U.S. patent application number 17/396312 was filed with the patent office on 2021-12-02 for azaindole compounds as histone methyltransferase inhibitors.
The applicant listed for this patent is GLOBAL BLOOD THERAPEUTICS, INC.. Invention is credited to Zhe Li, Chul Yu, Ming Yu, Manuel Zancanella.
Application Number | 20210371417 17/396312 |
Document ID | / |
Family ID | 1000005767282 |
Filed Date | 2021-12-02 |
United States Patent
Application |
20210371417 |
Kind Code |
A1 |
Yu; Chul ; et al. |
December 2, 2021 |
AZAINDOLE COMPOUNDS AS HISTONE METHYLTRANSFERASE INHIBITORS
Abstract
The present disclosure provides certain angular tricyclic
compounds that are histone methyltransferases G9a and/or GLP
inhibitors and are therefore useful for the treatment of diseases
treatable by inhibition of G9a and/or GLP such as cancers and
hemoglobinopathies (e.g., beta-thalassemia and sickle cell
disease). Also provided are pharmaceutical compositions containing
such compounds and processes for preparing such compounds.
Inventors: |
Yu; Chul; (San Ramon,
CA) ; Yu; Ming; (Foster City, CA) ;
Zancanella; Manuel; (San Mateo, CA) ; Li; Zhe;
(San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GLOBAL BLOOD THERAPEUTICS, INC. |
South San Francisco |
CA |
US |
|
|
Family ID: |
1000005767282 |
Appl. No.: |
17/396312 |
Filed: |
August 6, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16002408 |
Jun 7, 2018 |
11111243 |
|
|
17396312 |
|
|
|
|
62517410 |
Jun 9, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 487/04 20130101;
C07D 471/04 20130101; C07D 519/00 20130101; A61P 7/00 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61P 7/00 20060101 A61P007/00; C07D 519/00 20060101
C07D519/00; C07D 487/04 20060101 C07D487/04 |
Claims
1. A compound of Formula (I): ##STR00288## wherein: X is N or
CR.sup.1; Y is N or CR.sup.2; P, Q, T, and U are independently CH,
C (when R.sup.4 or R.sup.5 is attached), or N; provided that at
least one and not more than two of P, Q, T and U are N; Z is O, S,
or NR.sup.6, wherein R.sup.6 is hydrogen, alkyl, or cycloalkyl;
R.sup.1 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or
cycloalkyl; R.sup.2 is hydrogen, alkyl, alkoxy, halo, haloalkyl,
haloalkoxy, or cycloalkyl; R.sup.3 is --W-alkylene-R.sup.7,
wherein: W is bond, NH, O, or S; alkylene is optionally substituted
with R.sup.8, wherein R.sup.8 is halo, haloalkyl, haloalkoxy,
hydroxy, or alkoxy, and one CH.sub.2 in the alkylene is optionally
replaced with NH or O; and R.sup.7 is --NR.sup.aR.sup.b, wherein
R.sup.a and R.sup.b are independently hydrogen, alkyl, or
haloalkyl; or R.sup.a and R.sup.b together with the nitrogen to
which they are attached form heterocycloamino, bridged
heterocycloamino, or spiroheterocycloamino, wherein the
heterocycloamino, the bridged heterocycloamino and the
spiroheterocycloamino are optionally substituted with one or two
substituents independently selected from alkyl, halo, haloalkyl,
hydroxy, alkoxy, and haloalkoxy; or R.sup.7 is heterocyclyl that is
attached to the alkylene at a ring carbon atom and is optionally
substituted with one or two substituents independently selected
from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy;
R.sup.4 and R.sup.5 are independently alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, halo, hydroxy, haloalkoxy, alkoxy, cyano,
NH.sub.2, NR.sup.cR.sup.d, alkoxyalkylamino, hydroxyalkylamino,
aminoalkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio,
alkoxyalkyloxy, phenyl, heteroaryl, heteroaryloxy, heterocyclyl,
heterocyclyloxy, heterocyclylamino, 5-8 membered bridged
heterocycloamino or spiroheterocycloamino, wherein the phenyl, the
cycloalkyl, the heteroaryl, and the heterocyclyl either alone or as
part of another group are optionally substituted with one, two, or
three substituents independently selected from alkyl, halo,
haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxy, NH.sub.2,
alkylamino, dialkylamino, carboxy, carboxyalkyl, and
alkoxycarbonyl, and wherein the alkyl of R.sup.4 and R.sup.5 is
optionally substituted with cycloalkyl, and the alkenyl and the
alkynyl of R.sup.4 and R.sup.5 are independently optionally
substituted with hydroxy or cycloalkyl; R.sup.c is hydrogen, alkyl,
cycloalkyl, or heterocyclyl; R.sup.d is alkyl, cycloalkyl, or
heterocyclyl; or R.sup.c and R.sup.d together with the nitrogen to
which they are attached form a 4- to 7-membered heterocycloamino;
and v and w are independently 0 or 1; or a pharmaceutically
acceptable salt thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein Z is NR.sup.6.
3. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein R.sup.6 is H.
4. The compound of claim 1, 2, or 3, or a pharmaceutically
acceptable salt thereof, wherein X is CR.sup.1; and Y is
CR.sup.2.
5. The compound of any one of claims 1-4, or a pharmaceutically
acceptable salt thereof, wherein R.sup.2 is hydrogen.
6. The compound of any one of claims 1-4, or a pharmaceutically
acceptable salt thereof, wherein R.sup.2 is alkoxy.
7. The compound of claim 1, 2, or 3, or a pharmaceutically
acceptable salt thereof, wherein X is CR.sup.1; and Y is N.
8. The compound of any one of claims 1-7, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is hydrogen.
9. The compound of any one of claims 1-7, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is alkoxy.
10. The compound of claim 9, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is methoxy.
11. The compound of any one of claims 1-7, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is alkyl.
12. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P is N; and Q, T, and U are each
CH.
13. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P, Q and U are each CH; and T is
N.
14. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P and T are each N; and Q and U
are each CH.
15. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P is C (wherein R.sup.4 is
attached); Q is N; and T and U are each CH.
16. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P, T and U are each CH; and Q is
N.
17. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P, Q and T are each CH; and U is
N.
18. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P and U are each CH; T is C
(wherein R.sup.5 is attached) and Q is N.
19. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P is C (wherein R.sup.4 is
attached); Q is N; T is C (wherein R.sup.5 is attached); and U is
CH.
20. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P and T are each CH; Q and U is
N.
21. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P and Q are each CH; T is C
(wherein R.sup.5 is attached); and U is N.
22. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P is C (wherein R.sup.4 is
attached); Q is N; T is CH; and U is C (wherein R.sup.5 is
attached).
23. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P is C (wherein R.sup.4 is
attached); Q is N; T is CH; and U is N.
24. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein P is C (wherein R.sup.4 is
attached); Q is N; T is CR.sup.5 (wherein R.sup.5 is attached); and
U is N.
25. The compound of any one of claims 1-11, or a pharmaceutically
acceptable salt thereof, wherein Q is N; and P, T, and U are
independently CH or C (when R.sup.4 or R.sup.5 is attached).
26. The compound of claim 25, or a pharmaceutically acceptable salt
thereof, wherein P is CR.sup.4.
27. The compound of claim 25 or 26, or a pharmaceutically
acceptable salt thereof, wherein T is CH.
28. The compound of claim 25 or 26, or a pharmaceutically
acceptable salt thereof, wherein T is CR.sup.5.
29. The compound of any one of claims 25-27, or a pharmaceutically
acceptable salt thereof, wherein U is CH.
30. The compound of any one of claims 25-27, or a pharmaceutically
acceptable salt thereof, wherein U is CR.sup.5.
31. The compound of any one of claims 1-30, or a pharmaceutically
acceptable salt thereof, wherein W is O.
32. The compound of any one of claims 1-31, or a pharmaceutically
acceptable salt thereof, wherein the alkylene in
--W-alkylene-R.sup.7 is unsubstituted.
33. The compound of any one of claims 1-30, or a pharmaceutically
acceptable salt thereof, wherein --W-alkylene- in R.sup.3 is
--(CH.sub.2).sub.2--*, --(CH.sub.2).sub.3--*,
--(CH.sub.2).sub.4--*, --CH.sub.2CH(CH.sub.3)CH.sub.2--*,
*--CH.sub.2CH(CH.sub.3)CH.sub.2--, --O--(CH.sub.2)--*,
--O--(CH.sub.2).sub.2--*,
--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--*,
--O--(CH.sub.2).sub.3--*, --OCH.sub.2CH(F)CH.sub.2--*,
--OCH.sub.2CH(OH)CH.sub.2--*, --OCH.sub.2CH(OCH.sub.3)CH.sub.2--*,
or --OCH.sub.2CH(OCF.sub.3)CH.sub.2--*, wherein the * indicates the
point of attachment to R.sup.7.
34. The compound of any one of claims 1-30, or a pharmaceutically
acceptable salt thereof, wherein --W-alkylene- is
--(CH.sub.2).sub.2--*, --(CH.sub.2).sub.3--*,
--(CH.sub.2).sub.4--*, --CH.sub.2CH(CH.sub.3)CH.sub.2--*,
--O--(CH.sub.2).sub.2--*,
--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--*, or
--O--(CH.sub.2).sub.3--*, wherein the * indicates the point of
attachment to R.sup.7.
35. The compound of claim 34, or a pharmaceutically acceptable salt
thereof, wherein --W-alkylene- is --O--(CH.sub.2).sub.3--*, wherein
the * indicates the point of attachment to R.sup.7.
36. The compound of any one of claims 1-35, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 is --NR.sup.aR.sup.b,
wherein R.sup.a and R.sup.b are independently hydrogen, alkyl, or
haloalkyl.
37. The compound of claim 36, or a pharmaceutically acceptable salt
thereof, wherein R.sup.a and R.sup.b are independently methyl,
ethyl, n-propyl or isopropyl.
38. The compound of claim 36, or a pharmaceutically acceptable salt
thereof, wherein --NR.sup.aR.sup.b is NH.sub.2, methylamino,
ethylamino, dimethylamino, diethylamino, diisopropylamino or
(ethyl)(methyl)amino.
39. The compound of claim 38, or a pharmaceutically acceptable salt
thereof, wherein --NR.sup.aR.sup.b is dimethylamino.
40. The compound of any one of claims 1-35, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 is --NR.sup.aR.sup.b,
wherein --NR.sup.aR.sup.b together with the nitrogen to which they
are attached form a heterocycloamino, wherein the heterocycloamino
is optionally substituted with one or two substituents
independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy
and haloalkoxy.
41. The compound of claim 40, wherein the heterocycloamino is a
4-membered heterocycloamino or a 5-membered heterocycloamino
optionally substituted with one or two substituents independently
selected from alkyl, halo, haloalkyl, hydroxy, alkoxy and
haloalkoxy.
42. The compound of claim 40, or a pharmaceutically acceptable salt
thereof, wherein the heterocycloamino is azetidin-1-yl,
pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl,
thiomorpholin-4-yl or 3-azabicyclo[3.1.1]heptan-3-yl, each
heterocycloamino optionally substituted with one or two
substituents independently selected from methyl, hydroxy, methoxy,
and fluoro.
43. The compound of any one of claims 40-42, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 is --NR.sup.aR.sup.b,
wherein R.sup.a and R.sup.b together with the nitrogen to which
they are attached form pyrrolidin-1-yl, 3(S)-fluoropyrrolidin-1-yl,
3 (R)-fluoropyrrolidin-1-yl, 2-methylpyrrolidin-1-yl,
3,5-dimethylpyrrolidin-1-yl, or 3,3-dimethylpyrrolidin-1-yl.
44. The compound of claim 43, or a pharmaceutically acceptable salt
thereof, wherein R.sup.7 is --NR.sup.aR.sup.b, wherein R.sup.a and
R.sup.b together with the nitrogen to which they are attached form
pyrrolidin-1-yl.
45. The compound of any one of claims 1-35, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 is heterocyclyl that is
attached to the alkylene at a ring carbon atom and is optionally
substituted with one or two substituents independently selected
from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy.
46. The compound of claim 45, or a pharmaceutically acceptable salt
thereof, wherein R.sup.7 is piperidin-3-yl.
47. The compound of claim 45, or a pharmaceutically acceptable salt
thereof, wherein R.sup.7 is piperidin-3-yl optionally substituted
with alkyl.
48. The compound of any one of claims 1-30, or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is
--O--(CH.sub.2).sub.3-pyrrolidin-1-yl,
--O--(CH.sub.2).sub.3-piperidin-1-yl,
--O--(CH.sub.2)-piperidin-3-yl, or
--O--(CH.sub.2).sub.3-morpholin-4-yl, wherein pyrrolidin-1-yl,
piperidin-1-yl, piperidin-3-yl and morpholin-4-yl are each
optionally substituted with one or two substituents independently
selected from methyl, hydroxy, methoxy, and fluoro.
49. The compound of any one of claim 1-11, 18, 19, 21, 22 or 24-48,
or a pharmaceutically acceptable salt thereof, wherein w is 0.
50. The compound of any one of claims 1-48, or a pharmaceutically
acceptable salt thereof, wherein w is 1.
51. The compound of claim 50, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is NH.sub.2, halo, alkyl, hydroxy, alkoxy,
cycloalkyl, or hydroxyalkyl.
52. The compound of claim 51, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is NH.sub.2, fluoro, chloro, methyl,
ethyl, hydroxy, methoxy, cyclopropyl, cyclopentyl, or
hydroxymethyl.
53. The compound of claim 51, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is alkyl.
54. The compound of claim 51, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is cycloalkyl.
55. The compound of claim 51, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is halo.
56. The compound of claim 51, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is hydroxy or hydroxyalkyl.
57. The compound of claim 51, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is NH.sub.2.
58. The compound of claim 51, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is alkoxy.
59. The compound of any one of claim 1-11, 15, 19 or 22-58, or a
pharmaceutically acceptable salt thereof, wherein v is 0.
60. The compound of any one of claims 1-58, or a pharmaceutically
acceptable salt thereof, wherein v is 1.
61. The compound of claim 60, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is hydroxy.
62. The compound of claim 60, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, halo, haloalkoxy, alkoxy, cyano, NH.sub.2,
NR.sup.cR.sup.d, alkoxyalkylamino, hydroxyalkylamino,
aminoalkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio,
alkoxyalkyloxy, phenyl, heteroaryl, heteroaryloxy, heterocyclyl,
heterocyclyloxy, 5-8 membered bridged heterocycloamino or
spiroheterocycloamino, wherein the phenyl, the heteroaryl, and the
heterocyclyl either alone or as part of another group are
optionally substituted with one, two, or three substituents
independently selected from alkyl, halo, haloalkyl, haloalkoxy,
hydroxy, alkoxy, NH.sub.2, alkylamino, dialkylamino, carboxy,
carboxyalkyl, and alkoxycarbonyl, and wherein the alkyl of R.sup.4
is optionally substituted with cycloalkyl, and the alkenyl and the
alkynyl of R.sup.4 are optionally substituted with hydroxy or
cycloalkyl; R.sup.c is hydrogen, alkyl, cycloalkyl, or
heterocyclyl; and R.sup.d is alkyl, cycloalkyl, or heterocyclyl; or
R.sup.c and R.sup.d together with the nitrogen to which they are
attached form a 4- to 6-membered heterocycloamino.
63. The compound of claim 62, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is alkyl or cycloalkyl.
64. The compound of claim 63, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is cycloalkyl selected from the group
consisting of cyclopropyl, cyclobutyl, or cyclopentyl, wherein the
cyclopropyl, the cyclobutyl, and the cyclopentyl are optionally
substituted with one, two, or three substituents independently
selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy,
NH.sub.2, alkylamino, dialkylamino, carboxy, carboxyalkyl, and
alkoxycarbonyl.
65. The compound of claim 62, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is NH.sub.2, NR.sup.cR.sup.d,
alkoxyalkylamino, hydroxyalkylamino or aminoalkylamino.
66. The compound of claim 62, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is heteroaryl, heterocyclyl, 5-8 membered
bridged heterocycloamino or spiroheterocycloamino, wherein the
heteroaryl and the heterocyclyl either alone or as part of another
group are optionally substituted with one, two, or three
substituents independently selected from alkyl, halo, haloalkyl,
haloalkoxy, hydroxy, alkoxy, NH.sub.2, alkylamino, dialkylamino,
carboxy, carboxyalkyl, and alkoxycarbonyl.
67. The compound of claim 62 or 66, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4 is heterocyclyl.
68. The compound of claim 62, 66 or 67, or a pharmaceutically
acceptable salt thereof, wherein the heterocyclyl is a
heterocycloamino optionally substituted with one, two, or three
substituents independently selected from alkyl, halo, haloalkyl,
haloalkoxy, hydroxy, alkoxy, NH.sub.2, alkylamino, dialkylamino,
carboxy, carboxyalkyl, and alkoxycarbonyl, and wherein the alkyl,
alkenyl and alkynyl are optionally substituted with hydroxy and an
unsubstituted cycloalkyl.
69. The compound of claim 68, or a pharmaceutically acceptable salt
thereof, wherein the heterocycloamino is oxetanyl,
tetrahydrofuranyl, or tetrahydropyranyl.
70. The compound of claim 62 or 65, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4 is NR.sup.cR.sup.d.
71. The compound of claim 70, or a pharmaceutically acceptable salt
thereof, wherein R.sup.c and R.sup.d together with the nitrogen to
which they are attached form a 4- to 6-membered
heterocycloamino.
72. The compound of claim 62, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is methyl, ethyl, n-propyl, isopropyl,
tert-butyl, ethynyl, fluoro, chloro, cyclopropyl,
1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclopent-1-en-1-yl,
2-cyclopropylethynyl, 2-cyclopropylethenyl, 2-cyclopropylethyl,
pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,
2-isopropylpyrrolidin-1-yl, 2,2-dimethylpyrrolidin-1-yl,
2-isopropylpyrrolidin-1-yl, 2-(carboxymethyl)pyrrolidin-1-yl,
2-carboxypyrrolidin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,
4-hydroxypiperidin-1-yl, morpholin-4-yl, oxetan-3-yl, oxetan-2-yl,
oxan-2-yl, oxan-3-yl oxan-4-yl, tetrahydropyran-4-yl,
1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl,
tetrahydrofuran-3-yl, azetidine-1-yl, 3-hydroxyazetidin-1-yl,
pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, oxan-4-yloxy,
pyrrolidin-3-yloxy, 2-ethoxyeth-1-yl, 3-methoxyprop-1-yl,
methylamino, ethylamino, n-propylamino, n-butylamino,
isopropylamino, isobutylamino, tertbutylamino, cyclopropylamino,
cyclobutylamino, cyclopentylamino, cyclohexylamino,
cycloheptylamino, (cyclopropylmethyl)amino,
(cyclobutylmethyl)amino, (cyclopentylmethyl)amino,
(cyclohexylmethyl)amino, dimethylamino, diethylamino,
dimethylamino, di-(n-propyl)amino, di-(isopropyl)amino,
di-(n-butyl)amino, di-(isobutyl)amino, di-(tertbutyl)amino,
(methyl)(ethyl)amino, 2-ethoxyethylamino, 3-methoxyprop-2-ylamino,
thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyrazol-1-yl,
pyrazol-3-yl, pyrazol-4-yl, imidazole-1-yl, imidazole-2-yl,
imidazole-4-yl, imidazole-5-yl, oxazol-5-yl, oxazol-2-yl,
oxazol-4-yl, 1,2,4-triazol-5-yl, 1,2,4-triazol-3-yl,
1,2,4-triazol-1-yl, hydroxymethyl, 4-difluoromethoxyphenyl,
3-difluoromethoxyphenyl, 2-difluoromethoxypyridin-4-yl,
6-difluoromethoxypyridin-3-yl, 4-methylaminopyridin-2-yl,
2-methylaminopyridin-4-yl, 6-methylamino-pyridin-2-yl,
4-difluoromethylphenyl, 2-hydroxyprop-2-yl,
4-(2-hydroxypropyl)phenyl, 4-(2-hydroxypropan-2-yl)phenyl,
2-(carboxymethyl)phenyl, 2-carboxyphenyl, 2-methoxyethoxy, methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy and
tert-butoxy, hydroxy, methylsulfenyl,
3-hydroxy-3-methylbut-1-yn-1-yl, 3-hydroxy-3-methylbut-1-en-1-yl,
3-hydroxy-3-methylbutyl, 2-hydroxypropan-2-yl,
1-azaspiro[3,4]octan-1-yl, 4-azaspiro[2,4]heptan-4-yl,
5-azaspiro[3,4]octan-5-yl, 1-azaspiro[3,3]heptan-1-yl,
2-oxa-5-azaspiro[3,4]octan-5-yl, 6-oxa-1-azaspiro[3,3]heptan-1-yl,
6-oxa-1-azaspiro[3,4]octan-1-yl, 7-oxa-1-azaspiro[4,4]nonan-1-yl,
8-oxa-3-azabicyclo[3.2.1]octan-3-yl, or
7,7-dioxido-7-thia-1-azaspiro[4.4]nonan-1-yl.
73. The compound of claim 72, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is methyl, ethyl, n-propyl, isopropyl,
n-butyl, iso-butyl, or tert-butyl.
74. The compound of claim 73, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is methyl, ethyl, n-propyl, or
isopropyl.
75. The compound of claim 72, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is cyclopropyl, 1-methylcyclopropyl,
cyclobutyl, or cyclopentyl.
76. The compound of claim 75, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is cyclopropyl.
77. The compound of claim 72, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is pyrrolidin-1-yl,
3-hydroxypyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl,
2,2-dimethylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl,
2-(carboxymethyl)pyrrolidin-1-yl, 2-carboxypyrrolidin-1-yl,
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, piperidin-1-yl,
piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,
4-hydroxypiperidin-1-yl, morpholin-4-yl, oxetan-3-yl, oxetan-2-yl,
oxan-2-yl, oxan-3-yl oxan-4-yl, tetrahydropyran-4-yl,
1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl,
tetrahydrofuran-3-yl, azetidine-1-yl, 3-hydroxyazetidin-1-yl,
thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyrazol-1-yl,
pyrazol-3-yl, pyrazol-4-yl, imidazole-1-yl, imidazole-2-yl,
imidazole-4-yl, imidazole-5-yl, oxazol-5-yl, oxazol-2-yl,
oxazol-4-yl, 1,2,4-triazol-5-yl, 1,2,4-triazol-3-yl,
1,2,4-triazol-1-yl, hydroxymethyl, 4-difluoromethoxyphenyl,
3-difluoromethoxyphenyl, 2-difluoromethoxypyridin-4-yl,
6-difluoromethoxypyridin-3-yl, 4-methylaminopyridin-2-yl,
2-methylaminopyridin-4-yl, or 6-methylamino-pyridin-2-yl.
78. The compound of claim 77, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is pyrrolidin-1-yl,
3-hydroxypyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl,
2,2-dimethylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl,
2-(carboxymethyl)pyrrolidin-1-yl, or 2-carboxypyrrolidin-1-yl.
79. The compound of claim 72, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is 1-azaspiro[3,4]octan-1-yl,
4-azaspiro[2,4]heptan-4-yl, 5-azaspiro[3,4]octan-5-yl,
1-azaspiro[3,3]heptan-1-yl, 2-oxa-5-azaspiro[3,4]octan-5-yl,
6-oxa-1-azaspiro[3,3]heptan-1-yl, 6-oxa-1-azaspiro[3,4]octan-1-yl,
7-oxa-1-azaspiro[4,4]nonan-1-yl,
8-oxa-3-azabicyclo[3.2.1]octan-3-yl, or
7,7-dioxido-7-thia-1-azaspiro[4.4]nonan-1-yl.
80. The compound of claim 72, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is methylamino, ethylamino, n-propylamino,
n-butylamino, isopropylamino, isobutylamino, tertbutylamino,
cyclopropylamino, cyclobutylamino, cyclopentylamino,
cyclohexylamino, cycloheptylamino, (cyclopropylmethyl)amino,
(cyclobutylmethyl)amino, (cyclopentylmethyl)amino,
(cyclohexylmethyl)amino, dimethylamino, diethylamino,
dimethylamino, di-(n-propyl)amino, di-(isopropyl)amino,
di-(n-butyl)amino, di-(isobutyl)amino, di-(tertbutyl)amino, or
(methyl)(ethyl)amino.
81. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein X is CR.sup.1; Y is CR.sup.2, P is CH or CR.sup.4;
Q is N; T is CH or CR.sup.5; U is CH or N; R.sup.1 and R.sup.2 are
independently hydrogen or methoxy; R.sup.3 is
--O--(CH.sub.2).sub.2--R.sup.7, --O--(CH.sub.2).sub.3--R.sup.7 or
--O--(CH.sub.2).sub.4--R.sup.7; R.sup.7 is --NR.sup.aR.sup.b,
wherein R.sup.a and R.sup.b are independently methyl, ethyl,
n-propyl or isopropyl, or --NR.sup.aR.sup.b together with the
nitrogen to which they are attached form a 4-membered
heterocycloamino or a 5-membered heterocycloamino wherein each
heterocycloamino is optionally substituted with one or two
substituents independently selected from alkyl, halo, haloalkyl,
hydroxy, alkoxy and haloalkoxy; R.sup.4 is methyl, ethyl, n-propyl,
isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, heterocyclyl,
NH.sub.2, or NR.sup.cR.sup.d, wherein the cyclopropyl, the
cyclobutyl, and the cyclopentyl are optionally substituted with
one, two, or three substituents independently selected from alkyl,
halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, NH.sub.2, alkylamino,
dialkylamino, carboxy, carboxyalkyl, and alkoxycarbonyl; R.sup.5 is
NH.sub.2; R.sup.c is hydrogen, alkyl, cycloalkyl, or heterocyclyl;
and R.sup.d is alkyl, cycloalkyl or heterocyclyl; or R.sup.c and
R.sup.d together with the nitrogen to which they are attached form
a 4- to 7-membered heterocycloamino.
82. The compound of claim 81, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is methoxy; and R.sup.2 is hydrogen.
83. The compound of claim 81 or 82, or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is
--O--(CH.sub.2).sub.3--R.sup.7.
84. The compound of any one of claims 81-83, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 is --NR.sup.aR.sup.b,
wherein R.sup.a and R.sup.b are independently methyl, ethyl,
n-propyl or isopropyl.
85. The compound of claim 84, or a pharmaceutically acceptable salt
thereof, wherein R.sup.a and R.sup.b are each methyl.
86. The compound of any one of claims 81-85, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 is --NR.sup.aR.sup.b,
wherein --NR.sup.aR.sup.b together with the nitrogen to which they
are attached form a 4-membered heterocycloamino or a 5-membered
heterocycloamino wherein each heterocycloamino is optionally
substituted with one or two substituents independently selected
from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy.
87. The compound of claim 86, or a pharmaceutically acceptable salt
thereof, wherein NR.sup.aR.sup.b together with the nitrogen to
which they are attached form pyrrolidin-1-yl.
88. The compound of any one of claims 81-87, or a pharmaceutically
acceptable salt thereof, wherein P is CH.
89. The compound of any one of claims 81-87, or a pharmaceutically
acceptable salt thereof, wherein P is CR.sup.4.
90. The compound of claim 89, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is methyl, ethyl, n-propyl, isopropyl, or
cyclopropyl.
91. The compound of claim 89, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is cyclopropyl, cyclobutyl, or
cyclopentyl, wherein cyclopropyl, cyclobutyl, and cyclopentyl are
optionally substituted with one, two, or three substituents
independently selected from alkyl, halo, haloalkyl, haloalkoxy,
hydroxy, alkoxy, NH.sub.2, alkylamino, dialkylamino, carboxy,
carboxyalkyl, and alkoxycarbonyl.
92. The compound of claim 89, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is NH.sub.2, NR.sup.cR.sup.d, or 4- to
6-membered heterocyclyl.
93. The compound of any one of claims 81-92, or a pharmaceutically
acceptable salt thereof, wherein T is CH.
94. The compound of any one of claims 81-93, or a pharmaceutically
acceptable salt thereof, wherein U is CH.
95. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein the compound of Formula (I) is selected from the
group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,
32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,
49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,
67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,
84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,
100, 101 and 102 as shown in Table 1, or a parent compound of a
salt as shown in Table 1, or a pharmaceutically acceptable salt of
the parent compound.
96. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein the compound of Formula (I) is selected from the
group consisting of: la, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a, 10a, 11a,
12a, 13a, 14a, 15a, 16a, 17a, 18a, 19a, 20a, 21a, 22a, 23a, 24a,
25a, 26a, 27a, 28a, 29a, 30a, 31a, 32a, 33a, 34a, 35a, 36a, 37a,
38a, 39a, 40a, 41a, 42a, 43a, 44a, 45a, 46a, 47a, 48a, 49a, 50a,
51a, 52a, 53a, 54a, 55a, 56a, 57a, 58a, 59a, 60a, 61a, 62a, 63a,
64a, 65a, 66a and 67a as shown in Table 2.
97. A pharmaceutical composition comprising a compound of any one
of claims 1-96, or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable excipient.
98. A method of inhibiting the activity of G9a comprising
contacting a cell that contains G9a with an effective amount of a
compound of any one of claims 1-96, or a pharmaceutically
acceptable salt thereof, and thereby inhibiting the activity of the
G9a.
99. A method of inhibiting the activity of GLP comprising
contacting a cell that contains GLP with an effective amount of a
compound of any one of claims 1-96, or a pharmaceutically
acceptable salt thereof, and thereby inhibiting the activity of
GLP.
100. A method of increasing fetal hemoglobin (HbF) protein levels
comprising contacting a cell characterized as having impaired
production of .beta.-globin with an effective amount of a compound
of any one of claims 1-96, or a pharmaceutically acceptable salt
thereof, and thereby increasing fetal hemoglobin (HbF) protein
levels.
101. A method of inhibiting the polymerization of hemoglobin S
molecules comprising contacting a cell characterized as having a
hemoglobin S mutation with an effective amount of a compound of any
one of claims 1-96, or a pharmaceutically acceptable salt thereof,
and thereby inhibiting the polymerization of hemoglobin S
molecules.
102. A method of inhibiting G9a activity in a subject comprising
administering to the subject suffering from a disease that is
treatable by fetal hemoglobin an effective amount of a compound of
any one of claims 1-96, or a pharmaceutically acceptable salt
thereof.
103. A method of inhibiting GLP activity in a subject comprising
administering to the subject suffering from a disease that is
treatable by fetal hemoglobin an effective amount of a compound of
any one of claims 1-96, or a pharmaceutically acceptable salt
thereof.
104. A method for treating a disease comprising administrating to a
subject suffering from a disease treatable by fetal hemoglobin an
effective amount of a compound of any one of claims 1-96, or a
pharmaceutically acceptable salt thereof.
105. A method for treating a disease characterized by impaired
production of .beta.-globin comprising administrating to a subject
suffering from the disease characterized by impaired production of
.beta.-globin an effective amount of a compound of any one of
claims 1-96, or a pharmaceutically acceptable salt thereof.
106. The method of claim 105, wherein the disease is
beta-thalassemia.
107. A method for treating a disease characterized by increased
concentration of polymerized hemoglobin S molecules comprising
administrating to a subject suffering from the disease
characterized by increased concentration of polymerized hemoglobin
S molecules an effective amount of a compound of any one of claims
1-96, or a pharmaceutically acceptable salt thereof.
108. The method of claim 107, wherein the disease is sickle cell
disease.
109. A method of ameliorating or treating a hemoglobinopathy,
comprising administering an effective amount of a compound of any
one of claims 1-96, or a pharmaceutically acceptable salt thereof,
or the pharmaceutical composition of claim 97 to a subject in need
thereof.
110. The method of claim 109, wherein the hemoglobinopathy is
sickle cell disease.
111. The method of claim 109, wherein the hemoglobinopathy is
beta-thalassemia.
112. Use of an effective amount of a compound of any one of claims
1-96, or a pharmaceutically acceptable salt thereof, in the
preparation of a medicament for inhibiting the activity of G9a in a
cell that contains G9a.
113. Use of an effective amount of a compound of any one of claims
1-96, or a pharmaceutically acceptable salt thereof, in the
preparation of a medicament for inhibiting the activity of GLP in a
cell that contains GLP.
114. Use of an effective amount of a compound of any one of claims
1-96, or a pharmaceutically acceptable salt thereof, in the
preparation of a medicament for increasing fetal hemoglobin (HbF)
protein levels in a cell characterized as having impaired
production of .beta.-globin.
115. Use of an effective amount of a compound of any one of claims
1-96, or a pharmaceutically acceptable salt thereof, in the
preparation of a medicament for inhibiting the polymerization of
hemoglobin S molecules in a cell characterized as having a
hemoglobin S mutation.
116. Use of an effective amount of a compound of any one of claims
1-96, or a pharmaceutically acceptable salt thereof, in the
preparation of a medicament for treating a disease treatable by
fetal hemoglobin.
117. Use of an effective amount of a compound of any one of claims
1-96, or a pharmaceutically acceptable salt thereof, in the
preparation of a medicament for treating a disease treatable by
fetal hemoglobin.
118. Use of an effective amount of a compound of any one of claims
1-96, or a pharmaceutically acceptable salt thereof, in the
preparation of a medicament for treating a disease characterized by
impaired production of .beta.-globin.
119. The use of claim 118, wherein the disease is
beta-thalassemia.
120. Use of an effective amount of a compound of any one of claims
1-96, or a pharmaceutically acceptable salt thereof, in the
preparation of a medicament for treating a disease characterized by
increased concentration of polymerized hemoglobin S molecules.
121. The use of claim 120, wherein the disease is sickle cell
disease.
122. Use of an effective amount of a compound of any one of claims
1-96, or a pharmaceutically acceptable salt thereof, in the
preparation of a medicament for ameliorating or treating a
hemoglobinopathy.
123. The use of claim 122, wherein the hemoglobinopathy is sickle
cell disease.
124. The use of claim 122, wherein the hemoglobinopathy is
beta-thalassemia.
Description
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] Any and all applications for which a foreign or domestic
priority claim is identified, for example, in the Application Data
Sheet or Request as filed with the present application, are hereby
incorporated by reference under 37 CFR 1.57, and Rules 4.18 and
20.6, including U.S. Provisional Application No. 62/517,410, filed
Jun. 9, 2017.
FIELD OF THE DISCLOSURE
[0002] The present disclosure provides certain azaindole compounds
that are histone methyltransferases G9a and/or GLP inhibitors, and
are therefore useful for the treatment of diseases treatable by
inhibition of G9a and/or GLP such as cancers and hemoglobinopathies
(e.g., beta-thalassemia and sickle cell disease). Also provided are
pharmaceutical compositions containing such compounds and processes
for preparing such compounds.
BACKGROUND
[0003] Chromatin modification plays an essential role in
transcriptional regulation. These modifications, including DNA
methylation, histone acetylation and histone methylation, are
important in a variety of biological processes including protein
production and cellular differentiation, and are emerging as
attractive drug targets in various human diseases. Two particular
enzymes associated with histone methylation are G9a and GLP, also
known as EHMT2 and EHMT1 (Euchromatic histone-lysine
N-methyltransferase 2 and 1). G9a and GLP are the primary enzymes
for mono- and dimethylation at Lys 9 of histone H3 (H3K9me1 and
H3K9me2), and exist predominantly as a G9a-GLP heteromeric complex
that appears to be a functional H3K9 methyltransferase in vivo.
Structurally, either G9a or GLP is composed of a catalytic SET
domain, a domain containing ankyrin repeats (involved in
protein-protein interactions) and nuclear localization signals on
the N-terminal region. The SET domain is responsible for the
addition of methyl groups on H3, whereas the ankyrin repeats have
been observed to represent mono- and dimethyl lysine binding
regions. The G9a-GLP complex is thus not only able to both
methylate histone tails but also able to recognize this
modification, and can function as a scaffold for the recruitment of
other target molecules on the chromatin. See Shinkai et al., Genes
Dev., 2011; 25(8):781-8; and Shankar et al., Epigenetics, 2013;
8(1):16-22.
[0004] Many studies have reported that G9a and GLP play critical
roles in various biological processes. Several reports have
highlighted its link to a variety of cancers. See Cascielle et al.,
Front Immunol., 2015 25; 6:487. It is upregulated in hepatocellular
carcinoma, B cell acute lymphoblastic leukemia, and lung cancers.
In addition, elevated expression of G9a in aggressive lung cancer
correlates with poor prognosis, while its knockdown in highly
invasive lung cancer cells suppressed metastasis in an in vivo
mouse model. In prostate cancer cells (PC3), G9a knockdown caused
significant morphological changes and inhibition of cell growth.
See Liu et al., J. Med Chem., 2013; 56(21):8931-42; and Sweis et
al., ACS Med Chem Lett., 2014; 5(2):205-9. Loss of G9a has been
demonstrated to impair DNA damage repair and enhance the
sensitivity of cancer cells to radiation and chemotherapeutics. See
Yang et al., Proc. Natl. Acad. Sci. USA, 2017, doi:
10.1073/pnas.1700694114.
[0005] Interestingly, recent studies have also shown that the
inhibition of G9a and GLP by either genetic depletion or
pharmacological intervention increased fetal hemoglobin (HbF) gene
expression in erythroid cells. See Krivega et al., Blood, 2015;
126(5):665-72; and Renneville et al., Blood, 2015; 126(16):1930-9.
Inducing fetal globin gene would be potentially therapeutically
beneficial for the disease of hemoglobinopathies, including
beta-thalassemia where the production of normal .beta.-globin, a
component of adult hemoglobin, is impaired. Similarly, induction of
HbF would potentially be beneficial by diluting the concentration
of hemoglobin S (HbS) molecules, thereby reducing polymerization of
HbS. See Sankaran et al., Cold Spring Harb Perspect Med., 2013;
3(1): a011643. Moreover, G9a or GLP inhibitions may potentiate
other clinically used therapies, such as hydroxyurea or HDAC
inhibitors. These agents may act, at least in part, by increasing
.gamma.-globin gene expression through different mechanisms. See
Charache et al., Blood, 1992; 79(10):2555-65. Thus, there is a need
for the development of small molecules that are capable of
inhibiting the activity of G9a and/or GLP. The compounds of the
present disclosure fulfill this and related needs.
SUMMARY
[0006] In one aspect provided is a compound of Formula (I):
##STR00001##
[0007] wherein: [0008] X can be N (nitrogen) or CR.sup.1; [0009] Y
can be N (nitrogen) or CR.sup.2; [0010] P, Q, T, and U can be
independently CH, C (carbon) (when R.sup.4 or R.sup.5 is attached),
or N (nitrogen); provided that at least one and not more than two
of P, Q, T and U are N (nitrogen); [0011] Z can be O (oxygen), S
(sulfur), or NR.sup.6, wherein R.sup.6 can be hydrogen, alkyl, or
cycloalkyl; [0012] R.sup.1 can be hydrogen, alkyl, alkoxy, halo,
haloalkyl, haloalkoxy, or cycloalkyl; [0013] R.sup.2 can be
hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or
cycloalkyl; [0014] R.sup.3 can be --W-alkylene-R.sup.7, wherein:
[0015] W can be bond, NH, O (oxygen), or S (sulfur); [0016]
alkylene can be optionally substituted with R.sup.8, wherein
R.sup.8 can be halo, haloalkyl, haloalkoxy, hydroxy, or alkoxy, and
one CH.sub.2 in the alkylene can be optionally replaced with NH or
O (oxygen); and [0017] R.sup.7 can be --NR.sup.aR.sup.b, wherein
R.sup.a and R.sup.b can be independently hydrogen, alkyl, or
haloalkyl; or R.sup.a and R.sup.b can be together with the nitrogen
to which they are attached form heterocycloamino, bridged
heterocycloamino, or spiroheterocycloamino, wherein the
heterocycloamino, the bridged heterocycloamino and the
spiroheterocycloamino are optionally substituted with one or two
substituents independently selected from alkyl, halo, haloalkyl,
hydroxy, alkoxy, and haloalkoxy; or [0018] R.sup.7 can be
heterocyclyl that is attached to the alkylene at a ring carbon atom
and can be optionally substituted with one or two substituents
independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy
and haloalkoxy; [0019] R.sup.4 and R.sup.5 can be independently
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, halo, hydroxy,
haloalkoxy, alkoxy, cyano, NH.sub.2, NR.sup.cR.sup.d,
alkoxyalkylamino, hydroxyalkylamino, aminoalkylamino, hydroxyalkyl,
alkoxyalkyl, alkylthio, alkoxyalkyloxy, phenyl, heteroaryl,
heteroaryloxy, heterocyclyl, heterocyclyloxy, heterocyclylamino,
5-8 membered bridged heterocycloamino or spiroheterocycloamino,
wherein the phenyl, the cycloalkyl, the heteroaryl, and the
heterocyclyl either alone or as part of another group are
optionally substituted with one, two, or three substituents
independently selected from alkyl, halo, haloalkyl, haloalkoxy,
hydroxy, hydroxyalkyl, alkoxy, NH.sub.2, alkylamino, dialkylamino,
carboxy, carboxyalkyl, and alkoxycarbonyl, and wherein the alkyl of
R.sup.4 and R.sup.5 is optionally substituted with cycloalkyl, and
the alkenyl and the alkynyl of R.sup.4 and R.sup.5 are
independently optionally substituted with hydroxy or cycloalkyl;
[0020] R.sup.c is hydrogen, alkyl, cycloalkyl, or heterocyclyl;
[0021] R.sup.d is alkyl, cycloalkyl, or heterocyclyl; or [0022]
R.sup.c and R.sup.d together with the nitrogen to which they are
attached form a 4- to 7-membered heterocycloamino; and [0023] v and
w are independently 0 or 1; [0024] or a pharmaceutically acceptable
salt thereof.
[0025] In a second aspect, this disclosure is directed to a
pharmaceutical composition comprising a compound of Formula (I) (or
any of the embodiments thereof described herein), or a
pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable excipient.
[0026] In a third aspect, this disclosure is directed to a method
of treating a disease treatable by inhibition of G9a and/or GLP in
a subject in need thereof, comprising administering to the subject
a therapeutically effective amount of a compound of Formula (I) (or
any of the embodiments thereof described herein), or a
pharmaceutically acceptable salt thereof; or a pharmaceutical
composition comprising a compound of Formula (I) (or any of the
embodiments thereof described herein), or a pharmaceutically
acceptable salt thereof, in a therapeutically effective amount, and
a pharmaceutically acceptable excipient. In one embodiment, the
disease can be a hemoglobinopathy, such as beta-thalassemia and
sickle cell disease See Krivega et al., Blood, 2015; 126(5):665-72;
and Renneville et al., Blood. 2015 Oct. 15; 126(16):1930-9. In a
second embodiment, the disease can be a cancer or tumor, for
example, a cancer or tumor where G9a or GLP can be overexpressed.
See Cascielle et al., Front Immunol, 2015; 6:487. In a third
embodiment, treating a cancer and/or tumor comprises increasing
tumor free survival and/or reducing tumor mass and/or slowing tumor
growth. In a fourth embodiment, the disease can be a cancer
predisposition syndrome, such as Cowden syndrome. See You et al.,
Cancer Cell, 2012; 22(1):9-20. In a fifth embodiment, the disease
can be an inflammatory and/or autoimmune disease, such as treating
intestinal inflammation. See Antignano et al., J Clin Invest, 2014;
124(5):1945-55. In a sixth embodiment, the disease can be a
metabolic disease, such as diabetes and/or obesity, such as
diabetes and obesity See Wang et al., EMBO J., 2013; 32(1):45-59.
In a seventh embodiment, the disease can be related to skeletal
muscle development and regeneration. See Ling et al., Proc Natl
Acad Sci USA., 2012; 109(3):841-6. In an eighth embodiment, the
disease can be a viral disease, such as HIV-1 (human
immunodeficiency virus 1) and HBV (Hepatitis B Virus). See Imai et
al., J Biol Chem., 2010; 285(22):16538-45; and Merkling et al.,
PLoS Pathog., 2015; 11(4):e1004692. The compounds and compositions
described herein can be administered with one or more additional
therapeutic agents including, but not limited to, anticancer agents
and antiviral agents. See, e.g., Front Immunol., 2015; 6:487;
Agarwal et al., Cancer Lett. 2016:467 and Zhang et al., Oncotarget
2015, 6(5):2917.
[0027] In a fourth aspect provided is the use of a compound of
Formula (I) (or any of the embodiments thereof described herein),
or a pharmaceutically acceptable salt thereof, in the treatment of
the diseases provided in the third aspect herein.
[0028] In a fifth aspect, this disclosure is directed to a method
of inhibiting G9a and/or GLP, comprising contacting a cell with a
therapeutically effective amount of a compound of Formula (I) (or
any of the embodiments thereof described herein), or a
pharmaceutically acceptable salt thereof. In some embodiments, the
cell suffers from one or more of the diseases provided in the third
aspect herein.
DETAILED DESCRIPTION
Definitions
[0029] Unless otherwise stated, the following terms used in the
specification and claims are defined for the purposes of this
Application and have the following meaning:
[0030] "Alkyl" means a linear saturated monovalent hydrocarbon
radical of one to six carbon atoms or a branched saturated
monovalent hydrocarbon radical of three to six carbon atoms, e.g.,
methyl, ethyl, n-propyl, 2-propyl (isopropyl), n-butyl, sec-butyl,
iso-butyl, tert-butyl, pentyl (straight-chained or branched), hexyl
(straight-chained or branched), and the like.
[0031] "Alkylene" means a linear saturated divalent hydrocarbon
radical of one to six carbon atoms or a branched saturated divalent
hydrocarbon radical of three to six carbon atoms unless otherwise
stated, e.g., methylene, ethylene, propylene, 1-methylpropylene,
2-methylpropylene, butylene, pentylene, and the like.
[0032] "Alkenyl" means a linear hydrocarbon radical of two to six
carbon atoms or a branched hydrocarbon radial of 3 to 6 carbon
atoms that includes one or two double bonds, ethenyl, propenyl
(straight-changed or branched), allenyl, butenyl (straight-changed
or branched), pentenyl (straight-changed or branched) and hexenyl
(straight-changed or branched).
[0033] "Alkynyl" means a linear hydrocarbon radical of two to six
carbon atoms or a branched hydrocarbon radial of 3 to 6 carbon
atoms that includes one or two triple bonds, ethynyl, propynyl
(straight-changed or branched), butynyl (straight-changed or
branched), pentynyl (straight-changed or branched) and hexynyl
(straight-changed or branched).
[0034] "Alkoxy" means a --OR radical where R is alkyl as defined
above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or
tert-butoxy, and the like.
[0035] "Alkoxyalkyl" means alkyl as defined above which is
substituted with one or two alkoxy groups as defined above, e.g.,
methoxyethyl, ethoxyethyl, methoxypropyl, and the like.
[0036] "Alkoxyalkylamino" means --NHR radical where R is
alkoxyalkyl as defined above, e.g., methoxyethylamino, 1-, 2- or
3-methoxypropylamino, and the like.
[0037] "Alkoxyalkyloxy" means --OR radical where R is alkoxyalkyl
as defined above, e.g., methoxyethyloxy, ethoxyethyloxy, and the
like.
[0038] "Hydroxyalkylamino" means --NHR radical where R is
hydroxyalkyl as defined herein, e.g., hydroxyethylamino, 1-, 2- or
3-hydroxypropylamino, and the like.
[0039] "Alkylcarbonyl" or "Acyl" means a --COR radical where R is
alkyl as defined above, e.g., methylcarbonyl, ethylcarbonyl, and
the like.
[0040] "Aminoalkyl" means a -(alkylene)-NR'R'' radical where R' and
R'' are independently hydrogen or alkyl as defined above.
[0041] "Aminoalkylamino" means --NHR radical where R is aminoalkyl
as defined above, e.g., aminoethylamino, methylaminoethylamino,
dimethylaminoethylamino, diethylaminoethylamino, and the like.
[0042] "Alkylamino" means a --NHR' radical where R' is alkyl as
defined above.
[0043] "Alkylthio" means a --SR' radical where R' is alkyl as
defined above.
[0044] "Bridged heterocycloamino" means a saturated
heterocycloamino radical as defined herein of 5 to 8 ring atoms
wherein two non-adjacent carbon atoms or non-adjacent carbon and
nitrogen atom are linked with alkylene chain as defined herein.
[0045] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon
radical of three to ten carbon atoms, unless stated otherwise,
e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the
like.
[0046] "Cycloalkenyl" means a cyclic nonaromatic hydrocarbon
radical of three to ten carbon atoms containing one or two double
bonds, unless stated otherwise, e.g., cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, and the like.
[0047] "Carboxy" means a --C(.dbd.O)OH group.
[0048] "Carboxyalkyl" means an alkyl radical as defined above that
is substituted with a carboxy group.
[0049] "Dialkylamino" means an --NRR' radical where R and R' are
alkyl as defined above.
[0050] "Halo" or `halogen" means fluoro, chloro, bromo, or iodo,
preferably fluoro or chloro.
[0051] "Haloalkyl" means an alkyl radical as defined above, which
is substituted with one or more halogen atoms, such as one to five
halogen atoms, such as fluorine or chlorine, including those
substituted with different halogens, e.g., --CH.sub.2Cl,
--CF.sub.3, --CHF.sub.2, --CH.sub.2CF.sub.3, and
--CF.sub.2CF.sub.3, --CF(CH.sub.3).sub.2, and the like. When the
alkyl is substituted with only fluoro, it can be referred to in
this Application as fluoroalkyl.
[0052] "Haloalkoxy" means a --OR radical where R is haloalkyl as
defined herein, e.g., --OCF.sub.3, --OCH.sub.2Cl, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, and --OCF.sub.2CF.sub.3, --OCHF.sub.2, and the
like. When the haloalkyl of a haloalkoxy is an alkyl is substituted
with only fluoro, it is referred to as a fluoroalkoxy.
[0053] "Hydroxyalkyl" means alkyl as defined above which is
substituted with one or two hydroxy groups as defined above, e.g.,
hydroxyethyl, hydroxyethyl, 1,3-dihydroxypropyl, and the like.
[0054] "Heterocyclyl" means a saturated or unsaturated,
nonaromatic, monovalent monocyclic group of 3 to 8 ring atoms in
which one or two ring atoms are heteroatom independently selected
from N, O, and S(O).sub.n, where n is an integer from 0 to 2, and
the remaining ring atoms are C, unless stated otherwise.
Additionally, one or two ring carbon atoms in the heterocyclyl ring
can optionally be replaced by a --C(.dbd.O)-- group. More
specifically the term heterocyclyl includes, but is not limited to,
pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl,
2-oxopiperidinyl, morpholino, piperazino, dihydropyranyl,
thiomorpholino, and the like. When the heterocyclyl ring is
unsaturated, it can contain one or two ring double bonds provided
that the ring is not aromatic. When the heterocyclyl group contains
at least one nitrogen atom (e.g., pyrrolidino, piperidino,
homopiperidino, morpholino, piperazino, thiomorpholino, and the
like), the heterocyclyl ring can also be referred to herein as
"heterocycloamino" and is a subset of the heterocyclyl group.
[0055] "Heterocyclyloxy" means --OR radical where R is heterocyclyl
as defined above, e.g., pyrrolidinyloxy, tetrahydrofuranyloxy, and
the like.
[0056] "Heterocyclylamino" means --NHR radical where R is
heterocyclyl as defined above, e.g., pyrrolidinylamino,
tetrahydrofuranylamino, piperidinylamino, and the like.
[0057] "Heteroaryl" means a monovalent monocyclic or bicyclic
aromatic radical of 5 to 10 ring atoms, unless otherwise stated,
where one or more, (in one embodiment, one, two, or three), ring
atoms are heteroatom independently selected from N, O, and S, and
the remaining ring atoms are carbon. Representative examples
include, but are not limited to, pyrrolyl, thienyl, thiazolyl,
imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl,
benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the
like. When the heteroaryl ring contains 5- or 6 ring atoms, it is
also referred to herein as 5- or 6-membered heteroaryl.
[0058] "Heteroaryloxy" means --OR radical where R is heteroaryl as
defined above, e.g., pyridinyloxy, furanyloxy, and the like.
[0059] "Oxo" means .dbd.(O) group. As would be readily apparent to
one of skill in the art, "carbonyl" refers to an oxo radical
attached to a carbon atom, i.e., --C(.dbd.O)--.
[0060] "Spiroheterocycloamino" means a saturated bicyclic ring
having 7 to 10 ring atoms in which one, two, or three ring atoms
are heteroatom selected from N, N-oxide, O, and S(O).sub.n, where n
is an integer from 0 to 2, the remaining ring atoms being C,
provided that at least one ring atom is N, and the rings are
connected through only one atom. The connecting atom is also called
the spiroatom, and is most often a quaternary carbon ("spiro
carbon").
[0061] The present disclosure also includes protected derivatives
of compounds of the present disclosure. For example, when compounds
of the present disclosure contain groups such as hydroxy, carboxy,
thiol or any group containing a nitrogen atom(s), these groups can
be protected with a suitable protecting group. A comprehensive list
of suitable protective groups can be found in T. W. Greene,
Protective Groups in Organic Synthesis, John Wiley & Sons, Inc.
(1999), the disclosure of which is incorporated herein by reference
in its entirety. The protected derivatives of compounds of the
present disclosure can be prepared by methods well known in the
art.
[0062] A "pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. Such salts
include:
[0063] acid addition salts, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
formic acid, acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,
4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,
and the like; or
[0064] salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic base such as ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine, and the like. It
is understood that the pharmaceutically acceptable salts are
non-toxic. Additional information on suitable pharmaceutically
acceptable salts can be found in Remington's Pharmaceutical
Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985,
which is incorporated herein by reference in its entirety.
[0065] The compounds of the present disclosure may have asymmetric
centers. Compounds of the present disclosure containing an
asymmetrically substituted atom may be isolated in optically active
or racemic forms. It is well known in the art how to prepare
optically active forms, such as by resolution of materials. All
chiral, diastereomeric, all mixtures of chiral or diastereomeric
forms, and racemic forms are within the scope of this disclosure,
unless the specific stereochemistry or isomeric form is
specifically indicated. It will also be understood by a person of
ordinary skill in the art that when a compound is denoted as (R)
stereoisomer, it may contain the corresponding (S) stereoisomer as
an impurity i.e., the (S) stereoisomer in less than about 5%,
preferably 2% by wt. and then it is denoted as a mixture of R and S
isomers, the amounts of R or S isomer in the mixture is greater
than about 5%, preferably 2% w/w.
[0066] Certain compounds of the present disclosure can exist as
tautomers and/or geometric isomers. All possible tautomers and cis
and trans isomers, as individual forms and mixtures thereof are
within the scope of this disclosure. Additionally, as used herein
the term alkyl includes all the possible isomeric forms of said
alkyl group albeit only a few examples are set forth. Furthermore,
when the cyclic groups such as aryl, heteroaryl, heterocyclyl are
substituted, they include all the positional isomers albeit only a
few examples are set forth. Furthermore, all hydrates of a compound
of the present disclosure are within the scope of this
disclosure.
[0067] "Optional" or "optionally" means that the subsequently
described event or circumstance may but need not occur, and that
the description includes instances where the event or circumstance
occurs and instances in which it does not. For example,
"heterocyclyl group optionally substituted with an alkyl group"
means that the alkyl may but need not be present, and the
description includes situations where the heterocyclyl group is
substituted with an alkyl group and situations where the
heterocyclyl group is not substituted with alkyl.
[0068] It is to be understood that where compounds disclosed herein
have unfilled valencies, then the valencies are to be filled with
hydrogen.
[0069] Also provided herein are isotopologues (isotopically labeled
analogues) of the compounds described herein. Substitution with
isotopes such as deuterium may afford certain therapeutic
advantages resulting from greater metabolic stability, such as, for
example, increased in vivo half-life or reduced dosage
requirements. In some embodiments, at any position of a compound
described herein, or a pharmaceutically acceptable salt thereof,
that has a hydrogen, the hydrogen atom can be replaced with
hydrogen-2 (deuterium) or hydrogen-3 (tritium). For example, one or
more of R.sub.1, R.sup.2, R.sup.a, R.sup.b and/or R.sup.4 can
include one or more deuteriums (such as 1, 2 or 3 deuteriums).
[0070] A "pharmaceutically acceptable carrier or excipient" means a
carrier or an excipient that is useful in preparing a
pharmaceutical composition that is generally safe, non-toxic and
neither biologically nor otherwise undesirable, and includes a
carrier or an excipient that is acceptable for veterinary use as
well as human pharmaceutical use. "A pharmaceutically acceptable
carrier/excipient" as used in the specification and claims includes
both one and more than one such excipient.
[0071] A "subject" refers to an animal that is the object of
treatment, observation or experiment. "Animal" includes cold- and
warm-blooded vertebrates and invertebrates such as fish, shellfish,
reptiles and, in particular, mammals. "Mammal" includes, without
limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep,
goats, cows, horses, primates, such as monkeys, chimpanzees and
apes, and, in particular, humans. In some embodiments, the subject
can be human. In some embodiments, the subject can be a child
and/or an infant, for example, a child or infant with a fever. In
other embodiments, the subject can be an adult.
"Treating" or "treatment" of a disease includes:
[0072] (1) preventing the disease, i.e., causing the clinical
symptoms of the disease not to develop in a subject that may be
exposed to or predisposed to the disease but does not yet
experience or display symptoms of the disease;
[0073] (2) inhibiting the disease, i.e., arresting or reducing the
development of the disease or its clinical symptoms; or
[0074] (3) relieving the disease, i.e., causing regression of the
disease or its clinical symptoms.
[0075] A "therapeutically effective amount" means the amount of a
compound of the present disclosure, or a pharmaceutically
acceptable salt thereof, that, when administered to a subject for
treating a disease, is sufficient to effect such treatment for the
disease. The "therapeutically effective amount" will vary depending
on the compound, the disease and its severity and the age, weight,
etc., of the subject to be treated.
Embodiments
[0076] In further embodiments 1-61 below, the present disclosure
includes: 1. In embodiment 1, the compounds of Formula (I), or a
pharmaceutically acceptable salt thereof, are as defined in the
Summary. With embodiment 1, in a group of compounds, or a
pharmaceutically acceptable salt thereof, Z is NR.sup.6. With
embodiment 1, in another group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.6 is H when Z is NR.sup.6. With
embodiment 1, in yet another group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.6 is alkyl, such as
methyl or ethyl when Z is NR.sup.6. With embodiment 1, in yet
another group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.6 is cycloalkyl when Z is NR.sup.6. With embodiment
1, in yet another group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.6 is cyclopropyl when Z is NR.sup.6.
2. In embodiment 2, the compounds of embodiment 1 and the group of
compounds contained therein, or a pharmaceutically acceptable salt
thereof, are those wherein X is CR.sup.1 and Y CR.sup.2 where
R.sup.1 is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or
cycloalkyl and R.sup.2 is hydrogen, alkyl, alkoxy, halo, haloalkyl,
haloalkoxy, or cycloalkyl. Within embodiment 2, in a group of
compounds, or a pharmaceutically acceptable salt thereof, X is
CR.sup.1 and Y is CR.sup.2, where R.sup.1 is hydrogen. Within
embodiment 2, in a group of compounds, or a pharmaceutically
acceptable salt thereof, X is CR.sup.1 and Y is CR.sup.2, where
R.sup.2 is hydrogen. Within embodiment 2, in another group of
compounds, or a pharmaceutically acceptable salt thereof, X is
CR.sup.1 and Y is CR.sup.2, where R.sup.1 and R.sup.2 are each
hydrogen. Within embodiment 2, in another group of compounds, or a
pharmaceutically acceptable salt thereof, X is CR.sup.1, where
R.sup.1 is alkyl (e.g., methyl, ethyl, n-propyl or iso-propyl), and
Y is CR.sup.2. Within embodiment 2, in another group of compounds,
or a pharmaceutically acceptable salt thereof, X is CR.sup.1, where
R.sup.1 is alkoxy (such as methoxy, ethoxy, n-propoxy and
iso-propoxy), and Y is CR.sup.2. Within embodiment 2, in another
group of compounds, or a pharmaceutically acceptable salt thereof,
X is CR.sup.1, where R.sup.1 is halo (such as fluoro, or chloro),
and Y is CR.sup.2. Within embodiment 2, in another group of
compounds, or a pharmaceutically acceptable salt thereof, X is
CR.sup.1, where R.sup.1 is haloalkyl (e.g., CF.sub.3), and Y is
CR.sup.2. Within embodiment 2, in another group of compounds, or a
pharmaceutically acceptable salt thereof, X is CR.sup.1, where
R.sup.1 is haloalkoxy (e.g., OCF.sub.3), and Y is CR.sup.2. Within
embodiment 2, in another group of compounds, or a pharmaceutically
acceptable salt thereof, X is CR.sup.1, where R.sup.1 is cycloalkyl
(such as cyclopropyl), and Y is CR.sup.2. Within the groups in
embodiment 2, in a group of compounds, X is CR.sup.1 and Y is CH.
Within the groups in embodiment 2, in a group of compounds, R.sup.1
is methoxy. Within embodiment 2, in another group of compounds, or
a pharmaceutically acceptable salt thereof, X is CR.sup.1, where
R.sup.1 is alkoxy (such as methoxy, ethoxy, n-propoxy and
iso-propoxy), and Y is CR.sup.2, where R.sup.2 is hydrogen. Within
embodiment 2, in another group of compounds, or a pharmaceutically
acceptable salt thereof, X is CR.sup.1, where R.sup.1 is methoxy,
and Y is CR.sup.2, where R.sup.2 is hydrogen. Within embodiment 2,
in another group of compounds, or a pharmaceutically acceptable
salt thereof, X is CR.sup.1 and Y is CR.sup.2, where R.sup.2 is
alkoxy (e.g., methoxy, ethoxy, n-propoxy or iso-propoxy). Within
embodiment 2, in another group of compounds, or a pharmaceutically
acceptable salt thereof, X is CR.sup.1 and Y is CR.sup.2, where
R.sup.1 is hydrogen and R.sup.2 is alkoxy (e.g., methoxy, ethoxy,
n-propoxy or iso-propoxy). Within embodiment 2, in another group of
compounds, or a pharmaceutically acceptable salt thereof, X is
CR.sup.1, where R.sup.1 is alkyl and Y is CR.sup.2. Within
embodiment 2, in another group of compounds, or a pharmaceutically
acceptable salt thereof, X is CR.sup.1, where R.sup.1 is alkyl
(e.g., methyl, ethyl, n-propyl or iso-propyl), and Y is CR.sup.2,
where R.sup.2 is hydrogen. 3. In embodiment 3, the compounds of
embodiment 1, or a pharmaceutically acceptable salt thereof, are
those wherein X is CR.sup.1 and Y is N. Within embodiment 3, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
X is CR.sup.1, where R.sup.1 is hydrogen, and Y is N. Within
embodiment 3, in another group of compounds, or a pharmaceutically
acceptable salt thereof, X is CR.sup.1, where R.sup.1 is alkyl
(e.g., methyl, ethyl, n-propyl or iso-propyl), and Y is N. Within
embodiment 3, in a group of compounds, or a pharmaceutically
acceptable salt thereof, X is CR.sup.1, where R.sup.1 is alkoxy
(for example, methoxy, ethoxy, n-propoxy or iso-propoxy), and Y is
N. Within embodiment 3, in another group of compounds, or a
pharmaceutically acceptable salt thereof, X is CR.sup.1, where
R.sup.1 is halo (such as fluoro, or chloro), and Y is N. Within
embodiment 3, in another group of compounds, or a pharmaceutically
acceptable salt thereof, X is CR.sup.1, where R.sup.1 is haloalkyl
(e.g., CF.sub.3), and Y is N. Within embodiment 3, in another group
of compounds, or a pharmaceutically acceptable salt thereof, X is
CR.sup.1, where R.sup.1 is haloalkoxy (e.g., OCF.sub.3), and Y is
N. Within embodiment 3, in another group of compounds, or a
pharmaceutically acceptable salt thereof, X is CR.sup.1, where
R.sup.1 is cycloalkyl (such as cyclopropyl), and Y is N. 4. In
embodiment 4, the compounds of embodiment 1, 2 or 3, or a
pharmaceutically acceptable salt thereof, are those wherein Q is N,
and P, T, and U are CH or C (when R.sup.4 or R.sup.5 is attached).
Within embodiment 4, in a group of compounds, or a pharmaceutically
acceptable salt thereof, P is CR.sup.4. Within the groups in
embodiment 4, in another group of compounds, P is CR.sup.4 and T is
CR.sup.5. Within the groups in embodiment 4, in another group of
compounds, P is CR.sup.4 and T is CH. Within the groups in
embodiment 4, in another group of compounds, P is CR.sup.4 and U is
CR.sup.5. Within the groups in embodiment 4, in another group of
compounds, P is CR.sup.4 and U is CH. 5. In embodiment 5, the
compounds of embodiment 1, 2 or 3, or a pharmaceutically acceptable
salt thereof, are those wherein Q and U are each N, and P and T are
each CH or C (when R.sup.4 or R.sup.5 is attached). Within the
groups in embodiment 5, in another group of compounds, P is
CR.sup.4 and T is CR.sup.5. Within the groups in embodiment 5, in
another group of compounds, P is CR.sup.4 and T is CH. 6. In
embodiment 6, the compounds of embodiment 1, 2 or 3, or a
pharmaceutically acceptable salt thereof, are those wherein P is N
(nitrogen); and Q, T, and U are each CH. 7. In embodiment 7, the
compounds of embodiment 1, 2 or 3, or a pharmaceutically acceptable
salt thereof, are those wherein P, Q and U are each CH; and T is N
(nitrogen). 8. In embodiment 8, the compounds of embodiment 1, 2 or
3, or a pharmaceutically acceptable salt thereof, are those wherein
P and T are each N (nitrogen); and Q and U are each CH. 9. In
embodiment 9, the compounds of embodiment 1, 2 or 3, or a
pharmaceutically acceptable salt thereof, are those wherein P is C
(wherein R.sup.4 is attached); Q is N (nitrogen); and T and U are
each CH. 10. In embodiment 10, the compounds of embodiment 1, 2 or
3, or a pharmaceutically acceptable salt thereof, are those wherein
P, T and U are each CH; and Q is N (nitrogen). 11. In embodiment
11, the compounds of embodiment 1, 2 or 3, or a pharmaceutically
acceptable salt thereof, are those wherein P, Q and T are each CH;
and U is N (nitrogen). 12. In embodiment 12, the compounds of
embodiment 1, 2 or 3, or a pharmaceutically acceptable salt
thereof, are those wherein P and U are each CH; T is C (wherein
R.sup.5 is attached) and Q is N (nitrogen). 13. In embodiment 13,
the compounds of embodiment 1, 2 or 3, or a pharmaceutically
acceptable salt thereof, are those wherein P is C (wherein R.sup.4
is attached); Q is N (nitrogen); T is C (wherein R.sup.5 is
attached); and U is CH. 14. In embodiment 14, the compounds of
embodiment 1, 2 or 3, or a pharmaceutically acceptable salt
thereof, are those wherein P and T are each CH; Q and U is N
(nitrogen). 15. In embodiment 15, the compounds of embodiment 1, 2
or 3, or a pharmaceutically acceptable salt thereof, are those
wherein P and Q are each CH; T is C (wherein R.sup.5 is attached);
and U is N (nitrogen). 16. In embodiment 16, the compounds of
embodiment 1, 2 or 3, or a pharmaceutically acceptable salt
thereof, are those wherein P is C (wherein R.sup.4 is attached); Q
is N (nitrogen); T is CH; and U is C (wherein R.sup.5 is attached).
17. In embodiment 17, the compounds of embodiment 1, 2 or 3, or a
pharmaceutically acceptable salt thereof, are those wherein P is C
(wherein R.sup.4 is attached); Q is N (nitrogen); T is CH; and U is
N (nitrogen). 18. In embodiment 18, the compounds of embodiment 1,
2 or 3, or a pharmaceutically acceptable salt thereof, are those
wherein P is C (wherein R.sup.4 is attached); Q is N (nitrogen); T
is CR.sup.5 (wherein R.sup.5 is attached); and U is N (nitrogen).
19. In embodiment 19, the compounds of embodiment 1, 2 or 3, or a
pharmaceutically acceptable salt thereof, are those wherein Q is N
(nitrogen); and P, T, and U are independently CH or C (when R.sup.4
or R.sup.5 is attached). 20. In embodiment 20, the compounds of
embodiment 1, 2 or 3, or a pharmaceutically acceptable salt
thereof, are those wherein Q is N (nitrogen); and P, T, and U are
independently CH or C (when R.sup.4 or R.sup.5 is attached). Within
embodiment 20, in a group of compounds, or a pharmaceutically
acceptable salt thereof, P is CR.sup.4. Within embodiment 20, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
T is CH. Within embodiment 20, in another group of compounds, or a
pharmaceutically acceptable salt thereof, T is CR.sup.5. Within
embodiment 20, in a group of compounds, or a pharmaceutically
acceptable salt thereof, U is CH. Within embodiment 20, in another
group of compounds, or a pharmaceutically acceptable salt thereof,
U is CR.sup.5. Within embodiment 20, in another group of compounds,
or a pharmaceutically acceptable salt thereof, T and U are each CH.
21. In embodiment 21, the compounds of any one of embodiments 1 to
20 and groups contained therein, or a pharmaceutically acceptable
salt thereof, are those wherein R.sup.3 is --W-alkylene-R.sup.7,
where W is bond. 22. In embodiment 22, the compounds of any one of
embodiments 1 to 20 and groups contained therein, or a
pharmaceutically acceptable salt thereof, are those wherein R.sup.3
is --W-alkylene-R.sup.7, where W is NH. 23. In embodiment 23, the
compounds of any one of embodiments 1 to 20 and groups contained
therein, or a pharmaceutically acceptable salt thereof, are those
wherein R.sup.3 is --W-alkylene-R.sup.7, where W is O (oxygen). 24.
In embodiment 24, the compounds of any one of embodiments 1 to 20
and groups contained therein, or a pharmaceutically acceptable salt
thereof, are those wherein R.sup.3 is --W-alkylene-R.sup.7, where W
is S (sulfur). 25. In embodiment 25, the compounds of any one of
embodiments 21 to 24 and groups contained therein, or a
pharmaceutically acceptable salt thereof, are those wherein the
alkylene is an unsubstituted alkylene (such as an unsubstituted
C.sub.1-4 alkylene). 26. In embodiment 26, the compounds of any one
of embodiments 21 to 24 and groups contained therein, or a
pharmaceutically acceptable salt thereof, are those wherein the
alkylene is a substituted alkylene substituted with R.sup.8,
wherein R.sup.8 is halo (such as fluoro or chloro), haloalkyl
(e.g., --CH.sub.2Cl, --CF.sub.3, --CHF.sub.2, --CH.sub.2CF.sub.3,
and --CF.sub.2CF.sub.3), haloalkoxy (such as --OCF.sub.3,
--OCH.sub.2Cl, --OCHF.sub.2, --OCH.sub.2CF.sub.3, and
--OCF.sub.2CF.sub.3), hydroxy, or alkoxy (for example, methoxy,
ethoxy, n-propoxy or iso-propoxy), and/or one CH.sub.2 in the
alkylene is optionally replaced with NH or O (oxygen). Within
embodiment 26, in a group of compounds, or a pharmaceutically
acceptable salt thereof, wherein the one CH.sub.2 in the alkylene
being replaced is the CH.sub.2 after the first CH.sub.2 in the
alkylene after W. For example, replacement of the CH.sub.2 after
the first CH.sub.2 in the alkylene after W with an oxygen wherein
the alkylene initially is 3 carbons in length prior to replacement
(i.e., the second CH.sub.2 in the initial alkylene after W) would
result in a radical having the formula --CH.sub.2O--CH.sub.2--*,
wherein the * indicates the point of attachment to R.sup.7. Within
embodiment 26, in a group of compounds, or a pharmaceutically
acceptable salt thereof, wherein the one CH.sub.2 in the alkylene
being replaced is the CH.sub.2 after the second CH.sub.2 in the
alkylene after W. An example of replacing the CH.sub.2 after the
second CH.sub.2 in the alkylene after W is
--CH.sub.2CH.sub.2O--CH.sub.2--*, wherein the replacement is with
an oxygen, the initial alkylene is 4 carbons in length prior to
replacement and the * indicates the point of attachment to R.sup.7.
27. In embodiment 27, the compounds of embodiment 21, 23, 25 or 26
and groups contained therein, or a pharmaceutically acceptable salt
thereof, are those wherein --W-alkylene- in R.sup.3 is
--(CH.sub.2).sub.2--*, --(CH.sub.2).sub.3--*,
--(CH.sub.2).sub.4--*, --CH.sub.2CH(CH.sub.3)CH.sub.2--*,
*--CH.sub.2CH(CH.sub.3)CH.sub.2--, --O--(CH.sub.2)--*,
--O--(CH.sub.2).sub.2--*,
--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--*,
--O--(CH.sub.2).sub.3--*, --OCH.sub.2CH(F)CH.sub.2--*,
--OCH.sub.2CH(OH)CH.sub.2--*, --OCH.sub.2CH(OCH.sub.3)CH.sub.2--*,
or --OCH.sub.2CH(OCF.sub.3)CH.sub.2--*, wherein the * indicates the
point of attachment to R.sup.7. Within embodiment 27, in a group of
compounds, or a pharmaceutically acceptable salt thereof, wherein
--W-alkylene- is --(CH.sub.2).sub.2--*, --(CH.sub.2).sub.3--*,
--(CH.sub.2).sub.4--*, --CH.sub.2CH(CH.sub.3)CH.sub.2--*,
--O--(CH.sub.2).sub.2--*, or --O--(CH.sub.2).sub.3--*, wherein the
* indicates the point of attachment to R.sup.7. Within embodiment
27, in a group of compounds, or a pharmaceutically acceptable salt
thereof, wherein --W-alkylene- is --O--(CH.sub.2).sub.3--*, wherein
the * indicates the point of attachment to R.sup.7. 28. In
embodiment 28, the compounds of any one of embodiments 21 to 27 and
groups contained therein, or a pharmaceutically acceptable salt
thereof, are those wherein R.sup.7 is --NR.sup.aR.sup.b, where
R.sup.a and R.sup.b are independently hydrogen, alkyl, or
haloalkyl. Within embodiment 28, in a group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.7 is
--NR.sup.aR.sup.b, where --NR.sup.aR.sup.b is NH.sub.2,
methylamino, ethylamino, dimethylamino, diethylamino,
diisopropylamino or (ethyl)(methyl)amino.
29. In embodiment 29, the compounds of any one of embodiments 21 to
27 and groups contained therein, or a pharmaceutically acceptable
salt thereof, are those wherein R.sup.7 is --NR.sup.aR.sup.b, where
R.sup.a and R.sup.b together with the nitrogen to which they are
attached form heterocycloamino, bridged heterocycloamino, or
spiroheterocycloamino, wherein the heterocycloamino, the bridged
heterocycloamino and the spiroheterocycloamino are optionally
substituted with one or two substituents independently selected
from alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy.
Within embodiment 29, in a group of compounds, or a
pharmaceutically acceptable salt thereof, the heterocycloamino can
be unsubstituted. Within embodiment 29, in another group of
compounds, or a pharmaceutically acceptable salt thereof, the
heterocycloamino can be substituted with one or two substituents
independently selected from alkyl (such as methyl, ethyl, n-propyl
or iso-propyl), halo (e.g., as fluoro or chloro), haloalkyl (e.g.,
--CH.sub.2Cl, --CF.sub.3, --CHF.sub.2, --CH.sub.2CF.sub.3, and
--CF.sub.2CF.sub.3), hydroxy, alkoxy (for example, methoxy, ethoxy,
n-propoxy or iso-propoxy) and haloalkoxy (such as --OCF.sub.3,
--OCH.sub.2Cl, --OCHF.sub.2, --OCH.sub.2CF.sub.3, and
--OCF.sub.2CF.sub.3). Within embodiment 29, in a group of
compounds, or a pharmaceutically acceptable salt thereof, the
heterocycloamino can be azetidin-1-yl, pyrrolidin-1-yl,
piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl
or 3-azabicyclo[3.1.1]heptan-3-yl, each heterocycloamino optionally
substituted with one or two substituents independently selected
from alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy, such
as methyl, hydroxy, methoxy, and fluoro. Within embodiment 29, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.7 is --NR.sup.aR.sup.b, where R.sup.a and R.sup.b together
with the nitrogen to which they are attached form pyrrolidin-1-yl,
3(S)-fluoropyrrolidin-1-yl, 3 (R)-fluoropyrrolidin-1-yl,
2-methylpyrrolidin-1-yl, 3,5-dimethylpyrrolidin-1-yl, or
3,3-dimethylpyrrolidin-1-yl. Within embodiment 29, in other group
of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.7 is --NR.sup.aR.sup.b, where R.sup.a and R.sup.b together
with the nitrogen to which they are attached form pyrrolidin-1-yl.
30. In embodiment 30, the compounds of any one of embodiments 21 to
27 and groups contained therein, or a pharmaceutically acceptable
salt thereof, are those wherein R.sup.7 is heterocyclyl that is
attached to the alkylene at a ring carbon atom and is optionally
substituted with one or two substituents independently selected
from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy. Within
embodiment 30, in a group of compounds, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 is a nitrogen-containing
heterocyclyl. For example, the heterocyclyl for R.sup.7 can be
pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl,
2-oxopiperidinyl, morpholino, piperazino, dihydropyranyl, or
thiomorpholino. Within embodiment 30, in a group of compounds, or a
pharmaceutically acceptable salt thereof, wherein R.sup.7 is an
unsubstituted heterocyclyl, such as an unsubstituted
nitrogen-containing heterocyclyl. Within embodiment 30, in another
group of compounds, or a pharmaceutically acceptable salt thereof,
wherein R.sup.7 is a substituted heterocyclyl, such as a
substituted nitrogen-containing heterocyclyl, where the
heterocyclyl is one or two substituents independently selected from
alkyl (such as methyl, ethyl, n-propyl or iso-propyl), halo (e.g.,
as fluoro or chloro), haloalkyl (e.g., --CH.sub.2Cl, --CF.sub.3,
--CHF.sub.2, --CH.sub.2CF.sub.3, and --CF.sub.2CF.sub.3), hydroxy,
alkoxy (for example, methoxy, ethoxy, n-propoxy or iso-propoxy) and
haloalkoxy (such as --OCF.sub.3, --OCH.sub.2Cl, --OCHF.sub.2,
--OCH.sub.2CF.sub.3, and --OCF.sub.2CF.sub.3). Within embodiment
30, in a group of compounds, or a pharmaceutically acceptable salt
thereof, wherein R.sup.7 is piperidin-3-yl optionally substituted
with alkyl. 31. In embodiment 31, the compounds of any one of
embodiments 1 to 20 and groups contained therein, or a
pharmaceutically acceptable salt thereof, are those wherein R.sup.3
is --O--(CH.sub.2).sub.3-pyrrolidin-1-yl,
--O--(CH.sub.2).sub.3-piperidin-1-yl,
--O--(CH.sub.2)-piperidin-3-yl, or
--O--(CH.sub.2).sub.3-morpholin-4-yl, wherein pyrrolidin-1-yl,
piperidin-1-yl, piperidin-3-yl and morpholin-4-yl are each
optionally substituted with one or two substituents independently
selected from methyl, hydroxy, methoxy, and fluoro. 32. In
embodiment 32, the compounds of any one of embodiments 1 to 24 and
groups contained therein, or a pharmaceutically acceptable salt
thereof, are those wherein --W-alkylene- in R.sup.3 is
--(CH.sub.2)--O--(CH.sub.2).sub.2--*, or
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--*, wherein the * indicates
the point of attachment to --NR.sup.aR.sup.b. Within embodiment 32,
in a group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.7 is --NR.sup.aR.sup.b, where --NR.sup.aR.sup.b is
NH.sub.2, methylamino, ethylamino, dimethylamino, or diethylamino.
Within embodiment 32, in another group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.7 is
--NR.sup.aR.sup.b, where --NR.sup.aR.sup.b together with the
nitrogen to which they are attached form heterocycloamino wherein
the heterocycloamino is optionally substituted with one or two
substituents independently selected from alkyl, halo, haloalkyl,
hydroxy, alkoxy and haloalkoxy. Within embodiment 32, in another
group of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.7 is --NR.sup.aR.sup.b, where --NR.sup.aR.sup.b together with
the nitrogen to which they are attached form a saturated
heterocycloamino (such as azetidin-1-yl, pyrrolidin-1-yl,
piperidin-1-yl, morpholin-4-yl, or thiomorpholin-4-yl), optionally
substituted with one or two substituents independently selected
from methyl, hydroxy, methoxy, and fluoro. Within embodiment 32, in
another group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.3 is
--(CH.sub.2)--O--(CH.sub.2).sub.2-pyrrolidin-1-yl,
--(CH.sub.2)--O--(CH.sub.2).sub.2-piperidin-1-yl, or
--(CH.sub.2)--O--(CH.sub.2).sub.2-morpholin-4-yl, wherein the
pyrrolidin-1-yl, the piperidin-1-yl, and the morpholin-4-yl are
each optionally substituted with one or two substituents
independently selected from methyl, hydroxy, methoxy, and fluoro.
Within embodiment 32, in yet another group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.3 is
--(CH.sub.2)--O--(CH.sub.2).sub.2--NR.sup.aR.sup.b, where
NR.sup.aR.sup.b is pyrrolidin-1-yl,
3-hydroxy-3-methylpyrrolidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl,
3-fluoroazetidinyl, 3-fluoropyrrolidinyl, 3 (R)-fluoropyrrolidinyl,
3(S)-fluoropyrrolidinyl, 3,5-dimethylpyrrodin-1-yl, or
3,3-dimethylpyrrodin-1-yl, preferably pyrrolidin-1-yl. 33. In
embodiment 33, the compounds of any one of embodiments 1 to 32 and
groups contained therein, or a pharmaceutically acceptable salt
thereof, are those wherein w is 0. 34. In embodiment 34, the
compounds of any one of embodiments 1 to 32 and groups contained
therein, or a pharmaceutically acceptable salt thereof, are those
wherein w is 1. With embodiment 34, in a group of compounds, or a
pharmaceutically acceptable salt thereof, are those wherein R.sup.5
is NH.sub.2, halo, alkyl, hydroxy, alkoxy, cycloalkyl, or
hydroxyalkyl. Within embodiment 34, in a group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.5 is hydroxy,
NH.sub.2, fluoro, chloro, methyl, ethyl, hydroxy, methoxy,
cyclopropyl, cyclopentyl, or hydroxymethyl. Within embodiment 34,
in another group of compounds, or a pharmaceutically acceptable
salt thereof, R.sup.5 is NH.sub.2. Within embodiment 34, in another
group of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.5 is alkyl (such as a C.sub.1-6 alkyl). Within embodiment 34,
in a group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.5 is methyl. Within embodiment 34, in another group
of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.5 is cycloalkyl (for example a C.sub.3-6 alkyl). Within
embodiment 34, in a group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.5 is cyclopropyl. Within embodiment
34, in another group of compounds, or a pharmaceutically acceptable
salt thereof, R.sup.5 is halo (e.g., a fluoro or chloro). Within
embodiment 34, in another group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.5 is hydroxy or hydroxyalkyl
(hydroxy(C.sub.1-4 alkyl)). Within embodiment 34, in a group of
compounds, or a pharmaceutically acceptable salt thereof, R.sup.5
is hydroxymethyl. Within embodiment 34, in another group of
compounds, or a pharmaceutically acceptable salt thereof, R.sup.5
is alkoxy (such as a C.sub.1-6 alkoxy). Within embodiment 34, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.5 is methoxy. 35. In embodiment 35, the compounds of any one
of embodiments 1 to 34 and groups contained therein, or a
pharmaceutically acceptable salt thereof, are those wherein v is 0.
Within embodiment 35, in a group of compounds, or a
pharmaceutically acceptable salt thereof, w is 0. Within embodiment
35, in a group of compounds, or a pharmaceutically acceptable salt
thereof, w is 1. When w is 1, in a group or compounds, or a
pharmaceutically acceptable salt thereof, R.sup.5 can be selected
from any of the groups of compounds, or a pharmaceutically
acceptable salt thereof, provided within embodiment 34. 36. In
embodiment 36, the compounds of any one of embodiments 1 to 34 and
groups contained therein, or a pharmaceutically acceptable salt
thereof, are those wherein v is 1. Within embodiment 36, in a group
of compounds, or a pharmaceutically acceptable salt thereof, w is
0. Within embodiment 36, in a group of compounds, or a
pharmaceutically acceptable salt thereof, w is 1. When w is 1, in a
group or compounds, or a pharmaceutically acceptable salt thereof,
R.sup.5 can be selected from any of the groups of compounds, or a
pharmaceutically acceptable salt thereof, provided within
embodiment 34. 37. In embodiment 37, the compounds of embodiment 36
and groups contained therein, or a pharmaceutically acceptable salt
thereof, are those wherein R.sup.4 is hydroxy. 38. In embodiment
38, the compounds of embodiment 36 and groups contained therein, or
a pharmaceutically acceptable salt thereof, are those wherein
R.sup.4 is alkyl, cycloalkyl, cycloalkenyl, halo, haloalkoxy,
alkoxy, cyano, NH.sub.2, NR.sup.cR.sup.d, alkoxyalkylamino,
hydroxyalkylamino, aminoalkylamino, hydroxyalkyl, alkoxyalkyl,
alkylthio, alkoxyalkyloxy, phenyl, heteroaryl, heteroaryloxy,
heterocyclyl, heterocyclyloxy, 5-8 membered bridged
heterocycloamino or spiroheterocycloamino, wherein the phenyl, the
heteroaryl, and the heterocyclyl either alone or a part of another
group are optionally substituted with one, two, or three
substituents independently selected from alkyl, halo, haloalkyl,
haloalkoxy, hydroxy, alkoxy, NH.sub.2, alkylamino, dialkylamino,
carboxy, carboxyalkyl, and alkoxycarbonyl, and wherein the alkyl of
R.sup.4 is optionally substituted with unsubstituted cycloalkyl;
R.sup.c is hydrogen, alkyl, cycloalkyl, or heterocyclyl; and
R.sup.d is alkyl, cycloalkyl, or heterocyclyl; or R.sup.c and
R.sup.d together with the nitrogen to which they are attached form
a 4- to 7-membered heterocycloamino. Within embodiment 38, in
another group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.4 is alkyl or cycloalkyl. Within embodiment 38, in
another group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.4 is NH.sub.2, NR.sup.cR.sup.d, alkoxyalkylamino,
hydroxyalkylamino or aminoalkylamino. Within embodiment 38, in
another group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.4 is heteroaryl, heterocyclyl, 5-8 membered bridged
heterocycloamino or spiroheterocycloamino, wherein the heteroaryl
and the heterocyclyl either alone or as part of another group are
optionally substituted with one, two, or three substituents
independently selected from alkyl, halo, haloalkyl, haloalkoxy,
hydroxy, alkoxy, NH.sub.2, alkylamino, dialkylamino, carboxy,
carboxyalkyl, and alkoxycarbonyl. Within embodiment 38, in another
group of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.4 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, ethynyl,
fluoro, chloro, cyclopropyl, 1-methylcyclopropyl, cyclobutyl,
cyclopentyl, cyclopent-1-en-1-yl, 2-cyclopropylethynyl,
2-cyclopropylethenyl, 2-cyclopropylethyl, pyrrolidin-1-yl,
3-hydroxypyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl,
2,2-dimethylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl,
2-(carboxymethyl)pyrrolidin-1-yl, 2-carboxypyrrolidin-1-yl,
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, piperidin-1-yl,
piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,
4-hydroxypiperidin-1-yl, morpholin-4-yl, oxetan-3-yl, oxetan-2-yl,
oxan-2-yl, oxan-3-yl oxan-4-yl, tetrahydropyran-4-yl,
1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl,
tetrahydrofuran-3-yl, azetidine-1-yl, 3-hydroxyazetidin-1-yl,
pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, oxan-4-yloxy,
pyrrolidin-3-yloxy, 2-ethoxyeth-1-yl, 3-methoxyprop-1-yl,
methylamino, ethylamino, n-propylamino, n-butylamino,
isopropylamino, isobutylamino, tertbutylamino, cyclopropylamino,
cyclobutylamino, cyclopentylamino, cyclohexylamino,
cycloheptylamino, (cyclopropylmethyl)amino,
(cyclobutylmethyl)amino, (cyclopentylmethyl)amino,
(cyclohexylmethyl)amino, dimethylamino, diethylamino,
dimethylamino, di-(n-propyl)amino, di-(isopropyl)amino,
di-(n-butyl)amino, di-(isobutyl)amino, di-(tertbutyl)amino,
(methyl)(ethyl)amino, 2-ethoxyethylamino, 3-methoxyprop-2-ylamino,
thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyrazol-1-yl,
pyrazol-3-yl, pyrazol-4-yl, imidazole-1-yl, imidazole-2-yl,
imidazole-4-yl, imidazole-5-yl, oxazol-5-yl, oxazol-2-yl,
oxazol-4-yl, 1,2,4-triazol-5-yl, 1,2,4-triazol-3-yl,
1,2,4-triazol-1-yl, hydroxymethyl, 4-difluoromethoxyphenyl,
3-difluoromethoxyphenyl, 2-difluoromethoxypyridin-4-yl,
6-difluoromethoxypyridin-3-yl, 4-methylaminopyridin-2-yl,
2-methylaminopyridin-4-yl, 6-methylamino-pyridin-2-yl,
4-difluoromethylphenyl, 2-hydroxyprop-2-yl,
4-(2-hydroxypropyl)phenyl, 4-(2-hydroxypropan-2-yl)phenyl,
2-(carboxymethyl)phenyl, 2-carboxyphenyl, 2-methoxyethoxy, methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy and
tert-butoxy, hydroxy, methylsulfenyl,
3-hydroxy-3-methylbut-1-yn-1-yl, 3-hydroxy-3-methylbut-1-en-1-yl,
3-hydroxy-3-methylbutyl, 2-hydroxypropan-2-yl,
1-azaspiro[3,4]octan-1-yl, 4-azaspiro[2,4]heptan-4-yl,
5-azaspiro[3,4]octan-5-yl, 1-azaspiro[3,3]heptan-1-yl,
2-oxa-5-azaspiro[3,4]octan-5-yl, 6-oxa-1-azaspiro[3,3]heptan-1-yl,
6-oxa-1-azaspiro[3,4]octan-1-yl, 7-oxa-1-azaspiro[4,4]nonan-1-yl,
8-oxa-3-azabicyclo[3.2.1]octan-3-yl, or
7,7-dioxido-7-thia-1-azaspiro[4.4]nonan-1-yl. Within embodiment 38,
in another group of compounds, or a pharmaceutically acceptable
salt thereof, R
.sup.4 is methyl, ethyl, n-propyl, isopropyl, or tert-butyl. Within
embodiment 38, in another group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.4 is methyl, ethyl, n-propyl, or
isopropyl. Within embodiment 38, in another group of compounds, or
a pharmaceutically acceptable salt thereof, R.sup.4 is cyclopropyl,
1-methylcyclopropyl, cyclobutyl, or cyclopentyl. Within embodiment
38, in another group of compounds, or a pharmaceutically acceptable
salt thereof, R.sup.4 is cyclopropyl. Within embodiment 38, in
another group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.4 is pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,
2-isopropylpyrrolidin-1-yl, 2,2-dimethylpyrrolidin-1-yl,
2-isopropylpyrrolidin-1-yl, 2-(carboxymethyl)pyrrolidin-1-yl,
2-carboxypyrrolidin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,
4-hydroxypiperidin-1-yl, morpholin-4-yl, oxetan-3-yl, oxetan-2-yl,
oxan-2-yl, oxan-3-yl oxan-4-yl, tetrahydropyran-4-yl,
1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl,
tetrahydrofuran-3-yl, azetidine-1-yl, 3-hydroxyazetidin-1-yl,
thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyrazol-1-yl,
pyrazol-3-yl, pyrazol-4-yl, imidazole-1-yl, imidazole-2-yl,
imidazole-4-yl, imidazole-5-yl, oxazol-5-yl, oxazol-2-yl,
oxazol-4-yl, 1,2,4-triazol-5-yl, 1,2,4-triazol-3-yl,
1,2,4-triazol-1-yl, hydroxymethyl, 4-difluoromethoxyphenyl,
3-difluoromethoxyphenyl, 2-difluoromethoxypyridin-4-yl,
6-difluoromethoxypyridin-3-yl, 4-methylaminopyridin-2-yl,
2-methylaminopyridin-4-yl, or 6-methylamino-pyridin-2-yl. Within
embodiment 38, in another group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.4 is pyrrolidin-1-yl,
3-hydroxypyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl,
2,2-dimethylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl,
2-(carboxymethyl)pyrrolidin-1-yl, or 2-carboxypyrrolidin-1-yl.
Within embodiment 38, in another group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.4 is
pyrrolidin-1-yl. Within embodiment 38, in another group of
compounds, or a pharmaceutically acceptable salt thereof, R.sup.4
is 1-azaspiro[3,4]octan-1-yl, 4-azaspiro[2,4]heptan-4-yl,
5-azaspiro[3,4]octan-5-yl, 1-azaspiro[3,3]heptan-1-yl,
2-oxa-5-azaspiro[3,4]octan-5-yl, 6-oxa-1-azaspiro[3,3]heptan-1-yl,
6-oxa-1-azaspiro[3,4]octan-1-yl, 7-oxa-1-azaspiro[4,4]nonan-1-yl,
8-oxa-3-azabicyclo[3.2.1]octan-3-yl, or
7,7-dioxido-7-thia-1-azaspiro[4.4]nonan-1-yl. Within embodiment 38,
in another group of compounds, or a pharmaceutically acceptable
salt thereof, R.sup.4 is methylamino, ethylamino, n-propylamino,
n-butylamino, isopropylamino, isobutylamino, tertbutylamino,
cyclopropylamino, cyclobutylamino, cyclopentylamino,
cyclohexylamino, cycloheptylamino, (cyclopropylmethyl)amino,
(cyclobutylmethyl)amino, (cyclopentylmethyl)amino,
(cyclohexylmethyl)amino, dimethylamino, diethylamino,
dimethylamino, di-(n-propyl)amino, di-(isopropyl)amino,
di-(n-butyl)amino, di-(isobutyl)amino, di-(tertbutyl)amino, or
(methyl)(ethyl)amino. 39. In embodiment 39, the compounds of
embodiment 1, or a pharmaceutically acceptable salt thereof, are
those wherein Z is R.sup.6, wherein R.sup.6 is hydrogen; X is
CR.sup.1; Y is CR.sup.2, P is CH or CR.sup.4; Q is N; T is CH or
CR.sup.5; U is CH or N; R.sup.1 and R.sup.2 are independently
hydrogen or methoxy; R.sup.3 is --O--(CH.sub.2).sub.2--R.sup.7,
--O--(CH.sub.2).sub.3--R.sup.7 or --O--(CH.sub.2).sub.4--R.sup.7;
R.sup.7 is --NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b are
independently methyl, ethyl, n-propyl or isopropyl, or
--NR.sup.aR.sup.b together with the nitrogen to which they are
attached form a 4-membered heterocycloamino or a 5-membered
heterocycloamino wherein each heterocycloamino is optionally
substituted with one or two substituents independently selected
from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy;
R.sup.4 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
cyclobutyl, cyclopentyl, heterocyclyl, NH.sub.2, or
NR.sup.cR.sup.d, wherein the cyclopropyl, the cyclobutyl, and the
cyclopentyl are optionally substituted with one, two, or three
substituents independently selected from alkyl, halo, haloalkyl,
haloalkoxy, hydroxy, alkoxy, NH.sub.2, alkylamino, dialkylamino,
carboxy, carboxyalkyl, and alkoxycarbonyl; R.sup.5 is NH.sub.2;
R.sup.c is hydrogen, alkyl, cycloalkyl, or heterocyclyl; and
R.sup.d is alkyl, cycloalkyl or heterocyclyl; or R.sup.c and
R.sup.d together with the nitrogen to which they are attached form
a 4- to 7-membered heterocycloamino. Within embodiment 39, when X
is CR.sup.1; Y is CR.sup.2, P is CH or CR.sup.4; Q is N; T is CH or
CR.sup.5; and U is CH or N, the compound of Formula (I) has the
following structure (hereinafter referred to as a "compound of
Formula (Ia), or a pharmaceutically acceptable salt thereof"):
##STR00002##
Within embodiment 39, in a group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.1 is methoxy and
R.sup.2 is hydrogen. Within embodiment 39, in another group of
compounds, or a pharmaceutically acceptable salt thereof, R.sup.1
is hydrogen and R.sup.2 is methoxy. Within embodiment 39, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.3 is --O--(CH.sub.2).sub.2--R.sup.7. Within embodiment 39, in
another group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.3 is --O--(CH.sub.2).sub.3--R.sup.7. Within
embodiment 39, in another group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.3 is --O--(CH.sub.2).sub.4--R.sup.7.
Within embodiment 39, in a group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.7 is
--NR.sup.aR.sup.b, where R.sup.a and R.sup.b are independently
methyl, ethyl, n-propyl or isopropyl. Within embodiment 39, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.7 is --NR.sup.aR.sup.b, where R.sup.a and R.sup.b are
independently methyl, ethyl, n-propyl or isopropyl. Within
embodiment 39, in a group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.a and R.sup.b are each methyl.
Within embodiment 39, in another group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.7 is
--NR.sup.aR.sup.b, wherein --NR.sup.aR.sup.b together with the
nitrogen to which they are attached form a 4-membered
heterocycloamino or a 5-membered heterocycloamino wherein each
heterocycloamino is optionally substituted with one or two
substituents independently selected from alkyl, halo, haloalkyl,
hydroxy, alkoxy and haloalkoxy. Within embodiment 39, in a group of
compounds, or a pharmaceutically acceptable salt thereof,
NR.sup.aR.sup.b together with the nitrogen to which they are
attached form pyrrolidin-1-yl. Within embodiment 39, in another
group of compounds, or a pharmaceutically acceptable salt thereof,
NR.sup.aR.sup.b together with the nitrogen to which they are
attached form azetidin-1-yl. Within embodiment 39, in a group of
compounds, or a pharmaceutically acceptable salt thereof, v is 0
and w is 0. Within embodiment 39, in another group of compounds, or
a pharmaceutically acceptable salt thereof, v is 1 and w is 0.
Within embodiment 39, in a group of compounds, or a
pharmaceutically acceptable salt thereof, v is 0 and w is 1. Within
embodiment 39, in another group of compounds, or a pharmaceutically
acceptable salt thereof, v is 1 and w is 1. Within embodiment 39,
in a group of compounds, or a pharmaceutically acceptable salt
thereof, P is CH. Within embodiment 39, in a group of compounds, or
a pharmaceutically acceptable salt thereof, P is CR.sup.4, wherein
R.sup.4 is methyl, ethyl, n-propyl, or isopropyl. Within embodiment
39, in a group of compounds, or a pharmaceutically acceptable salt
thereof, P is CR.sup.4, wherein R.sup.4 is cyclopropyl, cyclobutyl,
or cyclopentyl, wherein the cyclopropyl, the cyclobutyl, or the
cyclopentyl are optionally substituted with one, two, or three
substituents independently selected from alkyl (such as C.sub.1-4
alkyl), halo (such as F), haloalkyl (such as CF.sub.3), haloalkoxy
(such as OCF.sub.3), hydroxy, alkoxy (such as C.sub.1-4 alkoxy),
NH.sub.2, alkylamino (such as C.sub.1-4 alkylamino), dialkylamino
(for example, a dialkylamino wherein each alkyl is independently a
C.sub.1-4 alkyl), carboxy, carboxyalkyl (such as C.sub.2-5
carboxyalkyl), and alkoxycarbonyl (such as C.sub.2-5
alkoxycarbonyl). Within embodiment 39, in a group of compounds, or
a pharmaceutically acceptable salt thereof, P is CR.sup.4, wherein
R.sup.4 is a 4- to 6-membered heterocyclyl (such as oxetanyl,
tetrahydrofuranyl, or tetrahydropyranyl). Within embodiment 39, in
another group of compounds, or a pharmaceutically acceptable salt
thereof, P is CR.sup.4, wherein R.sup.4 is NH.sub.2 or
NR.sup.cR.sup.d, wherein R.sup.c is hydrogen, alkyl, cycloalkyl, or
heterocyclyl; and R.sup.d is alkyl, cycloalkyl, or heterocyclyl.
Within embodiment 39, in a group of compounds, or a
pharmaceutically acceptable salt thereof, P is CR.sup.4, wherein
R.sup.4 is NR.sup.cR.sup.d, wherein R.sup.c and R.sup.d together
with the nitrogen to which they are attached form a 4- to
6-membered heterocycloamino (e.g., azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, or morpholinyl). Within embodiment 39, in
a group of compounds, or a pharmaceutically acceptable salt
thereof, T is CH. Within embodiment 39, in another group of
compounds, or a pharmaceutically acceptable salt thereof, T is
CR.sup.5, wherein R.sup.5 is NH.sub.2. Within embodiment 39, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
U is CH. Within embodiment 39, in a group of compounds, or a
pharmaceutically acceptable salt thereof, U is N. Any combination
of X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 (including R.sup.c and
R.sup.d), R.sup.5, R.sup.7 (including R.sup.a and R.sup.b), T, and
U as defined in embodiment 39 is encompassed by this disclosure.
40. In embodiment 40, the compounds of embodiment 1, or a
pharmaceutically acceptable salt thereof, are those wherein the
compound of Formula (I) has the structure of Formula (Ib), or a
pharmaceutically acceptable salt thereof:
##STR00003##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 (including R.sup.c and
R.sup.d), R.sup.5, R.sup.7 (including R.sup.a and R.sup.b), T, and
U are as defined in the Summary. Within embodiment 40, in a group
of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.1 is methoxy and R.sup.2 is hydrogen. Within embodiment 40,
in another group of compounds, or a pharmaceutically acceptable
salt thereof, R.sup.1 is hydrogen and R.sup.2 is methoxy. Within
embodiment 40, in a group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.3 is --O--(CH.sub.2).sub.2--R.sup.7.
Within embodiment 40, in another group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.3 is
--O--(CH.sub.2).sub.3--R.sup.7. Within embodiment 40, in another
group of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.3 is --O--(CH.sub.2).sub.4--R.sup.7. Within embodiment 40, in
a group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.7 is --NR.sup.aR.sup.b, where R.sup.a and R.sup.b
are independently methyl, ethyl, n-propyl or isopropyl. Within
embodiment 40, in a group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.a and R.sup.b are each methyl.
Within embodiment 40, in another group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.7 is
--NR.sup.aR.sup.b, wherein --NR.sup.aR.sup.b together with the
nitrogen to which they are attached form a 4-membered
heterocycloamino or a 5-membered heterocycloamino wherein each
heterocycloamino is optionally substituted with one or two
substituents independently selected from alkyl, halo, haloalkyl,
hydroxy, alkoxy and haloalkoxy. Within embodiment 40, in a group of
compounds, or a pharmaceutically acceptable salt thereof,
NR.sup.aR.sup.b together with the nitrogen to which they are
attached form pyrrolidin-1-yl. Within embodiment 40, in another
group of compounds, or a pharmaceutically acceptable salt thereof,
NR.sup.aR.sup.b together with the nitrogen to which they are
attached form azetidin-1-yl. Within embodiment 37, in a group of
compounds, or a pharmaceutically acceptable salt thereof, R.sup.4
is methyl, ethyl, n-propyl, or isopropyl. Within embodiment 40, in
a group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.4 is cyclopropyl, cyclobutyl, or cyclopentyl wherein
the cyclopropyl, the cyclobutyl, or the cyclopentyl are optionally
substituted with one, two, or three substituents independently
selected from alkyl (such as C.sub.1-4 alkyl), halo (such as F),
haloalkyl (such as CF.sub.3), haloalkoxy (such as OCF.sub.3),
hydroxy, alkoxy (such as C.sub.1-4 alkoxy), NH.sub.2, alkylamino
(such as C.sub.1-4 alkylamino), dialkylamino (for example, a
dialkylamino wherein each alkyl is independently a C.sub.1-4
alkyl), carboxy, carboxyalkyl (such as C.sub.2-5 carboxyalkyl), and
alkoxycarbonyl (such as C.sub.2-5 alkoxycarbonyl). Within
embodiment 40, in a group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.4 is a 4- to 6-membered heterocyclyl
(such as oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl). Within
embodiment 40, in another group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.4 is NH.sub.2 or NR.sup.cR.sup.d,
wherein R.sup.c is hydrogen, alkyl, cycloalkyl or heterocyclyl, and
R.sup.d is alkyl, cycloalkyl or heterocyclyl. Within embodiment 40,
in a group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.4 is NR.sup.cR.sup.d, wherein R.sup.c and R.sup.d
together with the nitrogen to which they are attached form a 4- to
6-membered heterocycloamino (e.g., azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, or morpholinyl). Within embodiment 40, in
a group of compounds, or a pharmaceutically acceptable salt
thereof, T is CH. Within embodiment 40, in another group of
compounds, or a pharmaceutically acceptable salt thereof, T is
CR.sup.5, wherein R.sup.5 is NH.sub.2. Within embodiment 40, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
U is CH. Within embodiment 40, in another group of compounds, or a
pharmaceutically acceptable salt thereof, U is N. Any combination
of R.sup.1, R.sup.2, R.sup.3, R.sup.4 (including R.sup.c and
R.sup.d), R.sup.5, R.sup.7 (including R.sup.a and R.sup.b), T, and
U as defined in embodiment 40 is encompassed by this disclosure.
41. In embodiment 41, the compounds of embodiment 1, or a
pharmaceutically acceptable salt thereof, are those wherein the
compound of Formula (I) has the structure of Formula (Ic), or a
pharmaceutically acceptable salt thereof:
##STR00004##
wherein R.sup.a, R.sup.b, and R.sup.4 (including R.sup.c and
R.sup.d) are as defined in the Summary. Within embodiment 41, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.a and R.sup.b are independently methyl, ethyl, n-propyl or
isopropyl. Within embodiment 41, in a group of compounds, or a
pharmaceutically acceptable salt thereof, R.sup.a and R.sup.b are
each methyl. Within embodiment 41, in a group of compounds, or a
pharmaceutically acceptable salt thereof, --NR.sup.aR.sup.b
together with the nitrogen to which they are attached form a
4-membered heterocycloamino or a 5-membered heterocycloamino
wherein each heterocycloamino is optionally substituted with one or
two substituents independently selected from alkyl, halo,
haloalkyl, hydroxy, alkoxy and haloalkoxy. Within embodiment 41, in
a group of compounds, or a pharmaceutically acceptable salt
thereof, NR.sup.aR.sup.b together with the nitrogen to which they
are attached form pyrrolidin-1-yl. Within embodiment 41, in a group
of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.4 is methyl, ethyl, n-propyl, or isopropyl. Within embodiment
41, in a group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.4 is cyclopropyl, cyclobutyl, or cyclopentyl wherein
the cyclopropyl, the cyclobutyl, or the cyclopentyl are optionally
substituted with one, two, or three substituents independently
selected from alkyl (such as C.sub.1-4 alkyl), halo (such as F),
haloalkyl (such as CF.sub.3), haloalkoxy (such as OCF.sub.3),
hydroxy, alkoxy (such as C.sub.1-4 alkoxy), NH.sub.2, alkylamino
(such as C.sub.1-4 alkylamino), dialkylamino (for example, a
dialkylamino wherein each alkyl is independently a C.sub.1-4
alkyl), carboxy, carboxyalkyl (such as C.sub.2-5 carboxyalkyl), and
alkoxycarbonyl (such as C.sub.2-5 alkoxycarbonyl). Within
embodiment 41, in a group of compounds, or a pharmaceutically
acceptable salt thereof, R.sup.4 is methyl, ethyl, n-propyl,
isopropyl, or cyclopropyl. Within embodiment 41, in a group of
compounds, or a pharmaceutically acceptable salt thereof, R.sup.a
and R.sup.b are each methyl; and R.sup.4 is methyl, ethyl,
n-propyl, isopropyl, or cyclopropyl. Within embodiment 41, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
R.sup.4 is a 4- to 6-membered heterocyclyl (such as oxetanyl,
tetrahydrofuranyl, or tetrahydropyranyl). Within embodiment 41, in
another group of compounds, or a pharmaceutically acceptable salt
thereof, R.sup.4 is NH.sub.2 or NR.sup.cR.sup.d, wherein R.sup.c is
hydrogen, alkyl, cycloalkyl or heterocyclyl, and R.sup.d is alkyl,
cycloalkyl or heterocyclyl. Within embodiment 41, in a group of
compounds, or a pharmaceutically acceptable salt thereof, R.sup.4
is NR.sup.cR.sup.d, wherein R.sup.c and R.sup.d together with the
nitrogen to which they are attached form a 4- to 6-membered
heterocycloamino (e.g., azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or morpholinyl). Any combination of R.sup.4 (including
R.sup.c and R.sup.d), R.sup.a, and R.sup.b as defined in embodiment
41 is encompassed by this disclosure. 42. In embodiment 42, the
compounds of embodiment 1, or a pharmaceutically acceptable salt
thereof, are those wherein the compound, or a pharmaceutically
acceptable salt thereof, is selected from compound numbers: 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,
38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55,
56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,
73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,
90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, la, 2a, 3a,
4a, 5a, 6a, 7a, 8a, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 17a,
18a, 19a, 20a, 21a, 22a, 23a, 24a, 25a, 26a, 27a, 28a, 29a, 30a,
31a, 32a, 33a, 34a, 35a, 36a, 37a, 38a, 39a, 40a, 41a, 42a, 43a,
44a, 45a, 46a, 47a, 48a, 49a, 50a, 51a, 52a, 53a, 54a, 55a, 56a,
57a, 58a, 59a, 60a, 61a, 62a, 63a, 64a, 65a, 66a and 67a as shown
in Table 1 or Table 2, or a parent compound of the salt as shown in
Table 1, or a pharmaceutically acceptable salt of the parent
compound. 43. In embodiment 43, the compounds of embodiment 1, or a
pharmaceutically acceptable salt thereof, are those wherein the
compound, or a pharmaceutically acceptable salt thereof, is
selected from compound numbers: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 60, 61, 62, 63,
64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,
81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,
98, 99, 100, 101 and 102, as shown in Table 1, or a parent compound
of a salt as shown in Table 1, or a pharmaceutically acceptable
salt of the parent compound. 44. In embodiment 44, the compounds of
embodiment 1, or a pharmaceutically acceptable salt thereof, are
those wherein the compound, or a pharmaceutically acceptable salt
thereof, is selected from compound numbers: la, 2a, 3a, 4a, 5a, 6a,
7a, 8a, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 17a, 18a, 19a, 20a,
21a, 22a, 23a, 24a, 25a, 26a, 27a, 28a, 29a, 30a, 31a, 32a, 33a,
34a, 35a, 36a, 37a, 38a, 39a, 40a, 41a, 42a, 43a, 44a, 45a, 46a,
47a, 48a, 49a, 50a, 51a, 52a, 53a, 54a, 55a, 56a, 57a, 58a, 59a,
60a, 61a, 62a, 63a, 64a, 65a, 66a and 67a. 45. Embodiment 45
provides a pharmaceutical composition comprising a compound of any
one of embodiments 1-44, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable excipient. 46.
Embodiment 46 provides a method of inhibiting the activity of G9a
comprising contacting a cell that contains G9a with an effective
amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, and thereby inhibiting
the activity of the G9a. Within embodiment 46, in a group of
methods, the method can be conducted in vitro. Within embodiment
46, in another group of methods, the cell can be in a subject, and
the subject is suffering from a disease treatable by inhibiting
G9a. 47. Embodiment 47 provides a method of inhibiting the activity
of GLP comprising contacting a cell that contains GLP with an
effective amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, and thereby inhibiting
the activity of GLP. Within embodiment 47, in a group of methods,
the method can be conducted in vitro. Within embodiment 47, in
another group of methods, the cell can be in a subject, and the
subject is suffering from a disease treatable by inhibiting GLP.
48. Embodiment 48 provides a method of increasing fetal hemoglobin
(HbF) protein levels comprising contacting a cell characterized as
having impaired production of .beta.-globin with an effective
amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, and thereby increasing
fetal hemoglobin (HbF) protein levels. 49. Embodiment 49 provides a
method of reducing the concentration of hemoglobin S molecules
comprising contacting a cell characterized as having a hemoglobin S
mutation with an effective amount of a compound of any one of
embodiments 1-44, or a pharmaceutically acceptable salt thereof,
and thereby reducing the concentration of hemoglobin S molecules.
Embodiment 49 also provides a method of inhibiting the
polymerization of hemoglobin S molecules comprising contacting a
cell characterized as having a hemoglobin S mutation with an
effective amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, and thereby inhibiting
the polymerization of hemoglobin S molecules. Those skilled in the
art understand that hemoglobin S can polymerize under hypoxic
conditions to form hemoglobin polymers that result in the red blood
cell (RBC) losing its deformability properties and taking on a
sickle-like shape. See, for example, Rees et al., Lancet 2010, 376,
2018-2031. As used herein, "inhibiting the polymerization of
hemoglobin S molecules" refers to inhibiting the formation of such
hemoglobin polymers. 50. Embodiment 50 provides a method of
inhibiting G9a activity in a subject comprising administering to
the subject suffering from a disease that is treatable by fetal
hemoglobin an effective amount of a compound of any one of
embodiments 1-44, or a pharmaceutically acceptable salt thereof.
51. Embodiment 51 provides a method of inhibiting GLP activity in a
subject comprising administering to the subject suffering from a
disease that is treatable by fetal hemoglobin an effective amount
of a compound of any one of embodiments 1-44, or a pharmaceutically
acceptable salt thereof. 52. Embodiment 52 provides a method for
treating a disease comprising administrating to a subject suffering
from the disease treatable by fetal hemoglobin an effective amount
of a compound of any one of embodiments 1-44, or a pharmaceutically
acceptable salt thereof. 53. Embodiment 53 provides method for
treating a disease characterized by impaired production of
.beta.-globin comprising administrating to a subject suffering from
the disease characterized by impaired production of .beta.-globin
an effective amount of a compound of any one of embodiments 1-44,
or a pharmaceutically acceptable salt thereof. Within embodiment
53, in a group of compounds, or a pharmaceutically acceptable salt
thereof, the disease is beta-thalassemia. 54. Embodiment 54
provides a method for treating a disease characterized by increased
concentration of polymerized hemoglobin S molecules comprising
administrating to a subject suffering from the disease
characterized by increased concentration of polymerized hemoglobin
S molecules an effective amount of a compound of any one of
embodiments 1-44, or a pharmaceutically acceptable salt thereof.
Within embodiment 54, in a group of compounds, or a
pharmaceutically acceptable salt thereof, the disease is sickle
cell disease. 55. Embodiment 55 provides a method of ameliorating
or treating a hemoglobinopathy, comprising administering an
effective amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, or the pharmaceutical
composition of embodiment 45 to a subject in need thereof. Within
embodiment 55, in a group of compounds, or a pharmaceutically
acceptable salt thereof, the hemoglobinopathy is sickle cell
disease. Within embodiment 55, in a group of compounds, or a
pharmaceutically acceptable salt thereof, the hemoglobinopathy is
beta-thalassemia. 56. Embodiment 56 provides a use of an effective
amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, in the preparation of a
medicament for inhibiting the activity of G9a in a cell that
contains G9a. 57. Embodiment 57 provides a use of an effective
amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, in the preparation of a
medicament for inhibiting the activity of GLP in a cell that
contains GLP. 58. Embodiment 58 provides a use of an effective
amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, in the preparation of a
medicament for increasing fetal hemoglobin (HbF) protein levels in
a cell characterized as having impaired production of
.beta.-globin. 59. Embodiment 59 provides a use of an effective
amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, in the preparation of a
medicament for reducing the concentration of hemoglobin S molecules
in a cell characterized as having a hemoglobin S mutation.
Embodiment 59 also provides a use of an effective amount of a
compound of any one of embodiments 1-44, or a pharmaceutically
acceptable salt thereof, in the preparation of a medicament for
inhibiting the polymerization of hemoglobin S molecules in a cell
characterized as having a hemoglobin S mutation. 60. Embodiment 60
provides a use of an effective amount of a compound of any one of
embodiments 1-44, or a pharmaceutically acceptable salt thereof, in
the preparation of a medicament for treating a disease treatable by
fetal hemoglobin. 61. Embodiment 61 provides a use of an effective
amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, in the preparation of a
medicament for treating a disease treatable by fetal hemoglobin.
62. Embodiment 62 provides a use of an effective amount of a
compound of any one of embodiments 1-44, or a pharmaceutically
acceptable salt thereof, in the preparation of a medicament for
treating a disease characterized by impaired production of
.beta.-globin. Within embodiment 62, in a group of compounds, or a
pharmaceutically acceptable salt thereof, the disease is
beta-thalassemia. 63. Embodiment 63 provides a use of an effective
amount of a compound of any one of embodiments 1-44, or a
pharmaceutically acceptable salt thereof, in the preparation of a
medicament for treating a disease characterized by increased
concentration of polymerized hemoglobin S molecules. Within
embodiment 63, in a group of compounds, or a pharmaceutically
acceptable salt thereof, the disease is sickle cell disease. 64.
Embodiment 64 provides a use of an effective amount of a compound
of any one of embodiments 1-44, or a pharmaceutically acceptable
salt thereof, in the preparation of a medicament for ameliorating
or treating a hemoglobinopathy. Within embodiment 64, in a group of
compounds, or a pharmaceutically acceptable salt thereof, the
hemoglobinopathy is sickle cell disease. Within embodiment 64, in a
group of compounds, or a pharmaceutically acceptable salt thereof,
the hemoglobinopathy is beta-thalassemia.
[0077] Representative compounds of Formula (I), or salts thereof,
are disclosed in Tables 1 and 2 below. Although Tables 1 and 2 may
show a specific salt of a compound of Formula (I), those skilled in
the art will be able to recognize the parent compound (wherein the
"parent compound" is a compound without a salt moiety present), and
other salts, such as pharmaceutically acceptable salts, of those
compounds in Tables 1 and 2.
TABLE-US-00001 TABLE 1 MS Compound # Structure of Parent Compound
Name Found 1 ##STR00005## 1-[3-({6-methoxy-5H-pyrido[3,2-
b]indol-7-yl}oxy)propyl]pyrrolidine 326.5 2 ##STR00006##
1-[3-({8-methoxy-5H-pyrido[3,2- b]indol-7-yl}oxy)propyl]pyrrolidine
326.5 3 ##STR00007## 1-[3-({6-methoxy-9H-pyrido[3,4-
b]indol-7-yl}oxy)propyl]pyrrolidine 326 4 ##STR00008##
1-[3-({8-methoxy-5H-pyrimido[5,4-
b]indol-7-yl}oxy)propyl]pyrrolidine 327 5 ##STR00009##
1-[3-({8-methoxy-1-methyl-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]pyrrolidine 340 6 ##STR00010##
1-[3-({8-methoxy-5H-pyrido[4,3- b]indol-7-yl}oxy)propyl]pyrrolidine
326.2 7 ##STR00011## 1-[3-({6-methoxy-9H-pyrido[2,3-
b]indol-7-yl}oxy)propyl]pyrrolidine 326 8 ##STR00012##
8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-5H-pyrido[4,3-b]indol-
3-amine 341.4 9 ##STR00013## 1-[3-({1-fluoro-8-methoxy-5H-
pyrido[4,3-b]indol-7- yl}oxy)propyl]pyrrolidine 344 10 ##STR00014##
8-methoxy-1-methyl-7-[3- (pyrrolidin-1-yl)propoxy]-5H-
pyrido[4,3-b]indol-3-amine 355 11 ##STR00015##
(3S)-1-{8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-5H-
pyrido[4,3-b]indol-1-yl}pyrrolidin- 3-ol 411.5 12 ##STR00016##
1-[3-({1-cyclopropyl-8-methoxy- 5H-pyrido[4,3-b]indol-7-
yl}oxy)propyl]pyrrolidine 366 13 ##STR00017##
(3R)-1-{8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-5H-
pyrido[4,3-b]indol-1-yl}pyrrolidin- 3-ol 411 14 ##STR00018##
8-methoxy-N-[(2S)-1- methoxypropan-2-yl]-7-[3-
(pyrrolidin-1-yl)propoxy]-5H- pyrido[4,3-b]indol-1-amine 413 15
##STR00019## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}pyrrolidine 395 16
##STR00020## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}piperidin-4-ol 425 17
##STR00021## 4-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}morpholine 411 18
##STR00022## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}azetidin-3-ol 397 19
##STR00023## 3-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}-8-oxa-3-
azabicyclo[3.2.1]octane 437.1 20 ##STR00024##
N-(2-ethoxyethyl)-8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-5H-
pyrido[4,3-b]indol-1-amine 413.4 21 ##STR00025##
1-[3-({8-methoxy-1-propyl-5H- pyrido[4,3-b]indol-7-yl}oxy)-
propyl]pyrrolidine 368.1 22 ##STR00026##
1-[3-({6-methoxy-9H-pyrimido- [4,5-b]indol-7-yl}oxy)propyl]-
pyrrolidine 326.8 23 ##STR00027## 8-methoxy-1-(pyridin-4-yl)-7-(3-
(pyrrolidin-1-yl)propoxy)-5H- pyrido[4,3-b]indole 403.3 24
##STR00028## 8-methoxy-1-(pyridin-3-yl)-7-(3-
(pyrrolidin-1-yl)propoxy)-5H- pyrido[4,3-b]indole 403.3 25
##STR00029## 8-methoxy-1-(pyridin-2-yl)-7-(3-
(pyrrolidin-1-yl)propoxy)-5H- pyrido[4,3-b]indole 403.3 26
##STR00030## 1-[3-({6-methoxy-5H-pyrido[3,2-
b]indol-7-yl}oxy)propyl]pyrrolidine hydrochloride 326.5 27
##STR00031## 1-[3-({8-methoxy-5H-pyrido[3,2-
b]indol-7-yl}oxy)propyl]pyrrolidine hydrochloride 326.5 28
##STR00032## 1-[3-({6-methoxy-9H-pyrido[3,4-
b]indol-7-yl}oxy)propyl]pyrrolidine hydrochloride 326.0 29
##STR00033## 1-[3-({8-methoxy-1-methyl-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]pyrrolidine hydrochloride 340.0 30 ##STR00034##
1-[3-({6-methoxy-9H-pyrido[2,3- b]indol-7-yl}oxy)propyl]pyrrolidine
hydrochloride 326.0 31 ##STR00035## 1-[3-({8-methoxy-5H-pyrido[4,3-
b]indol-7-yl}oxy)propyl]pyrrolidine hydrochloride 326.2 32
##STR00036## 8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 3-amine hydrochloride 341.4 33
##STR00037## 6-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-9H-pyrido[2,3-b]indol- 2-amine hydrochloride 340.9 34
##STR00038## 1-[3-({1-fluoro-8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]pyrrolidine hydrochloride 344.0 35 ##STR00039##
8-methoxy-1-methyl-7-[3- (pyrrolidin-1-yl)propoxy]-5H-
pyrido[4,3-b]indol-3-amine hydrochloride 355.0 36 ##STR00040##
(3S)-1-{8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-5H-
pyrido[4,3-b]indol-1-yl}pyrrolidin- 3-ol hydrochloride 411.5 37
##STR00041## (3R)-1-{8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-5H-
pyrido[4,3-b]indol-1-yl}pyrrolidin- 3-ol 411.0 38 ##STR00042##
8-methoxy-N-[(2S)-1- methoxypropan-2-yl]-7-[3-
(pyrrolidin-1-yl)propoxy]-5H- pyrido[4,3-b]indol-1-amine 413.1 39
##STR00043## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}pyrrolidine 395.0 40
##STR00044## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}piperidin-4-ol 425.0 41
##STR00045## 4-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}morpholine 411.0 42
##STR00046## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}azetidin-3-ol 397.0 43
##STR00047## 1-[3-({1-cyclopropyl-8-methoxy-
5H-pyrido[4,3-b]indol-7- yl}oxy)propyl]pyrrolidine 366.0 44
##STR00048## 1-[3-({8-methoxy-5H-pyrimido[5,4-
b]indol-7-yl}oxy)propyl]pyrrolidine 327.0 45 ##STR00049##
ethyl[3-({8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]methylamine hydrochloride 314.3 46 ##STR00050##
[3-({1-cyclopropyl-8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl](ethyl)methylamine hydrochloride 353.8 47
##STR00051## [3-({1-cyclopropyl-8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]dimethylamine hydrochloride 340.2 48 ##STR00052##
4-{7-[3-(dimethylamino)propoxy]- 8-methoxy-5H-pyrido[4,3-b]indol-
1-yl}-2-methylbut-3-yn-2-ol hydrochloride 382.1 49 ##STR00053##
4-{7-[3-(dimethylamino)propoxy]- 8-methoxy-5H-pyrido[4,3-b]indol-
1-yl}-2-methylbutan-2-ol hydrochloride 386.0 50 ##STR00054##
4-{7-[3-(dimethylamino)propoxy]- 8-methoxy-5H-pyrido[4,3-b]indol-
1-yl}but-3-yn-2-ol hydrochloride 368.0 51 ##STR00055##
(3-{[1-(2-cyclopropylethynyl)-8- methoxy-5H-pyrido[4,3-b]indol-7-
yl]oxy}propyl)dimethylamine hydrochloride 364.2 52 ##STR00056##
3-((1-(2-cyclopropylethyl)-8- methoxy-5H-pyrido[4,3-b]indol-7-
yl)oxy)-N,N-dimethylpropan-1- amine hydrochloride 368.2 53
##STR00057## {2-[2-({1-cyclopropyl-8-methoxy-
5H-pyrido[4,3-b]indol-7- yl}oxy)ethoxy]ethyl}dimethylamine
hydrochloride 370.4 55 ##STR00058## [3-({8-methoxy-1-propyl-5H-
pyrido[4,3-b]indol-7- yl}oxy)propyl]dimethylamine hydrochloride
342.2 56 ##STR00059## [3-({1-cyclopentyl-8-methoxy-5H-
pyrido[4,3-b]indol-7- yl}oxy)propyl]dimethylamine hydrochloride
368.1 57 ##STR00060## (3-{[1-(2-ethoxyethyl)-8-methoxy-
5H-pyrido[4,3-b]indol-7- yl]oxy}propyl)dimethylamine hydrochloride
372.2 58 ##STR00061## (3-{[8-methoxy-1-(3-
methoxypropyl)-5H-pyrido[4,3- b]indol-7-
yl]oxy}propyl)dimethylamine hydrochloride 372.2 59 ##STR00062##
[3-({1-ethynyl-8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]dimethylamine hydrochloride 324.0 60 ##STR00063##
1-[3-({1-cyclopropyl-8-methoxy- 5H-pyrido[4,3-b]indol-7-
yl}oxy)propyl]-2-methylpyrrolidine hydrochloride 380.4 61
##STR00064## [3-({1-cyclopropyl-8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]bis(propan-2- yl)amine hydrochloride 396.4 62
##STR00065## (3R)-1-[3-({1-cyclopropyl-8-
methoxy-5H-pyrido[4,3-b]indol-7- yl}oxy)propyl]-3-fluoropyrrolidine
hydrochloride 384.4 63 ##STR00066## (3S)-1-[3-({1-cyclopropyl-8-
methoxy-5H-pyrido[4,3-b]indol-7- yl}oxy)propyl]-3-fluoropyrrolidine
hydrochloride 384.4 64 ##STR00067##
1-(3-{[1-(3,6-dihydro-2H-pyran-4- yl)-8-methoxy-5H-pyrido[4,3-
b]indol-7-yl]oxy}propyl)pyrrolidine hydrochloride 408.4 65
##STR00068## 1-[3-{[8-methoxy-1-(oxan-4-yl)-
5H-pyrido[4,3-b]indol-7- yl]oxy}propyl)pyrrolidine hydrochloride
410.5 66 ##STR00069## 4-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}-1,2,3,6-tetrahydropyridine
bishydrochloride 407.3 67 ##STR00070##
(3-{[8-methoxy-1-(propan-2-yl)- 5H-pyrido[4,3-b]indol-7-
yl]oxy}propyl)dimethylamine hydrochloride 342.4 68 ##STR00071##
(3-{[8-methoxy-1-(oxan-4-yl)-5H- pyrido[4,3-b]indol-7-
yl]oxy}propyl)dimethylamine hydrochloride 384.4 69 ##STR00072##
[3-({1-cyclobutyl-8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]dimethylamine hydrochloride 354.4 70 ##STR00073##
[2-({8-methoxy-5H-pyrido[4,3- b]indol-7- yl}oxy)ethyl]dimethylamine
hydrochloride 286.4 71 ##STR00074## 1-[2-({8-methoxy-5H-pyrido[4,3-
b]indol-7-yl}oxy)ethyl]pyrrolidine hydrochloride 312.3 72
##STR00075## 1-[3-({8-methoxy-5H-pyrido[4,3-
b]indol-7-yl}oxy)propyl]azetidine hydrochloride 312.3 73
##STR00076## 1-(3-{[8-methoxy-1-(oxan-4-
yloxy)-5H-pyrido[4,3-b]indol-7- yl]oxy}propyl)pyrrolidine
trifluoroacetate 426.2 74 ##STR00077##
3-({8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}oxy)pyrrolidine bis(2,2,2-
trifluoroacetate) 411.2 75 ##STR00078##
1-(3-{[8-methoxy-1-(propan-2- yloxy)-5H-pyrido[4,3-b]indol-7-
yl]oxy}propyl)pyrrolidine trifluoroacetate 384.2 76 ##STR00079##
1-{8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-5H-pyrido[4,3-b]indol-
1-yl}-1H-imidazole trifluoroacetate 392.2 77 ##STR00080##
1-[8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-5H-pyrido[4,3-b]indol-
1-yl]-1H-pyrazole trifluoroacetate 384.2 78 ##STR00081##
5-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl}-1,3-thiazole
trifluoroacetate 409.1 79 ##STR00082##
{8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-5H-pyrido[4,3-b]indol-
3-yl}methanol trifluoroacetate 356.2 80 ##STR00083##
8-methoxy-7-(3-(pyrrolidin-1- yl)propoxy)-5H-pyrido[4,3-b]indol-
3-ol formate 342.2 81 ##STR00084## 4-[8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl]-1H-pyrazole hydrochloride
392.2 82 ##STR00085## 8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl]methanol trifluoroacetate
356.2 83 ##STR00086## 3-[8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol- 1-yl]-4H-1,2,4-triazole formate
393.2 84 ##STR00087## 1-(1H-imidazol-5-yl)-8-methoxy-7-
(3-(pyrrolidin-1-yl)propoxy)-5H- pyrido[4,3-b]indole
trifluoroacetate 392.2 85 ##STR00088## N,N-diethyl-8-methoxy-7-[3-
(pyrrolidin-1-yl)propoxy]-5H- pyrido[4,3-b]indol-1-amine bis-
formate 392.2 86 ##STR00089## 1-{4-chloro-8-methoxy-7-[3-
(pyrrolidin-1-yl)propoxy]-5H- pyrido[4,3-b]indol-1-yl}pyrrolidine
hydrochloride 429.2 87 ##STR00090## 3-[({8-methoxy-5H-pyrido[4,3-
b]indol-7-yl}oxy)methyl]piperidine hydrochloride 429.2 88
##STR00091## [3-({8-methoxy-5H-pyrido[4,3- b]indol-7-
yl}oxy)propyl]dimethylamine hydrochloride 300.1 89 ##STR00092##
1-{8-methoxy-4-methyl-7-[3- (pyrrolidin-1-yl)propoxy]-5H-
pyrido[4,3-b]indol-1-yl}pyrrolidine hydrochloride 408.9 90
##STR00093## [3-({8-methoxy-1-methyl-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]dimethylamine hydrochloride 314.5 91 ##STR00094##
[3-({1-ethyl-8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]dimethylamine hydrochloride 328.1 92 ##STR00095##
(3-{[8-methoxy-1-(pyrrolidin-1-yl)- 5H-pyrido[4,3-b]indol-7-
yl]oxy}propyl)dimethylamine hydrochloride 369.0 93 ##STR00096##
7-[3-(dimethylamino)propoxy]-8- methoxy-N,N-dimethyl-5H-
pyrido[4,3-b]indol-1-amine hydrochloride 343.3 94 ##STR00097##
1-[3-({8-methoxy-5-methyl-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]pyrrolidine hydrochloride 340.1 95 ##STR00098##
(3-{[8-methoxy-1-(methylsulfanyl)- 5H-pyrido[4,3-b]indol-7-
yl]oxy}propyl)dimethylamine hydrochloride 346.2 96 ##STR00099##
1-(3-{[8-methoxy-1-(2- methoxyethoxy)-5H-pyrido[4,3-
b]indol-7-yl]oxy}propyl)pyrrolidine trifluoroacetate 400.2 97
##STR00100## 8-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)-5H-pyrido[4,3-b]indol- 1-ol trifluoroacetate 342.2 98
##STR00101## 3-[3-({8-methoxy-5H-pyrido[4,3-
b]indol-7-yl}oxy)propyl]-3- azabicyclo[3.1.1]heptane hydrochloride
352.3 99 ##STR00102## 1-[3-({8-methoxy-3-methyl-5H-
pyrido[4,3-b]indol-7- yl}oxy)propyl]pyrrolidine hydrochloride 340.3
100 ##STR00103## 1-[3-({1,8-dimethoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]pyrrolidine hydrochloride 356.4 101 ##STR00104##
1-[3-({3-cyclopropyl-8-methoxy- 5H-pyrido[4,3-b]indol-7-
yl}oxy)propyl]pyrrolidine hydrochloride 366.4 102 ##STR00105##
[3-({1-cyclopropyl-8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]diethylamine hydrochloride 368.4
Additional compounds of Formula (I) are those disclosed in Table 2
below.
TABLE-US-00002 TABLE 2 Compound # Structure of Parent Compound Name
1a ##STR00106## 1-{4,8-dimethoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1- yl}pyrrolidine 2a ##STR00107##
1-{4-cyclopropyl-8-methoxy-7-[3-
(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3- b]indol-1-yl}pyrrolidine
3a ##STR00108## 12-methoxy-11-[3-(pyrrolidin-1-
yl)propoxy]-3-(pyrrolidin-3-yloxy)-8-oxa-
4-azatricyclo[7.4.0.0.sup.2,7]trideca- 1(13),2(7),3,5,9,11-hexaene
4a ##STR00109## 1-(3-{[8-methoxy-5-methyl-1-(pyrrolidin-
3-yloxy)-5H-pyrido[4,3-b]indol-7- yl]oxy}propyl)pyrrolidine 5a
##STR00110## 3-({8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1- yl}oxy)-1-methylpyrrolidine 6a
##STR00111## 3-[({8-methoxy-5H-pyrido[4,3-b]indol-7-
yl}oxy)methyl]-1-methylpiperidine 7a ##STR00112##
1-[3-({8-ethyl-5H-pyrido[4,3-b]indol-7- yl}oxy)propyl]-pyrrolidine
8a ##STR00113## 6-[3-({1-cyclopropyl-8-methoxy-5H-
pyrido[4,3-b]indol-7-yl}oxy)propyl]-2- oxa-6-azaspiro[3.3]heptane
9a ##STR00114## [3-({1-cyclopropyl-8-methoxy-5H-
pyrido[4,3-b]indol-7- yl}oxy)propyl](methyl)(2,2,2-
trifluoroethyl)amine 10a ##STR00115##
1-[3-({1-cyclopropyl-8-methoxy-5H-
pyrido[4,3-b]indol-7-yl}oxy)propyl]-2,5- dimethylpyrrolidine 11a
##STR00116## 1-[3-({1-cyclopropyl-8-methoxy-5H-
pyrido[4,3-b]indol-7- yl}oxy)propyl]piperidine 12a ##STR00117##
1-[3-({1-cyclopropyl-8-methoxy-5H-
pyrido[4,3-b]indol-7-yl}oxy)propyl]-3- fluoroazetidine 13a
##STR00118## 1-(3-{[8-methoxy-1-(propan-2-yl)-5H-
pyrido[4,3-b]indol-7- yl]oxy}propyl)pyrrolidine 14a ##STR00119##
1-(3-{[8-methoxy-1-(oxetan-3-yl)-5H- pyrido[4,3-b]indol-7-
yl]oxy}propyl)pyrrolidine 15a ##STR00120##
1-(3-{[8-methoxy-1-(oxetan-2-yl)-5H- pyrido[4,3-b]indol-7-
yl]oxy}propyl)pyrrolidine 16a ##STR00121## 1-(3-{[8-methoxy-1-(1-
methylcyclopropyl)-5H-pyrido[4,3-
b]indol-7-yl]oxy}propyl)pyrrolidine 17a ##STR00122##
1-[3-({1-tert-butyl-8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)propyl]pyrrolidine 18a ##STR00123##
1-(3-{[8-methoxy-1-(oxolan-3-yl)-5H- pyrido[4,3-b]indol-7-
yl]oxy}propyl)pyrrolidine 19a ##STR00124##
5-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 1,3-oxazole 20a
##STR00125## 2-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 1,3-thiazole 21a
##STR00126## 2-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 1,3-oxazole 22a
##STR00127## 4-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 4H-1,2,4-triazole 23a
##STR00128## 1-[3-({6-methoxy-4-methyl- 9H-pyrimido[4,5-b]indol-7-
yl}oxy)propyl]pyrrolidine 24a ##STR00129##
1-[3-({4-cyclopropyl-6-methoxy-9H- pyrimido[4,5-b]indol-7-
yl}oxy)propyl]pyrrolidine 25a ##STR00130##
1-{6-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-9H-pyrimido[4,5-b]indol-4- yl}pyrrolidine 26a
##STR00131## 1-(3-{[1-(cyclopent-1-en-1-yl)-8-
methoxy-5H-pyrido[4,3-b]indol-7- yl]oxy}propyl)pyrrolidine 27a
##STR00132## 1-({1-cyclopentyl-8-methoxy-5H-
pyrido[4,3-b]indol-7-yl}oxy)-3- (pyrrolidin-1-yl)propan-2-ol 28a
##STR00133## 1-({8-methoxy-1-methyl-5H-pyrido[4,3-
b]indol-7-yl}oxy)-3-(pyrrolidin-1- yl)propan-2-ol 29a ##STR00134##
1-({1-cyclopropyl-8-methoxy-5H- pyrido[4,3-b]indol-7-yl}oxy)-3-
(pyrrolidin-1-yl)propan-2-ol 30a ##STR00135##
1-[3-({1-cyclopentyl-8-methoxy-5H- pyrido[4,3-b]indol-7-yl}oxy)-2-
methoxypropyl]pyrrolidine 31a ##STR00136##
1-[2-methoxy-3-({8-methoxy-1-methyl- 5H-pyrido[4,3-b]indol-7-
yl}oxy)propyl]pyrrolidine 32a ##STR00137##
1-[3-({1-cyclopropyl-8-methoxy-5H- pyrido[4,3-b]indol-7-yl}oxy)-2-
methoxypropyl]pyrrolidine 33a ##STR00138##
1-[3-({1-[4-(difluoromethoxy)phenyl]-8-
methoxy-5H-pyrido[4,3-b]indol-7- yl}oxy)propyl]pyrrolidine 34a
##STR00139## 1-[3-({1-[3-(difluoromethoxy)phenyl]-8-
methoxy-5H-pyrido[4,3-b]indol-7- yl}oxy)propyl]pyrrolidine 35a
##STR00140## 2-(difluoromethoxy)-4-{8-methoxy-7-[3-
(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3- b]indol-1-yl}pyridine 36a
##STR00141## 2-(difluoromethoxy)-5-{8-methoxy-7-[3-
(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3- b]indol-1-yl}pyridine 37a
##STR00142## 1-[3-({1-[4-(difluoromethyl)phenyl]-8-
methoxy-5H-pyrido[4,3-b]indol-7- yl}oxy)propyl]pyrrolidine 38a
##STR00143## 2-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1- yl}propan-2-ol 39a
##STR00144## 4-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 4-azaspiro[2.4]heptane 40a
##STR00145## 5-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 5-azaspiro[3.4]octane 41a
##STR00146## 5-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}-
2-oxa-5-azaspiro[3.4]octane 42a ##STR00147##
1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 2,2-dimethylpyrrolidine
43a ##STR00148## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 2-(propan-2-yl)pyrrolidine
44a ##STR00149## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}-
6-oxa-1-azaspiro[3.3]heptane 45a ##STR00150##
1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 1-azaspiro[3.3]heptane 46a
##STR00151## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 6-oxa-1-azaspir[3.4]octane
47a ##STR00152## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- 1-azaspiro[3.4]octane 48a
##STR00153## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}-
7-oxa-1-azaspiro[4.4]nonane 49a ##STR00154##
1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}-
7.lamda..sup.6-thia-1-azaspiro[4.4]nonane-7,7-dione 50a
##STR00155## 1-[3-({4-cyclopentyl-6-methoxy-9H-
pyrimido[4,5-b]indol-7- yl}oxy)propyl]pyrrolidine 51a ##STR00156##
{2-[2-({6-methoxy-9H-pyrimido[4,5- b]indol-7-
yl}oxy)ethoxy]ethyl}dimethylamine 52a ##STR00157##
1-(3-{[4-(azetidin-1-yl)-6-methoxy-9H- pyrimido[4,5-b]indol-7-
yl]oxy}propyl)pyrrolidine 53a ##STR00158##
{2-[2-({8-methoxy-1-methyl-5H- pyrido[4,3-b]indol-7-
yl}oxy)ethoxy]ethyl}dimethylamine 54a ##STR00159##
[2-(2-{[8-methoxy-1-(pyrrolidin-1-yl)-5H- pyrido[4,3-b]indol-7-
yl]oxy}ethoxy)ethyl]dimethylamine 55a ##STR00160##
{2-[2-({1-cyclopentyl-8-methoxy-5H- pyrido[4,3-b]indol-7-
yl}oxy)ethoxy]ethyl}dimethylamine 56a ##STR00161##
6-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- N-methylpyridin-2-amine
57a ##STR00162## 4-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}- N-methylpyridin-2-amine
58a ##STR00163## 1-{[8-methoxy-1-(pyrrolidin-1-yl)-5H-
pyrido[4,3-b]indol-7-yl]oxy}-3- (pyrrolidin-1-yl)propan-2-ol 59a
##STR00164## 1-{8-methoxy-7-[2-methoxy-3-
(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3- b]indol-1-yl}pyrrolidine
60a ##STR00165## 1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1- yl}pyrrolidine-2-carboxylic
acid 61a ##STR00166## 2-(1-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1- yl}pyrrolidin-2-yl)acetic acid
62a ##STR00167## 2-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1- yl}benzoic acid 63a
##STR00168## 2-(2-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1- yl}phenyl)acetic acid 64a
##STR00169## 2-(4-{8-methoxy-7-[3-(pyrrolidin-1-
yl)propoxy]-5H-pyrido[4,3-b]indol-1- yl}phenyl)propan-2-ol 65a
##STR00170## 8-methoxy-7-((2-(pyrrolidin-1-
yl)ethoxy)methyl-5H-pyrido[4,3-b]indole 66a ##STR00171##
8-methoxy-1-methyl-7-((2-(pyrrolidin-1-
yl)ethoxy)methyl-5H-pyrido[4,3-b]indole 67a ##STR00172##
8-methoxy-3-methyl-7-((2-(pyrrolidin-1-
yl)ethoxy)methyl)-5H-pyrido[4,3-b]indole
General Synthetic Scheme
[0078] Compounds of this disclosure can be made by the methods
depicted in the reaction schemes shown below.
[0079] The starting materials and reagents used in preparing these
compounds are either available from commercial suppliers such as
Sigma-Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance,
Calif.), or are prepared by methods known to those skilled in the
art following procedures set forth in references such as Fieser and
Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley
and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5
and Supplementals (Elsevier Science Publishers, 1989); Organic
Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's
Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and
Larock's Comprehensive Organic Transformations (VCH Publishers
Inc., 1989). These schemes are merely illustrative of some methods
by which the compounds of this disclosure can be synthesized, and
various modifications to these schemes can be made and will be
suggested to one skilled in the art reading this disclosure. The
starting materials, the intermediates, and the final products of
the reaction(s) may be isolated and purified if desired using
conventional techniques, including but not limited to filtration,
distillation, crystallization, chromatography, and the like. Such
materials may be characterized using conventional means, including
physical constants and spectral data.
[0080] Unless specified to the contrary, the reactions described
herein take place at atmospheric pressure over a temperature range
from about -78.degree. C. to about 150.degree. C., such as from
about 0.degree. C. to about 125.degree. C. and further such as at
about room (or ambient) temperature, e.g., about 20.degree. C. The
routes shown and described herein are illustrative only and are not
intended, nor are they to be construed, to limit the scope of the
claims in any manner whatsoever. Those skilled in the art will be
able to recognize modifications of the disclosed syntheses and to
devise alternate routes based on the disclosures herein; all such
modifications and alternate routes are within the scope of the
claims.
[0081] Compounds of Formula (I) where Z is NR.sup.6 and X, Y, P, Q,
T, U, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, v and w are as
defined in the Summary, can be prepared by the following procedure
described in Scheme 1 below.
##STR00173##
[0082] Treatment of a compound of formula 1 where X.sup.1 is halo
(such as chloro, bromo, or iodo, preferably bromo), and R.sup.1,
R.sup.2, and R.sup.3 are as defined in the Summary or a precursor
group thereof, with nitric acid in sulfuric or acetic acid provides
a compound of formula 2. Compounds of formula 1 are either
commercially available or they can be prepared by methods well
known in the art. For example, compounds of formula 1 where R.sup.3
is --W-alkylene-R.sup.7, wherein W is NH, 0, or S; alkylene is
optionally substituted with R.sup.8 (wherein R.sup.8 is halo,
haloalkyl, haloalkoxy, hydroxy, or alkoxy) and one CH.sub.2 in the
alkylene chain is optionally replaced with NH or O, and R.sup.7 is
--NR.sup.aR.sup.b wherein R.sup.a and R.sup.b are as defined in the
Summary can be prepared by reacting commercially available starting
materials such as 4-bromo-2-methoxyphenol, 4-bromo-2-methylphenol,
4-bromo-2-ethylphenol, 4-bromo-2-methoxyaniline,
4-bromo-2-methoxybenzenethiol, 3-bromo-6-hydroxy-2-methylpyridine,
5-bromo-2-fluoro anisole, 4-bromo-1-iodo-2-methoxybenzene,
1-benzyloxy-4-bromo-2-methoxybenzene,
5-(benzyloxy)-2-bromo-4-methoxyphenol, 4-iodo-2-methoxyphenol, or
4-chloro-2-methylbenzamine with an amine of formula
LG-(alkylene)-NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b are as
defined in the Summary or a suitable amino protecting group and LG
is a suitable leaving group, such as halo under suitable alkylating
reaction conditions, e.g., by reacting a compound of formula 1 with
the above amine in the presence of a base, such as potassium
carbonate, cesium carbonate, diethylamine, and the like, and in a
suitable organic solvent, such as dimethylformamide,
tetrahydrofuran, and the like. Amines of formula
LG-(alkylene)-NR.sup.aR.sup.b such as
1-(3-chloropropropyl)pyrrolidine, 1-(3-chloropropyl)dimethylamine,
and 2-(2-chloroethoxy)ethyl]dimethylamine are commercially
available.
[0083] Treatment of a compound of formula 2 with a compound of
formula 3 where P, Q, T, U are as defined in the Summary, and
R.sup.4 and R.sup.5 are as defined in the Summary, or a precursor
group thereof, D is H or halo, and Y' is a boronic acid or boronic
ester under Suzuki coupling reaction conditions provides a compound
of formula 4. Compounds of formula 3 are either commercially
available or they can be prepared from corresponding halides of
formula 3 where Y' is halo by methods well known in the art.
Compounds of formula 3 where Y' is boronic acid or ester, or Y' is
halo, such as pyridine-3-boronic acid, pyridine-3-boronic acid
pinacol ester, 2-fluoropyridine-3-boronic acid,
2-methoxypyridine-3-boronic acid, 2-chloropyridine-3-boronic acid,
2-fluoropyridine-3-boronic acid, pinacol ester,
2-bromopyridine-3-boronic acid, 2-methylpyridine-3-boronic acid,
2-(t-butoxycarbonylamino)pyridine-3-boronic acid,
2-cyanopyridine-3-boronic acid pinacol ester,
2-ethyl-3-pyridinylboronic acid, 2-morpholinopyridine-3-boronic
acid, 2-(4-tert-butoxycarbonylpiperazinyl)pyridine-3-boronic acid
pinacol ester,
2-phenyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine,
2-(dimethylamino)pyridin-3-ylboronic acid,
N,N-dimethyl-2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-
-yl)oxy)ethanamine,
2-(4-methyl-1H-pyrazol-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)pyridine, 4-fluoropyridine-3-boronic acid,
4-fluoro-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbaldehyde,
2-chloro-6-methylpyridine-3-boronic acid,
(2-chloro-6-aminopyridin-3-yl)boronic acid,
5-chloro-2-fluoropyridine-3-boronic acid, 3-bromo-2-methylpyridine,
3-bromopyridine, 3-bromo-2-hydroxymethylpyridine,
3-bromo-2-cyclopropylpyridine,
2-(3-bromo-pyridin-2-yl)-propan-2-ol, 3-bromo-2-propylpyridine, and
3-bromo-2-(tert-butyl)pyridine are commercially available.
[0084] It will be also readily recognized by a person skilled in
the art that compounds of formula 2 where X' is halo can be
converted to corresponding boronic acid or ester and reaction with
a compound of formula 3 where Y' is halo provides a compound of
formula 4. Compound of formula 4 where D is hydrogen can be
converted to a compound of Formula (I) under Cadogan reaction
condition. See, for example, Majgier-Baranowska et al., Tetrahedron
Letters 53 (2012) 4785-4788; and Karimi et al., Tetrahedron Letters
58 (2017) 2223-2227 (particularly Scheme 3b). Alternatively, the
nitro group in a compound of formula 4 can be first reduced to
amino group to provide a compound of formula 5 that has an amino
which can then be converted to a compound of Formula (I) under aryl
cyclization reaction conditions.
[0085] A compound of Formula (I) can be converted to other
compounds of Formula (I). For example, compounds of Formula (I)
where R.sup.6 is alkyl or cycloalkyl can be prepared by reacting a
corresponding compounds of Formula (I) where R.sup.6 is hydrogen
with an alkyl or a cycloalkyl halide, respectively, under
alkylation reaction condition. Alkyl halides and cycloalkyl
halides, such as iodomethane, iodoethane, 2-iodo-propane,
1-bromobutane, and cyclopropyl bromide, are commercially
available.
[0086] Compounds of Formula (I), where R.sup.4 and/or R.sup.5 is
halo, can be displaced with NR.sup.cR.sup.d, alkoxyalkylamino,
heterocyclylamino, spiroheterocycloamino, 5-membered NH-containing
heteroaryl, phenyl, heteroarylbornic acid, heteroarylboronic ester
or an alcohol for example, methylamine, ethylamine, n-propylamine,
isopropylamine, dimethylamine, diethylamine, tert-butylamine,
azetidine, pyrrolidine, 3-amino-azetidine, 3-hydroxypyrrolidine,
imidazole, pyrazole, morpholine, N-methyl-morpholine,
4-hydroxy-piperidine, piperidine, 2-ethoxyethylamine,
4-azaspiro[2.4]heptane, 2-oxa-5-azaspiro[3.4]octane,
2-isopropylpyrrolidine, and 7-oxa-1-azaspiro[4.4]nonane, in the
presence of a base to provide a compound of Formula (I) where
R.sup.4 and/or R.sup.5 is alkoxy, NH.sub.2, NR.sup.cR.sup.d,
alkoxyalkyloxy, phenyl, heteroaryl, heteroaryloxy, heterocyclyloxy,
heterocyclylamino, 5-8 membered bridged heterocycloamino, or
spiroheterocycloamino, wherein the phenyl, the heteroaryl, and the
heterocyclyl either alone or a part of another group are optionally
substituted with one, two, or three substituents independently
selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy,
hydroxyalkyl, alkoxy, NH.sub.2, alkylamino, dialkylamino, carboxy,
carboxyalkyl, and alkoxycarbonyl, wherein the alkyl, the alkenyl
and the alkynyl are optionally substituted with hydroxy and
cycloalkyl.
[0087] Alternatively, compounds of Formula (I) where Z is NR.sup.6
and X, Y, P, Q, T, U, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
v and w are as defined in the Summary, can be prepared by the
following procedure described in Scheme 2 below.
##STR00174##
Alternatively, a compound of formula 1 as defined in Scheme 1 above
can be reacted with a compound of formula 6 that includes a nitro
where P, Q, T and U are as defined in the Summary and R.sup.4 and
R.sup.5 are as defined in the Summary or a precursor group thereof,
and Y' is a boronic acid or boronic ester under Suzuki coupling
reaction conditions provides a compound of formula 7. Compound 7 is
then reduced to a compound of Formula (I) as described in Scheme 1
above.
Testing
[0088] The G9a inhibitory activity of the compounds of the present
disclosure can be tested using the in vitro assay described in
Biological Examples 1 below. The ability of the compounds of the
disclosure to stimulated fetal hemoglobin can be tested using the
in vitro assay described in Biological Example 2 below.
Administration and Pharmaceutical Composition
[0089] In general, the compounds of this disclosure will be
administered in a therapeutically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. Therapeutically effective amounts of compounds this
disclosure may range from about 0.01 to about 500 mg per kg subject
body weight per day, which can be administered in single or
multiple doses. A suitable dosage level may be from about 0.1 to
about 250 mg/kg per day or about 0.5 to about 100 mg/kg per day. A
suitable dosage level may be about 0.01 to about 250 mg/kg per day,
about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50
mg/kg per day. Within this range the dosage can be about 0.05 to
about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per
day. For oral administration, the compositions can be provided in
the form of tablets containing about 1.0 to about 1000 milligrams
of the active ingredient, particularly about 1, 5, 10, 15, 20, 25,
50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or
1000 milligrams of the active ingredient. The actual amount of the
compound of this disclosure, i.e., the active ingredient, will
depend upon numerous factors such as the severity of the disease to
be treated, the age and relative health of the subject, the potency
of the compound being utilized, the route and form of
administration, and other factors.
[0090] In general, compounds of this disclosure will be
administered as pharmaceutical compositions by any one of the
following routes: oral, systemic (e.g., transdermal, intranasal or
by suppository), or parenteral (e.g., intramuscular, intravenous or
subcutaneous) administration. The preferred manner of
administration is oral using a convenient daily dosage regimen,
which can be adjusted according to the degree of affliction.
Compositions can take the form of tablets, pills, capsules,
semisolids, powders, sustained release formulations, solutions,
suspensions, elixirs, aerosols, or any other appropriate
compositions.
[0091] The choice of formulation depends on various factors such as
the mode of drug administration (e.g., for oral administration,
formulations in the form of tablets, pills or capsules, including
enteric coated or delayed release tablets, pills or capsules are
preferred) and the bioavailability of the drug substance. Recently,
pharmaceutical formulations have been developed especially for
drugs that show poor bioavailability based upon the principle that
bioavailability can be increased by increasing the surface area,
i.e., decreasing particle size. For example, U.S. Pat. No.
4,107,288 describes a pharmaceutical formulation having particles
in the size range from 10 to 1,000 nm in which the active material
is supported on a cross-linked matrix of macromolecules. U.S. Pat.
No. 5,145,684 describes the production of a pharmaceutical
formulation in which the drug substance is pulverized to
nanoparticles (average particle size of 400 nm) in the presence of
a surface modifier and then dispersed in a liquid medium to give a
pharmaceutical formulation that exhibits remarkably high
bioavailability.
[0092] The compositions are comprised of in general, a compound of
this disclosure in combination with at least one pharmaceutically
acceptable excipient. Acceptable excipients are non-toxic, aid
administration, and do not adversely affect the therapeutic benefit
of the compound of this disclosure. Such excipient may be any
solid, liquid, semi-solid or, in the case of an aerosol
composition, gaseous excipient that is generally available to one
of skill in the art.
[0093] Solid pharmaceutical excipients include starch, cellulose,
talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, magnesium stearate, sodium stearate, glycerol
monostearate, sodium chloride, dried skim milk and the like. Liquid
and semisolid excipients may be selected from glycerol, propylene
glycol, water, ethanol and various oils, including those of
petroleum, animal, vegetable or synthetic origin, e.g., peanut oil,
soybean oil, mineral oil, sesame oil, etc. Preferred liquid
carriers, particularly for injectable solutions, include water,
saline, aqueous dextrose and glycols.
[0094] Compressed gases may be used to disperse a compound of this
disclosure in aerosol form. Inert gases suitable for this purpose
are nitrogen, carbon dioxide, etc.
[0095] Other suitable pharmaceutical excipients and their
formulations are described in Remington's Pharmaceutical Sciences,
edited by E. W. Martin (Mack Publishing Company, 20th ed.,
2000).
[0096] The level of the compound in a formulation can vary within
the full range employed by those skilled in the art. Typically, the
formulation will contain, on a weight percent (wt. %) basis, from
about 0.01-99.99 wt. % of a compound of this disclosure based on
the total formulation, with the balance being one or more suitable
pharmaceutical excipients. For example, the compound is present at
a level of about 1-80 wt. %.
[0097] The compounds of this disclosure may be used in combination
with one or more other drugs in the treatment of diseases or
conditions for which compounds of this disclosure or the other
drugs may have utility. Such other drug(s) may be administered, by
a route and in an amount commonly used therefore, contemporaneously
or sequentially with a compound of the present disclosure. When a
compound of this disclosure is used contemporaneously with one or
more other drugs, a pharmaceutical composition in unit dosage form
containing such other drugs and the compound of the present
disclosure is preferred. However, the combination therapy may also
include therapies in which the compound of this disclosure and one
or more other drugs are administered on different overlapping
schedules. It is also contemplated that when used in combination
with one or more other active ingredients, the compounds of the
present disclosure and the other active ingredients may be used in
lower doses than when each is used singly.
[0098] Accordingly, the pharmaceutical compositions of the present
disclosure also include those that contain one or more other drugs,
in addition to a compound of the present disclosure.
[0099] The above combinations include combinations of a compound of
this disclosure not only with one other drug, but also with two or
more other active drugs. Likewise, a compound of this disclosure
may be used in combination with other drugs that are used in the
prevention, treatment, control, amelioration, or reduction of risk
of the diseases or conditions for which a compound of this
disclosure is useful. Such other drugs may be administered, by a
route and in an amount commonly used therefore, contemporaneously
or sequentially with a compound of the present disclosure. When a
compound of this disclosure is used contemporaneously with one or
more other drugs, a pharmaceutical composition containing such
other drugs in addition to the compound of this disclosure can be
used. Accordingly, the pharmaceutical compositions of the present
disclosure also include those that also contain one or more other
active ingredients, in addition to a compound of this disclosure.
The weight ratio of the compound of this disclosure to the second
active ingredient may be varied and will depend upon the effective
dose of each ingredient. Generally, an effective dose of each will
be used.
[0100] Where the subject in need is suffering from or at risk of
suffering from cancer, the subject can be treated with a compound
of this disclosure in any combination with one or more other
anti-cancer agents and/or anti-cancer therapies. In some
embodiments, the anti-cancer therapies can be surgery and/or
radiation therapy. In some embodiments, one or more of the
anti-cancer agents are proapoptotic agents. Examples of anti-cancer
agents include, but are not limited to, any of the following:
gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic
acid (ATRA), bryostatin, tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all
trans retinoic acid, doxorubicin, vincristine, etoposide,
gemcitabine, imatinib (Gleevec.TM.) geldanamycin,
17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,
LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or
PD184352, Taxol.TM., also referred to as "paclitaxel", which is a
well-known anti-cancer drug which acts by enhancing and stabilizing
microtubule formation, and analogs of docetaxel (Taxol.TM.), such
as Taxotere.TM.. Compounds that have the basic taxane skeleton as a
common structure feature, have also been shown to have the ability
to arrest cells in the G2-M phases due to stabilized microtubules
and may be useful for treating cancer in combination with the
compounds described herein.
[0101] Further examples of anti-cancer agents for use in
combination with a compound of this disclosure include inhibitors
of mitogen-activated protein kinase signaling, e.g., U0126,
PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY
43-9006, wortmannin, or LY294002; Syk inhibitors; antibodies (e.g.,
rituxan); MET inhibitor such as foretinib, carbozantinib, or
crizotinib; VEGFR inhibitor such as sunitinib, sorafenib,
regorafinib, lenvatinib, vandetanib, carbozantinib, or axitinib;
EGFR inhibitor such as afatinib, brivanib, carbozatinib, erlotinib,
gefitinib, neratinib, or lapatinib; PI3K inhibitor such as XL147,
XL765, BKM120 (buparlisib), GDC-0941, BYL719, IPI145, BAY80-6946.
BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, or TG100-115;
MTOR inhibitor such as rapamycin (sirolimus), temsirolimus,
everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, or
GDC0349; MEK inhibitor such as AZD6244, trametinib, PD184352,
pimasertinib, GDC-0973, or AZD8330; and proteasome inhibitor such
as carfilzomib, MLN9708, delanzomib, or bortezomib.
[0102] Other anti-cancer agents that can be employed in combination
with a compound of this disclosure include Adriamycin;
Dactinomycin; Bleomycin; Vinblastine; Cisplatin; acivicin;
aclarubicin; acodazole hydrochloride; acronine; adozelesin;
aldesleukin; altretamine; ambomycin; ametantrone acetate;
aminoglutethimide; amsacrine; anastrozole; anthramycin;
asparaginase; asperlin; azacitidine; azetepa; azotomycin;
batimastat; benzodepa; bicalutamide; bisantrene hydrochloride;
bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar
sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;
dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflornithine
hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole;
etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; flurocitabine; fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin
hydrochloride; ifosfamide; ilmofosine; interleukin II (including
recombinant interleukin II, or Ril2), interferon alfa-2a;
interferon alfa-2b; interferon alfa-n1; interferon alfa-n3;
interferon beta-1a; interferon gamma-1 b; iproplatin; irinotecan
hydrochloride; lanreotide acetate; letrozole; leuprolide acetate;
liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone
hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium;
metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;
mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine;
peplomycin sulfate; perfosfamide; pipobroman; piposulfan;
piroxantrone hydrochloride; plicamycin; plomestane; porfimer
sodium; porfiromycin; prednimustine; procarbazine hydrochloride;
puromycin; puromycin hydrochloride; pyrazofurin; riboprine;
rogletimide; safingol; safingol hydrochloride; semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; streptonigrin;
streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;
teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trestolone acetate; triciribine
phosphate; trimetrexate; trimetrexate glucuronate; triptorelin;
tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;
verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;
vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;
vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and
zorubicin hydrochloride.
[0103] Other anti-cancer agents that can be employed in combination
with a compound of the disclosure such as 20-epi-analogues of 1,25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK
antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; Bfgf
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;
docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflomithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; filgrastim; fmasteride; flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunorunicin
hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;
insulin-like growth factor-1 receptor inhibitor; interferon
agonists; interferons; interleukins; iobenguane; iododoxorubicin;
ipomeanol, 4-; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;
lamellarin-N triacetate; lanreotide; leinamycin; lenograstim;
lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting
factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid diethylstilbe cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitors, microalgal; protein tyrosine phosphatase
inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie
conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl
protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; R.sub.11 retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived 1; sense oligonucleotides; signal transduction inhibitors;
signal transduction modulators; single chain antigen-binding
protein; sizofuran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0104] Yet other anticancer agents that can be employed in
combination with a compound of this disclosure include alkylating
agents, antimetabolites, natural products, or hormones, e.g.,
nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,
chlorambucil, etc.), alkyl sulfonates (e.g., busulfan, etc.),
nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes
(decarbazine, etc.). Examples of antimetabolites include but are
not limited to folic acid analog (e.g., methotrexate), pyrimidine
analogs (e.g., cytarabine, etc.), or purine analogs (e.g.,
mercaptopurine, thioguanine, pentostatin, etc.).
[0105] Examples of natural products useful in combination with a
compound of this disclosure include but are not limited to vinca
alkaloids (e.g., vincristine, etc.), epipodophyllotoxins (e.g.,
etoposide, etc.), antibiotics (e.g., daunorubicin, doxorubicin,
bleomycin, etc.), enzymes (e.g., L-asparaginase, etc.), or
biological response modifiers (e.g., interferon alpha, etc.).
[0106] Examples of alkylating agents that can be employed in
combination a compound of this disclosure include, but are not
limited to, nitrogen mustards (e.g., mechloroethamine,
cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and
methylmelamines (e.g., hexamethlymelamine, thiotepa, etc.), alkyl
sulfonates (e.g., busulfan, etc.), nitrosoureas (e.g., carmustine,
lomusitne, semustine, streptozocin, etc.), or triazenes
(decarbazine, etc.). Examples of antimetabolites include, but are
not limited to folic acid analog (e.g., methotrexate, etc.),
pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine,
etc.), or purine analogs (e.g., mercaptopurine, thioguanine,
pentostatin, etc.).
[0107] Examples of hormones and antagonists useful in combination a
compound of this disclosure include, but are not limited to,
adrenocorticosteroids (e.g., prednisone, etc.), progestins (e.g.,
hydroxyprogesterone caproate, megestrol acetate, and
medroxyprogesterone acetate, etc.), estrogens (e.g.,
diethylstilbestrol, and ethinyl estradiol, etc.), antiestrogen
(e.g., tamoxifen, etc.), androgens (e.g., testosterone propionate,
fluoxymesterone, etc.), antiandrogen (e.g., flutamide, etc.), and
gonadotropin releasing hormone analog (e.g., leuprolide, etc.).
Other agents that can be used in the methods and compositions
described herein for the treatment or prevention of cancer include
platinum coordination complexes (e.g., cisplatin, carboblatin,
etc.), anthracenedione (e.g., mitoxantrone, etc.), substituted urea
(e.g., hydroxyurea, etc.), methyl hydrazine derivative (e.g.,
procarbazine, etc.) and adrenocortical suppressant (e.g., mitotane,
aminoglutethimide, etc.).
[0108] Examples of anti-cancer agents which act by arresting cells
in the G2-M phases due to stabilized microtubules and which can be
used in combination with an irreversible Btk inhibitor compound
include without limitation the following marketed drugs and drugs
in development: Erbulozole (also known as R-55104), Dolastatin 10
(also known as DLS-10 and NSC-376128), Mivobulin isethionate (also
known as CI-980), Vincristine, NSC-639829, Discodermolide (also
known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010),
Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C),
Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin
3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7,
Spongistatin 8 and Spongistatin 9), Cemadotin hydrochloride (also
known as LU-103793 and NSC-D-669356), Epothilones (such as
Epothilone A, Epothilone B, Epothilone C (also known as
desoxyepothilone A or dEpoA)), Epothilone D (also referred to as
KOS-862, dEpoB and desoxyepothilone B), Epothilone E, Epothilone F,
Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,
21-aminoepothilone B (also known as BMS-310705),
21-hydroxyepothilone D (also known as Desoxyepothilone F and
dEpoF), 26-fluoroepothilone, Auristatin PE (also known as
NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P
(Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known
as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378
(Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877
(Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198
(Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF,
also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis),
SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132
(Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),
Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also
known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known
as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A),
Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as
NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and
TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261
and WHI-261), H10 (Kansas State University), H16 (Kansas State
University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313
(Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2
(Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also
known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of
Medicine, also known as MF-569), Narcosine (also known as
NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott),
Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine,
also known as MF-191), TMPN (Arizona State University), Vanadocene
acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also
known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of
Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as
T-900607), RPR-115781 (Aventis), Eleutherobins (such as
Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A and
Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131
(Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620
(Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis),
A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as
NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica),
Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099
(Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110,
trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318
(Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium,
BPR-OY-007 (National Health Research Institutes) and SSR-250411
(Sanofi).
EXAMPLES
[0109] The following preparations of compounds of Formula (I)
(Examples) and intermediates (References) are given to enable those
skilled in the art to more clearly understand and to practice the
present disclosure. They should not be considered as limiting the
scope of the disclosure, but merely as being illustrative and
representative thereof.
Reference 1
Synthesis of 1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene
##STR00175##
[0110] Step 1
[0111] 4-Bromo-2-methoxyphenol (5.0 g, 24.6 mmol), benzyl bromide
(3.2 mL, 27.1 mmol), and potassium carbonate (6.8 g, 49.3 mmol)
were added to acetonitrile (123 mL), and the reaction mixture was
heated to 80.degree. C. for 6 h. The reaction was cooled to room
temperature and diluted with water, and extracted with ethyl
acetate. The combined organics were dried with MgSO.sub.4,
filtered, and concentrated under reduced pressure to afford
1-(benzyloxy)-4-bromo-2-methoxybenzene (7.2 g, 100%) as a crude
oil.
Step 2
[0112] Nitric acid (5.0 mL) was added to a solution of
1-(benzyloxy)-4-bromo-2-methoxybenzene (7.2 g, 24.6 mmol) in acetic
acid (40.0 mL) at 0.degree. C. The reaction mixture was stirred for
16 h at room temperature. The reaction mixture was concentrated
under reduced pressure to remove bulk acetic acid. Water was added,
and the reaction mixture was cooled to 0.degree. C. which resulted
in precipitation. The precipitates were filtered, washed solid with
water, and dried under reduced pressure to afford
1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene (8.30 g; 99%) as a
yellow solid.
Reference 2
Synthesis of 1-[3-(4-bromo-2-methoxyphenoxy)propyl]pyrrolidine
##STR00176##
[0114] A mixture of 4-bromo-2-methoxyphenol (1.6 g, 7.88 mmol),
1-(3-chloro-propyl)pyrrolidine hydrochloride (1.9 g, 9.46 mmol),
and potassium carbonate (3.3 g, 23.64 mmol) in DMF (39.4 mL) was
heated at 100.degree. C. for 16 h. The reaction mixture was diluted
reaction with water, and the aqueous layer with washed with ethyl
acetate. The combined organics were dried with MgSO.sub.4,
filtered, concentrated under reduced pressure, and purified by
silica gel using 10% MeOH in DCM to afford
1-[3-(4-bromo-2-methoxyphenoxy)-propyl]pyrrolidine (1.3 g, 53%) as
a brown oil.
Reference 3
Synthesis of
1-(3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl)pyrrolidine
##STR00177##
[0116] 1-[3-(4-Bromo-2-methoxyphenoxy)propyl]pyrrolidine (17.0 g,
54.10 mmol) in acetic acid (150.0 mL) was stirred, and then
HNO.sub.3 (65%/wt. %, 30.00 mL) was added dropwise at 0.degree. C.
The resulting reaction mixture was stirred for 2 h at room
temperature. Ice water (500 mL) was added, and the mixture stirred
for 1 h at room temperature, which resulted in the formation of a
precipitate. The solids were collected by filtration. The resulting
filter cake was washed with water (2.times.30 mL) and dried under
reduced pressure to afford
1-(3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl)pyrrolidine as a
yellow solid (10.6 g, 55%).
Reference 4
Synthesis of
1-{3-[4-(4,4-dimethyl-1,3,2-dioxaborolan-2-yl)-2-methoxy-5-nitrophenoxy]--
propyl}pyrrolidine
##STR00178##
[0118] A mixture of
1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine (8.0 g,
22.27 mmol), bis(pinacolato)diboron (8.51 g, 33.51 mmol), potassium
acetate (4.4 g, 44.63 mmol), and Pd(dppf).sub.2Cl.sub.2 DCM (1.63
g, 2.23 mmol) in 1,4-dioxanes (200 mL) was stirred and heated for 3
h at 110.degree. C. under N.sub.2. The mixture was concentrated
under reduced pressure. The resulting residue was purified by
silica gel column using 10% MeOH in DCM to afford
1-{3-[4-(4,4-dimethyl-1,3,2-dioxaborolan-2-yl)-2-methoxy-5-nitr-
ophenoxy]propyl}pyrrolidine (6.1 g, 67%) as a gray solid.
Reference 5
Synthesis of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
##STR00179##
[0119] Step 1
[0120] In a 20 mL microwave vial, Pd(dppf)2Cl2.DCM (63 mg, 0.08
mmol) was added to a solution of
1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene (870 mg, 2.57 mmol),
2-chloro-3-pyridinylboronic acid (526 mg, 3.34 mmol), and 2M
potassium acetate (3.3 mL, 6.69 mmol) in DMF (9 mL). In the
microwave, the reaction was heated to 130.degree. C. for 1 h. The
reaction mixture was diluted with ethyl acetate and filtered thru a
plug of Celite. Water was added to the filtrate. Ethyl acetate was
used to wash the aqueous layer. The combined organics were dried
with MgSO.sub.4, filtered, and concentrated under reduced pressure.
The resulting residue was purified by silica gel column using 0% to
50% ethyl acetate in hexanes to afford
3-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]-2-chloropyridine (560 mg,
59%) as a yellow oil.
Step 2
[0121] 3-[4-(Benzyloxy)-5-methoxy-2-nitrophenyl]-2-chloropyridine
(1.50 g, 4.05 mmol) in triethyl phosphite (8.0 mL) was stirred and
heated for 24 h at 130.degree. C. The reaction mixture was cooled
to room temperature. The reaction mixture was concentrated under
reduced pressure to afford
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole (1.37 g,
99%) as a crude orange solid.
Step 3
[0122] Di-tert-butyl dicarbonate (1.32 g, 6.07 mmol) was added to a
mixture containing
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole (1.37 g,
4.04 mmol), Hunig's base (1.0 mL, 6.07 mmol), and DMAP (0.10 g,
0.80 mmol) in 1,4-dioxane (11 mL). The reaction mixture was stirred
for 15 minutes, and then concentrated under reduced pressure. The
resulting residue was triturated with 10% DCM in hexanes to afford
the titled compound, tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(0.62 g; 34.93%), as a white solid. MS (ESI, pos. ion) m/z: 439.0
(M+1).
Reference 6
Synthesis of
7-(benzyloxy)-4-chloro-1-fluoro-8-methoxy-5H-pyrido[4,3-b]indole
##STR00180##
[0124] The title compound was prepared as described in Reference 5,
by substituting 2-chloro-3-pyridinylboronic acid with
(5-chloro-2-fluoropyridin-3-yl)boronic acid. MS (ESI, pos. ion)
m/z: 357.0 (M+1).
Reference 7
tert-butyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
##STR00181##
[0126] Combined tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(290.00 mg; 0.66 mmol; 1.00 eq.) and 10% palladium on carbon (70.32
mg; 0.07 mmol; 0.10 eq.) in methanol (20 mL) and DCM (10 mL).
Stirred in the presence of hydrogen gas (1 atm) via balloon. The
reaction was heated to 40.degree. C. for 1 hour. Afterwards the
reaction mixture was filtered thru a plug of Celite and the
filtrate was concentrated to afford tert-butyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate (207.69
mg; 100.00%) as a white solid. MS (ESI, pos. ion) m/z: 357.0
(M-56).
Reference 8
tert-butyl
1-cyclopropyl-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carb-
oxylate
##STR00182##
[0127] Step 1
[0128] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(10.00 g; 22.78 mmol; 1.00 eq.), cyclopropylboronic acid (6.85 g;
79.74 mmol; 3.50 eq.), tricyclohexylphosphane (638.93 mg; 2.28
mmol; 0.10 eq.) and potassium phosphate, tribasic (9.67 g; 45.57
mmol; 2.00 eq.) in toluene (113.92 mL) and water (5.70 mL) was
purged with nitrogen for 10 minutes. palladium acetate (511.52 mg;
2.28 mmol; 0.10 eq.) was then added and the mixture was heated to
100 C in a sealed flask for 4 hours. The mixture was diluted with
EtOAc and washed with water and brine. The organic layer was dried
over MgSO4, filtered and concentrated. The resulting residue was
purified by column chromatography eluting with 0-50% EtOAc in
heptane to obtain tert-butyl
7-(benzyloxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylat-
e (8.85 g; 87%) as an off-white solid. 1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.32 (d, J=5.7 Hz, 1H), 8.00 (s, 1H), 7.88
(d, J=5.7 Hz, 1H), 7.83 (s, 1H), 7.50-7.45 (m, 2H), 7.42-7.36 (m,
2H), 7.36-7.29 (m, 1H), 5.19 (s, 2H), 3.90 (s, 3H), 2.79 (p, J=6.5
Hz, 1H), 1.66 (s, 9H), 1.15-1.08 (m, 4H).
Step 2
[0129] A flask charged with mixture of tert-butyl
7-(benzyloxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylat-
e (9.02 g; 20.29 mmol; 1.00 eq.) in ethanol (902.00 mL) and the
flask was purged with N2 for 10 min. Palladium hydroxide (0.57 g;
4.06 mmol; 0.20 eq.) was added to the reaction mix and the system
purged with nitrogen and then hydrogen. The mixture was left
stirring under hydrogen gas via balloon for 2 hours. The reaction
mixture was filtered over celite and the filtrate concentrated to
dryness to afford tert-butyl
1-cyclopropyl-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(5.72 g; 79%). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.64 (s, 1H),
8.28 (d, J=5.7 Hz, 1H), 7.85-7.78 (m, 2H), 7.76 (s, 1H), 3.89 (s,
3H), 2.81-2.68 (m, 1H), 1.67 (s, 9H), 1.13-1.06 (m, 4H).
Reference 9
tert-butyl
1-chloro-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxyla-
te
##STR00183##
[0131] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(401 mg, 0.91 mmol) and Pd(OH).sub.2 (101 mg) in THF (25 mL) was
purged with N.sub.2 for 10 min, followed by treatment under
hydrogen gas via balloon for 10 minutes. The resulting mixture was
allowed to stir at room temperature under hydrogen atmosphere for 8
minutes. The reaction mixture was filtered through a small pad of
celite and rinsed with MeOH. The resulting filtrate were combined
and the organic solvents were removed under reduced pressure to
provide crude product of tert-butyl
1-chloro-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(260 mg, 80%).
Reference 10
4-chloro-1-fluoro-7,8-dimethoxy-5H-pyrido[4,3-b]indole
##STR00184##
[0132] Step 1
[0133] A mixture of 1-bromo-4,5-dimethoxy-2-nitrobenzene (3.4 g;
12.97 mmol; 1.00 eq.), (5-chloro-2-fluoropyridin-3-yl)boronic acid
(4.6 g; 25.95 mmol; 2.00 eq.), Pd(dppf)2Cl2.DCM (529.76 mg; 0.65
mmol; 0.05 eq.), and Potassium Carbonate (4.5 g; 32.44 mmol; 2.50
eq.) in 1,4-dioxane (90 mL) was heated to 100.degree. C. for 4
hours. Let the reaction cool to rt. The reaction mixture was
diluted with water. The aqueous layer was extracted with ethyl
acetate. The combined organics were dried with MgSO4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel using 0% to 50% ethyl acetate in hexanes to
afford 5-chloro-3-(4,5-dimethoxy-2-nitrophenyl)-2-fluoropyridine
(3.3 g; 81%). MS (ESI, pos. ion) m/z: 313.0 (M+1).
Step 2
[0134] A mixture of
5-chloro-3-(4,5-dimethoxy-2-nitrophenyl)-2-fluoropyridine (3.3 g;
10.5 mmol; 1.00 eq.) in triethyl phosphite (35 mL; 0.30 mol/L;
10.55 mmol; 1.00 eq.) was heated to 120.degree. C. for 16 hours.
The mixture was cooled to room temperature and concentrated under
reduced pressure. The resulting residue was triturated with 33% DCM
in heptanes, filtered, and dried under hi-vac to afford the title
compound (1.7 g; 57%) MS (ESI, pos. ion) m/z: 313.0 (M+1).
Reference 11
3-(4-bromo-2-methoxy-5-nitrophenoxy)-N,N-dimethylpropan-1-amine
##STR00185##
[0136] To a solution of
[3-(4-bromo-2-methoxyphenoxy)propyl]dimethylamine (22.38 g; 77.66
mmol; 1.00 eq.) in glacial acetic acid (194.15 mL) was added 15.8N
nitric acid (22.38 mL). The reaction was stirred at room
temperature for 18 hours. Yellow precipitation formed in the
reaction mixture. Removed bulk acetic acid under reduced pressure
using a water bath at 40.degree. C. Diluted with water. Slowly
added 2M NaOH until pH .about.4. Due to large volume of water,
solid NaOH was added and stirred until pH .about.9. Let the
heterogeneous mixture stir for 30 minutes and filtered. The solid
was washed with water during filtration. The title compound (22.60
g; 87.34%) was obtained as a light yellow solid after drying under
hi-vac. .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) .delta. 7.59
(s, 1H), 7.27 (s, 1H), 4.09 (t, J=6.5 Hz, 2H), 3.91 (s, 3H), 2.38
(t, J=7.0 Hz, 2H), 2.18 (s, 6H), 1.94-1.87 (m, 2H). MS (ESI, pos.
ion) m/z: 332.9 (M+1).
Example 1
Synthesis of
1-[3-({6-methoxy-5H-pyrido[3,2-b]indol-7-yl}oxy)propyl]pyrrolidine
##STR00186##
[0137] Step 1
[0138] In a 20 mL microwave vial, a mixture of
4-bromo-2-methoxyphenol (1.50 g, 7.39 mmol), bis(pinacolato)diboron
(2.44 g, 9.6 mmol), potassium acetate (2.18 g, 22.2 mmol), and
Pd(dppf).sub.2Cl.sub.2.DCM (150.83 mg, 0.2 mmol) in 1,4-dioxane
(8.0 mL) was heated to 130.degree. C. for 1 h in a microwave
reactor. The reaction mixture was filtered thru a plug of Celite
and concentrated under reduced pressure to afford
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(1.84 g, 100%) as a crude oil.
Step 2
[0139] In a 20 mL microwave vial, a mixture of
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(1.84 g, 8.1 mmol), 2-bromo-3-nitropyridine (1 65 g, 8.1 mmol),
potassium acetate (2.18 g, 22.2 mmol), and
Pd(dppf).sub.2Cl.sub.2.DCM (181.00 mg, 0.2 mmol) in DMF (8.0 mL)
was heated to 130.degree. C. for 30 minutes in a microwave reactor.
The reaction mixture was filtered thru a plug of Celite and
concentrated under reduced pressure. The resulting residue was
purified by prep-HPLC (Prep-C18, Phenomenex Luna column,
21.2.times.250 mm; gradient elution of 0-60% MeCN in water over a
16 min period, where water contains 0.1% HCl, flow rate: 20 mL/min)
to afford 2-methoxy-4-(3-nitropyridin-2-yl)phenol (0.40 g, 22%) as
a white solid.
Step 3
[0140] A mixture of 2-methoxy-4-(3-nitropyridin-2-yl)phenol (0.40
g, 1.6 mmol), 1-(3-chloropropyl)pyrrolidine hydrochloride (0.30 g,
1.6 mmol), and potassium carbonate (0.68 g, 4.9 mmol) in DMF (10.0
mL) was heated to 100.degree. C. for 16 h. The reaction mixture was
cooled to room temperature, diluted with water and extracted with
ethyl acetate. The combined organics were dried with MgSO.sub.4,
filtered, and concentrated under reduced pressure. The resulting
residue was purified by silica gel column using 0% to 10% MeOH in
DCM to afford
2-{3-methoxy-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}-3-nitropyridine
(0.31 g, 53%).
Step 4
[0141] A mixture of
2-{3-methoxy-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}-3-nitropyridine
(0.10 g, 0.3 mmol) and triethyl phosphite (2.0 mL) was stirred and
heated to 120.degree. C. for 24 h. The resulting residue was cooled
to room temperature and concentrated under reduced pressure. The
resulting residue was purified by prep-HPLC (Prep-C18, Phenomenex
Luna column, 21.2.times.250 mm; gradient elution of 0-60% MeCN in
water over a 16 min period, where water contains 0.1% HCl, flow
rate: 20 mL/min). The more polar compound is
1-[3-({8-methoxy-5H-pyrido[3,2-b]indol-7-yl}oxy)propyl]pyrrolidine
(7.0 mg, 7%) MS (ESI, pos. ion) m/z: 326.5 (M+1). The less polar
compound is
1-[3-({6-methoxy-5H-pyrido[3,2-b]indol-7-yl}oxy)propyl]pyrrolidine
(18.0 mg, 17%) MS (ESI, pos. ion) m/z: 326.5 (M+1).
Example 2
Synthesis of
1-[3-({6-methoxy-9H-pyrido[3,4-b]indol-7-yl}oxy)propyl]pyrrolidine
##STR00187##
[0142] Step 1
[0143] In a 5 mL microwave vial, a mixture of
1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene (0.40 g, 1.2 mmol),
4-pyridinylboronic acid (0.22 g; 1.8 mmol), 2M potassium carbonate
(1.77 mL, 3.6 mmol), and Pd(dppf).sub.2Cl.sub.2.DCM (24.2 mg, 0.03
mmol) in DMF (2.0 mL) was heated to 130.degree. C. for 30 minutes
in a microwave reactor. The reaction mixture was filtered thru a
plug of Celite. The filtrate was diluted with water and extracted
with ethyl acetate. The combined organics were dried with
MgSO.sub.4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by silica gel column using 0% to 50%
ethyl acetate in hexanes to afford
4-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]pyridine (0.30 g;
75%).
Step 2
[0144] A mixture of
4-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]pyridine (0.3 g, 0.9 mmol)
and triethyl phosphite (2.0 mL) was heated to 130.degree. C. for 24
h. The reaction was cooled to room temperature and concentrated
under reduced pressure. The resulting residue was purified by
silica gel column using 0% to 75% ethyl acetate in hexanes to
afford 7-(benzyloxy)-6-methoxy-9H-pyrido[3,4-b]indole (110.00 mg,
41%).
Step 3
[0145] Di-tert-butyl dicarbonate (95 mg, 0.43 mmol) was added to a
solution of 7-(benzyloxy)-6-methoxy-9H-pyrido[3,4-b]indole (110 mg,
0.36 mmol) and DMAP (9 mg; 0.07 mmol) in 1,4-dioxane (4.0 mL). The
reaction mixture was stirred at room temperature for 1 h and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column using 0% to 45% ethyl acetate in
hexanes to afford tert-butyl
7-(benzyloxy)-6-methoxy-9H-pyrido[3,4-b]indole-9-carboxylate (70.00
mg; 48%).
Step 4
[0146] A mixture of tert-butyl
7-(benzyloxy)-6-methoxy-9H-pyrido[3,4-b]indole-9-carboxylate (70
mg, 0.17 mmol) and 10% palladium on carbon (18 mg, 0.02 mmol) in
methanol (2.0 mL) was stirred at room temperature in 1 atm of
H.sub.2 via balloon. The reaction mixture was stirred for 1 h and
filtered thru plug of Celite. The filtrate was concentrated under
reduced pressure to afford tert-butyl
7-hydroxy-6-methoxy-9H-pyrido[3,4-b]indole-9-carboxylate (54 mg,
99%).
Step 5
[0147] A mixture of tert-butyl
7-hydroxy-6-methoxy-9H-pyrido[3,4-b]indole-9-carboxylate (54 mg,
0.2 mmol), 1-(3-chloropropyl)pyrrolidine hydrochloride (47 mg, 0.3
mmol), and potassium carbonate (71 mg, 0.5 mmol) in DMF (3.0 mL)
was heated to 100.degree. C. for 16 h. The reaction mixture was
diluted with water and extracted with ethyl acetate. The combined
organics were dried with MgSO.sub.4, filtered and concentrated
under reduced pressure. The resulting crude was treated with 1M HCl
(1.0 mL) and stirred for 1 h. The aqueous mixture was purified by
prep-HPLC (Prep-C18, Phenomenex Luna column, 21.2.times.250 mm;
gradient elution of 0-60% MeCN in water over a 16 min period, where
water contains 0.1% HCl, flow rate: 20 mL/min) to afford the titled
compound,
1-[3-({6-methoxy-9H-pyrido[3,4-b]indol-7-yl}oxy)propyl]pyrrolidine
(10 mg, 18%). MS (ESI, pos. ion) m/z: 326.0 (M+1).
Example 3
Synthesis of
1-[3-({8-methoxy-1-methyl-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidi-
ne
##STR00188##
[0149] The title compound was prepared as described in Example 2,
by substituting 4-pyridinylboronic acid with
(2-methylpyridin-3-yl)boronic acid. MS (ESI, pos. ion) m/z: 340.0
(M+1).
Example 4
Synthesis of
1-[3-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidine
and
1-[3-({6-methoxy-9H-pyrido[2,3-b]indol-7-yl}oxy)propyl]pyrrolidine
##STR00189##
[0150] Step 1
[0151] In a 5 mL microwave vial, a mixture of
1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene (0.62 g, 1.83 mmol),
3-pyridinylboronic acid (0.34 g; 2.75 mmol),
Pd(dppf).sub.2Cl.sub.2.DCM (37 mg; 0.05 mmol), and 2M potassium
carbonate (2.8 mL, 5.50 mmol) in DMF (2.00 mL) was heated to
130.degree. C. for 30 minutes in a microwave reactor. The reaction
mixture was diluted ethyl acetate and filtered thru a plug of
Celite. Water was added to the filtrate, and the layers were
separated. The aqueous layer was washed with ethyl acetate. The
combined organics were dried with MgSO.sub.4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel using 0% to 50% ethyl acetate in hexanes to
afford 3-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)pyridine (0.31 g;
50%) as a dark oil.
Step 2
[0152] Trifluoroacetic acid (2 mL) was added to
3-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)pyridine (0.31 g, 0.91
mmol) and stirred for 16 h at room temperature. The reaction
mixture was concentrated under reduced pressure. The resulting
reside was purified by silica column using 0% to 80% ethyl acetate
in hexanes to afford 2-methoxy-5-nitro-4-(pyridin-3-yl)phenol (0.1
g, 45%).
Step 3
[0153] A mixture of 2-methoxy-5-nitro-4-(pyridin-3-yl)phenol (0.1
g, 0.41 mmol), 1-(3-chloropropyl)pyrrolidine hydrochloride (92 mg,
0.61 mmol) and potassium carbonate (0.17 g, 1.22 mmol) in DMF (2.0
mL) was heated to 100.degree. C. for 18 h. The reaction mixture was
cooled to room temperature. The reaction mixture was diluted with
water. The aqueous solution was extracted with ethyl acetate. The
combined organics were dried with MgSO.sub.4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column using 0% to 10% MeOH in DCM to afford
3-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}pyridine
(0.1 g, 69%).
Step 4
[0154] A mixture of
3-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}pyridine
(0.1 g, 0.28 mmol) and triethyl phosphite (2.0 mL) was heated to
120.degree. C. for 24 h. The reaction mixture was cooled to room
temperature. The resulting residue was concentrated under reduced
pressure and purified by prep-HPLC (Prep-C18, Phenomenex Luna
column, 21.2.times.250 mm; gradient elution of 0-60% MeCN in water
over a 16 min period, where water contains 0.1% HCl, flow rate: 20
mL/min) to afford the more polar regio-isomer,
1-[3-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]-pyrrolidine
(8.0 mg, 3%), MS (ESI, pos. ion) m/z: 326.2 (M+1) and less polar
region-isomer,
1-[3-({6-methoxy-9H-pyrido[2,3-b]indol-7-yl}oxy)propyl]pyrrolidine
(18.0 mg; 10%), MS (ESI, pos. ion) m/z: 326.0 (M+1).
Example 5
Synthesis of
8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-3-amine
##STR00190##
[0155] Step 1
[0156] In a 5 mL microwave vial, a mixture of
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinylamine
(0.3 g, 1.36 mmol),
1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine (0.5 g,
1.36 mmol), Pd(dppf).sub.2Cl.sub.2.DCM (33 mg, 0.04 mmol), and 2M
potassium carbonate (1.4 mL, 2.73 mmol) in DMF (2.7 mL) was heated
to 120.degree. C. for 1 h in a microwave reactor. The reaction
mixture was diluted with water. The aqueous layer was extracted
with ethyl acetate. The combined organics were dried with
MgSO.sub.4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by silica gel column using 0% to 10%
MeOH in DCM to afford
5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}pyridin-2-amine
(0.33 g, 65%) as a brown oil.
Step 2
[0157] Di-tert-butyl dicarbonate (316.45 mg; 1.45 mmol) was added
to a mixture of
5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}pyridin-2-amine
(180.00 mg; 0.48 mmol) and N,N-dimethylaminopyridine (11.81 mg;
0.10 mmol) in acetonitrile (5 mL). The reaction mixture was heated
to 50.degree. C. for 1 h. The reaction mixture was cooled to room
temperature. The reaction mixture was concentrated under reduced
pressure. The resulting residue was purified by silica gel column
using 0% to 10% MeOH in DCM to afford tert-butyl
N-[(tert-butoxy)carbonyl]-N-(5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)p-
ropoxy]phenyl}pyridin-2-yl)carbamate (0.16 g, 57%).
Step 3
[0158] A mixture of tert-butyl
N-[(tert-butoxy)carbonyl]-N-(5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)p-
ropoxy]phenyl}pyridin-2-yl)carbamate (0.16 g, 0.28 mmol) and
triethyl phosphite (3.0 mL) was heated to 120.degree. C. for 24 h.
The reaction mixture was cooled to room temperature and
concentrated under reduced pressure. 1M HCl (3 mL) was added to the
resulting residue and heated to 50.degree. C. for 1 h. The solution
was purified by prep-HPLC (Prep-C18, Phenomenex Luna column,
21.2.times.250 mm; gradient elution of 0-60% MeCN in water over a
16 min period, where water contains 0.1% HCl, flow rate: 20 mL/min)
to afford the more polar regio-isomer
8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-3-amine
(20.0 mg, 21%). MS (ESI, pos. ion) m/z: 341.4 (M+1).
Example 6
Synthesis of
1-[3-({1-fluoro-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidi-
ne
##STR00191##
[0160] The title compound was prepared as described in Example 5,
by substituting
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinylamine
with (2-fluoropyridin-3-yl)boronic acid. MS (ESI, pos. ion) m/z:
344.0 (M+1).
Example 7
Synthesis of
8-methoxy-1-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-3-
-amine
##STR00192##
[0161] Step 1
[0162] Di-tert-butyl dicarbonate (2.6 g, 11.76 mmol) was added to a
mixture of 5-bromo-6-methylpyridin-2-amine (1.1 g, 5.88 mmol) and
DMAP (0.14 g, 1.18 mmol) in THF (20.0 mL). The reaction mixture was
heated to 50.degree. C. for 1 h. The reaction mixture was cooled to
room temperature. The reaction mixture was concentrated under
reduced pressure. The resulting residue was purified by silica gel
using 0% to 30% ethyl acetate in hexanes to afford tert-butyl
N-(5-bromo-6-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate
(2.1 g, 92%).
Step 2
[0163] In a 20 mL microwave vial, a mixture of tert-butyl
N-(5-bromo-6-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate
(1.4 g, 3.62 mmol), bis(pinacolato)diboron (1.4 g, 5.42 mmol),
Pd(dppf).sub.2Cl.sub.2.DCM (74 mg, 0.09 mmol), and potassium
carbonate (2.0 g, 14.46 mmol) in 1,4-dioxanes (12.0 mL) was heated
to 130.degree. C. for 7 h. The reaction mixture was diluted with
water. The aqueous layer was extracted with ethyl acetate. The
combined organics were dried with MgSO.sub.4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column using 0% to 50% ethyl acetate in
hexanes to afford tert-butyl
N-[(tert-butoxy)carbonyl]-N-[6-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-yl]carbamate (1.5 g, 95%).
Step 3
[0164] In a 5 mL microwave vial, a mixture of tert-butyl
N-[(tert-butoxy)carbonyl]-N-[6-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-yl]carbamate (0.40 g, 0.92 mmol),
1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine (0.33 g,
0.92 mmol), Pd(dppf).sub.2Cl.sub.2.DCM (23 mg, 0.03 mmol), and 2M
potassium carbonate (0.90 mL, 1.84 mmol) in NMP (2.5 mL) was heated
to 130.degree. C. for 30 minutes in a microwave reactor. The
reaction mixture was diluted with water. The aqueous layer was
extracted with ethyl acetate. The combined organics were dried with
MgSO.sub.4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by silica gel column using 0% to 10%
MeOH in DCM to afford tert-butyl
N-[(tert-butoxy)carbonyl]-N-(5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)p-
ropoxy]phenyl}-6-methylpyridin-2-yl)carbamate (0.35 g, 65%).
Step 4
[0165] A mixture of tert-butyl
N-[(tert-butoxy)carbonyl]-N-(5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)p-
ropoxy]phenyl}-6-methylpyridin-2-yl)carbamate (0.35 g, 0.60 mmol)
and triethyl phosphite (6 mL) was heated to 120.degree. C. for 24
h. The reaction mixture was concentrated under reduced pressure. 1M
hydrochloric acid (3.00 mL) solution was added to the resulting
residue and stirred for 3 h. The aqueous solution was purified by
prep-HPLC (Prep-C18, Phenomenex Luna column, 21.2.times.250 mm;
gradient elution of 0-60% MeCN in water over a 16 min period, where
water contains 0.1% HCl, flow rate: 20 mL/min) to afford the titled
compound
8-methoxy-1-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-3-
-amine (8 mg, 4%). MS (ESI, pos. ion) m/z: 355.0 (M+1).
Example 8
Synthesis of
(3S)-1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1--
yl}pyrrolidin-3-ol
##STR00193##
[0166] Step 1
[0167] In a 20 mL microwave vial, a mixture of Brettphos G1 (25 mg,
0.03 mmol), tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(270 mg, 0.62 mmol), (3S)-3-pyrrolidinol (161 mg, 1.85 mmol), and
potassium tert-butoxide (207 mg, 1.85 mmol) in NMP (6.0 mL) was
heated to 140.degree. C. for 1.5 h in a microwave reactor. The
reaction mixture was diluted with water. The aqueous layer was
extracted with ethyl acetate. The combined organics were dried with
MgSO.sub.4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by silica gel column using 0% to 80%
ethyl acetate in hexanes to afford
(3S)-1-[7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyrrolidin-3-o-
l (239 mg, 99%).
Step 2
[0168] Di-tert-butyl dicarbonate (269 mg, 1.23 mmol) was added to a
mixture of
(3S)-1-[7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyrrolidin-3-o-
l (239 mg, 0.62 mmol), DMAP (15 mg, 0.12 mmol), and Hunig's base
(0.21 mL, 1.23 mmol) in acetonitrile (3 mL). The reaction mixture
was stirred for 2 h at room temperature and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column using 0% to 30% ethyl acetate in hexanes to afford
tert-butyl
7-(benzyloxy)-1-[(3S)-3-{[(tert-butoxy)carbonyl]oxy}pyrrolidin-1-yl]-8-me-
thoxy-5H-pyrido[4,3-b]indole-5-carboxylate (363 mg, 99%).
Step 3
[0169] A mixture of tert-butyl
7-(benzyloxy)-1-[(3S)-3-{[(tert-butoxy)carbonyl]oxy}pyrrolidin-1-yl]-8-me-
thoxy-5H-pyrido[4,3-b]indole-5-carboxylate (363.00 mg, 0.62 mmol)
and 10% wt palladium on carbon (33 mg, 0.03 mmol) in methanol (10
mL) was stirred under hydrogen gas pressure via balloon for 1 h.
The reaction mixture was filtered thru a plug of Celite and
concentrated under reduced pressure to afford tert-butyl
1-[(3S)-3-{[(tert-butoxy)carbonyl]oxy}pyrrolidin-1-yl]-7-hydroxy-8-methox-
y-5H-pyrido[4,3-b]indole-5-carboxylate (300 mg, 97%).
Step 4
[0170] A mixture of tert-butyl
1-[(3S)-3-{[(tert-butoxy)carbonyl]oxy}pyrrolidin-1-yl]-7-hydroxy-8-methox-
y-5H-pyrido[4,3-b]indole-5-carboxylate (300 mg, 0.60 mmol),
1-(3-chloropropyl)pyrrolidine hydrochloride (240 mg, 1.20 mol), and
potassium carbonate (331 mg, 2.40 mol) in DMF (6 mL) was heated to
100.degree. C. for 16 h. The reaction mixture was cooled to room
temperature, filtered, and concentrated under reduced pressure. 1M
HCl (5 mL) was added to the resulting residue and heated to
50.degree. C. for 1 h. The aqueous solution was purified by
prep-HPLC (Prep-C18, Phenomenex Luna column, 21.2.times.250 mm;
gradient elution of 0-60% MeCN in water over a 16 min period, where
water contains 0.1% HCl, flow rate: 20 mL/min) to afford the titled
compound
(3S)-1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1--
yl}pyrrolidin-3-ol (110 mg, 38%).
Example 9
Synthesis of
(3R)-1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1--
yl}pyrrolidin-3-ol
##STR00194##
[0172] The title compound was prepared as described in Example 8,
by substituting (3S)-3-pyrrolidinol with (3R)-3-pyrrolidinol. MS
(ESI, pos. ion) m/z: 411.0 (M+1).
Example 10
Synthesis of
8-methoxy-N-[(2S)-1-methoxypropan-2-yl]-7-[3-(pyrrolidin-1-yl)propoxy]-5H-
-pyrido[4,3-b]indol-1-amine
##STR00195##
[0174] The title compound was prepared as described in Example 8,
by substituting (3S)-3-pyrrolidinol with
(2S)-1-methoxypropan-2-amine. MS (ESI, pos. ion) m/z: 413.0
(M+1).
Example 11
Synthesis of
1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}py-
rrolidine
##STR00196##
[0176] The title compound was prepared as described in Example 8,
by substituting (3S)-3-pyrrolidinol with pyrolidine. MS (ESI, pos.
ion) m/z: 395.0 (M+1).
Example 12
Synthesis of
1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}pi-
peridin-4-ol
##STR00197##
[0178] The title compound was prepared as described in Example 8,
but substituted (3S)-3-pyrrolidinol with 4-hydroxypiperidine. MS
(ESI, pos. ion) m/z: 425.0 (M+1).
Example 13
Synthesis of
4-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}mo-
rpholine
##STR00198##
[0180] The title compound was prepared as described in Example 8,
by substituting (3S)-3-pyrrolidinol with morpholine. MS (ESI, pos.
ion) m/z: 411.0 (M+1).
Example 14
Synthesis of
1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}az-
etidin-3-ol
##STR00199##
[0182] The title compound was prepared as described in Example 8,
by substituting (3S)-3-pyrrolidinol with 3-hydroxyazetidine. MS
(ESI, pos. ion) m/z: 397.0.0 (M+1).
Example 15
Synthesis of
3-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}-8-
-oxa-3-azabicyclo[3.2.1]octane
##STR00200##
[0184] The title compound was prepared as described in Example 8,
by substituting (3S)-3-pyrrolidinol with
8-oxa-3-azabicyclo[3.2.1]octane. MS (ESI, pos. ion) m/z: 437.1
(M+1).
Example 16
Synthesis of
N-(2-ethoxyethyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3--
b]indol-1-amine
##STR00201##
[0185] Step 1
[0186] In a 20 mL microwave vial, a mixture of
7-(benzyloxy)-4-chloro-1-fluoro-8-methoxy-5H-pyrido[4,3-b]indole
(600 mg, 1.68 mmol), 2-ethoxyethylamine (450 mg, 5.05 mmol), and
Hunig's base (0.29 mL, 1.68 mmol) in NMP (6 mL) was heated to
120.degree. C. for 5 h in a microwave reactor. The reaction mixture
was concentrated under reduced pressure. The resulting residue was
purified by silica gel column using 0% to 50% ethyl acetate in
hexanes to afford
7-(benzyloxy)-4-chloro-N-(2-ethoxyethyl)-8-methoxy-5H-pyrido[4,3-b]indol--
1-amine (320 mg; 44%).
Step 2
[0187] Di-tert-butyl dicarbonate (522 mg, 2.39 mmol) was added to a
mixture of
7-(benzyloxy)-4-chloro-N-(2-ethoxyethyl)-8-methoxy-5H-pyrido[4,3-b]indol--
1-amine (340 mg, 0.80 mmol) and DMAP (20 mg, 0.16 mmol) in
acetonitrile (4 mL). The reaction mixture was heated to 45.degree.
C. for 1 h. The reaction mixture was cooled to room temperature and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column using 0% to 30% ethyl acetate in
hexanes to afford tert-butyl
7-(benzyloxy)-1-{[(tert-butoxy)carbonyl](2-ethoxyethyl)amino}-4-chloro-8--
methoxy-5H-pyrido[4,3-b]indole-5-carboxylate (150 mg, 30%).
Step 3
[0188] A mixture of tert-butyl
7-(benzyloxy)-1-{[(tert-butoxy)carbonyl](2-ethoxyethyl)amino}-4-chloro-8--
methoxy-5H-pyrido[4,3-b]indole-5-carboxylate (150 mg, 0.24 mmol)
and 10% wt palladium on carbon (25 mg, 0.02 mmol) in methanol (2.40
mL) was stirred under hydrogen gas via balloon for 1 h. The
reaction mixture was filtered thru a plug of Celite and
concentrated under reduced pressure to afford tert-butyl
1-{[(tert-butoxy)carbonyl](2-ethoxyethyl)amino}-7-hydroxy-8-methoxy-5H-py-
rido[4,3-b]indole-5-carboxylate (120 mg, 99%).
Step 4
[0189] A mixture of tert-butyl
1-{[(tert-butoxy)carbonyl](2-ethoxyethyl)amino}-7-hydroxy-8-methoxy-5H-py-
rido[4,3-b]indole-5-carboxylate (120 mg, 0.24 mmol),
1-(3-chloropropyl)pyrrolidine hydrochloride (88 mg, 0.48 mmol), and
potassium carbonate (132 mg, 0.96 mmol) in DMF (2.4 mL) was heated
to 100.degree. C. for 16 h. The reaction mixture was diluted with
water. The aqueous layer was extracted with ethyl acetate. The
combined organics were dried with MgSO.sub.4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by prep-HPLC (Prep-C18, Phenomenex Luna column,
21.2.times.250 mm; gradient elution of 0-60% MeCN in water over a
16 min period, where water contains 0.1% HCl, flow rate: 20 mL/min)
to afford
N-(2-ethoxyethyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3--
b]indol-1-amine (65 mg, 56%). MS (ESI, pos. ion) m/z: 413.4
(M+1).
Example 17
Synthesis of
1-[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrr-
olidine
##STR00202##
[0191] The title compound was prepared as described in Example 7,
modifying Step 1 as follows. MS (ESI, pos. ion) m/z: 366.0.0
(M+1).
Step 1
[0192] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(100 mg, 0.23 mmol), cyclopropylboronic acid (69 mg, 0.80 mmol),
tricyclohexylphosphane (6 mg, 0.02 mmol), and potassium phosphate
tribasic (97 mg, 0.46 mmol) in toluene (1.1 mL) and water (0.06 mL)
was purged with nitrogen for 10 minutes. Palladium acetate (5.1 mg;
0.02 mmol) was then added, and the sealed vial was heated to
100.degree. C. for 5 h. The mixture was diluted with ethyl acetate
and washed with water and brine. The organic layer was dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. The
resulting residue was purified by silica gel column eluting with
0-60% ethyl acetate in hexanes to obtain tert-butyl
7-(benzyloxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylat-
e (90 mg, 88%) as an off-white solid.
Example 18
Synthesis of
1-[3-({8-methoxy-5H-pyrimido[5,4-b]indol-7-yl}oxy)propyl]pyrrolidine
##STR00203##
[0193] Step 1
[0194] A mixture of
1-{3-[2-methoxy-5-nitro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pr-
opyl}pyrrolidine (500 mg, 1.23 mmol), 4,5-dichloropyrimidine (220
mg, 1.48 mmol), Pd(amphos)Cl.sub.2 (59 mg, 0.08 mmol), and 2M
sodium carbonate (1.23 mL, 2.46 mmol) in 1,4-dioxane (5 mL) was
purged with N.sub.2 for 6 min. The resulting mixture was sealed and
left stirring at 90.degree. C. for 45 minutes. The resulting
mixture was cooled to room temperature, diluted with water and
extracted with ethyl acetate. The combined organic layers were
washed with water. After removal of the organic solvents under
reduced pressure, the residue was purified by flash chromatography
on silica gel column eluted with 0-100% solvent A in
CH.sub.2Cl.sub.2 (solvent A: 0.2% NH.sub.4OH/10% MeOH/88.9%
CH.sub.2Cl.sub.2) to provide
5-chloro-4-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}-pyrim-
idine as a brown solid (422 mg, 87%).
Step 2
[0195] A mixture of
5-chloro-4-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}-pyrim-
idine (420 mg, 1.07 mmol) in ethyl acetate (5 mL) was added into a
vial charged with anhydrous SnCl.sub.2 (439 mg, 2.3 mmol). This
mixture was left stirring at 95.degree. C. for 2 h. To the mixture
was added additional anhydrous SnCl.sub.2 (200 mg, 1.04 mmol) and
ethyl acetate (2.5 mL). The resulting mixture was sealed and
allowed to stir at 65.degree. C. for 24 h. The crude solution was
cooled to room temperature, treated with water and then 20% aqueous
NaOH. The mixture was extracted with a mixture solvent of 25%
.sup.iPrOH/75% chloroform thrice. After removal of the organic
solvents under reduced pressure, the residue was purified by flash
chromatography on silica gel column eluted with 0-100% solvent A in
solvent B (solvent A: 0.2% NH.sub.4OH/10% MeOH/88.9%
CH.sub.2Cl.sub.2; solvent B: 1% NH.sub.4OH/99% MeOH) to provide
2-(5-chloropyrimidin-4-yl)-4-methoxy-5-[3-(pyrrolidin-1-yl)propox-
y]aniline (150 mg, 39%) as a brown syrup.
Step 3
[0196] A mixture of
2-(5-chloropyrimidin-4-yl)-4-methoxy-5-[3-(pyrrolidin-1-yl)propoxy]anilin-
e (120 mg, 0.33 mmol), potassium tert-butoxide (371 mg, 3.31 mmol),
and Brettphos G1 (34 mg, 0.04 mmol) in 1,4-dioxane (10 mL) was
purged with N.sub.2 for 5 minutes. The resulting mixture was sealed
and allowed to stir at 90.degree. C. for 45 minutes. The crude
mixture was cooled to room temperature and treated with water.
After removal of the volatiles under reduced pressure, the residue
was dissolved in DMSO (6 mL) filtered through a small pad of
celite, and purified by prep-HPLC (Prep-C18, Phenomenex Luna
column, 21.2.times.250 mm; gradient elution of 0-60% MeCN in water
over a 16 min period, where water contains 0.1% HCl, flow rate: 20
mL/min) to provide the title compound
(1-[3-({8-methoxy-5H-pyrimido[5,4-b]indol-7-yl}oxy)propyl]pyrrolidine
(34 mg, 32%). MS (ESI, pos. ion) m/z: 327.0.0 (M+1).
Example 19
3-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}-8--
oxa-3-azabicyclo[3.2.1]octane
##STR00204##
[0198] The title compound was prepared as described in Example 36,
Steps 1-4, but substituting (3S)-3-pyrrolidinol with
8-oxa-3-azabicyclo[3.2.1]octane. MS (ESI, pos. ion) m/z: 437.1
(M+1).
Example 20
N-(2-ethoxyethyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b-
]indol-1-amine
##STR00205##
[0199] Step 1
[0200] Combined
7-(benzyloxy)-4-chloro-1-fluoro-8-methoxy-5H-pyrido[4,3-b]indole
(600 mg, 1.68 mmol), 2-ethoxyethylamine (450 mg, 5.05 mmol), and
Hunig's base (0.29 mL, 1.68 mmol) in NMP (6 mL) in a microwave
vial. Heated the reaction to 120.degree. C. for 5 hours in the
microwave. Concentrated under reduced pressure and purified
resulting residue by silica gel column using 0% to 50% ethyl
acetate in hexanes to afford
7-(benzyloxy)-4-chloro-N-(2-ethoxyethyl)-8-methoxy-5H-pyrido[4,3-b]indol--
1-amine (320 mg; 44%).
Step 2
[0201] Di-tert-butyl dicarbonate (522 mg, 2.39 mmol) was added to a
solution containing
7-(benzyloxy)-4-chloro-N-(2-ethoxyethyl)-8-methoxy-5H-pyrido[4,3-b]indol--
1-amine (340 mg, 0.80 mmol) and DMAP (20 mg, 0.16 mmol) in
acetonitrile (4 mL). Heated the reaction to 45.degree. C. for 1
hour. Concentrated and purified by silica gel column using 0% to
30% ethyl acetate in hexanes to afford tert-butyl
7-(benzyloxy)-1-{[(tert-butoxy)carbonyl](2-ethoxyethyl)amino}-4-chloro-8--
methoxy-5H-pyrido[4,3-b]indole-5-carboxylate (150 mg, 30%).
Step 3
[0202] Combined tert-butyl
7-(benzyloxy)-1-{[(tert-butoxy)carbonyl](2-ethoxyethyl)amino}-4-chloro-8--
methoxy-5H-pyrido[4,3-b]indole-5-carboxylate (150 mg, 0.24 mmol)
and 10% wt palladium on carbon (25 mg, 0.02 mmol) in methanol (2.40
mL). Stirred under hydrogen gas via balloon for 1 hour. Filtered
thru a plug of Celite and concentrated under reduced pressure to
afford tert-butyl
1-{[(tert-butoxy)carbonyl](2-ethoxyethyl)amino}-7-hydroxy-8-methoxy-5H-py-
rido[4,3-b]indole-5-carboxylate (120 mg, 99%).
Step 4
[0203] Combined tert-butyl
1-{[(tert-butoxy)carbonyl](2-ethoxyethyl)amino}-7-hydroxy-8-methoxy-5H-py-
rido[4,3-b]indole-5-carboxylate (120 mg, 0.24 mmol),
1-(3-chloropropyl)pyrrolidine hydrochloride (88 mg, 0.48 mmol), and
potassium carbonate (132 mg, 0.96 mmol) in DMF (2.4 mL). Heated the
reaction to 100.degree. C. for 16 hours. Diluted reaction with
water. Washed aqueous layer with ethyl acetate. Combined organics,
dried with MgSO.sub.4, filtered, and concentrated under reduced
pressure. Purified by prep HPLC (Prep-C18, Phenomenex Luna column,
21.2.times.250 mm; gradient elution of 0-60% MeCN in water over a
16 min period, where water contains 0.1% HCl, flow rate: 20 mL/min)
to afford the title compound (65 mg, 56%). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.91 (s, 1H), 7.67 (d, J=7.0 Hz, 1H),
7.26 (s, 1H), 7.11 (d, J=7.0 Hz, 1H), 4.28 (t, J=5.5 Hz, 2H), 4.03
(s, 3H), 3.92-3.76 (m, 4H), 3.58 (q, J=7.0 Hz, 2H), 3.50 (t, J=7.0
Hz, 2H), 3.16 (dt, J=10.0, 7.5 Hz, 2H), 2.34 (dq, J=12.6, 6.5, 6.0
Hz, 2H), 2.26-2.14 (m, 2H), 2.13-1.98 (m, 2H), 1.16 (t, J=7.0 Hz,
3H). MS (ESI, pos. ion) m/z: 413.4 (M+1).
Example 21
1-[3-({8-methoxy-1-propyl-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidin-
e Hydrochloride
##STR00206##
[0204] Step 1
[0205] A flask charged with a mixture of tert-butyl
7-(benzyloxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylat-
e, Reference 8, step 1 (1.77 g; 3.98 mmol; 1.00 eq.) and palladium
on carbon (0.88 g; 0.83 mmol; 0.21 eq.) in MeOH (60 mL) was purged
with N.sub.2 for 10 min, followed by hydrogen gas via balloon for
22 hours. The reaction mixture was filtered through a small pad of
celite and rinsed with MeOH. The organic solutions were combined.
After removal of the organic solvents under reduced pressure, the
resulting residue was purified by flash chromatography on silica
gel column eluted with 0-100% EtOAc in Hexanes to provide
tert-butyl
7-hydroxy-8-methoxy-1-propyl-5H-pyrido[4,3-b]indole-5-carboxylate
as white solid (0.52 g) and tert-butyl
1-cyclopropyl-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
as white solid (0.78).
Step 2
[0206] To a vial charged with tert-butyl
7-hydroxy-8-methoxy-1-propyl-5H-pyrido[4,3-b]indole-5-carboxylate
(44.00 mg; 0.14 mmol; 1.00 eq.) was added a solution of
(tributylphosphoranylidene)acetonitrile (130.76 mg; 0.54 mmol) in
CH.sub.2Cl.sub.2 (0.5 mL). The mixture was allowed to stir at
60.degree. C. with N.sub.2 line to blow off the solvents
completely. To the resulting residue was added
3-(pyrrolidin-1-yl)propan-1-ol (58.18 mg; 0.45 mmol; 1.50 eq.) in
CH.sub.2Cl.sub.2 (0.3 mL). After removal of the solvent under
N.sub.2 line, the vial was sealed and the residue was allowed to be
heated at 60.degree. C. for 1 hour. The mixture was purified by
flash chromatography on silica gel column eluted with 0-100%
solvent A (solvent A: 0.3% NH.sub.4OH/10% MeOH/89.7%
CH.sub.2Cl.sub.2) in CH.sub.2Cl.sub.2 to provide tert-butyl
8-methoxy-1-propyl-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indole--
5-carboxylate as a colorless solid (38 mg, 63%). MS (ESI, pos. ion)
m/z: 468.2 (M+1).
Step 3
[0207] A mixture of tert-butyl
8-methoxy-1-propyl-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indole--
5-carboxylate (38 mg, 0.08 mmol) in TFA (2.0 mL) was allowed to
stir at 90.degree. C. for 20 min. The resulting mixture was allowed
to cool to room temperature and the residue was purified by Prep
HPLC (Waters XSelect CSH C18 column, 19.times.150 mm; gradient
elution of 0-40% CH.sub.3CN in water 0.1% formic acid over a 20 min
period, flow rate 28 ml/min) to provide the title compound (11 mg,
28%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.09 (s, 1H),
10.76 (s, 1H), 8.35 (d, J=6.7 Hz, 1H), 7.78 (d, J=6.7 Hz, 1H), 7.58
(s, 1H), 7.32 (s, 1H), 4.21 (t, J=6.1 Hz, 2H), 3.91 (s, 3H),
3.58-3.44 (m, 4H), 3.27 (s, 2H), 3.00 (s, 2H), 2.23 (dq, J=12.7,
6.4 Hz, 2H), 1.98 (d, J=7.7 Hz, 2H), 1.87 (h, J=7.2 Hz, 4H), 0.99
(t, J=7.3 Hz, 3H). MS (ESI, pos. ion) m/z: 368.1 (M+1).
Example 22
1-[3-({6-methoxy-9H-pyrimido[4,5-b]indol-7-yl}oxy)propyl]pyrrolidine
Hydrochloride
##STR00207##
[0208] Step 1
[0209] To a mixture of
1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene, Reference 1 (2.0 g;
5.91 mmol; 1.00 eq.), 5-pyrimidinylboronic acid (1.1 mg; 8.87 mmol;
1.50 eq.), Pd(dppf).sub.2Cl.sub.2--CH.sub.2Cl.sub.2 (483.00 mg;
0.59 mmol; 0.10 eq.) and cesium carbonate (3.85 mg; 11.83 mmol;
2.00 eq.) in DMF (12 mL) was added saturated aqueous NaHCO.sub.3 (5
mL). The mixture was purged with N.sub.2 for 5 min, sealed and
allowed to stir at 120.degree. C. under N.sub.2 for 30 min. The
resulting reaction mixture was allowed to cool to rt, diluted with
water and extracted with 25% .sup.iPrOH/chloroform thrice. The
organic solutions were combined. After removal of the volatiles
under reduced pressure, the residue was purified by flash
chromatography on silica gel column eluted 0-100% solvent A
(solvent A: 0.3% NH.sub.4OH/10% MeOH/89.7% CH.sub.2Cl.sub.2) in
CH.sub.2Cl.sub.2 to provide
5-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]pyrimidine (2.05 g) as
colorless syrup. MS (ESI, pos. ion) m/z: 338.2 (M+1).
Step 2
[0210] To a vial charged with
5-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]pyrimidine (1.20 g, 3.56
mmol, 1.00 eq.) was added triethyl phosphite (5 mL). This mixture
was sealed and allowed to stir at 120.degree. C. for 30 h. After
removal of the volatiles under reduced pressure, the residue was
subjected to 25 g silica gel column for purification using 0-100%
solvent A (solvent A: 0.3% NH.sub.4OH/10% MeOH/89.7%
CH.sub.2Cl.sub.2) in CH.sub.2Cl.sub.2 to provide
7-(benzyloxy)-6-methoxy-9H-pyrimido[4,5-b]indole as brown syrup
(387 mg, 35%). MS (ESI, pos. ion) m/z: 306.1 (M+1).
Step 3
[0211] A mixture of
7-(benzyloxy)-6-methoxy-9H-pyrimido[4,5-b]indole (0.370 g, 1.21
mmol, 1.00 eq.), di-tert-butyl carbonate (310 mg, 1.82 mmol, 1.5
eq.), N,N-dimethylpyridin-4-amine (145 mg, 1.21 mmol, 1.0 eq.) in
CH.sub.2Cl.sub.2 (4 mL) and Et.sub.3N (1 mL) was allowed to stir at
rt for 12 hr. After removal of the volatiles under reduced
pressure, the residue was subjected to 10 g silica gel column for
purification using 0-50% solvent A (solvent A: 0.3% NH.sub.4OH/10%
MeOH/89.7% CH.sub.2Cl.sub.2) in CH.sub.2Cl.sub.2 to provide
tert-butyl
7-(benzyloxy)-6-methoxy-9H-pyrimido[4,5-b]indole-9-carboxylate as
colorless solid (284 mg, 58%). MS (ESI, pos. ion) m/z: 306.0
(M-100+1).
Step 4
[0212] A suspension of tert-butyl
7-(benzyloxy)-6-methoxy-9H-pyrimido[4,5-b]indole-9-carboxylate
(283.00 mg; 0.70 mmol) and Pd/C (80 mg) in MeOH (10 mL) was purged
with N.sub.2 followed with H.sub.2 for 5 mins respectively. The
mixture was allowed to stir at rt for 3.0 h. The solid was filtered
off through a small pad of celite and washed with MeOH thrice. The
organic solutions were combined. Removal of the volatiles under
reduced pressure provide tert-butyl
7-hydroxy-6-methoxy-9H-pyrimido[4,5-b]indole-9-carboxylate as a
crude solid (185 mg, 85%). MS (ESI, pos. ion) m/z: 215.8
(M-100+1).
Step 5
[0213] The title compound was made from tert-butyl
7-hydroxy-6-methoxy-9H-pyrimido[4,5-b]indole-9-carboxylate
following a synthetic sequence similar as described for Example 21.
The crude product was purified with preparative HPLC (Prep-C18,
Waters SunFire column, 19.times.150 mm; gradient elution of 0-40%
CH.sub.3CN in water over a 20 min period, where both solvents
contain 0.1% HCl) to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 13.53 (br, 1H), 10.85 (br, 1H), 9.60 (s,
1H), 9.18 (s, 1H), 8.01 (s, 1H), 7.21 (s, 1H), 4.21 (t, J=6.1 Hz,
2H), 3.86 (s, 3H), 3.55 (m, 2H), 3.28 (m, 2H), 2.99 (dq, J=10.3,
7.3 Hz, 2H), 2.23 (dq, J=12.7, 6.3 Hz, 2H), 2.04-1.77 (m, 4H); MS
(ESI, pos. ion) m/z: 326.8 (M+1).
Example 23
4-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}pyr-
idine bishydrochloride
##STR00208##
[0215] The title compound was prepared as described in Example 24,
Steps 1-4, but substituting 4-pyridinylboronic acid with
3-pyridinylboronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 13.58 (s, 1H), 11.06 (s, 1H), 9.10-9.04 (m, 2H), 8.58 (d,
J=6.6 Hz, 1H), 8.16-8.10 (m, 2H), 8.01 (d, J=6.6 Hz, 1H), 7.34 (s,
1H), 6.88 (s, 1H), 4.21-4.19 (m, 2H), 3.60 (s, 3H), 3.56-3.48 (m,
2H), 3.29-3.21 (m, 2H), 3.01-2.91 (m, 2H), 2.26-2.18 (m, 2H),
1.99-1.81 (m, 4H). MS (ESI, pos. ion) m/z: 403.3 (M+1).
Example 24
3-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}pyr-
idine bishydrochloride
##STR00209##
[0216] Step 1
[0217] Tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate,
Reference 5 (0.10 g; 0.23 mmol; 1.00 eq.) and 3-pyridinylboronic
acid (33.61 mg; 0.27 mmol; 1.20 eq.) were suspended in
1,2-dimethoxyethane (3.5 mL). The mixture was purged with argon
gas. Water (0.6 mL) and sodium carbonate solution (0.46 mL; 2.50
mol/L; 1.14 mmol; 5.00 eq.) were added next.
Tetrakis(triphenylphosphane) palladium (13.16 mg; 0.01 mmol; 0.05
eq.) was then added and the reaction vessel was sealed and stirred
in a heat block at 100.degree. C. After 6 h, the reaction was
cooled and found to be an .about.4:1 mixture of des-Boc:N-Boc
product. The reaction mixture was partitioned into ethyl acetate,
water and sodium bicarbonate solution. The phases were separated,
the aqueous phase was extracted 2.times. more with ethyl acetate,
and the combined organic phases were dried over magnesium sulfate.
After evaporation the mixture was purified by silica gel
chromatography (10-80% ethyl acetate/dichloromethane, then 0-10%
methanol/dichloromethane) to give a residue of tert-butyl
7-(benzyloxy)-8-methoxy-1-(pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxy-
late (40 mg, 14%) MS (ESI, pos. ion) m/z: 482.3 (M+1). and a solid
of 3-[7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyridine
(210 mg, 85%). MS (ESI, pos. ion) m/z: 482.3 (M+1).
Step 2
[0218]
3-[7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyridine
(0.21 g; 0.56 mmol; 1.00 eq.) was suspended in 1,4-dioxane (6 mL).
Hunig's base (0.20 mL; 1.13 mmol; 2.00 eq.), di-tert-butyl
dicarbonate (0.18 g; 0.85 mmol; 1.50 eq.) in 1,4-dioxane (1 mL) and
N,N-dimethylaminopyridine (6.89 mg; 0.06 mmol; 0.10 eq.) were added
and the reaction was stirred at 30.degree. C. for 16 h. The
solution was then partitioned into ethyl acetate, water and sodium
bicarbonate solution. The phases were separated. The aqueous phase
was extracted with ethyl acetate. The combined organic phases were
washed with sodium chloride solution and dried over magnesium
sulfate. After evaporation the residue was purified by silica gel
chromatography (10%-80% ethyl acetate/dichloromethane) to give a
film of tert-butyl
7-(benzyloxy)-8-methoxy-1-(pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxy-
late (266 mg, 98%). MS (ESI, pos. ion) m/z: 482.3 (M+1).
Step 3
[0219] Tert-butyl
7-(benzyloxy)-8-methoxy-1-(pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxy-
late (308.00 mg; 0.64 mmol; 1.00 eq.) was dissolved in ethanol (7
mL). 10% Palladium on carbon (10.21 mg; 0.01 mmol; 0.01 eq.)
(Aldrich 10%) was carefully added and the reaction vessel was then
charged with an H.sub.2 balloon. After 1.5 h, more palladium on
carbon (10.21 mg; 0.01 mmol; 0.01 eq.) was added and the reaction
stirred for 14 h. Over the next 9 h, two more portions or palladium
on carbon were added (85 mg total) and the reaction was allowed to
stir for 14 h more. The mixture was then purged with nitrogen gas,
filtered through Celite, rinsed through with methanol and
evaporated to a foamy residue of tert-butyl
7-hydroxy-8-methoxy-1-(pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate
(226 mg, 95%). MS (ESI, pos. ion) m/z: 392.2 (M+1).
Step 4
[0220] Tert-butyl
7-hydroxy-8-methoxy-1-(pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate
(226.00 mg; 0.58 mmol; 1.00 eq.) was dissolved in
N,N-dimethylformamide (6 mL). 1-(3-Chloropropyl)pyrrolidin-1-ium
chloride (159.45 mg; 0.87 mmol; 1.50 eq.) and potassium carbonate
(278.88 mg; 2.02 mmol; 3.50 eq.) were added and the reaction was
then stirred in a heat block at 98.degree. C. After 13 h, The
mixture was partitioned into ethyl acetate, water and sodium
bicarbonate solution. The phases were separated, the aqueous phase
was extracted 3.times. more with ethyl acetate, the combined
organic phases washed with sodium chloride solution and dried over
magnesium sulfate. After evaporation the residue was dissolved in
dichloromethane (6 mL) and trifluoroacetic acid (2.90 mL; 0.20
mol/L; 0.58 mmol; 1.00 eq.) was added slowly. The reaction was
evaporated to dryness after 1.5 h and then toluene (20 mL) was
added. The residue was triturated, and the solvent was evaporated.
The residue was purified by reverse phase chromatography
(Phenomenex Luna C18, 21.times.250 mm, 0-50% acetonitrile/0.1%
aqueous HCl gradient over 10 minutes, flow rate 28 ml/min) to give
a yellow solid of
3-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}py-
ridine bishydrochloride (102 mg, 37%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 15.46 (s, 1H), 13.56 (s, 1H), 11.07 (s, 1H),
9.19 (d, J=2.2 Hz, 1H), 9.02 (dd, J=5.0, 1.6 Hz, 1H), 8.60 (d,
J=6.7 Hz, 1H), 8.53 (dt, J=8.0, 2.0 Hz, 1H), 8.02 (d, J=6.6 Hz,
1H), 7.92 (dd, J=7.9, 5.0 Hz, 1H), 7.37 (s, 1H), 6.83 (s, 1H), 4.23
(t, J=6.2 Hz, 2H), 3.62-3.52 (m, 5H), 3.32-3.24 (m, 2H), 3.05-2.96
(m, 2H), 2.29-2.21 (m, 2H), 2.04-1.84 (m, 4H). MS (ESI, pos. ion)
m/z: 403.3 (M+1).
Example 25
2-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}pyr-
idine Bishydrochloride
##STR00210##
[0221] Step 1
[0222] Tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(0.25 g; 0.57 mmol; 1.00 eq.) (intermediate-) was suspended in
1,4-dioxane (7 mL) The mixture was purged with argon gas.
2-(Tributylstannyl)pyridine (0.20 mL; 0.63 mmol; 1.10 eq.) and then
tetrakis(triphenylphosphane) palladium (65.82 mg; 0.06 mmol; 0.10
eq.) were added and the reaction was sealed and stirred in a heat
block at 105.degree. C. After 3.5 h, the reaction was cooled and
found to have a mixture of 5:1 N-Boc product and des-Boc product.
The reaction was then filtered through Celite, rinsed through with
ethyl acetate and evaporated. The residue was purified by silica
gel chromatography (10-67% ethyl acetate/dichloromethane, then
0-10% methanol/dichloromethane) to give a solid of tert-butyl
7-(benzyloxy)-8-methoxy-1-(pyridin-2-yl)-5H-pyrido[4,3-b]indole-5-carboxy-
late (.about.0.25 g). MS (ESI, pos. ion) m/z: 482.2 (M+1).
Step 2
[0223] Tert-butyl
7-(benzyloxy)-8-methoxy-1-(pyridin-2-yl)-5H-pyrido[4,3-b]indole-5-carboxy-
late (308.00 mg; 0.64 mmol; 1.00 eq.) was suspended in ethanol (7
mL). 10% Palladium on carbon (10.21 mg; 0.01 mmol; 0.01 eq.)
(Aldrich 10%) was added carefully and the reaction vessel was
charged with an H.sub.2 balloon. After 30 m, more palladium on
carbon (10.21 mg; 0.01 mmol; 0.01 eq.) was added and the reaction
stirred for 14 h. Over the next 6 d, seven more portions of
palladium on carbon were added (485 mg total) and the reaction was
stirred further for 21 h. The reaction was then purged with
nitrogen gas, filtered through Celite, rinsed through with methanol
and ethanol, and evaporated. The crude was purified by silica gel
chromatography (0-10% methanol/dichloromethane) to separate
over-reduced products. Tert-butyl
7-hydroxy-8-methoxy-1-(pyridin-2-yl)-5H-pyrido[4,3-b]indole-5-carboxylate
(146 mg, 58%) was isolated as a glassy residue.
Step 3
[0224] Tert-butyl
7-hydroxy-8-methoxy-1-(pyridin-2-yl)-5H-pyrido[4,3-b]indole-5-carboxylate
(146.00 mg; 0.37 mmol; 1.00 eq.) was dissolved in
N,N-dimethylformamide (4 mL). 1-(3-chloropropyl)pyrrolidin-1-ium
chloride (103.01 mg; 0.56 mmol; 1.50 eq.) and potassium carbonate
(180.16 mg; 1.31 mmol; 3.50 eq.) were added and the mixture was
stirred in a heat block at 98.degree. C. After 5.5 h, the reaction
was cooled and partitioned into ethyl acetate, water and sodium
bicarbonate solution. The phases were separated, the aqueous phase
was extracted 3.times. more with ethyl acetate, the combined
organic phases were washed with sodium chloride solution and dried
over magnesium sulfate. Solvent was evaporated and the residue was
dissolved in dichloromethane (4 mL). Trifluoroacetic acid (1.85 mL;
0.20 mol/L; 0.37 mmol; 0.99 eq.) was added slowly and the solution
was stirred for 3 h. The reaction was evaporated to dryness and
then toluene (20 mL) was added. The residue was triturated, solvent
was evaporated and then purified by reverse phase chromatography
(Waters XSelect CSH C18 column, 19.times.250 mm, 0-65%
acetonitrile/0.1% aqueous HCl gradient over 10 minutes, flow rate
28 ml/min) to give an orange solid of
2-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}py-
ridine bishydrochloride (77 mg, 43%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.43 (s, 1H), 10.86 (s, 1H), 9.08-9.03 (m,
1H), 8.57 (d, J=6.7 Hz, 1H), 8.32-8.23 (m, 2H), 8.03 (d, J=6.6 Hz,
1H), 7.83 (ddd, J=6.8, 4.8, 1.9 Hz, 1H), 7.46 (s, 1H), 7.36 (s,
1H), 4.25 (t, J=6.2 Hz, 2H), 3.60-3.55 (m, 2H), 3.33-3.26 (m, 2H),
3.06-2.96 (m, 2H), 2.30-2.21 (m, 2H), 2.06-1.95 (m, 2H), 1.95-1.84
(m, 2H). MS (ESI, pos. ion) m/z: 403.3 (M+1).
Example 26
1-[3-({6-methoxy-5H-pyrido[3,2-b]indol-7-yl}oxy)propyl]pyrrolidine
Hydrochloride
##STR00211##
[0225] Example 27
1-[3-({8-methoxy-5H-pyrido[3,2-b]indol-7-yl}oxy)propyl]pyrrolidine
Hydrochloride
##STR00212##
[0226] Step 1
[0227] 4-bromo-2-methoxyphenol (1.50 g, 7.39 mmol),
bis(pinacolato)diboron (2.44 g, 9.6 mmol), potassium acetate (2.18
g, 22.2 mmol), and Pd(dppf).sub.2Cl.sub.2.DCM (150.83 mg, 0.2 mmol)
in 1,4-dioxane (8.0 mL) were combined in a microwave vial. The
mixture was heated to 130.degree. C. for 1 hour in a microwave
reactor. The mixture was then filtered through a plug of Celite and
concentrated under reduced pressure to afford
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(1.84 g, 100%) as a crude oil.
Step 2
[0228]
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(1.84 g, 8.1 mmol), 2-bromo-3-nitropyridine (1 65 g, 8.1 mmol),
potassium acetate (2.18 g, 22.2 mmol), and
Pd(dppf).sub.2Cl.sub.2.DCM (181.00 mg, 0.2 mmol) were combined in
DMF (8.0 mL) in a microwave vial. The mixture was heated to
130.degree. C. for 30 minutes in a microwave reactor. The mixture
was filtered through a plug of Celite, and then concentrated. The
residue was purified by prep HPLC (Prep-C18, Phenomenex Luna
column, 21.2.times.250 mm; gradient elution of 0-60% MeCN in water
over a 16 min period, where water contains 0.1% HCl, flow rate: 20
mL/min) to afford 2-methoxy-4-(3-nitropyridin-2-yl)phenol (0.40 g,
22%) as a white solid.
Step 3
[0229] 2-methoxy-4-(3-nitropyridin-2-yl)phenol (0.40 g, 1.6 mmol),
1-(3-chloropropyl)pyrrolidine hydrochloride (0.30 g, 1.6 mmol) and
potassium carbonate (0.68 g, 4.9 mmol) in DMF (10.0 mL) were
combined, and then heated to 100.degree. C. for overnight. The
mixture was diluted with water, extracted with ethyl acetate,
combined organics, dried with MgSO.sub.4, filtered, concentrated
under reduced pressure and purified by silica gel column using 0%
to 10% MeOH in DCM to afford
2-{3-methoxy-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}-3-nitropyridine
(0.31 g, 53%).
Step 4
[0230]
2-{3-methoxy-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}-3-nitropyridine
(0.10 g, 0.3 mmol) and triethyl phosphite (2.0 mL) were combined.
The mixture was heated to 120.degree. C. for 24 hours. The mixture
was concentrated under reduced pressure and purified by prep HPLC
(Prep-C18, Phenomenex Luna column, 21.2.times.250 mm; gradient
elution of 0-60% MeCN in water over a 16 min period, where water
contains 0.1% HCl, flow rate: 20 mL/min). The more polar compound
is
1-[3-({8-methoxy-5H-pyrido[3,2-b]indol-7-yl}oxy)propyl]pyrrolidine
(Example 26, 7.0 mg, 7%) MS (ESI, pos. ion) m/z: 326.5 (M+1). The
less polar compound is
1-[3-({6-methoxy-5H-pyrido[3,2-b]indol-7-yl}oxy)propyl]pyrrolidine
(Example 27, 18.0 mg, 17%) MS (ESI, pos. ion) m/z: 326.5 (M+1).
Example 28
1-[3-({6-methoxy-9H-pyrido[3,4-b]indol-7-yl}oxy)propyl]pyrrolidine
Hydrochloride
##STR00213##
[0231] Step 1
[0232] 1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene (0.40 g, 1.2
mmol), 4-pyridinylboronic acid (0.22 g; 1.8 mmol), 2M potassium
carbonate (1.77 mL, 3.6 mmol) and Pd(dppf).sub.2Cl.sub.2.DCM (24.2
mg, 0.03 mmol) were combined in DMF (2.0 mL) in a microwave vial.
The mixture was heated in the microwave at 130.degree. C. for 30
minutes. The mixture was filtered through a plug of Celite. The
mixture was then diluted with water, and extracted with ethyl
acetate. The combined organics were dried with MgSO.sub.4,
filtered, concentrated under reduced pressure and purified by
silica gel column using 0% to 50% ethyl acetate in hexanes to
obtain 4-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]pyridine (0.30 g;
75%). MS (ESI, pos. ion) m/z: 337.2 (M+1).
Step 2
[0233] 4-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]pyridine (0.3 g,
0.9 mmol) and triethyl phosphite (2.0 mL) were combined, and the
resulting mixture was heated to 130.degree. C. for 24 hours. The
reaction was cooled to room temperature, then concentrated under
reduced pressure and purified by silica gel column using 0% to 75%
ethyl acetate in hexanes to afford
7-(benzyloxy)-6-methoxy-9H-pyrido[3,4-b]indole (110.00 mg, 41%). MS
(ESI, pos. ion) m/z: 305.2 (M+1).
Step 3
[0234] 7-(benzyloxy)-6-methoxy-9H-pyrido[3,4-b]indole (110 mg, 0.36
mmol), DMAP (9 mg; 0.07 mmol), and di-tert-butyl dicarbonate (95
mg, 0.43 mmol) were combined in 1,4-dioxane (4.0 mL). The reaction
stirred at room temperature for 1 hour., then concentrated under
reduced pressure and purified by silica gel column using 0% to 45%
ethyl acetate in hexanes to afford tert-butyl
7-(benzyloxy)-6-methoxy-9H-pyrido[3,4-b]indole-9-carboxylate (70.00
mg; 48%). MS (ESI, pos. ion) m/z: 348.9 (M-56).
Step 4
[0235] Tert-butyl
7-(benzyloxy)-6-methoxy-9H-pyrido[3,4-b]indole-9-carboxylate (70
mg, 0.17 mmol) and 10% palladium on carbon (18 mg, 0.02 mmol) were
combined in methanol (2.0 mL). The mixture was stirred at room
temperature in 1 atm of H.sub.2 via balloon for 1 hour. The mixture
was filtered through a plug of Celite and then concentrated to
afford tert-butyl
7-hydroxy-6-methoxy-9H-pyrido[3,4-b]indole-9-carboxylate (54 mg,
99%). MS (ESI, pos. ion) m/z: 258.9 (M-56).
Step 5
[0236] Tert-butyl
7-hydroxy-6-methoxy-9H-pyrido[3,4-b]indole-9-carboxylate (54 mg,
0.2 mmol), 1-(3-chloropropyl)pyrrolidine hydrochloride (47 mg, 0.3
mmol), and potassium carbonate (71 mg, 0.5 mmol) were combined in
DMF (3.0 mL). The mixture was heated to 100.degree. C. for 16
hours. The mixture was diluted with water, and extracted with ethyl
acetate. The combined organics were dried with MgSO.sub.4, filtered
and concentrated to afford the crude product. The resulting crude
was treated with 1M HCl (1.0 mL), stirred for 1 hour and then
purified by prep HPLC (Prep-C18, Phenomenex Luna column,
21.2.times.250 mm; gradient elution of 0-60% MeCN in water over a
16 min period, where water contains 0.1% HCl, flow rate: 20 mL/min)
to afford the title compound (10 mg, 18%). MS (ESI, pos. ion) m/z:
326.0 (M+1).
Example 29
1-[3-({8-methoxy-1-methyl-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidin-
e Hydrochloride
##STR00214##
[0238] The title compound was prepared as described in Example 28,
Steps 1-5 above, but substituting 4-pyridinylboronic acid with
(2-methylpyridin-3-yl)boronic acid. MS (ESI, pos. ion) m/z: 340.0
(M+1).
Example 30
1-[3-({6-methoxy-9H-pyrido[2,3-b]indol-7-yl}oxy)propyl]pyrrolidine
Hydrochloride
##STR00215##
[0239] Step 1
[0240] 1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene (0.62 g, 1.83
mmol), 3-pyridinylboronic acid (0.34 g; 2.75 mmol),
Pd(dppf).sub.2Cl.sub.2.DCM (37 mg; 0.05 mmol) and 2M potassium
carbonate (2.8 mL, 5.50 mmol) were combined in DMF (2.00 mL) in a
microwave vial. The reaction was heated to 130.degree. C. for 30
minutes in the microwave. The mixture was diluted reaction with
ethyl acetate and filtered through a plug of Celite. Water was then
added, and the layers were separated. The aqueous layer was washed
with ethyl acetate. The combined organics were dried with
MgSO.sub.4, filtered, concentrated and purified by silica gel using
0% to 50% ethyl acetate in hexanes to afford
3-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)pyridine (0.31 g; 50%) as
a dark oil. MS (ESI, pos. ion) m/z: 337.0 (M+1).
Step 2
[0241] 3-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)pyridine (0.31 g,
0.91 mmol) were combined in TFA for 16 hours. The mixture was
concentrated under reduced pressure and purified by silica column
using 0% to 80% ethyl acetate in hexanes to afford
2-methoxy-5-nitro-4-(pyridin-3-yl)phenol (0.1 g, 45%).
Step 3
[0242] 2-methoxy-5-nitro-4-(pyridin-3-yl)phenol (0.1 g, 0.41 mmol),
1-(3-chloropropyl)pyrrolidine hydrochloride (92 mg, 0.61 mmol), and
potassium carbonate (0.17 g, 1.22 mmol) were combined in DMF (2.0
mL). The mixture was heated to 100.degree. C. for 18 hours, and
then cooled to room temperature. Water was added to the mixture,
and the mixture was then extracted with ethyl acetate. The combined
organics were dried with MgSO.sub.4, filtered, concentrated, and
purified by silica gel column using 0% to 10% MeOH in DCM to afford
3-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}pyridine
(0.1 g, 69%). MS (ESI, pos. ion) m/z: 358.1 (M+1).
Step 4
[0243]
3-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}pyridine
(0.1 g, 0.28 mmol) and triethyl phosphite (2.0 mL) were combined.
The mixture was heated to 120.degree. C. for 24 hours. The mixture
as then concentrated under reduced pressure and purified by prep
HPLC (Prep-C18, Phenomenex Luna column, 21.2.times.250 mm; gradient
elution of 0-60% MeCN in water over a 16 min period, where water
contains 0.1% HCl, flow rate: 20 mL/min) to afford the title
compound (18.0 mg; 10%) MS (ESI, pos. ion) m/z: 326.0 (M+1).
Example 31
1-[3-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidine
Hydrochloride
##STR00216##
[0245] Tert-butyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate, Reference
7 (300 mg; 0.95 mmol; 1.00 eq.), 1-(3-chloropropyl)pyrrolidine
hydrochloride (262 mg; 1.43 mmol; 1.50 eq.) and potassium carbonate
(395 mg; 2.86 mmol; 3.00 eq.) were combined in DMF (5 mL). The
reaction was heated to 100.degree. C. for 16 hours, then cooled to
rt. The mixture was filtered through a plug of celite and
concentrated. 1M HCl (5 mL) was added, and the mixture was heated
to 50.degree. C. for 1 hour. The mixture was concentrated under
reduced pressure. The resulting residue was purified by prep HPLC
(Prep-C18, Phenomenex Luna column, 21.2.times.250 mm; gradient
elution of 0-60% MeCN in water over a 16 min period, where water
contains 0.1% HCl, flow rate: 20 mL/min) to afford the title
compound (90 mg; 24%). .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 9.43 (d, J=0.8 Hz, 1H), 8.42 (dd, J=6.8, 0.9 Hz, 1H), 7.95
(s, 1H), 7.88 (dd, J=6.8, 0.7 Hz, 1H), 7.33 (s, 1H), 4.32 (t, J=5.5
Hz, 2H), 4.00 (s, 3H), 3.89-3.77 (m, 2H), 3.50 (t, J=7.1 Hz, 2H),
3.16 (ddt, J=10.9, 8.3, 4.6 Hz, 2H), 2.35 (ddd, J=12.7, 6.9, 5.3
Hz, 2H), 2.27-2.15 (m, 2H), 2.14-1.98 (m, 2H). MS (ESI, pos. ion)
m/z: 326.2 (M+1).
Example 32
8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-3-amine
Hydrochloride
##STR00217##
[0246] Example 33
6-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-9H-pyrido[2,3-b]indol-2-amine
Hydrochloride
##STR00218##
[0247] Step 1
[0248]
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinylamine
(0.3 g, 1.36 mmol),
1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine (0.5 g,
1.36 mmol), Pd(dppf).sub.2Cl.sub.2.DCM (33 mg, 0.04 mmol), and 2M
potassium carbonate (1.4 mL, 2.73 mmol) were combined in DMF (2.7
mL) in a microwave vial. The reaction was heated in a microwave to
120.degree. C. for 1 hour. The mixture was diluted with water. The
aqueous layer was washed with ethyl acetate. The combined organics
were dried with MgSO.sub.4, filtered, concentrated and purified by
silica gel column using 0% to 10% MeOH in DCM to afford
5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}pyridin-2-amine
(0.33 g, 65%) as a brown oil. MS (ESI, pos. ion) m/z: 373.2
(M+1).
Step 2
[0249]
5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}pyridin-2-
-amine (180.00 mg; 0.48 mmol; 1.00 eq.), di-tert-butyl dicarbonate
(316.45 mg; 1.45 mmol; 3.00 eq.), and N,N-dimethylaminopyridine
(11.81 mg; 0.10 mmol; 0.20 eq.) were combined in acetonitrile (4.83
mL). The reaction was heated to 50.degree. C. for 1 hour, and then
cooled to room temperature. The mixture was concentrated under
reduced pressure and then purified by silica gel column using 0% to
10% MeOH in DCM to afford tert-butyl
N-[(tert-butoxy)carbonyl]-N-(5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)p-
ropoxy]phenyl}pyridin-2-yl)carbamate (0.16 g, 57%).
Step 3
[0250] Tert-butyl
N-[(tert-butoxy)carbonyl]-N-(5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)p-
ropoxy]phenyl}pyridin-2-yl)carbamate (0.16 g, 0.28 mmol) and
triethyl phosphite (3.0 mL) were combined. The mixture was heated
to 120.degree. C. for 24 hours, and then cooled to room
temperature. The mixture was concentrated under reduced pressure,
and 1M HCl (3 mL) was added to the resulting residue. The aqueous
layer was heated to 50.degree. C. for 1 hour and then purified by
prep HPLC (Prep-C18, Phenomenex Luna column, 21.2.times.250 mm;
gradient elution of 0-60% MeCN in water over a 16 min period, where
water contains 0.1% HCl, flow rate: 20 mL/min) to afford the more
polar product
8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-3-amine
hydrochloride (Example 32, 20.0 mg, 21%). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.54 (s, 1H), 7.68 (s, 1H), 7.07 (s, 1H),
6.67 (s, 1H), 4.25 (t, J=5.5 Hz, 2H), 3.94 (s, 3H), 3.81 (s, 2H),
3.48 (d, J=7.0 Hz, 2H), 3.14 (s, 2H), 2.36-2.25 (m, 2H), 2.20 (s,
2H), 2.06 (s, 2H). MS (ESI, pos. ion) m/z: 341.4 (M+1) and less
polar product
6-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-9H-pyrido[2,3-b]indol-2-amine
hydrochloride (Example 33, 9.0 mgs, 9%). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.40 (d, J=8.7 Hz, 1H), 7.57 (s, 1H),
7.15 (s, 1H), 6.58 (d, J=8.8 Hz, 1H), 4.23 (t, J=5.5 Hz, 2H), 3.94
(s, 3H), 3.88-3.75 (m, 2H), 3.48 (t, J=7.0 Hz, 2H), 3.21-3.07 (m,
2H), 2.34-2.24 (m, 2H), 2.19 (dq, J=11.0, 6.2, 4.5 Hz, 2H), 2.08
(ddt, J=13.9, 10.9, 4.7 Hz, 2H). MS (ESI, pos. ion) m/z: 340.9
(M+1).
Example 34
1-[3-({1-fluoro-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidin-
e Hydrochloride
##STR00219##
[0252] The title compound was prepared as described in Example 7,
Steps 1-3 above, but substituting
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinylamine
with (2-fluoropyridin-3-yl)boronic acid. MS (ESI, pos. ion) m/z:
344.0 (M+1).
Example 35
8-methoxy-1-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-3--
amine Hydrochloride
##STR00220##
[0253] Step 1
[0254] 5-bromo-6-methylpyridin-2-amine (1.1 g, 5.88 mmol),
di-tert-butyl dicarbonate (2.6 g, 11.76 mmol), and DMAP (0.14 g,
1.18 mmol) were combined in THF (20.0 mL), and the reaction was
heated to 50.degree. C. for 1 hour. The mixture was concentrated
under reduced pressure and then purified resulting residue by
silica gel using 0% to 30% ethyl acetate in hexanes to afford
tert-butyl
N-(5-bromo-6-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate
(2.1 g, 92%). .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) .delta.
7.93 (d, J=8.4 Hz, 1H), 7.10 (dd, J=8.4, 0.7 Hz, 1H), 2.57 (s, 3H),
1.44 (s, 18H).
Step 2
[0255] Tert-butyl
N-(5-bromo-6-methylpyridin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate
(1.4 g, 3.62 mmol), bis(pinacolato)diboron (1.4 g, 5.42 mmol),
Pd(dppf).sub.2Cl.sub.2.DCM (74 mg, 0.09 mmol), and potassium
carbonate (2.0 g, 14.46 mmol) were combined in 1,4-dioxanes (12.0
mL) in a microwave vial. The reaction was heated in the microwave
at 130.degree. C. for 7 hours. The mixture was diluted with water.
The aqueous layer was washed with ethyl acetate. The combined
organics were dried with MgSO.sub.4, filtered, concentrated under
reduced pressure and purified by silica gel column using 0% to 50%
ethyl acetate in hexanes to afford tert-butyl
N-[(tert-butoxy)carbonyl]-N-[6-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-yl]carbamate (1.5 g, 95%). .sup.1H NMR (400 MHz,
Acetonitrile-d.sub.3) .delta. 8.00 (d, J=8.4 Hz, 1H), 7.17 (dd,
J=8.4, 0.7 Hz, 1H), 2.62 (s, 3H), 1.45 (s, 18H), 1.35 (s, 12H).
Step 3
[0256] Tert-butyl
N-[(tert-butoxy)carbonyl]-N-[6-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-yl]carbamate (0.40 g, 0.92 mmol),
1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine (0.33 g,
0.92 mmol), Pd(dppf).sub.2Cl.sub.2.DCM (23 mg, 0.03 mmol) and 2M
potassium carbonate (0.90 mL, 1.84 mmol) were combined in NMP (2.5
mL) in a microwave vial. The reaction was heated to 130.degree. C.
for 30 minutes in a microwave. The reaction was diluted with water.
Aqueous layer was washed with ethyl acetate The combined organics
were dried with MgSO.sub.4, filtered, concentrated under reduced
pressure and purified resulting residue by silica gel column using
0% to 10% MeOH in DCM to afford tert-butyl
N-[(tert-butoxy)carbonyl]-N-(5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)p-
ropoxy]phenyl}-6-methylpyridin-2-yl)carbamate (0.35 g, 65%). MS
(ESI, pos. ion) m/z: 587.6 (M+1).
Step 4
[0257] Tert-butyl
N-[(tert-butoxy)carbonyl]-N-(5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)p-
ropoxy]phenyl}-6-methylpyridin-2-yl)carbamate (0.35 g, 0.60 mmol)
and triethyl phosphite (6 mL) were combined, and then the reaction
was heated to 120.degree. C. for 24 hours. The mixture was
concentrated under reduced pressure. 1M HCl (3.00 mL) solution was
added. The mixture stirred for 3 hours and then purified by prep
HPLC (Prep-C18, Phenomenex Luna column, 21.2.times.250 mm; gradient
elution of 0-60% MeCN in water over a 16 min period, where water
contains 0.1% HCl, flow rate: 20 mL/min) to afford the title
compound (8 mg, 4%). MS (ESI, pos. ion) m/z: 355.0 (M+1).
Example 36
(3S)-1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-y-
l}pyrrolidin-3-ol Hydrochloride
##STR00221##
[0258] Step 1
[0259] Brettphos G1 (25 mg, 0.03 mmol) was added to a solution
containing tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(270 mg, 0.62 mmol), (3S)-3-pyrrolidinol (161 mg, 1.85 mmol), and
potassium tert-butoxide (207 mg, 1.85 mmol) in NMP (6.0 mL) in a
microwave vial. The reaction was heated to 140.degree. C. for 1.5
hours in a microwave. The reaction was diluted with water. The
aqueous layer was washed with ethyl acetate. The combined organics
were dried with MgSO.sub.4, filtered, and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column using 0% to 80% ethyl acetate in hexanes to afford
(3S)-1-[7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyrrolidin-3-o-
l (239 mg, 99%). MS (ESI, pos. ion) m/z: 390.3 (M+1).
Step 2
[0260]
(3S)-1-[7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyrrolid-
in-3-ol (239 mg, 0.62 mmol), di-tert-butyl dicarbonate (269 mg,
1.23 mmol), DMAP (15 mg, 0.12 mmol), and Hunig's base (0.21 mL,
1.23 mmol) were combined in acetonitrile (3 mL). The mixture was
stirred for 2 hours at room temperature. The mixture was then
concentrated under reduced pressure and purified by silica gel
column using 0% to 30% ethyl acetate in hexanes to afford
tert-butyl
7-(benzyloxy)-1-[(3S)-3-{[(tert-butoxy)carbonyl]oxy}pyrrolidin-1-yl]-8-me-
thoxy-5H-pyrido[4,3-b]indole-5-carboxylate (363 mg, 99%). MS (ESI,
pos. ion) m/z: 590.4 (M+1).
Step 3
[0261] Tert-butyl
7-(benzyloxy)-1-[(3S)-3-{[(tert-butoxy)carbonyl]oxy}pyrrolidin-1-yl]-8-me-
thoxy-5H-pyrido[4,3-b]indole-5-carboxylate (363.00 mg, 0.62 mmol),
and 10% wt palladium on carbon (33 mg, 0.03 mmol) were combined in
methanol (10 mL). The reaction was stirred under hydrogen gas
pressure via balloon for 1 hour. The mixture was filtered through a
plug of Celite and then concentrated under reduced pressure to
afford tert-butyl
1-[(3S)-3-{[(tert-butoxy)carbonyl]oxy}pyrrolidin-1-yl]-7-hydroxy-8-methox-
y-5H-pyrido[4,3-b]indole-5-carboxylate (300 mg, 97%). MS (ESI, pos.
ion) m/z: 500.4 (M+1).
Step 4
[0262] Tert-butyl
1-[(3S)-3-{[(tert-butoxy)carbonyl]oxy}pyrrolidin-1-yl]-7-hydroxy-8-methox-
y-5H-pyrido[4,3-b]indole-5-carboxylate (300 mg, 0.60 mmol),
1-(3-chloropropyl)pyrrolidine hydrochloride (240 mg, 1.20 mol) and
potassium carbonate (331 mg, 2.40 mol) were combined in DMF (6 mL).
The reaction was heated to 100.degree. C. for 16 hours, and then
cooled to room temperature. The mixture was filtered and then
concentrated under reduced pressure. 1M HCl (5 mL) was added, and
then mixture was then heated to 50.degree. C. for 1 hour. The
mixture was purified by prep HPLC (Prep-C18, Phenomenex Luna
column, 21.2.times.250 mm; gradient elution of 0-60% MeCN in water
over a 16 min period, where water contains 0.1% HCl, flow rate: 20
mL/min) to afford the title compound (110 mg, 38%). .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 7.67 (d, J=6.9 Hz, 1H), 7.63
(s, 1H), 7.22 (s, 1H), 7.14 (d, J=6.9 Hz, 1H), 4.68 (dq, J=5.3,
3.1, 2.4 Hz, 1H), 4.28 (t, J=5.6 Hz, 2H), 4.22-4.08 (m, 2H), 3.97
(s, 3H), 3.94-3.75 (m, 4H), 3.50 (t, J=7.1 Hz, 2H), 3.22-3.08 (m,
2H), 2.33 (tt, J=12.0, 5.1 Hz, 3H), 2.20 (qt, J=11.0, 4.5 Hz, 3H),
2.07 (td, J=7.3, 3.8 Hz, 2H). MS (ESI, pos. ion) m/z: 411.5
(M+1).
Example 37
(3R)-1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-y-
l}pyrrolidin-3-ol
##STR00222##
[0264] The title compound was prepared as described in Example 36,
Steps 1-4 above, but substituting (3S)-3-pyrrolidinol with
(3R)-3-pyrrolidinol. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 7.68 (d, J=6.9 Hz, 1H), 7.65 (s, 1H), 7.24 (s, 1H), 7.15
(d, J=6.9 Hz, 1H), 4.68 (m, 1H), 4.28 (t, J=5.5 Hz, 2H), 4.22-4.08
(m, 2H), 3.97 (s, 3H), 3.95-3.76 (m, 4H), 3.49 (t, J=7.0 Hz, 2H),
3.22-3.09 (m, 2H), 2.33 (h, J=5.3, 4.5 Hz, 3H), 2.21 (q, J=7.5, 6.9
Hz, 3H), 2.07 (dt, J=12.9, 9.1 Hz, 2H). MS (ESI, pos. ion) m/z:
411.0 (M+1).
Example 38
8-methoxy-N-[(2S)-1-methoxypropan-2-yl]-7-[3-(pyrrolidin-1-yl)propoxy]-5H--
pyrido[4,3-b]indol-1-amine
##STR00223##
[0266] The title compound was prepared as described in Example 36,
Steps 1-4 above, but substituting (3S)-3-pyrrolidinol with
(2S)-1-methoxypropan-2-amine. MS (ESI, pos. ion) m/z: 413.1
(M+1).
Example 39
1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}pyr-
rolidine
##STR00224##
[0268] The title compound was prepared as described in Example 36,
Steps 1-4 above, but modifying Step 1 as follows. MS (ESI, pos.
ion) m/z: 395.0 (M+1). (Step 1--No Brettphos G1 was used.
Substituted original amine, base, and solvent with pyrrolidine,
triethylamine and no solvent. The reaction was heated to
120.degree. C. for 3 hours.)
Example 40
1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}pip-
eridin-4-ol
##STR00225##
[0270] The title compound was prepared as described in Example 36,
Steps 1-4 above, but modifying Step 1 as follows. MS (ESI, pos.
ion) m/z: 425.0 (M+1). (Step 1--No Brettphos G1 was used.
Substituted original amine, base, and solvent with
4-hydroxypiperidine, potassium carbonate and DMSO. The reaction was
heated to 160.degree. C. for 48 hours.)
Example 41
4-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}mor-
pholine
##STR00226##
[0272] The title compound was prepared as described in Example 36,
Steps 1-4 above, but modifying Step 1 as follows. MS (ESI, pos.
ion) m/z: 411.0 (M+1). (Step 1--No Brettphos G1 was used.
Substituted original amine, base, and solvent with morpholine,
potassium carbonate and DMSO. The reaction was heated to
120.degree. C. for 3 hours.)
Example 42
1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}aze-
tidin-3-ol
##STR00227##
[0274] The title compound was prepared as described in Example 36,
Steps 1-4 above, but substituting (3S)-3-pyrrolidinol with
3-hydroxyazetidine. MS (ESI, pos. ion) m/z: 397.0.0 (M+1).
Example 43
1-[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrro-
lidine
##STR00228##
[0276] The title compound was prepared as described in Example 35,
Steps 1-4 above, modifying Step 1 as follows. MS (ESI, pos. ion)
m/z: 366.0.0 (M+1).
Step 1
[0277] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(100 mg, 0.23 mmol), cyclopropylboronic acid (69 mg, 0.80 mmol),
tricyclohexylphosphane (6 mg, 0.02 mmol) and potassium phosphate
tribasic (97 mg, 0.46 mmol) in toluene (1.1 mL) and water (0.06 mL)
was sparged with nitrogen for 10 minutes. Palladium acetate (5.1
mg; 0.02 mmol) was then added, and the sealed vial was heated to
100.degree. C. for 5 hours. The mixture was diluted with ethyl
acetate and washed with water and brine. The organic layer was
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel column
eluting with 0-60% ethyl acetate in hexanes to obtain tert-butyl
7-(benzyloxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylat-
e (90 mg, 88%) as an off-white solid.
Example 44
1-[3-({8-methoxy-5H-pyrimido[5,4-b]indol-7-yl}oxy)propyl]pyrrolidine
##STR00229##
[0278] Step 1
[0279]
1-{3-[2-methoxy-5-nitro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
oxy]propyl}pyrrolidine (500 mg, 1.23 mmol), 4,5-dichloropyrimidine
(220 mg, 1.48 mmol), Pd(amphos)Cl.sub.2 (59 mg, 0.08 mmol) and 2M
sodium carbonate (1.23 mL, 2.46 mmol) were combined in 1,4-dioxane
(5 mL). The mixture was purged with N.sub.2 for 6 min, sealed and
left stirring at 90.degree. C. for 45 minutes. The mixture was
cooled to room temperature, diluted with water and extracted with
ethyl acetate. The combined organic layers were washed with water.
After removal of the organic solvents under reduced pressure, the
residue was purified by flash chromatography on silica gel column
eluted with 0-100% solvent A in CH.sub.2Cl.sub.2 (solvent A: 0.2%
NH.sub.4OH/10% MeOH/88.9% CH.sub.2Cl.sub.2) to provide the title
compound as a brown solid (422 mg, 87%). MS (ESI, pos. ion) m/z:
393.0 (M+1).
Step 2
[0280] A mixture of
5-chloro-4-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}pyrimi-
dine (420 mg, 1.07 mmol) in ethyl acetate (5 mL) was added into a
vial charged with anhydrous SnCl.sub.2 (439 mg, 2.3 mmol). This
mixture was left stirring at 95.degree. C. for 2 hours. Additional
anhydrous SnCl.sub.2 (200 mg, 1.04 mmol) and ethyl acetate (2.5 mL)
were added. The mixture was sealed and allowed to stir at
65.degree. for 24 hours. The crude solution was cooled to room
temperature, treated with water and then 20% aqueous NaOH. The
mixture was extracted with a mixture solvent of 25% .sup.iPrOH/75%
chloroform (3.times.). After removal of the organic solvents under
reduced pressure, the residue was purified by flash chromatography
on silica gel column eluted with 0-100% solvent A in solvent B
(solvent A: 0.2% NH.sub.4OH/10% MeOH/88.9% CH.sub.2Cl.sub.2;
solvent B: 1% NH.sub.4OH/99% MeOH) to provide
2-(5-chloropyrimidin-4-yl)-4-methoxy-5-[3-(pyrrolidin-1-yl)propoxy]anilin-
e (150 mg, 39%) as a brown syrup. MS (ESI, pos. ion) m/z: 363.0.0
(M+1).
Step 3
[0281] A mixture of
2-(5-chloropyrimidin-4-yl)-4-methoxy-5-[3-(pyrrolidin-1-yl)propoxy]anilin-
e (120 mg, 0.33 mmol), potassium tert-butoxide (371 mg, 3.31 mmol)
and Brettphos G1 (34 mg, 0.04 mmol) in 1,4-dioxane (10 mL) was
purged with N.sub.2 for 5 minutes. The mixture was sealed and
allowed to stir at 90.degree. C. for 45 minutes. The crude mixture
was cooled to room temperature and treated with water. After
removal of the volatiles under reduced pressure, the residue was
dissolved in DMSO (6 mL) and filtered through a small pad of celite
and purified by prep HPLC (Prep-C18, Phenomenex Luna column,
21.2.times.250 mm; gradient elution of 0-60% MeCN in water over a
16 min period, where water contains 0.1% HCl, flow rate: 20 mL/min)
to provide the title compound (34 mg, 32%). MS (ESI, pos. ion) m/z:
327.0.0 (M+1).
Example 45
ethyl[3-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]methylamine
Hydrochloride
##STR00230##
[0282] Step 1
[0283] A mixture of tert-butyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate (200.00
mg; 0.64 mmol; 1.00 eq.), (3-chloropropyl)(ethyl)methylamine
hydrochloride (164.25 mg; 0.95 mmol; 1.50 eq.), and potassium
carbonate (439.02 mg; 3.18 mmol; 5.00 eq.) in N,N-dimethylformamide
(4.00 mL) was heated to 100.degree. C. for 90 minutes. The reaction
mixture was cooled to RT and filtered through a plug of Celite. The
filtrate was concentrated under reduced pressure to give the crude
tert-butyl
7-(3-(ethyl(methyl)amino)propoxy)-8-methoxy-5H-pyrido[4,3-b]indole-5-carb-
oxylate. MS (ESI, pos. ion) m/z: 415.0 (M+1) which also contained
some side product resulting from the loss of the Boc protecting
group MS (ESI, pos. ion) m/z: 315.0 (M+1). The crude mixture was
used in the next step without purification.
Step 2
[0284] A 3M solution of hydrogen chloride (4.84 mL), was added to a
flask containing crude tert-butyl
7-{3-[ethyl(methyl)amino]propoxy}-8-methoxy-5H-pyrido[4,3-b]indole-5-carb-
oxylate (150.00 mg; 0.36 mmol; 1.00 eq.) and the reaction mix was
left stirring overnight at RT. The solvent was removed under vacuum
and the residue was dissolved in 1 mL of water and treated with sat
solution of NaHCO3 until neutral pH. The solvent was removed under
vacuum and the product was taken in DMSO, and purified by prep HPLC
prep-HPLC (Prep-C18, Phenomenex Luna column, 21.2.times.250 mm;
gradient elution of 0-30% MeCN in water over a 16 min period, where
water contains 0.1% HCl, flow rate: 20 mL/min) to afford the titled
compound
N-ethyl-3-((8-methoxy-5H-pyrido[4,3-b]indol-7-yl)oxy)-N-methylpropan-1-am-
ine hydrochloride (42 mg, 30%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 14.79 (s, 1H), 12.96 (s, 1H), 10.08 (s, 1H), 9.57 (s, 1H),
8.51 (d, J=6.7 Hz, 1H), 8.05 (s, 1H), 7.90 (d, J=6.7 Hz, 1H), 7.29
(s, 1H), 4.19 (t, J=6.1 Hz, 2H), 3.88 (s, 3H), 3.13 (dddd, J=33.3,
13.0, 8.0, 6.5 Hz, 4H), 2.75 (d, J=4.9 Hz, 3H), 2.21 (t, J=7.4 Hz,
2H), 1.23 (t, J=7.2 Hz, 3H). MS (ESI, pos. ion) m/z: 314.3
(M+1).
Example 46
[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}-oxy)propyl](ethyl-
)methylamine Hydrochloride
##STR00231##
[0285] Step 1
[0286] A mixture of tert-butyl
1-cyclopropyl-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(105.00 mg; 0.30 mmol; 1.00 eq.),
(3-chloropropyl)(ethyl)methylamine hydrochloride (76.48 mg; 0.44
mmol; 1.50 eq.), and potassium carbonate (204.43 mg; 1.48 mmol;
5.00 eq.) in N,N-dimethylformamide (2.10 mL) was heated to
100.degree. C. for 16 hours. The reaction mixture was cooled to RT,
filtered through a plug of Celite and concentrated under reduced
pressure. The crude was a mixture of tert-butyl
1-cyclopropyl-7-(3-(ethyl(methyl)amino)propoxy)-8-methoxy-5H-pyrido[4,3-b-
]indole-5-carboxylate MS (ESI, pos. ion) m/z: 454.4 (M+1) which
also contained some side product resulting from the loss of the Boc
protecting group MS (ESI, pos. ion) m/z: 353.8 (M+1). The crude
mixture was used in the next step without purification.
Step 2
[0287] A 3M solution of hydrogen chloride (4.84 mL), was added to a
flask containing crude tert-butyl
1-cyclopropyl-7-(3-(ethyl(methyl)amino)propoxy)-8-methoxy-5H-pyrido[4,3-b-
]indole-5-carboxylate (150.00 mg; 0.36 mmol; 1.00 eq.) and the
reaction mix was left stirring overnight at RT. The solvent was
removed under vacuum and the residue was dissolved in 1 mL of water
and treated with sat solution of NaHCO3 until neutral pH. The
solvent was removed under vacuum and the product was taken in DMSO,
and purified by prep HPLC prep-HPLC (Prep-C18, Phenomenex Luna
column, 21.2.times.250 mm; gradient elution of 0-30% MeCN in water
over a 16 min period, where water contains 0.1% HCl, flow rate: 20
mL/min) to afford the title compound (12 mg, 10%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 14.03 (s, 1H), 13.03 (s, 1H),
10.37-10.14 (m, 1H), 8.21 (dd, J=6.7, 4.4 Hz, 1H), 7.85 (s, 1H),
7.74 (d, J=6.7 Hz, 1H), 7.33 (s, 1H), 4.20 (t, J=6.1 Hz, 2H), 3.91
(s, 3H), 3.22-2.97 (m, 5H), 2.74 (d, J=4.9 Hz, 3H), 2.23 (p, J=6.7
Hz, 2H), 1.43 (dt, J=8.3, 3.2 Hz, 2H), 1.37-1.31 (m, 2H), 1.23 (t,
J=7.2 Hz, 3H). MS (ESI, pos. ion) m/z: 353.8 (M+1).
Example 47
[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]dimethy-
lamine Hydrochloride
##STR00232##
[0288] Step 1
[0289] A mixture of tert-butyl
1-cyclopropyl-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(288.00 mg; 0.81 mmol; 1.00 eq.),
N-(3-chloropropyl)-N,N-dimethylamine hydrochloride (138.35 mg; 1.14
mmol; 1.40 eq.) and K.sub.2CO.sub.3 ((280.36 mg; 2.03 mmol; 2.50
eq.) in DMF (22 mL) was allowed to stir at 100.degree. C. for 6 h.
The mixture was then cooled to rt, diluted with water and extracted
with iPrOH/CHCl.sub.3 (1/3) twice. The combined organic phases were
then washed with water (30 mL), brine (20 mL), dried over
Na.sub.2SO.sub.4. After removal of the organic volatiles under
reduced pressure, the remaining crude product of tert-butyl
1-cyclopropyl-7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indo-
le-5-carboxylate was carried over to the next step.
Step 2.
[0290] A solution of the above crude product of tert-butyl
1-cyclopropyl-7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indo-
le-5-carboxylate in TFA (2.5 mL) was allowed to stir at 90.degree.
C. for 20 min. The resulting mixture was allowed to cool to rt and
the residue was subjected to (Waters XSelect CSH C18 column,
19.times.150 mm, gradient elution of 0-40% CH.sub.3CN in water over
a 20 min period, flow rate 28 ml/min) to provide the title compound
as a TFA salt solid (107 mg, 31%, two steps). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.18 (d, J=6.8 Hz, 1H), 7.93 (s, 1H),
7.73 (d, J=6.8 Hz, 1H), 7.36 (s, 1H), 4.33 (t, J=5.6 Hz, 2H), 4.03
(s, 3H), 3.45 (t, J=7.2 Hz, 2H), 3.01 (s, 6H), 3.02-2.91 (m, 1H),
2.41-2.30 (m, 2H), 1.61-1.49 (m, 2H), 1.35-1.23 (m, 2H). MS (ESI,
pos. ion) m/z: 340.2 (M+1).
Example 48
4-{7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indol-1-yl}-2-me-
thylbut-3-yn-2-ol Hydrochloride
##STR00233##
[0291] Step 1
[0292] Tert-butyl
1-chloro-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
was converted into tert-butyl
1-chloro-7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indole-5--
carboxylate following a synthetic sequence as described (Example
47, Step 1).
Step 2
[0293] A mixture of 2-methyl-3-butyn-2-ol (146 mg; 1.75 mmol; 6.00
eq.), copper iodide (12 mg; 0.05 mmol; 0.22 eq.),
tetrakis(triphenylphosphine) palladium (99 mg; 0.10 mmol; 0.30 eq.)
and tert-butyl
1-chloro-7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indole-5--
carboxylate (125 mg; 0.06 mmol; 1.00 eq.) in DMF/Et.sub.3N (1.2
mL/0.5 mL) was purged with N.sub.2 for 5 min. The reaction vial was
sealed and allowed to stir at 95.degree. C. for 90 minutes. The
resulting mixture was allowed to cool to rt, diluted with water,
and extracted with 20% PrOH/chloroform thrice. The combined organic
layers were concentrated under reduced pressure, and the remaining
residue was purified by flash chromatography on a 10 g silica gel
column eluted with 0-100% solvent A (solvent A: 0.3% NH.sub.4OH/10%
MeOH/89.7% CH.sub.2Cl.sub.2) in CH.sub.2Cl.sub.2 to provide
tert-butyl
7-[3-(dimethylamino)propoxy]-1-(3-hydroxy-3-methylbut-1-yn-1-yl)-8-methox-
y-5H-pyrido[4,3-b]indole-5-carboxylate as a brown syrup (55 mg,
42%).
Step 3
[0294] The title compound was synthesized from tert-butyl
7-[3-(dimethylamino)propoxy]-1-(3-hydroxy-3-methylbut-1-yn-1-yl)-8-methox-
y-5H-pyrido[4,3-b]indole-5-carboxylate, following a synthetic
sequence as described (Example 47, Step 2), as a white solid.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.35 (d, J=6.7 Hz,
1H), 8.07 (s, 1H), 7.82 (dd, J=15.2, 6.6 Hz, 1H), 7.36 (s, 1H),
4.33 (td, J=5.6, 2.8 Hz, 2H), 4.03 (d, J=3.2 Hz, 3H), 3.44 (t,
J=7.1 Hz, 2H), 3.00 (s, 6H), 2.36 (p, J=6.4 Hz, 2H), 1.75 (s, 6H).
MS (ESI, pos. ion) m/z: 382.1 (M+1).
Example 49
4-{7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indol-1-yl}-2-me-
thylbutan-2-ol Hydrochloride
##STR00234##
[0296] A flask charged with a mixture of
4-{7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indol-1-yl}-2-m-
ethylbut-3-yn-2-ol (Example 48, 35 mg, 0.09 mmol 1.00 eq.) and
palladium on carbon (20 mg) in MeOH (1.5 mL) was purged with
N.sub.2 for 3 min, followed by hydrogen gas via balloon and stirred
for 26 hours min. The reaction mixture was filtered through a small
pad of celite and rinsed with MeOH thrice. The organic solutions
were combined. After removal of the organic solvents under vacuum,
the resulting residue was purified by Prep HPLC (Waters XSelect CSH
C18 column, 19.times.150 mm; gradient elution of 0-25% CH.sub.3CN
in water 0.1% HCl over a 20 min period, flow rate 28 ml/min) to
provide the title compound (15 mg, 35%). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.25 (d, J=6.6 Hz, 1H), 7.87 (s, 1H),
7.71 (d, J=6.6 Hz, 1H), 7.30 (s, 1H), 4.32 (t, J=5.4 Hz, 2H), 3.99
(s, 3H), 3.57-3.42 (m, 4H), 3.01 (s, 6H), 2.37 (dd, J=8.8, 4.1 Hz,
2H), 1.99-1.90 (m, 2H), 1.36 (s, 6H). MS (ESI, pos. ion) m/z: 386.0
(M+1).
Example 50
4-{7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indol-1-yl}but-3-
-yn-2-ol Hydrochloride
##STR00235##
[0298] The title compound was synthesized from tert-butyl
1-chloro-7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indole-5--
carboxylate, following a synthetic sequence as described for
Example 48, except that but-3-yn-2-ol was used in the place of
2-methyl-3-butyn-2-ol. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.35 (dd, J=6.5, 2.3 Hz, 1H), 8.02 (s, 1H), 7.89-7.80 (m,
1H), 7.36 (d, J=9.7 Hz, 1H), 5.01 (q, J=6.7 Hz, 1H), 4.34 (t, J=5.5
Hz, 2H), 4.01 (s, 3H), 3.45 (t, J=7.1 Hz, 2H), 3.01 (s, 6H), 2.36
(p, J=6.2 Hz, 2H), 1.68 (d, J=6.7 Hz, 3H). MS (ESI, pos. ion) m/z:
368.0 (M+1).
Example 51
(3-{[1-(2-cyclopropylethynyl)-8-methoxy-5H-pyrido[4,3-b]indol-7-yl]oxy}pro-
pyl)dimethylamine Hydrochloride
##STR00236##
[0300] The title compound was synthesized from tert-butyl
1-chloro-7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indole-5--
carboxylate, following a synthetic sequence as described for
Example 48, except that ethynylcyclopropane was used in the place
of 2-methyl-3-butyn-2-ol. .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.29 (d, J=6.7 Hz, 1H), 7.88 (s, 1H), 7.78 (d, J=6.8 Hz,
1H), 7.35 (s, 1H), 4.33 (t, J=5.6 Hz, 2H), 4.03 (s, 3H), 3.45 (t,
J=7.2 Hz, 2H), 3.01 (s, 6H), 2.36 (s, 1H), 2.41-2.30 (m, 1H), 1.94
(tt, J=8.2, 5.0 Hz, 1H), 1.34-1.20 (m, 2H), 1.24-1.09 (m, 2H). MS
(ESI, pos. ion) m/z: 364.2 (M+1).
Example 52
3-((1-(2-cyclopropylethyl)-8-methoxy-5H-pyrido[4,3-b]indol-7-yl)oxy)-N,N-d-
imethylpropan-1-amine Hydrochloride
##STR00237##
[0302] A mixture of
(3-{[1-(2-cyclopropylethynyl)-8-methoxy-5H-pyrido[4,3-b]indol-7-yl]oxy}pr-
opyl)dimethylamine from Example 48 (5.60 mg; 0.02 mmol; 1.00 eq.)
was dissolved in in methanol (1.68 mL). The system was purged with
nitrogen and palladium on carbon (0.16 mg; 0.00 mmol; 0.10 eq.) was
added to the reaction flask. The reaction mix was hydrogenated
under atmospheric pressure for 90 minutes using H.sub.2 from a
balloon. The reaction mix was filtered over Celite and the cake
washed with methanol. The combined organics were concentrated to
dryness to give the desired
3-((1-(2-cyclopropylethyl)-8-methoxy-5H-pyrido[4,3-b]indol-7-yl)oxy)-N,N--
dimethylpropan-1-amine hydrochloride (3.9 mg, 69%). MS (ESI, pos.
ion) m/z: 368.2 (M+1).
Example 53
{2-[2-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)ethoxy]ethy-
l}dimethylamine Hydrochloride
##STR00238##
[0303] Step 1
[0304] To a vial charged with tert-butyl
1-cyclopropyl-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(48.00 mg; 0.15 mmol; 1.00 eq.) was added a solution of
tributylphosphoranylidene)acetonitrile (150.76 mg; 0.59 mmol) in
CH.sub.2Cl.sub.2 (0.5 mL). The mixture was allowed to stir at
60.degree. C. with N.sub.2 line to blow off the solvents
completely. To the resulting residue was added
2-[2-(dimethylamino)ethoxy]ethan-1-ol (60.13 mg; 0.45 mmol; 2.50
eq.) in CH.sub.2Cl.sub.2 (0.8 mL). After removal of the solvents
under N.sub.2 line, the vial was sealed and the residue was allowed
to be heated at 85.degree. C. for 90 min. The reaction mixture was
purified by flash chromatography on silica gel column eluted with
0-100% solvent A (solvent A: 0.3% NH.sub.4OH/10% MeOH/89.7%
CH.sub.2Cl.sub.2) in CH.sub.2Cl.sub.2 to provide tert-butyl
1-cyclopropyl-7-{2-[2-(dimethylamino)ethoxy]ethoxy}-8-methoxy-5H-pyrido[4-
,3-b]indole-5-carboxylate as yellow oil (26 mg, 41%).
Step 2
[0305] The title compound was synthesized from tert-butyl
1-cyclopropyl-7-{2-[2-(dimethylamino)ethoxy]ethoxy}-8-methoxy-5H-pyrido[4-
,3-b]indole-5-carboxylate, following a synthetic sequence as
described for Example 21, step 3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 132.51 (s, 1H), 8.18 (d, J=6.7 Hz, 1H),
7.91 (dd, J=4.8, 1.8 Hz, 1H), 7.73 (d, J=6.8 Hz, 1H), 7.35 (d,
J=1.8 Hz, 1H), 4.38-4.31 (m, 2H), 4.05-3.80 (m, 4H), 3.46-3.36 (m,
2H), 2.94 (s, 6H), 2.65 (dd, J=2.2, 1.3 Hz, 1H), 1.65-1.49 (m, 2H),
1.35-1.24 (m, 2H). MS (ESI, pos. ion) m/z: 370.4 (M+1).
Example 54
7-(3-chloropropoxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole
Hydrochloride
##STR00239##
[0307] The title compound was isolated as a secondary product from
the purification described in step 4 for Example 102 (7.9 mg; 26%);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.82 (s, 1H), 12.76
(s, 1H), 8.21 (d, J=6.7 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J=6.7 Hz,
1H), 7.34 (s, 1H), 4.22 (t, J=6.0 Hz, 2H), 3.90 (s, 3H), 3.82 (t,
J=6.4 Hz, 2H), 3.00 (td, J=8.6, 4.3 Hz, 1H), 2.24 (p, J=6.2 Hz,
2H), 1.42 (dt, J=6.9, 3.3 Hz, 2H), 1.33-1.27 (m, 2H). MS (ESI, pos.
ion) m/z: 331.3 (M+1).
Example 55
[3-({8-methoxy-1-propyl-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]dimethylamin-
e Hydrochloride
##STR00240##
[0309] The title compound was synthesized from tert-butyl
7-hydroxy-8-methoxy-1-propyl-5H-pyrido[4,3-b]indole-5-carboxylate,
following a synthetic sequence similar as described for Example 21,
except that 3-(dimethylamino)propan-1-ol was used in place of
3-(pyrrolidin-1-yl)propan-1-ol in step 2. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.29 (d, J=6.8 Hz, 1H), 7.77 (d, J=6.8
Hz, 1H), 7.64 (s, 1H), 7.37 (s, 1H), 4.33 (t, J=5.6 Hz, 2H), 4.03
(s, 3H), 3.51 (dd, J=8.5, 6.9 Hz, 2H), 3.45 (t, J=7.2 Hz, 2H), 3.00
(s, 6H), 2.41-2.29 (m, 2H), 2.00 (h, J=7.4 Hz, 2H), 1.13 (t, J=7.4
Hz, 3H). MS (ESI, pos. ion) m/z: 342.2 (M+1).
Example 56
[3-({1-cyclopentyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]dimethy-
lamine Hydrochloride
##STR00241##
[0310] Step 1
[0311] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(650.00 mg; 1.48 mmol; 1.00 eq.), 1-cyclopenten-1-ylboronic acid
(580.20 mg; 5.18 mmol; 3.50 eq.), tricyclohexylphosphane (41.53 mg;
0.15 mmol; 0.10 eq.) and potassium phosphate, tribasic (628.72 mg;
2.96 mmol; 2.00 eq.) in toluene (10 mL) and water (0.8 mL) was
spurge with nitrogen for 10 minutes. To the mixture was added
palladium acetate (33.25 mg; 0.15 mmol; 0.10 eq.). The mixture was
allowed to stir under reflux under N.sub.2 atmosphere for 2 h. The
reaction mixture was allowed to cool to rt, diluted with water and
extracted with EtOAc thrice. The combined organic solution was
concentrated under reduced pressure. The residue was purified by
flash chromatography on 25 g silica gel column eluted with 0-60%
EtOAc in hexanes to provide tert-butyl
7-(benzyloxy)-1-(cyclopent-1-en-1-yl)-8-methoxy-5H-pyrido[4,3-b]indole-5--
carboxylate (540 mg, 78%).
Step 2
[0312] A flask charged with a mixture of tert-butyl
7-(benzyloxy)-1-(cyclopent-1-en-1-yl)-8-methoxy-5H-pyrido[4,3-b]indole-5--
carboxylate (540 mg, 1.45 mmol; 1.00 eq.) and palladium on carbon
(0.32 g; 0.31 mmol; 0.21 eq.) in MeOH (24 mL) was purged with
N.sub.2 for 10 min, followed with H.sub.2 balloon for 8 min. The
resulting mixture was allowed to stir at rt under H.sub.2 balloon
at for 12 hr. The solid was filtered off through a small pad of
celite and rinsed with MeOH. The organic solutions were combined.
Removal of the organic solvents under reduced pressure provide the
crude product of tert-butyl
1-cyclopentyl-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(398 mg, 91%).
Step 3
[0313] The title compound was synthesized from the above crude
product of tert-butyl
1-cyclopentyl-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate,
following a synthetic sequence as described for Example 47, step 2.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.26 (d, J=6.8 Hz,
1H), 7.79-7.70 (m, 2H), 7.34 (s, 1H), 4.31 (t, J=5.6 Hz, 2H), 4.03
(s, 3H), 3.44 (t, J=7.2 Hz, 2H), 3.00 (s, 6H), 2.44 (s, 2H),
2.40-2.29 (m, 1H), 2.35 (s, 1H), 2.05-1.95 (m, 7H). MS (ESI, pos.
ion) m/z: 368.1 (M+1).
Example 57
(3-{[1-(2-ethoxyethyl)-8-methoxy-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)dim-
ethylamine Hydrochloride
##STR00242##
[0314] Step 1
[0315] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(450.00 mg; 1.03 mmol; 1.00 eq.),
2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(365.53 mg; 1.85 mmol; 1.80 eq.), Pd(dppf)2Cl2.DCM (83.73 mg; 0.10
mmol; 0.10 eq.) and Cesium carbonate (1 336.23 mg; 4.10 mmol; 4.00
eq.) in toluene (12 mL) and water (1 mL) was spurge with nitrogen
for 10 minutes. The resulting mixture was allowed to reflux under
N.sub.2 atmosphere for 4 h. The reaction mixture was allowed to
cool to rt, diluted with water and extracted with EtOAc thrice. The
combined organic solution was concentrated under reduced pressure.
The residue was purified by flash chromatography on 25 g silica gel
column eluted with 0-60% EtOAc in hexanes to provide tert-butyl
7-(benzyloxy)-1-[(E)-2-ethoxyethenyl]-8-methoxy-5H-pyrido[4,3-b]indole-5--
carboxylate as a white solid (393 mg, 81%).
Step 2
[0316] A flask charged with a mixture of tert-butyl
7-(benzyloxy)-1-(cyclopent-1-en-1-yl)-8-methoxy-5H-pyrido[4,3-b]indole-5--
carboxylate as a white solid (321 mg, 0.68 mmol; 1.00 eq.) and
palladium on carbon (139 mg; 0.13 mmol; 0.21 eq.) in MeOH (11 mL)
was purged with N.sub.2 for 10 min, followed with H.sub.2 balloon
for 8 min. The resulting mixture was allowed to stir at rt under
H.sub.2 balloon at for 12 hr. The solid was filtered off through a
small pad of celite and rinsed with MeOH. The organic solutions
were combined. Removal of the organic solvents under reduced
pressure provided the crude product of tert-butyl
1-(2-ethoxyethyl)-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylat-
e (209 mg, 81%).
Step 3
[0317] The title compound was synthesized from the above crude
product of tert-butyl
1-(2-ethoxyethyl)-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylat-
e, following a synthetic sequence as described for Example 47, step
2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.30 (d, J=6.6
Hz, 1H), 7.81-7.69 (m, 2H), 7.36 (s, 1H), 4.33 (t, J=5.3 Hz, 2H),
4.01 (d, J=7.5 Hz, 5H), 3.78 (t, J=5.6 Hz, 2H), 3.46 (q, J=7.0 Hz,
4H), 3.01 (s, 6H), 2.36 (t, J=6.1 Hz, 2H), 1.04 (t, J=6.9 Hz, 3H).
MS (ESI, pos. ion) m/z: 372.2 (M+1).
Example 58
(3-{[8-methoxy-1-(3-methoxypropyl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)d-
imethylamine Hydrochloride
##STR00243##
[0318] Step 1
[0319] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(150.00 mg; 0.34 mmol; 1.00 eq.),
trifluoro[(1E)-3-methoxyprop-1-en-1-yl]-.sub. 4-borane potassium
hydride (122.36 mg; 0.68 mmol; 2.00 eq.), palladium acetate (15.35
mg; 0.07 mmol; 0.20 eq.), tricyclohexylphosphine (14.38 mg; 0.05
mmol; 0.15 eq.) and potassium phosphate, tribasic (290.18 mg; 1.37
mmol; 4.00 eq.) in toluene and water (5 mL/1.2 mL) was purged with
N.sub.2 for 10 min. The mixture was allowed to stir at 110.degree.
C. under reflux N.sub.2 atmosphere for 70 min. The reaction mixture
was allowed to cool to room temperature, diluted with water and
extracted with EtOAc thrice. The organic solutions were combined.
After removal of the volatiles under reduced pressure, the residue
was purified by flash chromatography on silica gel column eluted
with 0-50% solvent A (solvent A: 0.3% NH.sub.4OH/10% MeOH/89.7%
CH.sub.2Cl.sub.2) in CH.sub.2Cl.sub.2 to provide tert-butyl
7-(benzyloxy)-8-methoxy-1-[(1E)-3-methoxyprop-1-en-1-yl]-5H-pyrido[4,3-b]-
indole-5-carboxylate as white solid (112 mgs, 69%).
Step 2
[0320] The title product was made from the above product of
tert-butyl
7-(benzyloxy)-8-methoxy-1-[(1E)-3-methoxyprop-1-en-1-yl]-5H-pyrido[4,3-b]-
indole-5-carboxylate, following a synthetic sequence as described
for Example 57, steps 2 and 3. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.25 (d, J=6.6 Hz, 1H), 7.75-7.64 (m,
2H), 7.27 (s, 1H), 4.30 (t, J=5.5 Hz, 2H), 3.98 (s, 3H), 3.59-3.42
(m, 6H), 3.36 (s, 3H), 3.02 (s, 6H), 2.37 (t, J=6.2 Hz, 2H),
2.14-2.05 (m, 2H). MS (ESI, pos. ion) m/z: 372.2 (M+1).
Example 59
[3-({1-ethynyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]dimethylami-
ne Hydrochloride
##STR00244##
[0321] Step 1
[0322] Tert-butyl
1-chloro-7-[3-(dimethylamino)propoxy]-8-methoxy-5H-pyrido[4,3-b]indole-5--
carboxylate was converted to tert-butyl
7-[3-(dimethylamino)propoxy]-8-methoxy-1-[2-(trimethylsilyl)ethynyl]-5H-p-
yrido[4,3-b]indole-5-carboxylate following a synthetic sequence as
described in Example 48, step 3, except that ethynyltrimethylsilane
was used in the place of 2-methyl-3-butyn-2-ol, as a white
solid.
Step 2
[0323] Combined a solution containing tert-butyl
7-[3-(dimethylamino)propoxy]-8-methoxy-1-[2-(trimethylsilyl)ethynyl]-5H-p-
yrido[4,3-b]indole-5-carboxylate (25 mg, 0.05 mml, 1.0 eq.) in
CH.sub.2Cl.sub.2 (0.8 mL) and TFA (0.3 mL). The reaction mixture
was allowed to stir at rt for 30 minutes. The resulting solution
was concentrated under reduced pressure. The remaining residue was
treated with TBAF (1.0 mL, 1.0 mmol, 1.0 M in THF) and the
resulting mixture was allowed to stir at rt for 16 hours. After
removal of the organic solvents under reduced pressure the
resulting residue was purified on the Prep HPLC (Waters XSelect CSH
C18 column, 19.times.150 mm; gradient elution of 0-45% CH.sub.3CN
in water 0.1% HCl over a 20 min period, flow rate 28 ml/min) to
provide the title compound (4 mg, 20%). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.39 (d, J=6.6 Hz, 1H), 8.01 (s, 1H),
7.89 (d, J=6.6 Hz, 1H), 7.37 (s, 1H), 5.27 (s, 1H), 4.34 (t, J=5.4
Hz, 2H), 4.00 (s, 3H), 3.44 (t, J=7.1 Hz, 2H), 3.00 (s, 6H), 2.36
(q, J=6.2 Hz, 2H). MS (ESI, pos. ion) m/z: 324.0 (M+1).
Example 60
1-[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]-2-me-
thylpyrrolidine Hydrochloride
##STR00245##
[0324] Step 1
[0325] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(reference 5; 1 000.00 mg; 2.28 mmol; 1.00 eq.), cyclopropylboronic
acid (684.98 mg; 7.97 mmol; 3.50 eq.), tricyclohexylphosphane
(63.89 mg; 0.23 mmol; 0.10 eq.) and potassium phosphate, tribasic
(967.26 mg; 4.56 mmol; 2.00 eq.) in toluene (11.39 mL) and water
(0.57 mL) was sparged with nitrogen for 10 minutes. Palladium
acetate (51.15 mg; 0.23 mmol; 0.10 eq.) was then added, and the
mixture was heated to 100.degree. C. After 3.5 h the mixture was
diluted with EtOAc and washed with water and brine. The organic
layer was dried over MgSO.sub.4, filtered and concentrated. The
residue was purified by column chromatography (40 G ISCO Gold)
eluting with 0-60% EtOAc in heptane to obtain the desired product
as an off-white solid (900 mg; 89% yield).
Step 2
[0326] A mixture of tert-butyl
7-(benzyloxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylat-
e (700.00 mg; 1.57 mmol; 1.00 eq.) and palladium on carbon (5.03
mg; 0.05 mmol; 0.03 eq.) in methanol (15.75 mL) was stirred under
an atmosphere of H.sub.2 from a balloon (after evacuating
back-filling with H.sub.2 three times). After 17 h the mixture was
filtered with additional MeOH and concentrated to provide a crude
off-white solid which was used in further steps without further
purification.
Step 3
[0327] A mixture of tert-butyl
1-cyclopropyl-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(50.00 mg; 0.14 mmol; 1.00 eq.), 1-chloro-3-iodopropane (0.03 mL;
0.28 mmol; 2.00 eq.) and potassium carbonate (21.42 mg; 0.16 mmol;
1.10 eq.) in acetonitrile (0.71 mL) was heated to 80.degree. C.
After 3.5 h the mixture was diluted with EtOAc, washed with brine,
dried over MgSO.sub.4, filtered and concentrated to provide a
yellow oil. The crude material was purified by column
chromatography (12 G ISCO Gold) eluting with 0-40% EtOAc/hexanes to
obtain a semi-pure colorless oil. This material (40 mg) was used in
the following step without further purification.
Step 4
[0328] A mixture of tert-butyl
7-(3-chloropropoxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carb-
oxylate (40.00 mg; 0.09 mmol; 1.00 eq.), potassium iodide (1.54 mg;
0.01 mmol; 0.10 eq.) and 2-methylpyrrolidine (0.07 mL; 0.60 mmol;
6.50 eq.) in N,N-dimethylformamide (0.46 mL) was heated to
70.degree. C. After 2 h the mixture was cooled to ambient
temperature, diluted with 1:1 PhMe/EtOAc, washed with an equal
amount of H.sub.2O, dried over MgSO4, filtered and concentrated.
The crude orange solid was dissolved in DCM (1 mL) and treated with
TFA (0.5 mL) at ambient temperature. After 2 h the mixture was
concentrated in vacuo. The oily residue was taken up in 1N HCl
(.about.1.0 mL) and purified by Prep HPLC (Phenomenex Luna C18,
21.times.250 mm, 0-60% acetonitrile/0.1% aqueous HCl gradient over
13 minutes, flow rate 22 ml/min) to provide the title compound. (6
mg; 17%).sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.79 (s, 1H),
12.84 (s, 1H), 9.65 (s, 1H), 8.21 (d, J=6.6 Hz, 1H), 7.85 (s, 1H),
7.73 (s, 1H), 7.32 (s, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.91 (s, 3H),
3.67-3.63 (m, 1H), 3.50-3.40 (m, 2H), 3.15-307 (m, 2H), 3.03-2.97
(m, 1H), 2.23-2.16 (m, 2H), 1.99-1.87 (m, 2H), 1.65-1.55 (m, 2H),
1.47-1.39 (m, 2H), 1.35 (d, J=6.4 Hz, 3H), 1.31-1.26 (s, 2H); MS
(ESI, pos. ion) m/z: 380.4 (M+1).
Example 61
[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]bis(pro-
pan-2-yl)amine Hydrochloride
##STR00246##
[0330] The title compound was prepared using the synthetic sequence
described for Example 60, changing step 4 as follows. A mixture of
7-(3-chloropropoxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole
(45.00 mg; 0.14 mmol; 1.00 eq.), potassium iodide (2.26 mg; 0.01
mmol; 0.10 eq.) and N,N-diisopropylamine (89.47 mg; 0.88 mmol; 6.50
eq.) in N,N-dimethylformamide (0.68 mL) was heated to 80.degree. C.
After overnight the mixture (still showing incomplete conversion)
was cooled to ambient temperature, diluted H.sub.2O, acidified with
1N HCl and purified via Prep HPLC (Phenomenex Luna C18,
21.times.250 mm, 0-70% acetonitrile/0.1% aqueous HCl gradient over
13 minutes, flow rate 22 ml/min) to provide
[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]bis(pr-
opan-2-yl)amine as an off-white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.08 (s, 1H), 9.75 (s, 1H), 8.21 (dd, J=6.8,
3.6 Hz, 1H), 7.85 (s, 1H), 7.74 (d, J=6.7 Hz, 1H), 7.31 (s, 1H),
4.22 (t, J=6.0 Hz, 2H), 3.91 (s, 3H), 3.63 (ddd, J=13.1, 8.8, 5.6
Hz, 2H), 3.24 (ddd, J=11.4, 6.9, 4.1 Hz, 2H), 3.06-2.97 (m, 1H),
2.30-2.22 (m, 2H), 1.46-1.40 (m, 2H), 1.37 (dt, J=5.5, 2.9 Hz, 2H),
1.33 (d, J=6.5 Hz, 6H), 1.29 (d, J=6.5 Hz, 6H). MS (ESI, pos. ion)
m/z: 396.4 (M+1).
Example 62
(3R)-1-[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]-
-3-fluoropyrrolidine Hydrochloride
##STR00247##
[0332] The title compound was prepared using the synthetic sequence
described for Example 60, changing step 4 as follows:
[0333] A mixture of tert-butyl
7-(3-chloropropoxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carb-
oxylate (50.00 mg; 0.12 mmol; 1.00 eq.), potassium iodide (1.93 mg;
0.01 mmol; 0.10 eq.) and (3R)-3-fluoropyrrolidin-1-ium chloride
(94.71 mg; 0.75 mmol; 6.50 eq.) in N,N-dimethylformamide (0.58 mL)
was heated to 80.degree. C. After 3.5 h the mixture was cooled to
ambient temperature, diluted with 1:1 PhMe/EtOAc, washed with
H.sub.2O, dried over MgSO.sub.4, filtered and concentrated.
[0334] The crude orange oil was dissolved in DCM (1.2 mL) and
treated with TFA (0.6 mL) at ambient temperature. After 4.5 h the
mixture was concentrated in vacuo. The oily residue was taken up in
1N HCl (.about.1.2 mL) and purified by Prep HPLC (Phenomenex Luna
C18, 21.times.250 mm, 0-70% acetonitrile/0.1% aqueous HCl gradient
over 13 minutes, flow rate 22 ml/min) to provide
(3R)-1-[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl-
]-3-fluoropyrrolidine as a white fluffy powder. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 12.97 (s, 1H), 11.27 (s, 1H), 10.72 (s,
1H), 8.21 (d, J=6.7 Hz, 1H), 7.85 (s, 1H), 7.73 (d, J=6.7 Hz, 1H),
7.32 (s, 1H), 5.46 (d, J=53.4 Hz, 1H), 4.20 (d, J=6.2 Hz, 2H), 3.91
(s, 3H), 3.72 (br s, 1H), 3.40-3.35 (m, 2H), 3.28-3.20 (m, 2H),
3.07-2.94 (m, 1H), 2.24 (t, J=7.4 Hz, 2H), 2.21-2.05 (m, 2H), 1.42
(dt, J=8.3, 3.2 Hz, 2H), 1.34 (dq, J=7.7, 4.8, 4.2 Hz, 2H). MS
(ESI, pos. ion) m/z: 384.4 (M+1).
Example 63
(3S)-1-[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]-
-3-fluoropyrrolidine Hydrochloride
##STR00248##
[0336] The title compound was prepared using the synthetic sequence
described for Example 60, changing step 4 as follows:
[0337] A mixture of tert-butyl
7-(3-chloropropoxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carb-
oxylate (38.00 mg; 0.09 mmol; 1.00 eq.), potassium iodide (1.46 mg;
0.01 mmol; 0.10 eq.), Hunig's base (0.10 mL; 0.57 mmol; 6.50 eq.)
and (3S)-3-fluoropyrrolidin-1-ium chloride (71.98 mg; 0.57 mmol;
6.50 eq.) in N,N-dimethylformamide (0.44 mL) was heated to
80.degree. C. After 2 h the mixture was cooled to ambient
temperature, diluted with 1:1 PhMe/EtOAc, washed with H.sub.2O,
dried over MgSO.sub.4, filtered and concentrated.
[0338] The crude orange oil was dissolved in DCM (1.0 mL) and
treated with TFA (0.5 mL) at ambient temperature. After 2 h the
mixture was concentrated in vacuo. The oily residue was taken up in
1N HCl (.about.1 mL) and purified by Prep HPLC (Phenomenex Luna
C18, 21.times.250 mm, 0-70% acetonitrile/0.1% aqueous HCl gradient
over 13 minutes, flow rate 22 ml/min) to provide title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.03 (s, 1H), 11.46
(s, 1H), 10.89 (s, 1H), 8.20 (d, J=6.7 Hz, 1H), 7.85 (s, 1H), 7.73
(d, J=6.7 Hz, 1H), 7.32 (s, 1H), 5.45 (d, J=53.4 Hz, 1H), 4.21 (t,
J=6.1 Hz, 2H), 3.91 (s, 3H), 3.72 (s, 1H), 3.40-3.32 (m, 2H),
3.28-3.21 (m, 2H), 3.01 (tt, J=8.5, 5.4 Hz, 1H), 2.35-2.12 (m, 4H),
1.47-1.39 (m, 2H), 1.36 (tt, J=5.3, 2.9 Hz, 2H). MS (ESI, pos. ion)
m/z: 384.4 (M+1).
Example 64
1-(3-{[1-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-5H-pyrido[4,3-b]indol-7-yl]-
oxy}propyl)pyrrolidine hydrochloride and
1-(3-{[8-methoxy-1-(oxan-4-yl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)pyrr-
olidine Hydrochloride (2:1 Mixture)
##STR00249##
[0339] Step 1
[0340] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(Reference 5; 150.00 mg; 0.34 mmol; 1.00 eq.),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran
(107.69 mg; 0.51 mmol; 1.50 eq.),
1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (25.01
mg; 0.03 mmol; 0.10 eq.) and sodium carbonate (108.67 mg; 1.03
mmol; 3.00 eq.) in 1,4-dioxane (1.14 mL) and water (0.34 mL) was
heated to 100.degree. C. After 2 hours, the mixture was cooled to
ambient temperature, diluted with EtOAc, washed with water and
brine, dried over MgSO.sub.4, filtered and concentrated. The
residue was purified by column chromatography (12 G ISCO Gold)
eluting with 0-80% EtOAc in hexanes to provide tert-butyl
7-(benzyloxy)-1-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-5H-pyrido[4,3-b]ind-
ole-5-carboxylate (76 mg; 46% yield).
Step 2
[0341] A mixture of tert-butyl
7-(benzyloxy)-1-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-5H-pyrido[4,3-b]ind-
ole-5-carboxylate (76.00 mg; 0.16 mmol; 1.00 eq.) and palladium on
carbon (0.50 mg; 0.00 mmol; 0.03 eq.) in methanol (1.56 mL) was
stirred under an atmosphere of H.sub.2 from a balloon. After
overnight (still incomplete conversion) more catalyst was added and
the mixture was stirred for an additional 7 h. The mixture was then
filtered with additional MeOH and concentrated. The crude off-white
solid (.sup.1H NMR showed dihydropyran with traces of
tetrahydropyran; both masses were detected by LC/MS) was taken on
without further purification assuming 100% yield (62 mg, 100%
yield).
Step 3
[0342] A mixture of tert-butyl
1-(3,6-dihydro-2H-pyran-4-yl)-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole--
5-carboxylate (62.00 mg; 0.16 mmol; 1.00 eq.) (containing also the
reduced tetrahydropyran), 1-(3-chloropropyl)pyrrolidin-1-ium
chloride (57.59 mg; 0.31 mmol; 2.00 eq.) and potassium carbonate
(86.33 mg; 0.63 mmol; 4.00 eq.) in N,N-dimethylformamide (1.56 mL)
was stirred at 100.degree. C. After 7 h the mixture was cooled to
ambient temperature, diluted with 1:1 PhMe/EtOAc, washed with
water, dried over MgSO.sub.4, filtered and concentrated to provide
an orange oil.
[0343] The oil was dissolved in 2.0 mL of DCM and treated with 1.0
mL TFA at ambient temperature. After 2 hours, the reaction mixture
was concentrated in vacuo. The residue was taken up in 1N HCl
(.about.1.5 mL) and purified by Prep HPLC (Phenomenex Luna C18,
21.times.250 mm, 0-70% acetonitrile/0.1% aqueous HCl gradient over
13 minutes, flow rate 22 ml/min) to provide
1-(3-{[1-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-5H-pyrido[4,3-b]indol-7-yl-
]oxy}propyl)pyrrolidine hydrochloride and
1-(3-{[8-methoxy-1-(oxan-4-yl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)pyrr-
olidine hydrochloride (2:1 mixture) as a yellow powder. 1H NMR
(only major component) (400 MHz, DMSO-d.sub.6) .delta. 13.13 (s,
1H), 10.71 (s, 1H), 8.39 (d, J=6.7 Hz, 1H), 7.82 (d, J=6.8 Hz, 1H),
7.48 (s, 1H), 7.32 (s, 1H), 6.58 (d, J=2.9 Hz, 1H), 4.41 (q, J=2.8
Hz, 2H), 4.20 (d, J=6.1 Hz, 2H), 4.00 (t, J=5.3 Hz, 2H), 3.84 (s,
3H), 3.60-3.50 (m, 2H), 3.29-3.24 (m, 2H), 3.05-2.95 (m, 2H),
2.69-2.62 (m, 2H), 2.26-2.18 (m, 2H), 2.02-1.94 (m, 2H), 1.92-1.84
(m, 2H). MS (ESI, pos. ion) m/z: 408.4 (M+1).
Example 65
1-(3-{[8-methoxy-1-(oxan-4-yl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)pyrro-
lidine Hydrochloride and
1-(3-{[1-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-5H-pyrido[4,3-b]indol-7-yl-
]oxy}propyl)pyrrolidine Hydrochloride (4:1 Mixture)
##STR00250##
[0345] The title compound was prepared using the synthetic
procedures described for Example 64 changing step 2 as follows:
[0346] A mixture of tert-butyl
7-(benzyloxy)-1-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-5H-pyrido[4,3-b]ind-
ole-5-carboxylate (50.00 mg; 0.10 mmol; 1.00 eq.) and rhodium (5%
wt on alumina) (1.06 mg; 0.01 mmol; 0.10 eq.) in methanol (1.03 mL)
was stirred under an atmosphere of H.sub.2 from a balloon. After 48
the mixture was filtered with additional MeOH and concentrated. The
crude off-white was taken on without further purification assuming
100% yield (40 mg)
[0347] After step 3 (as described for Example 64
1-(3-{[8-methoxy-1-(oxan-4-yl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)pyrr-
olidine hydrochloride and
1-(3-{[1-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-5H-pyrido[4,3-b]indol-7-yl-
]oxy}propyl)pyrrolidine hydrochloride and (4:1 mixture) were
obtained as a white powder. 1H NMR (only major component) (400 MHz,
DMSO-d.sub.6) .delta. 13.07 (s, 1H), 10.47 (s, 1H), 8.34 (d, J=6.7
Hz, 1H), 7.81 (d, J=7.0 Hz, 1H), 7.64 (s, 1H), 7.33 (s, 1H), 4.22
(t, J=6.1 Hz, 2H), 4.08-4.04 (m, 2H), 3.93 (s, 3H), 3.73 (td,
J=11.7, 1.9 Hz, 2H), 3.61-3.52 (m, 2H), 3.28-3.25 (m, 2H),
3.05-2.97 (m, 2H), 2.65-2.62 (m, 1H), 2.26-2.18 (m, 2H), 2.11 (td,
J=12.3, 4.2 Hz, 2H), 2.02-1.84 (m, 6H). MS (ESI, pos. ion) m/z:
410.5 (M+1).
Example 66
4-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}-1,-
2,3,6-tetrahydropyridine Bishydrochloride
##STR00251##
[0348] Step 1
[0349] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(reference 5; 200.00 mg; 0.46 mmol; 1.00 eq.), tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridin-
ecarboxylate (211.35 mg; 0.68 mmol; 1.50 eq.),
1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.34
mg; 0.05 mmol; 0.10 eq.) and sodium carbonate (144.89 mg; 1.37
mmol; 3.00 eq.) in 1,4-dioxane (1.52 mL) and water (0.46 mL) was
heated to 100.degree. C. The mixture was then cooled to ambient
temperature, diluted with EtOAc, washed with water and brine, dried
over MgSO4, filtered and concentrated. The residue was purified by
column chromatography (24 G ISCO Gold) eluting with 0-100% EtOAc in
heptane to provide tert-butyl
4-[7-(benzyloxy)-5-[(tert-butoxy)carbonyl]-8-methoxy-5H-pyrido[4,3-b]indo-
l-1-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate as a white foam.
166 mg; 62% yield.
Step 2
[0350] A mixture of tert-butyl
4-[7-(benzyloxy)-5-[(tert-butoxy)carbonyl]-8-methoxy-5H-pyrido[4,3-b]indo-
l-1-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (50.00 mg; 0.09
mmol; 1.00 eq.) and palladium on carbon (0.91 mg; 0.01 mmol; 0.10
eq.) in methanol (0.85 mL) was stirred under an atmosphere of
H.sub.2 from a balloon. After overnight stirring the mixture was
filtered with additional MeOH and concentrated. This material was
taken on without further purification assuming 100% yield (40
mg).
Step 3
[0351] A mixture of tert-butyl
4-{5-[(tert-butoxy)carbonyl]-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indol-1--
yl}-1,2,3,6-tetrahydropyridine-1-carboxylate (40.00 mg; 0.08 mmol;
1.00 eq.), 1-(3-chloropropyl)pyrrolidin-1-ium chloride (29.72 mg;
0.16 mmol; 2.00 eq.) and potassium carbonate (44.55 mg; 0.32 mmol;
4.00 eq.) in N,N-dimethylformamide (0.81 mL) was stirred at
100.degree. C. The mixture was then cooled to ambient temperature,
diluted with 1:1 PhMe/EtOAc, washed with water, dried over
MgSO.sub.4, filtered and concentrated to provide an orange oil.
[0352] The oil was taken up in DCM (1 mL) and treated with TFA (0.5
mL) at ambient temperature. After 2 h the mixture was concentrated
in vacuo. The residue was taken up in 1.5 mL 1N HCl, filtered
through a syringe filter and purified by Prep HPLC ((Phenomenex
Luna C18, 21.times.250 mm, 0-70% acetonitrile/0.1% aqueous HCl
gradient over 13 minutes, flow rate 22 ml/min) to provide
4-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}-1-
,2,3,6-tetrahydropyridine bishydrochloride as a yellow solid, 20.2
mg. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.11 (s, 1H),
10.49 (s, 1H), 9.76 (br s, 2H), 8.41 (d, J=6.7 Hz, 1H), 7.83 (s,
1H), 7.62 (s, 1H), 7.29 (s, 1H), 6.54 (s, 1H), 4.20 (t, J=6.0 Hz,
2H), 3.96-3-91 (m, 4H), 3.61-3.52 (m, 2H), 3.48-3.41 (m, 2H),
3.28-3.24 (m, 2H), 3.04-2.93 (m, 4H), 2.25-2.17 (m, 2H), 2.02-1.95
(m, 2H), 1.92-1.82 (m, 2H); MS (ESI, pos. ion) m/z: 407.3
(M+1).
Example 67
(3-{[8-methoxy-1-(propan-2-yl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)dimet-
hylamine Hydrochloride
##STR00252##
[0353] Step 1
[0354] To a mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(Reference 5; 300 mg; 0.68 mmol; 1.00 eq.), and
tris((3Z)-4-hydroxypent-3-en-2-one) iron (12 mg; 0.03 mmol; 0.05
eq.) in tetrahydrofuran (5 mL) and NMP (0.5 mL) at ambient
temperature was added (isopropyl)magnesium bromide (0.8 mL; 1.00
mol/L; 0.82 mmol; 1.20 eq.) and the mixture was stirred at ambient
temperature. After 0.5 h the mixture was diluted with EtOAc, washed
with water, dried over MgSO.sub.4, filtered and concentrated. The
residue was purified by column chromatography (24 G ISCO Gold)
eluting with 0-60% EtOAc in heptane to obtain NO SEPARATION of the
product from the unreacted starting material. The semi-purified
material was taken up in DMF and purified by Prep HPLC (Phenomenex
Luna C18, 21.times.250 mm, 5-95% acetonitrile/0.1% aqueous HCl
gradient over 13 minutes, flow rate 22 ml/min) to provide
tert-butyl
7-(benzyloxy)-8-methoxy-1-(propan-2-yl)-5H-pyrido[4,3-b]indole-5-carboxyl-
ate as a white powder (60 mg. 19%)
Step 2
[0355] A mixture of tert-butyl
7-(benzyloxy)-8-methoxy-1-(propan-2-yl)-5H-pyrido[4,3-b]indole-5-carboxyl-
ate (60 mg; 0.13 mmol; 1.00 eq.) and palladium on carbon (2 mg;
0.01 mmol; 0.10 eq.) in methanol (3 mL) was stirred under an
atmosphere of H.sub.2 from a balloon. After 4 the mixture was
filtered with additional MeOH and concentrated. The crude white
solid was taken on to the next step without further purification
assuming 100% yield.
Step 3
[0356] A mixture of tert-butyl
7-hydroxy-8-methoxy-1-(propan-2-yl)-5H-pyrido[4,3-b]indole-5-carboxylate
(47 mg; 0.13 mmol; 1.00 eq.), (3-chloropropyl)dimethylamine (32 mg;
0.26 mmol; 2.00 eq.) and potassium carbonate (73 mg; 0.53 mmol;
4.00 eq.) in DMF (2 mL) was stirred at 100.degree. C. After 2 h the
mixture was cooled to ambient temperature, diluted with 1:1
PhMe/EtOAc, washed with water, dried over MgSO.sub.4, filtered and
concentrated to provide a colorless oil. The oil was taken up in
DCM (1 mL) and treated with TFA (0.5 mL) at ambient temperature.
After 1.5 h the mixture was concentrated in vacuo. The residue was
taken up in 1.5 mL 1N HCl and purified by R-Phase HPLC (Phenomenex
Luna C18, 21.times.250 mm, 0-60% acetonitrile/0.1% aqueous HCl
gradient over 13 minutes, flow rate 22 ml/min) to provide
(3-{[8-methoxy-1-(propan-2-yl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)dime-
thylamine hydrochloride as a white powder. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.11 (s, 1H), 10.40 (s, 1H), 8.34 (d, J=6.7
Hz, 1H), 7.79 (d, J=6.7 Hz, 1H), 7.68 (s, 1H), 7.33 (s, 1H), 4.21
(dt, J=11.9, 6.4 Hz, 3H), 3.92 (s, 3H), 3.25-3.18 (m, 2H), 2.78 (s,
3H), 2.77 (s, 3H), 2.22 (p, J=6.2 Hz, 2H), 1.54 (s, 3H), 1.52 (s,
3H). MS (ESI, pos. ion) m/z: 342.4 (M+1).
Example 68
(3-{[8-methoxy-1-(oxan-4-yl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)dimethy-
lamine Hydrochloride
##STR00253##
[0358] The title compound was prepared using the synthetic
procedures described for Example 64 changing step 2 and 3 as
follows:
Step 2
[0359] A mixture of tert-butyl
7-(benzyloxy)-1-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-5H-pyrido[4,3-b]ind-
ole-5-carboxylate (100.00 mg; 0.21 mmol; 1.00 eq.) and palladium on
carbon (2.19 mg; 0.02 mmol; 0.10 eq.) in ethyl acetate (2.06 mL)
was stirred under an atmosphere of H.sub.2 from a balloon. After
overnight the mixture was heated to 50.degree. C. for 6 h. The
mixture was then filtered with additional EtOAc and concentrated.
The crude material was taken on to the next step without further
purification assuming 100% yield.
Step 3
[0360] A mixture of tert-butyl
7-hydroxy-8-methoxy-1-(oxan-4-yl)-5H-pyrido[4,3-b]indole-5-carboxylate
(80.00 mg; 0.20 mmol; 1.00 eq.), (3-chloropropyl)dimethylamine
(48.83 mg; 0.40 mmol; 2.00 eq.) and potassium carbonate (110.83 mg;
0.80 mmol; 4.00 eq.) in N,N-dimethylformamide (2.01 mL) was stirred
at 100.degree. C. After 1.5 the mixture was cooled to ambient
temperature, diluted with 1:1 PhMe/EtOAc, washed with water, dried
over MgSO.sub.4, filtered and concentrated to provide a yellow wax.
The wax was taken up in DCM (1.5 mL) and treated with TFA (0.7 mL)
at ambient temperature. After 1.5 h the mixture was concentrated in
vacuo. The residue was taken up in 1.5 mL 1N HCl and purified by
Prep HPLC (Phenomenex Luna C18, 21.times.250 mm, 0-60%
acetonitrile/0.1% aqueous HCl gradient over 13 minutes, flow rate
22 ml/min) to provide
(3-{[8-methoxy-1-(oxan-4-yl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)dimeth-
ylamine hydrochloride as a white powder. (39 mg).sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 14.28 (s, 1H), 13.17 (s, 1H), 10.46 (s,
1H), 8.35 (d, J=6.7 Hz, 1H), 7.81 (d, J=6.7 Hz, 1H), 7.64 (s, 1H),
7.34 (s, 1H), 4.20 (t, J=6.2 Hz, 2H), 4.06 (dd, J=11.4, 4.1 Hz,
3H), 3.93 (s, 3H), 3.73 (td, J=11.6, 1.8 Hz, 2H), 3.22 (s, 2H),
2.78 (s, 3H), 2.77 (s, 3H), 2.26-2.19 (m, 2H), 2.14 (td, J=12.4,
4.3 Hz, 1H), 1.97-1.90 (m, 2H). MS (ESI, pos. ion) m/z: 384.4
(M+1).
Example 69
[3-({1-cyclobutyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]dimethyl-
amine Hydrochloride
##STR00254##
[0362] The title compound was prepared using the synthetic
procedures described for Example 67 changing step 1 as follows:
[0363] To a mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(Reference 5; 300.00 mg; 0.68 mmol; 1.00 eq.) and
1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50.01
mg; 0.07 mmol; 0.10 eq.) in 1,4-dioxane (6.84 mL) at ambient
temperature under Argon was added bromo(cyclobutyl)zinc (2.73 mL;
0.50 mol/L; 1.37 mmol; 2.00 eq.) drop-wise. After complete addition
the mixture was heated to 80.degree. C. under Argon. After 2h the
mixture was cooled to ambient temperature, water was added and the
suspension was stirred vigorously for 10 minutes. The mixture was
then extracted with EtOAc. The organic phase was washed once with
brine and the combined aqueous phase back-extracted with EtOAc. The
combined organic phase was dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by column chromatography (24
G ISCO Gold) eluting with 0-50% EtOAc in heptane to obtain almost
complete separation of tert-butyl
7-(benzyloxy)-1-cyclobutyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
from the unreacted starting material. This material was taken on to
the next step without further purification (95 mg; 30% yield).
[0364] After step 3
[3-({1-cyclobutyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]dimethy-
lamine hydrochloride was obtained as a white powder (54 mg).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 14.25 (s, 1H), 13.09
(s, 1H), 10.45 (s, 1H), 8.34 (d, J=6.8 Hz, 1H), 7.79 (d, J=6.7 Hz,
1H), 7.67 (s, 1H), 7.31 (s, 1H), 4.73 (p, J=8.7 Hz, 1H), 4.19 (t,
J=6.1 Hz, 2H), 3.94 (s, 3H), 3.22 (q, J=7.3, 5.7 Hz, 2H), 2.78 (s,
3H), 2.77 (s, 3H), 2.60 (td, J=8.8, 8.3, 5.7 Hz, 4H), 2.31-2.23 (m,
1H), 2.24-2.16 (m, 2H), 2.01-1.92 (m, 1H). MS (ESI, pos. ion) m/z:
354.4 (M+1).
Example 70
[2-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)ethyl]dimethylamine
Hydrochloride
##STR00255##
[0365] Step 1
[0366] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(Reference 5; 610.00 mg; 1.39 mmol; 1.00 eq.) and palladium on
carbon (29.58 mg; 0.28 mmol; 0.20 eq.) in tetrahydrofuran (13.90
mL) was stirred under an atmosphere of H.sub.2 from a balloon.
After 24 h the mixture was filtered with additional MeOH and
concentrated. The crude orange oil was taken on to the next step
without further purification assuming 100% yield.
Step 2
[0367] A mixture of tert-butyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate (100.00
mg; 0.32 mmol; 1.00 eq.), 2-(dimethylamino)ethanol (0.04 mL; 0.35
mmol; 1.10 eq.) and (tributylphosphoranylidene)acetonitrile (153.56
mg; 0.64 mmol; 2.00 eq.) in toluene (1.06 mL) was heated to
110.degree. C. After 30 minutes, the mixture was cooled to ambient
temperature and concentrated in vacuo. The residue was taken up in
DMF and 1N HCl (total of 1.5 mL) and purified by Prep HPLC
(Phenomenex Luna C18, 21.times.250 mm, 0-60% acetonitrile/0.1%
aqueous HCl gradient over 13 minutes, flow rate 22 ml/min) to
provide
[2-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)ethyl]dimethylamine
hydrochloride as a tan solid. 12.9 mg. .sup.1H NMR (400 MHz,
DMSO-d.sub.6; containing 2 drops of D.sub.2O) .delta. 9.53 (s, 1H),
8.47 (dd, J=6.7, 0.9 Hz, 1H), 8.04 (s, 1H), 7.90 (d, J=6.7 Hz, 1H),
7.38 (s, 1H), 4.46 (t, J=5.0 Hz, 2H), 3.87 (s, 3H), 3.57 (t, J=5.0
Hz, 2H), 2.88 (s, 6H). MS (ESI, pos. ion) m/z: 286.4 (M+1).
Example 71
1-[2-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)ethyl]pyrrolidine
Hydrochloride
##STR00256##
[0369] The title compound was prepared using the synthetic
procedures described for Example 70 changing step 2 as follows:
[0370] A mixture of tert-butyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate (100.00
mg; 0.32 mmol; 1.00 eq.), 2-(1-pyrrolidinyl)ethanol (146.56 mg;
1.27 mmol; 4.00 eq.) and (tributylphosphoranylidene)acetonitrile
(153.56 mg; 0.64 mmol; 2.00 eq.) in toluene (1.06 mL) was heated to
115.degree. C. After 1 h the mixture was cooled to ambient
temperature and concentrated in vacuo. The crude dark oil was taken
up in DCM (1 mL) and treated with TFA (0.5 mL) at ambient
temperature. After 3 h the mixture was concentrated in vacuo. The
residue was taken up in 1N HCl (total of 1.5 mL) and purified by
Prep HPLC (Phenomenex Luna C18, 21.times.250 mm, 0-40%
acetonitrile/0.1% aqueous HCl gradient over 13 minutes, flow rate
22 ml/min) to provide
1-[2-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)ethyl]pyrrolidine
hydrochloride as an off-white solid 28.9 mg. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.09 (s, 1H), 11.19 (s, 1H), 9.60 (s, 1H),
8.51 (d, J=6.7 Hz, 1H), 8.10 (s, 1H), 7.91 (d, J=6.7 Hz, 1H), 7.36
(s, 1H), 4.50 (t, J=5.0 Hz, 2H), 3.89 (s, 3H), 3.68-3.57 (m, 4H),
3.13 (br s, 2H), 1.99 (br s, 2H), 1.88 (br s, 2H). MS (ESI, pos.
ion) m/z: 312.3 (M+1).
Example 72
1-[3-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]azetidine
Hydrochloride
##STR00257##
[0372] The title compound was prepared using the synthetic
procedures described for Example 70 changing step 2 as follows:
[0373] A mixture of tert-butyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate (140.00
mg; 0.45 mmol; 1.00 eq.), 3-(azetidin-1-yl)propan-1-ol (205.19 mg;
1.78 mmol; 4.00 eq.) and (tributylphosphoranylidene)acetonitrile
(214.99 mg; 0.89 mmol; 2.00 eq.) in toluene (1.48 mL) was heated to
115.degree. C. After 0.5 h LC/MS the mixture was cooled to ambient
temperature and concentrated in vacuo. The crude dark oil was taken
up in DCM (1.5 mL) and treated with TFA (1.3 mL) at ambient
temperature. After 2 h the mixture was concentrated in vacuo. The
residue was taken up in 1N HCl (1.5 mL) and DMF (0.5 mL) and
purified by Prep HPLC (Phenomenex Luna C18, 21.times.250 mm, 0-40%
acetonitrile/0.1% aqueous HCl gradient over 13 minutes, flow rate
22 ml/min) to provide
1-[3-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]azetidine
hydrochloride, 12.5 mg. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
13.00 (s, 1H), 10.56 (s, 1H), 9.57 (s, 1H), 8.51 (d, J=6.7 Hz, 1H),
8.05 (s, 1H), 7.90 (d, J=6.7 Hz, 1H), 7.28 (s, 1H), 4.17 (t, J=6.1
Hz, 2H), 4.10 (dt, J=8.8, 5.5 Hz, 2H), 4.03-3.94 (m, 2H), 3.18-3.28
(m, 2H), 2.42-2.33 (m, 1H), 2.26 (ddd, J=10.7, 7.9, 4.4 Hz, 1H),
2.02 (p, J=6.5 Hz, 2H). MS (ESI, pos. ion) m/z: 312.3 (M+1).
Example 73
1-(3-{[8-methoxy-1-(oxan-4-yloxy)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)py-
rrolidine Trifluoroacetate
##STR00258##
[0374] Step 1
[0375] Into a 100-mL round-bottom flask, was placed
3-bromopyridin-2-ol (4 g, 22.99 mmol, 1.00 eq.), tetrahydrofuran
(40 mL), tetrahydro-2H-pyran-4-ol (2.34 g, 22.91 mmol, 1.00 eq.),
PPh.sub.3 (7.23 g, 27.56 mmol, 1.20 eq.), then added DEAD (4.8 g,
27.56 mmol, 1.20 eq.) by dropwise. The resulting solution was
stirred for 1 h at 25.degree. C. The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:5). The collected
fractions were combined and concentrated under vacuum. This
resulted in 2.58 g (43%) of
3-bromo-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine as colorless oil.
MS (ESI, pos. ion) m/z: 258.1 (M+1).
Step 2
[0376] Into a 100-mL round-bottom flask, was placed
2-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane (850 mg, 2.21 mmol, 1.00 eq.), dioxane (30 mL), water (10
mL), 3-bromo-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine (570 mg,
2.21 mmol, 1.00 eq.), Cs.sub.2CO.sub.3 (2158 mg, 6.62 mmol, 3.00
eq.), Pd(PPh.sub.3).sub.4 (255 mg, 0.22 mmol, 0.10 eq.). The
resulting solution was stirred for 6 h at 100.degree. C. The
resulting mixture was concentrated under vacuum. The resulting
solution was diluted with 50 mL of EA and washed with 2.times.30 mL
of water. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:3). The collected fractions were
combined and concentrated under vacuum. This resulted in 285 mg
(30%) of
3-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)-2-((tetrahydro-2H-pyran-4-yl)ox-
y)pyridine as yellow solid. MS (ESI, pos. ion) m/z: 437.2
(M+1).
Step 3
[0377] Into a 50-mL round-bottom flask, was placed
3-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)-2-((tetrahydro-2H-pyran-4-yl)ox-
y)pyridine (285 mg, 0.65 mmol, 1.00 eq.), P(OEt).sub.3 (8 mL). The
resulting solution was stirred for 24 h at 130.degree. C. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(1:1). The collected fractions were combined and concentrated under
vacuum. This resulted in 120 mg (45%) of
7-(benzyloxy)-8-methoxy-1-((tetrahydro-2H-pyran-4-yl)oxy)-5H-pyrido[4,3-b-
]indole as light yellow solid. MS (ESI, pos. ion) m/z: 405.2
(M+1).
Step 4
[0378] Into a 50-mL round-bottom flask, was placed
7-(benzyloxy)-8-methoxy-1-((tetrahydro-2H-pyran-4-yl)oxy)-5H-pyrido[4,3-b-
]indole (120 mg, 0.30 mmol, 1.00 eq.), tetrahydrofuran (10 mL),
4-dimethylaminopyridine (36 mg, 0.29 mmol, 1.00 eq.), Boc.sub.2O
(65 mg, 0.30 mmol, 1.00 eq.). The resulting solution was stirred
for 6 h at 25.degree. C. The resulting mixture was concentrated
under vacuum. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:4). The collected fractions were
combined and concentrated under vacuum. This resulted in 130 mg
(87%) of tert-butyl
7-(benzyloxy)-8-methoxy-1-((tetrahydro-2H-pyran-4-yl)oxy)-5H-pyrido[4,3-b-
]indole-5-carboxylate as yellow solid. MS (ESI, pos. ion) m/z:
405.2 (M+1).
Step 5
[0379] To a solution of tert-butyl
7-(benzyloxy)-8-methoxy-1-((tetrahydro-2H-pyran-4-yl)oxy)-5H-pyrido[4,3-b-
]indole-5-carboxylate 120 mg, 0.24 mmol, 1.00 eq.) in MeOH (12 mL)
was added 12 mg of 10% Pd/C (50% water moistened). The mixture was
degassed and purged with hydrogen for three times. The resulting
mixture was stirred for 4h at room temperature under H.sub.2
atmosphere. The solids were filtered out. The resulting mixture was
concentrated under vacuum. This resulted in 80 mg (81%) of
tert-butyl
7-hydroxy-8-methoxy-1-((tetrahydro-2H-pyran-4-yl)oxy)-5H-pyrido[4,3-b]ind-
ole-5-carboxylate as light yellow solid. MS (ESI, pos. ion) m/z:
405.2 (M+1).
Step 6
[0380] Into a 50-mL round-bottom flask, was placed tert-butyl
7-hydroxy-8-methoxy-1-(oxan-4-yloxy)-5H-pyrido[4,3-b]indole-5-carboxylate
(80 mg, 0.19 mmol, 1.00 eq.), MeCN (6 mL),
1-(3-chloropropyl)pyrrolidine hydrochloride (36 mg, 0.20 mmol, 1.00
eq.), potassium carbonate (80 mg, 0.58 mmol, 3.00 eq.). The
resulting solution was stirred for 3 h at 60.degree. C. The
reaction mixture was cooled to room temperature. The solids were
filtered out. The resulting mixture was concentrated under vacuum.
This resulted in 98 mg (97%) of tert-butyl
8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-1-((tetrahydro-2H-pyran-4-yl)oxy-
)-5H-pyrido[4,3-b]indole-5-carboxylate as yellow solid. MS (ESI,
pos. ion) m/z: 526.3 (M+1).
Step 7
[0381] Into a 50-mL round-bottom flask, was placed tert-butyl
8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-1-((tetrahydro-2H-pyran-4-yl)oxy-
)-5H-pyrido[4,3-b]indole-5-carboxylate (88 mg, 0.17 mmol, 1.00
eq.), dichloromethane (5 mL), hydrogen chloride (g)/dioxane (1 mL,
2M). The resulting solution was stirred for 1 h at 25.degree. C.
The resulting mixture was concentrated under vacuum. The crude
reaction mixture was filtered and subjected to reverse phase
preparative HPLC (Waters SunFire column, 19.times.150 mm; gradient
elution of 10% MeCN in water to 20% MeCN in water over a 10 min
period, where both solvents contain 0.05% TFA) to provide the title
compound as light yellow solid (18.4 mg, 20%). .sup.1H NMR (300
MHz, DMSO-d.sub.6): .delta. 11.60 (br, 1H), 9.50 (s, 1H), 7.90 (d,
J=5.9 Hz, 1H), 7.62 (s, 1H), 7.21-7.07 (m, 2H), 5.54 (dq, J=8.2,
4.3, 3.8 Hz, 1H), 4.17 (t, J=5.9 Hz, 2H), 4.02-3.89 (m, 2H), 3.65
(qd, J=9.8, 7.9, 5.2 Hz, 4H), 3.37 (q, J=6.8 Hz, 2H), 3.08 (dq,
J=13.9, 7.5 Hz, 2H), 2.27-1.87 (m, 10H). MS (ESI, pos. ion) m/z:
426.2 (M+1).
Example 74
3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}ox-
y)pyrrolidine bis(2,2,2-trifluoroacetate)
##STR00259##
[0383] The title compound was prepared as described in Example 73,
Steps 1-7 above, but substituting tetrahydro-2H-pyran-4-ol with
tert-butyl 3-hydroxypyrrolidine-1-carboxylate. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.63 (s, 1H), 9.70 (br, 1H), 9.30 (br,
1H), 9.14 (br, 1H), 7.91 (d, J=5.7 Hz, 1H), 7.64 (s, 1H), 7.16-7.13
(m, 2H), 5.87 (d, J=3.6 Hz, 1H), 4.15 (t, J=5.9 Hz, 2H), 3.90 (s,
3H), 3.66-3.49 (m, 6H), 3.47-3.40 (m, 2H), 3.47-3.33 (m, 2H),
3.13-3.05 (m, 2H), 2.42-2.38 (m, 2H), 2.28-2.17 (m, 2H), 2.13-2.06
(m, 2H), 1.95-1.87 (m, 2H). MS (ESI, pos. ion) m/z: 411.2
(M+1).
Example 75
1-(3-{[8-methoxy-1-(propan-2-yloxy)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)-
pyrrolidine Trifluoroacetate
##STR00260##
[0385] The title compound was prepared as described in Example 73,
Steps 1-7 above, but substituting tetrahydro-2H-pyran-4-ol with
isopropanol. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.60 (s,
1H), 9.48 (br, 1H), 7.90 (d, J=6.0 Hz, 1H), 7.59 (s, 1H), 7.14 (s,
1H), 7.10 (d, J=6.0 Hz, 1H), 5.54-5.46 (m, 1H), 4.16 (t, J=6.0 Hz,
2H), 3.88 (s, 3H), 3.67-3.65 (m, 2H), 3.41-3.34 (m, 2H), 3.11-3.05
(m, 2H), 2.22-2.17 (m, 2H), 2.07-1.93 (m, 2H), 1.95-1.89 (m, 2H),
1.46 (d, J=6.0 Hz, 3H) MS (ESI, pos. ion) m/z: 384.2 (M+1).
Example 76
1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}-1H-
-imidazole Trifluoroacetate
##STR00261##
[0386] Step 1
[0387] Into a 40-mL vial purged and maintained with an inert
atmosphere of nitrogen, was placed a mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate,
Reference 5 (1.0 g, 2.28 mmol, 1.00 eq.), DMSO (20 mL), imidazole
(1.55 g, 22.77 mmol, 10.00 eq.), Cu.sub.2O (33 mg, 0.23 mmol, 0.10
eq.), Ninhydrin (81 mg, 0.456 mmol, 0.20 eq.) and potassium
hydroxide (255 mg, 4.54 mmol, 2.00 eq.). The resulting mixture was
stirred for 24 hours at 150.degree. C. under nitrogen atmosphere.
The reaction mixture was cooled to room temperature. The resulting
solution was poured into H.sub.2O (200 mL), extracted with ethyl
acetate (3.times.150 mL). The combined organic layers were washed
with brine (150 mL), dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was purified by flash column
eluted with EtOAc/DCM (3/1). This resulted in 500 mg (59%) of the
title compound as a brown solid. MS (ESI, pos. ion) m/z: 371.1
(M+1).
Step 2
[0388] Into a 40-mL vial, was placed a mixture of
1-[7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]-1H-imidazole
(500 mg, 1.35 mmol, 1.00 eq.), tetrahydrofuran (10 mL), Boc.sub.2O
(443 mg, 2.03 mmol, 1.50 eq.) and 4-dimethylaminopyridine (41 mg,
0.34 mmol, 0.25 eq.). The resulting solution was stirred for 1 hour
at room temperature. The solution was concentrated under vacuum.
The residue was triturated with MeOH (50 mL). The solids were
collected by filtration. This resulted in 365 mg (57%) of
tert-butyl
7-(benzyloxy)-1-(1H-imidazol-1-yl)-8-methoxy-5H-pyrido[4,3-b]indole-5-car-
boxylate. MS (ESI, pos. ion) m/z: 471.2 (M+1).
Step 3
[0389] Into a 50-mL round-bottom flask, was placed a solution of
tert-butyl
7-(benzyloxy)-1-(1H-imidazol-1-yl)-8-methoxy-5H-pyrido[4,3-b]indole-5-car-
boxylate (350 mg, 0.74 mmol, 1.00 eq.) in methanol (20 mL). To
which was added 10% palladium on carbon (105 mg, wet). The flask
was evacuated and flushed three times with hydrogen. The mixture
was stirred 16 hours at room temperature under an atmosphere of
hydrogen (balloon). The solids were filtered out. The filter cake
was washed with methanol (3.times.50 mL) and DCM/MeOH (V/V=10/1, 20
mL). The filtrate was concentrated under vacuum. This resulted in
215 mg (76%) of the tert-butyl
7-hydroxy-1-(1H-imidazol-1-yl)-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxy-
late. MS (ESI, pos. ion) m/z: 381.1 (M+1).
Step 4
[0390] Into a 40-mL vial, was placed a mixture of tert-butyl
7-hydroxy-1-(1H-imidazol-1-yl)-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxy-
late (100 mg, 0.26 mmol, 1.00 eq.), CH.sub.3CN (15 mL),
1-(3-chloropropyl)pyrrolidine hydrochloride (73 mg, 0.39 mmol, 1.50
eq.), Cs.sub.2CO.sub.3 (257 mg, 3.00 eq.) and KI (66 mg, 0.39 mmol,
1.50 eq.). The resulting mixture was stirred for 16 hours at
80.degree. C. The crude reaction mixture was filtered and subjected
to reverse phase preparative HPLC (Waters SunFire column,
19.times.150 mm; gradient elution of 2% MeCN in water to 15% MeCN
in water over a 10 min period, where both solvents contain 0.05%
TFA). This resulted in 10.9 mg (11%) of the title compound as brown
oil. .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): 12.17 (s, 1H), 9.97
(s, 1H), 8.46 (d, J=1.5 Hz, 1H), 8.33-8.29 (m, 2H), 8.18 (s, 1H),
7.67 (d, J=5.7 Hz, 1H), 7.10 (s, 1H), 6.91 (s, 1H), 4.44 (d, J=6.9
Hz, 2H), 3.75 (s, 3H), 2.53-2.50 (m, 2H), 2.48-2.44 (m, 4H),
2.18-2.09 (m, 2H), 1.70-1.63 (m, 4H). MS (ESI, pos. ion) m/z: 392.2
(M+1).
Example 77
1-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl]-1H-
-pyrazole Trifluoroacetate
##STR00262##
[0392] The title compound was prepared as described in Example 76,
Steps 1-4 above, but substituting imidazole with pyrazole. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.60 (s, 1H), 9.48 (br, 1H),
7.90 (d, J=6.0 Hz, 1H), 7.59 (s, 1H), 7.14 (s, 1H), 7.10 (d, J=6.0
Hz, 1H), 5.54-5.46 (m, 1H), 4.16 (t, J=6.0 Hz, 2H), 3.88 (s, 3H),
3.67-3.65 (m, 2H), 3.41-3.34 (m, 2H), 3.11-3.05 (m, 2H), 2.22-2.17
(m, 2H), 2.07-1.93 (m, 2H), 1.95-1.89 (m, 2H), 1.46 (d, J=6.0 Hz,
3H) MS (ESI, pos. ion) m/z: 384.2 (M+1).
Example 78
5-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl}-1,-
3-thiazole Trifluoroacetate
##STR00263##
[0393] Step 1
[0394] Into a 25-mL round-bottom flask purged and maintained with
an inert atmosphere of nitrogen, was placed a mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(1.0 g, 2.28 mmol, 1.00 eq.), toluene (10 mL),
5-(tributylstannyl)-1,3-thiazole (1278 mg, 3.42 mmol, 1.50 eq.),
Pd(PPh.sub.4).sub.3 (132 mg, 0.11 mmol, 0.05 eq.). The resulting
solution was stirred for 16 h at 110.degree. C. The reaction
mixture was concentrated under vacuum. The residue was purified by
a silica gel column eluted with ethyl acetate/petroleum ether (1:1)
to provide tert-butyl
7-(benzyloxy)-8-methoxy-1-(1,3-thiazol-5-yl)-5H-pyrido[4,3-b]indole-5-car-
boxylate (610 mg, 55%) as a white solid. MS (ESI, pos. ion) m/z:
488.2 (M+1).
Step 2
[0395] Into a 10-mL round-bottom flask, was placed a solution of
tert-butyl
7-(benzyloxy)-8-methoxy-1-(1,3-thiazol-5-yl)-5H-pyrido[4,3-b]indole-5-car-
boxylate (300 mg, 0.62 mmol, 1.00 eq.) in trifluoroacetic acid (5
mL). The resulting solution was stirred for 16 h at 50.degree. C.
The solution was concentrated under vacuum to provide
8-methoxy-1-(1,3-thiazol-5-yl)-5H-pyrido[4,3-b]indol-7-ol (400 mg,
crude) as a yellow solid. MS (ESI, pos. ion) m/z: 298.1 (M+1).
Step 3
[0396] Into a 10-mL round-bottom flask purged and maintained with
an inert atmosphere of nitrogen, was placed a mixture of
8-methoxy-1-(1,3-thiazol-5-yl)-5H-pyrido[4,3-b]indol-7-ol (300 mg,
1.01 mmol, 1.00 eq.), N,N-dimethylformamide (5 mL),
1-(3-chloropropyl)pyrrolidine hydrochloride (94 mg, 0.50 mmol, 0.50
eq.), Cs.sub.2CO.sub.3 (659 mg, 2.02 mmol, 2.00 eq.) and KI (17 mg,
0.10 mmol, 0.10 eq.). The resulting mixture was stirred for 16 h at
80.degree. C. The crude reaction mixture was filtered and subjected
to reverse phase preparative HPLC (Waters SunFire column,
19.times.150 mm; gradient elution of 15% MeCN in water to 29% MeCN
in water over a 10 min period, where both solvents contain 0.05%
TFA) to provide the title compound (36.9 mg, 9%) as a light yellow
solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.83 (s, 1H),
9.31 (s, 1H), 8.53 (s, 1H), 8.37 (d, J=5.4 Hz, 1H), 7.50 (s, 1H),
7.47 (d, J=5.7 Hz, H), 7.18 (s, 1H), 4.19 (t, J=6.0 Hz, 2H), 3.75
(s, 3H), 3.39-3.30 (m, 2H), 3.20-3.12 (m, 4H), 2.21-2.14 (m, 2H),
1.94-1.85 (m, 4H). MS (ESI, pos. ion) m/z: 409.1 (M+1).
Example 79
{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-3-yl}metha-
nol Trifluoroacetate
##STR00264##
[0397] Step 1
[0398] Into a 100-mL round-bottom flask, was placed a mixture of
1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene (2.0 g, 5.91 mmol,
1.00 eq.), dioxane (50 mL), water (10 mL),
[6-(methoxycarbonyl)pyridin-3-yl]boronic acid (1.61 g, 8.90 mmol,
1.50 eq.), Cs.sub.2CO.sub.3 (5.78 g, 17.74 mmol, 3.00 eq.) and
Pd(PPh.sub.3).sub.4 (0.34 g, 0.30 mmol, 0.05 eq.). The resulting
mixture was stirred for 3 h at 80.degree. C. under N.sub.2 and
concentrated under vacuum. The residue was purified by a silica gel
column eluted with ethyl acetate/petroleum ether (1/1) to provide
methyl 5-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)picolinate (1.47 g,
63%). MS (ESI, pos. ion) m/z: 395.1 (M+1).
Step 2
[0399] A solution of methyl
5-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]pyridine-2-carboxylate
(1.45 g, 3.68 mmol, 1.00 eq.) in P(OEt).sub.3 (20 mL) was stirred
for 16 h at 130.degree. C. The reaction mixture was concentrated
under vacuum. The residue was dissolved in DMF (10 mL), filtered
and subjected to reverse phase preparative HPLC (Waters SunFire
column, 19.times.150 mm; gradient elution of 20% MeCN in water to
30% MeCN in water over a 10 min period, where both solvents contain
0.05% TFA) to provide methyl
7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indole-3-carboxylate (0.32
g, 24%). MS (ESI, pos. ion) m/z: 363.1 (M+1).
Step 3
[0400] Into a 25-mL round-bottom flask, was placed a solution of
methyl 7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indole-3-carboxylate
(500 mg, 1.38 mmol, 1.00 eq.), THF (10 mL), 4-dimethylaminopyridine
(17 mg, 0.14 mmol, 0.10 eq.) and Boc.sub.2O (602 mg, 2.76 mmol,
2.00 eq.). The resulting solution was stirred for 6 h at room
temperature and concentrated under vacuum. The residue was purified
by a silica gel column eluted with ethyl acetate/petroleum ether
(1/1) to provide 5-(tert-butyl) 3-methyl
7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indole-3,5-dicarboxylate
(140 mg, 22%). MS (ESI, pos. ion) m/z: 463.2 (M+1).
Step 4
[0401] To a mixture of 5-tert-butyl 3-methyl
7-(benzyloxy)-8-methoxy-5H-pyrido[4,3-b]indole-3,5-dicarboxylate
(130 mg, 0.28 mmol, 1.00 eq.) in methanol (26 mL) was added 130 mg
of 10% Pd/C (60% water moistened). The mixture was degassed and
purged with hydrogen for three times. The resulting mixture was
stirred for 6 h at room temperature under H.sub.2 atmosphere. The
solids were filtered out and the filtrate was concentrated under
vacuum. This resulted in 100 mg (96%) of 5-(tert-butyl) 3-methyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-3,5-dicarboxylate. MS
(ESI, pos. ion) m/z: 373.1 (M+1).
Step 5
[0402] Into a 25-mL round-bottom flask, was placed a mixture of
5-tert-butyl 3-methyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-3,5-dicarboxylate (100
mg, 0.27 mmol, 1.00 eq.), MeCN (10 mL),
1-(3-chloropropyl)pyrrolidine hydrochloride (49 mg, 0.27 mmol, 1.00
eq.) and potassium carbonate (111 mg, 0.80 mmol, 3.00 eq.). The
resulting mixture was stirred for 6 h at 60.degree. C. and
concentrated under vacuum. The residue was purified by a silica gel
column eluted with ethyl acetate/petroleum ether (1/1) to provide
5-(tert-butyl) 3-methyl
8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5H-pyrido[4,3-b]indole-3,5-dicar-
boxylate (98 mg, 75%). MS (ESI, pos. ion) m/z: 484.2 (M+1).
Step 6
[0403] To a mixture of 5-tert-butyl 3-methyl
8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indole-3,5-dicar-
boxylate (98 mg, 0.20 mmol, 1.00 eq.) in THF (10 mL) at 0.degree.
C. was added LiAlH.sub.4 (15 mg, 0.40 mmol, 2.00 eq.) in portions.
The resulting mixture was stirred for 1 h at 25.degree. C. under
N.sub.2. The reaction mixture was diluted with THF (10 mL),
quenched by water (0.1 mL) and concentrated under vacuum. The
residue was dissolved in DMF (5 mL), filtered and subjected to
reverse phase preparative HPLC (Waters SunFire column, 19.times.150
mm; gradient elution of 15% MeCN in water to 25% MeCN in water over
a 10 min period, where both solvents contain 0.05% TFA) to provide
the title compound as a gray solid (19.1 mg, 16%). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 14.46 (br, 1H), 12.76 (s, 1H), 9.62 (br,
1H), 9.54 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.28 (s, 1H), 6.20
(br, 1H), 4.91 (s, 2H), 4.21 (t, J=5.4 Hz, 2H), 3.91 (s, 3H),
3.75-3.65 (m, 2H), 3.37-3.31 (m, 2H), 3.12-3.05 (m, 2H), 2.24-2.14
(m, 2H), 2.06-1.96 (m, 2H), 1.94-1.88 (m, 2H). MS (ESI, pos. ion)
m/z: 356.2 (M+1).
Example 80
8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5H-pyrido[4,3-b]indol-3-ol
Formate
##STR00265##
[0404] Step 1
[0405] Into a 250-mL round-bottom flask, was placed a mixture of
1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene, Reference 1 (2.0 g,
5.91 mmol, 1.00 eq.), dioxane (100 mL), water (20 mL),
2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.1 g,
8.93 mmol, 1.50 eq.), Cs.sub.2CO.sub.3 (5.78 g, 17.74 mmol, 3.00
eq.) and Pd(PPh.sub.3).sub.4 (340 mg, 0.29 mmol, 0.05 eq.). The
resulting mixture was stirred for 8 h at 80.degree. C. under
N.sub.2. The reaction mixture was cooled to room temperature and
concentrated under vacuum. The residue was purified by a silica gel
column eluted with ethyl acetate/petroleum ether (1/2) to provide
5-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)-2-methoxypyridine (1.25
g, 58%). MS (ESI, pos. ion) m/z: 367.1 (M+1).
Step 2
[0406] A solution of
5-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]-2-methoxypyridine (1.15
g, 3.14 mmol, 1.00 eq.) in P(OEt).sub.3 (20 mL) was stirred for 24
h at 130.degree. C. The reaction solution was cooled to room
temperature and concentrated under vacuum. The residue was purified
by a silica gel column eluted with ethyl acetate/petroleum ether
(1/1) to provide 7-(benzyloxy)-3,8-dimethoxy-5H-pyrido[4,3-b]indole
(210 mg, 20%). MS (ESI, pos. ion) m/z: 335.1 (M+1).
Step 3
[0407] Into a 25-mL round-bottom flask, was placed a solution of
7-(benzyloxy)-3,8-dimethoxy-5H-pyrido[4,3-b]indole (210 mg, 0.63
mmol, 1.00 eq.), THF (10 mL), 4-dimethylaminopyridine (7 mg, 0.06
mmol, 0.10 eq.) and Boc.sub.2O (270 mg, 1.24 mmol, 2.00 eq.). The
resulting solution was stirred for 3 h at 25.degree. C. and
concentrated under vacuum. The residue was purified by a silica gel
column eluted with ethyl acetate/petroleum ether (1/3) to provide
tert-butyl
7-(benzyloxy)-3,8-dimethoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(230 mg, 84%). MS (ESI, pos. ion) m/z: 435.2 (M+1).
Step 4
[0408] To a mixture of tert-butyl
7-(benzyloxy)-3,8-dimethoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(220 mg, 0.51 mmol, 1.00 eq.) in MeOH (22 mL) was added 220 mg of
10% Pd/C (60% water moistened). The mixture was degassed and purged
with hydrogen for three times. The resulting mixture was stirred
for 6 h at room temperature under H.sub.2 atmosphere. The solids
were filtered out and the filtrate was concentrated under vacuum.
This resulted in 156 mg (89%) of tert-butyl
7-hydroxy-3,8-dimethoxy-5H-pyrido[4,3-b]indole-5-carboxylate. MS
(ESI, pos. ion) m/z: 345.1 (M+1).
Step 5
[0409] Into a 25-mL round-bottom flask, was placed a mixture of
tert-butyl
7-hydroxy-3,8-dimethoxy-5H-pyrido[4,3-b]indole-5-carboxylate (150
mg, 0.44 mmol, 1.00 eq.), MeCN (10 mL),
1-(3-chloropropyl)pyrrolidine hydrochloride (80 mg, 0.43 mmol, 1.00
eq.) and potassium carbonate (181 mg, 1.31 mmol, 3.00 eq.). The
resulting mixture was stirred for 6 h at 60.degree. C. The reaction
mixture was cooled to room temperature. The solids were filtered
out and the filtrate was concentrated under vacuum. This resulted
in 135 mg (68%) of tert-butyl
3,8-dimethoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5H-pyrido[4,3-b]indole-5-car-
boxylate. MS (ESI, pos. ion) m/z: 456.2 (M+1).
Step 6
[0410] Into a 25-mL round-bottom flask, was placed a solution of
tert-butyl
3,8-dimethoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indole-5-car-
boxylate (125 mg, 0.27 mmol, 1.00 eq.), ethanol (5 mL) and conc.
HCl (aq., 5 mL). The resulting solution was stirred for 16 h at
80.degree. C. The reaction mixture was cooled to room temperature
and concentrated under vacuum. The residue was dissolved in DMF (5
mL), filtered and subjected to reverse phase preparative HPLC
(Waters SunFire column, 19.times.150 mm; gradient elution of 15%
MeCN in water to 25% MeCN in water over a 10 min period, where both
solvents contain 0.1% formic acid) to provide the title compound as
a light yellow solid (42.6 mg, 40%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.0 (s, 1H), 8.69 (s, 1H), 8.15 (s, 1H),
7.45 (s, 1H), 6.98 (s, 1H), 6.62 (s, 1H), 4.11 (t, J=6.0 Hz, 2H),
3.88 (s, 3H), 3.14-3.03 (m, 6H), 2.11-2.06 (m, 2H), 1.90-1.85 (m,
4H). MS (ESI, pos. ion) m/z: 342.2 (M+1).
Example 81
4-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl]-1H-
-pyrazole Hydrochloride
##STR00266##
[0411] Step 1
[0412] To a solution of
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole (Reference
5, step 2) (3.2 g, 9.45 mmol, 1.00 eq.) in dichloromethane (50 mL)
at 0.degree. C. was added TEA (1.9 g, 18.90 mmol, 2.00 eq.)
followed by TsCl (2.2 g, 11.34 mmol, 1.20 eq.) and
4-dimethylaminopyridine (116 mg, 0.95 mmol, 0.10 eq.). The
resulting solution was stirred for 1 h at room temperature and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel eluted with ethyl acetate/petroleum
ether (1/1) to provide
7-(benzyloxy)-1-chloro-8-methoxy-5-[(4-methylbenzene)sulfonyl]-5H-pyrido[-
4,3-b]indole (3.8 g, 82%). MS (ESI, pos. ion) m/z: 493.2 (M+1).
Step 2
[0413] A solution of
7-(benzyloxy)-1-chloro-8-methoxy-5-[(4-methylbenzene)sulfonyl]-5H-pyrido[-
4,3-b]indole (3.8 g, 7.71 mmol, 1.00 eq.) in trifluoroacetic acid
(30 mL) was stirred for 16 h at room temperature. The resulting
solution was concentrated under vacuum. The residue was purified by
column chromatography on silica gel eluted with
dichloromethane/methanol (10/1) to provide methyl
1-chloro-8-methoxy-5-[(4-methylbenzene)sulfonyl]-5H-pyrido[4,3-b]indol-7--
ol (4.03 g). MS (ESI, pos. ion) m/z: 403.1 (M+1).
Step 3
[0414] Into a 250-mL round-bottom flask, was placed a mixture of
1-chloro-8-methoxy-5-[(4-methylbenzene)sulfonyl]-5H-pyrido[4,3-b]indol-7--
ol (4.3 g, 10.67 mmol, 1.00 eq.), CH.sub.3CN (150 mL),
1-(3-chloropropyl)pyrrolidine hydrochloride (2.15 g, 11.74 mmol,
1.10 eq.), Cs.sub.2CO.sub.3 (10.4 g, 32.01 mmol, 3.00 eq.) and KI
(178 mg, 1.07 mmol, 0.10 eq.). The resulting mixture was stirred
for 2 h at 85.degree. C. under N.sub.2. The mixture was filtered
and the filter cake was washed with CH.sub.3CN (2.times.50 mL). The
combined filtrate was concentrated under vacuum. The residue was
purified by column chromatography on silica gel eluted with
dichloromethane/methanol (10/1) to provide
1-[3-([1-chloro-8-methoxy-5-[(4-methylbenzene)sulfonyl]-5H-pyrido[4,3-b]i-
ndol-7-yl]oxy)propyl]pyrrolidine (1.6 g, 29%). MS (ESI, pos. ion)
m/z: 514.1 (M+1).
Step 4
[0415] Into a 40-mL vial, was placed a mixture of
1-[3-([1-chloro-8-methoxy-5-[(4-methylbenzene)sulfonyl]-5H-pyrido[4,3-b]i-
ndol-7-yl]oxy)propyl]pyrrolidine (300 mg, 0.58 mmol, 1.00 eq.),
dioxane (20 mL), water (2 mL),
1-[(tert-butoxy)carbonyl]-1H-pyrazol-4-ylboronic acid (250 mg, 1.16
mmol, 2.00 eq.), Cs.sub.2CO.sub.3 (567 mg, 1.74 mmol, 3.00 eq.) and
Pd(PPh.sub.3).sub.4 (35 mg, 0.03 mmol, 0.05 eq.). The resulting
mixture was stirred for 8 h at 80.degree. C. under N.sub.2 and then
concentrated under vacuum. The residue was purified by column
chromatography on silica gel eluted with dichloromethane/methanol
(5/1) to provide
4-[8-methoxy-5-[(4-methylbenzene)sulfonyl]-7-[3-(pyrrolidin-1-yl)propoxy]-
-5H-pyrido[4,3-b]indol-1-yl]-1H-pyrazole (310 mg, 97%). MS (ESI,
pos. ion) m/z: 546.3 (M+1).
Step 5
[0416] Into a 40-mL vial, was placed a mixture of
4-[8-methoxy-5-[(4-methylbenzene)sulfonyl]-7-[3-(pyrrolidin-1-yl)propoxy]-
-5H-pyrido[4,3-b]indol-1-yl]-1H-pyrazole (350 mg, 0.64 mmol, 1.00
eq.), dioxane (10 mL), water (2 mL) and sodium hydroxide (76.8 mg,
1.92 mmol, 3.00 eq.). The resulting mixture was stirred for 16 h at
80.degree. C. and then concentrated under vacuum. The residue was
purified by column chromatography on silica gel eluted with
dichloromethane/methanol (6/1) to afford the free title compound.
To the obtained compound in DCM (5 mL) was added HCl/dioxane (4
M/dioxane, 1 mL) and stirred for 0.5 h. The solid was collected by
filtration to provide the title compound as a yellow solid (125.7
mg, 46%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 14.96 (br,
1H), 13.46 (s, 1H), 11.20 (br, 1H), 8.50 (s, 1H), 8.48 (s, 1H),
8.40 (d, J=6.0 Hz, 1H), 7.84 (d, J=6.6 Hz, 1H), 7.43 (s, 1H), 7.33
(s, 1H), 4.24 (t, J=5.7 Hz, 2H), 3.76 (s, 3H), 3.59-3.54 (m, 2H),
3.39-3.27 (m, 2H), 3.07-2.99 (m, 2H), 2.32-2.23 (m, 2H), 2.05-1.81
(m, 4H). MS (ESI, pos. ion) m/z: 392.2 (M+1).
Example 82
8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl]methan-
ol Trifluoroacetate
##STR00267##
[0417] Step 1
[0418] Into a 50-mL sealed tube, was placed a mixture of
1-[3-([1-chloro-8-methoxy-5-[(4-methylbenzene)sulfonyl]-5H-pyrido[4,3-b]i-
ndol-7-yl]oxy)propyl]pyrrolidine (Example 81, step 3) (320 mg, 0.62
mmol, 1.00 eq.), methanol (10 mL), TEA (182 mg, 1.80 mmol, 3.00
eq.) and Pd(dppf)Cl.sub.2 (22 mg, 0.03 mmol, 0.05 eq.). The mixture
was degassed and purged with CO for 3 times and then stirred for 16
h at 80.degree. C. under CO (20 atm). The reaction mixture was
concentrated under vacuum. The residue was purified by column
chromatography on silica gel eluted with dichloromethane/methanol
(10/1) to provide methyl
8-methoxy-5-[(4-methylbenzene)sulfonyl]-7-[3-(pyrrolidin-1-yl)propoxy]-5H-
-pyrido[4,3-b]indole-1-carboxylate (135 mg, 40%). MS (ESI, pos.
ion) m/z: 538.1 (M+1).
Step 2
[0419] To a mixture of
[8-methoxy-5-[(4-methylbenzene)sulfonyl]-7-[3-(pyrrolidin-1-yl)propoxy]-5-
H-pyrido[4,3-b]indol-1-yl]methanol (135 mg, 0.25 mmol, 1.00 eq.) in
tetrahydrofuran (10 mL) cooled at 0.degree. C. was added LAH (19
mg, 0.5 mmol, 2.0 eq.) with stirring. The resulting mixture was
stirred for 1 h at room temperature. The reaction mixture was
diluted with tetrahydrofuran (10 mL), quenched with water (0.02
mL), 15% aqueous solution of sodium hydroxide (0.02 mL) and water
(0.06 mL). The mixture was filtered and the filtrate was
concentrated under vacuum. The residue was diluted with DMF (5 mL)
and subjected to reverse phase preparative HPLC (Waters SunFire
column, 19.times.150 mm; gradient elution of 2% MeCN in water to
17% MeCN in water over a 10 min period, where both solvents contain
0.05% TFA) to provide the title compound as light yellow solid
(30.4 mg, 17%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 14.18
(br, 1H), 13.06 (s, 1H), 9.76 (br, 1H), 8.39 (d, J=6.6 Hz, 1H),
7.88 (d, J=6.6 Hz, 1H), 7.62 (s, 1H), 7.36 (s, 1H), 5.47 (s, 2H),
4.23 (t, J=6.0 Hz, 2H), 3.96 (s, 3H), 3.69-3.65 (m, 2H), 3.37-3.35
(m, 2H), 3.10-3.03 (m, 2H), 2.27-2.25 (m, 2H), 2.10-2.06 (m, 2H),
1.96-1.90 (m, 2H). MS (ESI, pos. ion) m/z: 356.2 (M+1).
Example 83
3-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-1-yl]-4H-
-1,2,4-triazole Formate
##STR00268##
[0420] Step 1
[0421] Into a 40-mL vial, was placed a solution of methyl
8-methoxy-5-[(4-methylbenzene)sulfonyl]-7-[3-(pyrrolidin-1-yl)propoxy]-5H-
-pyrido[4,3-b]indole-1-carboxylate (Example 82, step 1) (350 mg,
0.65 mmol, 1.00 eq.), ethanol (10 mL) and N.sub.2H.sub.4.H.sub.2O
(98%, 5 mL). The resulting solution was stirred for 16 h at
80.degree. C. The reaction solution was concentrated under vacuum
to provide the title compound as brown oil (320 mg crude). MS (ESI,
pos. ion) m/z: 384.2 (M+1).
Step 2
[0422] Into a 40-mL vial, was placed a solution of
8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indole-1-carbohy-
drazide (320 mg, 0.83 mmol, 1.00 eq.), dichloromethane (10 mL) and
DMFDMA (1 mL). The resulting solution was stirred for 3 h at
50.degree. C. and then concentrated under vacuum. The residue was
purified by column chromatography on silica gel eluted with
dichloromethane/methanol (10/1) to provide
N'-(8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5H-pyrido[4,3-b]indole-1-car-
bonyl)-N,N-dimethylformohydrazonamide (135 mg, 37%). MS (ESI, pos.
ion) m/z: 439.3 (M+1).
Step 3
[0423] Into a 5-mL vial, was placed a solution of
N'-(8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5H-pyrido[4,3-b]indole-1-car-
bonyl)-N,N-dimethylformohydrazonamide (135 mg, 0.31 mmol, 1.00
eq.), acetic acid amine (71.6 mg, 0.93 mmol, 3.00 eq.) and acetic
acid (5 mL). The resulting solution was stirred for 16 h at
100.degree. C. and then concentrated under vacuum. The residue was
diluted with MeOH (5 mL), filtered and subjected to reverse phase
preparative HPLC (Waters Xbridge column, 19.times.150 mm; gradient
elution of 2% MeCN in water to 18% MeCN in water over a 6 min
period, where both solvents contain 0.1% formic acid) to provide
the title compound as light brown solid (22.5 mg, 17%). .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 11.74 (br, 1H), 9.26 (s, 1H), 8.46
(d, J=5.4 Hz, 1H), 8.36 (s, 1H), 8.24 (s, 2H), 7.57 (d, J=5.4 Hz,
1H), 7.13 (s, 1H), 4.16 (t, J=6.0 Hz, 2H), 3.88 (s, 3H), 2.87-2.82
(m, 2H), 2.80-2.77 (m, 4H), 2.12-2.04 (m, 2H), 1.82-1.75 (m, 4H).
MS (ESI, pos. ion) m/z: 393.2 (M+1).
Example 84
1-(1H-imidazol-5-yl)-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5H-pyrido[4,-
3-b]indole Trifluoroacetate
##STR00269##
[0424] Step 1
[0425] Into a 50-mL round-bottom flask, was placed
1-(3-[[1-chloro-8-methoxy-5-(4-methylbenzenesulfonyl)-5H-pyrido[4,3-b]ind-
ol-7-yl]oxy]propyl)pyrrolidine (200 mg, 0.39 mmol, 1 eq.), dioxane
(5 mL), water (1 mL),
1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazol-
e (130 mg, 0.47 mmol, 1.20 eq.), K.sub.2CO.sub.3 (161 mg, 1.17
mmol, 3.00 eq.), Pd(PPh.sub.3).sub.4 (23 mg, 0.02 mmol, 0.05 eq.).
The resulting solution was stirred for 16 hr at 100.degree. C.
under N.sub.2. The reaction mixtures were combined and concentrated
under vacuum. The product was subjected to reverse phase
preparative HPLC (Waters SunFire column, 19.times.150 mm; gradient
elution of 20% MeCN in water to 30% MeCN in water over a 10 min
period, where both solvents contain 0.05% TFA) to provide
8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-1-(1-(tetrahydro-2H-pyran-2-yl)--
1H-imidazol-5-yl)-5-tosyl-5H-pyrido[4,3-b]indole (150 mg, 61%). MS
(ESI, pos. ion) m/z: 630.3 (M+1).
Step 2
[0426] Into a 50-mL round-bottom flask, was placed
8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-1-(1-(tetrahydro-2H-pyran-2-yl)--
1H-imidazol-5-yl)-5-tosyl-5H-pyrido[4,3-b]indole (105 mg, 0.17
mmol, 1 eq.), water (5 mL), hydrogen chloride (12M, 1 mL). The
resulting solution was stirred for 1 hr at 25.degree. C. The
resulting mixture was concentrated. This resulted in 100 mg (crude)
of
1-(1H-imidazol-5-yl)-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5-tosyl-5H--
pyrido[4,3-b]indole as light yellow solid. MS (ESI, pos. ion) m/z:
546.2 (M+1).
Step 3
[0427] Into a 50-mL round-bottom flask, was placed
1-(1H-imidazol-5-yl)-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5-tosyl-5H--
pyrido[4,3-b]indole (100 mg, 0.18 mmol, 1 eq.), water (2 mL),
dioxane (2 mL), NaOH (15 mg, 0.37 mmol, 2 eq.). The resulting
solution was stirred for 8 hr at 80.degree. C. The resulting
mixture was concentrated under vacuum. The crude reaction mixture
was filtered and subjected to reverse phase preparative HPLC
(Waters SunFire column, 19.times.150 mm; gradient elution of 20%
MeCN in water to 30% MeCN in water over a 10 min period, where both
solvents contain 0.05% TFA) to provide the title compound as brown
solid (20.1 mg, 22%). .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta.13.09 (s, 1H), 9.80 (br, 1H), 8.84 (s, 1H), 8.42-8.40 (m,
1H), 8.34 (s, 1H), 8.27 (s, 1H), 7.82 (d, J=6.7 Hz, 1H), 7.31 (s,
1H), 4.23-4.17 (m, 2H), 3.88 (s, 3H), 3.65 (2, 3H), 3.35 (m, 2H),
3.08 (m, 2H), 2.23-1.90 (m, 6H). MS (ESI, pos. ion) m/z: 392.2
(M+1).
Example 85
N,N-diethyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-
-1-amine Bis Formate
##STR00270##
[0428] Step 1
[0429] In a microwave vial, a mixture of
7-(benzyloxy)-4-chloro-1-fluoro-8-methoxy-5H-pyrido[4,3-b]indole,
Reference 6 (210 mg; 0.59 mmol; 1.00 eq.) and diethylamine (215 mg;
2.94 mmol; 5.00 eq.) in NMP (2 mL) was heated to 100.degree. C. for
6 hours. The reaction mixture was concentrated under reduced
pressure and purified by silica gel using 0% to 50% ethyl acetate
in hexanes to afford
7-(benzyloxy)-4-chloro-N,N-diethyl-8-methoxy-5H-pyrido[4,3-b]indol-1-amin-
e (200 mg; 82%). MS (ESI, pos. ion) m/z: 410.0 (M+1).
Step 2
[0430] In a 50 mL round bottom flask, di-tert-butyl dicarbonate
(160 mg; 0.73 mmol; 1.50 eq.) was added to a mixture of
7-(benzyloxy)-4-chloro-N,N-diethyl-8-methoxy-5H-pyrido[4,3-b]indol-1-amin-
e (200 mg; 0.49 mmol; 1.00 eq.) and DMAP (12 mg; 0.10 mmol; 0.20
eq.) in acetonitrile (5 mL). The reaction was stirred for 2 hours.
The reaction mixture was concentrated under reduced pressure and
purified by silica gel column using 0% to 30% ethyl acetate in
hexanes to afford tert-butyl
7-(benzyloxy)-4-chloro-1-(diethylamino)-8-methoxy-5H-pyrido[4,3-b]indole--
5-carboxylate (240 mg; 96%).
Step 3
[0431] In a 50 mL round bottom flask, a mixture of tert-butyl
7-(benzyloxy)-4-chloro-1-(diethylamino)-8-methoxy-5H-pyrido[4,3-b]indole--
5-carboxylate (240 mg; 0.47 mmol; 1.00 eq.) and palladium on carbon
(50 mg; 0.05 mmol; 0.10 eq.) in methanol (5 mL) was stirred for 2
hours under hydrogen gas via balloon. The reaction mixture was
filtered thru a plug of Celite and concentrated under reduced
pressure to afford tert-butyl
1-(diethylamino)-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(180 mg; 99%). MS (ESI, pos. ion) m/z: 329.9 (M-56).
Step 4
[0432] A mixture of tert-butyl
1-(diethylamino)-7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(200 mg; 0.52 mmol; 1.00 eq.), 1-(3-chloropropyl)pyrrolidine (143
mg; 0.78 mmol; 1.50 eq.), and potassium carbonate (215 mg; 1.56
mmol; 3.00 eq.) in 10 mL of DMF was heated to 100.degree. C. for 16
hours. The reaction mixture was cooled to rt. The reaction mixture
was diluted with water. The aqueous layer was extracted with ethyl
acetate. The combined organics were dried with MgSO4, filtered, and
concentrated under reduced pressure. The resulting residue was
diluted with 1M HCl (4 mL) and heated to 50.degree. C. for 1 hour.
The aqueous layer was purified by Prep HPLC (Phenomenex Luna C18,
21.times.250 mm, 0-60% acetonitrile/0.1% aqueous formic acid
gradient over 13 minutes, flow rate 22 ml/min) to afford the titled
compound (42 mg; 20%). .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.45 (s, 2H), 7.93 (d, J=6.3 Hz, 1H), 7.54 (s, 1H), 7.22
(d, J=6.3 Hz, 1H), 7.20 (s, 1H), 4.28 (t, J=5.5 Hz, 2H), 3.98 (s,
3H), 3.63 (q, J=7.1 Hz, 4H), 3.47 (t, J=7.0 Hz, 6H), 2.40-2.23 (m,
2H), 2.21-2.05 (m, 4H), 1.19 (t, J=7.1 Hz, 6H). MS (ESI, pos. ion)
m/z: 392.2 (M+1).
Example 86
1-{4-chloro-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-
-1-yl}pyrrolidine Hydrochloride
##STR00271##
[0433] Step 1
[0434] A mixture of
7-(benzyloxy)-4-chloro-1-fluoro-8-methoxy-5H-pyrido[4,3-b]indole,
Reference 6 (810 mg; 2.27 mmol; 1.00 eq.) and pyrrolidine (807 mg;
11.35 mmol; 5.00 eq.) in NMP (8 mL) was heated in the microwave at
100.degree. C. for 2 hours. The reaction mixture was diluted with
water and extracted with ethyl acetate. The combined organics were
dried with MgSO4, filtered and concentrated under reduced pressure
to afford crude
1-[7-(benzyloxy)-4-chloro-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyrrolidin-
e (926 mg; 99%).
Step 2
[0435] A mixture of
1-[7-(benzyloxy)-4-chloro-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyrrolidin-
e (310 mg; 0.76 mmol; 1.00 eq.) and rhodium (5% wt on alumina) (78
mg; 0.04 mmol; 0.05 eq.) in methanol (8 mL) was stirred under
hydrogen pressure via balloon for 30 minutes. Reaction mixture was
filtered thru a plug of Celite and concentrated under reduced
pressure to afford crude
4-chloro-8-methoxy-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indol-7-ol
(241 mg; 99%). MS (ESI, pos. ion) m/z: 317.7 (M+1).
Step 3
[0436] A mixture of
4-chloro-8-methoxy-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indol-7-ol
(241 mg; 0.76 mmol; 1.00 eq.), 1-(3-chloropropyl)pyrrolidine (208
mg; 1.14 mmol; 1.50 eq.), and potassium carbonate (314 mg; 2.28
mmol; 3.00 eq.) in DMF (5 mL) was heated to 100.degree. C. for 16
hours. The reaction mixture was cooled to rt. Filtered and purified
by prep HPLC (Phenomenex Luna C18, 21.times.250 mm, 0-60%
acetonitrile/0.1% aqueous formic acid gradient over 13 minutes,
flow rate 22 ml/min) to afford the titled compound (12 mg; 4%).
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.78 (s, 1H), 7.63
(s, 1H), 7.26 (s, 1H), 4.30 (t, J=5.6 Hz, 2H), 3.97 (s, 7H),
3.89-3.76 (m, 2H), 3.50 (t, J=7.1 Hz, 2H), 3.16 (ddt, J=11.3, 8.2,
4.4 Hz, 2H), 2.34 (t, J=6.2 Hz, 2H), 2.20 (h, J=3.4, 2.7 Hz, 6H),
2.07 (dq, J=10.8, 5.8, 4.7 Hz, 2H). MS (ESI, pos. ion) m/z: 429.2
(M+1).
Example 87
3-[({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)methyl]piperidine
Hydrochloride
##STR00272##
[0438] A mixture of tert-butyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate, Reference
7 (200.00 mg; 0.64 mmol; 1.00 eq.), tert-butyl
3-(bromomethyl)-1-piperidinecarboxylate (265.50 mg; 0.95 mmol; 1.50
eq.), and potassium carbonate (175.61 mg; 1.27 mmol; 2.00 eq.) in
acetonitrile (7 mL) was heated to 85.degree. C. for 4 hours. The
reaction mixture was cooled to rt and filtered thru a plug of
Celite. The reaction mixture was concentrated under reduced
pressure and diluted with 5 mL of 1M HCl. The acidic solution was
heated to 50.degree. C. for 1 hour and purified by prep HPLC
(Phenomenex Luna C18, 21.times.250 mm, 0-60% acetonitrile/0.1%
aqueous HCl gradient over 13 minutes, flow rate 22 ml/min) to
afford the titled compound (146.00 mg; 60%). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 9.40 (s, 1H), 8.41 (dd, J=6.7, 0.9 Hz,
1H), 7.91 (s, 1H), 7.87 (dd, J=6.8, 0.7 Hz, 1H), 7.30 (s, 1H), 4.18
(dd, J=9.6, 4.8 Hz, 1H), 4.06 (dd, J=9.6, 6.9 Hz, 1H), 3.97 (s,
3H), 3.62 (dd, J=12.6, 3.9 Hz, 1H), 3.44-3.33 (m, 1H), 3.00 (dd,
J=13.3, 10.7 Hz, 2H), 2.41 (dq, J=7.9, 3.9 Hz, 1H), 2.13-1.97 (m,
2H), 1.93-1.73 (m, 1H), 1.67-1.50 (m, 1H). MS (ESI, pos. ion) m/z:
429.2 (M+1).
Example 88
[3-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]dimethylamine
Hydrochloride
##STR00273##
[0440] The title compound was synthesized from tert-butyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate, Reference
7, following a synthetic sequence as described for Example 87,
except that (3-chloropropyl)dimethylamine was used in place of
tert-butyl 3-(bromomethyl)-1-piperidinecarboxylate. .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 9.40 (s, 1H), 8.41 (dd, J=6.7,
0.9 Hz, 1H), 7.91 (s, 1H), 7.87 (dd, J=6.8, 0.7 Hz, 1H), 7.30 (s,
1H), 4.18 (dd, J=9.6, 4.8 Hz, 1H), 4.06 (dd, J=9.6, 6.9 Hz, 1H),
3.62 (dd, J=12.6, 3.9 Hz, 1H), 3.44-3.33 (m, 1H), 3.00 (dd, J=13.3,
10.7 Hz, 2H), 2.41 (dq, J=7.9, 3.9 Hz, 1H), 2.13-1.97 (m, 2H),
1.93-1.73 (m, 1H), 1.67-1.50 (m, 1H). MS (ESI, pos. ion) m/z: 300.1
(M+1).
Example 89
1-{8-methoxy-4-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-5H-pyrido[4,3-b]indol-
-1-yl}pyrrolidine Hydrochloride
##STR00274##
[0441] Step 1
[0442] A mixture of
1-[7-(benzyloxy)-4-chloro-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyrrolidin-
e, Example 86, step 1 (1.50 g; 3.68 mmol; 1.00 eq.), di-tert-butyl
dicarbonate (1.2 g; 5.52 mmol; 1.50 eq.), and
N,N-dimethylaminopyridine (90 mg; 0.74 mmol; 0.20 eq.) in
dichloromethane (20 mL) was stirred for overnight. The reaction
mixture was concentrated under reduced pressure and purified by
silica gel column using 0% to 40% ethyl acetate in hexanes to
afford tert-butyl
7-(benzyloxy)-4-chloro-8-methoxy-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indo-
le-5-carboxylate (1.45 g; 78%). MS (ESI, pos. ion) m/z: 508.2
(M+1).
Step 2
[0443] A mixture of tert-butyl
7-(benzyloxy)-4-chloro-8-methoxy-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indo-
le-5-carboxylate (300 mg; 0.59 mmol; 1.00 eq.),
tricyclohexylphosphine (17 mg; 0.06 mmol; 0.10 eq.), methylboronic
acid (106 mg; 1.77 mmol; 3.00 eq.), diacetoxypalladium (13 mg; 0.06
mmol; 0.10 eq.), and potassium carbonate (245 mg; 1.77 mmol; 3.00
eq.) in DMF (3 mL) was heated in the microwave at 140.degree. C.
for 1 hour. The reaction mixture was diluted with water. The
aqueous layer was extracted with ethyl acetate. The combined
organics were dried with MgSO.sub.4, filtered, concentrated and
purified by silica gel column using 0% to 45% ethyl acetate in
hexanes to afford tert-butyl
7-(benzyloxy)-8-methoxy-4-methyl-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indo-
le-5-carboxylate (200 mg; 69%). MS (ESI, pos. ion) m/z: 488.0
(M+1).
Step 3
[0444] A mixture of tert-butyl
7-(benzyloxy)-8-methoxy-4-methyl-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indo-
le-5-carboxylate (200 mg; 0.41 mmol; 1.00 eq.) and palladium on
carbon (44 mg; 0.04 mmol; 0.10 eq.) in methanol (5 mL) was stirred
under hydrogen pressure via balloon. The reaction mixture was
stirred for 1 hour. The reaction mixture was filtered thru a plug
of Celite and concentrated under reduced pressure to afford crude
tert-butyl
7-hydroxy-8-methoxy-4-methyl-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indole-5-
-carboxylate (163.00 mg; 99%).
Step 4
[0445] A mixture of tert-butyl
7-hydroxy-8-methoxy-4-methyl-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indole-5-
-carboxylate (163 mg; 0.41 mmol; 1.00 eq.),
1-(3-chloropropyl)pyrrolidine (113 mg; 0.62 mmol; 1.50 eq.), and
potassium carbonate (141 mg; 1.03 mmol; 2.50 eq.) in DMF (3 mL) was
heated to 100.degree. C. for 16 hours. The reaction mixture was
cooled to rt, filtered thru a plug of Celite, and concentrated
under reduced pressure. The resulting residue was diluted with 1M
HCl (5 mL) and heated to 50.degree. C. for 1 hour. The aqueous
layer was purified by prep HPLC (Phenomenex Luna C18, 21.times.250
mm, 0-60% acetonitrile/0.1% aqueous HCl gradient over 13 minutes,
flow rate 22 ml/min) to afford the titled compound (47 mg; 28%).
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.65 (s, 1H), 7.49
(d, J=1.2 Hz, 1H), 7.24 (s, 1H), 4.29 (t, J=5.5 Hz, 2H), 3.97 (s,
3H), 3.96-3.90 (m, 4H), 3.83-3.81 (m, 2H), 3.50 (t, J=7.1 Hz, 2H),
3.16 (q, J=8.7, 7.9 Hz, 2H), 2.46 (d, J=1.1 Hz, 3H), 2.33 (p, J=6.5
Hz, 2H), 2.18 (p, J=3.2 Hz, 6H), 2.07 (dd, J=7.8, 4.9 Hz, 2H). MS
(ESI, pos. ion) m/z: 408.9 (M+1).
Example 90
[3-({8-methoxy-1-methyl-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]dimethylamin-
e Hydrochloride
##STR00275##
[0446] Step 1
[0447] A mixture of tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(250 mg; 0.57 mmol; 1.00 eq.), methylboronic acid (68 mg; 1.14
mmol; 2.00 eq.), potassium carbonate (314 mg; 2.28 mmol; 4.00 eq.),
and Pd(dppf)2Cl2.DCM (46 mg; 0.06 mmol; 0.10 eq.) in NMP (3 mL)
were placed in a microwave vial. Heated the reaction to 120.degree.
C. for 1 hour in the microwave. Diluted reaction with water.
Extracted aqueous layer with ethyl acetate, combined organics,
dried with MgSO4, filtered, and concentrated under reduced
pressure. Resulting residue was purified by silica gel column using
0% to 50% ethyl acetate in hexanes to afford tert-butyl
7-(benzyloxy)-8-methoxy-1-methyl-5H-pyrido[4,3-b]indole-5-carboxylate
(180 mg; 75%). MS (ESI, pos. ion) m/z: 363.0 (M-56).
Step 2
[0448] Combined tert-butyl
7-(benzyloxy)-8-methoxy-1-methyl-5H-pyrido[4,3-b]indole-5-carboxylate
(180 mg; 0.43 mmol; 1.00 eq.), 10% palladium on carbon (45 mg; 0.04
mmol; 0.10 eq.), and methanol (5 mL). Stirred under hydrogen
pressure for 3 hours via balloon. Filtered thru celite plug and
concentrated under reduced pressure to afford tert-butyl
7-hydroxy-8-methoxy-1-methyl-5H-pyrido[4,3-b]indole-5-carboxylate
(140 mg; 99%) as crude. MS (ESI, pos. ion) m/z: 273.0 (M-56).
Step 3
[0449] Combined tert-butyl
7-hydroxy-8-methoxy-1-methyl-5H-pyrido[4,3-b]indole-5-carboxylate
(140 mg; 0.43 mmol; 1.00 eq.), (3-chloropropyl)dimethylamine (104
mg; 0.85 mmol; 2.00 eq.), and potassium carbonate (118 mg; 0.85
mmol; 2.00 eq.) in DMF (5 mL). The reaction was heated to
100.degree. C. for 5 hours. Let the reaction cool to rt. Filtered
thru a plug of Celite and concentrated under reduced pressure.
Added 1M HCl to the resulting residue and heated to 50.degree. C.
for 1 hour. Purified residue by prep HPLC (Phenomenex Luna C18,
21.times.250 mm, 0-60% acetonitrile/0.1% aqueous HCl gradient over
13 minutes, flow rate 22 ml/min) to afford the titled compound
(90.00 mg; 67%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
8.26 (d, J=6.8 Hz, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.72 (s, 1H), 7.35
(s, 1H), 4.32 (t, J=5.6 Hz, 2H), 4.04 (s, 3H), 3.45 (t, J=7.2 Hz,
2H), 3.20 (s, 3H), 3.01 (s, 6H), 2.43-2.28 (m, 2H). MS (ESI, pos.
ion) m/z: 314.5 (M+1).
Example 91
[3-({1-ethyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]dimethylamine
Hydrochloride
##STR00276##
[0451] The title compound was synthesized from tert-butyl
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate,
Reference 5, following a synthetic sequence analogous to that
described for Example 90, using ethylboronic acid in place of
methylboronic acid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
8.29 (d, J=6.8 Hz, 1H), 7.76 (d, J=6.8 Hz, 1H), 7.68 (s, 1H), 7.36
(s, 1H), 4.33 (t, J=5.6 Hz, 2H), 4.03 (s, 3H), 3.57 (q, J=7.6 Hz,
2H), 3.44 (q, J=7.5 Hz, 2H), 3.00 (s, 6H), 2.40-2.28 (m, 2H), 1.56
(t, J=7.6 Hz, 3H). MS (ESI, pos. ion) m/z: 328.1 (M+1).
Example 92
(3-{[8-methoxy-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)d-
imethylamine Hydrochloride
##STR00277##
[0452] Step 1
[0453] A mixture of
7-(benzyloxy)-4-chloro-1-fluoro-8-methoxy-5H-pyrido[4,3-b]indole,
Reference 6 (810 mg; 2.27 mmol; 1.00 eq.) and pyrrolidine (807 mg;
11.35 mmol; 5.00 eq.) in NMP (7.5 mL) was heated in the microwave
at 100.degree. C. for 2 hours. The reaction mixture was diluted
with water and extracted with ethyl acetate. The combined organics
were dried with MgSO4, filtered and concentrated under reduced
pressure to afford
1-[7-(benzyloxy)-4-chloro-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyrrolidin-
e (926 mg; 99%).
Step 2
[0454] A mixture of
1-[7-(benzyloxy)-4-chloro-8-methoxy-5H-pyrido[4,3-b]indol-1-yl]pyrrolidin-
e (1.5 g; 3.68 mmol; 1.00 eq.), di-tert-butyl dicarbonate (1.2 g;
5.52 mmol; 1.50 eq.), and DMAP (90 mg; 0.74 mmol; 0.20 eq.) in
dichloromethane (18 mL) was stirred for overnight. The reaction
mixture was concentrated under reduced pressure and purified by
silica gel column using 0% to 40% ethyl acetate in hexanes to
afford tert-butyl
7-(benzyloxy)-4-chloro-8-methoxy-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indo-
le-5-carboxylate (1.45 g; 78%). MS (ESI, pos. ion) m/z: 508.2
(M+1).
Step 3
[0455] In a 50 mL round bottom flask, tert-butyl
7-(benzyloxy)-4-chloro-8-methoxy-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indo-
le-5-carboxylate (750 mg; 1.48 mmol; 1.00 eq.), 10% palladium on
carbon (157 mg; 0.15 mmol; 0.10 eq.), and methanol (15 mL) were
stirred under hydrogen pressure via balloon. The reaction was
stirred for 3 hours. The reaction mixture was filtered thru a plug
of celite and concentrated to obtain tert-butyl
7-hydroxy-8-methoxy-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indole-5-carboxyl-
ate (566 mg; 99%) as crude. MS (ESI, pos. ion) m/z: 327.8
(M-56).
Step 4
[0456] In a 10 mL scintillation vial, tert-butyl
7-hydroxy-8-methoxy-1-(pyrrolidin-1-yl)-5H-pyrido[4,3-b]indole-5-carboxyl-
ate (170 mg; 0.44 mmol; 1.00 eq.), (3-chloropropyl)dimethylamine
(70 mg; 0.58 mmol; 1.30 eq.), and potassium carbonate (183 mg; 1.33
mmol; 3.00 eq.) in DMF (3 mL) were heated to 100.degree. C. for 3
hours. The reaction mixture was cooled to rt. Filtered the reaction
thru a plug of Celite and concentrated under reduced pressure.
Added 1M HCl to the resulting residue and stirred at 50.degree. C.
for 1 hour. The resulting mixture was concentrated under reduced
pressure and purified by prep HPLC (Phenomenex Luna C18,
21.times.250 mm, 0-60% acetonitrile/0.1% aqueous HCl gradient over
13 minutes, flow rate 22 ml/min) to afford the title compound (100
mg; 51%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.65 (d,
J=6.9 Hz, 1H), 7.60 (s, 1H), 7.21 (s, 1H), 7.10 (d, J=6.9 Hz, 1H),
4.28 (t, J=5.6 Hz, 2H), 3.96 (d, J=7.1 Hz, 7H), 3.44 (t, J=7.2 Hz,
2H), 3.00 (s, 6H), 2.33 (p, J=6.5 Hz, 2H), 2.25-2.09 (m, 4H). MS
(ESI, pos. ion) m/z: 369.0 (M+1).
Example 93
7-[3-(dimethylamino)propoxy]-8-methoxy-N,N-dimethyl-5H-pyrido[4,3-b]indol--
1-amine Hydrochloride
##STR00278##
[0458] The title compound was prepared using the synthetic sequence
described for Example 92, changing step 1 as follows:
[0459] In a capped microwave vial,
7-(benzyloxy)-4-chloro-1-fluoro-8-methoxy-5H-pyrido[4,3-b]indole
Reference 6 (220 mg; 0.62 mmol; 1.00 eq.) and 2M sodium hydroxide
(0.40 mL; 0.80 mmol; 1.30 eq.) in DMF (4 mL) were placed in a
microwave reactor. Heated the reaction in the microwave for 1 hour
at 160.degree. C. Let the reaction cool to rt. Diluted reaction
with water and extracted aqueous layer with ethyl acetate. Combined
organics, dried with MgSO4, filtered and concentrated to afford
7-(benzyloxy)-4-chloro-8-methoxy-N,N-dimethyl-5H-pyrido[4,3-b]indol-1-ami-
ne (235 mg; 99%) as a crude mixture.
[0460] The title compound was made from
7-(benzyloxy)-4-chloro-8-methoxy-N,N-dimethyl-5H-pyrido[4,3-b]indol-1-ami-
ne following procedures used to make Example 92, steps 2 thru 4.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.78 (d, J=6.8 Hz,
1H), 7.40 (s, 1H), 7.27 (d, J=6.9 Hz, 1H), 7.24 (s, 1H), 4.28 (t,
J=5.6 Hz, 2H), 3.99 (s, 3H), 3.46 (t, J=7.2 Hz, 2H), 3.36 (s, 6H),
3.01 (s, 6H), 2.35 (t, J=6.5 Hz, 2H). MS (ESI, pos. ion) m/z: 343.3
(M+1).
Example 94
1-[3-({8-methoxy-5-methyl-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidin-
e Hydrochloride
##STR00279##
[0462] A mixture of
1-[3-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidine,
Example 88 (70 mg; 0.22 mmol; 1.00 eq.), dimethyl carbonate (39 mg;
0.43 mmol; 2.00 eq.), and potassium carbonate (59 mg; 0.43 mmol;
2.00 eq.) in DMF (2 mL) were placed in a microwave vial. Heated the
reaction to 100.degree. C. for 30 minutes in the microwave. The
reaction mixture was filtered and purified by prep HPLC (Phenomenex
Luna C18, 21.times.250 mm, 0-60% acetonitrile/0.1% aqueous HCl
gradient over 13 minutes, flow rate 22 ml/min) to afford the title
compound (10 mg; 11%). .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 9.42 (s, 1H), 8.47 (dd, J=6.9, 0.9 Hz, 1H), 8.00 (d, J=8.3
Hz, 2H), 7.46 (s, 1H), 4.43-4.36 (m, 2H), 4.08 (s, 3H), 4.00 (s,
3H), 3.91-3.75 (m, 2H), 3.50 (q, J=6.4, 5.8 Hz, 2H), 3.17 (dt,
J=13.3, 7.1 Hz, 2H), 2.36 (h, J=7.5, 7.0 Hz, 2H), 2.20 (d, J=7.6
Hz, 2H), 2.13-2.00 (m, 2H). MS (ESI, pos. ion) m/z: 340.1
(M+1).
Example 95
(3-{[8-methoxy-1-(methylsulfanyl)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl)di-
methylamine Hydrochloride
##STR00280##
[0463] Step 1
[0464] To a mixture of
[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]dimethylamine (300 mg;
0.90 mmol; 1.00 eq.) and 2-chloro-3-pyridinylboronic acid (240 mg;
1.53 mmol; 1.70 eq.) in DMF (5 mL) was added potassium carbonate
(0.90 mL; 2.00 mol/L; 1.80 mmol; 2.00 eq.) followed by
Pd(dppf).sub.2Cl.sub.2.DCM (37 mg; 0.05 mmol; 0.05 eq.) in a
microwave vial. The reaction was heated to 120.degree. C. for 30
minutes. The reaction was diluted with water and extracted with
ethyl acetate. The combined organics were dried with MgSO.sub.4,
filtered, and concentrated to afford
{3-[4-(2-chloropyridin-3-yl)-2-methoxy-5-nitrophenoxy]propyl}dimethylamin-
e (250 mg; 76%) as crude. MS (ESI, pos. ion) m/z: 366.2 (M+1).
Step 2
[0465] Sodium methanethiolate (144 mg; 2.05 mmol; 3.00 eq.) was
added to a solution containing
{3-[4-(2-chloropyridin-3-yl)-2-methoxy-5-nitrophenoxy]propyl}dimethylamin-
e (250 mg; 0.68 mmol; 1.00 eq.) in DMSO (3 mL) in a microwave vial.
Heated the reaction to 100.degree. C. for 40 minutes in the
microwave. Diluted reaction with 1M HCl (10 mL) and washed with
ethyl acetate. Collected acidic aqueous layer and purified product
by prep HPLC (Phenomenex Luna C18, 21.times.250 mm, 0-60%
acetonitrile/0.1% aqueous HCl gradient over 13 minutes, flow rate
22 ml/min) to afford
(3-{2-methoxy-4-[2-(methylsulfanyl)pyridin-3-yl]-5-nitrophenoxy}propyl)di-
methylamine (50 mg; 19%). MS (ESI, pos. ion) m/z: 378.1 (M+1).
Step 3
[0466] In a capped 20 mL scintillation vial, a solution of
(3-{2-methoxy-4-[2-(methylsulfanyl)pyridin-3-yl]-5-nitrophenoxy}propyl)di-
methylamine (50 mg; 0.13 mmol; 1.00 eq.) in triethyl phosphite (2
mL) was heated to 120.degree. C. for 18 hours. The reaction was
cooled to rt and concentrated under reduced pressure. The resulting
residue was diluted with 1M HCl and purified by prep HPLC
(Phenomenex Luna C18, 21.times.250 mm, 0-60% acetonitrile/0.1%
aqueous HCl gradient over 13 minutes, flow rate 22 ml/min) to
afford the title compound (4 mg; 7%). .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.27 (d, J=6.8 Hz, 1H), 7.87 (s, 1H),
7.69 (d, J=6.8 Hz, 1H), 7.35 (s, 1H), 4.32 (t, J=5.6 Hz, 2H), 4.02
(s, 3H), 3.44 (t, J=7.1 Hz, 2H), 3.01 (s, 3H), 3.00 (s, 6H), 2.35
(ddd, J=12.7, 7.0, 5.5 Hz, 2H). MS (ESI, pos. ion) m/z: 346.2
(M+1).
Example 96
1-(3-{[8-methoxy-1-(2-methoxyethoxy)-5H-pyrido[4,3-b]indol-7-yl]oxy}propyl-
)pyrrolidine Trifluoroacetate
##STR00281##
[0467] Step 1
[0468] Combined
1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine,
Reference 3 (800 mg; 2.23 mmol; 1.00 eq.),
2-fluoro-3-pyridinylboronic acid (627 mg; 4.45 mmol; 2.00 eq.),
Potassium Carbonate (3.3 mL; 2.00 mol/L; 6.68 mmol; 3.00 eq.) and
Pd(dppf).sub.2Cl.sub.2.DCM (182 mg; 0.22 mmol; 0.10 eq.) in DMF (8
mL) in a microwave vial. Heated the reaction to 130.degree. C. for
1 hour in the microwave reactor. The reaction was filtered thru a
plug of Celite, diluted filtrate with water and washed aqueous
layer with ethyl acetate. Combined organics, dried with MgSO4,
filtered, and concentrated under reduced pressure. The resulting
residue was purified with silica gel using 0% to 20% methanol in
DCM to afford
2-fluoro-3-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}pyridi-
ne (316.00 mg; 38%).
Step 2
[0469] Into a 50-mL round-bottom flask, was placed
2-fluoro-3-[5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl]pyridi-
ne (300 mg, 0.80 mmol, 1.00 eq.), N,N-dimethylformamide (10 mL),
2-methoxyethan-1-ol (91.2 mg, 1.20 mmol, 1.50 eq.),
Cs.sub.2CO.sub.3 (782 mg, 2.40 mmol, 3.00 eq.). The resulting
solution was stirred for 3 h at 100.degree. C. The crude reaction
mixture was filtered and subjected to reverse phase preparative
MPLC (Prep-C18, 120 g, Tianjin Bonna-Agela Technologies; gradient
elution of 10% MeCN in water to 20% MeCN in water over a 10 min
period, where both solvents contain 0.1% formic acid) to provide
3-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-2-(2-m-
ethoxyethoxy)pyridine as yellow solid (0.18 g, 52%). MS (ESI, pos.
ion) m/z: 432.2 (M+1).
Step 3
[0470] Into a 50-mL round-bottom flask, was placed
3-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-2-(2-methoxyet-
hoxy)pyridine (150 mg, 0.35 mmol, 1.00 eq.), P(OEt).sub.3 (8 mL).
The resulting solution was stirred for 16 h at 120.degree. C. The
mixture was concentrated under vacuum. The crude reaction mixture
was filtered and subjected to reverse phase preparative HPLC
(Prep-C18, Waters SunFire column, 19.times.150 mm; gradient elution
of 20% MeCN in water to 30% MeCN in water over a 10 min period,
where both solvents contain 0.05% TFA) to provide the title
compound as light yellow semi-solid (15.9 mg, 8.9%) .sup.1HNMR (300
MHz, DMSO-d.sub.6) .delta.11.58 (s, 1H), 9.59 (br, 1H), 7.89 (d,
J=5.9 Hz, 1H), 7.60 (s, 1H), 7.16-7.07 (m, 2H), 4.62 (dd, J=5.8,
3.7 Hz, 2H), 4.15 (t, J=5.8 Hz, 2H), 3.83 (d, J=4.4 Hz, 1H), 3.66
(dt, J=11.1, 6.0 Hz, 2H), 3.39 (d, J=10.5 Hz, 6H), 3.07 (dq,
J=14.3, 7.5 Hz, 2H), 2.19 (dq, J=12.4, 6.4 Hz, 2H), 2.04 (q, J=6.9,
5.9 Hz, 2H), 1.89 (p, J=5.3 Hz, 2H). MS (ESI, pos. ion) m/z: 400.2
(M+1).
Example 97
8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5H-pyrido[4,3-b]indol-1-ol
Trifluoroacetate
##STR00282##
[0471] Step 1
[0472] Into a 50-mL round-bottom flask, was placed
7-(benzyloxy)-1-chloro-8-methoxy-5H-pyrido[4,3-b]indole, Reference
5 (400 mg, 1.18 mmol, 1.00 eq.), sodium methylate-MeOH (30%, 10
mL). The resulting solution was stirred for 48 h at 120.degree. C.
The resulting mixture was concentrated under vacuum. The residue
was applied onto a silica gel column with ethyl acetate/petroleum
ether (1:1). This resulted in 285 mg (72%) of
7-(benzyloxy)-1,8-dimethoxy-5H-pyrido[4,3-b]indole as yellow solid.
MS (ESI, pos. ion) m/z: 335.1 (M+1).
Step 2
[0473] Into a 50-mL round-bottom flask, was placed
7-(benzyloxy)-1,8-dimethoxy-5H-pyrido[4,3-b]indole (275 mg, 0.82
mmol, 1.00 eq.), tetrahydrofuran (10 mL), 4-dimethylaminopyridine
(100 mg, 0.82 mmol, 1.00 eq.), Boc.sub.2O (180 mg, 0.82 mmol, 1.00
eq.). The resulting solution was stirred for 4 h at 25.degree. C.
The resulting mixture was concentrated under vacuum. The residue
was applied onto a silica gel column with ethyl acetate/petroleum
ether (1:3). This resulted in 260 mg (73%) of tert-butyl
7-(benzyloxy)-1,8-dimethoxy-5H-pyrido[4,3-b]indole-5-carboxylate as
yellow solid. MS (ESI, pos. ion) m/z: 435.2 (M+1).
Step 3
[0474] To a solution of tert-butyl
7-(benzyloxy)-1,8-dimethoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(250 mg, 0.58 mmol, 1.00 eq.) in MeOH (25 mL) was added 25 mg of
10% Pd/C (50% water moistened). The mixture was degassed and purged
with hydrogen for three times. The resulting mixture was stirred
for 6h at room temperature under H.sub.2 atmosphere. The solid was
filtered out. The filtration was concentrated under vacuum. This
resulted in 200 mg (crude) of tert-butyl
1,7-dihydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate as
light yellow solid. MS (ESI, pos. ion) m/z: 331.1 (M+1).
Step 4
[0475] Into a 50-mL round-bottom flask, was placed tert-butyl
1,7-dihydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate (190
mg, 0.55 mmol, 1.00 eq.), MeCN (8 mL), potassium carbonate (229 mg,
1.66 mmol, 3.00 eq.), 1-(3-chloropropyl)pyrrolidine hydrochloride
(101.5 mg, 0.55 mmol, 1.00 eq.). The resulting solution was stirred
for 3 h at 60.degree. C. The solid was filtered out. The filtration
was concentrated under vacuum. This resulted in 120 mg (48%) of
tert-butyl
1,8-dimethoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5H-pyrido[4,3-b]indole-5-car-
boxylate as light yellow solid. MS (ESI, pos. ion) m/z: 456.2
(M+1).
Step 5
[0476] Into a 50-mL round-bottom flask, was placed tert-butyl
1,8-dimethoxy-7-(3-(pyrrolidin-1-yl)propoxy)-5H-pyrido[4,3-b]indole-5-car-
boxylate (110 mg, 0.24 mmol, 1.00 eq.), ethanol (3 mL), hydrogen
chloride (3 mL). The resulting solution was stirred for 24 h at
100.degree. C. The resulting mixture was concentrated under vacuum.
The crude reaction mixture was filtered and subjected to reverse
phase preparative HPLC (Prep-C18, Waters SunFire column,
19.times.150 mm; gradient elution of 20% MeCN in water to 30% MeCN
in water over a 10 min period, where both solvents contain 0.05%
TFA) to provide the title compound as off-white solid (39.1 mg,
28%). .sup.1H NMR (300 MHz, DMSO-d6) .delta. 11.48 (s, 1H), 11.01
(d, J=5.8 Hz, 1H), 9.53 (br, 1H), 7.62 (s, 1H), 7.20 (t, J=6.5 Hz,
1H), 7.08 (s, 1H), 6.48 (d, J=7.1 Hz, 1H), 4.12 (t, J=5.8 Hz, 2H),
3.85 (s, 3H), 3.65 (s, 2H), 3.36 (q, J=7.0 Hz, 2H), 3.03-3.12 (m,
2H), 2.15-2.20 (m, 2H), 2.06-2.10 (m, 2H), 1.87-1.96 (m, 2H). MS
(ESI, pos. ion) m/z: 342.2 (M+1).
Example 98
3-[3-({8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]-3-azabicyclo[3.1.1-
]heptane Hydrochloride
##STR00283##
[0477] Step 1
[0478] Tert-butyl
7-hydroxy-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate, Reference
7 (65.00 mg; 0.21 mmol; 1.00 eq.) was suspended in acetonitrile (3
mL). 1-Chloro-3-iodopropane (44 .mu.L; 0.41 mmol; 2.00 eq.) and
then potassium carbonate (37 mg; 0.268 mmol; 1.28 eq.) were added.
The reaction was stirred in a heat block at 80.degree. C. After 6 h
the reaction was cooled, filtered, rinsed with warm acetonitrile
and evaporated. The mixture was purified by silica gel
chromatography (methanol/dichloromethane gradient) to give some
tert-butyl
7-(3-chloropropoxy)-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(9 mg, 11%). MS (ESI, pos. ion) m/z: 391.2 (M+1).
Step 2
[0479] Tert-butyl
7-(3-chloropropoxy)-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(38.00 mg; 0.10 mmol; 1.00 eq.) was dissolved in DMF (1 mL).
3-Azabicyclo[3.1.1]heptane hydrochloride (19.49 mg; 0.15 mmol; 1.50
eq.) dissolved in N,N-dimethylformamide (0.5 mL), potassium iodide
(16.14 mg; 0.10 mmol; 1.00 eq.) and potassium carbonate (33.54 mg;
0.24 mmol; 2.50 eq.) were added. The reaction was stirred in a heat
block at 80.degree. C. After 14 h, the reaction was evaporated. The
residue was taken up in heptanes, evaporated again and placed under
vacuum. Purification by reverse phase chromatography (Waters
XSelect CSH C18 column. 19.times.250 mm, 0-60% acetonitrile/0.1%
aqueous HCl gradient) gave the title compound (5.6 mg, 13%).
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 9.58 (s, 1H), 8.53
(d, J=6.9 Hz, 1H), 7.89-7.81 (m, 2H), 7.13 (s, 1H), 4.75 (t, J=7.3
Hz, 2H), 4.03 (s, 3H), 3.91-3.86 (m, 2H), 3.42-3.36 (m, 4H),
2.64-2.59 (m, 2H), 2.55-2.52 (m, 2H), 2.42-2.37 (m, 1H), 2.33-2.27
(m, 1H), 2.02-1.98 (m, 1H), 1.58-1.51 (m, 1H). MS (ESI, pos. ion)
m/z: 352.3 (M+1).
Example 99
1-[3-({8-methoxy-3-methyl-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidin-
e Hydrochloride
##STR00284##
[0481] The title compound was prepared using the synthetic
procedures described for Example 29 changing step 1 as follows:
[0482] A mixture of 1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene
(Reference 1; 500.00 mg; 1.48 mmol; 1.00 eq.),
6-methyl-3-pyridinylboronic acid (222.74 mg; 1.63 mmol; 1.10 eq.),
sodium carbonate (235.07 mg; 2.22 mmol; 1.50 eq.) and
1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (54.10
mg; 0.07 mmol; 0.05 eq.) in 1,4-dioxane (14.79 mL) and water (1.10
mL) was subjected to three cycles of evacuation/back-filling with
argon then it was heated under an argon atmosphere to 85.degree. C.
After 36 h the mixture was cooled to ambient temperature and
concentrated. The residue was taken up in EtOAc, washed with water
and brine, dried over MgSO.sub.4, filtered and concentrated to
obtain a dark oil. This material was absorbed onto a plug of silica
gel and purified by column chromatography (24 G ISCO Gold) eluting
with 0-70% EtOAc in heptane to provide
5-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]-2-methylpyridine (219 mg;
42%).
[0483] After step 5, the title compound was obtained as a colorless
free flowing powder (8.2 mg; 50%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.65 (s, 1H), 9.99 (s, 1H), 9.40 (s, 1H),
7.97 (s, 1H), 7.69 (s, 1H), 7.22 (s, 1H), 4.18 (t, J=6.0 Hz, 2H),
3.87 (s, 3H), 3.59 (br. s, 2H), 3.36-3.30 (m, 2H), 3.02 (br. s,
2H), 2.71 (s, 3H), 2.19 (p, J=7.4 Hz, 2H), 2.02 (br. s, 2H), 1.86
(br. s, 2H). MS (ESI, pos. ion) m/z: 340.3 (M+1).
Example 100
1-[3-({1,8-dimethoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrrolidine
Hydrochloride
##STR00285##
[0485] The title compound was prepared using the synthetic
procedures described for Example 29 changing step 1 as follows:
[0486] A mixture of 1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene
(Reference 1; 488.00 mg; 1.44 mmol; 1.00 eq.), (RSM from previous
reactions) 2-methoxy-3-pyridinylboronic acid (242.79 mg; 1.59 mmol;
1.10 eq.), sodium carbonate (229.43 mg; 2.16 mmol; 1.50 eq.) and
1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52.80
mg; 0.07 mmol; 0.05 eq.) in 1,4-dioxane (14.43 mL) and water (1.07
mL) was subjected to three cycles of evacuation/back-filling with
argon then it was heated under an argon atmosphere to 85.degree. C.
After 17 h the mixture was cooled to ambient temperature and
concentrated. The residue was taken up in EtOAc, washed with water
and brine, dried over MgSO.sub.4, filtered and concentrated to
obtain a dark oil. This material was absorbed onto a plug of silica
gel and purified by column chromatography (24 G ISCO Gold) eluting
with 0-40% EtOAc in heptane to provide
3-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]-2-methoxypyridine (200
mg; 38%).
[0487] After step 5, the title compound was obtained as a colorless
free flowing powder (75.2 mg; 71%). MS (ESI, pos. ion) m/z: 356.4
(M+1).
Example 101
1-[3-({3-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]pyrro-
lidine Hydrochloride
##STR00286##
[0489] The title compound was prepared using the synthetic
procedures described for Example 29 changing step 1 and adding step
4A (between steps 4 and 5) as described below:
Step 1
[0490] A mixture of 1-(benzyloxy)-4-bromo-2-methoxy-5-nitrobenzene
(Reference 1; 600.00 mg; 1.77 mmol; 1.00 eq.),
6-chloro-3-pyridinylboronic acid (307.14 mg; 1.95 mmol; 1.10 eq.),
sodium carbonate (282.09 mg; 2.66 mmol; 1.50 eq.) and
1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (64.91
mg; 0.09 mmol; 0.05 eq.) in 1,4-dioxane (17.74 mL) and water (1.31
mL) was subjected to three cycles of evacuation/back-filling with
argon then it was heated under an argon atmosphere to 85.degree. C.
After 17 h the mixture was cooled to ambient temperature and
concentrated. The residue was taken up in EtOAc, washed with water
and brine, dried over MgSO.sub.4, filtered and concentrated to
obtain a dark oil. This material was absorbed onto a plug of silica
gel and purified by column chromatography (40 G ISCO Gold) eluting
with 0-50% EtOAc in hexanes to provide
5-[4-(benzyloxy)-5-methoxy-2-nitrophenyl]-2-chloropyridine (462 mg;
70%)
Step 4A
[0491] A mixture of tert-butyl
7-(benzyloxy)-3-chloro-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylate
(71.00 mg; 0.16 mmol; 1.00 eq.), cyclopropylboronic acid (48.63 mg;
0.57 mmol; 3.50 eq.), tricyclohexylphosphane (4.54 mg; 0.02 mmol;
0.10 eq.) and potassium phosphate, tribasic (68.68 mg; 0.32 mmol;
2.00 eq.) in toluene (0.81 mL) and water (0.04 mL) was sparged with
nitrogen for 10 minutes. Palladium acetate (3.63 mg; 0.02 mmol;
0.10 eq.) was then added and the sealed vial was heated to
100.degree. C. overnight. The mixture was then cooled to ambient
temperature, diluted with EtOAc and washed with water and brine.
The organic layer was dried over MgSO.sub.4, filtered and
concentrated.
[0492] The residue was purified by column chromatography (4 G ISCO
Gold) eluting with 0-40% EtOAc in heptane to obtain tert-butyl
7-(benzyloxy)-3-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carboxylat-
e as a white solid.
[0493] After step 5, the title compound was obtained as a colorless
free flowing powder (75.2 mg; 71%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.58 (s, 1H), 10.33 (s, 1H), 9.34 (s, 1H),
8.00 (s, 1H), 7.45 (s, 1H), 7.21 (s, 1H), 4.17 (t, J=6.0 Hz, 2H),
3.86 (s, 3H), 3.62-3.52 (m, 2H), 3.32-3.29 (m, 2H), 3.06-2.95 (m,
2H), 2.40 (dq, J=8.7, 5.2, 4.4 Hz, 1H), 2.20 (p, J=6.2 Hz, 2H),
2.05-1.95 (m, 2H), 1.92-1.81 (m, 2H), 1.26-1.19 (d, J=8.1 Hz, 2H),
1.14-1.08 (m, 2H). MS (ESI, pos. ion) m/z: 366.4 (M+1).
Example 102
[3-({1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indol-7-yl}oxy)propyl]diethyl-
amine Hydrochloride
##STR00287##
[0495] The title compound was prepared using the synthetic sequence
described for Example 29, changing step 4 as follows:
[0496] A mixture of tert-butyl
7-(3-chloropropoxy)-1-cyclopropyl-8-methoxy-5H-pyrido[4,3-b]indole-5-carb-
oxylate (40.00 mg; 0.09 mmol; 1.00 eq.), potassium iodide (1.54 mg;
0.01 mmol; 0.10 eq.) and N-ethylethanamine (0.06 mL; 0.60 mmol;
6.50 eq.) in N,N-dimethylformamide (0.46 mL) was heated to
70.degree. C. After 3 h the mixture was cooled to ambient
temperature, diluted with 1:1 PhMe/EtOAc, washed with water, dried
over MgSO.sub.4, filtered and concentrated.
[0497] The crude oil was dissolved in DCM (1.5 mL) and treated with
TFA (0.7 mL) at ambient temperature. After 3 h the mixture was
concentrated in vacuo. The oily residue was taken up in 1N HCl
(.about.1.5 mL) and purified by prep HPLC (Phenomenex Luna C18,
21.times.250 mm, 0-70% acetonitrile/0.1% aqueous HCl gradient over
13 minutes, flow rate 22 ml/min) to provide the title compound (18
mg; 53%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.95 (s,
1H), 12.96 (s, 1H), 10.05 (s, 1H), 8.21 (d, J=6.7 Hz, 1H), 7.85 (s,
1H), 7.73 (d, J=6.7 Hz, 1H), 7.32 (s, 1H), 4.21 (t, J=6.0 Hz, 2H),
3.91 (s, 3H), 3.22 (p, J=5.0 Hz, 2H), 3.14 (td, J=7.3, 4.8 Hz, 4H),
3.02 (ddd, J=13.8, 8.6, 5.3 Hz, 1H), 2.20 (q, J=7.4, 6.7 Hz, 2H),
1.46-1.39 (m, 2H), 1.35-1.30 (m, 2H), 1.22 (t, J=7.2 Hz, 6H). MS
(ESI, pos. ion) m/z: 368.4 (M+1).
BIOLOGICAL EXAMPLES
Example 1
Determination of G9a Enzymatic Activity Assay
[0498] The G9a AlphaLISA assay was used to detect the methyl
modifications of a biotinylated histone H3 peptide by the
compounds. These modifications are done by the histone methyl
transferase activity of the G9a enzyme. The assay consists of
reading a chemiluminescent signal at 615 nm; this signal is
generated by a laser excitation at 680 nm that transfers a reactive
singlet oxygen between the donor beads and acceptor beads. Donor
beads are streptavidin conjugated and bind to the biotin on the
peptide. Acceptor beads are conjugated with an antibody that
recognizes the specific G9a methyl mark on the peptide. If there is
a methyl mark on the peptide, the acceptor beads will bind to the
peptide. Upon binding, the acceptor beads will be in close
proximity (<200 nm) of the donor beads and when the donor beads
are excited, the transfer of the oxygen can occur and a strong
signal will be generated. If there is no methyl mark, the
interaction between beads will not occur and signal will be at
background levels.
[0499] For the assay, the following buffer was used to set up
reactions: 50 mM Tris-HCl pH9, 50 mM NaCl, 0.01% Tween-20 and 1 mM
DTT (added fresh prior to starting the reactions). The assay is set
up by adding a final concentration of 0.15 nM G9a, 10 uM
S-adenosyl-methionine and, 100 nM biotinylated histone 3 peptide
(1-21). The reaction is incubated at room temperature for 1 h, and
subsequently quenched by the addition of the acceptor beads
(anti-H3k9me2 AlphaLISA acceptor beads, PerkinElmer #AL117) at a
final concentration of 20 ug/mL. The acceptor beads are incubated
for 1 h. After 1 h, the donor beads are added at a final
concentration of 20 ug/mL (Alpha Streptavidin donor beads,
PerkinElmer #6760002). Donor beads are incubated for 0.5 h. Both
donor and acceptor beads are resuspended in AlphaLISA 5X
Epigenetics Buffer 1 Kit (PerkinElmer #AL008) prior to addition to
the reaction. All manipulations and incubations with the donor and
acceptor beads are done in subdued light. Signal is detected in an
EnVision plate reader in Alpha mode (See ACS Med Chem Lett. 2014
Jan. 2; 5(2):205-9)
[0500] Percent inhibition was calculated for each compound dilution
and the concentration that produced 50% inhibition was calculated.
This value is presented as the IC.sub.50. The IC.sub.50 values
IC.sub.50 values (nM) for a representative number of compounds of
the disclosure are provided below.
TABLE-US-00003 TABLE B Table 1 Compound G9a IC50 # (nM) 1 250 2 150
3 60 4 170 5 1.2 6 3.2 7 280 8 5.3 9 590 10 4.5 11 8.2 12 1-3 13 34
14 6.5 15 3.3 16 61 17 370 18 12 19 300 20 7 21 3.3 22 570 23 100
24 93 25 140 26 250 27 150 28 60 29 1.2 30 280 31 3.6 32 5.3 33 320
34 590 35 4.5 36 8.2 37 34 38 6.5 39 5.7 40 61 41 370 42 12 43 1.3
44 170 45 56 46 24 47 9.4 48 1300 49 45 50 690 51 470 52 100 53 62
55 18 56 15 57 61 58 86 59 160 60 51 61 480 62 53 63 130 64 12 65
8.2 66 5.6 67 9.5 68 26 69 30 70 400 71 52 72 9.1 73 960 74 6.7 75
1000 76 960 77 2500 78 260 79 140 80 >10000 81 22 82 4.5 83 N/A
84 17 85 17 86 180 87 240 88 12 89 12 90 7.1 91 6.7 92 51 93 61 94
54 95 560 96 3300 97 68 98 2800 99 16 100 380 101 120 102 140
Example 2
Fetal Hemoglobin Induction Assay
[0501] Cryopreserved bone marrow CD34.sup.+ hematopoietic cells
obtained from healthy adult human donors were used for all studies.
A 21 day ex vivo serum free culture system was utilized that
consists of two phases. In culture phase I (culture days 1-7),
CD34.sup.+ cells were placed in media containing StemPro-34
complete media (1-glutamine, pen-strep and StemPro-34 nutrient
supplement) (Invitrogen, Carlsbad, Calif.) supplemented with 50
ng/mL SCF (HumanZyme, Chicago, Ill.), 50 ng/mL FLT3-Ligand
(HumanZyme) and 10 ng/mL IL-3 (HumanZyme). During the first phase
of culture (days 0-7), the CD34.sup.+ cells differentiate into
progenitor cell populations that include erythroblasts. After 7
days, the cells were transferred to erythropoietin (EPO; Stemcell)
supplemented medium (phase 2; culture days 7-21) which is comprised
of the following: StemPro-34 complete medium, 4 U/mL EPO, 3 .mu.M
mifepristone (Sigma Aldrich, St. Louis, Mo.), 10 .mu.g/mL insulin
(Sigma Aldrich), 3 U/mL heparin (Sigma Aldrich) and 0.8 mg/mL holo
transferrin (Sigma Aldrich). The Compounds are added during phase
2; days 7-21 to test fetal hemoglobin production (See Blood. 2015
Jul. 30; 126(5):665-72).
[0502] Expression levels of .alpha.-, .beta.- and .gamma.-globin
genes are assessed by quantitative PCR analyses. HbF protein levels
are assessed by the human Hemoglobin F enzyme-linked immunosorbent
assay (ELISA) Quantitation Kit (Bethyl Laboratory, Montgomery,
Tex., USA). Percentages of cells expressing HbF are assessed by
flow cytometry analysis. In brief, RNA samples were prepared and
complementary DNA was synthesized, according to the manufacturer's
instructions (Qiagen, Germany). The qRT-PCR analysis of human
globin genes was performed using the TaqMan Gene Expression
Master.
TABLE-US-00004 TABLE C Table 1 Compound Fold Compound # Conc.
Induction 29 (n = 1) 0.3 3.8 31 (n = 1) 0.3 4.8 35 (n = 2) 0.3 4.3
36 (n = 2) 0.3 3.0 38 (n = 1) 0.3 3.3 39 (n = 1) 0.3 2.8 43 (n = 1)
0.3 2.0 46 (n = 1) 0.3 2.6 47 (n = 4) 0.4 4.7 55 (n = 1) 0.3 2.6 56
(n = 1) 0.3 3.8 65 (n = 1) 0.3 6.3 66 (n = 1) 0.3 1.3 67 (n = 5)
0.3 3.9 69 (n = 1) 0.3 2.9 88 (n = 2) 0.3 3.5 89 (n = 2) 0.3 3.2 90
(n = 1) 0.3 2.4 91 (n = 5) 0.3 4. 92 (n = 1) 0.3 2.3 99 (n = 1) 0.3
3.6
Formulation Examples
[0503] The following are representative pharmaceutical formulations
containing a compound of the present disclosure.
Tablet Formulation
[0504] The following ingredients are mixed intimately and pressed
into single scored tablets.
TABLE-US-00005 Quantity per tablet Ingredient mg compound of this
disclosure 400 cornstarch 50 croscarmellose sodium 25 lactose 120
magnesium stearate 5
Capsule Formulation
[0505] The following ingredients are mixed intimately and loaded
into a hard-shell gelatin capsule.
TABLE-US-00006 Quantity per capsule Ingredient mg compound of this
disclosure 200 lactose spray dried 148 magnesium stearate 2
Injectable Formulation
[0506] Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1%
Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20
mg/mL
Inhalation Composition
[0507] To prepare a pharmaceutical composition for inhalation
delivery, 20 mg of a compound disclosed herein is mixed with 50 mg
of anhydrous citric acid and 100 mL of 0.9% sodium chloride
solution. The mixture is incorporated into an inhalation delivery
unit, such as a nebulizer, which is suitable for inhalation
administration.
Topical Gel Composition
[0508] To prepare a pharmaceutical topical gel composition, 100 mg
of a compound disclosed herein is mixed with 1.75 g of
hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of
isopropyl myristate and 100 mL of purified alcohol USP. The
resulting gel mixture is then incorporated into containers, such as
tubes, which are suitable for topical administration.
Ophthalmic Solution Composition
[0509] To prepare a pharmaceutical ophthalmic solution composition,
100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl
in 100 mL of purified water and filtered using a 0.2 micron filter.
The resulting isotonic solution is then incorporated into
ophthalmic delivery units, such as eye drop containers, which are
suitable for ophthalmic administration.
Nasal Spray Solution
[0510] To prepare a pharmaceutical nasal spray solution, 10 g of a
compound disclosed herein is mixed with 30 mL of a 0.05M phosphate
buffer solution (pH 4.4). The solution is placed in a nasal
administrator designed to deliver 100 .mu.L of spray for each
application.
* * * * *