole-7-carboxamide
O;S_O
~
N
ON
N
H
O NH2
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (15.0 mg, 0.034 mmol), morpholine (3.5
ul, 0.04
mmol) and NaBH(OAc)3 (23.0 mg, 0.102 mmol) were reacted to give the title
compound
(7.5 mg, 43%).
LC/MS: m/z 511.2 (M+H), r.t: 1.58 min.
Alternatively, example 3 may be prepared as follows:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-
indole-7-
carboxamide (20 mg, 0.046 mmol) in dichloromethane (1.5 mL) and methanol (1.5
mL)
was added morpholine (0.070 mL, 0.276 mmol) and 1 drop of acetic acid. This
mixture
was stirred for 2 h at room temperature and then sodium borohydride (11 mg,
0.276
mmol) was added. After 30 min the mixture was poured onto an SCX cartridge
(5.0 g),
and EtOAc (10.0 mL) and MeOH (10.0 mL) were used to flush the cartridge. A 2 M
solution of NH3/MeOH (10.0 mL) was used to elute the product and was then
concentrated. The residue was dissolved in dimethyl sulfoxide (1.0 mL) and
purified by
Gilson Preparatory HPLC to give the title compound (17.6 mg, 75%).
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Example 4: 3-f1-(ethylsulfonyl)-4-piperidinyll-543-ff methylf2-
(methylsulfonyl)ethyllamino}methyl)phenyll-1 I,f'indole-7-carboxamide
r
O;S,O
N
S/~N
O/\\
O N
H
O NH2
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (42.0 mg, 0.096 mmol), N-methyl-2-
(methylsulfonyl)ethanamine (12.0 mg, 0.087 mmol) and NaBH(OAc)3 (58.0 mg,
0.261
mmol) were reacted to give the title compound (15.1 mg, 28.0%).
LC/MS: m/z 561.2 (M+H), r.t: 1.58 min.
Example 5: 5-(3-{ff2-(dimethylamino)ethyll(methyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
O;S;O
N
I I N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (45.0 mg, 0.101 mmol) in DCM (2 mL) was added N,N,N-trimethyl-1,2-
ethanediamine (116 ul, 0.90 mmol). The reaction solution was stirred at
ambient
temperature for 1 hr prior to addition of NaBH(OAc)3 (69 mg, 0.326 mmol). The
resulting
mixture was stirred overnight at ambient temperature, and additional
NaBH(OAc)3 (128
mg, 0.606 mmol) was added. The reaction was stirred for another 2 h, after
which time
the solvent was removed under reduced pressure. The crude product was purified
by
reverse phase HPLC (water/CH 3CN, 0.1 % TFA 10-90%) to give the title compound
(16.0 mg, 29.6%).
LC/MS: m/z 526.8 (M+H), r.t: 1.28 min.
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Example 6: 3-f1-(ethylsulfonyl)-4-piperi.dinyll-5-f3-f(4-d2-f(2-
hydroxyethyl)oxylethyl}-
1-piperazinyl)methyllphenyl}-1 H-indole-7-carboxamide
OH
r-I
O_ O
CN
N
\ I ~
N
H
H2N O
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-{[2-(1-
piperazinyl)ethyl]oxy}ethanol (150 mg, 0.87 mmol) and NaBH(OAc)3 (58.0 mg,
0.303
mmol) were reacted to give the title compound (16.7 mg, 25%).
LC/MS: m/z 598.4 (M+H), r.t: 1.48 min.
Example 7: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(34 f3-(hydroxymethyl)-1-
piperidinyllmethyl}phenyl)-114 indole-7-carboxamide
0
0=g~
-~
N
HO N I
N
H
H 2 N O
Following the general procedure of example 1, 3-[1 -(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 3-
piperidinylmethanol
(98.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give
the
title compound(10.2 mg, 17%).
LC/MS: m/z 539.4 (M+H), r.t: 1.52 min.
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Example 8: 5-f3-(Ibisf2-(methyloxy)ethyllamino}methvl)phenyll-3-f1-
(ethylsulfonVl)-
4-piperidinyll-1 H-indole-7-carboxamide
0
O
N
O
N
\ I \
N
H
H2N O
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(methyloxy)-N-
[2-
(methyloxy)ethyl]ethanamine (114.3 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg,
0.303
mmol) were reacted to give the title compound (10.5 mg, 16%).
LC/MS: m/z 557.6 (M+H), r.t: 1.62 min.
Example 9: 5-f3-f(2,6-dimethyl-4-morpholinyl)methyllphenyl}-3-f1-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
O
OI O=S"//
N
\ I \
N
H
H2N O
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2,6-
dimethylmorpholine
(98.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give
the
title compound (19.6 mg, 32%).
LC/MS: m/z 539.2 (M+H), r.t: 1.75 min.
Example 10: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-f f2-(1,3-thiazol-2-yl)-1-
pyrrolidinyllmethyl}phenyl)-1 H-indole-7-carboxamide
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0
O=s/
N
N
~
N~
\ I ~
N
H
H2N O
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(2-
pyrrolidinyl)-1,3-
thiazole (132.4 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were
reacted to
give the title compound (20.0 mg, 30.4 %).
LC/MS: m/z 578.6 (M+H), r.t: 1.57 min.
Example 11: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-(3-ff2-(2-thienyl)-1-
pyrrolidinyllmethyl}phenyl)-1 H-indole-7-carboxamide
S \
~ 0
O=S~-/
VH
H2N O
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(2-
thienyl)pyrrolidine
(132.4 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to
give the
title compound (20.0 mg, 30.4 %).
LC/MS: m/z 577.4 (M+H), r.t: 1.78 min.
Example 12: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-ff(2-hydroxy-2-
phenylethyl)-
(methyl)aminolmethyl}phenyl)-1 FI-indole-7-carboxamide

CA 02613068 2007-12-20
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O~SCH3
N
IZ CH3 /
HO N \ I \ \
N
H
H2N O
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(methylamino)-
1-
phenylethanol (129.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were
reacted to give the title compound (22.1 mg, 36.6 %).
LC/MS: m/z 575.4 (M+H), r.t: 1.66 min.
Example 13: 5-(3-ffethyl(methyl)aminolmethyl}phenyl)-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
O'S
0
N N -\
N
H
H2N O
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50.0 mg, 0.112 mmol), N-
methylethanamine
(50.7 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give
the
title compound (11.5 mg, 21 %).
LC/MS: mlz 483.4 (M+H), r.t: 1.57 min.
Example 14: 543-(aminomethyl)phenyll-341-(ethylsulfonyl)-4-piperidinyll-1 H-
indole-
7-carboxamide
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1/0
0=S
H2N N ~
/ I
N
H
H2 N O
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (30.0
mg, 0.072 mmol), Cs2CO3 (95 mg, 0.290 mmol) and 1-[3-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)phenyl]methanamine (82 mg, 0.350 mmol) in dioxane/H20 (2
mU0.7
mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (7.5 mg,
0.0072
mmol). The reaction mixture was heated in a microwave reactor (Smith
synthesizer) for
20 minutes at 160 C. The solvent was evaporated, and the residue was
partitioned
between ethyl acetate and water. The organic layer was washed with brine (10
mL), dried
over MgSO4, filtered, concentrated, and purified by reverse phase HPLC method
A
(water/CH3CN, 0.1 % TFA 10-90%) to give the title compound (2.7 mg, 8.5%).
LC/MS: m/z 441.4 (M+H), r.t: 1.54 min.
Example 15: 5-f3-f(cyclopentylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
O
HN
N
I / \
H
H2N O
Following the general procedure of example 5, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (45 mg, 0.101 mmol), cyclopentylamine
(90 uL,
0.090 mmol) and NaBH(OAc)3 (197 mg, 0.93 mmol) were reacted to give the title
compound (33.0 mg, 64%).
LC/MS: m/z 509.4 (M+H), r.t: 1.64 min.
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Example 16: 5-f3-(Tf(3,4-dihydroxyphenyl)methyllamino}methyl)phenyll-3-f 1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
HO
HO
H O~ S/
N
N
N
H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in dichloroethane (2 mL) was added 4-
(aminomethyl)-
1,2-benzenediol (12.1 mg, 0.087mmol). The reaction solution was stirred at
ambient
temperature for 10 min prior to addition of NaBH(OAc)3 (58 mg, 0.261 mmol).
The
resulting mixture was shaken overnight at ambient temperature after which time
the
solvent was removed under reduced pressure. The crude product was purified by
reverse phase HPLC (water/CH 3CN, 0.1 % TFA 10-90%) to give the title compound
(7.4
mg, 12 %).
LC/MS: m/z 563.2 (M+H), r.t: 1.67 min.
Example 17: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-ff(3-
thienylmethyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
0
N
N
N
H
H2N O
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50 mg, 0.114 mmol), 1-(3-
thienyl)methanamine
(9.83 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give
the
title compound (4.7 mg, 7.8 %).
LC/MS: m/z 537.2 (M+H), r.t: 1.62 min.
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Example 18: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(f f(1 R)-1-
(hydroxymethyl)-2-.
methylpropyllamino}methyl)phenyll-1 H-indole-7-carboxamide
0
O
N
N
HOT N
H
H2N O
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50 mg, 0.114 mmol), (2R)-2-amino-3-
methyl-l-
butanol (10.2 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted
to
give the title compound (14.9 mg, 25 %).
LC/MS: m/z 527.6 (M+H), r.t: 1.48 min.
Example 19: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-(3-df(2-hydroxy-l-
methylethyl)
aminolmethyl}phenyl)-1 Fl-indole-7-carboxamide:
0
N
N
HO N
H
H2N O
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50 mg, 0.114 mmol), 2-amino-l-propanol
(6.5
mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the
title
compound (3.4 mg, 6.0 %).
LC/MS: m/z 499.6 (M+H), r.t: 1.46 min.
Example 20: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-(34 f(trans-4-
hydroxycyclohexyl)aminolmethyl}phenyl)-1 Fl-indole-7-carboxamide
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HO,1,. H
N
N
\ ~ \
N
H
H2N O
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50 mg, 0.114 mmol), trans-4-
aminocyclohexanol
(10 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give
the title
compound (6.0 mg, 9.8 %).
LC/MS: m/z 539.2 (M+H), r.t: 1.54 min.
Example 21: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-{34(ff1-(1-
piperidinyl)cyclohexyllmethyl}amino)methyllphenyl}-1 FNindole-7-carboxamide
ON o_-//
N
N
\ ~ \
N
H
H2N O
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50 mg, 0.114 mmol), 1-[1-(1-
piperidinyl)cyclohexyl]methanamine (17 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg,
0.261
mmol) were reacted to give the title compound (18.7 mg, 27 %).
LC/MS: m/z 620.6 (M+H), r.t: 1.6 min.
Example 22: 341-(ethylsulfonyl)-4-piperidinyll-5-f3-(ff(2S)-2-
hydroxypropyllamino}methyl)phenyll-1 H-indole-7-carboxamide
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HO0
O~ S/
~N
N
N
H
H2N O
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50 mg, 0.114 mmol), (2S)-1-amino-2-
propanol
(6.5 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give
the title
compound (13.1 mg, 23 %).
LC/MS: m/z 499.6 (M+H), r.t: 1.46 min.
Example 23: 5-d3-f(ethylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-
indole-7-carboxamide
O\
HN /~
N
N
H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (20 mg, 0.045 mmol) in dichloromethane (0.5 mL) and methanol (0.5
mL)
was added ethylamine (130 uL, 0.27 mmol). This mixture was stirred for 1 h at
room
temperature, and then sodium borohydride (10 mg, 0.27 mmol) was added. The
reaction
was stirred at ambient temperature overnight, and the solvent was removed
under
reduced pressure. The crude product was purified by reverse phase HPLC
(water/CH3CN, 0.1 % TFA 10-90%) to give the title compound (13.2 mg, 63 %).
LC/MS: m/z 469.4 (M+H), r.t: 1.54 min.
Example 24: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-
f(propylamino)methyllphenyl}-
1 H-indole-7-carboxamide
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O
HN
N
N
H
H2N O
To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (20 mg, 0.046 mmol) in dichloromethane (0.7 mL) and methanol (0.7
mL)
was added propylamine (22 uL, 0.27 mmol) and 1 drop of acetic acid. This
mixture was
stirred for 1 h at room temperature and then sodium borohydride (10 mg, 0.27
mmol) was
added. The reaction was stirred overnight at ambient temperature, and the
solvent was
removed under reduced pressure. The crude product was purified by reverse
phase
HPLC (water/CH3CN, 0.1 % TFA 10-90%) to give the title compound (22.1 mg, 99
%).
LC/MS: m/z 483.2 (M+H), r.t: 1.58 min.
Example 25: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-df(1-
methylethyl)aminolmethyl}phenyl)-1 FNindole-7-carboxamide:
Y O_ ~
S
HN
N ~
N
H
H2N O
Following the general procedure of example 24, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (20 mg, 0.045 mmol), isopropylamine (23
uL,
0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give the title
compound (11.5
mg, 53 %).
LC/MS: m/z 483.2 (M+H), r.t: 1.52 min.
Example 26: 5-(3-f f(1-ethylpropyl)aminolmethyl}phenyl)-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
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H'''
O~\S
\ ~ \
N
H
H2N O
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (20 mg, 0.045 mmol), 3-pentanamine (32
uL,
0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give the title
compound (18.5
mg, 80 %).
LC/MS: m/z 511.4 (M+H), r.t: 1.66 min.
Example 27: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f4-(1-
piperidinylmethyl)phenyll-1 F/-
i ndole-7-carboxamide:
0=S=0
N
VH
O NH2
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (40 mg, 0.09 mmol), piperidine (0.009
mL, 0.09
mmol) and NaBH(OAc)3 (58 mg, 0.27 mmol) were reacted to give the title
compound (8
mg, 17.5 %).
LC/MS: m/z 509.4(M+H), r.t: 1.71 min.
Example 28: 3-f1-(ethylsulfonyl)-4-piperidinyll-
5434(methylamino)methyllphenyl}-
1 H-indole-7-carboxamide
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HN O~~ ~0
N -IS
I / \
N
H
H2N O
Following the general procedure of example 24, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (20 mg, 0.045 mmol), methylamine (130
uL, 0.27
mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give title compound (17.0
mg, 83
%).
LC/MS: m/z 455.2 (M+H), r.t: 1.48 min.
Example 29: 3-f 1-(ethylsulfonyl)-4-piperidinyll-544-(4-
morpholinylmethyl)phenyll-
1H-indole-7-carboxamide
0
O
N N
N
H
H2N O
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(4-
formylphenyl)-1 H-indole-7-carboxamide (50 mg, 0.114 mmol), morpholine (18 uL,
0.206
mmol) and NaBH(OAc)3 (290 mg, 1.37 mmol) were reacted to give the title
compound
(2.1 mg, 13 %).
LC/MS: m/z 511.4 (M+H), r.t: 1.63 min.
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Example 30: 5-f4-(aminomethyl)phenyll-34 1-(ethylsulfonyl)-4-piperidinyll-1 H-
indole-
7-carboxamide
O "S/
NH2 N
/ I
N
H
H2N O
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (30.0
mg, 0.072 mmol), Cs2CO3 (95 mg, 0.290 mmol) and [4-(aminomethyl) phenyl
boronic acid
(55 mg, 0.290 mmol) in dioxane/H20 (1.5 mU0.5 mL) was bubbled argon for 5
minutes
prior to addition of Pd(PPh3)4 (7.5 mg, 0.0072 mmol). The reaction mixture was
heated in
a microwave reactor (Smith synthesizer) for 20 minutes at 160 C. The solvent
was
evaporated, and the residue was partitioned between ethyl acetate and water.
The
organic layer was washed with brine (10 mL), dried over MgSO4, filtered,
concentrated,
and purified by reverse phase HPLC (water/ CH3CN, 0.1 % TFA 10-90%) to give
the title
compound (9.8 mg, 31 %).
LC/MS: m/z 424.4 (M-NH2), r.t: 1.48 min.
Example 31: 5-f3-f(cyclopropylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 F/-indole-7-carboxamide
ly OO
HN
YH
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.113 mmol) in DCM (2 mL) was added cyclopropanamine (19.3
mg, 0.339 mmol). The reaction solution was stirred at ambient temperature for
30 min
prior to addition of HOAc (1 drop) and NaBH(OAc)3 (75 mg, 0.545 mmol). The
resulting
mixture was stirred overnight at ambient temperature after which time the
solvent was
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removed under reduced pressure. The crude product was purified by reverse
phase
HPLC (water/CH3CN, 0.1 % TFA 10-90%) to give the title compound (18.2 mg, 34
%).
LC/MS: m/z 481.2 (M+H), r.t: 1.52 min.
Example 32: 5-f3-f(cyclobutylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
O
HN O jS
N
N
H
H2N O
Following the general procedure of example 31, 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-
formylphenyl)-1 H-indole-7-carboxamide (50 mg, 0.113 mmol), cyclobutanamine
(24.1 mg,
0.339 mmol) and NaBH(OAc)3 (75 mg, 0.545 mmol) were reacted to give the title
compound (19.3 mg, 35 %).
LC/MS: m/z 495.6 (M+H), r.t: 1.55 min.
Example 33: 3-f1-(ethylsulfonyl)-4-piperidinyll-543-f(2-methylpropyl)aminol-
2,3-
dihydro-1 Ftiinden-5-yl}-1 H-indole-7-carboxamide trifluoroacetate
rl-
O
N
O
N F 44
H F
H2N O F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-11--1-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane
(3.0 mL)
and H20 (1.0 mL) was added 6-bromo-2,3-dihydro-1 f/ inden-1-one (274 mg, 1.30
mmol),
and potassium carbonate (360 mg, 2.60 mmol) in a microwave tube. The reaction
mixture was degassed for 5 min before the addition of tetrakis
(triphenylphosphosphine)
palladium (0) (50 mg, 0.043 mmol). The reaction was then heated in the
microwave for
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30 min at 1602 C. The reaction was then filtered and the solid was dissolved
in EtOAc
and H20. The organic layer was separated and concentrated. The crude residue
was
purified by Gilson Preparatory HPLC to yield 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(3-oxo-
2,3-diliydro-1 H-inden-5-yl)-1 H-indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-oxo-2,3-dihydro-1 H-
inden-5-yl)-1 H-
indole-7-carboxamide (45 mg, 0.097 mmol) in EtOH (2 mL) and acetic acid (200
L) was
added 2-methyl-l-propanamine (170 L, 1.93 mmol) and sodium cyanoborohydride
(20
mg, 0.291 mmol). The resulting mixture was reacted in a CEM microwave tube at
150 C
for 40 min. it was then purified by Gilson Preparatory HPLC to give 4.5 mg of
the title
compound (8.9 %).
LC/MS = m/z 523.4 [M+H] Ret. Time: 1.72
Example 34: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f8-I'(2-methylpropyl)aminol-
5,6,7,8-
tetrahydro-2-naphthalenyl)-1 H-indole-7-carboxamide trifluoroacetate
NH 0
N
F o
N
H
HZN O F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane
(3.0 mL)
and H20 (1.0 mL) was added 7-bromo-3,4-dihydro-1(2H)-naphthalenone (292 mg,
1.30
mmol), and potassium carbonate (360 mg, 2.60 mmol) in a microwave tube. The
reaction
mixture was degassed for 5 min before the addition of tetrakis
(triphenylphosphosphine)
palladium (0) (50 mg, 0.043 mmol). The reaction was then heated in the
microwave for
min at 1609 C. The reaction was then filtered and the solid was dissolved in
EtOAc
25 and H20. The organic layer was separated and concentrated. The crude
residue was
purified by Gilson Preparatory HPLC to yield 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-(8-oxo-
5,6,7,8-tetrahydro-2-naphthalenyl)-11-1-indole-7-carboxamide.
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(8-oxo-5,6,7,8-
tetrahydro-2-
naphthalenyl)-1 H-indole-7-carboxamide (40 mg, 0.08 mmol) in EtOH (2 mL) and
acetic
acid (0.2 mL) was added 2-methyl-l-propanamine (140 L, 1.6 mmol) and sodium
cyanoborohydride (15 mg, 0.24 mmol). The resulting mixture was reacted in a
CEM
microwave tube at 1500 C for 40 min. It was then purified by Gilson
Preparatory HPLC to
give 3.2 mg of the title compound (7.5 %).
LC/MS = m/z 537.4 [M+H] Ret. Time: 1.71
Example 35: 5-(5-{f(2-cyanoethyl)aminolmethyll-2-fluorophenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
"O
s--o
N N
N
H
KF H
F O
O
NH2
F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane
(3.0 mL)
and H20 (1.0 mL) was added 3-bromo-4-fluorobenzaidehyde (264 mg, 1.30 mmol),
and
K2CO3 (360 mg, 2.60 mmol) in microwave tube. The reaction mixture was degassed
for 5
min before addition of tetrakis (triphenylphosphosphine) palladium (0) (48 mg,
0.043
mmol). The reaction was heated in a microwave for 30 min at 1609 C. The
organic layer
was separated and concentrated. The residue was dissolved in MeOH until solid
precipitated to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-
formylphenyl)-1 H-
indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-
formylphenyl)-1 H-indole-7-
carboxamide (40 mg, 0.087 mmol) in dichloromethane (2 mL) and methanol (I mL)
was
added 3-aminopropanenitrile (53 L, 0.524 mmol), and 1 drop of acetic acid.
The
reaction mixture was stirred at room temperature for 48 h. Sodium borohydride
(20 mg,
0.524 mmol) was then added and reacted for 30 min at room temperature.
Purified by
Gilson Preparatory HPLC to give 14.4 mg of the title compound (32.4 %).
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CA 02613068 2007-12-20
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LC/MS = m/z 512.2 [M+H] Ret. Time: 1.45
Example 36: 3-f1-(ethylsuifonyl)-4-piperi:dinyll-5-(2-fluoro-5-ff(2,2,2-
trifluoroethyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
pso
N F
r+ F
N F
H
N
H
F
H2N F O
0
F II /\i
F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-
formylphenyl)-1 H-indole-7-
carboxamide (20 mg, 0.04 mmol) in dichloromethane (4 mL) and methanol (2 mL)
was
added 2 drops of acetic acid and 2,2,2-trifluoroethanamine (23 L, 0.26 mmol).
The
resulting mixture was stirred overnight. All solvent was evaporated and
dissolved in
dimethyl sulfoxide (1 mL). Purified by Gilson Preparatory HPLC to give 5.2 mg
of the title
compound (24.0 %).
LC/MS = m/z 541.4 [M+H] Ret. Time. 1.67
Example 37: 3-f1-(ethylsulfonyl)-4-piperidinyIl-5-(1,2,3,4-tetrahydro-7-
isoauinolinyl)-1 H-indole-7-carboxamide trifluoroacetate
0
N
N
N F O
H
H2N O F
F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (60 mg, 0.13 mmol) in dioxane (2
mL) and
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water (1 mL) was added 7-bromo-1,2,3,4-tetrahydroisoquinoline (97 mg, 0.39
mmol) and
potassium carbonate (108 mg, 0.78 mmol). This mixture was degassed for 5 min
before
the addition of tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol).
The
resulting mixture was reacted in a CEM microwave tube at 160 C for 30 min.
The
organic layers were separated and concentrated. The resulting residue was
dissolved in
dimethyl sulfoxide (1 mL) and purified by Gilson Preparatory HPLC to give 3.5
mg of the
title compound (5.7 %).
LC/MS = m/z 467.2 [M+H] Ret. Time. 1.48
Example 38: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-ff(2,2,2-
trifluoroethvl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
HN
0
5,J
F N F-P
F
F O
F
HC p O F OH
z
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (200
mg, 0.483 mmol) in dioxane (3.0 mL) and H20 (1.0 mL) was added (3-
formylphenyl)boronic acid (317 mg, 1.93 mmol), and Cs2CO3 (315 mg, 0.97 mmol)
in a
microwave tube. The reaction mixture was degassed for 5 min before addition of
tetrakis
(triphenylphosphosphine) palladium (0) (48 mg, 0.043 mmol). The reaction was
heated in
a microwave for 30 min at 160 C. The organic layer was separated and
concentrated.
The residue was dissolved in MeOH until solid precipitated to yield 3-[1-
(ethylsulfonyl)-4-
piperidinyl]-5-(3-formylphenyl)-1 H-indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-
indole-7-
carboxamide (40 mg, 0.09 mmol) and 2,2,2-trifluoroethylamine (78 L, 0.55
mmol) in
dichloromethane (2 mL) and methanol (1 mL) was added 2 drops of acetic acid.
The
mixture was then stirred overnight. Sodium borohydride (20.8 mg, 0.55 mmol)
was then
added and the mixture was stirred for 30 min. The resulting mixture was
concentrated
and dissolved in dimethyl sulfoxide followed by purification by Gilson
Preparatory HPLC
to give 29.4 mg of the title compound (62.5%).
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CA 02613068 2007-12-20
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LC/MS = m/z 523.2 [M+H] Ret. Time. 1.66
Example 39: 5-(3-{f(2-amino-2-oxoethyl)(methyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-I'ndole-7-carboxamide trifluoroacetate
0
H2N-~ O\ O
N
SCH3
H2C YN,! i
F
O
F
H2N 0
F OH
To a solution 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (44 mg, 0.1 mmol) and N2-methylglycinamide (76 mg, 0.6 mmol) in
dichloromethane (3 mL) and methanol (1.5 mL) was added 3 drops of acetic acid.
The
mixture was stirred overnight. Sodium triacetoxyborohydride (134 mg, 0.6 mmol)
was
then added and stirred overnight. The resulting reaction was quenched with
sodium
biocarbonate (2 mL) and brine (2 mL). Organic layer was then collected and
concentrated. The resulting residue was then purified by Gilson Preparatory
HPLC to
give 13 mg of the title compound (25.4 %).
LC/MS = m/z 512.6 [M+H] Ret. Time. 1.20
Example 40: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(2-ff(2,2,2-
trifluoroethyl)aminolmethyl}-1,3-thiazol-4-yl)-1 H-indole-7-carboxamide
trifluoroacetate
O\~ S
" H~
F
p S\N
N F F
F O
F+~
N F OH
H NH2
O
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CA 02613068 2007-12-20
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To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM
(4.0
mL) was added acetic acid (3 drops) and 2,2,2-trifluoroethanamine (120 pL, 1.5
mmol).
The reaction was stirred overnight. Sodium triacetoxyborohydride (335 mg, 1.5
mmol)
was then added and reaction was stirred for 6 h. It was then quenched with
sodium
bicarbonate to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-1/-l-indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2
mL) and
water (0.7 mL) was added N-[(4-bromo-1,3-thiazol-2-yl)methyl]-2,2,2-
trifluoroethanamine
(30 mg, 0.11 mmol) and potassium carbonate (83 mg, 0.6 mmol). The resulting
mixture
was degassed for 5 min before the addition of
tetrakis(triphenylphosphine)palladium(0)
(11 mg, 0.01 mmol). The mixture was reacted in a CEM microwave tube at 160 C
for 20
min. Organic layers were separated and concentrated. The resulting residue was
purified by Gilson Preparatory HPLC to give 25 mg of the title compound
(47.2%).
LC/MS = m/z 530.2 [M+H] Ret. Time. 1.94
Example 41: 5-(3-cyano-5-M2,2,2-trifluoroethyl)aminolmethyllphenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
H3C N
\\
S\ F F
N N~F
F 0
H F-H
O NH2 F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborofan-2-yl)-1 H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2.0
mL, 0.7
mL) was added 3-bromo-5-formylbenzonitrile (68 mg, 0.3 mmol) and K2CO3 (83 mg,
0.6
mmol) in a microwave tube. The reaction mixture was degassed for 5 min before
addition
of tetrakis (triphenylphosphosphine) palladium (0) (11 mg, 0.01 mmol). The
reaction was
heated in a microwave for 20 min at 160 C. It was then purified by Gilson
Preparatory
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HPLC to give 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide.
To a solution of 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-
carboxamide (52 mg, 0.11 mmol) in dichloromethane (3 mL) and methanol (1 mL)
was
added 20 drops of acetic acid and 2,2,2-trifluoroethanamine (53 L, 0.66
mmol). The
mixture was stirred for 48 h followed by addition of sodium
triacetoxyborohydride (140
mg, 0.66 mmol). The mixture was then stirred for 48 h. The resulting reaction
was
quenched with sodium biocarbonate and brine was added. The organic layer was
separated and purified by Gilson Preparatory HPLC to give 3.6 mg of the title
compound
(6.0 %).
LC/MS = m/z 548.2 [M+H] Ret. Time. 1.88
Example 42: 3-f1-(ethylsulfonyl)-4-pi.peridinyll-5-(54 finethyl(1-methyl-4-
piperidinyl)aminolmethyl}-3-thienyl)-1 M-indole-7-carboxamide trifluoroacetate
o~
o::::S--\
N
S
N
I \ ~
O H
F I '
F pH 0 NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-
indole-7-
carboxamide (50 mg, 0.11 mmol) in dimethyl sulfoxide (2 mL) was added N,1-
dimethyl-4-
piperidinamine (128.22 mg, 1.0 mmol), 2 drops of acetic acid and reacted
overnight.
Sodium triacetoxyborohydride (212 mg, 1 mmol) was then added and reacted
overnight
at room temperature. It was then purified by Gilson Preparatory HPLC to give 8
mg of the
title compound (13.0 %).
LC/MS = m/z 558.4 [M+H] Ret. Time: 1.32 min
Example 43: 5-(5-df(2-cyanoethyl)(methyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 F/-indole-7-carboxamide trifluoroacetate
113

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O\
N
S
NN
CH3
F
+~o H
F OH 0 NHz
The title compound was prepared according to the general procedure for 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-
piperidinyl)amino]methyl}-3-thienyl)-
1 H-indole-7-carboxamide trifluoroacetate, substituting
3-(methylamino)propanenitrile (84.12 mg, 1.0 mmol) for N,1-dimethyl-4-
piperidinamine to
afford 24 mg of the title compound (42.5 %).
LC/MS = m/z 514.4 [M+H] Ret. Time: 1.55 min
Example 44: 5-(5-{f(2-amino-2-oxoethyl)(methyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
0
F 0 II /
j O=S~/
F N
~H g
~N
0y,
NHZ H
0 NH2
The title compound was prepared according to the general procedure for 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-
piperidinyl)amino]methyl}-3-thienyl)-
1 H-indole-7-carboxamide trifluoroacetate, substituting
N'-methylglycinamide (88.11 mg, 1.0 mmol) for N,1-dimethyl-4-piperidinamine to
afford
19 mg of the title compound (33.3 %).
LC/MS = m/z 518.2 [M+H] Ret. Time: 1.43 min
Example 45: 341-(ethylsulfonyl)-4-piperidinyll-5-f5-(f methylf2-
(phenylsulfonyl)ethyllamino}methyl)-3-thienvll-1 H-indole-7-carboxamide
trifluoroacetate
114

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0
/
11
0=s~/
N
s
~~ N
F I
F OH / I
I
0= N
S;0 H
0 NHZ
The title compound was prepared according to the general procedure for 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-
piperidinyl)amino]methyl}-3-thienyl)-
1 H-indole-7-carboxamide trifluoroacetate, substituting N-methyl-2-
(phenylsulfonyl)ethanamine (199.27 mg, 1.0 mmol) for N,1-dimethyl-4-
piperidinamine to
afford 30 mg of the title compound (47.3 %).
LC/MS = m/z 629.4 [M+H] Ret. Time: 1.57 min
Example 46: 341-(ethylsulfonyl)-4-piperidinyll-5-{5-f(2-phenyl-l-
pyrrolidinyl)methyll-3-thienyl}-1 Fl-indole-7-carboxamide
0
I \ ii
o=s-J
N
S
N
I \ ~
N
H
0 NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2-phenylpyrrolidine
(147
mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 120 C
for 10
min. Sodium triacetoxyborohydride (220 mg, 1.0 mmol) was then added and the
reaction
was reacted at room temperature overnight. It was then purified by Gilson
Preparatory
HPLC to give 14.0 mg of the title compound (22 %).
LC/MS = m/z 577.2 [M+H] Ret. Time: 1.65 min.
Example 47: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-df2-(1-piperidinylmethyl)-
1-
pyrrolidinyllmethyl}-3-thienyl)-1 H-indole-7-carboxamide
115

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O
I I /
O=S/
N N
s
N
I \ ~
N
H
O NH2
The title compound was prepared according to the general procedure for 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-indole-7-
carboxamide, substituting 1-(2-pyrrolidinylmethyl)piperidine (168.3 mg, 1.0
mmol) for 2-
phenylpyrrolidine to afford 21 mg of the title compound (32 %).
LC/MS = m/z 598.4 [M+H] Ret. Time: 1.34
Example 48: 5-(5-ff(2R)-2-(aminocarbonyl)-1-pyrrolidinyllmethyl}-3-thienyl)-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
O
I I /
O=S-/
H2N~~0 N
S
N
H
D NH2
The title compound was prepared according to the general procedure for 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-indole-7-
carboxamide, substituting D-prolinamide (114 mg, 1.0 mmol) for 2-
phenylpyrrolidine to
afford 14 mg of the title compound (23 %).
LC/MS = m/z 544.2 [M+H] Ret. Time: 1.39
Example 49: 5-(5-df(3S)-3-(dimethylamino)-1-pyrrolidinyilmethyl}-3-thienyl)-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
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0 /Chiral
O=S_/
N
S
N \ ~
I \ ~
N
N
H
0 NH2
The title compound was prepared according to the general procedure for 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-indole-7-
carboxamide, substituting (2R)-N,N-dimethyl-2-pyrrolidinamine (114 mg, 1.0
mmol) for 2-
phenylpyrrolidine to afford 11 mg of the title compound (18 %).
LC/MS = m/z 544.2 [M+H] Ret. Time: 1.36
Example 50: 5-(1-f2-f4-(dimethylamino)-1-piperidinyllethyl)-1 H-pyrazol-4-yl)-
3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
Q-
\ S=0
N N N
N
F 0 N~
F
F OH I \ ~
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane
(750 pL)
and H20 (250 pL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-l-
(2-
chloroethyl)-1 H-pyrazole (26 mg, 0.126 mmol). The reaction mixture was
flushed under
Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0)
(5 mg, 0.004
mmol). The reaction was heated in a microwave at 120 C for 20 min. It was
then diluted
with EtOAc (10 mL), filtered thru celite, followed by an aqueous work-up. The
compound
was purified by Gilson Preparatory HPLC to give 10 mg of 5-[1-(2-chloroethyl)-
1H-
pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide
(24%).
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To a solution of 5-[1-(2-chloroethyl)-1 H-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide (33 mg, 0.071 mmol) in tetrahydrofuran (500 uL) was added
N,N-
dimethyl-4-piperidinamine (100 pL,0.71 mmol) and Sodium Iodide (5 mg, 0.018
mmol).
The resulting mixture was reacted in a microwave tube at 130 C for 2 h.
Performed
aqueous wash with EtOAc and water, isolated organic layers and removed all
solvent. It
was then purified by Gilson Preparatory HPLC to give 7.0 mg of the title
compound (14.7
LC/MS = m/z 556 [M+H] Ret. Time: 1.23 min.
Example 51: 5-f3-f(dimethylamino)methyll-4,5-bis(methyloxy)phenyll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
O-~
N
O
I I
/N \ I \ \
N
H
O NHZ
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (500 mg, 1.09 mmol) in dioxane
(9.0 mL)
and H20 (3.0 mL) was added sodium carbonate (690 mg, 6.51 mmol), and 5-bromo-
2,3-
bis(methyloxy)benzaldehyde (7.95 mg, 3.25 mmol). The reaction mixture was
flushed
under Argon for 10 min before addition of
tetrakis(triphenylphosphine)palladium (0) (63
mg, 0.054 mmol). The reaction was then heated in a microwave at 120 C for 30
min. All
solvent was then concentrated and an aqueous wash was performed with EtOAc and
H20. The desired compound then percipiated and was filtered to give 322 mg of
3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4,5-bis(methyloxy)phenyl]-1 H-
indole-7-
carboxamide (59%).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4,5-
bis(methyloxy)phenyl]-
1 H-indole-7-carboxamide (30 mg, 0.06 mmol) in methanol (2 mL), zinc chloride
(5 mg,
0.03 mmol), sodium cyanoborohydride (5 mg, 0.06 mmol) and dimethylamine (100
pL,
0.30 mmol). The mixture was stirred at room temperature for 2 h then reacted
in the
microwave at 100 C for 30 min. The resulting mixture was purified by Gilson
Preparatory
HPLC to give 11 mg of the title compound (34.7 %).
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LC/MS = m/z 529 [M+H] Ret. Time: 1.67 min.
Example 52: 5-f3,4-bis(methyloxy)-5-(4-morpholinylmethyl)phenyll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
S
N \O
N
Jr O NHz
The title compound was prepared according to the general procedure of 5-[3-
[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide, substituting morpholine (20 pL, 0.30 mmol) for
dimethylamine to
afford 8.0 mg of the title compound (23.4 %).
LC/MS = m/z 571 [M+H] Ret. Time: 1.59 min.
Example 53: 3-f1-(ethylsulfonyl)-4-piperidinyll-543-{f(1-
methylethyl)aminolmethyl}-
4,5-bis(methyloxy)phenyll-1 H-indole-7-carboxamide
O.~
S,
N~O
O
N
H
O NHZ
The title compound was prepared according to the general procedure of 5-[3-
[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide, substituting 2-propanamine (20 pL, 0.30 mmol) for
dimethylamine
to afford 15 mg of the title compound (46.1 %).
LC/MS = m/z 543 [M+H] Ret. Time: 1.59 min.
Example 54: 341-(ethylsulfonyl)-4-piperidinyll-5434 f(1-
methvlethyl)aminolmethyl}-
4,5-bis(methyloxy)phenyll-1 H-indole-7-carboxamide
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o' )
s
N
O
H
I ~ ~
N
H
O NHZ
The title compound was prepared according to the general procedure of 5-[3-
[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide , substituting 40 wt. % methylamine (50 pL, 0.30 mmol)
for
dimethylamine to afford 6 mg of the title compound (19.4 %).
LC/MS = m/z 515 jM+HJ Ret. Time: 1.46 min.
Example 55: 5-f3-{f(2,2-dimethylpropyl)aminolmethyl}-4 5-bis(methyloxy)pheny11-
3-
r1-(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
O~
N
O
N
N
H
O NHz
The title compound was prepared according to the general procedure of 5-[3-
[(dimethylamino)methyl]-4,5-bis(methy)oxy)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide , substituting (2,2-dimethylpropyl)amine (20 uL, 0.30
mmol) for
dimethylamine to afford 10 mg of the title compound (29.2 %).
LC/MS = m/z 571 [M+H] Ret. Time: 1.75 min.
Example 56: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-f3-{f (2-
hydroxyethyl)(methyl)aminolmethvl}-4,5-bis(methyloxy)phenyll-1 H-indole-7-
carboxamide
120

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O,~
N S\O
O
N
S N
HO H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide , substituting 2-(methylamino)ethanol (20 pL, 0.30 mmol)
for
dimethylamine to afford 10 mg of the title compound (29.8 %).
LC/MS = m/z 559 [M+H] Ret. Time: 1.54 min.
Example 57: 5-f3,4-bis(methyloxy)-5-(1-pyrrolidinylmethyl)phenyll-3-f1-
(ethylsulfonyl)-4-piperidinyil-1 H-indole-7-carboxamide
S
N \0
I \ ~
N
H
O NHZ
The title compound was prepared according to the general procedure of 5-[3-
[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide , substituting pyrrolidine (50 pL, 0.30 mmol) for
dimethylamine to
afford 13 mg of the title compound (39.1 %).
LC/MS = m/z 555 [M+H] Ret. Time: 1.61 min.
Example 58: 5-f4-f(dimethylamino)methyll-2,3-dihydro-l-benzofuran-6-yl}-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
121

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O~
s
, --O
O N
~I \ I \
N
H
O NHz
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (113
mg, 0.274 mmol) in dioxane (9.0 mL) and H20 (3.0 mL) was added sodium
carbonate
(174 mg, 1.64 mmol), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-
dihydro-l-
benzofuran-4-carbaidehyde (150 mg, 0.547 mmol). The reaction mixture was
flushed
under Argon for 10 min before addition of
tetrakis(triphenylphosphine)palladium (0) (16
mg, 0.014 mmol). The reaction was heated in a microwave at 120 C for 30 min.
All
solvent was then concentrated and purified by flash chromatography using DCM
and
MeOH to give 120 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2,3-
dihydro-l-
benzofuran-6-yl)-1 H-indole-7-carboxamide (91 %).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2,3-dihydro-l-
benzofuran-6-
yl)-1 f-l-indole-7-carboxamide (20 mg, 0.042 mmol) in methanol (2 mL) was
added
dimethylamine (3 pL ,0.050 mmol), zinc chloride (3 mg, 0.021 mmol) and sodium
cyanoborohydride (4 mg, 0.062 mmol). This mixture was reacted in the microwave
at
100 C for 1 h and then removed all solvent. The residue was washed with EtOAc
and
water. All solvent was removed and purified by Gilson Preparatory HPLC to give
6.0 mg
of the title compound (19.6 %).
LC/MS = m/z 525 [M+H] Ret. Time: 1.56 min.
Example 59: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(4-{f(1-
methylethyl)aminolmethyl}-
2,3-dihydro-l-benzofuran-6-yl)-1 H-indole-7-carboxamide
O~
O
0
~N \ \
N
H
O NHZ
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The title compound was prepared according to the general procedure of 5-{4-
[(dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide , substituting 2-propanamine (3 mg ,0.050 mmol) for
dimethylamine to afford 9.0 mg of the title compound (28.6 %).
LC/MS = m/z 511 [M+H] Ret. Time: 1.58 min.
Example 60: 3-f 1-(ethylsulfonyl)-4-piperidinyll-54444-morpholinylmethyl)-2,3-
dihvdro-l-benzofuran-6-yll-1 H-indole-7-carboxamide
O",/
S
,--0
O N
N I
I
N
H
O NHz
The title compound was prepared according to the general procedure of 5-{4-
[(dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-(ethylsulfonyl)-4-
piperidinyl]-
1 H-indole-7-carboxamide, substituting 2,2-dimethyl-1 -propanamine (4 mg,
0.050 mmol)
for dimethylamine to afford 8.0 mg of the title compound (24.1 %).
LC/MS = m/z 554 [M+H] Ret. Time: 1.71 min.
Example 61: 341-(ethylsulfonyl)-4-piperidinyll-545-({f 1-methyl-2-
(methyloxy)ethyllamino}methyl)-2-thienyll-1 /+indole-7-carboxamide
o; o
N
H3Ci\
O-~_H
N ~ I
H3C s
\ I \
N
H
HZN O
[5-({[1-methyl-2-(methyloxy)ethyl]amino}methyl)-2-thienyl]baronic acid (60 mg,
0.262
mmol) was transferred to a CEM microwave tube with methanol. The methonol was
evaporated under a stream of N2. To this was added 5-bromo-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-11--/-indole-7-carboxamide (80 mg, 0.19 mmol), potassium
carbonate (160mg,
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1.16 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol),
dioxane (1.5
mL), and water (0.5 mL). The vial was capped and reacted in a CEM microwave at
1500
C for 30 min. This solution was loaded onto a 2 g SCX SPE cartridge primed
with 3 mL
of methanol. The cartidge was then sequentially eluted with water (3 mL),
methanol (9
mL), and 2M NH3 in MeOH (6 mL). The NH3 in MeOH fractions were dried under a
stream of N2 at 40 C. The crude product was taken up in dimethyl sulfoxide (1
mL) and
purified on an Agilent MDAP with UV (230 nm) and MS detection. The desired
fractions
were passed thru two sequential 500 mg Pharmasil CHQAX cartridge primed with 1
mL of
methanol and 1 mL of water. The solvents were evaporated under a stream of N2
at 60
C to give 34.7 mg of the title compound (34 %).
LC/MS = m/z 430 [M+H] Ret. Time: 1.32 min.
Example 62: 5-(54 f(2-cyanoethyl)aminolmethyl}-3-pyridinyl)-341-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
o S o
N
N
N
~ N
H
H2N O
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (30
mg, 0.072
mmol) was added 3-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-
pyridinyl]methyl}amino)propanenitrile (24.8 mg, 0.086 mmol). To this mixture
was added
dioxane (0.75 mL), followed by a solution of potassium carbonate (60 mg, 0.434
mmol) in
water (0.25 mL) and SK-CC02-A (4.4 mg, 0.007 mmol). The vials were capped and
reacted in a CEM microwave at 150 C for 30 min. The reaction was loaded onto
a 2 g
SCX SPE cartidge primed with 3 mL of methanol. The cartridge was then
sequentially
eluted with water (3 mL), methanol (9 mL), and 2M NH3 in MeOH (6 mL). The NH3
in
MeOH fractions were dried under a stream of N2 at 40 C. The crude product was
purified on the Agilent MDAP with UV (230 nm) and MS detection. The desired
fractions
were passed thru a 5 g CHQAX cartridge primed with 4 mL of methanol and 4 mL
of
water. The solvents were evaporated under a stream of N2 at 65 C to give 6.2
mg of the
title compound (17.4 %).
LC/MS = m/z 495 [M+H] Ret. Time: 1.29 min.
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Example 63: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-f f(2,2,2-
trifluoroethyl)aminolmethyl}-3-pyridinyl)-1 H-indole-7-carboxamide
o; o
N
N
F F
Y-1-1N
F
N
H
H2N O
The title compound was prepared according to the general procedure of 5-(5-
{[(2-
cyanoethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide, substituting 2,2,2-trifluoro-N-{[5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-
yl)-3-pyridinyl]methyl}ethanamine (24.3 mg, 0.077 mmol) for 3-({[5-(4,4,5,5-
tetramethyl-
1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amino)propanenitrile to afford 8.3
mg of the
title compound (22.0 %).
LC/MS = m/z 524 [M+H] Ret. Time: 1.55 min.
Example 64: 5-13-f(dimethylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-
1 H-indole-7-carboxamide
0
N
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (45 mg, 0.10 mmol) in DMSO (2 mL) was added 2 M dimethylamine in
THF
(500 pL ,1.0 mmol). The reaction mixture was stirred at room temperature for 5
h before
addition of sodium triacetoxyborohydride (220 mg, 1.04 mmol). The reaction was
then
stirred overnight. Compound was purified by Gilson Preparatory HPLC to give
9.0 mg of
the title compound (19.2 %).
LC/MS = m/z 469 [M+H] Ret. Time: 1.55 min
125

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Example 65: 5-(54 fethyl(methyl)aminolmethyl}-3-thienyl)-3-f1-(ethylsulfonyl)-
4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O~
o=S'\
N
S
/-N \
F O
FI~ H
F OH
0 NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.11 mmol) in dimethyl sulfoxide (2 mL) was added N-
methylethanamine (59.1 mg, 1.0 mmol), 2 drops of acetic acid and reacted
overnight.
Sodium triacetoxyborohydride (212 mg, 1 mmol) was then added and reacted
overnight
at room temperature. It was then purified by Gilson Preparatory HPLC to give
20.0 mg of
the title compound (33.2 %).
LC/MS = m/z 489 [M+H] Ret. Time: 1.50 min
Example 66: 5-(5-fff2-(diethylamino)ethyll(methyl)aminolmethyl}-3-thienyl)-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O\
o=,s'\
N
S
/-N--N \
F O N
H
F
F OH 0 NH2
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-11-
/-indole-7-
carboxamide trifluoroacetate , substituting N,N-diethyl-N-methyl-1,2-
ethanediamine (130
mg, 1.0 mmol) for N-methylethanamine to afford 30.0 mg of the title compound
(44.5 %).
LC/MS = m/z 560 [M+H] Ret. Time: 1.41 min.
126

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Example 67: 5-(54 fbutyl(methyl)aminolmethyl}-3-thienyl)-3-f1-(ethylsulfonyl)-
4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
o=s~
N
S
N
xl-~ \ I
F H
~O N
F OH O NH2
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting butyl(methyl)amine (87 mg, 1.0
mmol) for N-
methylethanamine to afford 10 mg of the title compound (15.8 %).
LC/MS = m/z 517 [M+H] Ret. Time: 1.61 min.
Example 68: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-
{finethyl(propyl)aminolmethyl}-
3-thienyl)-1l+indole-7-carboxamide trifluoroacetate
o~
~
N
s
F O N
F H
F OH O NHz
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate, substituting methyl(propyl)amine (73 mg, 1.0
mmol) for IV
methylethanamine to afford 20.0 mg of the title compound (32.4 %).
LC/MS = m/z 503 [M+H] Ret. Time: 1.54 min.
Example 69: 5-(5-{Tf2-(dimethylamino)ethyll(methyl)aminolmethyl}-3-thienyl)-3-
f 1-
(ethyisulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
127

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O
O~S--\
N
S
\ \ / \
F p H
F OH 0 NH2
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting [2-
(dimethylamino)ethyl]methylamine (102 mg,
1.0 mmol) for N-methylethanamine to afford 26.0 mg of the title compound (40.3
%).
LC/MS = m/z 532 [M+H] Ret. Time: 1.48 min.
Example 70: 5-(5-fff3-(dimethylamino)propyll(methyl)aminolmethyl}-3-thienyl)-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O\
O~S--\
N
SN S
'-N
\ ~
I ~iO
F--~-~( H
F \ LH2
IF 'OH
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting [3-
(dimethylamino)propyl]methylamine (116
mg, 1.0 mmol) for N-methylethanamine to afford 21.0 mg of the title compound
(31.8 %).
LC/MS = m/z 546 [M+H] Ret. Time: 1.49 min.
Example 71: 5-(5-ffcyclopentyl(methyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-
4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
128

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O~
N
s
N \ \ / \
F O
F-H H
F OH
O NH2
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting cyclopentyl(methyl)amine (99 mg,
1.0 mmol)
for N-methylethanamine to afford 5.0 mg of the title compound (7.78 %).
LC/MS = m/z 529 [M+H] Ret. Time: 1.65 min.
Example 72: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(54
finethyl(pentyl)aminolmethyl}-
3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate
O\
o;s'\
N
S
N \ ~
F 0
N
F
H
F OH
O NH2
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting methyl(pentyl)amine (101 mg, 1.0
mmol) for N-
methylethanamine to afford 19.0 mg of the title compound (29.5 %).
LC/MS = m/z 531 [M+H] Ret. Time: 161 min.
Example 73: 3-f1-(ethylsulfonyl)-4-piperidinvll-5-(5-f finethyl(2-
methylpropyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
129

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O~
O5~S--\
N
s
N
~ \ I \ ~
F H
~O N
F OH O NH2
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting methyl(2-methylpropyl)amine (87
mg, 1.0
mmol) for N-methylethanamine to afford 3.0 mg of the title compound (4.8 %).
LC/MS = m/z 517 [M+H] Ret. Time: 1.61 min.
Example 74: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-
dfinethyl(phenylmethyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
O
O=S__/
N
S
N
I \ ~
O H
F
F OH O NHz
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1I1 indole-7-
carboxamide trifluoroacetate , substituting methyl(phenylmethyl)amine (121 mg,
1.0
mmol) for N-methylethanamine to afford 15 mg of the title compound (22.6 %).
LC/MS = m/z 551 [M+H] Ret. Time: 1.67 min.
Example 75: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-ff(2-
hydroxyethyl)(methyl)aminolmethyl}-3-thienyl)-1 Ff-indole-7-carboxamide
trifluoroacetate
130

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F O O
F-F< O =S
F OH N
S
N
I \ ~
OH N
H
O NH2
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting 2-(methylamino)ethanol (75 mg, 1.0
mmol) for
N-methylethanamine to afford 27.0 mg of the title compound (43.6 %).
LC/MS = m/z 505 [M+H] Ret. Time: 1.46 min.
Example 76: 3-f1-(ethylsuifonyl)-4-piperidinyil-5-f5-({methylf2-(2-
pyridinyl)ethyllamino}methyl)-3-thienyll-1H-indole-7-carboxamide
trifluoroacetate
ii
o-s,/
N
s
N
I
, N
N H
0 NH2
O
F44
F OH
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-11-
f-indole-7-
carboxamide trifluoroacetate , substituting methyl [2- (2-pyridi nyl) ethyl]
am i ne (75 mg, 1.0
mmol) for N-methylethanamine to afford 5.0 mg of the title compound (7.36 %).
LC/MS = m/z 566 [M+H] Ret. Time: 1.59 min.
Example 77: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-f f(2-
furanylmethyl)(methyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
131

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O
11 /
O=S-/
N
s
N
O ~ N
\ F O H
F-H O NH2
F OH
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting 1-(2-furanyl)-N-methylmethanamine
(111 mg,
1.0 mmol) for N-methylethanamine to afford 19.0 mg of the title compound (29.0
%).
LC/MS = m/z 541 [M+H] Ret. Time: 1.59 min.
Example 78: 3-f1-(ethylsulfonyi)-4-piperidinyll-5-(54 finethyl(4-
pyridinyimethyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
0
n
O=S-/
N
S
N
I \ ~
~
~
N / F O H
F--~--~( 0 NHz
IF 'OH
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting methyl(4-pyridinylmethyl)amine
(122 mg, 1.0
mmol) for N-methylethanamine to afford 31.0 mg of the title compound (46.6 %).
LC/MS = m/z 552 [M+H] Ret. Time: 1.37 min.
Example 79: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f 5-f(methylf fl -(1 -
methylethyl)-3-
pyrrolidinyllmethyl}amino)methyll-3-thienyl}-11-f-indole-7-carboxamide
trifluoroacetate
132

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O
O=S--/
N
S
N
I \ ~
N
N H
F ,.O
F II_/\/ O NH2
F OH
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting methyl{[1-(1-methylethyl)-3-
pyrrolidinyl]methyl}amine (156 mg, 1.0 mmol) for N-methylethanamine to afford
21.0 mg
of the title compound (30.0 %).
LC/MS = m/z 586 [M+H] Ret. Time: 1.43 min.
Example 80: 341-(ethylsulfonyl)-4-piperidinyll-5-(54 finethyl(2-
thienyimethyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
O
O S__/
N
S
N
~
~ S F
O H
F O NH2
F OH
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting methyl(2-thienylmethyl)amine (127
mg, 1.0
mmol) for N-methylethanamine to afford 26.0 mg of the title compound (38.8 %).
LC/MS = m/z 557 [M+H] Ret. Time: 1.72 min.
Example 81: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-(dmethylfl-(2-
thienyl)ethyllaminolmethyl)-3-thienyll-1 H-indole-7-carboxamide
trifluoroacetate
133

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OOS__I/
N
S
Cs N\ I \ ~
N
F O H
F O NHZ
F OH
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting methyl[1-(2-thienyl)ethyl]amine
(141 mg, 1.0
mmol) for N-methylethanamine to afford 6.0 mg of the title compound (8.76 %).
LC/MS = m/z 571 [M+H] Ret. Time: 1.78 min.
Example 82: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-ffinethyi(3-
thienylmethyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
o
O S
N
S Isi
\
F 0 N
F H
F OH O NH2
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino}methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting methyl(3-thienylmethyl)amine (127
mg, 1.0
mmol) for N-methylethanamine to afford 7.0 mg of the title compound (10.4 %).
LC/MS = m/z 557 [M+H] Ret. Time: 1.78 min.
Example 83: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-ffinethyl(tetrahydro-2H-
pyran-4-
ylmethyl)aminolmethyll-3-thienyl)-1 M indole-7-carboxamide trifluoroacetate
134

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O
O--/
N
O
S
I
N I
F N
O H
F O NH2
F OH
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting methyl(tetrahydro-2H-pyran-4-
ylmethyl)amine
(129 mg, 1.0 mmol) for N-methylethanamine to afford 11.0 mg of the title
compound (16.4
%).
LC/MS = m/z 559 [M+H] Ret. Time: 1.63 min.
Example 84: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(54 finethyl(3-
pyridinylmethyl)aminolmethyl}-3-thienyl)-1H-indole-7-carboxamide
trifluoroacetate
O
o ~S
N
N
S
F O H
F O NH2
F OH
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
111 indole-7-
carboxamide trifluoroacetate , substituting methyl(3-pyridinylmethyl)amine
(122 mg, 1.0
mmol) for N-methylethanamine to afford 9.5 mg of the title compound (14.3 %).
LC/MS = mlz 552 [M+H] Ret. Time: 1.56 min.
Example 85: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-{finethyl(4-
pyrimidinylmethyl)aminolmethyl}-3-thienyl)-1 F/-indole-7-carboxamide
trifluoroacetate
135

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O
N
N-
/N S
\
F O N
~ H
F O NH2
F OH
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate , substituting methyl(4-pyrimidinylmethyl)amine
(123 mg, 1.0
mmol) for N-methylethanamine to afford 4.0 mg of the title compound (6.0 %).
LC/MS = m/z 555 [M+H] Ret. Time: 1.65 min.
Example 86: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-f5-(finethylf2-
(methyloxy)ethyllamino}methyl)-3-thienyil-1/+indole-7-carboxamide
trifluoroacetate
0
N
S
O--\,_ \
F-H H
O
F OH O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-11-
-1-indole-7-
carboxamide (884 mg, 1.98 mmol) in dimethyl sulfoxide (5 mL) was added
methyl[2-
(methyloxy)ethyl]amine (1.86 g, 21 mmol) and HOAc (2 mL, 35 mmol). The
reaction was
stirred overnight at room temperature, and sodium triacetoxyborohydride (212
mg, 1
mmol) was added. Stirring continued for 1 hr, and CHCI3 (50 mL) was added. The
mixture was filtered, the CHCI3 was concentrated under reduced pressure, and
the crude
product/dmso solution was purified by Gilson Prepatory HPLC to give the title
compound
(590 mg, 47%).
LC/MS = m/z 519 [M+H] Ret. Time: 1.50 min.
136

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Example 87: 5-f3-f(dimethylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyil-
1 FI-indole-7-carboxamide trifluoroacetate
F p
0
F-H OH ~ O
F ~SJ
N~ N
\ \ ~
N
H
0 NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (45 mg, 0.1 mmol) in DMSO (2 mL) was added 2 M methylamine in THF
(500 pL, 1.0 mmol) and stirred at room temperature for 5 h. To the mixture,
was then
added sodium triacetoxyborohydride (220 mg, 1.0 mmol) and stirred overnight.
It was
then purified by Gilson Preparatory HPLC to give 9.0 mg of the title compound
(15.4 %).
LC/MS = m/z 469 [M+H] Ret. Time: 1.55 min.
Example 88: 341-(ethylsulfonyl)-4-piperidinyll-5-(54 finethyl(1-
methylethyl)aminolmethyl}-3-thienyl)-1 FNindole-7-carboxamide trifluoroacetate
o\
o=s~/
N
s
N
A
I
-I/ H
FI \
F OH O NH
z
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (46.0 mg, 0.1 mmol) in DMSO (2.0 mL) was added N-methyl-2-
propanamine (73.1 mg, 1.0 mmol). The reaction mixture was then reacted in a
microwave at 160 C for 10 min. Sodium triacetoxyborohydride (220 mg, 1.0
mmol) was
then added and the reaction was reacted at room temperature overnight. It was
then
purified by Gilson Preparatory HPLC to give 24.0 mg of the title compound
(44.2 %).
LC/MS = m/z 543 [M+H] Ret. Time: 1.70 min.
137

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Example 89: 3-f1-(ethylsulfonyl)-4-piperidinyIl-545-f(2-propyl-1-
pyrrolidinyl)methyll-
3-thienyl}-1 H-indole-7-carboxamide
O
O=S
N
S
N
I \ ~
N
H
O NHz
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2-propylpyrrolidine
(113
mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 1200 C
for 10
min. Sodium triacetoxyborohydride (220 mg, 1.0 mmol) was then added and the
reaction
was reacted at room temperature overnight. It was then purified by Gilson
Preparatory
HPLC to give 21.0 mg of the title compound (38.7 %).
LC/MS = m/z 543 [M+H] Ret. Time: 1.70 min.
Example 90: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-{f2-(3-pyridinyl)-1-
pyrrolidinyllmethyl}-3-thienyl)-1 H-indole-7-carboxamide
O
II /
O=S
N
S
N
I \ ~
N
H
O NHz
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-indole-7-
carboxamide , substituting 3-(2-pyrrolidinyl)pyridine (148 mg, 1.0 mmol) for 2-
propylpyrrolidine to afford 13.0 mg of the title compound (22.5 %).
LC/MS = m/z 578 [M+H] Ret. Time: 1.52 min.
138

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Example 91: 5-(5-ff2-(1,1-dimethylethyl)-1-pyrrolidinyllmethyl}-3-thienyl)-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 F/-indole-7-carboxamide trifluoroacetate
0
ii
o=S~
N
F S
N \ I \ ~
F
O H
F OH o NHZ
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 I I indole-7-
carboxamide , substituting 2-(1,1-dimethylethyl)pyrrolidine (127 mg, 1.0 mmol)
for 2-
propylpyrrolidine to afford 11.0 mg of the title compound (16.4 %).
LC/MS = m/z 557 [M+H] Ret. Time: 1.65 min.
Example 92: 5454(2-ethyl-1 -pyrrolidinyl)methyll-3-thienyl}-341-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
0
11 /
O S
N
S
N
I \ ~
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-indole-7-
carboxamide , substituting 2-ethylpyrrolidine (99.0 mg, 1.0 mmol) for 2-
propylpyrrolidine
to afford 15.0 mg of the title compound (28.4 %).
LC/MS = m/z 529 [M+H] Ret. Time: 1.66 min.
Example 93: 3-f1-(ethylsulfonyl)-4-piperidiny11-5-(54 f2-(2-methylpropyl)-1-
pyrrolidinyllmethyl}-3-thienyl)-1 FI-indole-7-carboxamide trifluoroacetate
139

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O
I I
O S~/
N
S
N
I \ ~
F
O H
F
F OH 0 NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-indole-7-
carboxamide , substituting 2-(2-methylpropyl)pyrrolidine (127 mg, 1.0 mmol)
for 2-
propylpyrrolidine to afford 7.0 mg of the title compound (10.4 %).
LC/MS = m/z 557 [M+H] Ret. Time: 1.74 min.
Example 94: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-(5-df2-(1-methylethyl)-1-
pyrrolidinyllmethyl}-3-thienyl)-1 H-indole-7-carboxamide
O
11 /
O=S-/
N
S
N
I \ ~
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-indole-7-
carboxamide , substituting 2-(1-methylethyl)pyrrolidine (113 mg, 1.0 mmol) for
2-
propylpyrrolidine to afford 16.0 mg of the title compound (29.5 %).
LC/MS = m/z 543 [M+H] Ret. Time: 1.61 min.
Example 95: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-(d(2S)-2-
f(methyloxy)methyll-l-
pyrrolidinyl}methyl)-3-thienyll-1 H-indole-7-carboxamide
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NS~O
O~ N S
I \ ~
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-indole-7-
carboxamide , substituting (2S)-2-[(methyloxy)methyl]pyrrolidine (115 mg, 1.0
mmol) for
2-propylpyrrolidine to afford 22.0 mg of the title compound (40.4 %).
LC/MS = m/z 544 [M+H] Ret. Time: 1.44 min.
Example 96: 5-(5-ffcyclohexyl(methyl)aminolmethyl}-3-thienyl)-3-f 1-
(ethylsulfonyl)-
4-piperidinyil-1 H-indole-7-carboxamide
O
I I
O=S~/
N
S
N
I \ ~
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-indole-7-
carboxamide , substituting cyclohexyl(methyl)amine (113 mg, 1.0 mmol) for 2-
propylpyrrolidine to afford 15.0 mg of the title compound (27.6 %).
LC/MS = m/z 543 [M+H] Ret. Time: 1.64 min.
Example 97: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-ff2-(2-methylpropyl)-1-
pyrrolidinyllmethyl}-3-thienyl)-1 Ftiindole-7-carboxamide
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O
I I
O=S~/
N
S
N
I \ ~
N
H
O NHz
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-
thienyl}-1 H-indole-7-
carboxamide , substituting 2-(2-methylpropyl)pyrrolidine (127 mg, 1.0 mmol)
for 2-
propylpyrrolidine to afford 12.0 mg of the title compound (21.6 %).
LC/MS = m/z 557 [M+H] Ret. Time: 1.74 min.
Example 98: 5-(54 fethyl(methyl)aminolmethyl}-3-thienyl)-3-f1-(ethylsuIfonyl)-
4-
pi peridi nyll-1 I+i ndole-7-carboxamide
O-1
O::~S'\
N
S
N\
N
H
0 NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2 drops of acetic
acid,
ethyl(methyl)amine (59 mg, 1.0 mmol), and stirred at room temperature for 5 h.
To this
was then added sodium triacetoxyborohydride (212 mg, 1.0 mmol) and reacted
overnight.
It was then purified by Gilson Preparatory HPLC to give 30.0 mg of the title
compound
(61.4%).
LC/MS = mlz 489 [M+H] Ret. Time: 1.50 min.
Example 99: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-
ffinethyl(propyl)aminolmethyl}-
3-thienyl)-1 H-indole-7-carboxamide
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0
O~S--\
N
S
N
H
0 NH2
The title compound was prepared according to the general procedure of 5-(5-
{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide, substituting methyl(propyl)amine (73 mg, 1.0 mmol) for 2-
propylpyrrolidine
to afford 32.0 mg of the title compound (63.7 %).
LC/MS = m/z 503 [M+H] Ret. Time: 1.54 min.
Example 100: 3-f 140 -methylethyl)sulfonyil-4-piperidinyl}-5-(5-
{finethyl(propyl)aminolmethyl)-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
0
O=S--IC
N
S
--N
\ ~
N
F O H
LH2
F~OH 10 F
To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-
piperidinyl}-1 H-
indole-7-carboxamide (46 mg, 0.10 mmol) in DMSO (2.0 mL) was added 2 drops of
acetic
acid, methyl(propyl)amine (73 mg, 1.0 mmol), and stirred at room temperature
for 5 h. To
this was then added sodium triacetoxyborohydride (212 mg, 1.0 mmol) and
reacted
overnight. It was then purified by Gilson Preparatory HPLC to give 25.0 mg of
the title
compound (39.6 %).
LC/MS = m/z 517 [M+H] Ret. Time: 1.61 min.
Example 101: 5-(5-{fethyl(methyl)aminolmethyl}-3-thienyl)-3-{'1-f(1-
methylethyl)sulfonyil-4-piperidinyl}-1 H-indole-7-carboxamide
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0
O=S-,(
N
S
N
N
H
O NH2
The title compound was prepared according to the general procedure of 3-{1-[(1-
methylethyl)sulfonyl]-4-piperidinyl}-5-(5-{[methyl(propyl)amino]methyl}-3-
thienyl)-1 F-l-
indole-7-carboxamide trifluoroacetate, substituting ethyl(methyl)amine (59 mg,
1.0 mmol)
for methyl(propyl)amine to afford 8.0 mg of the title compound (15.9 %).
LC/MS = m/z 503 [M+H] Ret. Time: 1.59 min.
Example 102: 3-f1-f(1-methylethyl)sulfonyll-4-piperidinyl}-5-f5-(fmethylf2-
(methyloxy)ethyllamino}methyl)-3-thienyll-1 H-indole-7-carboxamide
0
O=S---(
N
S
'N
I \ ~
N
I H
0 NH2
The title compound was prepared according to the general procedure of 3-{1-[(1-
methylethyl)sulfonyl]-4-piperidinyl}-5-(5-{[methyl(propyl)amino]methyl}-3-
thienyl)-1 F1-
indole-7-carboxamide trifluoroacetate, substituting methyl[2-
(methyloxy)ethyl]amine (89
mg, 1.0 mmol) for methyl(propyl)amine to afford 37.0 mg of the title compound
(69.4 %).
LC/MS = m/z 533 [M+H] Ret. Time: 1.58 min.
Example 103: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-{5-f(methylamino)methyll-2-
thienyl}-1 H-indole-7-carboxamide
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NH S" O
N
S
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1
H-indole-7-
carboxamide (35 mg, 0.078 mmol) in DMSO (1.0 mL) was added acetic acid (3
drops), 2
M methylamine in THF (0.24 mL, 0.471 mmol), and reacted for 3 h. Sodium
triacetoxyborohydride (100 mg, 0.471 mmol) was then added and reaction was
stirred
overnight. All solvent was removed in vacuo and purified by Gilson Preparatory
HPLC.
The impure desired fraction was concentrated under reduced pressure and loaded
onto a
500 mg SCX SPE cartidge primed with 10 mL of methanol. The cartridge was then
sequentially eluted with 2M NH3 in MeOH (10 mL x 2). The NH3 in MeOH fractions
were
concentrated to give 7.3 mg of the title compound (20%).
LC/MS = m/z 459.6 [M+H] Ret. Time: 1.25 min.
Example 104: 3-f1-(ethylsulfonyl)-4-piperidinyll-545-f(2-methyl-1-
pyrrolidinyl)methyll-3-thienyl}-1 H-indole-7-carboxamide trifluoroacetate
~
O;S;O
N N
S
~ ~
F O I \ ~
F~ ~ N
F OH H
O NH2
To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (3.0 mL) was added acetic acid (3
drops), 2-
methylpyrrolidine (0.12 mL, 1.12 mmol) and reacted for 4 h. Sodium
triacetoxyborohydride (238 mg, 1.12 mmol) was then added and the reaction was
stirred
overnight. The reaction mixture was purified by reverse phase Gilson
Preparatory HPLC
to give 17 mg of the title compound (30%).
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LCMS: 515.4 (M+H), Rt 1.60 min
Example 105: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-df(2-
methylpropyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
O;r
S;O
H N
N
S
F O I \ ~
F~ N
F OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL) was added acetic acid (4
drops),
(2-methylpropyl)amine (0.17 mL, 1.68 mmol), and sodium triacetoxyborohydride
(356 mg,
1.68 mmol) were reacted. The reaction mixture was purified by reverse phase
Gilson
Preparatory HPLC to give 15 mg of the title compound (27%).
LCMS: 503.4 (M+H), Rt 1.60 min
Example 106: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-f(propylamino)methyll-3-
thienyi}-1 M-indole-7-carboxamide trifluoroacetate
O;
rO
N
N
S
F O I \ ~
N
F OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL) was added acetic acid (3
drops),
(2-methylpropyl)amine (0.17 mL, 1.68 mmol), and sodium triacetoxyborohydride
(356 mg,
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1.68 mmol) were reacted. The reaction mixture was purified by reverse phase
Gilson
Preparatory HPLC to give 15 mg of the titie compound (27%).
LCMS: 489 (M+H), Rt 1.61 min
Example 107: 5-f5-f(diethylamino)methyll-3-thienyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 M-indole-7-carboxamide trifluoroacetate
O;
--O
N N
S
F
F+~O
N
F OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL), was added acetic acid (3
drops),
diethylamine (0.12 mL, 1.12 mmol) and stirred for 4 h at room temperature.
Sodium
triacetoxyborohydride (238 mg, 1.12 mmol) was then added and the reaction was
stirred
overnight. The reaction mixture was purified by reverse phase Gilson
Preparatory HPLC
to give 7.0 mg of the title compound (13%).
LCMS: 501.4 (M+H), Rt 1.51 min
Example 108: 5-(5-ff(2R,5R)-2,5-dimethyl-l-pyrrolidinyilmethyl}-3-thienyl)-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 FI-indole-7-carboxamide trifluoroacetate
O;
,=~ \O
N N
S
F O I \ ~
F+~ N
F OH H
O NH2
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (3
drops),
(2R,5R)-2,5-dimethylpyrrolidine (151 mg, 1.123 mmol), and reacted for 4 h.
Sodium
triacetoxyborohydride (238 mg, 1.123 mmol) was then added. The reaction
mixture was
purified by reverse phase Gilson Preparatory HPLC to give 27 mg of the title
compound
(46%).
LCMS: 529.4 (M+H), Rt 1.64 min
Example 109: 545-f(cyclopropylamino)methyll-3-thienyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O;
S;O
L~\-"N N
S
F O
F OH N
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL), was added acetic acid (5
drops),
and cyclopropylamine (0.12 mL, 1.68 mmol) and reacted for 6 h. Sodium
triacetoxyborohydride (356 mg, 1.68 mmol) was then added and the reaction was
stirred
overnight. The reaction mixture was purified by reverse phase Gilson
Preparatory HPLC
to give 8.0 mg of the title compound (10%).
LCMS: 487.2 (M+H), Rt 1.64 min and 1.68 min
Example 110: 545-f(cyclobutylamino)methyll-3-thienyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 M-indole-7-carboxamide trifluoroacetate
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O; r
S;O
0--N N
S
F O
F-H V
F OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL), was added acetic acid (4
drops),
and cyclobutylamine (0.15 mL, 1.68 mmol) and reacted for 4 h. Sodium
triacetoxyborohydride (356 mg, 1.68 mmol) was then added and the reaction was
stirred
overnight. The reaction mixture was purified by reverse phase Gilson
Preparatory HPLC
to give 5.0 mg of the title compound (10%).
LCMS: 501.4 (M+H), Rt 1.51 min
Example 111: 5-f5-f(dimethylamino)methyll-3-thienyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O\)
S~O
~
---N N
S
F O
F-~-/< I
F OH N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2-thienyl)-1
H-indole-7-
carboxamide (300 mg, 0.67 mmol) in DMSO (4 mL), was added a solution of 2 M
dimethylamine in THF (3.36 mL, 6.7 mmol). The reaction was stirred at room
temperature for 7 h, and sodium triacetoxyborohydride (1.42 g, 6.7 mmol) was
added.
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Stirring continued overnight at room temperature. The reaction mixture was
purified by
reverse phase Gilson Prepatory HPLC to give the title compound (205 mg, 64%).
LCMS: 475.2 (M+H), Rt 1.51 min
Example 112: 5-(5-df(cyclopentylmethyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 FNindole-7-carboxamide trifluoroacetate
NH N
S
F
O
F
F OH H
-H
O NH2
To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), acetic acid (3 drops),
(cyclopentylmethyl)amine (112 mg, 1.123 mmol), and was reacted for 4h. Sodium
triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was
stirred
overnight. The reaction mixture was purified by reverse phase Gilson
Preparatory HPLC
to give 8.0 mg of the title compound (14%).
LCMS: 529.4 (M+H), Rt 1.61 min and 1.64 min
Example 113: 5-f5-(df(1R)-1,2-dimethylpropyllamino}methyl)-3-thienyll-3-f1-
(ethylsulfonyl)-4-piperidinyil-1 H-indole-7-carboxamide trifluoroacetate
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O) _
~O
NH N
S
F O I \ ~
F~ N
OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (3
drops),
(2R)-3-methyl-2-butanamine (98 mg, 1.123 mmol), and reacted for 4 h. Sodium
triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was
stirred
overnight. The reaction mixture was purified by reverse phase Gilson
Preparatory HPLC
to give5.0 mg of the title compound (10%).
LCMS: 517.2 (M+H), Rt 1.65 min
Example 114: 5-f5-I'(cyclopentylamino)methyll-3-thienyll-3-f1-(ethylsulfonyl)-
4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
0)
~ O
0--NH N
S
F p
F OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (3
drops),
cyclopentanamine (0.11 mL, 1.123 mmol), and reacted for 4 h. Sodium
triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was
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reacted overnight. The reaction mixture was purified by reverse phase Gilson
Preparatory HPLC to give 5.0 mg of the title compound (6.0%).
LCMS: 515.6 (M+H), Rt 1.38 min
Example 115: 5-(5-{f(cyclopropylmethyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O~S~O
NH N
S
F O
F
F OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), acetic acid (3 drops), 1-
cyclopropylmethanamine (0.10 mL, 1.123 mmol), and was reacted for 6 h. Sodium
triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was
stirred
overnight. The reaction mixture was purified by reverse phase Gilson
Preparatory HPLC
to give 5.0 mg of the title compound (10%).
LCMS: 501.4 (M+H), Rt 1.53 min
Example 116: 545-ff f(1 S)-1 2-dimethylpropyllamino}methyl)-3-thienyil-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O
NH N
S
F F O
~
F OH H
O NH2
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), acetic acid (3 drops), (2S)-
3-
methyl-2-butanamine (98 mg, 1.123 mmol), and was reacted for 6 h. Sodium
triacetoxyborohyd ride (238 mg, 1.123 mmol) was then added and the reaction
was stirred
overnight. The reaction mixture was purified by reverse phase Gilson
Preparatory HPLC
to give 8.0 mg of the title compound (15%).
LCMS: 517.2 (M+H), Rt 1.65 min
Example 117: 5-(5-ff(2,2-dimethylpropyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyil-1 H-indole-7-carboxamide trifluoroacetate
o O
N
HN
S
F p I \ ~
F--~-- H
IF OH
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (3
drops),
(2,2-dimethylpropyl)amine (0.13 mL, 1.123 mmol), and reacted for 6 h. Sodium
triacetoxyborohydride (238 mg, 1.123 mmol) was then added and stirred
overnight. The
reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give
4.0 mg
of the title compound (7%).
LCMS: 517.2 (M+H), Rt 1.68 min and 1.71 min
Example 118= 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(54
f(phenyimethyl)aminolmethyl}-
3-thienyl)-1 M indole-7-carboxamide trifluoroacetate
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O
NS~O
HN
S
F O I \ ~
F---~ N
OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (5
drops),
(phenylmethyl)amine (0.14 mL, 1.123 mmol), and reacted for 6 h. Sodium
triacetoxyborohydride (238 mg, 1.123 mmol) was then added and stirred
overnight. The
reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give
5.0 mg
of the title compound (8%).
LCMS: 537.2 (M+H), Rt 1.68 min
Example 119: 3-f1-(ethylsuifonyl)-4-piperidinyil-5-f5-(ff(2S)-tetrahydro-2-
furanylmethyllamino}methyl)-3-thienyll-1 M indole-7-carboxamide
trifluoroacetate
Co
O~ S
O
N
HN
S
F O I \ ~
F_ N
OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-
indole-7-
carboxamide (50 mg, 0.112 mmol) in dichloromethane (3.0 mL) and methanol (1.5
mL),
acetic acid (5 drops), 1-[(2S)-tetrahydro-2-furanyl]methanamine (0.12 mL,
1.123 mmol),
and reacted for 6 h. Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was
then
added and the reaction mixture was stirred at room temperature overnight. The
reaction
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mixture was purified by reverse phase Gilson Preparatory HPLC to give 23 mg of
the title
compound (8%).
LCMS: 531.4 (M+H), Rt 1.58 min
Example 120: 341-(ethylsulfonyl)-4-piperidinyll-5-(5-f f(tetrahydro-2H-pyran-4-
ylmethyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate
O ~
O S\O
R H N
N
S
F O ~ ~
F--~--~( ~ /
IF OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), acetic acid (5 drops), and
(tetrahydro-2H-pyran-4-ylmethyl)amine (130 mg, 1.123 mmol), and reacted for 6
h.
Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the
reaction
was stirred overnight. The reaction mixture was purified by reverse phase
Gilson
Preparatory HPLC to give 7.0 mg of the title compound (11 %).
LCMS: 545.4 (M+H), Rt 1.52 min
Example 121: 5-f5-f(butylamino)methyll-3-thienyl}-3-f 1-(ethylsulfonyl)-4-
piperi.dinyll-1 F/-indole-7-carboxamide trifluoroacetate
O~/
O
NS~
N
S
F 0 I \ ~
F-H N
F OH H
O NH2
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in dichloromethane (3.0 mL) and methanol (1.5
mL),
was added 5 drops of acetic acid, butylamine (0.11 mL, 1.123 mmol) and reacted
for 6 h.
Sodium borohydride (43 mg, 1.123 mmol) was then added and stirred at room
temperature overnight. All solvent was removed in vacuo and dissolved in DMSO
(1.0
mL). It was then purified by reverse phase Gilson Preparatory HPLC to give 5.0
mg of
the title compound (10%). -
LCMS: 503.4 (M+H), Rt 1.63 min
Example 122: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-(df(2R)-tetrahydro-2-
furanvlmethyllamino}methyl)-3-thienyll-1 H-indole-7-carboxamide
trifluoroacetate
no
O S~ O
N
HN
S
F
' O
F-~---~(
IF OH N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (5
drops), 1-
[(2R)-tetrahydro-2-furanyl]methanamine (130 mg, 1.123 mmol), and the reaction
mixture
was reacted for 6 h. Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was
then
added and the reaction was stirred overnight. Additional 1-[(2R)-tetrahydro-2-
furanyl]methanamine (130 mg, 1.123 mmol) was then added followed by sodium
triacetoxyborohydride after 6 h. The reaction mixture was purified by reverse
phase
Gilson Preparatory HPLC to give 5.0 mg of the title compound (8.0%).
LCMS: 531.4 (M+H), Rt 1.50 min
Example 123: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-(f (2S)-
24(methyloxy)methyll-1-
pyrrolidinyl}methyl)-3-thienyll-1 H-indole-7-carboxamide trifluoroacetate
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Oz~)
N S\ O
N
S
F O ~ \ \
F-Fl< N
F 0H H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in dichloromethane (3.0 mL) and methanol (1.5
mL),
was added 5 drops of acetic acid, (2S)-2-[(methyloxy)methyl]pyrrolidine (129
mg, 1.123
mmol) and recated at room temperature for 6 h. Sodium borohydride (43 mg,
1.123
mmol) was than added and the reaction was stirred at room temperature
overnight. The
reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give
8.0 mg
of the title compound the (13%).
LCMS: 545.2 (M+H), Rt 1.62 min and 1.66 min.
Example 124: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-(d(2R)-2-
f(methyloxy)methyll-1-
pyrrolidinyl}methyl)-3-thienyll-1 H-indole-7-carboxamide trifluoroacetate
O"~
NS\
O N
S
~ ~
I \ ~
F 0
F~ ~ H
F OH
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-
indole-7-
carboxamide (50 mg, 0.112 mmol) in dichloromethane (3.0 mL) and methanol (1.5
mL),
was added acetic acid (5 drops), (2R)-2-[(methyloxy)methyl]pyrrolidine (129
mg, 1.123
mmol) and stirred at room temperature for 6 h. Sodium borohydride (43 mg,
1.123 mmol)
was then added and the reaction was stirred at room temperature overnight. The
mixture
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was purified by reverse phase Gilson Preparatory HPLC to give 5.0 mg of the
title
compound (13%).
LCMS: 545.2 (M+H), Rt 1.62 min and 1.66 min.
Example 125: 3-f1-(ethylsulfonyl)-4-piperidinvll-5-f4-f2-
(methylamino)ethyllphenyl}-
1 H-indole-7-carboxamide
O
O=S-\
HN N
N
H
H2N O
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (200
mg, 0.48 mmol) in dioxane and H20 was added was added [4-
(cyanomethyl)phenyl]boronic acid (232 mg, 0.144 mmol), potassium carbonate
(400 mg,
2.88 mmol), and tetrakis(triphenylphosphine)palladium (0) (30 mg, 0.048 mmol).
The
solution was stirred and heated in the microwave at 1602 C for 40 min. The
reaction was
diluted with EtOAc and H20 and filtered to obtain a yellow crystal as desired
product. The
solution was washed with brine and H20 and then EtOAc was concentrated. To the
reside was added MEOH which precipitated the desired product and then washed
again
with MeOH to give 5-[4-(cyanomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide.
To 5-[4-(cyanomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
(78 mg, 0.173 mmol) in DCM was added 1.5 M diisobutylaluminum hydride solution
in
toluene (240 mL, 0.346 mmol) at 00 C. The reaction was stirred at 00 C for 20
min. The
reaction was then quenched with saturated KNa tartrate solution. The bi-layer
was
filtered, and the solid was the desired product. Additionally, the organic
layer was
concentrated to give the desired compound, 3-[1-(ethylsulfonyl)-4-piperidinyl]-
5-[4-(2-
oxoethyl)phenyl]-1 H-indole-7-carboxamide, which was taken on without further
purification.
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-
1 H-indole-7-
carboxamide (50 mg, 0.11 mmol) in methanol (5 mL) and methylene chloride (5
mL) at
room temperature was added 2 M methylamine in tetrahydrofuran (0.4 mL)
followed by 1
drop of acetic acid. The reaction was stirred at room temperature for 2 h
followed by an
addition of sodium triacetoxyborohydride (200 mg, 0.94 mmol). This reaction
was stirred
overnight. It was then purified by flash chromatography to give 10 mg of the
title
compound (19.4%).
LC/MS = m/z 469.4 [M+H] Ret. Time: 1.63 min.
Example 126: 341-(ethylsulfonyl)-4-piperidinyll-54442-
(propylamino)ethyllphenyl}-
1 H-indole-7-carboxamide
O
11
-\
O=S
HN
VHN
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-1 H-indole-7-
carboxamide,
substituting 2 M propylamine in tetrahydrofuran (0.4 mL) for methylamine to
afford 15 mg
of the title compound (27.5%).
LC/MS = m/z 497.6 [M+H] Ret. Time: 1.63 min.
Example 127: 54442-(ethylamino)ethyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-
1 H-indole-7-carboxamide
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O
O=S-\
HN N
N
H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-
1 H-indole-7-
carboxamide (50 mg, 0.11 mmol) in methanol (5 mL) and methylene chloride (5
mL) at
room temperature was added 2 M ethylamine in tetrahydrofuran (0.4 mL),
followed by 1
drop of acetic acid. The reaction was stirred at room temperature for 2 h
followed by an
addition of sodium triacetoxyborohydride (200 mg, 0.94 mmol). This reaction
was stirred
overnight. It was then purified by flash chromatography to give 15 mg of the
title
compound (28.3%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.57 min.
Example 128: 5-f4-f (f f 1-(1,1-di methylethyl)-3-methyl-1 H-pyrazol-5-
yllcarbonyl}amino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-piperidinyll-1 H-
indole-7-
carboxamide trifluoroacetate
0
0 O_S--\
NH N
N-N
F O
F-I ' H
F OH
H2N O
To a solution of [4-(aminomethyl)phenyl]boronic acid (145 mg, 0.966 mrnol) in
DMF (2
mL) was added 1-(1,1-dimethylethyl)-3-methyl-lH-pyrazole-5-carbonyl chloride
(290 mg,
1.45 mmol) and triethylamine (403 pL, 2.90 mmol). The reaction was stirred for
2 h. It
was then quenched and partitioned between EtOAc and H20 and the organic layer
was
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concentrated to give {4-[({[1-(1,1-dimethylethyl)-3-methyl-1 H-pyrazol-5-
yl]carbonyl}amino)methyl]phenyl}boronic acid.
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (50
mg, 0.120 mmol)in dioxane (1 mL) and water (0.4 mL) was added potassium
carbonate
(74 mg, 0.484 mmol) and {4-[({[1-(1,1-dimethylethyl)-3-methyl-1 H-pyrazol-5-
yl]carbonyl}amino)methyl]phenyl}boronic acid (153 mg, 0.483 mmol). The
reaction
mixture was stirred and bubbled with argon for 5 min. before the addition of
chloro(di-2-
norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium (II) (7 mg,
0.012
mmol). The reaction was stirred for 10 min then heated to 150 C. The reaction
was
evaporated and purified by Gilson Preparatory HPLC to give 5 mg of the title
compound
(5.8%).
LC/MS = m/z 605.4 [M+H] Ret. Time: 2.14 min.
Example 129: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(4-{f(4-
pyridinylcarbonyi)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
0
0 O=S11
--\
I \ NH N
N /
I \ ~
N
H
H2N O
The title compound was prepared according to the general procedure of 5-{4-
[({[1-(1,1-
dimethylethyl)-3-methyl-1 H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate ,
substituting (4-
{[(4-pyridinylcarbonyl)amino]methyl}phenyl)boronic acid (124 mg, .480 mmol)
for {4-[({[1-
(1,1-dimethylethyl)-3-methyl-1 H-pyrazol-5-
yl]carbonyl}amino)methyl]phenyl}boronic acid
to afford 30 mg of the title compound (45.8%).
LC/MS = m/z 537 [M+H] Ret. Time: 2.04 min.
Example 130: 5-(4-ff(cyclopentylcarbonyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
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O
O O=S~
NH N
N
H
H2N O
The title compound was prepared according to the general procedure of 5-{4-
[({[1-(1,1-
dimethylethyl)-3-methyl-1 H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate ,
substituting (4-
{[(cyclopentylcarbonyl)amino]methyl}phenyl)boronic acid (119 mg, 0.480 mmol)
for {4-
[({[1-(1,1-dimethylethyl)-3-methyl-1 H-pyrazol-5-
yl]carbonyl}amino)methyl]phenyl}boronic
acid to afford 30 mg of the title compound (47%).
LC/MS = m/z 537 [M+H] Ret. Time: 2.04 min.
Example 131: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(4-{T(2-
furanylcarbonyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
O
O 0=S11
-\
~ NH N
\ O
N
H
H2N O
The title compound was prepared according to the general procedure of 5-{4-
[({[1-(1,1-
dimethylethyl)-3-methyl-1 H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate ,
substituting (4-
{[(2-furanylcarbonyl)amino]methyl}phenyl)boronic acid (118 mg, 0.480 mmol) for
{4-[({[1-
(1,1-dimethylethyl)-3-methyl-1 H-pyrazol-5-
yl]carbonyl}amino)methyl]phenyl}boronic acid
to afford 16 mg of the title compound (25%).
LC/MS = m/z 535.5 [M+H] Ret. Time: 1.99 min.
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Example 132: 5-(4-{2-f(cyclobutylcarbonyl)aminolethyl}phenyl)-3-f1-
(ethylsulfonyl)-
4-piperidinyll-1 H-indole-7-carboxamide
O ~
CI-Y O=S-\
HN N
N
H
H2N O
The title compound was prepared according to the general procedure of 5-{4-[2-
(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide ,
substituting IV [2-(4-bromophenyl)ethyl]cyclobutanecarboxamide (100 mg, 0.324
mmol)
for N-[2-(4-bromophenyl)ethyl]acetamide. Purified by flash chromatography to
afford
28 mg of the title compound (48.3%).
LC/MS = m/z 537.2 [M+H] Ret. Time: 1.99 min.
Example 133: 5-(4424(cyclohexylcarbonyl)aminolethyl}phenyl)-34 1-
(ethylsulfonyl)-
4-piperidinyll-1 H-indole-7-carboxamide
(DY O ~
O=S~
HN
N
N
H
H2N O
The title compound was prepared according to the general procedure of 5-{4-[2-
(acetylamino)ethyl]phenyl}-3-[1-(ethylsuifonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide,
substituting N-[2-(4-bromophenyl)ethyl]cyclohexanecarboxamide (100 mg, 0.324
mmol)
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for N-[2-(4-bromophenyl)ethyl]acetamide. Purified by flash chromatography to
afford
32 mg of the title compound (52.5%).
LC/MS = m/z 565.4 [M+H] Ret. Time: 2.14 min.
Example 134: 5-(342-f(cyclohexylcarbonyl)aminolethyll phenyl)-341-
(ethylsulfonyl)-
4-piperidinyll-1 H-indole-7-carboxamide
0 "
N
N
N
H
H2N 0
The title compound was prepared according to the general procedure of 5-{4-[2-
(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide,
substituting N-[2-(3-bromophenyl)ethyl]cyclohexanecarboxamide (100 mg, 0.324
mmol)
for N-[2-(4-bromophenyl)ethyl]acetamide. The concentrated reaction mixture was
purified
by Gilson Preparatory HPLC followed by re-purification by flash chromatography
to give
the title compound.
LC/MS = m/z 565.2 [M+H] Ret. Time: 2.16 min.
Example 135: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f6-(1-piperazinyl)-3-
pyridinyll-1H-
indole-7-carboxamide trifluoroacetate
HN NS
N N
(
F O
F-+4 ~ N
F OH H
H2N O
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (100
mg, 0.241 mmol) in dioxane (1.0 mL) and H20 (0.8 mL) was added cesium
carbonate
(314 mg, 0.964 mmol), and [6-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-
piperazinyl)-3-
pyridinyl]boronic acid (297 mg, 0.964 mmol). The reaction mixture was stirred
before
addition of tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol). The
reaction
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was heated in a microwave at 1602 C for 20 min. Mixture was concentrated and
taken up
in EtOAc (10 mL) and H20 (5.0 mL). Compound was purified by Gilson Preparatory
HPLC to give 129 mg of 1,1-dimethylethyl 4-(5-{7-(aminocarbonyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indol-5-yl}-2-pyridinyl)-1-piperazinecarboxylate and 3-[1-
(ethylsulfonyl)-4-
piperidinyl]-5-[6-(1-piperazinyl)-3-pyridinyl]-1 H-indole-7-carboxamide (44%).
To a solution of 1,1-dimethylethyl 4-(5-{7-(aminocarbonyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indol-5-yl}-2-pyridinyl)-1-piperazinecarboxylate (130 mg,
0.218 mmol) in
methanol (0.3 mL) was added 4 M HCI in dioxane (0.3 mL). The reaction was
heated at
LO 509 C and stirred for 3 h. Reaction mixture was concentrated and
neautralized on a SCX
cartridge primed with CH2CI2, followed by MeOH and collection with ammonia in
MeOH.
20 mg of desired fraction was concentrated and purified using MDAP HPLC to
give 9.4
mg of the title compound (7%).
LC/MS = m/z 497.2 [M+H] Ret. Time: 1.45 min
Example 136: 5-f6-(4-ethyl-l-piperazinyl)-3-pyridinyll-3-f 1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
0
N~ N"S ~O
~N N
F O
F-+-4 I
F OH N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperazinyl)-3-
pyridinyl]-1H-
indole-7-carboxamide (40 mg, 0.081 mmol) in dichloromethane was added
acetaldehyde
(7 mg, 0.162 mmol) and sodium triacetoxyborohydride (100 mg, 0.472 mmol). The
reaction was stirred overnight at room temperature. Reaction mixture was then
concentrated and dissolved in EtOAc and H20. Salts were filtered and organic
layer was
concentrated and purified by Gilson Preparatory HPLC to give 39 mg of the
title
compound (92%).
LC/MS = mlz 525.6 [M+H] Ret. Time: 1.44 min
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Example 137: 3-f1-(ethylsulfonyl)-4-piperidinyll-544-(1-piperidinylmethyl)
phenyll-
1 M indole-7-carboxamide trifluoroacetate
(Do
/SO
F F-~-F
y
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (40 mg, 0.09 mmol) in dichloromethane was added piperidine (9 pL,
0.09
mmol). The reaction was stirred for 1 h before addition of sodium
triacetoxyborohydride
(58 mg, 0.27 mmol). The reaction mixture was stirred overnight at room
temperature.
Mixture was then concentrated and purified by Gilson Preparatory HPLC to give
8.0 mg of
the title compound (14%).
LC/MS = m/z 509.4 [M+H] Ret. Time: 1.71 min
Example 138: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(1-
piperidinylmethyl)phenyll-
1 H-indole-7-carboxamide trifluoroacetate
Oz:--~
S, O
Q N
/ I
\ \
F O I ~
F- / H
F OH
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in dichloromethane (2 mL) and acetic acid (1
drop)
was added piperidine (46 pL, 0.456 mmol). The reaction was stirred for 2 h at
room
temperature before the addition of sodium triacetoxyborohydride (75 mg, 0.342
mmol).
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The reaction was then stirred an additional 3 h. The mixture was then purified
by Gilson
Preparatory HPLC to give 36 mg of the title compound (61%).
LC/MS = m/z 509.4 [M+H] Ret. Time: 1.80 min
Example 139: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f4-
f(methylamino)methyllphenyl}-
1 H-indole-7-carboxamide trifluoroacetate
O-::~-S
~O
NH N
F F-~4 N
H
F OH
p
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (20 mg, 0.045 mmol) in dichloromethane (12 mL), Methanol (2 mL)
and
acetic acid was added methylamine in THF (20 pL, 0.54 mmol). The reaction
mixture
was stirred at room temperature for 2 h before addition of sodium
triacetoxyborohydride
(10.3 mg, 0.270 mmol). The mixture was then stirred for another 3 h before the
mixure
was concentrated and purified by Gilson Preparatory HPLC to give 6 mg of the
title
compound (10%).
LC/MS = m/z 454.6 [M+H] Ret. Time: 1.23 min
Example 140: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-(4-ff(1-
methylethyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
O,-S
/ - O
/\NH N
N
H
O NH2
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (40 mg, 0.09 mmol) in DMSO (900 pL) and acetic acid (2 drops) was
added
2-propanamine (93 pL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (172
mg,
0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was
purified
by Gilson Preparatory HPLC to afford 30 mg of the title compound (69%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.56 min
Example 141: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-f4-
f(propylamino)methyllphenyl}-
1 M indole-7-carboxamide trifluoroacetate
O S\o
~\NH N
FI //O
F-~---~(
I~H H
F '
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (20 mg, 0.045 mmol) in DMSO (900 pL) and acetic acid (2 drops) was
added propylamine (45 pL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride
(172 mg,
0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was
purified
by Gilson Preparatory HPLC to afford 21.1 mg of the title compound (74%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.54 min.
Example 142: 5-(44 f(1-ethylpropyl)aminolmethyl}phenyl)-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
Ozz~S
~O
NH N
N
H
O NH2
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (40 mg, 0.09 mmol) in DMSO (900 pL) and acetic acid (2 drops) was
added
3-pentanamine (108 pL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride
(172 mg,
0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was
purified
by Gilson Preparatory HPLC to afford 34.5 mg of the title compound (74%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.69 min
Example 143: 5-d4-f(cyclopentylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 F/-indole-7-carboxamide trifluoroacetate
O
S~O
NH N
F O
F~ I \ ~
F OH N
H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (40 mg, 0.09 mmol) in DMSO (900 pL) and acetic acid (2 drops) was
added
cyclopentylamine (108 pL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride
(172 mg,
0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was
purified
by Gilson Preparatory HPLC to afford 11.1 mg of the title compound (20%).
LC/MS = m/z 509.4 [M+H] Ret. Time: 1.66 min.
Example 144: 544-f(cyclobutylamino)methyllphenyl}-341-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
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Oz~-
S
,-O
NH N
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (40 mg, 0.091 mmol) in DMSO (900 pL) and acetic acid (2 drops) was
added cyclobutylamine (94 p L, 1.08 mmol). After 2 h, sodium
triacetoxyborohydride (120
mg, 1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was
purified by Gilson Preparatory HPLC to afford 26.3 mg of the title compound
(59%).
LC/MS = m/z 495.4 [M+H] Ret. Time: 1.37 min
Example 145: 5-f4-f(ethylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-
1 H-indole-7-carboxamide
O,-~_
S,o
NH N
N
H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (20 mg, 0.046 mmol) in DMSO and acetic acid was added ethylamine
(32
pL, 0.547 mmol). After 2 h, sodium triacetoxyborohydride (120 mg, 1.10 mmol)
was
added. Reaction mixture was stirred overnight. Compound was purified by Gilson
Preparatory HPLC to afford 11.5 mg of the title compound (55%).
LC/MS = m/z 469.4 [M+H] Ret. Time: 1.52 min.
170

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Example 146: 5-d4-f(dimethylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
O--_-
S~O
N N
N
H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added N-
dimethylamine (170 pL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride
(290 mg,
1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was
purified
by Gilson Preparatory HPLC to afford 28.9 mg of the title compound (54%).
LC/MS = m/z 469.4 [M+H] Ret. Time: 1.52 min.
Example 147: 5-f4-f(diethylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-
1 H-indole-7-carboxamide
O-'-S r-_
~ ~ \O
N N
\ \ ~
N
H
H 2 N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added
diethylamine (36 pL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290
mg, 1.36
mmol) was added. Reaction mixture was stirred overnight. Compound was purified
by
Gilson Preparatory HPLC to afford 37.6 mg of the title compound (67%).
171

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LC/MS = m/z 497.6 [M+H] Ret. Time: 1.52 min.
Example 148: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f4-(4-
morpholinylmethyl)pheny_I1-
1 H-indole-7-carboxamide
O
0
O ;/
N N
N
H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added
morpholine (30 pL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290
mg, 1.36
mmol) was added. Reaction mixture was stirred overnight. Compound was purified
by
Gilson Preparatory HPLC to afford 40.3 mg of the title compound (70%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.53 min
Example 149: 3-f1-(ethylsulfonyl)-4-piperidinyll-544-(1-
pyrrolidinylmethyl)phenyll-
1 H-indole-7-carboxamide trifIuoroacetate
S\_O
N N
F O
F--~ / H
F OH
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyi]-5-(4-formylphenyi)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added
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cyclopentylamine (28 pL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride
(290 mg,
1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was
purified
by Gilson Preparatory HPLC to afford 20.1 mg of the title compound (36%).
LC/MS = m/z 495.4 [M+H] Ret. Time: 1.58 min
Example 150: 3-f1-(ethylsulfonyl)-4-piperidiny11-5-f4-(ff(1 S)-2-hydroxy-l-
methylethyllamino}methyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
HO
o S;o
NH N
F 0 \ I ~ \
F+-/< N
F OH H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added
(2S)-2-amino-l-propanol (56 pL, 0.745 mmol). After 2 h, sodium
triacetoxyborohydride
(290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight.
Compound
was purified by Gilson Preparatory HPLC to afford 25.9 mg of the title
compound (15%).
LC/MS = m/z 499.6 [M+H] Ret. Time: 1.54 min
Example 151: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-f4-(ff(1 R)-2-hydroxy-l-
methylethyllamino}methyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
HO
O S
NH N
F O \ ~ \
F~
F OH H
H2N O
173

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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added
(2R)-2-amino-l-propanol (56 pL, 0.745 mmol). After 2 h, sodium
triacetoxyborohydride
(290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight.
Compound
was purified by Gilson Preparatory HPLC to afford 29.6 mg of the title
compound (53%).
LC/MS = m/z 499.6 [M+H] Ret. Time: 1.47 min
Example 152: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-f4-(ff(2R)-2-
hvdroxypropyllamino}methyl)phenyll-1 FNindole-7-carboxamide trifluoroacetate
HO _ ~
O~SZ::~O
NH N
F O
Fi4 \ \ ~
F OH
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added
(2R)-1-amino-2-propanol (56 pL, 0.745 mmol). After 2 h, sodium
triacetoxyborohydride
(290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight.
Compound
was purified by Gilson Preparatory HPLC to afford 14.7 mg of the title
compound (26%).
LC/MS = m/z 499.6 [M+H] Ret. Time: 1.46 min.
Example 153: 341-(ethylsulfonyl)-4-piperidinyll-544-(ff2-hydroxy-1-
(hydroxymethyl)ethyllamino}methyl)phenyll-1 FI-indole-7-carboxamide
trifluoroacetate
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OH
Szz~O
N N
OH
F O \ I \ ~
F OH H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-
indole-7-
carboxamide (40 mg, 0.091 mmol) in DMSO was added 2-amino-1,3-propanediol (50
mg,
0.55 mmol) and acetic acid (1 drop). After 2 h, sodium triacetoxyborohydride
(232 mg,
1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was
purified
by Gilson Preparatory HPLC to afford 15.9 mg of the title compound (28%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.45 min.
Example 154: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-(34 f(1-
methylbutyl)aminolmethyl}phenyl)-1 Ftiindole-7-carboxamide trifluoroacetate
F O ~
F~ O\S
F O NH N
\ I \
N
H
H2N O
To a solution -~ of-=---3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-
1 H-indole-7-
carboxamide (50 mg, 0.114 mmol) in DMSO (3.0 mL) was added 1-2-pentanamine
(324
pL, 2.74 mmol) and acetic acid (1 drop). After 2 h, sodium
triacetoxyborohydride (290
mg, 1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was
then filtered and concentrated. It was then purified by Gilson Preparatory
HPLC to afford
9.5 mg of the title compound (13%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.66 min
175

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Example 155: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(df(1 R)-1-
methylpropyllamino}methyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
O~ S\
NH O
N
\ \ ~
F O I
N
F ~ \ H
F OH
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DMSO (2.0 mL) was added (2R)-2-butanamine
(69
iaL, 0.684 mmol) and acetic acid (1 drop). After 2 h, sodium
triacetoxyborohydride (0.435
mg, 2.05 mmol) was added. Reaction mixture was stirred overnight. Compound was
then filtered and concentrated. It was then purified by Gilson Preparatory
HPLC to afford
18.6 mg of the title compound (33%).
LC/MS = m/z 497.6 [M+H] Ret. Time: 1.70 min
Example 156: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-{f(2-
methylpropyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
O~r
S-0
NH N
N
H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL), MeOH (1.5 mL), and acetic
acid (4
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drops) was added 2-methyl-l-propanamine (137 pL, 1.37 mmol) and stirred at
room
tempertuare. After 2 h, sodium borohydride (23 mg, 0.684 mmol) was added and
the
reaction mixture was purified by SCX cartridge to give 47.8 mg of the title
compound
(85%).
LC/MS = m/z 497.2 [M+H] Ret. Time: 1.69 min
Example 157: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(ff(1 S)-1-
methylpropyllamino}methyl)phenyll-1--Nindole-7-carboxamide acetate
O_
O S ~
ZZ-O
NH N
AOH
N
H
Nh2 O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]methyl}phenyl)-1 H-
indole-7-
carboxamide , substituting (2S)-2-butanamine (138 pL, 1.37 mmol) for 2-methyl-
l-
propanamine to afford 43.2 mg of the title compound (76%).
LC/MS = m/z 497.4 [M+H] Ret. Time: 1.84 min
Example 158: 5-(44 f(cyclopropylcarbonyl)aminolmethyi}phenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
0 O,-S\
O
NH N
N
H
H2N O
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The title compound was prepared according to the general procedure of 5-{4-
[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
substituting cyclopropanecarbonyl chloride (14 IaL, 1.37 mmol) for acetyl
chloride.
Compound was purified by Gilson Preparatory HPLC to afford 19.1 mg of the
title
compound (28%).
LC/MS = mlz 509.2 [M+H] Ret. Time: 1.86 min
Example 159: 5-(4-{f(cyclobutylcarbonyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-
4-piperidinyll-1 FI-indole-7-carboxamide
0 O-,-S\
O
C71, NH N
N
H
H2N O
The title compound was prepared according to the general procedure of 5-{4-
[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indoie-7-
carboxamide
substituting cyclobutanecarbonyl chloride (17 pL, 1.37 mmol) for acetyl
chloride.
Compound was purified by Gilson Preparatory HPLC to afford 20.2 mg of the
title
compound (28%).
LC/MS = m/z 523.2 [M+H] Ret. Time: 1.94 min
Example 160: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(4-df(2-
thienylacetyl)aminolmethyl}phenyl)-11,f'indole-7-carboxamide
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~
C 0 ~" S~o
S NH N
N
H
H2N O
The title compound was prepared according to the general procedure of 5-{4-
[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
substituting (3Z)-3-(methylthio)-3,5-hexadienoyl chloride (18 pL, 1.37 mmol)
for acetyl
chloride. Compound was purified by Gilson Preparatory HPLC to afford 13.5 mg
of the
title compound (18%).
LC/MS = m/z 565.2 [M+H] Ret. Time: 1.98 min
Example 161: 544-W(1 S)-1 2-dimethylpropyllamino}methyl)phenyil-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O
'
>NH N
F O \ I \ ~
F+2< N
F OH H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (40 mg, 0.091 mmol) in DCM (1.5 mL), MeOH (1.5 mL) and acetic acid
was
added (2S)-3-methyl-2-butanamine (128 pL, 1.10 mmol) and stirred at room
temperature
for 2 h. Sodium borohydride (19 mg, 0.546 mmol) was then added and stirred for
48 h.
Compound was then purified by Gilson Preparatory HPLC to give 5.8 mg of the
title
compound (12%).
LC/MS = m/z 511.2 [M+H] Ret. Time: 1.76 min
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To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (50
mg, 0.121 mmol) in dioxane (1 mL) and H20 (0.4 mL) was added potassium
carbonate (74 mg, 0.484 mmol), and
(4{[(methylsulfonyl)amino]methyl}phenyl)boronic
acid (110 mg, 0.50 mmol). The reaction mixture was stirred and bubbled thru
with Argon
for 5 min before addition of chloro(di-2-norbornylphosphino)(2-
dimethylaminomethylferrocen-1-yl)palladium (II) (7 mg, 0.012 mmol). The
reaction was
then stirred and heated for 10 min in a microwave at 160 C. The mixture was
concentrated and purified by Gilson Preparatory HPLC to afford 34.3 mg of the
title
compound (55%).
LC/MS = m/z 519.4 [M+H] Ret. Time: 1.77 min
Example 162: 543-M(1 R)-1,2-dimethylpropyllamino}methyl)phenyll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O---
F
O HN N \O
F-H
F OH
N
H
H 2 N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL), MeOH (1.5 mL) and acetic acid
was
added (2R)-3-methyl-2-butanamine (160 pL, 1.37 mmol) and stirred at room
temperature
for 2 h. Sodium borohydride (19 mg, 0.546 mmol) was then added and stirred for
48 h.
Compound was then purified by Gilson Preparatory HPLC to give 50 mg of the
title
compound (86%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.65 min
Example 163: 5-(6-amino-2-pyridinyl)-3-f 1-(ethylsulfonyl)-4-piperidinyll-1
I+indole-7-
carboxamide trifluoroacetate
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O~ S ~-
~
/ \.
N O
H2N
N
F O
F OH H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (83 mg, 0.18 mmol) in dioxane (5
mL) was
added 6-bromo-2-pyridinamine (93 mg, 0.54 mmol), potassium carbonate (149 mg,
1.08
mmol) in H20 (1.5 mL) and chloro(di-2-norbornylphosphino)(2-
dimethylaminomethylferrocen-1-yl)palladium (II) (19 mg, 0.031 mmol). The
reaction was
heated in the microwave at 150 C for 20 min. The reaction mixture was then
concentrated and an aqueous extraction was performed. Organic layer was then
concentrated and purified on a Mass Directed Auto Prep HPLC to give 22.3 mg of
the title
compound (29%).
LC/MS = m/z 428.6 [M+H] Ret. Time: 1.34 min
Example 164: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(1 H-pyrazol-l-
yl)phenyll-1 H-
indole-7-carboxamide
o z:zsz:-
N
/
N
~ N
H
0 NH2
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (20
mg,
0.048 mmol) was added [3-(1 H-pyrazol-1 -yl) phenyl] boron ic acid (36 mg,
0.193 mmol},
dioxane (2.8 mL) and a solution of potassium carbonate (20 mg) in water (1.2
mL). To
this mixture was added chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-
(dinorbornylphosphine)palladium(II) (3 mg, 0.005 mmol). The resulting mixture
was
reacted in a CEM microwave for 10 min at 160 C then concentrated under a
stream of
nitrogen (greenhouse) at 80 C. The crude product was partitioned between
water (2 mL)
and CH2CL2 (2 mL). The layers were separated with a hydrophobic frit, and the
aqueous
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layer was extracted with CH2CL2 (2 x 2 mL). The organic layers were pooled and
concentrated under a stream of nitrogen at 80 C. Dimethyl sulfoxide (0.8 mL)
was
added to residue, which was sonicated for 10 sec, filtered through a cotton
plug, and then
filtered through a 0.2 m filter. The crude product was purified on an Agilent
MDAP using
a Zorbax Eclipse XDB 610 21.2 x 50 mm column to afford 2.3 mg of the title
compound
(10%).
LC/MS = m/z 478.2 [M+H] Ret. Time: 2.05 min.
Example 165: 5-f4-(dimethylamino)phenyll-3-f1-(ethylsulfonyl)-4-piperidinyll-1
H-
indole-7-carboxamide
o zz:
szzo
N
I \ ~
N
H
o NH2
To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-
indole-7-carboxamide (40 mg, 0.097 mmol), dioxane (2.8 mL) and a solution of
potassium
carbonate (40 mg, 0.289 mmol) in water (1.2 mL). To this mixture was added [4-
(dimethylamino)phenyl]boronic acid (65 mg, 0.386 mmol) and chloro-2-
(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (1 mg,
0.002
mmol). The vial was capped and the reaction was reacted in a CEM microwave for
10
min at 160 C. The reaction was concentrated under a stream of nitrogen at 80
C. The
crude product was taken up in dimethyl sulfoxide (1 mL) and purified through a
1 g silica
SPE cartridge eluting with dimethyl sulfoxide (4 mL). The dimethyl sulfoxide
was
concentrated in a Genevac at 65 C for 3 h, and the residue was reconstituted
in dimethyl
sulfoxide (1 mL) and filtered through an acrodisc. The solution of crude
product was then
purified on the Agilent MDAP (UV 214 selection). The purified product was
passed
through a polymer-bound carbonate SPE cartridge to afford 2.7 mg of the title
compound
(6.2%).
LC/MS = m/z 455.2 [M+H] Ret. Time: 1.71 min.
Example 166: 5-(3-aminophenyl)-341-(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-
carboxamide
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O;S'O
NH2 N
N
H
O NH2
To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-
indole-7-carboxamide (40 mg, 0.0965 mmol), potassium carbonate (80 mg, 0.578
mmol)
and (3-aminophenyl)boronic acid sulfate (145 mg, 0.386 mmol). The mixture was
taken
up in water (1.2 mL) and dioxane (2.8 mL), and chloro-2-(dimethylaminomethyl)-
ferrocen-
1-yl-(dinorbornylphosphine)palladium(II) (1 mg, 0.002 mmol) was added. The
mixture
was then reacted in a CEM microwave for 10 min at 150 C. Ethyl acetate (2 mL)
was
added and the layers were separated. The aqueous layer was washed with ethyl
acetate
(1 x 2 mL). The organic layers were pooled, concentrated under a stream of
nitrogen,
and taken up in dimethyl sulfoxide (0.89 mL) and trifluoroacetic acid (0.15
mL). This
solution of crude product was purified on an Agilent MDAP eluting with a
linear gradient of
30% CH3CN/H20 (0.1 % TFA) to 70% CH3CN/H20 (0.1 % TFA) at 20 mUmin over 9 min.
To the HPLC fraction containing product was added a solution of saturated
K2CQ3 (1 mL),
a 1 M solution of sodium hydroxide (1 mL), and ethyl acetate (2 mL). The
layers were
separated and the aqueous layer was extracted with ethyl acetate (2 x 2 mL).
The
organic layers were pooled, filtered through a plug of magnesium sulfate, and
concentrated under a stream of nitrogen to give 14.9 mg of the title compound
(36%).
LC/MS = m/z 427.2 [M+H] Ret. Time: 1.39 min.
Example 167: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-f(2-methyl-l-
pyrrolidinyl)methyll-2-thienyl}-1 H-indole-7-carboxamide
::~s,o
cJ N
s
N
H
O NH2
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The {5-[(2-methyl-l-pyrrolidinyl)methyl]-2-thienyl}boronic acid used to
prepare 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-2-
thienyl}-1 H-indole-7-
carboxamide was prepared in three separate batches using the procedures shown
below:
Batch 1: NaBH(OAc)3 (271 mg, 1.28 mmol), HOAc (0.07 mL), and 2-
Methylpyrrolidine
(0.043 mL, 0.42 mmol) were added to a solution of (5-formyl-2-thienyl)boronic
acid (100
mg, 0.64 mmol) in CH2CI2 (4 mL) in a 2-dram vial. The vial was capped and the
reaction
was stirred at room temperature for 15 h. The reaction mixture was loaded
directly onto a
2 g SCX cartridge (pre-equilibrated with MeOH), eluting in sequence with MeOH
(12 mL)
and a 2 M solution of NH3/MeOH (8 mL). The fractions containing the boronic
acid crude
product were concentrated under a stream of N2 and dried under high vacuum to
give 45
mg of crude product. The crude product was taken up in saturated NaHCO3 (2 mL)
and
extracted with EtOAc (3 x 2 mL) to give 6.6 mg of crude {5-[(2-methyl-l-
pyrrolidinyl)methyl]-2-thienyl}boronic acid.
Batch 2: NaBH(OAc)3 (271 mg, 1.28 mmol), HOAc (0.07 mL), and 2-
Methylpyrrolidine
(0.043 mL, 0.42 mmol) were added to a solution of (5-formyl-2-thienyl)boronic
acid (100
mg, 0.64 mmol) in 1:1 CH2CI2/MeOH (4 mL) in a 2-dram vial. The vial was capped
and
the reaction was stirred at room temperature for 15 h. The reaction mixture
was loaded
directly onto a 2 g SCX cartridge (pre-equilibrated with MeOH), eluting in
sequence with
MeOH (12 mL) and a 2 M solution of NH3/MeOH (8 mL). The fractions containing
the
boronic acid crude product were concentrated under a stream of N2 and dried
under high
vacuum to give 45 mg of crude product. The crude product was taken up in
saturated
NaHCO3 (2 mL) and extracted with EtOAc (3 x 2 mL) to give 5 mg of crude {5-[(2-
methyl-
1-pyrrolidinyl)methyl]-2-thienyl}boronic acid.
Batch 3: 2-Methylpyrrolidine (0.033 mL, 0.32 mmol) was added to a solution of
(5-formyl-
2-thienyl)boronic acid (50 mg, 0.32 mmol) in MeOH (1 mL) in a 2-dram vial. The
vial was
capped and the reaction was stirred at room temperature for 2 h. NaCNBH3 (40
mg, 0.64
mol) was added, and stirring continued for 19 h. The reaction mixture was
loaded directly
onto a 2 g SCX cartridge (pre-equilibrated with MeOH), eluting in sequence
with MeOH
(12 mL) -and a 2 M solution of NH3/MeOH (9 mL). The fractions containing the
boronic
acid crude product were concentrated under a stream of N2 and dried under high
vacuum
to give 45 mg of crude product. The crude product was taken up in saturated
NaHCO3 (2
mL) and extracted with EtOAc (3 x 2 mL) to give 7.8 mg of crude {5-[(2-methyl-
1-
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pyrrolidinyl)methyl]-2-thienyl}boronic acid. The crude boronic acid from the
above three
reactions were pooled and carried on for the preparation of 3-[1-
(ethylsulfonyl)-4-
piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}-1 H-indole-7-
carboxamide (final
weight after pooling the three batches of {5-[(2-methyl-l-pyrrolidinyl)methyl]-
2-
thienyl}boronic acid was 19 mg).
A solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-11-1-indole-7-
carboxamide (36 mg,
0.0862 mmol), {5-[(2-methyl-1 -pyrrolidinyl)methyl]-2-thienyl}boronic acid (19
mg, 0.0862
mmol) and potassium carbonate (71 mg, 0.517 mmol) was combined in a CEM
microwave tube. To this mixture was added water (0.25 mL), dioxane (0.75 mL)
and
tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol). The vial was
capped and
reacted in a CEM microwave for 20 min at 150 C. To this reaction was added
tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and reacted in a
microwave for 20 min at 150 C. Additional
tetrakis(triphenylphosphine)palladium(0) (10
mg, 0.009 mmol) was added, and the reaction was heated in the CEM microwave
for an
additional 20 min at 150 C. The reaction mixture was filtered through a 2 g
SCX
cartridge (pre-equilibrated with with 3 mL H20), eluting in sequence with
water (3 mL),
MeOH (9 mL), and a 2 M solution of NH3/MeOH (9 mL). The fraction containing
crude
product solution was concentrated under a stream of nitrogen, and the residue
was taken
up in DMSO (3 mL). This DMSO solution of crude product was purified as three
separate
injections (1 mL each) on the Agilent MDAP (Zorbax Eclipse XDB-C18 column:
21.2 x 50
mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H20 (0.1 % TFA) then a
linear
gradient of -10% CH3CN/H20 (0.1 % TFA) to 95% CH3CN/H20 (0.1 % TFA) over 8 min
and
holding at the final concentration for 30 sec. The two fractions containing
product were
filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium
hydroxide; United Chemical Technologies) to remove TFA (2 columns used per
fraction)
and concentrated under a stream of nitrogen at 40 C to give 13 mg of the
title
compound (29.3%).
LC/MS = m/z 515.6 [M+H] Ret. Time: 1.62 min.
Example 168: 5-{5-f(ethylamino)methyll-2-thienyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
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o_s o
N
\_N
S
N
H
H2N O
The {5-[(ethylamino)methyl]-2-thienyl}boronic acid used to prepare 5-{5-
[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-
7-carboxamide
was prepared as follows: A 2 M solution of ethylamine in THF (0.16 mL, 0.32
mmol) was
added to a solution of (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol) in
MeOH (1
mL) in a 2-dram vial. The vial was capped and the reaction was stirred at room
temperature for 2 h. NaCNBH3 (40 mg, 0.64 mmol) was added, and stirring
continued for
17 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-
equilibrated with
with 3 mL MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of
NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of
nitrogen
to give 47 mg of crude {5-[(ethylamino)methyl]-2-thienyl}boronic acid.
To a CEM microwave tube containing {5-[(ethylamino)methyl]-2-thienyl}boronic
acid (47
mg, 0.254 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16
mmol), dioxane (1.5 mL), H20 (0.5 mL) and
tetrakis(triphenylphosphine)palladium(0) (5
mg, 0.004 mmol). The reaction was heated in a CEM microwave for 30 min at 150
C.
(This run was aborted prior to 30 min due to excessive pressure build-up). The
reaction
mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3
mL MeOH),
eluting in sequence with H20 (3 mL), MeOH (9 mL) and a 2 M solution of
NH3/MeOH (6
mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40 C, and
the
crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an
Agilent MDAP
(Zorbax Eclipse XDB-C18 column: 21.2 x 50 mm) eluting at 20 mL per min for 1
min with
10% CH3CN/H20 (0.1 % TFA) then a linear gradient of 10% CH3CN/H20 (0.1 % TFA)
to
95% CH3CN/H20 (0.1 % TFA) over 8 min and holding at the final concentration
for 30 sec.
The fractions containing product were filtered through a 500 mg Pharmasil
CHQAX
column (polymer bound ammonium hydroxide; United Chemical Technologies) to
remove
TFA (2 columns used per fraction) and concentrated under a stream of nitrogen
at 60 C
to give 8.8 mg of the title compound (10%).
LC/MS = mlz 429.8 [M+H] Ret. Time: 1.25 min.
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Example 169: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-ff(1-
methylethyl)aminolmethyl}-2-thienyl)-1 H-indole-7-carboxamide
o ~~
N
H
-N
s
N
H
HZN O
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), isopropylamine (0.027 mL, 0.32 mmol), and NaCNBH3 (40 mg,
0.64
mmol) were reacted to give 41 mg of crude (5-{[(1-methylethyl)amino]methyl}-2-
thienyl)boronic acid. The crude (5-{[(1-methylethyl)amino]methyl}-2-
thienyl)boronic acid
was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1// indole-7-
carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and
tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 74 mg of
the title
compound (37%).
LC/MS = m/z 430.2 [M+H] Ret. Time: 1.29 min.
Example 170: 545-f(cyclopropylamino)methyll-2-thienyl}-3-f1-(ethylsulfonyl)-4-
piperidinyii-1 H-indole-7-carboxamide
O ; o
N
~----N
s
N
H
HZN O
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), cyclopropylamine (0.022 mL, 0.32 mmol), and NaCNBH3 (40
mg,
0.64 mmol) were reacted to give 63 mg of crude {5-[(cyclopropylamino)methyl]-2-
thienyl}boronic acid. The crude {5-[(cyclopropylamino)methyl]-2-
thienyl}boronic acid was
then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (80
mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and
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tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give impure
title
compound. The impure title compound was purified again with the Agilent MDAP
and
isolated as the free base according to the procedure shown in Example 5 to
give 6.8 mg
of the title compound (7.2%).
LC/MS = m/z 430.2 [M+H] Ret. Time: 1.62 min.
Example 171: 5-(5-ff(2,2-dimethylpropyl)aminolmethyll-2-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
o / o
N
N
s
N
H
H2N O
Following the general procedure of 5-15-[(ethylamino)methyl]-2-thienyl}-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), (2,2-dimethylpropyl)amine (0.037 mL, 0.32 mmol), and
NaCNBH3
(40 mg, 0.64 mmol) were reacted to give 73 mg of crude (5-{[(2,2-
dimethylpropyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(2,2-
dimethylpropyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-
bromo-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (80 mg, 0.193 mmol),
potassium
carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5
mg,
0.004 mmol) to give 21 mg of the title compound (21 %).
LC/MS = m/z 430.2 [M+H] Ret. Time: 1.45 min.
Example 172: 5-(5-{f(cyclopropylmethyl)aminolmethyl}-2-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
; o
N
H
N ~ I
s
N
H
HZN 0
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-
(ethylsulfonyl)-4-piperidinylj-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
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(50 mg, 0.32 mmol), (cyclopropylmethyl)amine (0.027 mL, 0.32 mmol), and
NaCNBH3 (40
mg, 0.64 mmol) were reacted to give 73 mg of crude (5-
{[(cyclopropylmethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-
{[(cyclopropylmethyl)amino]methyl}-2-thienyl)boronic acid was then reacted
with 5-bromo-
3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (80 mg, 0.193
mmol),
potassium carbonate (160 mg, 1.16 mmol), and
tetrakis(triphenylphosphine)palladium(0)
(5 mg, 0.004 mmol) to give 19.1 mg of the title compound (20%).
LC/MS = m/z 430.2 [M+H] Ret. Time: 1.33 min.
Example 173: 5-(5-ff(cyclopropylmethyl)aminolmethyl}-3-pyridinyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
0; o
N
N
N
H
HZN O
The (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-
pyridinyl]methyl}amine used to prepare 5-(5-{[(cyclopropylmethyl)amino]methyl}-
3-
pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide was
prepared as
follows: (Cyclopropylmethyl)amine (0.011 mL, 0.129 mmol) was added to a
solution of 5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg,
0.129
mmol) in MeOH (1 mL) in a 2-dram vial. The vial was capped and the reaction
was
stirred at room temperature for 17 h. NaCNBH3 (16 mg, 0.258 mmol) was added,
and
stirring continued for 30 h. The reaction mixture was filtered through a 2 g
SCX cartridge
(pre-equilibrated with with 3 mL MeOH), eluting in sequence with MeOH (6 mL)
and a 2 M
solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a
stream
of nitrogen to give 21 mg of crude (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-3-pyridinyl]methyl}amine.
To a CEM microwave tube containing (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (21 mg, 0.0725 mmol) was added 5-
bromo-3-
[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (30 mg, 0.0723
mmol), dioxane
(0.75 mL), a solution of potassium carbonate (60 mg, 0.434 mmol) in H20 (0.25
mL), and
chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(I
I) (4.4
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mg, 0.00723 mmol). The reaction was heated in a CEM microwave for 30 min at
150 C.
The reaction mixture was filtered through a 2 g SCX cartridge (pre-
equilibrated with with 3
mL MeOH), eluting in sequence with H20 (3 mL), MeOH (6 mL) and a 2 M solution
of
NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at
40
C and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 50
mm)
eluting at 20 mL per min for 1 min with 10% CH3CN/H20 (0.1% TFA) then a linear
gradient of 10% CH3CN/H20 (0.1 % TFA). to 95% CH3CN/H20 (0.1 % TFA) over 8 min
and
holding at the final concentration for 30 sec. The fractions containing
product were
filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium
hydroxide;
United Chemical Technologies) to remove TFA and concentrated under a stream of
nitrogen at 65 C to give impure title compound, which was repurified on the
Agilent
MDAP as shown above to give 25 mg of the title compound (70%).
LC/MS = m/z 496.6 [M+H] Ret. Time: 1.35 min.
Example 174: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-({f2-
(methyloxy)ethyllamino}methyl)-3-pyridinyll-1 H-indole-7-carboxamide
o; o
N
N
H
N
H
H2N 0
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-
pyridinyl)-
3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [2-
(methyloxy)ethyl]amine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol)
were reacted to give 19 mg of crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [2-(methyloxy)ethyl]{[5-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted
with 5-
bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (30 mg,
0.0723 mmol),
potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-
ferrocen-
1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 15 mg
of the title
compound (46%).
LC/MS = m/z 500.6 [M+H] Ret. Time: 1.52 min.
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Example 175: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-f5-(ff3-
(methyloxy)propyllamino}methyl)-3-pyridinyll-1 H-indole-7-carboxamide
; o
N
N
/N
N
H
HZN O
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-
pyridinyl)-
3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [3-
(methyloxy)propyl]amine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258
mmol)
were reacted to give 22 mg of crude [3-(methyloxy)propyl]{[5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [3-
(methyloxy)propyl]{[5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted
with 5-
bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (30 mg,
0.0723 mmol),
potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-
ferrocen-
1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 31 mg
of the title
compound (83%).
LC/MS = mlz 514.4 [M+H] Ret. Time: 1.46 min.
Example 176: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-(4-morpholinylmethyl)-3-
pyridinyil-1 H-indole-7-carboxamide
; o
N
0 N
N
H
H2N O
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-
pyridinyl)-
3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), morpholine
(0.011 mL,
0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 28 mg of
crude 4-
{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-
pyridinyl]methyl}morpholine. The
crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yi)-3-
pyridinyl]methyl}morpholine
was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
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carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and
chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(I
I) (4.4
mg, 0.00723 mmol) to give 15.8 mg of the title compound (43%).
LC/MS = m/z 512.2 [M+H] Ret. Time: 1.38 min.
Example 177: 5454(ethylamino)methyll-3-pyridinyl}-3-f1-(ethylsulfonyl)-4-
Piperidinyll-1 H-indole-7-carboxamide
0-
o
N
N
i I
N
\ I N
H
HZN O
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-
pyridinyl)-
3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution
of
ethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were
reacted to give 19 mg of crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-
pyridinyl]methyl}amine. The crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-
3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1 -(ethylsulfonyl)-4-
piperidinyl]-
1hl-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg,
0.434
mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-
(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.3 mg of
the title
compound (36%).
LC/MS = m/z 470.4 [M+H] Ret. Time: 1.44 min.
Example 178: 5-f5-f(dimethylamino)methyll-3-pyridinyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
0
; o
N
N
N
H
HZN O
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-
pyridinyl)-
3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-
tetramethyl-1,3,2-
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dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution
of
dimethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol)
were
reacted to give 23 mg of crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-
3-pyridinyl]methyl}amine. The crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-
2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium
carbonate (60
mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-
(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 5.4 mg of
the title
compound (16%).
LC/MS = m/z 470.6 [M+H] Ret. Time: 1.35 min.
Example 179: 3-f1-(ethylsulfonyl)-4-piperidinyli-5-{5-f(2-methyl-l-
pyrrolidinyl)methyll-3-pyridinyl}-1 H-indole-7-carboxamide
0; o
N
N
~N 1
I
N
H
HZN O
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-
pyridinyl)-
3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), 2-
methylpyrrolidine
(0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give
25 mg
of crude 3-[(2-methyl-l-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-
yl)pyridine. The crude 3-[(2-methyl-l-pyrrolidinyl)methyl]-5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)pyridine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-
4-
piperidinyl]-1 H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium
carbonate (60
mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-
(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 6 mg of the
title
compound (16%).
LC/MS = m/z 512.6 [M+H] Ret. Time: 1.67 min.
Example 180: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-(5-ff(2-
methvlpropyl)aminolmethyl}-3-pyridinyl)-1 H-indole-7-carboxamide
193

CA 02613068 2007-12-20
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O ~ o
N
N
I
\/N
N
H
H2N O
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-
pyridinyl)-
3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), isobutylamine
(0.013
mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 21 mg of
crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-
pyridinyl]methyl}amine. The crude (2-methylpropyl){[5-(4,4,5,5- tetramethyl-
1,3,2-
dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (30 mg, 0.0723 mmol),
potassium
carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-
yl-
(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.5 mg of
the title
compound (35%).
LC/MS = m/z 498.2 [M+H] Ret. Time: 1.38 min.
Example 181: 5-(5-ff(2,2-dimethylpropyl)aminolmethyll-3-pyridinyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
O ; o
N
N
N
N
H
HzN O
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-
pyridinyl)-
3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), (2,2-
dimethylpropyl)amine (0.015 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol)
were
reacted to give 25 mg of crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2,2-dimethylpropyl){[5-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted
with 5-
bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (30 mg,
0.0723 mmol),
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potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-
ferrocen-
1-yI-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.7
mg of the
title compound (34%).
LC/MS = m/z 512.4 [M+H] Ret. Time: 1.51 min.
Example 182: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-(5-ff(2-
methvlbutyl)aminolmethyl}-2-thienyl)-1 H-indole-7-carboxamide
Or
N
N
H
s
N
H
HZN O
The {5-[(ethylamino)methyl]-2-thienyl}boronic acid used to prepare 3-[1 -
(ethylsulfonyl)-4-
piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-
carboxamide was
prepared as follows: A solution of (5-formyl-2-thienyl)boronic acid (50 mg,
0.32 mmol) in
MeOH (0.5 mL) and a solution of NaCNBH3 (40 mg, 0.64 mmol) in MeOH (0.5 mL)
were
added to (2-methylbutyl)amine (28 mg, 0.32 mmol) in a 2-dram vial. The vial
was capped
and the reaction was stirred at room temperature for 20 h. The reaction
mixture was
filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH),
eluting in
sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH
fraction was concentrated under a stream of nitrogen to give 43 mg of crude (5-
{[(2-
methylbutyl)amino]methyl}-2-thienyl)boronic acid.
To a CEM microwave tube containing the crude (5-{[(2-methylbutyl)amino]methyl}-
2-
thienyl)boronic acid (43 mg, 0.188 mmol) was added 5-bromo-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg,
0.942 mmol),
dioxane (1.5 mL), H20 (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (4
mg,
0.003 mmol). The reaction was heated in a CEM microwave for 30 min at 150 C.
The
reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated
with with 3 mL
MeOH), eluting in sequence with H20 (3 mL), MeOH (9 mL) and a 2 M solution of
NH3/MeOH (6 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at
40
C, and the crude product was taken up in dimethyl sulfoxide (1 mL) and
purified on an
Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 50 mm) eluting at 20 mL
per min
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for 1 min with 10% CH3CN/H20 (0.1% TFA) then a linear gradient of 10%
CH3CN/H20
(0.1% TFA) to 95% CH3CN/H20 (0.1% TFA) over 8 min and holding at the final
concentration for 30 sec. The fractions containing product were filtered
through a 2 g
Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical
Technologies) to remove TFA and concentrated under a stream of nitrogen at 50
C to
give 16.2 mg of the title compound (17%).
LC/MS = m/z 430.4 [M+H] Ret. Time: 1.75 min.
Example 183: 5-f5-({f(1 R)-1,2-dimethylpropyllamino}methyl)-2-thienyll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
Chiral
C ~ O
N N
H
s
N
H
HzN O
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-
{[(2-
methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid (50 mg, 0.32 mmol), [(1 R)-1,2-dimethylpropyl]amine (28
mg, 0.32
mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-
({[(1 R)-
1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1 R)-
1,2-
dimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-
bromo-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol),
K2CO3 (130
mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003
mmol) to
give 20.5 mg of the title compound (30%).
LC/MS = mlz 430.4 [M+H] Ret. Time: 1.75 min.
Example 184: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-d5-f(pentylamino)methyll-2-
thienyl}-1 H-indole-7-carboxamide
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O i o
N N
H
S
N
H
H2N O
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-
{[(2-
methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid (50 mg, 0.32 mmol), pentylamine (29 mg, 0.32 mmol), and
NaCNBH3
(40 mg, 0.64 mmol) were reacted to give 45 mg of crude {5-
[(pentylamino)methyl]-2-
thienyl}boronic acid. The crude {5-[(pentylamino)methyl]-2-thienyl}boronic
acid was then
reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (65 mg,
0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and
tetrakis(triphenylphosphine)palladium(0)
(4 mg, 0.003 mmol) to give 20.7 mg of the title compound (20%).
LC/MS = m/z 430.6 [M+H] Ret. Time: 1.75 min.
Example 185: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-({f(2S)-2-
methylbutyllamino}methyl)-2-thienyll-1 H-indole-7-carboxamide
O' O
N N
H
/
N
H
tNO
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-
{[(2-
methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid (50 mg, 0.32 mmol), [(2S)-2-methylbutyl]amine (28 mg,
0.32 mmol),
and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude [5-({[(2S)-
2-
methylbutyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(2S)-2-
methylbutyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-
3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol),
K2CO3 (130
mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003
mmol) to
give 37.6 mg of the title compound (39%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.67 min.
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Example 186: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-{f(1-
methylbutyl)aminolmethyl}-2-thienyl)-1 H-indole-7-carboxamide
; o
N N
H
S
N
H
HZN O
Following the general procedure of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-
{[(2-
methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid (50 mg, 0.32 mmol), (1-methylbutyl)amine (29 mg, 0.32
mmol), and
NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude (5-{[(1-
methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(1-
methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-
3-[1 -
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol),
K2C03 (130
mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003
mmol) to
give 35.2 mg of the title compound (60%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.62 min.
Example 187: 5-{54(butylamino)methyll-2-thienyi}-3-f 1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
o ~r
S--
N
N
H
s
N
H
H2N O
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-
{[(2-
methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid (50 mg, 0.32 mmol), butylamine (24 mg, 0.32 mmol), and
NaCNBH3
(40 mg, 0.64 mmol) were reacted to give 49 mg of crude {5-[(butylamino)methyl]-
2-
thienyl}boronic acid. The crude {5-[(butylamino)methyl]-2-thienyl}boronic acid
was then
reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (65 mg,
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0.157 mmol), K2C03 (130 mg, 0.942 mmol), and
tetrakis(triphenylphosphine)palladium(0)
(4 mg, 0.003 mmol) to give 27.2 mg of the title compound (24%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.56 min.
Example 188: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-f5-(ff2-
(methyloxy)ethyllamino}methyl)-2-thienyll-1 H-indole-7-carboxamide
N O
N
H
s
N
H
HZN O
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-
{[(2-
methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid (50 mg, 0.32 mmol), [2-(methyloxy)ethyl]amine (24 mg,
0.32 mmol),
and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 42 mg of crude [5-({[2-
(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[2-
(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-
bromo-3-
[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157
mmol), K2CO3
(130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg,
0.003 mmol)
to give impure title compound. The impure title compound was repurified using
the HPLC
and ammonium hydroxide SPE workup shown in preparation of 3-[1-(ethylsulfonyl)-
4-
piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-
carboxamide to
give 15 mg of the title compound (15%).
LC/MS = m/z 430.2 [M+H] Ret. Time: 1.33 min.
Example 189: 5-f5-f(cyclopentylamino)methyll-2-thienyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
4
N
N
H
s
N
H
HZN O
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Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-
{[(2-
methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid (50 mg, 0.32 mmol), cyclopentylamine (28 mg, 0.32 mmol),
and
NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 48 mg of crude {5-
[(cyclopentylamino)methyl]-2-thienyl}boronic acid. The crude {5-
[(cyclopentylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-
bromo-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol),
K2CO3 (130
mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003
mmol) to
give 93.5 mg of the title compound (85%).
LC/MS = m/z 430.4 [M+H] Ret. Time: 1.64 min.
Example 190: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-(5-df(3-
methylbutyl)aminolmethyl}-2-thienyl)-1 H-indole-7-carboxamide
0; o
N N
H
~ I N
H
HZN O
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-
{[(2-
methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid (50 mg, 0.32 mmol), (3-methylbutyl)amine (28 mg, 0.32
mmol), and
NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 46 mg of crude (5-{[(3-
methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3-
methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-
3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol),
K2C03 (130
mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003
mmol) to
give 38.3 mg of the title compound (37%).
LC/MS = m/z 430.4 [M+H] Ret. Time: 1.75 min.
Example 191: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-(54 f(1-
methylethyl)aminolmethyl}-3-pyridinyl)-1 H-indole-7-carboxamide
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O%S O
N
N
i I
N \ I \
N
H
0 NH2
The (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-
pyridinyl]methyl}amine used to prepare 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-
(5-{[(1-
methylethyl)amino]methyl}-3-pyridinyl)-1 H-indole-7-carboxamide was prepared
as
follows: isopropylamine (0.011 mL, 0.129 mmol) was added to a solution of 5-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129
mmol) in
MeOH (1 mL) in a 2-dram vial. NaCNBH3 (16 mg, 0.258 mmol) was then added, the
vial
was capped and the reaction was stirred at room temperature for 24 h. The
reaction
mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3
mL MeOH),
eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL).
The
NH3/MeOH fraction was concentrated under a stream of nitrogen to give 22 mg of
crude
(1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-
pyridinyl]methyl}amine.
To a CEM microwave tube containing (1-methylethyl){[5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (22 mg, 0.080 mmol) was added 5-
bromo-3-
[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (50 mg, 0.121
mmol), K2C03
(100 mg, 0.724 mmol), dioxane (1.5 mL), H20 (0. 5 mL), and chloro-2-
(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(I I) (7.3
mg,
0.012 mmol). The reaction was heated in a CEM microwave for 30 min at 150 C.
The
reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated
with with 3 mL
MeOH), eluting in sequence with H20 (3 mL), MeOH (6 mL) and a 2 M solution of
NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at
50
C and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 100
mm)
eluting at 20 mL per min for 1 min with 10% CH3CN/H20 (0.1 % TFA) then a
linear
gradient of 10% CH3CN/H20 (0.1 % TFA) to 95% CH3CN/H20 (0.1 % TFA) over 8 min
and
holding at the final concentration for 30 sec. The fractions containing
product were
filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium
hydroxide;
United Chemical Technologies) to remove TFA and concentrated under a stream of
nitrogen at 50 C to give 27.2 mg of the title compound (70%).
LC/MS = m/z 484 [M+H] Ret. Time: 1.25 min.
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Example 192: 5-(5-df(2-ethylbutyl)aminolmethyl}-2-thienyl)-3-f1-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
o --s
N N
H
s
= ~ \
N
H
O NH2
The {5-[(ethylamino)methyl]-2-thienyl}boronic acid used to prepare 5-(5-{[(2-
ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide was prepared as follows: A solution of (5-formyl-2-thienyl)boronic
acid (50
mg, 0.32 mmol) in MeOH (0.5 mL) and a solution of NaCNBH3 (40 mg, 0.64 mmol)
in
MeOH (0.5 mL) were added to (2-ethylbutyl)amine (32 mg, 0.32 mmol) in a 2-dram
vial.
The vial was capped and the reaction was stirred at room temperature for 20 h.
The
reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated
with with 3 mL
MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9
mL).
The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 48
mg of
crude (5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)boronic acid.
To a CEM microwave tube containing the crude (5-{[(2-ethylbutyl)amino]methyl}-
2-
thienyl)boronic acid (48 mg, 0.199 mmol) was added a solution of 5-bromo-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol) in
dioxane
(1.75 mL), a solution of K2C03 (130 mg, 0.942 mmol) in H20 (0.25 mL), and
tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The reaction was
heated
in a CEM microwave for 30 min at 150 C. The reaction mixture was filtered
through a 2
g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence
with MeOH
(3 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried
under
a stream of nitrogen at 50 C, and the crude product was taken up in dimethyl
sulfoxide
(1.1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2
x 100
mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H20 (0.1% TFA) then a
linear
gradient of 10% CH3CN/H20 (0.1 % TFA) to 95% CH3CN/H20 (0.1 % TFA) over 8 min
and
holding at the final concentration for 30 sec. The fractions containing
product were
filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium
hydroxide;
United Chemical Technologies) to remove TFA and concentrated under a stream of
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nitrogen at 50 C to give impure title compound. The impure title compound was
repurified on an Agilent MDAP and free based with the ammonium hydroxide
column as
shown above to give 8.5 mg of the title compound (10%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.72 min.
Example 193: 5-f5-(ff3-(ethyloxy)propyllamino}methyl)-2-thienyll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
Szzzo
%r
N
N
H
s
N
H
O NH2
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), [3-(ethyloxy)propyl]amine (34 mg, 0.32 mmol), and NaCNBH3
(40
mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-
(ethyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-
(ethyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-
bromo-3-
[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157
mmol), I<2CO3
(130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg,
0.0079 mmol)
to give 8.1 mg of the title compound (10%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.62 min.
Example 194: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-(ff3-
(methyloxy)propyllamino}methyl)-2-thienyll-1 H-indole-7-carboxamide
o __
~ _s\
N
N
H
s
N
H
O NHZ
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
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(50 mg, 0.32 mmol), [3-(methyloxy)propyl]amine (29 mg, 0.32 mmol), and NaCNBH3
(40
mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-
(methyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-
(methyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-
bromo-3-
[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol),
K2C03
(130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg,
0.0079 mmol). The crude product was purified once on an Agilent MDAP using the
procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide to give 7.6 mg of the
title
compound (9%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.50 min.
Example 195: 5-(5-ff(cyclohexylmethyl)aminolmethyl}-2-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyil-1 H-indole-7-carboxamide
O Nr
N
H
s
N
H
0 NH2
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), (cyclohexylmethyl)amine (37 mg, 0.32 mmol), and NaCNBH3
(40
mg, 0.64 mmol) were reacted to give 30 mg of crude (5-
{[(cyclohexylmethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-
{[(cyclohexylmethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with
5-bromo-
3-[1-(ethylsulfonyl)-4-piperidinylr-1 H-indole-7-carboxamide (65 mg, 0.157
mmol), K2CO3
(130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg,
0.0079 mmol). The crude product was purified once on an Agilent MDAP using the
procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide. The purified product
was washed
with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL)
and
washed with saturated K2C03 (1 mL). The organic layer was concentrated to give
4.7 mg
of the title compound (6%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.82 min.
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Example 196: 3-[i-(ethylsutfonyl)-4-piperidinyll-5-f'5-f({3-f(1-
methylethvl)oxylpropyf}amino)methyll-2-thienyl}-1 H-indole-7-carboxamide
=s;o
N N
H
N
H
O NHZ
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), {3-[(1-methylethyl)oxy]propyl}amine (38 mg, 0.32 mmol),
and
NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude {5-[({3-[(1-
methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid. The crude {5-[({3-
[(1-
methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid was then reacted
with 5-
bromo-3-[1-(ethylsuifonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg,
0.157 mmol),
K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9
mg,
0.0079 mmol). After purification on an Agilent MDAP twice as shown in
preparation of 5-
(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-
carboxamide, the impure title compound was washed with a 20:4:1 mixture of
hexanes/EtOAc/MeOH (2.5 mL) to give 7.6 mg of the title compound (9%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.62 rnin.
Example 197: 5-f5-!{f2-(ethyloxy)ethyllaminolmethyl)-2-thienylt 3-f 1-
ethylsulfonyl)-
4-piperidinyll-1 H-indole-7-carboxamide
1-
'--\ ;S'
N N
N
H
O NHZ
Following the general procedure of 5-(5-{[(2-ethyfbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsu(fonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), [2-(ethyloxy)ethyl]amine (30 mg, 0.32 mmol), and NaCNBH3
(40 mg,
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0.64 mmol) were reacted to give 30 mg of crude [5-({[2-
(ethyloxy)ethyl]amino}methyl)-2-
thienyl]boronic acid. The crude [5-({[2-(ethyloxy)ethyl]amino}methyl)-2-
thienyl]boronic
acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and
tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude
product was
purified once on an Agilent MDAP using the procedure shown for preparation of
5-(5-{[(2-
ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide to give 6 mg of the title compound (7%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.66 min.
Example 198: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-f5-(ff3-
(propyloxy)propyllamino}methyl)-2-thienyll-1 H-indole-7-carboxamide
0~
~
~s~
N
N
H
s
N
H
O NHZ
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), [3-(propyloxy)propyl]amine (38 mg, 0.32 mmol), and NaCNBH3
(40
mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-
(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-
(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-
bromo-3-
[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157
mmol), K2CO3
(130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg,
0.0079 mmol). The crude product was purified twice on an Agilent MDAP using
the
procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide. The purified product
was washed
with a 20:4:1 mixture of hexaness/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2
mL) and
washed with saturated K2C03 (1 mL). The organic layer was concentrated to give
to give
1.4 mg of the title compound (2%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.66 min.
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Example 199: 5-(5-ff(3,3-dimethylbutyl)aminolmethyl}-2-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
o ~r
szz~o
N
N
H
N
H
O NHZ
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), (3,3-dimethylbutyl)amine (32 mg, 0.32 mmol), and NaCNBH3
(40
mg, 0.64 mmol) were reacted to give 30 mg of crude (5-{[(3,3-
dimethylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3,3-
dimethylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-
bromo-3-[1 -
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol),
K2C03 (130
mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079
mmol) to
give 4.5 mg of the title compound (5%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.79 min.
Example 200: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-({f(1S)-1,2,2-
trimethylpropyllamino}methyl)-2-thienyll-1 H-indole-7-carboxamide
o,~
~-/N N
H
s
N
H
O NHZ
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), [(1 S)-1,2,2-trimethylpropyl]amine (32 mg, 0.32 mmol), and
NaCNBH3
(40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1S)-1,2,2-
trimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1S)-
1,2,2-
trimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-
bromo-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol),
K2CO3 (130
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mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079
mmol) to
give 10.3 mg of the title compound (12%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.62 min.
Example 201: 3-f1-(ethylsulfonyl)-4-piperidiny11-5-{'5-f(hexylamino)methyll-2-
thienyl}-1 H-indole-7-carboxamide
O %
N
N
H
s
N
H
O NH2
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-
thienyl)-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-
thienyl)boronic acid
(50 mg, 0.32 mmol), hexylamine (33 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64
mmol)
were reacted to give 30 mg of crude {5-[(hexylamino)methyl]-2-thienyl}boronic
acid. The
crude {5-[(hexylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-
bromo-3-[1-
(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol),
K2C03 (130
mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079
mmol).
The crude product was purified once on an Agilent MDAP using the procedure
shown in
preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide to give 13 mg of the title compound
(16%).
LC/MS = m/z 430.6 [M+H] Ret. Time: 1.92 min.
Example 202: 5-f2-(dimethylamino)-4-pyridinyll-3-f1-(ethylsulfonyl)-4-
piperidinyll-
1 H-indole-7-carboxamide trifluoroacetate
O~ ~-
N/ S~O
N
N
\ \ ~
F O
F-~ H
F OH
O NH2
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To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-4-pyridinyl)-1 H-indole-7-
carboxamide (40
mg, 0.093 mmol) was added dimethylamine (1 mL, 0.015 mmol) and DMF (0.3 mL).
The
resulting mixture was reacted in a microwave for 1 h at 180 C. All solvent
was
evaporated and the mixture was then purified by Gilson Preparatory HPLC to
give 18.2
mg of the title compound (34.4%).
LC/MS = m/z 456.2 [M+H] Ret. Time: 1.54 min.
Example 203: 5-d6-fethyl(methyl)aminol-3-pyridinyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
0 O~ ~
S" O
N N
N
I
I \ ~
F F 0 N
140H H
O NH2
The title compound was prepared according to the general procedure of 5-[2-
(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
trifluoroacetate, substituting pyrrolidine (1 mL) for dimethylamine to afford
48.9 mg of the
title compound (27.1 %).
LC/MS = m/z 482.2 [M+H] Ret. Time: 1.62 min.
Example 204: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f2-(4-morpholinyl)-4-
pyridinyll-1 H-
indole-7-carboxamide trifluoroacetate
O
O ~
/ S~ O
N N
N
I
I \ ~
F ,.O
F---{( N
H
F H
O NH2
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The title compound was prepared according to the general procedure of 5-[2-
(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
trifluoroacetate, substituting morpholine (1 mL) for dimethylamine to afford
12 mg of the
title compound (21.1 %).
LC/MS = m/z 498.6 [M+H] Ret. Time: 1.47 min.
Example 205: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-{'2-f(2-methylpropyl)aminol-
4-
pyridinyl}-1 H-indole-7-carboxamide trifluoroacetate
O /-
iS~
NH N
N
F 0
F N
F OH H
O NH2
The title compound was prepared according to the general procedure of 5-[2-
(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
trifluoroacetate, substituting 2-methyl-1 -propanamine (1 mL) for
dimethylamine to afford
11.1 mg of the title compound (20%).
LC/MS = m/z 484.2 [M+H] Ret. Time: 1.68 min.
Example 206: 5-f2-f(2,2-dimethylpropyl)aminol-4-pyridinyl}-3-f1-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O ~S 0
NH N
N
1
F O N
F-H H
F OH
O NH2
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CA 02613068 2007-12-20
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The title compound was prepared according to the general procedure of 5-[2-
(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
trifluoroacetate, substituting 2,2-dimethyi-1-propanamine (1 mL) for
dimethylamine to
afford 9 mg of the title compound (15.8%).
LC/MS = mlz 498.6 [M+H] Ret. Time: 1.75 min.
Example 207: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-[2-(propylamino)-4-
pyridinyll-1 H-
indole-7-carboxamide trifluoroacetate
0\ /--
~S"
p
NH N
N
(
~ i 0 N
F ~ ' H
F OH
O NHZ
The title compound was prepared according to the general procedure of 5-[2-
(dimethylamino)-4-pyridiny{]-3-[1-(ethy(sulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
trifluoroacetate, substituting propylamine (1 mL) for dimethylamine to afford
18.2 mg of
the title compound (33.5%).
LCIMS = m/z 470.4 [M+H] Ret. Time: 1.57 min.
Example 208: 3-[1-(ethyisulfonyl)-4-piperidinyll-5-f4-f(methylamino)methyll-2-
thienyl}-1 H-indole-7-carboxamide trifluoroacetate
S~ O
N
S
N
H ! \ ~
F O
Ft H
OH
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2-thienyl)-1
ff-indole-7-
carboxamide (45 mg, 0.1 mmol) in methylene chloride (2 mL) and methanol (1 mL)
was
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added 2 M methylamine (0.5 mL). The reaction mixture was stirred at room
temperature
for 5 h followed by an addition of sodium tetrahydridoborate (37.83 mg, 1
mmol). The
resulting mixture was stirred at room temperature overnight. The solvent was
concentrated and purified using Gilson Preparatory HPLC to give 16.8 mg of the
title
compound (29.2%).
LC/MS = m/z 461.6 [M+H] Ret. Time: 1.40 min.
Example 209: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f4-(1-pyrrolidinylmethyl)-2-
thienyll-1 H-indole-7-carboxamide trifluoroacetate
O\
N /_-
S~ O
S
F 140H O N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting pyrrolidine (0.083 mL) for 2 M
methylamine to
afford 14.8 mg of the title compound (24.1 %).
LC/MS = m/z 470.4 [M+H] Ret. Time: 1.57 min.
Example 210: 3-f1-(ethylsulfonyl)-4-piperidinvll-5-(4-{f(2-
methylpropyl)aminolmethyl}-2-thienvi)-1 H-indole-7-carboxamide
trifluoroacetate
O~, /--
S~
N
S
N
H
F O
F-+4 H
F OH
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1Windole-
7-
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carboxamide trifluoroacetate, substituting 2-methyl-1 -propanamine (0.1 mL)
for 2 M
methylamine to afford 15.4 mg of the title compound (25%).
LC/MS = m/z 503.2 [M+H] Ret. Time: 1.42 min.
Example 211: 5-{4-f(dimethvlamino)methyll-2-thienyll-3-f 1-(ethylsuffonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
o
N 0
S
'-N
F F N
44
F OH H
Q NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-44-[(methylamino)methyl]-2-thienyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting dimethylamine (0.5 mL) for 2 M
methylamine to
afford 9 mg of the title compound (15.3%).
LC/MS = m/z 475.2 [M+H] Ret. Time: 1.27 min.
Example 212: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-{5-f(1 S)-1-(1-
pyrrolidinyl)ethyll-3-
thienyl}-1 H-indole-7-carboxamide
O S/r-
N 0
S
N
I \ ~
N
H
O NH2
To 5-(5-acetyl-3-thienyl)-3-[1-(ethyfsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (10
mg, 0.02 mmol) was added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and
pyrrolidine (0.03 mL, 0.30 mmol). The resulting mixture was reacted in a
microwave for
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40 min at 1500 C. All the solvent was evaporated and the crude product was
partitioned
between ethyl acetate (1.5 mL) and 1 M sodium hydroxide (0.2 mL). The reaction
was
purified by SFC to give the title compound as 100% chirally pure.
LC/MS = mlz 515.4 [M+H] Ret. Time: 1.54 min.
Example 213: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-{5-f(1 R)-1-(1-
pyrrolidinyl)ethyll-3-
thienyl}-1 H-indole-7-carboxamide
O~
/-
~
N S
S
N ~ I
N
H
O NH2
To 5-(5-acetyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (10
mg, 0.02 mmol) was added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and
pyrrolidine (0.03 mL, 0.30 mmol). The resulting mixture was reacted in a
microwave for
40 min at 150 C. AII the solvent was evaporated and the crude product was
partitioned
between ethyl acetate (1.5 mL) and 1 M sodium hydroxide (0.2 mL). The reaction
was
purified by SFC to give the title compound as 100% chirally pure.
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.54 min.
Example 214: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-f4-({f3-
(methyloxy)propyllamino}methyl)-2-thienyll-1 H-indole-7-carboxamide
trifluoroacetate
N /S'<p
S
F 0
-o F N
F OH H
O NH2
To a solution of 5-[(1 Z)-1-(ethenylthio)-4-oxo-1-buten-1-yl]-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide (45 mg, 0.1 mmol) in methylene chloride
(2 mL) and
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methanol (1 mL) was added 3 drops of acetic acid and 3-(methyloxy)-1-
propanamine
(89.14 mg,1 mmol). The resulting mixture was stirred for 6 h followed by an
addition of
sodium borohydride (37.83 mg, 1 mmol). The reaction was stirred at room
temperature
overnight. The solvent was evaporated and the mixture was then purified by
Gilson
Preparatory HPLC to give 23.7 mg of the title compound (37.5%).
LC/MS = mlz 519.4 [M+H] Ret. Time: 1.69 min.
Example 215: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-f4-(T(2S)-2-
f(methyloxy)methyll-l-
pyrrolidinyl}methyl)-2-thienyll-1 H-indole-7-carboxamide trifluoroacetate
/ S~ O
N
o S
DN
N
H
F O 0 NH2
F
F OH
The title compound was prepared according to the general procedure of 3-[1 -
(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-2-
thienyl]-1 H-
indole-7-carboxamide trifluoroacetate
, substituting (2S)-2-[(methyloxy)methyl]pyrrolidine (115.18 mg, 1 mmol) for 3-
(methyloxy)-1-propanamine to afford 3 mg of the title compound (4.6%).
LC/MS = m/z 545.2 [M+H] Ret. Time: 1.78 min.
Example 216: 5-(4-{f(2R,5R)-2,5-dimethyl-l-pyrrolidinyilmethyl}-2-thienyl)-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
Chiral S~ O
N
S
N
-1õ1 I \ ~
~F O N
F FOH H
O NH2
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The titie compound was prepared according to the general procedure of 3-[1-
(ethylsulfony!)-4-piperidinyl]-5-[4-(([3-(methyloxy)propyl]amino}methyl)-2-
thienyl]-1 H-
indole-7-carboxamide trifluoroacetate
(64.3 mg, 1 mmol) for 3-(methyloxy)-1-propanamine to afford 6.4 mg of the
title
compound (10%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.69 min.
Example 217: 3-f1-(ethylsulfonyl)-4-piperidiinyll-5-(5-{f(2S)-2-methvl-l-
pyrrolidinyllmethyl}-3-thienvl)-1 H-indole-7-carboxamide
N S-O
N
H
0 NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (600 mg, 1.348 mmol) in dimethyl sulfoxide (10 mL) was added of 20
drops
of acetic acid and (2S)-1,2-dimethylpyrrolidine (1.37 mL, 13.483 mmol). The
resulting
mixture was stirred at room temperature for 6 h followed by an addition of
sodium
triacetoxyborohydride (2.858 g, 13.483 mmol). The reaction was stirred at room
temperature overnight then purified by SFC. This compound was separated by RTP
CASS Group. The fraction of enantiomer #1 is 99.7% chirally pure to give 119.9
mg of
the title compound (17.3%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.56 min.
Example 218: 3- 1- eth lsu{fon I-4- i eridin 1-5- 5- 2R -2-meth 1-1-
pyrrolidinyilmethyi}-3-thienyl)-1 H-indole-7-carboxamide
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S_ O
N
S
DN
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (600 mg, 1.35 mmol) in dimethyl sulfoxide (10 mL) was added of 20
drops
of acetic acid and 2-methylpyrrolidine (1.37 mL, 13.5 mmol). The resulting
mixture was
stirred at room temperature for 6 h followed by an addition of sodium
triacetoxyborohydride (2.86 g, 13.5 mmol). The reaction was stirred at room
temperature
overnight then purified by Gilson Preparatory HPLC. This compound was then
separated
to give the title compound as 98.6% chirally pure.
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.56 min.
Example 219: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-f1-(1-
pyrrolidinyl)propyll-3-
thienyl}-1 H-indole-7-carboxamide trif I uoroacetate
O"//
S~O
N
S
N
F O
F~ H
F OH O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (250 mg, 0.541 mmol) in dioxane
(4.5 mL)
and H20 (1.5 mL) was added 1-(4-bromo-2-thienyl)-1-propanone (356 mg, 1.62
mmol),
potassium carbonate (447 mg, 3.24 mmol), and
tetrakis(triphenylphosphine)palladium(0)
(64 mg, 0.055 mmol). The reaction was run in the microwave at 1502 C for 20
min. An
aqueous work-up was performed using EtOAc and H20 followed by addition of MeOH
(20
mL) to the crude product. The desired product percpitated and was filtered to
give 110
mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-propanoyl-3-thienyl)-1 H-indole-
7-
carboxamide (43%).
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To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-propanoyl-3-thienyl)-1 H-indole-7-
carboxamide
(60 mg, 0.13 mmol) was added sodium cyanoborohydride (49.2 mg, 0.78 mmol),
pyrrolidine (0.2 mL, 1.95 mmol), ethanol (3 mL) and acetic acid (0.4 mL). The
resulting
mixture was reacted in a microwave for 30 min at 1500 C. All solvent was
evaporated
and the mixture was then purified by Gilson Preparatory HPLC to give 12 mg of
the title
compound (14.4%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.65 min.
Example 220: 5-f5-f(dimethylamino)methyll-3-thienyl}-3-f1-f(1-
methylethyl)sulfonyll-
4-piperidinyl}-1 H-indole-7-carboxamide trifluoroacetate
O-~-, ~-
N i Slz~O
S
_-N
F 0
F-~--~( H
IF 'OH O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.11 mmol) in dimethyl sulfoxide (2 mL) was added 3 drops
of
acetic acid and trimethylamine (0.55 mL, 1.1 mmol). The resulting mixture was
stirred at
room temperature for 6 h followed by an addition of sodium
triacetoxyborohydride
(233 mg, 1 mmol). This was then stirred at room temperature overnight then
purified by
Gilson Preparatory HPLC to give 29.4 mg of the title compound (44.3%).
LC/MS = m/z 489.4 [M+H] Ret. Time: 1.32 min.
Example 221: 545-(aminomethyl)-3-thienyll-3-f1-(ethylsulfonyl)-4-piperi.dinyll-
1 H-
indole-7-carboxamide trifluoroacetate
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0__j
0=S
N
S
H2N
F
F I // N
H
F pH 0 NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.11 mmol) in methylene chloride (2 mL) and methanol (1
mL) was
added ammonium acetate (84.7 mg, 1.1 mmol) and sodium cyanoborohydride (4.84
mg,
0.077 mmol). The resulting mixture was stirred at room temperature overnight.
All
solvent was evaporated and the mixture was then purified by Gilson Preparatory
HPLC to
give 1.8 mg of the title compound (2.9%).
LC/MS = m/z 447.2 [M+H] Ret. Time: 1.53 min.
Example 222: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-{2-r(2-
methylpropyl)aminolethyl}-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate
O
0=S
N
S
N
H F p
F-H H
F OH O NH2
To a solution of [2-(4-bromo-2-thienyl)ethyl]amine (100 mg, 0.48 mmol) in DCM
(2.0 mL)
and MeOH (1.0 mL) was added acetic acid (3 drops) and 2-methylpropanal (105
mg, 1.44
mmol). The reaction was stirred overnight at room temperature before addition
of Sodium
borohydride (53.3 mg, 1.44 mmol). Reaction run for 1 h and then treated with
EtOAc and
brine. Organic layers were then dried and concentrated to give 80mg of [2-(4-
bromo-2-
thienyl)ethyl](1-methylethyl)amine (64%).
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (139 mg, 0.3 mmol) in dioxane (3
mL) and
water (1 mL) was added [2-(4-bromo-2-thienyl)ethyl](1-methylethyl)amine (50
mg,
0.2 mmol), potassium carbonate (82.8 mg, 0.6 mmol) and
tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol). The resulting
mixture was
reacted in a microwave for 20 min at 150 C. All solvent was evaporated and
the mixture
was then purified by Gilson Preparatory HPLC to give 18 mg of the title
compound
(9.5%).
LC/MS = m/z 517.2 [M+H] Ret. Time: 1.68 min.
Example 223: 54542-(dimethylamino)ethyll-3-thienyl}-3-f 1-(ethylsulfonyl)-4-
piperidinyil-1 H-indole-7-carboxamide trifluoroacetate
O
0=S
N
S
\ ~ I
N F O
H N
F H
F OH
O NH2
To a solution of [2-(4-bromo-2-thienyl)ethyl]amine (100 mg, 0.48 mmol) in DCM
(2.0 mL)
and MeOH (1.0 mL) was added acetic acid (3 drops) and formaldehyde, 37% in H20
(105
mg, 1.44 mmol). The reaction was stirred overnight at room temperature before
addition
of Sodium borohydride (53.3 mg, 1.44 mmol)-. Reaction run for 1 h and then
treated with
EtOAc and brine. Organic layers were then dried and concentrated to give 50mg
of
2-(4-bromo-2-thienyl)-N,N-dimethylethanamine (44%).
To a solution of of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (139 mg, 0.345 mmol) in dioxane (3
mL) and
water (1 mL) was added 2-(4-bromo-2-thienyl)-N,N-dimethylethanamine (50 mg,
0.23 mmol), potassium carbonate (82.8 mg, 0.69 mmol) and
tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol). The resulting
mixture was
reacted in a microwave for 20 min at 1500 C. All solvent was evaporated and
the mixture
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was then purified by Gilson Preparatory HPLC to give 12 mg of the title
compound
(5.8%).
LC/MS = mlz 489.2 [M+H] Ret. Time: 1.54 min.
Example 224: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f6-(1-pyrrolidinyl)-3-
pyridinyll-1 H-
indole-7-carboxamide trifluoroacetate
O~ ~-
S~ O
N
N N
I
F F O N
1~0H H
O NH2
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (110
mg, 0.27 mmol) in dioxane (2.0 mL) and H20 (0.7 mL) was added (6-fluoro-3-
pyridinyl)boronic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16
mmol),
and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.026 mmol). The reaction
was run
in the microwave for 20 min at 150 C. The reaction was then treated with
EtOAc and
brine and purified by flash chromatography to give 50 mg of 3-[1-
(ethylsulfonyl)-4-
piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-indole-7-carboxamide (43%).
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-indole-7-
carboxamide (25
mg, 0.058 mmol) was added pyrrolidine (3 mL). The resulting mixture was
reacted in a
microwave for 30 min at 100 C. All extra pyrrolidine was evaporated and it
was then
purified by Gilson Preparatory HPLC to give 25 mg of the title compound
(72.4%).
LC/MS = m/z 482.2 [M+H] Ret. Time: 1.67 min.
Example 225: 5-f6-fethyl(methyl)aminol-3-pyridinyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
221

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O,/-
S" O
N N N
\ I
F O I
Ft40H / H
O NH2
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (110
mg, 0.27 mmol) in dioxane (2.0 mL) and H20 (0.7 mL) was added (6-fluoro-3-
pyridinyl)boronic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16
mmol),
and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.026 mmol). The reaction
was run
in the microwave for 20 min at 150 C. The reaction was then treated with
EtOAc and
brine and purified by flash chromatography to give 50 mg of 3-[1-
(ethylsulfonyl)-4-
piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-indole-7-carboxamide (43%).
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-indole-7-
carboxamide (40
mg, 0.093 mmol) was added dimethylamine (1 mL) and DMF (0.3 mL). The resulting
mixture was reacted in a microwave for 1 h at 200 C. The resulting mixture
was washed
with water. Ethyl acetate was added and the organic layer was evaporated and
purified
by Gilson Preparatory HPLC to afford 34.4 mg of the title compound (63.4%).
LC/MS = mlz 470 [M+H] Ret. Time: 1.50 min.
Example 226: 5-f6-(dimethylamino)-3-pyridinyil-3-f1-(ethylsuifonyl)-4-
piperidinyll-
1 H-indole-7-carboxamide trifluoroacetate
N S" O
~
_,N N
I \ ~
F O N
~
F OH H
O NH2
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To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (110
mg, 0.27 mmol) in dioxane (2.0 mL) and H20 (0.7 mL) was added (6-fluoro-3-
pyridinyl)boronic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16
mmol),
and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.026 mmol). The reaction
was run
in the microwave for 20 min at 1500 C. The reaction was then treated with
EtOAc and
brine and purified by flash chromatography to give 50 mg of 3-[1-
(ethylsulfonyl)-4-
piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-indole-7-carboxamide (43%).
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-indole-7-
carboxamide (50
mg, 0.116 mmol) was added dimethylamine (1 mL) and DMF (0.3 mL). The resulting
mixture was reacted in a microwave for 1 h at 200 C the purified by Gilson
Preparatory
HPLC to afford 8.4 mg of the title compound (12.7%).
LC/MS = mlz 456.2 [M+H] Ret. Time: 1.39 min.
Example 227: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-f6-(propylamino)-3-
pyridinyll-1 H-
indole-7-carboxamide trifluoroacetate
O"/-
S O
~
H N
,,~N N
F O
F-H H N
F OH
O NH2
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (110
mg, 0.27 mmol) in dioxane (2.0 mL) and H20 (0.7 mL) was added (6-fluoro-3-
pyridinyl)boronic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16
mmol),
and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.026 mmol). The reaction
was run
in the microwave for 20 min at 150 C. The reaction was then treated with
EtOAc and
brine and purified by flash chromatography to give 50 mg of 3-[1-
(ethylsulfonyl)-4-
piperidinyl]-5-(6-fluoro-3-pyridinyl)-1/--1-indole-7-carboxamide (43%).
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-indole-7-
carboxamide (50
mg, 0.116 mmol) was added propylamine (1 mL) and DMF (0.3 mL). The resulting
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mixture was reacted in a microwave for 5 h at 2000 C was purified by Gilson
Preparatory
HPLC to afford 24.5 mg of the title compound (36.2%).
LC/MS = m/z 470.2 [M+H] Ret. Time: 1.49 min.
Example 228: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-{6-f(1-methylethyl)aminol-3-
pyridinyl}-1 H-indole-7-carboxamide trifluoroacetate
O"/-
S" O
I H N
/\. N N
\ I
F 0 ~
F-H H
F OH
O NH2
The title compound was prepared according to the general procedure of 5-{6-
[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide trifluoroacetate, substituting 2-propanamine (64.3 mg, 1 mmol) for
dimethylamine to afford 9.8 mg of the title compound (14.5%).
LC/MS = m/z 470.4 [M+H] Ret. Time: 1.52 min.
Example 229: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f6-(4-morpholinyl)-3-
pyridinyll-1 H-
indole-7-carboxamide
o,.S/-
O N O
N N
f \ \
N
H
O NH2
The title compound was prepared according to the general procedure of 5-{6-
[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide trifluoroacetate, substituting morpholine (1 mL) for dimethylamine
to afford
40.1 mg of the title compound (69.5%).
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LC/MS = m/z 498.6 [M+H] Ret. Time: 1.44 min.
Example 230: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-15-f(methylamino)methyll-3-
thienyl}-1 H-indole-7-carboxamide trifluoroacetate
S O
N
S
H
I \ ~
N F O
H F
F OH
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (20 mg, 0.045 mmol) in methanol (1.5 mL) and methylene chloride
(1.5 mL)
was added methylamine (0.13 mL). The resulting mixture was stirred at room
temperature for 2 h followed by the addition of sodium tetrahydridoborate
(9.18 mg,
0.27 mmol). This was stirred at room temperature for 1 h. All solvent was
evaporated
and it was then purified by Gilson Preparatory HPLC to give 12.4 mg of the
title
compound (48%).
LC/MS = m/z 461.4 [M+H] Ret. Time: 1.48 min.
Example 231: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-df(1-
methylethyl)aminolmethyl}-
3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate
O~
N ~-
S'<O
S
H
F 0
THH
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-
1-indole-7-
carboxamide (30 mg, 0.067 mmol) in methanol (0.5 mL) and methylene chloride (1
mL)
was added 2-propanamine (23.8 mg, 0.402 mmol). The resulting mixture was
stirred for
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2.5 h followed by an addition of sodium tetrahydridoborate (15.2 mg, 0.402
mmol). The
reaction was stirred at room temperature for 1 h. All solvent was evaporated
and it was
then purified by Gilson Preparatory HPLC to give 19.5 mg of the title compound
(48.3%).
LC/MS = m/z 489.2 [M+H] Ret. Time: 1.54 min.
Example 232: 3-f1-(ethylsulfonyl)-4-piperidinyll-545-(1-pyrrolidinylmethyl)-3-
thienyll-1 H-indole-7-carboxamide trifluoroacetate
N
S
N
I \ ~
F ~,O
F~',~ N
F OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (30 mg, 0.067 mmol) in methanol (0.5 mL) and methylene chloride (1
mL)
was added pyrrolidine (85 mg, 1.195 mmol). The resulting mixture was stirred
for 1.5 h
followed by an addition of sodium triacetoxyborohydride (85 mg, 0.402 mmol).
The
reaction was stirred at room temperature for 2 h. All solvent was evaporated
and it was
then purified by Gilson Preparatory HPLC to give 22.5 mg of the title compound
(54.6%).
LC/MS = m/z 501.4 [M+H] Ret. Time: 1.52 min.
Example 233: 545-f(ethylamino)methyll-3-thienyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-
1 H-indole-7-carboxamide trif I uoroacetate
S~ O
N
S
/"'-H
I \ ~
F O
F-'-~,~ N
F OH H
O NH2
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (30 mg, 0.067 mmol) in methanol (3 mL), methylene chloride (3 mL)
was
added ethylamine (0.2 mL, 0.402 mmol). After 2 h sodium tetrahydridoborate (27
mg,
0.402 mmol) was added and the mixture was allowed to rest 1 h. All solvent was
evaporated and it was then purified by Gilson Preparatory HPLC to give 15 mg
of the title
compound (38%).
LC/MS = m/z 475.4 [M+H] Ret. Time: 1.52 min.
Example 234: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-(f f(1 R)-2-hydroxy-1-
methylethyllamino}methyl)-3-thienyll-1 H-indole-7-carboxamide trifluoroacetate
salt
O~ ~-
~S~ O
N
S
H O J N
F O
F-H H
F OH
O NH2
The title compound was prepared according to the general procedure of 5-{5-
[(ethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-
7-carboxamide
trifluoroacetate, substituting (2R)-2-amino-l-propanol (0.031 mL, 0.402 mmol)
for
ethylamine to afford 16.2 mg of the title compound (39.1 %).
LC/MS = m/z 505.4 [M+H] Ret. Time: 1.42 min.
Example 235: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-(1-piperidinyimethyl)-3-
thienyll-
1 H-i ndole-7-carboxamide trifluoroacetate
O
O
N
S
N ~ I
O I \ ~
1HH
O NH2
227

CA 02613068 2007-12-20
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (30 mg, 0.067 mmol) in dimethyl sulfoxide (2 mL) was added
piperidine (70
mg, 0.670 mmol). The resulting mixture was allowed to rest for 2 h then socium
triacetoxyborohydride (142 mg, 0.670 mmol) was added. This mixture was stirred
at
room temperature overnight then purified by Gilson Preparatory HPLC to give
16.2 mg of
the title compound (38.5%).
LC/MS = m/z 514.8 [M+H] Ret. Time: 1.37 min.
Example 236: 3-f1-(ethylsulfonyl)-4-piperidinyll-545-(4-morpholinylmethyl)-3-
thienyll-1 H-indole-7-carboxamide trifluoroacetate
O~ /-
S~
N O
S
O F O
N
F OH H
O NH2
The title compound was prepared according to the general procedure of 3-[1 -
(ethylsulfonyl)-4-piperidinyl]-5-[5-(1 -pyrrolidinylmethyl)-3-thienyl]-1 H-
indole-7-
carboxamide trifluoroacetate, substituting morpholine (70 mg, 0.670 mmol) for
piperidine
to afford 6.3 mg of the title compound (14.9%).
LC/MS = m/z 517 [M+H] Ret. Time: 1.54 min.
Example 237: 3-f1-(ethylsulfonyl)-4-piperidinyll-5454(methylamino)methyll-3-
furanyl)-1 H-indole-7-carboxamide trifluoroacetate
O,
S" O
N
O
\N \ I \
H
F O
F H
F OH
O NH2
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3.0
mL) and
H20 (1.0 mL) was added 4-bromo-2-furancarbaldehyde (58 mg, 0.33 mmol),
potassium
carbonate (89.8 mg, 0.66 mmol), and tetrakis(triphenylphosphine)palladium(0)
(14 mg,
0.012 mmol). The reaction was heated in the microwave for 20 min at 150 C to
give 58
mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1 H-indole-7-
carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1
H-indole-7-
carboxamide (20.6 mg, 0.05 mmol) in DMSO (0.5 mL) was added methylamine (0.24
mL,
0.5 mmol) in 2 M tetrahydrofuran. The resulting mixture was reacted for 6 h
followed by
an addition of sodium triacetoxyborohydride was added. This was then purified
by Gilson
Preparatory HPLC to afford 5.5 mg of the title compound (32.8%).
LC/MS = m/z 459.4 [M+H] Ret. Time: 1.42 min.
Example 238: 3-f1-(ethylsulfonyl)-4-piperidinyll-54541-(1-pyrrolidinyl)ethyll-
3-
thienyl}-1 H-indole-7-carboxamide trifluoroacetate
N S O
S
N
~ F O
F N
F OH H
0 NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (300 mg, 0.65 mmol) in dioxane (9
mL) and
H20 (3 mL) was added 1-(4-bromo-2-thienyl)ethanone (400 mg, 1.95 mmol),
potassium
carbonate (538 mg, 3.90 mmol), and tetrakis(tri ph enylphosph in e) pal ladi u
m (0) (70 mg,
0.060 mmol). The reaction was run in the microwave at 150 C for 20 min. An
aqueous
work-up was performed using EtOAc and H20 followed by addition of MeOH (3 mL)
to the
crude product. The desired product percpitated and was filtered to give 230 mg
of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-propanoyl-3-thienyl)-1 H-indole-7-
carboxamide (77%).
To a solution of 5-(5-acetyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide (50 mg, 0.11 mmol) in DMF (0.8 mL) and acetic acid (0.2 mL) was
added
pyrrolidine (30.92 mg, 0.44 mmol) and N,N-dimethylformamide (30 mg, 0.44
mmol). The
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reaction mixture was reacted in a microwave for 20 min at 150 C. The results
were then
purified twice by Gilson Preparatory HPLC to give 3.7 mg of the title compound
(5.3%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.62 min.
Example 239: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-(1-pyrrolidinylmethyl)-2-
thienyll-1 H-indole-7-carboxamide trifluoroacetate
OZ~, ~-
S" O
CN N
S
F 0
F-H H
F OH
O NH2
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-11I indole-7-
carboxamide (40
mg, 0.09 mmol) in dilmethyl sulfoxide (0.5 mL) was added 2M pyrrolidine (0.074
mL, 0.90
mmol). The resulting mixture was allowed to rest for 6 h followed by an
addition of
sodium triacetoxyborohydride (233 mg, 9.90 mmol). This was then allowed to
rest for 2 h
then purified by Gilson Preparatory HPLC to give 6.5 mg of the title compound
(11.7%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.62 min.
Example 240: 5-f5-f(dimethylamino)methyll-2-thienyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
\ s~ o
N N
/
S
F O
F+~ N
F OH H
O NH2
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1 H-indole-7-
carboxamide (35
mg, 0.09 mmol) in dilmethyl sulfoxide (0.5 mL) was added 2M dimethylamine (0.4
mL,
0.90 mmol). The resulting mixture was allowed to rest for 6 h followed by an
addition of
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sodium triacetoxyborohydride (233 mg, 9.90 mmol). This was then allowed to
rest for 2 h
then purified by Gilson Preparatory HPLC to give 17.8 mg of the title compound
(33.6%).
LC/MS = m/z 475.2 [M+H] Ret. Time: 1.53 min.
Example 241: 341-(ethylsulfonyl)-4-piperidinyll-5454(propylamino)methyll-2-
thienyl}-1 H-indole-7-carboxamide trifluoroacetate
s
S~ O
N N
H
S
F C
F N
F CH H
O NH2
The title compound was prepared according to the general procedure of 5-{5-
[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide trifluoroacetate, substituting propylamine (0.064 mL, 0.90 mmol)
for 2M
dimethylamine to afford 8.9 mg of the title compound (16.4%).
LC/MS = m/z 487.2 [M+H] Ret. Time: 1.80 min.
Example 242: 5454(diethylamino)methyll-2-thi'enyl}-3-f1-(ethylsulfonyl)-4-
piperidinyil-1 H-indole-7-carboxamide trifluoroacetate
O~S/-
- N N i~ 0
s
F 0 ~ /.
F N
H
F OH
O NH2
The title compound was prepared according to the general procedure of 5-{5-
[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide trifluoroacetate, substituting diethylamine (0.081 mL, 0.90 mmol)
for 2M
dimethylamine to afford 16.6 mg of the title compound (29.9%).
LC/MS = m/z 502.0 [M+H] Ret. Time: 1.71 min.
231

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Example 243: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-ff(2-
methylpropyl)aminolmethyl}-2-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
O,/,--
~ S, o
N
H
S
F 0
F
~ N
OH H
O NH2
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1 H-indole-7-
carboxamide (30
mg, 0.09 mmol) in dilmethyl sulfoxide (0.5 mL) was added 2-methyl-1 -
propanamine
(0.068 mL, 0.90 mmol). The resulting mixture was allowed to rest for 6 h
followed by an
addition of sodium triacetoxyborohydride (233 mg, 9.90 mmol). This was then
allowed to
rest for 2 h then purified by Gilson Preparatory HPLC to give 2.7 mg of the
title compound
(4.9%).
LC/MS = m/z 501.4 [M+H] Ret. Time: 1.79 min.
Example 244: 5-(5-ff(2,2-dimethylpropyl)aminolmethyl}-3-furanyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
C ~S ~
N
O
N
H F O
F-I-~ H
F OH O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3.0
mL) and
H20 (1.0 mL) was added 4-bromo-2-furancarbaldehyde (58 mg, 0.33 mmol),
potassium
carbonate (89.8 mg, 0.66 mmol), and tetrakis(triphenylphosphine)palladium(0)
(14 mg,
0.012 mmol). The reaction was heated in the microwave for 20 min at 150 C to
give 58
mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1 H-indole-7-
carboxamide.
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To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1 H-indole-7-
carboxamide (60
mg, 0.14 mmol) was added 2,2-dimethyl-l-propanamine (60 mg, 0.14 mmol) in
dimethyl
sulfoxide (0.5 mL) was added 2,2-dimethyl-1-propanamine (122 mg, 1.40 mmol).
The
resulting mixture was allowed to rest for 6 h followed by an addition of
sodium
triacetoxyborohydride (233 mg, 9.90 mmol). This was then allowed to rest for 2
h then
purified by Gilson Preparatory HPLC to give 23.8 mg of the title compound
(27.7%).
LC/MS = m/z 501.1 [M+H] Ret. Time: 1.67 min.
Example 245: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-(5-df(2-
methylpropyl)aminolmethyl}-3-furanyl)-1 H-indole-7-carboxamide
trifluoroacetate
O\\ ~_
S~ O
N
O
H ~ \ \
F
F-H H
F OH O NH2
The title compound was prepared according to the general procedure of 5-(5-
{[(2,2-
dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate, substituting 2-methyl-l-propanamine (102.4 mg,
1.4 mmol)
for 2,2-dimethyl-1-propanamine to afford 31.7 mg of the title compound
(37.7%).
LC/MS = m/z 487.2 [M+H] Ret. Time: 1.44 min.
Example 246: 5-(5-ff(cyclopentylmethyl)aminolmethyl}-3-furanyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
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O, /1-
~S~
N O
O
N
H F O
F-~4 H
F OH
O NH2
The title compound was prepared according to the general procedure of 5-(5-
{j(2,2-
dimethylpropyl)aminoJmethyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate, substituting 1 -cyclopentylmethanamine (137 mg,
1.4 mmol)
for 2,2-dimethyl-1 -propanamine to afford 22 mg of the title compound (25.1
%).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.59 min.
Example 247: 3-f1-(ethvlsulfonyl)-4-piperidinyll-5-f5-(1-pyrrolidinylmethyl)-3-
furanyli-1 H-indole-7-carboxamide trifluoroacetate
S~ O
O
F O
F~ H
F OH
O NH2
The title compound was prepared according to the general procedure of 5-(5-
{[(2,2-
dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyi]-1
H-indole-7-
carboxamide trifluoroacetate, substituting pyrrolidine (99.6 mg, 1.4 mmol) for
2,2-
dimethyl-1 -propanamine to afford 6 mg of the title compound (7.2%).
LC/MS - m/z 485.2 [M+H] Ret. Time: 1.50 min.
Example 248: 5-f5-f(diethylamino)methyll-3-furanyl}-3-f1-(ethvtsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
234

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N
O
N I \ \
F O N
F_+4 H
F OH
O NH2
The title compound was prepared according to the general procedure of 5-(5-
{[(2,2-
dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide trifluoroacetate, substituting 2M diethylamine (102.4 mg, 1.4
mmol) for 2,2-
dimethyl-1-propanamine to afford 10.1 mg of the title compound (12%).
LC/MS = m/z 487.4 [M+H] Ret. Time: 1.50 min.
Example 249: 3-f1-(ethylsulfonyl)-4-piperidinyll-545-(1-pyrrolidinylmethyl)-
1,3-
thiazol-2-yll-1 H-indole-7-carboxamide trifluoroacetate
O~ /-
S"< O
CN_ N
S
N I \ \
F p
F-4 H
F OH
Q NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1/--1-indole-7-carboxamide (500 mg, 1.1 mmol) in dioxane
(12 mL) and
H20 (4 mL) was added 2-bromo-1,3-thiazole-5-carbaldehyde (634 mg, 3.3 mmol),
potassium carbonate (898 mg, 8.8 mmol) and
tetrakis(triphenylphosphine)palladium(0)
(210 mg, 0.181 mmol). Reaction was run in the microwave at 150 C for 20 min.
Aqueous work-up performed to give crude product. The reaction was then
repeated in
the microwave at 1500 C for 30 min to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-
5-(5-formyl-
1,3-thiazol-2-yl)-1 H-indole-7-carboxamide.
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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-1,3-thiazol-2-
yl)-1 H-indole-7-
carboxamide (25 mg, 0.06 mmol) in dimethyl sulfoxide (1 mL) was added
pyrrolidine (0.05
mL, 0.60 mmol). The resulting mixture was stirred at room temperature for 6 h
followed
by an addition of sodium triacetoxyborohydride (160 mg, 0.60 mmol). The
resulting
mixture was stirred overnight then purified by Gilson Preparatory HPLC to give
6.3 mg of
the title compound (17.1 %).
LC/MS = m/z 502.2 [M+H] Ret. Time: 1.35 min.
Example 250: 3-f7-(ethylsulfonyl)-4-piperidinyll-54542-methyl-l-(1-
pyrrolidinyl)propyll-3-thienyl}-1 H-indole-7-carboxamide trifluoroacetate
0' s~
N ~O
S
N I \ \
F N
F-H H
F OH O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3
mL) and
H20 (1 mL) was added potassium carbonate (89.8 mg, 0.66 mmol), 1-(4-bromo-2-
thienyl)-2-methyl-1 -propanone (87 mg, 0.33 mmol) and
tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol). The reaction was
run in a
microwave for 20 min at 1502 C followed by an aqueous work-up with EtOAd and
H20.
The reaction was then concentrated and treated with 1 N NaOH and extracted
with
EtOAc. The compound was purified by flash chromatography using DCM and MeOH to
give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-methylpropanoyl)-3-thienyl]-1
H-indole-7-
carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-methylpropanoyl)-
3-thienyl]-1 H-
indole-7-carboxamide (40 mg, 0.02 mmol) in EtOH (1.5 mL) and acetic acid (0.2
mL) was
added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and pyrrolidine (0.03 mL,
0.3
mmol). The resulting mixture was reacted in a microwave for 40 min at 150 C.
All
solvent was then evaporated, and basified in sodium hydroxide and extracted
with ethyl
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acetate. This was then purified by Gilson Preparatory HPLC to give 13 mg of
the title
compound.
LC/MS = m/z 543.4 [M+H] Ret. Time: 1.71 min.
Example 251: 341-(ethylsulfonyl)-4-piperidinyll-5-f4-(1-pyrrolidinylmethyl)-
1,3-
thiazol-2-yll-1 H-indole-7-carboxamide trifluoroacetate
O~~ ~
S~
N p
N
F O
F-I-~ H
F OH
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-formyl-1,3-thiazol-4-
yl)-1 H-indole-7-
carboxamide (42 mg, 0.094 mmol) in DMSO (2 mL) was added pyrrolidine (0.08 mL,
0.940 mmol). The resulting mixture was stirred at room temperature for 6 h
followed by
an addition of sodium triacetoxyborohydride. This mixture was stirred at room
temperature overnight then purified by Gilson Preparatory HPLC to give 15.1 mg
of the
title compound (26.1 %).
LC/MS = m/z 502.4 [M+H] Ret. Time: 1.54 min.
Example 252: 5-{1-f2-(dimethylamino)ethyll-1 H-pyrazol-4-yl}-3-f1-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
O;S;O
,N N
N
I \ ~
N
H
O NH2
237

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A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-
2-yl)-1 H-indole-7-carboxamide (40 mg, 0.084 mmol), [2-(4-bromo-1 H-pyrazol-1 -
yl)ethyl]dimethylamine (27 mg, 0.126 mmol) and sodium carbonate (53 mg, 0.5
mmol)
was suspended in dioxane (750 pL) and water (250 pL). This was flushed with
argon for
10 min before the addition of tetrakis(triphenylphosphine)palladium(0) (5 mg,
0.004
mmol). The resulting mixture was reacted in a microwave for 20 min at 120 C
then
diluted with EtOAc (10 mL). The mixture was filtered through Celite and an
aqueous
wash was performed. It was then purified by Gilson Preparatory HPLC to give 6
mg of
the title compound (15%).
LC/MS = m/z 473.4 [M+H] Ret. Time: 1.48 min.
Example 253: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f1-f2-(1-
pyrrolidinyl)ethyll-1 H-
pyrazol-4-yl}-1 H-indole-7-carboxamide trifluoroacetate
OS;O
CN,N F O I ~ ~
F--H N
F OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane
(750 pL)
and H20 (250 pL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-l-
(2-
chloroethyl)-1 H-pyrazole (26 mg, 0.126 mmol). The reaction mixture was
flushed under
Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0)
(5 mg, 0.004
mmol). The reaction was heated in a microwave at 120 C for 20 min. It was
then diluted
with EtOAc (10 mL), filtered thru celite, followed by an aqueous work-up. The
compound
was purified by Gilson Preparatory HPLC to give 10 mg of 5-[1-(2-chloroethyl)-
1 f-f-
pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide
(24%).
To a solution of 5-[1-(2-chloroethyl)-1 H-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1/ /
indole-7-carboxamide (33 mg, 0.071 mmol), pyrrolidine (60 pL, 0.710 mmol) and
sodium
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iodide (5 mg, 0.018 mmol) was added tetrahydrofuran (500 pL). This mixture was
reacted in a microwave for 2 h at 130 C and given an aqueous wash with EtOAc
and
water. Organic layer was then isolated and all solvent was removed. It was
then purified
by Gilson Preparatory HPLC to give 11 mg of the title compound (25%).
LC/MS = m/z 499.6 [M+H] Ret. Time: 1.34 min.
Example 254: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f 142-(4-morpholinyl)ethyll-
1 H
pyrazol-4-yl}-1 H-indole-7-carboxamide trif I uoroacetate
OSO
N N
oN
F 0
F+j< N
F OH H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(1-pyrrolidinyl)ethyl]-1 H-pyrazol-4-
yl}-1 H-indole-7-
carboxamide trifluoroacetate, substituting morpholine (70 pL, 0.71 mmol) for
the
pyrrolidine to afford 15 mg of the title compound (34%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.46 min.
Example 255: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(1-f2-f(2-
hydroxyethyl)aminolethyl}-1 H-pyrazol-4-yi)-1 H-indole-7-carboxamide
trifluoroacetate
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HO
OSO
N N
H_~ N
N"
F
O
F-H / N
F OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane
(750 pL)
and H20 (250 pL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-1-
(2-
chloroethyl)-1 H-pyrazole (26 mg, 0.126 mmol). The reaction mixture was
flushed under
Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0)
(5 mg, 0.004
mmol). The reaction was heated in a microwave at 120 C for 20 min. It was
then diluted
with EtOAc (10 mL), filtered thru celite, followed by an aqueous work-up. The
compound
was purified by Gilson Preparatory HPLC to give 10 mg of 5-[1-(2-chloroethyl)-
1 H-
pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-11-/-indole-7-carboxamide
(24%).
A solution of 5-[1-(2-chloroethyl)-1 f-/-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 FI
indole-7-carboxamide (20 mg, 0.043 mmol), 2-aminoethanol (26 mg, 0.43 mmol)
and
sodium iodide (5 mg, 0.022 mmol) in tetrahydrofuran (1 mL) was reacted in a
microwave
for 2 h at 130 C. The tetrahydrofuran was then removed and the mixture was
given an
aqueous was of EtOAc and water. The organic layer was then separated and all
solvent
was removed. The mixture was then purified by Gilson Preparatory HPLC to give
8 mg of
the title compound (31 %).
LC/MS = m/z 489.2 [M+H] Ret. Time: 1.40 min.
Example 256: 5-d142-(butylamino)ethyll-1 H-pyrazol-4-yl}-3-f 1-(ethylsulfonyl)-
4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
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CA 02613068 2007-12-20
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O S_ _
O
N N
H--\, N
N
F O
F~ H
F OH
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1 H-
pyrazol-4-yl)-1 H-
indole-7-carboxamide trifluoroacetate, substituting 1 -butanamine (31 mg, 0.43
mmol) for
the 2-aminoethanol to afford 7 mg of the title compound (26%).
LC/MS = m/z 499.4 [M+H] Ret. Time: 1.39 min.
Example 257: 5-f1-f2-(cyclobutylamino)ethyil-1 H-pyrazol-4-yl}-3-f1-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O~
S=0
N N
H N
N --
F O V
F-~4 N
F OH H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1 H-
pyrazol-4-yl)-1 H-
indole-7-carboxamide trifluoroacetate, substituting cyclobutanamine (31 mg,
0.43 mmol)
for the 2-aminoethanol to afford 10 mg of the title compound (38%).
LC/MS. = m/z 501.4 [M+H] Ret. Time: 1.48 min.
Example 258: 5-f1-(2-ff2-(diethylamino)ethyllamino}ethyl)-1 H-pyrazol-4-yll-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
241

CA 02613068 2007-12-20
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~-N /_
~ OSO
N N
H--\, N
N"
F O ~
F
-H ~ N
F OH H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1 H-
pyrazol-4-yl)-1 H-
indole-7-carboxamide trifluoroacetate, substituting N,N-diethyl-1,2-
ethanediamine (50 mg,
0.43 mmol) for the 2-aminoethanol to afford 12 mg of the title compound (42%).
LC/MS = m/z 545.2 [M+H] Ret. Time: 1.25 min.
Example 259: 3-r1-(ethylsuifonyl)-4-piperidinyil-5-(1-f2-r(1-
methylethyl)aminolethyl}-
1 H-pyrazol-4-yl)-1 H-indole-7-carboxamide trifluoroacetate
_
So
O_
N~ N
H
N. N
FI //~ I \ ~
F-~--~( / N
IF \O H H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1 H-
pyrazol-4-yl)-1 H-
indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (25 mg, 0.43
mmol) for
the 2-aminoethanol to afford 9 mg of the title compound (35%).
LC/MS = m/z 487.2 [M+H] Ret. Time: 1.47 min.
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Example 260: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-(1-{'2-f(2-
methylpropyl)aminolethyll-1 H-pyrazol-4-yl)-1 H-indole-7-carboxamide
trifluoroacetate
OS_o
N N
Ns N
F
O
F N
OH H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1 H-
pyrazol-4-yl)-1 H-
indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1 -propanamine
(31 mg, 0.43
mmol) for the 2-aminoethanol to afford 8 mg of the title compound (30%).
LC/MS = m/z 501.2 [M+H] Ret. Time: 1.45 min.
Example 261: 5-(1-f2-f(cyclopentylmethyl)aminolethyl}-1 H-pyrazol-4-yl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
0=
SO
N
H -N,N
F 0
F--/< N
F OH H
0 NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1 H-
pyrazol-4-yl)-1 H-
indole-7-carboxamide trifluoroacetate, substituting cyclopentanamine (37 mg,
0.43 mmol)
for the 2-aminoethanol to afford 11 mg of the title compound (40%).
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CA 02613068 2007-12-20
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LC/MS = m/z 513.4 [M+H] Ret. Time: 1.47 min.
Example 262: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-f4-(methyloxy)-3-(1-
pyrrolidinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
OZZ:S=O
N
N N
U H
F O O NH2
F
F OH
To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzaldehyde (610 mg, 2.33 mmol) in dioxane (19 mL) and H20 (6.3 mL), was
added
5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (963 mg,
2.33 mmol),
and sodium carbonate (1.48 g, 13.9 mmol). After flushing with Agron for 10
min,
tetrakis(triphenylphosphine)palladium(0) (134 mg, 0.166 mmol) was added. The
reaction
was heated in the microwave 120 C for 120 min. Compound was purified by flash
chromatography using DCM and MeOH to give 632 mg of 3-[1 -(ethylsulfonyl)-4-
piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1 H-indole-7-carboxamide (58%).
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-
(methyloxy)phenyl]-11-1-indole-
7-carboxamide (50 mg, 0.107 mmol), pyrrolidine (45 pL, 0.214 mmol), zinc
chloride (10
mg, 0.054 mmol) and sodium cyanoborohydride (7 mg, 0.107 mmol) in methanol (5
mL)
was stirred at room temperature for 2 h. To this mixture was added 0.1 normal
solution of
sodium hydroxide in water (2 mL). The methanol was then evaporated. The
aqueous
phase was extracted with EtOAc (5 mL) three times. The organic phase was then
washed with brine (5 mL) twice. All solvent was then removed. The mixture was
purified
by Gilson Preparatory HPLC to give 9 mg of the title compound (13%).
LC/MS = m/z 525.6 [M+H] Ret. Time: 1.67 min.
Example 263: 5-[3-f(dimethylamino)methyll-4-(methyloxy)phenyll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
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0=S=0
I
N
/O
N
F O H
F O NH2
F OH
To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzaldehyde (610 mg, 2.33 mmol) in dioxane (19 mL) and H20 (6.3 mL), was
added
5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (963 mg,
2.33 mmol),
and sodium carbonate (1.48 g, 13.9 mmol). After flushing with Agron for 10
min,
tetrakis(triphenylphosphine)palladium(0) (134 mg, 0.166 mmol) was added. The
reaction
was heated in the microwave 120 C for 120 min. Compound was purified by flash
chromatography using DCM and MeOH to give 632 mg of 3-[1-(ethylsulfonyl)-4-
piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1/-1-indole-7-carboxamide (58%).
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-
(methyloxy)phenyl]-1 H-indole-
7-carboxamide (50 mg, 0.214 mmol), dimethylamine (107 pL, 0.214 mmol), zinc
chloride
(10 mg, 0.054 mmol) and sodium cyanoborohydride (7 mg, 0.107 mmol) in methanol
(5
mL) was stirred at room temperature for 2 h. To this mixture was added 0.1
normal
solution of sodium hydroxide in water (2 mL). The methanol was then
evaporated. The
aqueous phase was extracted with EtOAc (5 mL) three times. The organic phase
was
then washed with brine (5 mL) twice. All solvent was then removed. The mixture
was
purified by Gilson Preparatory HPLC to give 4 mg of the title compound (6.1
%).
LC/MS = m/z 499.4 [M+H] Ret. Time: 1.56 min.
Example 264: 3-f1-(ethylsulfonyl)-4-piperidinyll-544-(methyloxy)-3-(4-
morpholinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
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O=S=O
I
N
(N) N
H
O O NH2
F O
F
F OH
The title compound was prepared according to the general procedure of 5-[3-
[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide trifluoroacetate, substituting morpholine (20 pL, 0.214
mmol) for the
dimethylamine to afford 12 mg of the title compound (17%).
LC/MS = m/z 541.6 [M+H] Ret. Time: 1.69 min.
Example 265: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-{f(1-
methylethyl)aminolmethyl}-
4-(methyloxy)phenyll-1 H-indole-7-carboxamide trifluoroacetate
0=S=0
I
N
O
I \ ~
NH F O
F-H H
F 00 NH2
The title compound was prepared according to the general procedure of 5-[3-
[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (15 p L,
0.214 mmol)
for the dimethylamine to afford 16 mg of the title compound (24%).
LC/MS = m/z 513.2 [M+H] Ret. Time: 1.62 min.
246

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Example 266: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-f(methylamino)methyll-4-
meth loxy)phenyll-1 H-indole-7-carboxamide trifluoroacetate
0=S=0
I
N
I \ ~
N
F O H
F-}--~
F OH O NH2
The title compound was prepared according to the general procedure of 5-[3-
[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide trifluoroacetate, substituting methylamine (50 pL, 0.214
mmol) for
the dimethylamine to afford 10 mg of the title compound (16%).
LC/MS = m/z 485.2 [M+H] Ret. Time: 1.57 min.
Example 267: 5-f3-ff(2,2-dimethylpropyl)aminolmethyl)-4-(methyloxy)phenyll-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O=S=O
I
N
NH N
H
O NH2
F p
F
F OH
The title compound was prepared according to the general procedure of 5-[3-
[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
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indole-7-carboxamide trifluoroacetate, substituting 2,2-dimethyl-1-propanamine
(20 pL,
0.214 mmol) for the dimethylamine to afford 11 mg of the title compound (16%).
LC/MS = m/z 541.2 [M+H] Ret. Time: 1.77 min.
Example 268: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-(1-f2-f(2-
hydroxyethyl)(methyl)aminolethyl}-1 H-pyrazol-4-yl)-1 H-indole-7-carboxamide
O-
N ~O
N
--\,N,N
HO//
N
H
O NH2
A solution of 5-[1-(2-chloroethyl)-1 f-f-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 f-1-
indole-7-carboxamide (30 mg, 0.065 mmol), 2-(methylamino) ethanol (500 pL, 6.5
mmol)
and sodium iodide (3 mg, 0.016 mmol) in tetrahydrofuran (1 mL) was reacted in
a
microwave for 2 h at 130 C. An aqueous work-up was performed on the resulting
mixture. This was then purified by Gilson Preparatory HPLC to give 9 mg of the
title
compound (17%).
LC/MS = mlz 503.2 [M+H] Ret. Time: 1.40 min.
Example 269: 3-f1-(ethylsulfonyl)-4-piperidinyli-5-f4-fluoro-3-
f(methylamino)methyllphenyl}-1 H-indole-7-carboxamide trifluoroacetate
HN ~ 0
O-
F N
N
H ~O
F
H2N O F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-fluoro-3-
formylphenyl)-1 H-indole-7-
carboxamide (16.0 mg, 0.035 mmol) in dichloromethane (1 mL) and methanol (1
mL) was
added 2M methylamine in THF (105 pL, 0.21 mmol) and 1 drop of acetic acid.
This
mixture was stirred for 3 h. Sodium tetrahydridoborate (8.4 mg, 0.21 mmol) was
added
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and the mixture was stirred for 1 h. The resulting mixture was concentrated
and
dissolved in dimethyl sulfoxide (1.5 mL). It was then purified by Gilson
Preparatory HPLC
to give 6.4 mg of the title compound (31.2%).
LC/MS = m/z 473.4 [M+H] Ret. Time: 1.50 min.
Example 270: 5-d3,5-bisf(methylamino)methyllphenyi}-3-f 1-(ethylsulfonyl)-4-
pi peridi nyll-1 H-i ndole-7-carboxamide trifI uoroacetate
I
HN 0%s/Q
N
H
/
N F O
H F~
F OH
H2N O
To a solution of 5-(3,5-diformylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide (10 mg, 0.2 mmol) in dichloromethane (1 mL) and methanol (1 mL)
was
added methylamine (64 iaL, 0.128 mmol) and 1 drop of acetic acid. The
resulting mixture
was stirred for 3 h at room temperature then sodium tetrahydridoborate (5.1
mg, 0.128
mmol) was added. This was stirred for 1 h then concentrated and purified by
Gilson
Preparatory HPLC to give 3 mg of the title compound (23.4%).
LC/MS = m/z 498.6 [M+H] Ret. Time: 1.17 min.
Example 271: 5-d3-f(ethylamino)methyll-4-fluorophenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
0
HN O,-s~/
F N
I / \ FI-i~O
H F I ~
F OH
H2N O
To a solution'43-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-fluoro-3-formylphenyl)-
1 H-indole-7-
carboxamide (35 rng, 0.076 mmol) in dichloromethane (1 mL) and methanol (1 mL)
was
added 2 M ethylamine (230 pL, 0.46 mmol) and 1 drop of acetic acid. The
mixture was
stirred for 1 h at room temperature then tetrahydrofuran (1 mL) was added. The
mixture
was stirred for 30 min followed by the addition of sodium tetrahydridoborate
(17.5 mg,
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0.46 mmol). The resulting mixture was stirred for an additional 1 h,
concentrated and
purified by Gilson Preparatory HPLC to give 20 mg of the title compound
(43.8%).
LC/MS = m/z 487.4 [M+H] Ret. Time: 1.46 min.
Example 272: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-r4-fluoro-3-(ff2-hydroxy-l-
(hydroxymethyl)ethyllamino}methyl)phenyll-1 H-indole-7-carboxamide
trifiuoroacetate (salt)
QH,OH
N
F N
I \ ~
H F ,,O
F--~(
HzN O F OH
The title compound was prepared according to the general procedure of 5-{3-
[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide trifluoroacetate, substituting 2-amino-1,3-propanediol (42 mg,
0.46 mmol)
for ethylamine to afford 21 mg of the title compound (42.7%).
LC/MS = mlz 533.2 [M+H] Ret. Time: 1.39 min.
Example 273: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f4-fluoro-3-({f(1S)-2-
hydroxy-l-
methylethyllamino}methyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
(salt)
QH
HYN N,/
F
N F
H F-~-Q
F OH
HzN O
The title compound was prepared according to the general procedure of 5-{3-
[(ethylamino)methyl]-4-fluorophenyl}-3-[i -(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide trifluoroacetate, substituting (2S)-2-amino-1 -propanol (37 mg,
0.46mmol) for
ethylamine to afford 26 mg of the title compound (54.2%).
LC/MS = m/z 517.2 [M+H] Ret. Time: 1.44
Example 274: 5-{3-f(cyclopropylamino)methyll-4-fluorophenyl}-3-f1-
(ethylsulfonyl)-
4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
250

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HN o
N
F
\ I \
H F F
F OH
HZN O
The title compound was prepared according to the general procedure of 5-{3-
[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide trifluoroacetate, substituting cyclopropylamine (32 mg, 0.46 mmol)
for
ethylamine to afford 23 mg of the title compound (49.4%).
LC/MS = m/z 499.6 [M+H] Ret. Time: 1.75 min.
Example 275: 5-f'3-f(cyclobutylamino)methyll-4-fluorophenyl}-3-f1-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
-,~? O o
HN NIs
F /
\ I \
H F O
F
H 2 N O F OH
The title compound was prepared according to the general procedure of 5-{3-
[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide trifluoroacetate, substituting cyclobutanamine (39 mg, 0.46 mmol)
for
ethylamine to afford 20 mg of the title compound (42%).
LC/MS = m/z 513.2 [M+H] Ret. Time: 1.58 min.
Example 276: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(1-
pyrrolidinylmethyl)phenyll-
1 H-i ndole-7-carboxamide trifl uoroacetate
C1 o
N
N F O
H F-H
F OH
H2N O
251

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To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (33 mg 0.74 mmol) in dichloromethane (0.5 mL) and methanol (0.5
mL) was
added pyrrolidine (32 mg, 0.444 mmol) and 1 drop of acetic acid. The mixture
was stirred
for 2 min then sodium tetrahydridoborate (17.8 mg, 0.444 mmol) was added. This
was
then stirred overnight then concentrated and by Gilson Preparatory HPLC to
give 9.7 mg
of the title compound (21.5%)
LC/MS = m/z 495.4 [M+H] Ret. Time: 1.67 min.
Example 277: 543,5-bisf(ethylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
Piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
\ O
H -s~~/
N
H F O
NH I / \
F
HZN O F OH
To a solution of 5-(3,5-diformylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-
11/ indole-7-
carboxamide (27 mg, 0.058 mmol) in dichloromethane (1.5 mL) and methanol (1.5
mL)
was added ethylamine (31.4 mg, 0.696 mmol) and 1 drop of acetic acid. The
resulting
mixture was stirred for 2 h then sodium tetrahydridoborate (13.2 mg, 0.348
mmol) was
added. This was stirred for another 50 min then purified by Gilson Preparatory
HPLC to
give 20 mg of the title compound (53.9%).
LC/MS = m/z 526.6 [M+H] Ret. Time: 1.41 min.
Example 278: 5-(3,5-bisf(dimethylamino)methyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
0
/N j8//
N
~N~ N F
H F
F OH
HZN O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formyl-5-
mercaptophenyl)-1 H-
indole-7-carboxamide (34 mg, 0.058 mmol) in dichloromethane (1.5 mL) and
methanol
(1.5 mL) was added dimethylamine (31.4 mg, 0.696 mmol) and a drop of acetic
acid. The
resulting mixture was stirred for 2 h at room temperature then sodium
tetrahydridoborate
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CA 02613068 2007-12-20
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(13.2 mg, 0.348 mmol) was added. This was stirred for another 30 min then
purified by
Gilson Preparatory HPLC to give 11 mg of the title compound (29.6%).
LC/MS = m/z 526.6 [M+H] Ret. Time: 1.27 min.
Example 279: 3-f1-(ethyisulfonyl)-4-piperidinyll-543-(2-piperidinyl)phenyll-1H-
indole-7-carboxamide trifluoroacetate
HVNH js~
F
F HZN O F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2
mL) and
H20 (0.7 mL) was added 2-(3-chlorophenyl)piperidine (46 mg, 0.2 mmol).
Potassium
carbonate (55 mg, 0.4 mmol) and, after being degassed for 5 min,
tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.5 mmol) was added. The
resulting
mixture was reacted in a 300W CEM microwave for 30 min at 160 C then the
solids were
filtered off. The solvent was evaporated and the solution was purified by
Gilson
Preparatory HPLC to give 13.2 mg of the title compound (21.7%).
LC/MS = m/z 495.4 [M+H] Ret. Time: 1.76
Example 280: 54341-(ethylamino)ethyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-
1 H-indole-7-carboxamide trifluoroacetate
HNr O'-S~~
N
N F O
H F
H 2 N O F O
H
A solution of 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide (50 mg, 0.11 mmol), ethylamine (19.9 mg, 0.441 mmol) and sodium
cyanoborohydride (30 mg, 0.441 mmol) in N,N-dimethylformamide (0.8 mL) and
acetic
acid (0.2 mL) was reacted in a microwave for 20 min at 150 C. The reaction
was purified
by Gilson Preparatory HPLC to give 20.6 mg of the title compound (39%).
253

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LC/MS = m/z 483.2 [M+H] Ret. Time: 1.67
Example 281: 5-d3-f1-(dimethylamino)ethyllphenyl}-3-f1-(ethylsulfonyl)-4-
Piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 0
O j
N
I / N IFl/O
H F I ~
HZN O F OH
5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 ! / indole-7-
carboxamide (50 mg,
0.11 mmol), dimethylamine (220 pL, 0.44 mmol) and sodium cyanoborohydride (30
mg,
0.44 mmol) were dissolved in N,N-dimethylformamide (400 pL) and acetic acid
(100 pL).
The resulting mixture was reacted in a Smith 150 W microwave for 20 min. at
150 C.
The reaction was purified by Gilson Preparatory HPLC to give 14.6 mg of the
title
compound (22.2%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.63
Example 282: 3-f1-(ethylsulfonvl)-4-piperidinvll-5-f3-fluoro-5-
[(methylamino)methyllphenyl}-1 H-indole-7-carboxamide trifluoroacetate
0
HN O AS~
~
N
F
H F
F
H2N 0 F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-
formylphenyl)-1 H-indole-7-
carboxamide (32 mg, 0.07 mmol) in dichloromethane (1.5 mL) and methanol (1.5
mL)
was added 2 M methylamine in THF (210 lal, 0.42 mmol) and 1 drop of acetic
acid. The
resulting mixture was stirred for 3 h at room temperature then sodium
tetrahydridoborate
(15 mg, 0.42 mmol) was added. This mixture was stirred for 1 hour then
concentrated
and purified by Gilson Preparatory HPLC to give 30 mg of the title compound
(73.1 %).
LC/MS = m/z 473.6 [M+H] Ret. Time: 1.73 min.
254

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Example 283: 5-{3-f(ethylamino)methyll-5-fluorophenyll-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
HN O
o ~s~~
N
/ I
F
~ ~ \
I / N F O
H F-{--Q
HZN O F OH
The title compound was prepared according to the general procedure of 3-[1 -
(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting 2 M ethanamine in THF (210 ul, 0.42
mmol) for
methanamine to afford 6.5 mg of the title compound (15.5%).
LC/MS = m/z 487.4 [M+H] Ret. Time: 1.64 min.
Example 284: 3-f1-(ethylsulfonyl)-4-piperidinyll-543-fluoro-5-
f(propylamino)methyllphenyl}-1 H-indole-7-carboxamide trifluoroacetate
0
HN O
N
F
N IF /~O
H F I ~
H2N O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting propylamine (21 mg, 0.42 mmol) for
methanamine to afford 31 mg of the title compound (72%).
LC/MS = m/z 501.4 [M+H] Ret. Time: 1.54
Example 285: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-fluoro-5-ff(1-
methylethyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
255

CA 02613068 2007-12-20
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~ o
HN
F F O F-~- ~
y
F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting 2-propanamine (21 mg, 0.42 mmol)
for
methanamine to afford 28.5 mg of the title compound (66.2%).
LC/MS = m/z 501.4 [M+H] Ret. Time: 1.53 min.
Example 286: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-fluoro-5-ff(2-
methylpropyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
O
HN O jS~~
N
F
( \ F O
H FJ4OH
HZN 0
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting 2-methyl-1 -propanamine (21 mg,
0.42 mmol)
for methanamine to afford 10 mg of the title compound (22.7%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.72 min.
Example 287: 5-f3-f(cyclobutylamino)methyll-5-fluorophenyl}-3-f1-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
1~ 0
HN
N
F
N F O
H F+/<
HZN 0 F OH
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CA 02613068 2007-12-20
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The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting cyclobutylamine (21.5 mg, 0.42
mmol) for
methanamine to afford 33 mg of the title compound (75.2%).
LC/MS = m/z 513.2 [M+H] Ret. Time: 1.50 min.
Example 288: 5-{3-f(dimethylamino)methyll-5-fluorophenyl}-3-f1-(ethylsulfonyl)-
4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O j0
N
F
N F O
H F-H
H2N O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting 2M dimethylamine in THF (210 ul,
0.42 mmol)
for methanamine to afford 33.7 mg of the title compound (80.2%).
LC/MS = m/z 487.2 [M+H] Ret. Time: 1.43 min.
Example 289: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-fluoro-5-(1-
pyrrolidinyimethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
0
C O ,-S~~
N
/ I
F
N F ,,O
H F-I-'(
F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1 -
(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting pyrrolidine (20.4 mg, 0.42 mmol)
for
methanamine to afford 18 mg of the title compound (41 %).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.63 min.
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CA 02613068 2007-12-20
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Example 290: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-f3-fluoro-5-(4-
morpholinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
N
N
F
N F ,.O
H F--~~
F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1 -
(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting morpholine (22 mg, 0.42 mmol) for
methanamine to afford 22.9 mg of the title compound (50.9%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.47 min.
Example 291: 3-['1-(ethylsulfonyl)-4-piperidinyll-5-f3-fluoro-5-(1-
piperidinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
N O 'S/ 0
~
N
/ I
F
I / N F 0
H F
HZN O ~OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting piperidine (22 mg, 0.42 mmol) for
methanamine
to afford 13.4 mg of the title compound (29.9%).
LC/MS = m/z 527.6 [M+H] Ret. Time: 1.62
Example 292: 341-(ethylsulfonyl)-4-piperidinyll-54341-
(methylamino)ethyllphenyl}-
1 H-indole-7-carboxamide trifluoroacetate
258

CA 02613068 2007-12-20
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HN piS//
N
N F O
H F
HZN O F OH
To a solution of 5-(3-acetylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide (20 mg, 0.044 mmol) in ethanol was added methylamine hydrochloride
salt
and 1 drop of concentrated hydrochloride. The mixture was reacted in a CEM
microwave
at 1000 C for 10 min then sodium tetrahydridoborate was added. The resulting
mixture
was reacted in a CEM microwave at 50 C for 5 min then all solvent was
evaporated. It
was again dissolved in dimethyl sulfoxide then purified by Gilson Preparatory
HPLC to
afford 16.5 mg of the title compound (64.4%).
LC/MS = m/z 469.4 [M+H] Ret. Time: 1.45 min.
Example 293: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-f1-f(1-
methylethyl)aminolethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
HN
N
I / \
H F O
F
H2N O F OH
To a solution of 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/--/-
indole-7-
carboxamide (20 mg, 0.044 mmol), in N,N-dimethylformamide (0.8 mL) and acetic
acid
(0.2 mL) was added 2-propanamine (75 pL, 0.88 mmol) and sodium
cyanoborohydride (6
mg, 0.09 mmol). The resulting mixture was reacted in a Smith microwave at 70
C for
1 h. The solid was filtered off and then purified by Gilson Preparatory HPLC
to afford
19.4 mg of the title compound (72.2%).
LC/MS = m/z 497.4 [M+H] Ret. Time: 1.44 min.
Example 294: 3-r1-(ethylsulfonvl)-4-piperidinyll-5-(3-f1-f(2-
methylpropyl)aminolethyl}phenvl)-1 H-indole-7-carboxamide trifluoroacetate
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HN O%s
N
I / \
H F O
F
H2N O F OH
To a solution of 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide (30 mg, 0.066 mmol), in ethanol (1.2 mL) and acetic acid (0.3 mL)
was
added (2-methylpropyl)amine (101 mg, 1.98 mmol) and sodium cyanoborohydride
(13.5
mg, 0.198 mmol). The resulting mixture was reacted in a Smith microwave at 70
C for
1 h. All solvent was evaporated and dimethyl sulfoxide was used to dissolve
the solid. It
was then purified by Gilson Preparatory HPLC to afford 22.7 mg of the title
compound
(55.1%).
LC/MS = m/z 511.2 [M+H] Ret. Time: 1.52 min.
Example 295: 5-d3-f1-(cyclobutylamino)ethyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
I
HN O
O ~S~
N
F~//O
H FI \
F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl)amino]ethyl}phenyl)-1
H-indole-7-
carboxamide trifluoroacetate, substituting cyclobutylamine (101 mg, 1.98 mmol)
for (2-
methylpropyl)amine to afford 29.1 mg of the title compound (70.8%).
LC/MS = m/z 509.4 [M+H] Ret. Time: 1.52 min.
Example 296: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-f1-(1-
pyrrolidinyl)ethyllphenyl}-1 H-indole-7-carboxamide trifluoroacetate
260

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C O,-S 0
N
F O
H F I ~
F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl)amino]ethyl}phenyl)-1
H-indole-7-
carboxamide trifluoroacetate, substituting pyrrolidine (101 mg, 1.98 mmol) for
(2-
methylpropyl)amine to afford 29.2 mg of the title compound (71 %).
LC/MS = m/z 509.4 [M+H] Ret. Time: 1.49 min.
Example 297: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(3-
thiomorpholinyl)phenyll-1 H-
indole-7-carboxamide trifluoroacetate
s-"')
NH O ,-
N
I / \
H F O
F
H2N O F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (60 mg, 0.13 mmol) in dioxane (1.5
mL) and
water (0.5 mL) was added 3-(3-chlorophenyl)thiomorpholine (84 mg, 0.39 mmol)
and
potassium carbonate (107.6 mg, 0.78 mmol). This mixture was degassed for 5 min
then
tetrakis(triphenylphosphine)palladium(0) (14.0 mg, 0.013 mmol) was added. The
resulting mixture was reacted in a microwave for 30 min at 160 C. The solid
was filtered
off and all solvents were evaporated. The resulting solution was re-dissolved
in
dichloromethane and separator was used to remove water. The mixture was
concentrated to give organic solvent and then purified by Gilson Preparatory
HPLC to
give 7.4 mg of the title compound (11 %).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.54
Example 298: 3-f1-(ethylsulfonyl)-4-piperidinyll-545-(2-piperazinvl)-2-
thienyll-1 H-
indole-7-carboxamide trifluoroacetate
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rl"~ NH p
HN js
N
s
I \ ~
N
H F F O
H2N O F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (60 mg, 0.13 mmol) in dioxane (1.5
mL) and
water (0.5 mL) was added 2-(5-bromo-2-thienyl)piperazine (102 mg, 0.39 mmol)
and
potassium carbonate (108 mg, 0.78 mmol). This mixture was degassed for 5 min
then
tetrakis(triphenylphosphine)palladium(0) (15.0 mg, 0.013 mmol) was added. The
resulting mixture was reacted in a microwave for 30 min at 160 C. The solid
was filtered
off and all solvents were evaporated. The resulting solution was re-dissolved
in
dichloromethane and separator was used to remove water. The mixture was
concentrated to give organic solvent and then purified by Gilson Preparatory
HPLC to
give 29.1 mg of the title compound (36.4%).
LC/MS = m/z 502.4 [M+H] Ret. Time: 1.31
Example 299: 3-f1-(ethylsulfonyl)-4-piperidinyll-544-(2-piperazinyl)phenyll-1
H-
indole-7-carboxamide trifluoroacetate
ozzzzs~0~
rNH N
HN
\ I \
H F O
F
HzN O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-piperazinyl)-2-thienyl]-1 H-indole-7-
carboxamide
trifluoroacetate, substituting 2-(4-bromophenyl)piperazine (94 mg, 0.39 mmol)
for 2-(5-
bromo-2-thienyl)piperazine to afford 20.5 mg of the title compound (25.9%).
LC/MS = m/z 496.4 [M+H] Ret. Time: 1.25
Example 300: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(2-piperazinyl)phenyll-1
H-
indole-7-carboxamide trifluoroacetate
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HN
NH
N
H F ,,O
F-~-~(
NH O F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 f-l-indole-7-carboxamide (60 mg, 0.13 mmol) in dioxane
(1.5 mL) and
water (0.5 mL) was added 2-(3-chlorophenyl)piperazine (63.7 mg, 0.325 mmol)
and
potassium carbonate (90 mg, 0.650 mmol). This mixture was degassed for 5 min
then
tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.011 mmol) was added. The
resulting
mixture was reacted in a microwave for 30 min at 160 C. The solid was
filtered off and
all solvents were evaporated. The resulting solution was re-dissolved in
dichloromethane
and separator was used to remove water. The mixture was concentrated to give
organic
solvent and then purified by Gilson Preparatory HPLC to give 21.7 mg of the
title
compound (27.4%).
LC/MS = m/z 496.4 [M+H] Ret. Time: 1.28 min.
Example 301: 3-f1-(ethylsulfonyi)-4-piperidinyll-5-f6-(4-morpholinyl)-3-
pyridazinyll-
1 H-indole-7-carboxamide trifluoroacetate
~N N,N N
I
N F O H F
t OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1 H-indole-7-
carboxamide
trifluoroacetate, substituting 4-(6-chloro-3-pyridazinyl)morpholine (65 mg,
0.325 mmol) for
2-(3-chlorophenyl)piperazine to afford 3.1 mg of the title compound (3.9%).
LC/MS = m/z 499.6 [M+H] Ret. Time: 1.57 min.
Example 302: 3-f1-(ethylsulfonyl)-4-piperidinvll-5-f6-(1-pyrrolidinyl)-3-
pyridazinyll-
1 H-i ndole-7-carboxamide trif I uoroacetate
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jS0
N
N N, N
\ I \
H F F ,.O
H2N O -F~OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1 H-indole-7-
carboxamide
trifluoroacetate, substituting 3-chloro-6-(1-pyrrolidinyl)pyridazine (60 mg,
0.325 mmol) for
2-(3-chlorophenyl)piperazine to afford 4.1 mg of the title compound (5.3%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.44 min.
Example 303: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-f2-
f(methylamino)methyllphenyl}-
1 H-indole-7-carboxamide trifluoroacetate
NH
N
\ \ ~
~ /. N F O
H F-H
F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1 H-indole-7-
carboxamide
trifluoroacetate, substituting 1-(2-bromophenyl)-N-methylmethanamine (65 mg,
0.325
mmol) for 2-(3-chlorophenyl)piperazine to afford 14.6 mg of the title compound
(19.8%).
LC/MS = m/z 455.0 [M+H] Ret. Time: 1.57 min.
Example 304: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-df(2-
thienylmethyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
HN O
O AYN
F O
F H
F OH
NH O
2
64

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To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (44 mg, 0.1 mmol) in dichloromethane (2 mL) and methanol (2 mL)
was
added 1-(2-thienyl)methanamine (33.6 mg, 0.6 mmol) and 1 drop of acetic acid.
This
mixture was stirred for 2 h then sodium tetrahydridoborate (22.8 mg, 0.6 mmol)
was
added. The resulting mixture was stirred for 1 h. It was then concentrated and
again
dissolved in dimethyl sulfoxide (3 mL). It was then purified by Gilson
Preparatory HPLC
to give 41.7 mg of the title compound (74.5%).
LC/MS = m/z 537.2 [M+H] Ret. Time: 1.81 min.
Example 305: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(df(5-methyl-2-
furanyl)methyllamino}methyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
0
HN O
O ss/~/
N
F O
N F-~-~
H F OH
NH O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1
H-indole-7-
carboxamide trifluoroacetate, substituting 1-(5-methyl-2-furanyl)methanamine
(32 mg, 0.6
mmol) for 1-(2-thienyl)methanamine to afford 29.3 mg of the title compound
(54.7%).
LC/MS = m/z 535.2 [M+H] Ret. Time: 1.74 min.
Example 306: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(ff(2R)-tetrahydro-2-
furanylmethyllamino}methyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
0
HN O z:
N
H F O
F
HZN 0 F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1
H-indole-7-
carboxamide trifluoroacetate, substituting 1-[(2R)-tetrahydro-2-
furanyl]methanamine (31.5
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mg, 0.6 mmol) for 1-(2-thienyl)methanamine to afford 36.9 mg of the title
compound
(70.3%).
LC/MS = m/z 525.6 [M+H] Ret. Time: 1.63 min.
Example 307: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(ff(2S)-tetrahydro-2-
furanylmethyllaminolmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
0
HN O
N
N F õO
H F-I-,(
HZN O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1
H-indole-7-
carboxamide trifluoroacetate, substituting 1-[(2S)-tetrahydro-2-
furanyl]methanamine (31.5
mg, 0.6 mmol) for 1-(2-thienyl)methanamine to afford 39.2 mg of the title
compound
(74.7%).
LC/MS = m/z 525.6 [M+H] Ret. Time: 1.61 min.
Example 308: 5-(3-ff(2,2-dimethylpropyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-
4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
0
HN O ~S~~
N
N F O
H F-~ -~
HZN O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1
H-indole-7-
carboxamide trifluoroacetate, substituting 2,2-dimethyl-1 -propanamine (30.6
mg, 0.6
mmol) for 1-(2-thienyl)methanamine to afford 30.4 mg of the title compound
(59.5%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.69 min.
Example 309: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-ff(2-
methylbutyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
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O
HN
N
N
H
NH O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (44 mg, 0.1 mmol) in dichloromethane (2 mL) and methanol (1 mL)
was
added 2-methyl-1 -butanamine (52 mg, 0.6 mmol) and 1 drop of acetic acid. This
mixture
was stirred for 2 h then sodium tetrahydridoborate (22.8 mg, 0.6 mmol) was
added. The
resulting mixture was stirred for 1 h. It was then concentrated and again
dissolved in
dimethyl sulfoxide (3 mL). It was then purified by Gilson Preparatory HPLC to
give 28.4
mg of the title compound (55.6%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.71
Example 310: 3-f1-(ethylsulfonvl)-4-piperidinvll-5-f3-(ff(2S)-2-
methvlbutyllaminolmethyl)phenyll-1 H-indole-7-carboxamide
,o
HN o /s~/
N
N
H
NH O
The title compound was prepared according to the general procedure of 3-[1 -
(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-1 H-
indole-7-
carboxamide, substituting (2S)-2-methyl-1 -butanamine (52 mg, 0.6 mmol) for 2-
methyl-1 -
butanamine to afford 30 mg of the title compound (58.7%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.68
Example 311: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-({f(1 R)-1 2,2-
trimethylpropyllamino}methvl)phenyll-1 H-indole-7-carboxamide
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4y o
HN
N
N
H
HzN O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-1 H-
indole-7-
carboxamide, substituting (2R)-3,3-dimethyl-2-butanamine (60 mg, 0.6 mmol) for
2-
methyl-l-butanamine to afford 24.5 mg of the title compound (46.7%).
LC/MS = m/z 525.6 [M+H] Ret. Time: 1.67
Example 312: 3-f1-(ethylsulfonvl)-4-piperidinyll-5-f3-fluoro-5-({f(2S)-
tetrahydro-2-
furanvimethyllamino}methyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
0
HN O
/S~
N
F \ I ~ ~ F 0
H F-~-~
F OH
HZN O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-
formylphenyl)-1 H-indole-7-
carboxamide (40 mg, 0.087 mmol) in dichloromethane (2 mL) and methane (1 mL)
was
added 1-[(2S)-tetrahydro-2-furanyl]methanamine (53 mg , 0.525 mmol) and 2
drops of
acetic acid. The resulting mixture was stirred for 2 h at room temperature
followed by an
addition of sodium tetrahydridoborate (20 mg, 0.525 mmol). This mixture was
stirred for
30 min then concentrated and purified by Gilson Preparatory HPLC to give 26.6
mg of the
title compound (46.6%).
LC/MS = m/z 543.4 [M+H] Ret. Time: 1.60 min.
Example 313: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-fluoro-5-({T(2R)-
tetrahydro-2-
furanylmethyllamino}methyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
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oCI
HN
N
F
~io
H
N F I '
H2N O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 1-[(2R)-tetrahydro-2-furanyl]methanamine (53 mg, 0.525 mmol)
for 1-[(2S)-
tetrahydro-2-furanyl]methanamine to afford 27.1 mg of the title compound
(47.4%).
LC/MS = m/z 543.4 [M+H] Ret. Time: 1.58 min.
Example 314: 5-f3-(df(1S)-1,2-dimethylpropyllaminolmethyl)-5-fluorophenyil-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
HN O ZZ:S~/
N
F
N
H
H,.N 0
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting (2S)-3-methyl-2-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 19.3 mg of the title compound (42%).
LC/MS = m/z 529.6 [M+H] Ret. Time: 1.65
Example 315: 5-f3-(ff(1 R)-1,2-dimethylpropyllamino}methyl)-5-fluorophenyll-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
269

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HN
N
F \ I \ ~ F ,,O
N F II~\/
H F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting (2R)-3-methyl-2-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 19.5 mg of the title compound (34.9%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.82 min.
Example 316: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-(3-f1 uoro-5-f f(1-
methylpropyl)aminolmethyllphenyl)-1 H-indole-7-carboxamide trifluoroacetate
HN 0 ~ ~~
N
F ~O
H F
HzN O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furany[methyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 2-butanamine (37 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-
furanyl]methanamine to afford 27.7 mg of the title compound (50.6%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.63 min.
Example 317: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-fluoro-5-({'f(1 S)-1.2,2-
!0 trimethylpropyllamino}methyl)phenyll-1 H-indole-7-carboxamide
trifluoroacetate
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HN
F N O
H F-H
H2N O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsu Ifonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting (2S)-3,3-dimethyl-2-butanamine (52 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-
2-furanyl]methanamine to afford 19.8 mg of the title compound (34.7%).
LC/MS = m/z 543.4 [M+H] Ret. Time: 1.78 min.
Example 318: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-fluoro-5-(ff(2S)-2-
methylbutyllamino}methyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
HN O --
F
FO
H
N F I '
HzN O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting (2S)=2-methyl-l-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 23.3 mg of the title compound (41.7%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.62 min.
Example 319: 3-f1-(ethylsulfonyl)-4-piperidinyl1-5-(3-fluoro-5-{f(2-
10 methylbutyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
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CA 02613068 2007-12-20
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HN O S'
N
F
~ F O
N F-H
H F O
HZN O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 2-methyl-1 -butanamine (45 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 30.5 mg of the title compound (54.5%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.73 min.
Example 320: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-f3-fluoro-5-({f(1 R)-1,2,2-
trimethylpropyllaminolmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
HN O
N
F ~O
F
H F OH
HZN O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trlfluoroacetate
, substituting (2R)-3,3-dimethyl-2-butanamine (52 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-
2-furanyi]methanamine to afford 24.9 mg of the title compound (43.6%).
LC/MS = m/z 543.4 [M+H] Ret. Time: 1.73 min.
Example 321: 5-(3-ff(2,2-dimethylpropyl)aminolmethyi}-5-fluorophenyi)-3 J'1-
(ethylsulfony!)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
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r~- 0
HN O zz-:s//
N
F F O
IN-{ F I ~
F OH
HZN O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 2,2-dimethyl-1-propanamine (45 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 14 mg of the title compound (25%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.79 min.
Example 322: 5-(3-ff(cyclopropylmethyl)aminolmethyl}-5-fluorophenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
HN
N
F
F o
N F
H F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furany[methyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 1 -cyclopropylmethanamine (37 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 21.1 mg of the title compound (38.7%).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.69 min.
Example 323: 5-(3-{f(cyclopentylmethyl)aminolmethyl}-5-fluorophenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
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HN O
O
N
F
N F~ o
H
HZN O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 1-cyclopentylmethanamine (52 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 21.6 mg of the title compound (37.9%).
LC/MS = m/z 541.4 [M+H] Ret. Time: 1.82 min.
Example 324: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-fluoro-5-f f(tetrahydro-
2H-
pyran-4-ylmethyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
trifluoroacetate
0
HN O ~S~ 0
N
F F O
H F I ~
F OH
HZN O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furany[methyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 1-(tetrahydro-2H-pyran-4-yl)methanamine (60 mg, 0.525 mmol) for
1-[(2S)-
tetrahydro-2-furanyl]methanamine to afford 40.1 mg of the title compound
(68.7%).
LC/MS = m/z 557.4 [M+H] Ret. Time: 1.54 min.
Example 325: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-fluoro-5-f f(2-
thienyimethyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
274

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p
HN O /S~L/
N
F
H F~ o
N
H2N O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furany[methyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 1-(2-thienyl)methanamine (59 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 24.4 mg of the title compound (41.9%).
LC/MS = m/z 555.4 [M+H] Ret. Time: 1.67 min.
Example 326: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-f3-fluoro-5-(ff2-
(methvloxy)ethyllamino}methyl)phenyll-1 H-indole-7-carboxamide
trifluoroacetate
/
HN O /g~~
N
F F O
H F I 4
F OH
HZN O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 2-(methyloxy)ethanamine (39 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 31 mg of the title compound (56.5%).
LC/MS = m/z 517.2 [M+H] Ret. Time: 1.52 min.
Example 327: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-fluoro-5-({f3-
(methyloxy)propyllamino}methyl)phenyll-1 H-indole-7-carboxamide
trifluoroacetate
275

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HN
S~ O
O s/
N
F
F O
N F
H
F OH
HZN O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 3-(methyloxy)-1-propanamine (46 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 27.3 mg of the title compound (48.7%).
LC/MS = m/z 531.4 [M+H] Ret. Time: 1.54 min.
Example 328: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-fluoro-5-ff(2-
furanylmethyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
HN O ~S~
N
F
F O
H F-~-~
F OH
H 2 N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyi)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 1-(2-furanyl)methanamine (50 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 24.8 mg of the title compound (43.7%).
LC/MS = m/z 539.4 [M+H] Ret. Time: 1.63 min.
Example 329: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-(3-fluoro-5-df (3-
methylbutyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
276

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HN O --/
N
F \ I \ ~
/ H F O
F II~(\\~
H2N O F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furany[methyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 3-methyl-1 -butanamine (45 mg, 0.525 mmol) for 1-[(2S)-
tetrahydro-2-
furanyl]methanamine to afford 27.6 mg of the title compound (49.4%).
LC/MS.= m/z 529.4 [M+H] Ret. Time: 1.67 min.
Example 330: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-fluoro-5-(ff(5-methyl-2-
furanvl)methyllamino}methyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
O ~
~
HN O sS~/
N
F \ I ~ ~ F O
H F~
F OH
HzN O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-
furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate
, substituting 1-(5-methyl-2-furanyl)methanamine (58 mg, 0.525 mmol) for 1-
[(2S)-
tetrahydro-2-furanyl]methanamine to afford 28.3 mg of the title compound
(48.8%).
LC/MS = m/z 553.6 [M+H] Ret. Time: 1.78 min.
Example 331: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-(3-{f(2-
methylpropyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
277

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HN
N
F O
F
+l< N
H
F OH
HZN O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in dichloromethane (2 mL) and methanol (1 mL)
was
added 2-methyl-1 -propanamine (70 pL, 0.683 mmol) and 2 drops of acetic acid.
This
mixture was stirred for 2 h at room temperature and then sodium
tetrahydridoborate
(26 mg, 0.683 mmol) was added. After 30 min the mixture was concentrated and
was
dissolved in dimethyl sulfoxide (2 mL) and purified by Gilson Preparatory HPLC
to give
19.8 mg of the title compound (61 %).
LC/MS = m/z 497.4 [M+H] Ret. Time: 1.57
Example 332: 3-f1-(ethylsulfonvl)-4-piperidinyll-5-f3-(2-pyrrolidinyl)phenyll-
1 H-
indole-7-carboxamide trifluoroacetate
NH O z
N
F O
F+~ H
F OH H2N O
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-
2-yl)-1 H-indole-7-carboxamide (70 mg, 0.151 mmol), 2-(3-
iodophenyl)pyrrolidine (70 mg,
0.456 mmol) in potassium carbonate (126 mg, 0.910 mmol) in dioxane (2 mL) and
water
(1 mL) was degassed for 5 min and tetrakis(triphenylphosphine)palladium(0) (17
mg,
0.015 mmol) was added. The mixture was reacted in a CEM microwave for 20 min
at
160 C. The organic layers were then separated and concentrated. This was then
dissolved in dimethyl sulfoxide (1 mL) and purified by Gilson Preparatory HPLC
to give 48
mg of the title compound (59.5%).
LC/MS = m/z 481.0 [M+H] Ret. Time:1.47
278

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Example 333: 3-f1-(ethylsulfonvl)-4-piperidinyil-5-f2-fluoro-5-
I(methylamino)methyllphenyl}-1 H-indole-7-carboxamide trifluoroacetate
H~I Q 0
N
N
F O H
F-F< H2N O
F OH
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-
formylphenyl)-1 H-indole-7-
carboxamide (40 mg, 0.087 mmol) in dichloromethane (2 mL) and methanol (1 mL)
was
added methanamine (262 pL, 0.524 mmol) and 1 drop of acetic acid. After being
stirred
for 2 h at room temperature, sodium tetrahydridoborate (20 mg, 0.524 mmol) was
added
and allowed to stand for 30 min. The mixture was then purified by Gilson
Preparatory
HPLC to give 12.3 mg of the title compound (58.6%).
LC/MS = m/z 473.4 [M+H] Ret. Time:1.55.
Example 334: 3-f 1-(ethylsulfonyl)-4-piperidinvll-5-f2-fluoro-5-
f(propylamino)methyllphenyl}-1 H-indole-7-carboxamide trifluoroacetate
HN
N
\ I \
F p F N
~ H
F
F OH H2N 0
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting propylamine (44 pL, 0.524 mmol) for
methanamine to afford 15.4 mg of the title compound (61.5%).
LC/MS = m/z 501.4[M+H] Ret. Time: 1.55
279

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Example 335: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-(2-fluoro-5-('f(2-
methylpropyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
O
H N O%S/\
N
F N
F O H
F-H H 2 N O
F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting 2-methyl-l-propanamine (53 pL,
0.524 mmol)
for methanamine to afford 15 mg of the title compound (62.9%)
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.55
Example 336: 5-(54 f(2,2-dimethvlpropyl)aminolmethyl}-2-fluorophenyl)-3-f1-
(ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O
HN O ----S\
N
N
F O H
F I
F-~4 H2N F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting 2,2-dimethyl-1 -propanamine (46 pL,
0.524
mmol) for methanamine to afford 14.3 mg of the title compound (64.3%).
LC/MS = m/z 530.2[M+H] Ret. Time: 1.59
280

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Example 337: 5-f5-(df(1 S)-1,2-dimethylpropyllamino}methyl)-2-fluorophenyil-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O
HN O ,-S\~
N
F O F N
F // H
F \OH H2N 0
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting (2S)-3-methyl-2-butanamine (46 pL,
0.524
mmol) for methanamine to afford 17.3 mg of the title compound (64.3%)
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.69
Example 338: 5-f5-(ff(1 R)-1,2-dimethylpropyllaminolmethyl)-2-fluorophenyll-3-
f 1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O
HN 0%S\
N
F
O F
// N
F--~--~( H
IF 'OH HN O
The title compound was prepared according to the general procedure of 3-[1 -
(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting (2R)-3-methyl-2-butanamine (46 pL,
0.524
mmol) for methanamine to afford 15 mg of the title compound (64.3%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.70
281

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Example 339: 5-(5-{f(cyclopropylmethyl)aminolmethyl}-2-fluorophenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O
HN O eS~~
N
\ \ ~
F O F N
F~ H
F OH H2N 0
The title compound was prepared according to the general procedure of 3-[1 -
(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting 2-methyl-1 -butanamine (38 NL,
0.524 mmol) for
methanamine to afford 16.2 mg of the title compound (62.7%).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.57
Example 340: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f2-fluoro-5-(1-
pyrrolidinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
N O ss //
N
\ \ ~
F O F N
F ~ // H
IF 'OH H 2 N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting pyrrolidine (44 pL, 0.524 mmol) for
methanamine to afford 10 mg of the title compound (62.7%).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.62
Example 341: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f2-fluoro-5-(4-
morpholinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
282

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O O
~
N O s
N
\
F O F N
F~ H
F OH H2N 0
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-
indole-7-
carboxamide trifluoroacetate, substituting morpholine (45 pL, 0.524 mmol) for
methanamine to afford 15 mg of the title compound (64.3%)
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.52
Example 342: 3-f1-(ethylsulfonyi)-4-piperidinvil-5-f2-fluoro-5-({f2-
(methyloxy)ethyllamino}methyl)phenyll-1 H-indole-7-carboxamide
trifluoroacetate
O O
HN O\ ~
N
F 0 F N
F-~--~( H
IF 'OH H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-
formylphenyl)-1 H-indole-7-
carboxamide (40 mg, 0.087 mmol) in dichloromethane (2 mL) and methanol (1 mL)
was
added 2-(methyloxy)ethanamine (54 NL, 0.524 mmol) and 1 drop of acetic acid.
After
being stirred over the weekend at room temperature, sodium tetrahydridoborate
(20 mg,
0.524 mmol) was added and allowed to stand for 30 min. The mixture was then
purified
by Gilson Preparatory HPLC to afford 11.4 mg of the title compound (63%).
LC/MS = m/z 517.2 [M+H] Ret. Time: 1.57
Example 343: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-[2-fluoro-5-({f3-
(methyloxy)propyllamino}methyl)phenyll-1 H-indole-7-carboxamide
trifluoroacetate
283

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O
O
H O oS~~
N
F
O F N
F H
F OH
H2N 0
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[2-
(methyloxy)ethyl]amino}methyl)phenyl]-1 H-
indole-7-carboxamide trifluoroacetate, substituting 3-(methyloxy)-1-
propanamine (53 pL,
0.524 mmol) for 2-(methyloxy)ethanamine to afford 15 mg of the title compound
(64.5%)
LC/MS = m/z 531.4 [M+H] Ret. Time: 1.60
Example 344: 341-(ethylsulfonyl)-4-piperidinyll-5-[3-(1-methyl-2-
pyrrolidinyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate
O
N~ O
N
/ I
\ \
4 ~ N
F p ~ ~
F H
F ~HH2N 0
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-
pyrrolidinyl)phenyl]-1 H-indole-7-
carboxamide (20 mg, 0.04 mmol), formaldehyde (9.5 mL, 0.125 mmol) and sodium
triacetoxyborohydride in dichloromethane (2 mL) was added 2 drops of acetic
acid. The
resulting mixture was stirred overnight at room temperature. All solvent was
evaporated
and the result was re-dissolved in dimethyl sulfoxide (1 mL). The mixture was
then
separated twice by Gilson Preparatory HPLC to afford 8.9 mg of the title
compound
(60.9%).
LC/MS = m/z 495.4 [M+H] Ret. Time: 1.54
284

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Example 345: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-d2-f(2-
methylpropyl)aminolethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
HN
O', ,O
S
N
F O
F N
I \ H
F OH
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (60 mg, 0.13 mmol), [2-(3-
bromophenyl)ethyl](2-methylpropyl)amine (100 mg, 0.39 mmol) and potassium
carbonate
(108 mg, 0.780 mmol) in dioxide (2 mL) and water (0.7 mL). The resulting
mixture was
degassed for 5 min then tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.013
mmol)
was added. This was reacted in a CEM microwave for 20 min at 160 C. The
reaction
was then purified using Gilson Preparatory HPLC to afford 44 mg of the title
compound
(62.5%).
LC/MS = m/z 511.2 [M+H] Ret. Time: 1.79
Example 346: 5-f3-f2-(ethylamino)ethyllphenyl}-3-f1-(ethylsuifonyl)-4-
piperidiny1l=
1 H-indole-7-carboxamide trifluoroacetate
j
HN
O"
S
N
F O
~j N
F I ' H
F OH H2N O
285

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A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-
2-yl)-1 H-indole-7-carboxamide (40.4 mg, 0.09 mmol), 2-(3-bromophenyl)-N-
ethylethanamine (60 mg, 0.263 mmol) and potassium carbonate (72 mg, 0.526
mmol) in
dioxane (2 mL) and water (0.7 mL) was degassed for 5 min. To this was added
tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.009 mmol). The resulting
mixture was
reacted in a CEM microwave for 20 min at 160 C. The reaction was then
purified using
Gilson Preparatory HPLC to afford 38.6 mg of the title compound (59.7%)-:
LC/MS = m/z 482.8 [M+H] Ret. Time: 1.54
Example 347: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-{3-f2-
(propylamino)ethyllphenyl}-
1 H-indole-7-carboxamide trifluoroacetate
HN
O--% S ,O
N
F O I \ ~
F- H H
F OH
H2N O
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-
2-yl)-1 H-indole-7-carboxamide (25 mg, 0.055 mmol), potassium carbonate (46
mg, 0.33
mmol) and [2-(3-bromophenyl)ethyl]propylamine (40 mg, 0.165 mmol) in dioxane
(2 mL)
and water (0.7 mL) was degassed for 5 min then
tetrakis(triphenylphosphine)palladium(0)
(7 mg, 0.006 mmol) was added. The resulting mixture was reacted in a CEM
microwafe
for 20 min at 160 C. The reaction was then separated using Gilson Preparatory
HPLC to
afford 17.6 mg of the title compound (61 %).
LC/MS = m/z 497.4 [M+H] Ret. Time: 1.97
Example 348: 5-{3-f2-(dimethylamino)ethyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
286

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N
O\~
S O
PNN
= F O
F-~-~( H
IF 'OH H2N O
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-
2-yl)-1 H-indole-7-carboxamide (60 mg, 0.13 mmol), potassium carbonate (108
mg, 0.78
mmol) and 2-(3-bromophenyl)-N,N-dimethylethanamine (90 mg, 0.39 mmol) in
dioxane (2
mL) and water (0.7 mL) was degassed for 5 min then
tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) was added. The
resulting
mixture was reacted in a CEM microwafe for 20 min at 1600 C. The reaction was
then
separated using Gilson Preparatory HPLC to afford 30 mg of the title compound
(59.7%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.60
Example 349: 5-f3-f2-(dipropylamino)ethyllphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O, e0
S
N
F 0
F~ H
F OH H2N O
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-
2-yl)-1 H-indole-7-carboxamide (66 mg, 0.14 mmol), potassium carbonate (120
mg, 0.86
mmol) and (2-phenylethyl)dipropylamine (120 mg, 0.43 mmol) in dioxane (2 mL)
and-
287

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water (0.7 mL) was degassed for 5 min then
tetrakis(triphenylphosphine)palladium(0) (15
mg, 0.014 mmol) was added. The resulting mixture was reacted in a CEM
microwafe for
20 min at 1600 C. The reaction was then separated using Gilson Preparatory
HPLC to
afford 9 mg of the title compound (65.3%).
LC/MS = m/z 455.0 [M+H] Ret. Time: 1.55
Example 350: 5-[3-(f[2-(3,5-dimethyl-1 H-pyrazol-l-
yl)ethyllamino}methyl)phenyll-3-
f1-(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
CN
N
O
HN OI
S
N
F O
F N
H
F OH
H2N O
To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (44 mg, 0.1 mmol), 2-(3,5-dimethyl-lH-pyrazol-1-yl)ethanamine (105
mg,
0.6 mmol) in dichloromethane (3 mL) and methanol (1.5 mL) was added 3 drops of
acetic
acid. The resulting mixture was stirred overnight then sodium
triacetoxyborohydride (134
mg, 0.6 mmol) was added. This mixture was stirred overnight. The resulting
mixture was
quenched with sodium bicarbonate (2 mL) and brine (2 mL) and organic layer was
collected and concentrated. The reaction was then separated using Gilson
Preparatory
HPLC to afford 26 mg of the title compound (67.7%)
LC/MS = m/z 563.2 [M+H] Ret. Time: 1.51
Example 351: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-I'2-(4-morpholinylmethyl)-
1,3-
thiazol-4-yll-1 H-indole-7-carboxamide trifluoroacetate
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0 O~, S O
~
PN
N
F g
N p
F~ H
F OH H2N O
To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM
(4.0
mL) was added morpholine (1 30ul, 1.5 mmol) and 3 drops of AcOH. The mixture
was
stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6
hr, the
mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic
layer
was separated and concentrated to give 200 mg of 4-[(4-bromo-1,3-thiazol-2-
yl)methyl]morpholine (76 %).
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-
2-yl)-1 H-indole-7-carboxamide (46 mg, 0.1 mmol), 4-[(4-bromo-1,3-thiazol-2-
yl)methyl]morpholine (79 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6
mmol) in
dioxane (2 mL) and water (0.7 mL) was degassed for 5 min then
triacetoxyborohydride
(11 mg, 0.1 mmol) was added. This mixture was reacted in a CEM microwave for
20 min
at 160 C. The organic layer was collected and concentrated. The residue was
re-
dissolved with dimethyl sulfoxide (1 mL) and was then purified using Gilson
Preparatory
HPLC to afford 26.6 mg of the title compound (63.2%)
LC/MS = m/z 518.2 [M+H] Ret. Time: 1.49
Example 352: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(2-f f (2-
methylpropyl)aminolmethvl}-1,3-thiazol-4-vl)-1 H-indole-7-carboxamide
trifluoroacetate
O\\ S O
H P
N S
\ I N
FI O
F-~--~( N
H
F OH
H 2 N O
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To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM
(4.0
mL) was added iso-propyl amine (152u1, 1.5 mmol) and 3 drops of AcOH. The
mixture
was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After
6 hr,
the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The
organic
layer was separated and concentrated to give 145 mg of the title compound (58
%).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carbaldehyde (46 mg, 0.1 mmol), 2-methyl-1 -
propanamine
(70 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) in dioxane (2 mL)
and
water (0.7 mL) was added triacetoxyborohydride (11 mg, 0.01 mmol). This
solution was
degassed for 5 min then reacted in a CEM microwave for 20 min at 160 C. The
organic
layer was separated and concentrated. It was then purified using Gilson
Preparatory
HPLC to afford 24 mg of the title compound (61.8%)
LC/MS = m/z 504.2 [M+H] Ret. Time: 1.43
Example 353: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f2-(1-pyrrolidinylmethyl)-
1,3-
thiazol-4-yll-1 H-indole-7-carboxamide
O\\ O QS
N S P
N
N
H
H2N O
To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM
(4.0
mL) was added pyrrolidine (124u1, 1.5 mmol) and 3 drops of AcOH. The mixture
was
stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6
hr, the
mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic
layer
was separated and concentrated to give 200 mg of the title compound (82 %).
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-
thiazol-4-yl)-1 H-
indole-7-carboxamide trifluoroacetate
, substituting pyrrolidine (74 mg, 0.3 mmol) for 2-methyl-l-propanamine to
afford 6.3 mg
of the title compound (50%)
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LC/MS = m/z 500.4 [M+H] Ret. Time: 1.22
Example 354: 3-[1-(ethylsulfonyl)-4-piperidinyll-5-f2-(1-piperidinylmethvl)-
1,3-
thiazol-4-vll-1 H-indole-7-carboxamide
O\~S O
CN) S P
\ I
N YH
N
H2N O
To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM
(4.0
mL) was added piperidine (150u1, 1.5 mmol) and 3 drops of AcOH. The mixture
was
stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6
hr, the
mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic
layer
was separated and concentrated to give 166 mg of the title compound (64 %).
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-
thiazol-4-yl)-1 H-
indole-7-carboxamide trifluoroacetate
, substituting piperidine (78 mg, 0.3 mmol) for 2-methyl-1 -propanamine to
afford 15.5 mg
of the title compound (51.6%).
LC/MS = m/z 517.4 [M+H] Ret. Time: 1.29
Example 355: 5-f2-f(dimethylamino)methvll-1,3-thiazol-4-vl)-3-f 1-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O\~S O
-N / S N'
i I
N I
F O N
F--/< H
F OH H2N O
To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM
(4.0
mL) was added dimethyl amine (2.OM, 3.0 mL) and 3 drops of AcOH. The mixture
was
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stirred for 48 hr and then Na(OAc)3BH (1.33g, 6.0 mmol) was added. After 12
hr, the
mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL) and
separator was
used to get the DCM organic layer. The organic layer was concentrated to give
90 mg of
desired product (40%).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (46 mg, 0.1 mmol), dimethylamine
(69 mg,
0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) in dioxane (2 mL) and
water
(0.7 mL) was added triacetoxyborohydride (12 mg, 0.01 mmol). This mixture was
degassed for 5 min. The mixture was then reacted in a microwave for 20 min at
160 C.
The organic layers were separated and concentrated. It was then purified using
Gilson
Preparatory HPLC to afford 23 mg of the title compound (59%)
LC/MS = m/z 474.4 [M+H] Ret. Time: 1.20
Example 356: 5-(2-ffethyl(methyl)aminolmethyl}-1,3-thiazol-4-yl)-3-I'1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O~, S
\-N S P
\ I
N I \ ~
F 0 ~
F+J< H
F OH H2 N O
To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM
(4.0
mL) was added N-methylethanamine (470u1, 6.0 mmol) and 3 drops of AcOH. The
mixture was stirred for 48 hr and then Na(OAc)3BH (1.33g, 6.0 mmol) was added.
After
12 hr, the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL)
and
separator was used to get the DCM organic layer. The organic layer was
concentrated to
give 160 mg of the title compound (68 %).
The title compound was prepared according to the general procedure of 5-{2-
[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-7-
carboxamide trifluoroacetate, substituting ethyl(methyl)amine (73 mg, 0.3
mmol) for
dimethylamine to afford 25 mg of the title compound (60.4%).
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LC/MS = m/z 490.4 [M+H] Ret. Time: 1.25
Example 357: 5-(3-cyano-5-ff(2-methylpropyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-4-piperidinvll-7 H-indole-7-carboxamide trifluoroacetate
/I~ ,~O
H N S\o
F 0
F--~----
F '
IO)H N
H 2 N 0 H
To a solution of 3-formylbenzonitrile (1.0 g, 7.6 mmol) in TFA (4.0 mL) at 00
C under
argon atmosphere was added concentrated H2SO4 (6.0 mL) dropwise followed by
addition of NBS in small portion. The mixture was warmed to room temperature
slowly
and then stirred for 12 h under argon atmosphere. Upon reaction completion,
the mixture
was poured into ice-H20 (80 mL), PdCI2 (117 mg, 0.658 mmol) and the solid was
collected and dried over vacuum overnight to give 1.50 g of 3-bromo-5-
formylbenzamide
(86%).
LC/MS = m/z 228.2 [M+H] Ret. Time: 1.37
To a solution of 3-bromo-5-formylbenzamide (1.5 g, 6.58 mmol) in H20 (50.0 mL)
and
MeCN (50.0 mL) was added PdC12 (117 mg, 0.658 mmol). The mixture was stirred
for 72
h at room temperature and another portion of H20 (100 mL) and MeCN (100 mL)
was
added followed with addition of PdC12 (100mg, 0.56mo1). The mixture was
stirred for
another 12 hr and concentrated. The residue was dissolved in EtOAc (200 mL),
washed
with brine (3 X 50.0 mL), dried over Na2SO4 and concentrated, and then was
purified by
chromatography (10% EtOAc in hexanes) to give 550 mg of 3-bromo-5-
formylbenzonitrile
(40%).
Toa solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2.0
mL) and
H20 (0.7 mL) was added 3-bromo-5-formylbenzonitrile (68 mg, 0.3 mmol), and
potassium
carbonate (83 mg, 0.6 mmol). The mixture was degassed for 5 min befire
addition of
tetrakis (triphenylphosphine) palladium (0) (12 mg, 0.01 mmol). The mixture
was reacted
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in the microwave at 1602 C for 20 min. The compound was purified by Gilson
Preparatory
HPLC to give 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide.
To a solution of 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-
carboxamide (47 mg, 0.1 mmol) in dichloromethane (3 mL) and methanol (1 mL)
was
added a few drops of acetic acid and methyl(2-methylpropyl)amine (64 pL, 0.6
mmol).
This mixture was stirred overnight followed,by an addition of 20 drops of
acetic acid and
sodium triacetoxyborohydride (0.6 mmol). The reaction was mixed for 4 h
followed by an
addition of methyl (2-methylpropyl) amine (64 pL, 0.6 mmol) and sodium
triacetoxyborohydride (0.6 mmol). The mixture was stirred overnight then
quenched with
sodium biocarbonate and brine. The organic layer was separated by SOX
cartridge and
concentrated. It was then separated using Gilson Preparatory HPLC to afford
10.3 mg of
the title compound (63.6%).
LC/MS = m/z 522.4 [M+H] Ret. Time: 1.65
Example 358: 5-f3-cyano-5-f(dimethylamino)methyllphenvl}-3-f1-(ethylsulfonyl)-
4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
-N
N O
F O
$H2N ,'O
F~ F OH ~
H
O
The title compound was prepared according to the general procedure of 5-(3-
cyano-5-
{[(2-methylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-
indole-7-
carboxamide trifluoroacetate, substituting trimethylamine (300 pL, 0.3 mmol)
for methyl(2-
methylpropyl)amine to afford 10.5 mg of the title compound (61 %).
LC/MS = m/z 494.4 [M+H] Ret. Time: 1.48
Example 359: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-[3-(4-
morpholinylmethyl)phenyil-
1 F/-indole-7-carboxamide trifluoroacetate
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p~ 0
OS~
~N i
N
F F p
F pH I ~ ~
N
H
H2N O
To a solution of 3-[1 -(ethylsulf onyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (80 mg, 0.181 mmol) in DCM was added morpholine (50 NL, 0.545
mmol).
The reaction was stirred at room temperature for 30 min before the addition of
sodium
triacetoxyborohydride (120 mg, 0.545 mmol). The reaction was run at room
temperature
overnight and then concentrated. Compound was purified by Gilson Preparatory
HPLC to
afford 28.6 mg of the title compound (25%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.48 min
Example 360: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(ff(4-
fluorophenyl)carbonyllamino}methyl)phenyll-1 F/-indole-7-carboxamide
trifluoroacetate
O~
,S~O
N
N ~
O N
F p H
F~ O NH2
F OH
The title compound was prepared according to the general procedure of 5-{3-
[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
substituting 4-fluoro-N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]methyl}benzamide (125 mg, 0.352 mmol) for N-{[3-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)phenyl]methyl}acetamide. Compound was purified by Gilson
Preparatory HPLC to give 18.3 mg of the title compound (27%).
LC/MS = m/z 563.1 [M+H] Ret. Time: 2.07 min
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Example 361: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-{f(2-
furanylcarbonyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate
LIO
O\N
N \ / \
CO H
0 N
F 0 H
F O N H
2
F OH
The title compound was prepared according to the general procedure of 5-{3-
[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-
2-
furancarboxamide (115 mg, 0.352 mmol) for N-{[3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl]methyl}acetamide. Compound was purified by Gilson
Preparatory HPLC to give 8.1 mg of the title compound (12%).
LC/MS = m/z 535 [M+H] Ret. Time: 1.89 min
Example 362: 5-(3-f[(cyclopentylcarbonyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 M-indole-7-carboxamide trifluoroacetate
~
o~ S~ O
N Cly N
0 F O N
F---/< H
F OH O NH2
The title, compound was prepared according to the general procedure of 5-{3-
[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide
substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]methyl}cyclopentanecarboxamide (116 mg, 0.352 mmol) for N-{[3-
(4,4,5,5-
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tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}acetamide. Compound was
purified by
Gilson Preparatory HPLC to give 9.2 mg of the title compound (14%).
LC/MS = m/z 535 [M+H] Ret. Time: 1.89 min
Example 363: 5-(3-{f(1-benzothien-2-ylcarbonvl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 htiindole-7-carboxamide
S p
0
O
NH N
. I ~
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1// indole-
7-
carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]methyl}-1-benzothiophene-2-carboxamide (57 mg, 0.144 mmol) for N-{[3-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide.
Compound was
purified by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 601.2 [M+H] Ret. Time: 2.18 min
Example 364: 5-f3-(df(1-acetyl-4-piperidinyl)carbonyllamino}methyl)phenyll-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 M-indole-7-carboxamide
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O
O N ~
S,-O
NH N
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-indole-
7-
carboxamide substituting 1 -acetyl-N-{[3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-
yl)phenyl]methyl}-4-piperidinecarboxamide (56 mg, 0.144 mmol) for IV {[3-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was
purified
by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 594.4 [M+H] Ret. Time: 1.87 min
Example 365: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(f f(1-methyl-1 F/-
pyrrol-2-
yl)carbonyllamino}methyl)phenyil-1 H-indole-7-carboxamide
N
O
O N \O
NH
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-indole-
7-
carboxamide substituting 1-methyl-N-{[3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-
yl)phenyl]methyl}-1 H-pyrrole-2-carboxamide (49 mg, 0.144 mmol) for N-{[3-
(4,4,5,5-
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tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was
purified
by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 548.4 [M+H] Ret. Time: 2.02 min
Example 366: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-ff(2-
thienylacetyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
S /
O
ON~O
HN
N
H
H 2 N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-indole-
7-
carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]methyl}-2-(2-thienyl)acetamide (51 mg, 0.144 mmol) for N-{[3-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was
purified
by Mass Directed Auto Prep HPLC to give 10.3 mg of the title compound (18.2%).
LC/MS = m/z 565.2 [M+H] Ret. Time: 1.95 min
Example 367: 5-(3-ff(cyclobutylcarbonyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-
4-piperidinyll-1 F/-indole-7-carboxamide
~
0--f O~S~O
HN N
N
H
H2N O
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The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-indole-
7-
carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]methyl}cyclobutanecarboxamide (45 mg, 0.144 mmol) for N-{[3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was
purified
by Mass Directed Auto Prep HPLC to give 4.3 mg of the title compound (8%).
LC/MS = m/z 523.4 [M+H] Ret. Time: 1.90 min
Example 368: 5-(3-ff(cyclopropylcarbonyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
O r-
11- 0N\O
HN
N
H
H2N 0
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 f /
indole-7-
carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]methyl}cyclopropanecarboxamide (43 mg, 0.144 mmol) for N-{[3-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was
purified
by Mass Directed Auto Prep HPLC to give 5.5 mg of the title compound (11 %).
LC/MS = m/z 509.2 [M+H] Ret. Time: 1.85 min
Examples 369: 5-(3-ff(cyclopropylsulfonyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
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O
II~
S' O--SZ~--O
N N
N
H
O NH2
To a solution of 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-
11-1-indole-7-
carboxamide (35 mg, 0.079 mmol) in DMF (1.0 mL) and DCM (1.0 mL) was added
cyclopropanesulfonyl chloride (11 mg, 0.079 mmol) and DIEA (14 pL, 0.079
mmol).
Reaction was sirred at room temperature overnight. Compound was purified by
Gilson
Preparatory HPLC to give 7.2 mg the title compound (17%).
.LC/MS = m/z 545.4 [M+H] Ret. Time: 1.94 min
Example 370: 543-ff f(2,5-dichlorophenyl)sulfonyilamino}methyl)phenyll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
/ cI
( ~O
cl \ 3=0 O-~S\
NH ~ ~
N
N
H
O NHZ
To a solution of 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-
1 H-indole-7-
carboxamide (40 mg, 0.096 mmol) in DMF (1.0 mL) and DCM (1.0 mL) was added 2,5-
dichlorobenzenesulfonyl chloride (86 mg, 0.352 mmol) and DIEA (62 NL, 0.352
mmol).
Reaction was sirred at room temperature for 6 h. Reaction mixture was then
concentrated and purified by Gilson Preparatory HPLC,to give 6.6 mg the title
compound
(11 %).
.LC/MS = m/z 649.2 [M+H] Ret. Time: 2.25 min
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Example 371: 5-f3-({f(4-bromophenyl)sulfonyllamino}methyl)phenyll-3-f1-
eth Isulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
Br
O
L-O
S 0
NH N N
H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 4-bromobenzenesulfonyl chloride (90 mg, 0. 352
mmol) for
2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated
and
purified by Gilson Preparatory HPLC to give 19.4 mg the title compound (31 %).
LC/MS = m/z 659.4 [M+H] Ret. Time: 2.20 min
Example 372: 543-(f f(4-chlorophenyl)sulfonyllamino}methyl)phenyll-3-f 1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
CI /
10, S" O~ S~
NHO ~O
N
N
H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting (2E,4E)-5-chloro-2,4,6-heptatriene-2-sulfonyl
chloride (80 mg,
0. 352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was
then
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concentrated and purified by Gilson Preparatory HPLC to give 7.5 mg the title
compound
(13%).
LC/MS = m/z 615.2 [M] Ret. Time: 2.19 min
Example 373: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-(ff(3-
fluorophenyl)sulfonyllamino}methvl)phenyll-1 H-indole-7-carboxamide
F
O
S=0 p~g,-NH ~
N
N
H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 f 1 indole-
7-carboxamide substituting 3-fluorobenzenesulfonyl chloride (69 mg, 0. 352
mmol) for
2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated
and
purified by Gilson Preparatory HPLC to give 7.3 mg the title compound (13%).
LC/MS = m/z 599.2 [M+H] Ret. Time: 2.15 min
Example 374: 5-f3-(ff(2-chlorophenyl)sulfonyllamino}methyl)phenyll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
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CI
\ I /O ~
NHO S,O
N
N
H
O NHZ
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 2-chlorobenzenesulfonyl chloride (74 mg, 0. 352
mmol) for
2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated
and
purified by Gilson Preparatory HPLC to give 17.3 mg the title compound (29%).
LC/MS = m/z 615.2 [M] Ret. Time: 2.15 min
Example 375: 543-ff f(2,5-dichloro-3-thienyl)sulfonyllamino}methyl)phenyll-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
CI
S 0,
,O ~
O _
CI NH S~O
N
N
H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 2,5-dichloro-3-thiophenesulfonyl chloride (86 mg,
0. 352
mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then
concentrated
and purified by Gilson Preparatory HPLC to give 16.7 mg the title compound
(27%).
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LC/MS = m/z 655.2 [M] Ret. Time: 2.24 min
Example 376: 5-f3-(ff(2-chloro-6-methylphenyl)sulfonvllamino}methyl)phenyll-3-
f1
eth Isulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
I
O
// ~
~
-O O~\
S
\ O
CI NH N ,
\ I \
N
H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 2-chloro-6-methylbenzenesulfonyl chloride (86 mg,
0. 352
mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then
concentrated
and purified by Gilson Preparatory HPLC to give 17.9 mg the title compound
(30%).
LC/MS = m/z 629.4 [M] Ret. Time: 2.19 min
Example 377: 3-f1-(ethylsulfonyl)-4-piperidinyll-543-({f(5-fluoro-2-
methylphenyl)sulfonyllamino}methyl)phenyll-1 H-indole-7-carboxamide
F \
0=S=0 O\S~\
I NH O
N
\ / \
N
H
O NH2
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The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 5-fluoro-2-methylbenzenesulfonyl chloride (86 mg,
0. 352
mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then
concentrated
and purified by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 613.2 [M+H] Ret. Time: 2.18 min
Example 378: 543-ff f(1,2-dimethyl-1 H-imidazol-4-
vl)sulfonyllaminolmethyl)phenyll-
3-f 1-(ethylsulfonyl)-4-piperidinyll-1 H-i ndole-7-carboxamide
N ~
~;S%0 0\S~ ZZ~
NH O
N
N
H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 1,2-dimethyl-1 H-imidazole-4-sulfonyl chloride (69
mg, 0. 352
mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then
concentrated
and purified by Gilson Preparatory HPLC to give 1.9 mg the title compound
(3.3%).
LC/MS = m/z 599.2 [M+H] Ret. Time: 1.76 min
Example 379: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-
{f(phenyisulfonyl)aminolmethyl}phenyl)-1/-/-indole-7-carboxamide
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\
I /
0=S=0 0\S\
NH / O
N
N
H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting benzenesulfonyl chloride (62 mg, 0. 352 mmol) for
2,5-
dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and
purified
by Gilson Preparatory HPLC to give 13.4 mg the title compound (24%).
LC/MS = m/z 581.6 [M+H] Ret. Time: 2.10 min
Example 380: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f3-({f(4-
fluorophenyl)sulfonyllamino}methyl)phenyll-1 H-indole-7-carboxamide
F
0=5=0 OS
NH / O
N
N
H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-11-I-indole-
7-carboxamide substituting 4-fluorobenzenesulfonyl chloride (69 mg, 0. 352
mmol) for
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2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated
and
purified by Gilson Preparatory HPLC to give 11.5 mg the title compound (20%).
LC/MS = m/z 599.2 [M+H] Ret. Time: 2.10 min
Example 381: 5-f3-({f(4-bromo-2-ethylphenyl)sulfonyllamino}methyl)phenyll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
Br
O=S=O O~S~
NH N O
N
H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 4-bromo-2-ethylbenzenesulfonyl chloride (100 mg, 0.
352
mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then
concentrated
and purified by Gilson Preparatory HPLC to give 2.7 mg the title compound
(4%).
LC/MS = m/z 687.6 [M] Ret. Time: 2.38 min
Example 382: 5-(3-ff(1-benzothien-3-ylsulfonyl)aminolmethyl}phenyl)-3-f1-
(ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide
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/
In S
0=S=0 O~S
NH N ~O
/ I
N
H
O NF112
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 1-benzothiophene-3-sulfonyl chloride (82 mg, 0. 352
mmol)
for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then
concentrated and
purified by Gilson Preparatory HPLC to give 3.9 mg the title compound (6%).
LC/MS = m/z 637.4 [M+H] Ret. Time: 2.19 min
Example 383: 5-{3-f({f4-(1,1-
dimethylethyl)phenyilsulfonyl}amino)methyllphenyl}-3-
f1-(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
I
0=S=0 O~S
NH / O
N
N
H
O NH2
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 4-(1,1-dimethylethyl)benzenesulfonyl chloride (82
mg, 0. 352
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CA 02613068 2007-12-20
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mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then
concentrated
and purified by Gilson Preparatory HPLC to give 15.6 mg the title compound
(26%).
LC/MS = m/z 637.4 [M+H] Ret. Time: 2.35 min
Example 384: 5-f3-(ff(3,4-difluorophenyl)sulfonyllamino}methyl)phenyll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
F
F
0=S=0 O~S'
O
NH I
N
\ I ~
N
H
O NHZ
The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 3,4-difluorobenzenesulfonyl chloride (75 mg, 0. 352
mmol) for
2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated
and
purified by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 617.2 [M+H] Ret. Time: 2.16 min
Example 385: 5-(3-ff(2,1,3-benzoxadiazol-4-ylsulfonyl)aminolmethyl}phenyl)-3-
f1-
(ethylsulfonyl)-4-piperidinyil-1 H-indole-7-carboxamide
0 N' q
N 0=S=0 0~S
NH N ~O
N
H
O NH2
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CA 02613068 2007-12-20
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The title compound was prepared according to the general procedure of 5-[3-
({[(2,5-
dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-
7-carboxamide substituting 2,1,3-benzoxadiazole-4-sulfonyl chloride (77 mg, 0.
352
mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then
concentrated
and purified by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 623.4 [M+H] Ret. Time: 2.10 min
Example 386: 3-f1-(ethylsulfonyl)-4-piperidinyil-5-(3-{f(tetrahydro-3-
furanvlcarbonyl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
Lo
D\N
O N
0 N
H
O NH2
To a solution of tetrahydro-3-furancarboxylic acid (17 mg, 0.144 mmol) in DCM
(2.0 mL)
was added pyridine (3 drops) and oxalyl chloride (18 mg, 0.144 mmol). Reaction
mixture
was stirred overnight at room temperature. To the mixture was then added 5-[3-
(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-
carboxamide (40 mg,
0.096 mmol) in DMF (1.0 mL) and DIEA (33 pL, 0.192 mmol). Reaction mixture was
stirred at room temperature overnight. Reaction mixture was concentrated under
nitrogen
and purifed by Gilson Preparatory HPLC to give 5.3 mg the title compound
(10%).
LC/MS = m/z 539.2 [M+H] Ret. Time: 1.80 min
Example 387: 5-f4-f(cyclopentylsulfonyl)aminolphenyl}-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
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Ozz~
S
,-O
0=S=0 N
I
HN
F O
F+~ N
H
F OH
O NH2
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (20
mg, 0.048
mmol) was added chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-
l-
yl)palladium (II) (10 mg, 0.016 mmol), potassium carbonate (13.4 mg, 0.097
mmol), and
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]cyclopentanesulfonamide (34
mg, 0.097 mmol) in dioxane (3 mL) and H20 (1 mL). The reactin mixture was
heated in a
microwave at 160 C for 10 min. The reaction mixture was concentrated under
nitrogen
and purified by Gilson Preparatory HPLC to give 8.6 mg the title compound
(32%).
LC/MS = m/z 559.2[M+H] Ret. Time: 2.00 min
Example 388: 3-f1-(ethylsulfonvl)-4-piperidinyll-5-f4-(4-methyl-2-oxo-1-
piperazinyl)phenyil-1 l+indole-7-carboxamide
Oz:-.~
S~ O
NO N
~ \ \
N
H
O NH2
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (20
mg, 0.048
mmol) was added 4-methyl-1 -[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]-2-
piperazinone (31 mg, 0.097 mmol) in dioxane (3.0 mL) and H20 (1.0 mL),
potassium
carbonate (13 mg, 0.097 mmol) and
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chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium
(II) (10
mg, 0.016 mmol). The reaction mixture was reacted in a microwave at 1602 C for
10 min.
The reaction mixture was heated in a microwave at 160 C for 10 min. The
reaction
mixture was concentrated under Nitrogen and purified by Gilson Preparatory
HPLC. The
desired fraction in CH3CN and H20 was treated with saturated potassium
carbonate to
neautralize salts and then concentrated to give 1.9 mg the title compound
(8%).
LC/MS = m/z 524.6 [M+H] Ret. Time: 1.49 min
Example 389: 5-f6-(4-acetyl-l-piperazinyl)-3-pyridinyll-3-f1-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
-4O
~
N Sr
~N O
'N N
F 0
F-H
F OH ~ \ \
H
o NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperazinyl)-3-
pyridinyl]-1 H-
indole-7-carboxamide (40 mg, 0.080 mmol) in dicloromethane at 0 C, was added
acetyl
chloride (7 pL, 0.096 mmol) and DIEA (11.6 pL, 0.12 mmol). Reaction mixture
was
reacted for 0.5 h from 0 C to room temperature and then quenched with H20.
Compound was purified by MDAP HPLC to give 7 mg of the title compound (40%).
LC/MS = m/z 539.4 [M+H] Ret. Time: 1.27 min
Example 390: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(4-
ff(methyloxy)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
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CA 02613068 2007-12-20
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- s
~o
O,
NH N
N
H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL) and MeOH (1.5 mL) was added 0-
methylhydroxylamine (114 mg, 1.71 mmol). The reaction was stirred overnight.
The
solvent was then concentrated and purified by Gilson Preparatory HPLC to give
38 mg of
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-([(methyloxy) imino]methyl}phenyl)-1
H-indole-7-
carboxamide (76%).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-
{[(methyloxy)imino]methyl}phenyl)-
1ll indole-7-carboxamide (21.5 mg, 0.046 mmol) in DCM (3.0 mL) and MeOH (3.0
mL)
was added drops of HCI in 1,4-dioxane to maintain pH = 4 at 0 C. Sodium
cyanoborohydride (29 mg, 0.46 mmol) was then added and stirred overnight at
room
temperature. Additional HCI in 1,4-dioxane was added to maintain pH = 4 in
addition to
sodium cyanoborohydride (45 mg, 0.72 mmol). Reaction mixture then stirred over
48 h.
Additional HCI in 1,4-dioxane was added to maintain pH = 4 at 00 C and stirred
till room
temperature was achieved. Mixture was quenched with H20. DCM was then added
for
aqueous work-up and mixture was concentrated. The reside was then take up in
DCM
and purified on the SCX SPE cartridge to afford 15.2 mg of the title compound
(70%).
LC/MS = m/z 471.6 [M+H] Ret. Time: 1.67 min
Example 391: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(3-
f((methyloxy)aminolmethyl}phenyl)-1 H-indole-7-carboxamide
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CA 02613068 2007-12-20
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O O-I-S
NH
N
N
H
H2N O
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-
indole-7-
carboxamide (50 mg, 0.114 mmol) in DMSO (3.0 mL) was added
O-methylhydroxylamine (57 mg, 0.684 mmol). The reaction was stirred overnight.
Additional O-methylhydroxylamine (0.342 mmol) was added to ther eaction
mixture and
stirred for 48 h. The solvent was then concentrated and purified by Gilson
Preparatory
HPLC to give 29.8 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-
{[(methyloxy)imino]methyl}phenyl)-1 H-indole-7-carboxamide (56%).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-
{[(methyloxy)imino]methyl}phenyl)-
1 H-indole-7-carboxamide (58 mg, 0.123 mmol) in DCM (3.0 mL) and MeOH (3.0 mL)
was
added HCI in 1,4-dioxane to maintain pH = 4 at 0 C. Sodium cyanoborohydride
(176 mg,
3.69 mmol) was then added and stirred overnight for 48 h. The compound was
purified
by Gilson Preparatory HPLC to give 20.0 mg of the title compound (89%).
LC/MS = m/z 471.6 [M+H] Ret. Time: 1.75 min
Example 392: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-ff4-(1-pyrrolidinyl)-1-
piperidinyllmethyl}-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate
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CA 02613068 2007-12-20
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N
O O
N
N
S
F YNN
FF OH H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL) was added 4-(1-
pyrrolidinyl)piperidine (173 mg, 1.12 mmol) and acetic acid (5 drops). After 6
h, sodium
triacetoxyborohydride (238 mg, 1.12 mmol) was added and the reaction was
stirred
overnight, The reaction mixture was purified by Gilson Preparatory HPLC to
give 17.0 mg
of the title compound (26%).
LC/MS = m/z 584.4 [M+H] Ret. Time: 1.38 min
Example 393: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-df(2S)-2-
(trifluoromethyl)-1-
pyrrolidinyllmethyl}-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate
S~O
F N
N
S
F
F
F' O I \ ~
F--~-~( ~ N
IF OH H
'
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (50 mg, 0.112 mmol) in DCM (3.0 mL) and MeOH (1.5 mL) was added
(2S)-
2-(trifluoromethyl)pyrrolidine (156 mg, 1.12 mmol) and acetic acid (5 drops).
After 6 h of
stirring at room temperature, sodium borohydride (43 mg, 1.12 mmol) was added
and the
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CA 02613068 2007-12-20
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reaction was stirred overnight at room temperature. The reaction mixture was
purified by
Gilson Preparatory HPLC to give 5.0 mg of the title compound (8%).
LC/MS = m/z 569.4 [M+H] Ret. Time: 2.37 min
Example 394: 5-(5-dt'(2R)-2-(hydroxymethyl)-1-pyrrolidinvllmethyl}-3-thienyl)-
3-f1-
f(1-methylethyl)sulfonyll-4-piperidinyl}-1 H-indole-7-carboxamide
O,-
/ ~'O
N
HO N S
N
H
HZN O
To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-
piperidinyl}-1 H-
indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added (2R)-2-
pyrrolidinylmethanol (101.15 mg, 1 mmol) and 2 drops of acetic acid. The
resulting
mixture was stirred at room temperature for 4 h followed by an addition of
sodium
triacetoxyborohydride (212 mg, 0.54 mmol). The mixture was reacted overnight.
It was
then purified by Gilson Preparatory HPLC to give 20.5 mg of the title compound
(69.7%).
LC/MS = m/z 546 [M+H] Ret. Time: 1.47 min.
Example 395: 5-(5-{f(3S)-3-hydroxy-l-pyrrolidinyllmethyl}-3-thienyl)-3-{1-f(1-
methylethyl)sulfonyll-4-piperidinyl}-1 H-indole-7-carboxamide
O~~~S
/ ~ ~O
N
HO'
N S
N
H
H 2 N O
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The title compound was prepared according to the general procedure of 5-(5-
{[(2R)-2-
(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-
piperidinyl}-1 H-indole-7-carboxamide, substituting (3S)-3-pyrrolidinol (90.13
mg, 1.20
mmol) for (2R)-2-pyrrolidinylmethanol to afford 12.8 mg of the title compound
(53.1 %).
LC/MS = m/z 532 [M+H] Ret. Time: 1.45 min.
Example 396: 5-(54 fcyclopentyl(methyl)aminolmethyl}-3-thienyl)-3-{14(1-
methylethyl)sulfonyll-4-piperidinyl}-1 H-indole-7-carboxamide
p,j
~S
/ ~'O
N
O-N S
N
H
H2N O
The title compound was prepared according to the general procedure of 5-(5-
{[(2R)-2-
(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-
piperidinyl}-1 H-indole-7-carboxamide, substituting N-methylcyclopentanamine
(90.13 mg,
1.20 mmol) for (2R)-2-pyrrolidinylmethanol to afford 10 mg of the title
compound (54.3%)
LC/MS = m/z 544.2 [M+H] Ret. Time: 1.65 min.
Example 397: 5-(5-{f(2-hydroxyethyl)(methyl)aminolmethyl}-3-thienyl)-3-{1-f(1-
methylethyl)sulfonyll-4-piperidinyl}-1 H-indole-7-carboxamide
~
O~Z -
/ ~'O
N
O~N S
N
H2N O
318

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The title compound was prepared according to the general procedure of 5-(5-
{[(2R)-2-
(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-
piperidinyl}-1 H-indole-7-carboxamide, substituting 2-(methylamino)ethanol
(90.13 mg,
1.20 mmol) for (2R)-2-pyrrolidinylmethanol to afford 8 mg of the title
compound (51.9%),
LC/MS = m/z 520 [M+H] Ret. Time: 1.44 min.
Example 398: 5-(5-ff(2-amino-2-oxoethyl)(methyl)aminolmethyl}-3-thienyl)-3-{1-
f(l-
methylethyl)sulfonyll-4-piperidinyl}-1 H-indole-7-carboxamide
LO
O N
H2N--~_ /
N S
N
H
H2N O
The title compound was prepared according to the general procedure of 5-(5-
{[(2R)-2-
(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-
methylethyl)sulfonyl]-4-
piperidinyl}-1 H-indole-7-carboxamide, substituting N2-methylglycinamide
(90.13 mg,
1.200 mmol) for (2R)-2-pyrrolidinylmethanol to afford 15 mg of the title
compound
(53.2%).
LC/MS = m/z 520 [M+H] Ret. Time: 1.44 min.
Example 399: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-ffinethyl(2-propen-l-
yl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
0 i~
N
S
N
H
O NH2
Allylamine (0.034 mL, 0.449 mmol) and HOAc (0.026 mL, 0.449 mmol) were added
to a
solution of 3-[1-(ethyisulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-
indole-7-
carboxamide (20 mg, 0.0449 mmol) in DMSO (0.5 mL) in a 1-dram vial. NaBH(OAc)3
(95
319

CA 02613068 2007-12-20
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mg, 0.449 mmol) was then added, the vial was capped and the reaction was
stirred at
room temperature for 15 h. NaCNBH3 (28 mg, 0.449 mmol) and MeOH were added,
and
the reaction was stirred for an additional 4 h. An aqueous solution of 37 wt%
formaldehyde (0.069 mL, 0.898 mmol) was added, and the reaction was stirred
for an
additional 1 h. The reaction mixture was filtered through a 2 g SCX cartridge
(pre-
equilibrated with with 3 mL MeOH), eluting in sequence with MeOH (3 mL) and a
2 M
solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a
stream
of nitrogen at 50 C, and the residue was dissolved in DMSO (1 mL) and
purified on a
Gilson HPLC (Xbridge Prep C18 column: 19 x 100 mm) eluting at 20 mL per min
with a
linear gradient running from 10% CH3CN/H20 (0.1 % NH4OH) to 70% CH3CN/H20 (0.1
%
NH4OH) over 15 min. The fractions containing the title compound were
concentrated
under a stream of nitrogen at 50 C to give 5.2 mg of the title compound
(23%).
LC/MS = m/z 501.4 [M+H] Ret. Time: 1.48 min.
Example 400: 5-(5-fff(3,5-dimethyl-1 H-pyrazol-4-
yl)methyll(methyl)aminolmethyl}-3-
thienyl)-3-f 1-(ethylsuifonyl)-4-piperidi nyil-1 H-indole-7-carboxamide
O
0=S
N
N S
N,,
N~
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-11-
-/-indole-7-
carboxamide (45 mg, 100 pmol) in dimethyl sulfoxide (1.0 mL) was added 1-(3,5-
dimethyl-1 H-pyrazol-4-yl)-N-methylmethanamine ( 320 Nmol ) and 2 to 3 drops
of glacial
acetic acid. The resulting mixture is agitated overnight. After 18 h, sodium
triacetoxyborohydride (200 mg, 1000 pmol) is added. This mixture is agitated
for 1.5 h
followed by purification by Gilson Preparatory HPLC to give 6.24 mg of the
title compound
(11.0%).
LC/MS'= m/z 569.3 [M+H] Ret. Time: 1.42 min.
Example 401: 5-(5-ff(cyanomethyl)(methyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
320

CA 02613068 2007-12-20
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O l
0=S_J
N
N S
N\
N
H
O NH2
The title compound was prepared according to the general procedure of 5-(5-
{[[(3,5-
dimethyl-1 H-pyrazol-4-yl)methyl](methyl)amino]methyl}-3-thienyl)-3-[1-
(ethylsulfonyl)-4-
piperidinyl]-1 H-indole-7-carboxamide
, substituting (methylamino)acetonitrile (320 pmol) for 1-(3,5-dimethyl-1 H-
pyrazol-4-yl)-N-
methylmethanamine to afford 6.36 mg of the title compound (12.7%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.70 min.
Example 402: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-ffinethyl(1-
methylpropyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
O /
0=S-J
N
-N S
~ ~.
I \ ~
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (45 mg, 0.1 mmol) in dimethyl sulfoxide (1 mL) was added 2-
butanamine (1
mmol), 1 to 2 drops of acetic acid and sodium triacetoxyborohydride (211 mg, 1
mmol).
The resulting mixture was capped and stirred for 18 h followed by an addition
of sodium
cyanoborohydride (62 mg, 1 mmol) in methanol (0.5 mL). This was stirred for 3
h
followed by an addition of formaldehyde, 37% in water, (1.5 mL). This was
purified
through SCX (2 g) cartridge eluting with methanol followed by NH3 in methanol.
Further
purification was performed by Gilson Preparatory HPLC. XBridge C18 Column (P/N
321

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186002978) using a gradient of 10% acetonitrile to 70% acetronile in water
with 0.1 %
NH4OH to give 14.4 mg of the title compound (27.9%).
LC/MS = m/z 517.3 [M+H] Ret. Time: 1.58 min.
Example 403: 5-(5-ff f2-(ethyloxy)ethyll(methyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide
j ~/
O O=S-
/
N
-N S
I \ \
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-
thienyl)-1 H-
indole-7-carboxamide
, substituting 2-(ethyloxy)ethanamine (1 mmol) for added 2-butanamine to
afford 6.1 mg
of the title compound (11.5%).
LC/MS = m/z 533.2 [M+H] Ret. Time: 1.57 min.
Example 404: 5-(5-d(cyclobutyl(methvl)aminolmethvl}-3-thienyl)-3-f 1-
(ethylsulfonyl)-
4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
--
O\S,-O
N N
S
F O \ I ~
N
-I~ H
F OH H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-
thienyl)-1 H-
indole-7-carboxamide
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substituting cyclobutylamine (1 mmol) for added 2-butanamine to afford 3.7 mg
of the
title compound (5.9%).
LC/MS = m/z 515.3 [M+H] Ret. Time: 1.64 min.
Example 405: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-f5-({2-f(methyloxy)methyll-
l-
pyrrolidinyl}methyl)-3-thienyil-1 H-indole-7-carboxamide trifluoroacetate
/
O
o::S--o
N N
S
F 0
F N
H
F OH H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-
thienyl)-1 H-
indole-7-carboxamide
, substituting 2-[(methyloxy)methyl]pyrrolidine (1 mmol) for added 2-
butanamine to afford
5 mg of the title compound (7.6%).
LC/MS = m/z 545.3 [M+H] Ret. Time: 1.65 min.
Example 406: 5-(5-ff(1,1-dimethvlethyl)(methyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O-/
0=S
v N
-N/~ S
\ I \
F 0
F
14 N
H
F OH
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-
thienyl)-1 H-
indole-7-carboxamide
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substituting 2-methyl-2-propanamine (1 mmol) for added 2-butanamine to afford
10.9
mg of the title compound (17.3%).
LC/MS = m/z 517.3 [M+H] Ret. Time: 1.61 min.
Example 407: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-(5-{f3-(trifluoromethyl)-1-
piperidinyllmethyl}-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate
F
F Oz:~S~O
FN
N
N
s
F 44 a 1
F N
H
F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-
thienyl)-1 H-
indole-7-carboxamide
, substituting 3-(trifluoromethyl)piperidine (1 mmol) for added 2-butanamine
to afford 5.4
mg of the title compound (7.8%).
LC/MS = m/z 583.3 [M+H] Ret. Time: 1.73 min.
Example 408: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(54 ff(1 S)-2-hydroxy-1-
methylethyll(methyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
O\S--O
N
H ON s
\ I /
F O \ I ~
F N
H
F OH
H2N O
To a vial containing (2R)-2-amino-1-propanol (90.13 mg, 1.2 mmol) was added a
solution
of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-indole-7-
carboxamide (30
mg, 0.067 mmol) in DMSO (300 pL) and acetic acid (50 pL). The resulting
mixture was
shaken for 5 min followed by an addition of sodium triacetoxyborohydride (250
mg, 1.20
324

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
mmol) in DMSO (800 pL). The mixture was shaken overnight. Sodium
cyanoborohydride
(79 mg, 1.20 mmol) in methanol (300 pL) was then added and stirred for 48 h.
This was
followed by an addition of formaldehyde (100 pL). The reaction was then
stirred for 1 h
followed by a 2g SCX crude cartridge separation. The solids were then filtered
off,
solution was concentrated and purification was repeated on a 5 g SCX cartridge
eluting
with ammonia in MeOH. The ammonia in MeOH fraction collection was concentrated
and
separated using Gilson Preparatory HPLC to afford 18.6 mg of the title
compound
(43.9%).
LC/MS = m/z 519.3 [M+H] Ret. Time: 1.49 min.
Example 409: 5-(5-df(cyclopropylmethyl)(methyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
O~S'-O
N
N S
\ I /
FI fi0
F-~-'( H
IF OH
H 2 N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-
3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting
(cyclopropylmethyl)amine (1.20 mmol) for (2R)-2-amino-1-propanol to afford 6.2
mg of
the title compound (14.7%).
LC/MS = m/z 515.3 [M+H] Ret. Time: 1.61 min.
Example 410: 5-(5-{ff2-(acetylamino)ethyll(methyl)aminolmethyl}-3-thienyl)-3-
f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
325

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
_
O o S'O
N
HN S
I
p
F
F-j~ H
IF OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-
3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting N-(2-
aminoethyl)acetamide (1.20 mmol) for (2R)-2-amino-1 -propanol to afford 13.6
mg of the
title compound (30.8%)
LC/MS = m/z 546.2 [M+H] Ret. Time: 1.47 min.
Example 411: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-(5-f ff(1 R,2R)-2-
hydroxycyclopentyll(methyl)aminolmethyll-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
~ Chiral
D,S\O
N
OH
N S
F p \ ~
F N
H
F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-
3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting (1
R,2R)-2-
aminocyclopentanol (1.20 mmol) for (2R)-2-amino-1 -propanol to afford 9.6 mg
of the title
compound (21.8%)
LC/MS = mlz 545.3 [M+H] Ret. Time: 1.54 min.
Example 412: 5-(5-{f(1,1-dimethylpropyl)(methyl)aminolmethyl}-3-thienyl)-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate
326

CA 02613068 2007-12-20
WO 2007/005534 PCT/US2006/025402
O~S--O
N
\\-+N S
F 0
F N
H
F OH H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-
3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting (1,1-
dimethylpropyl)amine (1.20 mmol) for (2R)-2-amino-1-propanol to afford 13.1 mg
of the
title compound (30.3%)
LC/MS = rri/z 531.3 [M+H] Ret. Time: 1.65 min.
Example 413: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-?ff(2S)-2-
hydroxypropyll(methyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate
~ Chiral
O~S'
O
N
O~N S
F O
F N
H
F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-
3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting (2S)-
1-amino-2-
propanol (1.20 mmol) for (2R)-2-amino-1-propanol to afford 15.3 mg of the
title compound
(36.1%)
LC/MS = m/z 519.3 [M+H] Ret. Time: 1.49 min.
Example 414: 3-f1-(ethylsuifonyl)-4-piperidinyl]-5-f5-(fmethylf(2R)-tetrahydro-
2-
furanyimethyllamino}methyl)-3-thienyll-1 H-indole-7-carboxamide
trifluoroacetate
327

CA 02613068 2007-12-20
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O~S~O
O N
N S
F 0
F~ N
F OH H
H 2 N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-
3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting
[(2R)-tetrahydro-2-
furanylmethyl]amine (1.20 mmol) for (2R)-2-amino-1 -propanol to afford 15.5 mg
of the
title compound (35.1 %)
LC/MS = m/z 545.3 [M+H] Ret. Time: 1.58 min.
Example 415: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-fff2-f(2-
hydroxyethyl)oxylethyl}(methyl)aminolmethyl}-3-thienyl)-1 H-indole-7-
carboxamide
trifluoroacetate
HO /S~_O
O\
N
N S
F O
F N
H
F OH
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-
3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting 2-
[(2-
aminoethyl)oxy]ethanol (1.20 mmol) for (2R)-2-amino-1 -propanol to afford 17.2
mg of the
title compound (38.7%).
LC/MS = m/z 549.5 [M+H] Ret. Time: 1.48 min.
?0
Example 416: 3-f1-(ethylsulfonyl)-4-piperidinyll-545-(1-f methylf2-
(methyloxy)ethyllamino)ethyl)-3-thienyll-1lY-indole-7-carboxamide
trifluoroacetate
328

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O~ /O
O /
N
-N SI
F O N
F-" H
F OH HZN O
To a solution of 5-(5-acetyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide (46 mg, 0.1 mmol) in EtOH (2.0 mL) and AcOH (0.2 mL) was added
methyl[2-(methyloxy)ethyl]amine (200 pL, 2.0 mmol) and sodium cyanoborohydride
(50
mg, 0.8 mmol). The mixture was reacted in the microwave at 1209 C for 2 h.
Additional
methyl[2-(methyloxy)ethyl]amine (100 pL, 1.0 mmol) and sodium cyanoborohydride
(25
mg, 0.4 mmol) was added and reacted for another 3 h in the microwave at 1202 C
for 2 h.
This was then followed by another addition of methyl[2-(methyloxy)ethyl]amine
(100 pL,
2.0 mmol) and sodium cyanoborohydride (25 mg, 0.4 mmol) and reacted for
another 3 h
in the microwave at 1202 C for 2h. All solvent was concentrated and purified
by
Gilson Preparatory HPLC to afford 20 mg of the title compound (38%).
LC/MS = m/z 533.2 [M+H] Ret. Time: 1.46 min.
Example 417: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-{1-
finethyl(propyl)aminolethyl}-
3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate
O
N
-N S
FI /,O N
F-~--~( H
IF \OH H2N 0
To a solution of 5-(5-acetyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1
H-indole-7-
carboxamide (46 mg, 0.1 mmol) in EtOH (2.0 mL) and AcOH (0.2 mL) was added N-
methyl-l-propanamine (200 NL, 2.0 mmol) and sodium cyanoborohydride (50 mg,
0.8
?0 mmol). The mixture was reacted in the microwave at 1209 C for 120 min.
Additional N-
methyl-l-propanamine (100 pL, 1.0 mmol) and sodium cyanoborohydride (25 mg,
0.4
mmol) was added and reacted for another 3 h in the microwave at 1202 C for 120
min. All
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CA 02613068 2007-12-20
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solvent was concentrated, dissolved in DMSO and solids were filtered. It was
then
purified by Gilson Preparatory HPLC to afford 18 mg of the title compound
(35%).
LC/MS = m/z 517.2 [M+H] Ret. Time: 1.52 min.
Example 418: 5-(2,3-dihydro-1H-isoindol-5-y1)-341-(ethylsulfonyl)-4-
piperidinyll-1 FI-
indole-7-carboxamide
's=o
N
HN
N
H
O NHZ
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1 H-indole-7-carboxamide (150 mg, 0.325 mmol) in dioxane
(0.75 mL)
and water (0.25 mL), was added 5-bromo-2,3-dihydro-1 H-isoindole hydrochloride
(130
mg, 0.651 mmol), and cesium carbonate (636 mg, 1.952 mmol). The reaction
mixture
was kept under argon for 10 min before addition of
tetrakis(tripehnylphosphine)palladium(0) (19 mg, 0.016 mmol). The resultant
mixture was
heated in a microwave for 20 min at 150 C. Mixture was then purified by HPLC
to give
11 mg of the title compound.
LC/MS = m/z 453 [M+H] Ret. Time: 1.33 min.
Example 419: 5-(2-ethyl-2,3-dihydro-1 F/-isoindol-5-yl)-341-(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
O,
~S
, '
N 0
\-
N
N
H
O NHZ
330

CA 02613068 2007-12-20
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To a solution of 5-(2,3-dihydro-1 H-isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide (20 mg, 0.044 mmol) in MeOH (1 mL), was added
acetaldehyde (6
mg, 0.133 mmol), sodium cyanoborohydride (6 mg, 0.088 mmol) and zinc chloride
(6 mg,
0.044 mmol). The resultant mixture was heated in a microwave for 30 min at
1009 C.
Mixture was then concentrated, filtered and purified by Gilson Preparatory
HPLC to give
8.2 mg of the title compound.
LC/MS = m/z 481 [M+H] Ret. Time: 1.40 min.
Example 420: 3-f1-(ethylsulfonyl)-4-piperidinvll-5-f2-(1-methylethyl)-2,3-
dihydro-1 H-
isoindol-5-y11-1H-indole-7-carboxamide
O"O
N
N
N
H
O NH2
To a solution of 5-(2,3-dihydro-1 H-isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide (30 mg, 0.066 mmol) in MeOH (0.5 mL), was added 2-
propanone
(12 mg, 0.198 mmol), sodium cyanoborohydride (8 mg, 0.133 mmol) and zinc
chloride (9
mg, 0.066 mmol). The resultant mixture was heated in a microwave for 30 min at
100 C.
Mixture was then concentrated, filtered and purified by Gilson Preparatory
HPLC to give
0.8 mg of the title compound.
LC/MS = m/z 495.5 [M+H] Ret. Time: 1.56 min.
Example 421: 5-f2-(1,2-dimethylpropyl)-2,3-dihydro-1 H-isoindol-5-yll-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 Ftiindole-7-carboxamide
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CA 02613068 2007-12-20
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~
O"S;O
N
N
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/--/-isoindol-
5-yl]-1 H-indole-
7-carboxamide, substituting 3-methyl-2-butanone (17 mg, 0.198 mmol) for 2-
propanone
to afford 14.6 mg of the title compound.
LC/MS = m/z 523 [M+H] Ret. Time: 1.55 min.
Example 422: 3-f1-(ethylsuifonyl)-4-piperidinyll-5-f2-(1-methylpropyl)-2,3-
dihydro-
1 FF-isoindol-5-yll-1 H-indole-7-carboxamide
r
O
"SO
N
N
\ ~ ~
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 f-l-isoindol-
5-yl]-1 H-indole-
7-carboxamide, substituting 2-butanone (14 mg, 0.198 mmol) for 2-propanone to
afford
14.6 mg of the title compound.
LC/MS = m/z 509 [M+H] Ret. Time: 1.48 min.
Example 423: 542-(1-ethylpropyl)-2,3-dihydro-1 H-isoindol-5-yll-3-f1-
(ethylsulfonyl)-
4-piperidinyll-1 H-indole-7-carboxamide
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O~ ~
.S'O
N
N
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H-isoindol-5-
yl]-1 H-indole-
7-carboxamide, substituting 3-pentanone (17 mg, 0.198 mmol) for 2-propanone to
afford
13.8 mg of the title compound.
LC/MS = m/z 523 [M+H] Ret. Time: 1.58 min.
Example 424: 5-(2-cyclopentyl-2,3-dihydro-1 H-isoindol-5-yl)-341-
(ethylsulfonyl)-4-
piperidinyll-1 H-indole-7-carboxamide
O"
SO
N
N
H
O NHZ
The title compound was prepared according to the general procedure of 3-[1 -
(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 f-f-
isoindol-5-yl]-1 H-indole-
7-carboxamide, substituting cyclopentanone (17 mg, 0.198 mmol) for 2-propanone
to
afford 4.8 mg of the title compound.
LC/MS = m/z 521 [M+H] Ret. Time: 1.54 min.
Example 425: 5-[2-(cyclopropylmethyl)-2,3-dihydro-1 H-isoindol-5-yil-3-f1-
(ethylsulfonyl)-4-piperidinyll-1 Ff-indole-7-carboxamide
333

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O~ ~
.O
N
/( \ \
N
H
O NHZ
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H-isoindol-5-
yl]-1 H-indole-
7-carboxamide, substituting cyclopropanecarbaidehyde (14 mg, 0.198 mmol) for 2-
propanone to afford 10.8 mg of the title compound.
LC/MS = m/z 507 [M+H] Ret. Time: 1.47 min.
Example 426: 5-f2-(2,2-dimethylpropyl)-2,3-dihydro-1 Fl-isoindol-5-yll-3-f 1-
(ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide
O.
.S;o
N
~NI3L3
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1 -
(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 h--isoindol-
5-yl]-1 H-indole-
7-carboxamide, substituting 2,2-dimethylpropanal (17 mg, 0.198 mmol) for 2-
propanone
to afford 12.7 mg of the title compound.
LC/MS = m/z 523 [M+H] Ret. Time: 1.60 min.
Example 427: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(2-methyl-2,3-dihydro-1 P-
Nisoindol-
5-yl)-1 H-indole-7-carboxamide
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O" r---
S' O
N
-N
N
H
O NH2
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H-isoindol-5-
yl]-1 H-indole-
7-carboxamide, substituting formaldehyde (6 mg, 0.198 mmol) for 2-propanone to
afford
1.2 mg of the title compound.
LC/MS = m/z 467 [M+H] Ret. Time: 1.37 min.
Example 428: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(2-
fl_(phenylsulfonyl)aminolcarbonyl}-2,3-dihydro-1H-isoindol-5-yl)-1 H-indole-7-
carboxamide
S,-O
N
0
O~-N
g_H
0-11~
O
N
H
O NH2
To a solution of 5-(2,3-dihydro-1 H-isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-
piperidinyl]-1 H-
indole-7-carboxamide (30 mg, 0.066 mmol) in DMSO (1.0 mL), was added
benzenesulfonyl isocyanate (15 mg, 0.079 mmol). The resultant mixture was
stirred
overnight at room temperature. Mixture purified by Gilson Preparatory HPLC to
give 15.5
mg of the title compound.
LC/MS = m/z 637 [M+H] Ret. Time: 1.94 min.
335

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Example 429: 5-(5-ff(2R)-2-(aminocarbonyl)-1-pyrrolidinyilmethyl}-3-thienyl)-3-
f1-
f (1-methylethyl)sulfonyll-4-pi peridi nyl}-1 H-indole-7-carboxamide
o~~
S
/ ~~O
N
H2N N S
O
N
H
HZN O
To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-
piperidinyl}-1 H-
indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added D-
prolinamide
(114 mg, 1 mmol) and 2 drops of acetic acid. The resulting mixture was stirred
at room
temperature for 4 h followed by an addition of sodium triacetoxyborohydride
(212 mg, 1.0
mmol). The mixture was reacted overnight. It was then purified by Gilson
Preparatory
HPLC to give 20.4 mg of the title compound.
LC/MS = m/z 557 [M+H] Ret. Time: 1.56 min.
Example 430: 3-f 1-(ethylsulfonyl)-4-piperidinyll-5-(5-If f2-
(ethylthio)ethyll(methyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
o;s~
o
N
S--
N S
N
H
H2N
To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methyl(ithyl)sulfonyl]-4-
piperidinyl}-1 H-
indole-7-carboxamide (40 mg, 0.09 mmol) in DMSO (2 mL) was added [2-
(ethylthio)ethyl]amine (105 mg, 1 mmol), acetic acid (50 NL), and sodium
triacetoxyborohydride (212 mg, 1.0 mmol). The resulting mixture was stirred
overnight.
To the mixture was added sodium cyanoborohydride (80 mg, 1.2 mmol) and stirred
overnight followed by addition of formaldehyde (100 L, 1.2 mmol). The mixture
was
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then stirred for an additional 3 h. It was then purified by Gilson Preparatory
HPLC to give
7.0 mg of the title compound.
LC/MS = m/z 550 [M+H] Ret. Time: 1.68 min.
Example 431: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-fff2-[(2-
hydroxyethyl)thio1ethyl}(methyl)aminolmethyl}-3-thienyl)-1 H-indole-7-
carboxamide
HO O\S~~O
N
SN S
N
H
H2N O
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[2-
(ethylthio)ethyl](methyl)amino]methyl}-3-thienyl)-1 H-
indole-7-carboxamide substituting 2-[(2-aminoethyl)thio]ethanol (121 mg, 1.0
mmol) for
[2-(ethylthio)ethyl]amine to afford 16.0 mg of the title compound.
LC/MS = m/z 566 [M+H] Ret. Time: 1.52 min.
Example 432: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-{ff2-hydroxy-l-
(hydroxymethyl)ethyll(methvl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
OH
HO /-~N 1-1
S
0'
N
O
H2N N
O H
The title compound was prepared according to the general procedure of 3-[1-
(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[2-
(ethylthio)ethyl](methyl)amino]methyl}-3-thienyl)-1 H-
indole-7-carboxamide substituting 2-amino-1,3-propanediol (91 mg, 1.0 mmol)
for [2-
(ethylthio)ethyl]amine to afford 15.0 mg of the title compound.
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LC/MS = m/z 535 [M+H] Ret. Time: 1.44 min.
Example 433: ethyl ((44 7-(aminocarbonyl)-341-(ethylsulfonyl)-4-piperidinyll-1
H-
indol-5-yl}-2-thienyl)methyllmethylcarbamate
o;s
N
O g
/'ON
N
H
O NH2
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-
[(methylamino)methyl]-3-thienyl}-
1 H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMF (1.0 mL) at 00 C was added
triethylamine (0.06 mL, 0.44 mmol), and ethyl chloridocarbonate (0.021 mL,
0.22 mmol).
The resultant mixture was reacted for 30 min followed by purification on
Gilson
Preparatory HLPC to afford 31.4 mg of the title compound (53.5%).
LC/MS = m/z 533.2 [M+H] Ret. Time: 2.06 min.
Example 434: ethyl /1Fi'(4-17-(aminocarbonyl)-341-(ethylsulfonyl)-4-
piperidinyll-1 fti
indol-5-yl}-2-thienyl)methyll-Iwmethylalycinate
0
oJ o=s--j
O N
/ sl
N
H
O NH2
To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1
H-indole-7-
carboxamide (45 mg, 100 pmol) in dimethyl sulfoxide (1.0 mL) was added ethyl
/V
methylglycinate (320 pmol ) and 2 to 3 drops of glacial acetic acid. The
resulting mixture
is agitated overnight. After 18 h, sodium triacetoxyborohydride (200 mg, 1000
pmol) is
added. This mixture is agitated for 1.5 h followed by purification by Gilson
Preparatory
HPLC to give 16.5 mg of the title compound (30.0%).
LC/MS = m/z 547.1 [M+H] Ret. Time: 1.55 min.
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Example 435: 3-f1-(ethylsulfonyl)-4-piperidinyll-5-(5-fff(1 S)-2-hydroxy-l-
methylethyll(methyl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide
trifluoroacetate (salt)
o ~ o
N
0
N S
N
H
p
HZN O F
F OH
To a vial containing (2S)-2-amino-l-propanol (91 mg, 1.2 mmol) was added a
solution of
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-indole-7-
carboxamide (30 mg,
0.067 mmol) in DMSO (300 pL) and acetic acid (50 pL). The resulting mixture
was
shaken for 5 min followed by an addition of sodium triacetoxyborohydride (250
mg, 1.20
mmol) in DMSO (800 pL). The mixture was shaken overnight. Sodium
cyanoborohydride
(79 mg, 1.20 mmol) in methanol (300 pL) was then added and stirred for 48 h.
This was
followed by an addition of formaldehyde (100 pL). The reaction was then
stirred for 1 h
followed by a 2g SCX cartridge separation. The solids were then filtered off,
solution was
concentrated and purification was repeated on a 5 g SCX cartridge eluting with
ammonia
in MeOH. The ammonia in MeOH fraction collection was concentrated and
separated
using Gilson Preparatory HPLC to afford 18.7 mg of the title compound.
LC/MS = m/z 519.3 [M+H] Ret. Time: 1.49 min.
Example 436: 5-(5-ff(1,1-dioxidotetrahydro-3-thienyl)(methyl)aminolmethyl}-3-
thienyl)-3-f1-(ethylsulfonyl)-4-piperidinyll-1 IY-indole-7-carboxamide
trifluoroacetate
ols--o
N
O
O=S~N S
\ I ~
N
H
H2N O F ,,O
F 'I C\~
F OH
The title compound was prepared according to the general procedure of 3-[1-
(ethylsuifonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1-
methylethyl](methyl)amino]methyl}-
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3-thienyl)-1H-indole-7-carboxamide trifluoroacetate, substituting (1,1-
dioxidotetrahydro-3-
thienyl)amine (1.20 mmol) for (2S)-2-amino-l-propanol to afford 9.3 mg of the
title
compound.
LC/MS = m/z 579 [M+H] Ret. Time: 1.54 min.
Biological Data
IKK2 Assay
Recombinant human IKK(3 (residues 1-737) was expressed in baculovirus as a C-
terminal
GST-tagged fusion protein, and its activity was assessed using a time-resolved
fluorescence resonance energy transfer (TR-FRET) assay. Briefly, IKK2 (0.5 nM -
5nM
final) diluted in assay buffer (50 mM HEPES, 10 mM MgCI2, 1 mM CHAPS pH 7.4
with 1
mM DTT and 0.01 % w/v BSA) was added to wells containing various
concentrations of
compound or DMSO vehicle (1.7% final). The reaction was initiated by the
addition of
GST-IB substrate (25 nM final)/ATP (1 pM final), in a total volume of 6 NI.
The reaction
was incubated for 15 minutes at room temperature, then terminated by the
addition of 3 pl
of detection reagent in buffer containing 50mM EDTA (100 mM HEPES pH 7.4, 150
mM
NaCl, 50mM EDTA and 0.01% w/v BSA) containing antiphosphoserine-IB-32/36
monoclonal antibody 12C2 (Cell Signalling Technology, Beverly Massachusetts,
USA)
labelled with W-1024 europium chelate (Wallac OY, Turku, Finland), and an APC-
labelled
anti-GST antibody (Prozyme, San Leandro, California, USA) was added and the
reaction
was further incubated for 60 minutes at room temperature. The degree of
phosphorylation of GST-IB was measured using a BMG Rubystar plate reader (BMG
Labtech, Aylesbury, UK) as a ratio of specific 665 nm energy transfer signal
to reference
europium 620 nm signal.
Results
The compounds of Examples 1-31, 33, 35-51, 53-58, 60-97, 100-116, 118-121, 123-
137,
139-163, 165-172, 174-197, 199-220, 222-242, 244-276, 279-330, 332-358, 360-
385,
387-402, 404-419, 421-426, and 428-436 were tested for activity against IKK2
and these
Examples were found to be inhibitors of IKK2. These compounds had a pIC50 of
5.0 or
greater. Examples 277 and 278 were also tested for activity against IKK2 and
these two
compounds were found to have a pIC50 of less than 5Ø
Monocyte Assay
Effect of IKK-0 inhibition on human monocyte stimulated cytokine production
was
assessed as follows: Monocytes were isolated from heparinized whole blood by
Ficoll
gradient, followed by purification of CD14+ cells using MACS magnetic cell
separation
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beads. Isolated monocytes were then adhered to 96-well culture plates at 1 x
106
cells/mL in RPMI 1640 10% FBS (JRH Biosciences, Lenexa KS) for 2h. Test
compounds
are added to the wells 30 minutes prior to stimulation with a final vehicle
concentration of
0.1 % DMSO. Monocytes were activated by the addition of 200 ng/mL endotoxin
(LPS; E.
coli serotype 026:B6)(Sigma, St. Louis, MO.) and incubated for 24 hrs at 37 C.
Cell-free
supernates were analyzed by ELISA or Alphascreen for TNF-a. ELISAs were
performed
using Pharmingen matched pair Abs, and Alphascreen was performed using
Alphascreen
acceptor and donor beads from Perkin Elmer and anti-human TNF and biotinylated
anti-
human TNF Abs from R&D Systems. Viability of the cells was determined by 10%
trypan
blue exclusion.
Results
Certain Examples of this invention were tested in the monocyte assay. Examples
1-3, 5-
13, 16-23, 25-31, 33, 37, 42-44, 61, 65-69, 71-73, 75-78, 83, 86-89, 92, 96,
100-117, 119-
121, 123-127, 129-131, 139, 141, 144, 151, 154-157, 160-164, 166-167, 169-172,
182,
191, 208-214, 216-220, 222, 223, 227, 230-248, 250, 251, 269, 271, 273-276,
279-83,
285-90, 292-296, 298, 304-327, 329, 332-337, 342, 343, 346, 348, 353, 356-358,
361,
366-368, 370-373, 376, 380, 382, 391, 394-397, 399-404, 406, 408, 409, 412,
417-419,
432, 434, and 435 were found to have an IC50 of <2 M in this assay.
Examples 4, 15, 24, 34-36, 50, 70, 118, 128, 132-134, 136, 137, 140, 143, 146-
148, 153,
158, 159, 165, 168, 192-194, 196, 197, 200-207, 224, 249, 253-262, 270, 272,
299-303,
330, 338-341, 360, 362, 363, 365, 374, 375, 377-379, 381, 383, 385, 388-390,
392, and
393 did not inhibit by >65 % at 1 M (top dose tested).
Examples 39, 40, 45-49, 58-60, 62, 63, 74, 79-81, 84, 85, 90, 91, 94, 95, 97,
173-181,
184-190, 195, 198, 328, 345, 347, 349-353, 345, 355, 429-431, 433, and 436
showed
< 60% inhibition at 300 nM.
Variable results were obtain in the monocyte assay for Examples 38, 64, 82,
215, 297,
344, 364, and 369.
341

Dessin représentatif